SECTION
VI Pain
Overview and Controversies
Kim J. Burchiel, Feridun Acar, and Andrew C. Zacest
This chapter is divided into several components: an initial over-
view of the topics contained in the pain section, a history of the
neurosurgical management of pain, and a series of reflections on
controversies and unresolved questions related to pain.
Pain, originating from the Greek poine, which means “penalty”
or “punishment,” has been described since the dawn of writing.
In Greek civilization, pain secondary to disease was believed to
be caused by supernatural forces. According to a Latin inscription
attributed to Hippocrates of Kos (460-370 bc), alleviating pain
was the work of the divine: sedare dolorem opus divinum est. In
Greek mythology, drugs (including opium, hashish, and man-
drake), magic, and even surgery were used by the gods to produce
hypnosis and amnesia and to heal pain. However, as the myth of
the wounded centaur Chiron shows, even an immortal would give
up divinity to avoid a life of unrelieved pain.1
OVERVIEW OF PAIN SECTION
The “Pain” section of this book is composed of 18 chapters,
divided into the following four subsections:
“Basic Science,” which comprises Chapters 166 (“Anatomy
and Physiology of Pain”) and 167 (“Molecular Basis of
Nociception”)
“Nonsurgical Therapy,” which comprises Chapters 168
(“Approach to the Patient with Chronic Pain”) and 169
(“Pharmacologic Treatment of Pain”)
“Treatment of Trigeminal Neuralgia,” which comprises Chapters
170 (“Evidence-Based Approach to the Treatment of Facial
Pain”), 171 (“Trigeminal Neuralgia: Diagnosis and Nonop-
erative Management”), 172 (“Percutaneous Procedures for
Trigeminal Neuralgia”), 173 (“Stereotactic Radiosurgery for
Trigeminal Neuralgia”), and 174 (“Microvascular Decom-
pression for Trigeminal Neuralgia”)
“Surgical Procedures for Nontrigeminal Pain,” which begins
with Chapter 175, an initial overview (“Neurosurgical Man-
agement of Intractable Pain”), and then is divided into two
parts: “Neuromodulation,” which comprises Chapters 176
(“Evidence-Based Neurostimulation for Pain”), 177 (“Periph-
eral Nerve Stimulation for Neuropathic Pain”), and 178
(“Spinal Cord Stimulation”); and “Destructive Procedures,”
which comprises Chapters 179 (“Evidence Base for Destruc-
tive Procedures”), 180 (“Dorsal Rhizotomy and Dorsal Root
Ganglionectomy”), 181 (“Diagnosis and Management of
Painful Neuromas”), 182 (“Dorsal Root Entry Zone Lesions
for Pain”), and 183 (“Percutaneous Cordotomy and Trigemi-
nal Tractotomy-Nucleotomy”)
In summary, content of the “Pain” section focuses on the
general principles of pain and nociception, with special emphasis
on the role that neurosurgeons may play in this subspecialty. We
believe that substantial progress has been made in understanding
the physiologic features of pain perception and its distributed
nature in the central nervous system. The understanding of the
molecular basis of nociception has also made great strides. To
some degree, this progress contrasts with the relatively static
condition of, perhaps even a retreat from, surgical management
of pain.
HISTORICAL OVERVIEW OF NEUROSURGICAL
MANAGEMENT OF PAIN
The modern era in the neurosurgical management of pain began
at the start of the 19th century. In 1809, Walker2 proposed that
the anterior and posterior spinal roots serve distinct motor and
sensory functions. Bell3 subsequently expanded this idea, and
Magendie4 in 1822 provided evidence of the role of the posterior
spinal roots in the transmission of pain. However, it was almost
100 years later that Spiller5 and Schüller6 described the pain
conduction pathways in the anterolateral columns of the spinal
cord. Although debate concerning the anatomic and physiologic
substrate serving pain continued, evidence for the specificity
theory of pain accumulated, and neurosurgeons exploited the
existing knowledge of pain pathways to perform pain surgery,
often with great success. Neurosurgeons were also quick to adapt
new technology—most notably, stereotaxy, radiofrequency gen-
erators, and the operating microscope,—for pain procedures.
A chronology of neurosurgical management of pain is presented
in Table VI-1, which covers techniques introduced from 1873
to 1991.
A procedure for the relief of pain was probably first reported
in 1873, when Létiévant7 published his description of peripheral
and cranial nerve rhizotomies. Sectioning of the posterior spinal
roots for the relief of pain in humans was first proposed by Dana8
in 1887 and performed by Bennet9 in 1889 and also by Abbe10,11
in four patients. Otrid Foerster of Breslau, Germany, a neurolo-
gist by training, obtained enough experience with the operation
of posterior rhizotomy to perform it himself. Foerster12 later
presented his landmark paper mapping the dermatomes in
humans.
Neurosurgical management of pain has been focused primar-
ily in six areas: trigeminal neuralgia, cordotomy, stereotaxy,
gate theory of pain, intraspinal opioids, and evidence-based
medicine.
Trigeminal Neuralgia
Early pain surgeons were also interested in cranial nerve patho-
logic conditions, especially tic douloureux, a condition that had
vexed patients and physicians alike for more than two centuries.13
Bell14 had established that the trigeminal nerve was the sensory
nerve for the face in 1844. Victor Horsley is credited with the
first gasserian ganglionectomy and retrogasserian neurotomy in
1891, but in truth, the contributory efforts of several other neu-
rosurgical pioneers helped transform the management of tri-
geminal neuralgia. Horsley and colleagues15 used the extradural
temporal approach described by Hartley16 and Krause,17 but
1373
1374 SECTION 6  Pain

TABLE VI-1  Chronology of Neurosurgical Management of Pain Cordotomy

Year Investigator Technique
Bell,14 with the aid solely of the naked eye and the scalpel, had
1873 Létiévant7 Neurotomies for facial and extremity also traced the posterior spinal roots up the spinal cord into the
neuralgias brainstem and cerebrum. Accurately filling in the details would
1889 Abbe10 and Bennet9 Spinal dorsal rhizotomy take the rest of the 19th century. Both Moritz Schiff and Charles
1891 Horsley et al15 Gasserian ganglionectomy for trigeminal Edouard Brown-Séquard had performed numerous experiments
neuralgia
trying to locate the sensory tracts in the spinal cord35 when, in
1899 François-Franck84 Conception of the potential of
sympathectomy
1871, Müller36 cited a case of a stab wound involving half of the
1901 Spiller and Frazier19 Open trigeminal rhizotomy (middle fossa) spinal cord and the opposite dorsal column that produced bilat-
1905 Spiller5 Spinothalamic tract in the anterolateral eral anesthesia for touch but caused analgesia only on the side
cord opposite the lesion. Gowers37 later reported a case that he had
1912 Spiller and Martin39 First cordotomy seen in 1876 of a student who had shot himself through the
1913 Leriche85 Sympathectomy for pain in extremities mouth. The patient had intact tactile sensibility in his left limbs,
1916 Jonesco86 Sympathectomy for angina pectoris but pain sensation was abolished. Postmortem examination
1922 Läwen87 Diagnostic nerve blocks revealed that the injury to the spinal cord was a spicule of bone
1925 Dandy20 Trigeminal rhizotomy (posterior fossa) that had effectively caused unilateral sectioning of the cervical
1927 Armour88 Midline commissural myelotomy
1933 Foerster12 Mapping of the spinal dermatomes in
cord and destroyed the continuity of the anterior and lateral
humans columns on the right side. Gowers concluded that this part of the
1938 Sjöqvist89 Trigeminal tractotomy cord carries the fibers for the transmission of contralateral pain
1941 Schwartz and Open medullary spinothalamic impulses. Edinger38 in 1889 demonstrated the existence of the
O’Leary45 and tractotomy spinothalamic tract in newborn cats and amphibians. It remained
White47 for Spiller, however, to prove conclusively that the spinothalamic
1942 Walker46 Open mesencephalic tractotomy tract carries pain and temperature impulses. In 1905, Spiller5
1953 Spiegel and Wycis48 Stereotactic thalamotomy and described a patient with pain and temperature sensory loss in the
mesencephalotomy lower part of the body who at autopsy was confirmed to have
1960 Heath and Mickle61 Deep brain (septal) stimulation for pain
Mazars et al62 Thalamic (VPL) stimulation for pain
bilateral tuberculomas involving the lower thoracic anterolateral
1962 Foltz and White90 Bilateral cingulotomy for pain tracts. Schüller6 in 1910 sectioned the anterolateral tract in
1963 Mullan et al41 First percutaneous cordotomy monkeys. At the instigation of Spiller in 1912, Martin performed
1965 Melzack and Wall57 Gate theory of pain the first “cordotomy” in another patient with a tuberculoma of
1966 Sano et al54 Posteromedial hypothalamotomy for pain the cord.39 The short- and long-term results were encouraging
Kudo et al56 Pulvinotomy and established the technique for treating intractable pain. In
1967 Jannetta25,26 Trigeminal microvascular decompression 1931, Stookey40 was probably the first to perform a high cervical
Shealy et al59 Spinal cord stimulation cordotomy for pain in the chest and upper extremity. Mullan
1969 Kapur and Dalton91 Hypophysectomy for cancer pain and colleagues introduced a technique for percutaneous cordot-
1970 Hitchcock49 Extralemniscal myelotomy
omy at the C1-C2 level that involved use of a radioactive needle
1971 Leksell51 Gamma Knife for trigeminal neuralgia
1972 Sindou68 DREZ lesions tip and reported it in 1963.41 The utility of radiofrequency
1973 Hitchcock92 Stereotactic pontine spinothalamic thermocoagulation for creating lesions was applied to the tech-
tractotomy nique by Rosomoff and coworkers,42 and cord penetration
1974 Sweet and Wepsic93 Radiofrequency trigeminal rhizolysis as determined by electrical impedance was described by Gilden-
1976 Sweet33 and Peripheral nerve stimulation berg and associates.43 Kanpolat and colleagues44 described a com-
Nashold et al69 puted tomography–guided percutaneous procedure. Despite the
1979 Wang et al73 Intrathecal morphine obvious efficacy of this procedure, particularly for malignant
Behar et al72 Epidural morphine disease and with low rates of morbidity when performed with the
1981 Hakanson32 Glycerol trigeminal chemoneurolysis
most recent advances, cordotomy is unfortunately being used less
1983 Mullan and Lichtor34 Trigeminal balloon microcompression
1991 Tsubokawa et al67 Motor cortex stimulation
and less, in part because of advances in pain management, lack of
referral, and patient unwillingness to undergo ablative and poten-
DREZ, dorsal root entry zone; VPL, nucleus ventroposterolateralis. tially irreversible procedures.

because the patient died, retrogasserian neurotomy was aban-
doned until it was revived by Tiffany18 in 1896 and by Spiller and
Frazier19 in 1901. Dandy20 described the posterior fossa approach
for retrogasserian neurotomy in 1925, although this was probably
not his own original idea.21 His experience led him to conclude
that subtotal section spared significant sensation without a major
increase in pain recurrence.22 Although Dandy frequently
observed vascular loops compressing the trigeminal nerve and,
like Gardner and Miklos23 more than 30 years later, suspected
this to be the cause of neuralgia, Dandy did not conceive of
decompression as a solution. With the introduction of better
medical therapy and percutaneous procedures with the use of the
Härtel approach to the foramen ovale,24 open surgical procedures
for trigeminal neuralgia fell into decline until Jannetta25 in 1967
reported his experience with microvascular decompression, a
procedure that has stood the test of time.26-34
Stereotaxy
Pain affecting the face, head, and shoulder could not be managed
effectively by cordotomy, so open brainstem spinothalamic trac-
totomies were attempted.45-47 Unfortunately, the analgesic effects
were short-lived, and morbidity and mortality rates were high.
Spiegel and Wycis,48 the great pioneers of human stereotaxy,
applied their technique to perform mesencephalotomy and
thalamotomy with greater accuracy and success. Subsequently,
Hitchcock49,50 introduced a stereotactic technique for pontine
spinothalamic and trigeminal tractotomy.
Stereotaxy not only enabled more accurate localization of
targets51 but also generated important insight into the patho-
physiologic mechanisms of chronic denervation pain.52 Lesions
in the thalamic somatosensory ventrocaudal nuclei (which receive
input from the neospinothalamic system) were not very successful
in relieving chronic pain and were often associated with postop-
erative ataxia and dysesthesias.53 Attention was focused on lesion-
ing targets of the paleoreticulospinothalamic system, especially

the nonspecific intralaminar nuclei54,55 and the pulvinar nuclei,56
with greater success.
Gate Theory of Pain
A major milestone in the neurosurgical management of pain came
with the publication in 1965 of Melzack and Wall’s57 gate theory.
Their proposal that afferent pain transmission might be modu-
lated by a spinal gating mechanism introduced the possibility of
pain management by neuromodulation. This motivated Wall and
Sweet58 in 1967 to perform peripheral nerve stimulation, the first
augmentative procedure for pain relief. In 1967, Shealy and
coworkers59 performed the first trial of spinal dorsal column
stimulation. Heath, after observing pain relief in psychiatric
patients with septal stimulation,60 repeated these results in non-
psychiatric patients in 1960.61 That same year, Mazars and associ-
ates62 showed that thalamic nucleus ventroposterolateralis
stimulation was also effective for chronic pain. As stimulation
technology improved, other groups confirmed these results.63,64
Encouraged by the phenomenon of stimulation-induced analge-
sia in animals after electrical stimulation of the periaqueductal
gray matter and the suggestion that this was mediated by endog-
enous opioids, Richardson and Akil65,66 implanted a stimulating
electrode in the periventricular gray matter in humans and
reported effective pain relief. Years later, Tsubokawa and col-
leagues67 described the efficacy of motor cortex stimulation for
deafferentation pain of thalamic origin.
Many ablative techniques have since been supplanted by aug-
mentative techniques. One notable exception was the introduc-
tion by Sindou68 in 1972 of dorsal root entry zone (DREZ)
ablation for deafferentation pain associated with brachial plexus
avulsion and traumatic paraplegia. This pain had remained
intractable to all previously attempted ablative and augmenta-
tive techniques. Nashold and coworkers69 further popularized
this procedure by using a radiofrequency thermocoagulation
technique.
Intraspinal Opioids
The discoveries of morphine receptors in the central nervous
system in 197370 and in the spinal cord in 197771 were soon fol-
lowed by the display of their utility for analgesia in the spinal
fluid and epidural space.72,73 Controlled opiate delivery from
implanted pumps was introduced as an analgesic technique in the
late 1970s for a variety of neuropathic pain syndromes and has
become a mainstay neuromodulatory procedure. Pump technol-
ogy has become more sophisticated, and drugs other than opioids
have been delivered to the spinal fluid. Despite initial enthusiasm
for this therapy, prospective studies have shown modest analgesic
gains (36% of patients reported better than 50% improvement
at 2 years), and the complications of therapy—including catheter
malfunction, catheter granulomas,74,75 and hypogonadism76-78—
have become more greatly appreciated. The result has been a
steady decline in the number of devices implanted for intrathecal
opioid delivery. The expertise acquired from this complex therapy
may be realized in the future with novel intrathecal drugs cur-
rently under investigation (e.g., gabapentin).
Evidence-Based Medicine
Today, as in other branches of medicine, neurosurgical treatments
of pain are increasingly scrutinized by regulatory authorities,
insurance providers, and the medical profession itself. This
was demonstrated most dramatically when the Food and Drug
Administration (FDA) demanded evidence for the efficacy of
deep brain stimulation for the treatment of pain. Two industry-
sponsored trials failed to show a significant benefit of this therapy;
FDA approval was thus denied, and deep brain stimulation was
SECTION 6  Pain 1375
designated an experimental procedure for pain relief. In a similar
manner, insurance approval in the United States for motor cortex 
stimulation for relief of pain has become increasingly difficult to
obtain, in part because of the lack of trials demonstrating clear
efficacy.
Against this backdrop, higher levels of medical evidence of
efficacy have been demanded in the pain medicine literature, and
the results have been sobering. In a 2008 review79 of ablative
neurosurgical procedures published in the previous three decades,
level I evidence from randomized clinical studies could be estab-
lished only for rhizotomy for trigeminal neuralgia and facet syn-
dromes. Using a similar method for neuromodulatory therapies
to relieve non–cancer-related pain, Coffey and Lozano80 con-
cluded that there has been no successful clinical study focused on
establishing the efficacy of neurostimulation for pain, despite
randomized trials in which spinal cord stimulation is compared
with best medical management and repeated surgery. Although
an inherent difficulty of trials of spinal cord stimulation is the
issue of sham stimulation, most of the criticisms of trial design
from this report are valid and must be addressed in future work.
These reviews have raised the benchmark for future studies of
pain relief efficacy, thus underscoring the need for investigators
to provide unambiguous entry diagnosis, suitable controls that
receive sham treatment, long-term follow-up, and randomization
and establishment of blind conditions of patients, investigators,
and device programmers.
CURRENT CONTROVERSIES AND UNRESOLVED
QUESTIONS RELATED TO NEUROSURGICAL
MANAGEMENT OF PAIN
The status of surgical procedures for pain control has always
lagged behind the understanding of the “pain matrix.” The role
of top-down modulation of pain circuits is still not well under-
stood and is the subject of intense continuing basic research.
Furthermore, the multiple molecules that have been implicated
in pain and chronic pain contribute to the difficulty in finding
effective therapeutic agents. Alternative strategies now include
the idea of medicines individualized on the basis of genetic pro-
files and neurostimulation of pain circuits. An emerging idea is
that there are common brain mechanisms involved in reward
processing, addiction, and chronic pain.81 Thus the basic science
of nociception and chronic pain continues to support multidisci-
plinary integrated approaches to treat chronic pain.
Outlined as follows are several areas of ongoing controversies
and unresolved questions related to the neurosurgical manage-
ment of pain.
Spinal Cord Stimulation
Spinal cord stimulation (SCS) is one of the foundations of neu-
romodulation therapy for pain. In the past, the colocalization of
evoked paresthesias encompassing the painful area has been a
dictum of SCS; however, results of more recent studies indicate
that high-frequency stimulation appears to be associated with
pain relief without the need for stimulation-induced paresthesias.
High-frequency stimulation results in physiologic changes in
cells that appear unrelated to the membrane depolarization block
that had been previously considered one of the potential mecha-
nisms of SCS. Spinal cord stimulator leads can be implanted
while the patient is under general anesthesia, but it remains
unclear whether the lack of patient feedback might compromise
the pain relief obtained postoperatively. There is also experimen-
tal evidence that SCS can be used for the treatment of ischemia,
but the results of prospective clinical studies have been mixed. A
closed-loop design for SCS might potentially improve the effi-
cacy and efficiency of SCS, and a new generation of sensing
technologies that can, in turn, modulate stimulation is now
1376 SECTION 6  Pain
coming to market. This could allow SCS to be a true closed-loop
therapy—a potentially transformational development.
Nerve Grafts and Conduits
The surgical treatment of neuromas now includes, in addition to
neuroma excision and burying into muscle or bone, the use of
nerve grafts and conduits that provide an environment that can
help prevent neuroma re-formation. The outcomes data to
support any minimally invasive techniques (e.g., radiofrequency
ablation, chemical neurolysis) or open techniques (e.g., excision,
burying into muscle, conduit to nowhere) are lacking. It is diffi-
cult to recommend any one therapy over another on the basis of
actual evidence.
Limitations of Destructive Techniques
The reader should be aware that classic neuroma pain (confined
to the distribution of the injured nerve, reproduced as Tinel’s
sign, and temporarily abolished by a nerve block) is appropriately
treated with a destructive technique. Centralized pain (spread
beyond the confines of the injured nerve, associated with complex
findings outside the nerve distribution such as allodynia, color
changes, and trophic changes) often responds poorly to destruc-
tive techniques and may in fact worsen.
Genetics and Pain Syndromes
One of the more intriguing questions in the field of nerve injury
is why only a small fraction of patients who sustain a nerve injury
actually develop a pain syndrome. This variability suggests that
either patient genetics or epigenetics are in play. Several studies
have suggested that genetics may have a major influence on the
development of neuropathic pain in general82 and phantom pain
specifically.83 Considerable ongoing work is directed at genes that
may predispose individuals to the development of neuropathic
pain. Knowledge of these genetic predispositions, if they exist,
will help direct future pharmacologic and gene therapies for
neuropathic pain.
Lesions in the Dorsal Root Entry Zone
DREZ lesions for nerve root avulsion pain remain one of the
most effective, and probably underutilized, therapies for chronic
deafferentation pain. It is the first choice of therapy for brachial
plexus avulsion pain, a condition in which SCS is uniformly inef-
fective. DREZ lesions should also be considered in cases of seg-
mental pain after spinal cord or cauda equina injury, in which
SCS is of marginal benefit, if any. The ineffectiveness of SCS in
these instances is related to the degeneration of dorsal column
fibers up to the level of the dorsal column nuclei within the
medulla, leaving no spinal cord substrate (dorsal column) for
stimulation at the segmental level of the spinal cord. Until phar-
macologic interventions can be devised to create selective inhibi-
tion of deafferentation hyperactivity within the pain transmission
neurons of the spinal cord segment (nucleus proprius), DREZ
lesions will remain an important treatment modality for certain
types of posttraumatic deafferentation pain.
Limitations of Cordotomy
Cordotomy was devised as a result of the discovery of the func-
tion of the anterolateral spinothalamic tracts, and spinal cord
stimulation emerged from the gate control theory. If anything,
the concept that pain is represented in a complex set of central
nervous system centers poses a new challenge to the surgical
amelioration of pain. The “labeled line” theory of Descartes—a
line that could simply be disrupted by surgical intervention—is
not applicable. Despite these limitations, image-guided cordot-
omy is reemerging as a viable strategy for managing certain types
of pain related to cancer, particularly in patients with a limited
life expectancy. However, the practice of image-guided cordot-
omy will remain limited, in part, by the numbers of neurosur-
geons who are trained to perform the procedure.
CONCLUSION
We offer some predictions for the future, as well as some con-
cerns about the future in relation to neurosurgeons’ involvement
in pain management. If history is to repeat, we expect that out of
new knowledge regarding pain transmission, representation, and
regulation, new formulations of surgical pain management will
emerge. The surgical procedures of the future will probably
involve reconstruction of the spinal dorsal horn, and possibly sub-
cortical structures, that have been fundamentally altered by
peripheral or central nervous system injury. Our prediction is
that although neuromodulator and neurodestruction will con-
tinue to play an important role in surgical pain management,
restorative neurosurgery will become a third aspect of the treat-
ment armamentarium.
Training in the fundamentals of pain management must also
continue. Few neurosurgeons devote themselves to this, and the
lack of expertise has hampered progress in this area. Further-
more, procedures that have proved effective, such as percutane-
ous gangliolysis for trigeminal neuralgia or DREZ lesions for
brachial plexus avulsion pain, will fall into disuse if the current
generation of neurosurgical residents has no experience with
these procedures. Similarly, if clinical research into percutaneous
cordotomy or trigeminal tractotomy falters, these potentially
useful and minimally invasive procedures will disappear. It would
be unfortunate if patients had to await the next historical cycle
for physicians to rediscover these approaches to pain relief.
The current model of pain medicine is to attempt to classify
pain syndromes as nociceptive, neuropathic, or some combina-
tion of the two; the goal is to choose appropriate therapy tailored
to the type of pain. In general, conservative, augmentative, or
modulatory techniques are preferred over ablative approaches. In
part, this is because of the lack of contemporary data on destruc-
tive techniques, the dearth of preoperative predictors that a
destructive procedure will be effective, the possibility of worsen-
ing the pain, and the irreversibility of the approaches. Challenges
for the future of pain medicine are twofold: first, to discover new
therapies that work at the molecular or genetic level to target the
pathophysiologic mechanisms of pain and, second, to design
studies that conform to the requirements for level I or II evidence
so that these benefits may be realized for patients. In doing so,
physicians should take advantage of the wisdom gleaned from
more than a century of discovery.
SUGGESTED READINGS
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Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment
of nonmalignant pain: a structured literature review. J Neurosurg.
2008;109:389-404.
Coffey RJ, Lozano AM. Neurostimulation for chronic noncancer pain:
an evaluation of the clinical evidence and recommendations for future
trial designs. J Neurosurg. 2006;105:175-189.
Finger S. Origins of Neuroscience: A History of Explorations into Brain Func-
tion. New York: Oxford University Press; 2001.
Hakanson S. Trigeminal neuralgia treated by the injection of glycerol into
the trigeminal cistern. Neurosurgery. 1981;9:638-646.
Härtel F. Ueber die intracranielle Injektionsbehandlung der tri-
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PART 1 Basic Science
166 Anatomy and Physiology of Pain
Mary M. Heinricher and Daniel R. Cleary
SENSORY TRANSMISSION OF
PAIN-RELATED INFORMATION
Nociceptive information is conveyed from the periphery to the
spinal cord by small myelinated and unmyelinated primary affer-
ents that travel through the dorsal root to synapse in the dorsal
horn. These afferents enter the dorsal horn and terminate both
superficially (in laminae I and II) and more deeply (in laminae V,
VI, and VII), as well as around the central canal. Second-order
neurons in the nociceptive pathways are found in the same layers
and are usually divided into two classes: wide dynamic range
(WDR) and nociceptive-specific. WDR neurons receive conver-
gent input from both nociceptive and nonnociceptive primary
afferents, which can allow normally nonpainful stimuli such as
touch to give rise to a sensation of pain under certain conditions.
Nociceptive information is conveyed to the brain via the
spinoreticular, spinomesencephalic, spinoparabrachial, and spi-
nothalamic tracts, all of which ascend through the anterolateral
quadrant. Direct spinothalamic projections terminate in both the
medial and lateral thalamus, and these two targets are considered
more in the affective-motivational and sensory-discriminative
aspects of pain, respectively. Parallel spinoreticular and spinomes-
encephalic pathways may contribute to conscious sensation, but
these pathways may be more important for arousal, autonomic
and motor responses to noxious input and for recruitment of
descending control systems. The spinoparabrachial pathway con-
sists of projections of neurons primarily in lamina I and relays
information to the amygdala and hypothalamus, as well as to the
midbrain periaqueductal gray matter (PAG) and caudal ventro-
lateral medulla.
The advent of functional imaging approaches has stimulated
interest in the cortical representation of pain, and it is now appre-
ciated that no single cortical “pain center” mediates all aspects
of the complex sensation that is pain. Rather, a reasonably well-
defined cortical network is recruited as a result of acute noxious
stimulation. Although no lesion at a single site can eliminate
the perception of pain, stimulation of any one of many sites
can elicit painful perceptions, in conjunction with or indepen-
dent of other somatosensory sensations. Experiments involving
such stimulation, along with advances in both noninvasive and
invasive techniques, have shed light on the contributions that
the numerous cortical regions make to the “pain matrix,” which
includes somatosensory cortex, insula, and anterior cingulate
cortex (ACC). Of importance is that the cortical representation
of longstanding chronic pain adds new layers of complexity to
this picture.
DESCENDING MODULATION OF PAIN
A recurrent theme in clinical and experimental approaches to
pain has been that the relationship between the presumed
1378
stimulus (i.e., tissue damage) and the ensuing sensory experience
is rarely straightforward. This is true even in the simplest situa-
tion in which a reasonably uniform sensory experience might be
expected, such as acute injury to healthy tissue.
Cognitive and emotional factors, including attention, learn-
ing, and mood, can all influence pain perception in situations
nowhere nearly as extreme as the battlefield. The brain is not a
passive receiver of information about noxious stimuli but actively
regulates its own input. Indeed, the coding of afferent informa-
tion is now known to be shaped dynamically by descending
modulatory systems that influence nociceptive processing at the
first central relay, the dorsal horn. These descending control
systems are themselves regulated by afferent sensory input but
are also recruited by higher centers to modulate spinal nocicep-
tive processing in accord with behavioral priorities. The most
important descending control system has links in the midbrain
PAG and to the rostral ventromedial medulla (RVM), which
constitute the PAG/RVM system. Electrical stimulation at either
site can enhance or inhibit pain, depending on the exact site,
current level, and the behavioral context. These effects are medi-
ated by modulation of nociceptive activity in the dorsal horn. The
anatomic substrate for this descending control is a significant
projection from the PAG to the RVM, which in turn projects via
the dorsolateral funiculus to the dorsal horn to influence sensory
processing. The PAG/RVM system is well situated to mediate the
effects of cognitive and emotional variables on pain transmission.
It also functions as a positive-feedback loop, so that discrete
noxious stimuli or more prolonged inflammatory events activate
descending facilitation, thereby amplifying responses to subse-
quent input
Much information about primary afferents and nociceptive
signal transduction has become available, but it must be empha-
sized that pain as a sensory experience requires transmission and
integration of sensory input within the central nervous system. It
is now recognized that pain reflects activation of parallel ascend-
ing pathways that engage a distributed thalamocortical network,
a network sometimes referred to as a “pain matrix.” This network
is not a passive receiver, and input in the ascending pain system
is dynamically regulated in accord with behavioral priorities by a
descending modulatory system. Finally, there is increasing evi-
dence that as pain becomes chronic, the systems engaged shift to
reflect the growing importance of conditioning and other higher
order processes. Understanding and manipulating these dynamic
aspects of pain sensing and modulation is crucial for future
advances in therapeutic approaches to pain.
Full text of this chapter is available online at ExpertConsult.com
PART 1 Basic Science
166 Anatomy and Physiology of Pain
Mary M. Heinricher and Daniel R. Cleary
This chapter outlines current thinking concerning mechanisms
and pathways for transmission and modulation of pain, with a
focus on central nervous system mechanisms. Dorsal horn pro-
cessing of nociceptive information, and ascending pathways car-
rying the nociceptive signal to the brain are described, as are
thalamocortical circuits that play important roles in pain. Next,
we discuss the malleability of pain. We consider how the nocicep-
tive transmission pathways are sensitized after injury to either the
tissue or to the central nervous system itself, which leads to
hyperalgesia and allodynia (i.e., pain evoked by innocuous stimu-
lation). Finally, we focus on descending modulatory systems that
regulate transmission pathways, as part of positive and negative-
feedback loops and through top-down control mechanisms.
These systems can enhance or suppress the nociceptive signal in
accord with behavioral priorities, during stress, or after adminis-
tration of analgesic drugs, including opioids.
PRIMARY AFFERENT NOCICEPTORS
Nociceptive information is conveyed from the periphery to the
spinal cord by small myelinated and unmyelinated primary affer-
ents that travel through the dorsal root to synapse in the dorsal
horn. As described in detail in Chapter 167 (focused on periph-
eral transduction and properties of nociceptive primary affer-
ents), information about the mechanisms of nociceptive signal
transduction and the properties of primary afferents has become
plentiful. Individual afferents manifest a high degree of specific-
ity; nociceptive neurons are different from low-threshold affer-
ents in terms of physiology, morphology, and neurochemistry.
The primary afferent fibers also exhibit significant plasticity in
response to tissue conditions, with alterations of neuronal phe-
notype and enhanced responsiveness during inflammation or in
response to damage to the nerve itself. Such primary afferent
sensitization is now recognized to be an important contributor
to hyperalgesia and abnormal pain states.
DORSAL HORN AND ASCENDING PATHWAYS
Nociceptive afferents enter the dorsal horn and terminate both
superficially (laminae I and II) and more deeply (in laminae V,
VI, and VII), as well as around the central canal. Low-threshold
tactile afferents, in contrast, spare the superficial laminae and
send their terminals primarily to laminae III and IV (sometimes
called the nucleus proprius).1,2 The different terminations of noci-
ceptive and low-threshold inputs to the dorsal horn highlights the
link between anatomic and functional organization of nocicep-
tive and nonnociceptive somatosensory pathways and extends the
specificity at the level of primary afferents to the central nervous
system. Second-order neurons in the nociceptive pathways are
present primarily in the superficial layers and in laminae V and
VI of the dorsal horn and are usually divided into two classes:
WDR and nociceptive-specific.3,4 WDR neurons receive conver-
gent inputs from both nociceptive and nonnociceptive primary
afferents. They consequently exhibit low thresholds, within the
innocuous range, but unlike low-threshold tactile dorsal horn
neurons, WDR neurons code stimulus intensity through the
166
noxious range. WDR neurons are distributed somatotopically
within the dorsal horn, and although receptive fields are rela-
tively large, they are not so large as to preclude a contribution
to stimulus localization. WDR neurons are more common in
the deeper dorsal horn but are also present more superficially,
in laminae I and II. Nociceptive-specific neurons do not receive
nonnociceptive input and respond exclusively to noxious stimuli,
carried either by A delta mechanoreceptors or by both A delta and
C nociceptors. Their receptive fields are small, which indicates an
important role in stimulus localization. They are concentrated in
the more superficial layers.
Nociceptive information is conveyed to the brain primarily
via the spinoreticular, spinomesencephalic, spinoparabrachial,
and spinothalamic tracts, all of which ascend through the antero-
lateral quadrant (Fig. 166-1). The importance of the anterolateral
systems in pain (and temperature) sensibility is confirmed by the
ability of anterolateral cordotomy to relieve pain, at least in
the short term, in both patients and experimental studies.1,5,6
The spinothalamic tract also carries nonnociceptive information
(innocuous warming and cooling, innocuous tactile information).
Tactile information is in addition conveyed by the spinocervical
tract and through the dorsal columns (which includes ascending
branches of large-diameter, low-threshold primary afferents,
as well as the postsynaptic dorsal column system, which com-
prises second-order projections of low-threshold dorsal horn
neurons).
Direct spinothalamic projections terminate in both the medial
and lateral thalamus, and these two targets can be considered
more important in the affective-motivational and sensory-
discriminative aspects of pain, respectively.7,8 Parallel spinoreticu-
lar and spinomesencephalic pathways may contribute to conscious
sensation, but these pathways may be more important for arousal,
for autonomic and motor responses to noxious inputs, and for
recruitment of descending control systems (see “Descending
Modulatory Systems” section). The spinoparabrachial pathway
comprises projections of neurons primarily in lamina I and relays
information to the amygdala and hypothalamus, as well as mid-
brain PAG and caudal ventrolateral medulla. The spinoparabra-
chial pathway is considered particularly important in emotional
and autonomic aspects of pain.9
Role of Dorsal Column Pathway in Visceral Pain
The classic view that ascending pathways through the dorsal
columns are involved exclusively in transmission of nonnoxious
information has been called into question by evidence that a
postsynaptic dorsal column component contributes to visceral
pain sensibility.10 These studies were motivated by the clinical
observation that midline myelotomy relieved pain in patients
with cancer involving pelvic visceral structures. Experimental
studies subsequently revealed a significant projection ascending
ipsilaterally through the dorsal columns and transmitting infor-
mation to the ventroposterolateral nucleus of the thalamus. Of
importance is that this pathway may not contribute to pain sensa-
tion under normal conditions, but it could become sensitized by
visceral inflammation.11,12
e593
e594 SECTION 6  Pain
PFC
S-I
ACC
M-T l
S-II
L-T
Insula
hal
ha
Hyp
PB
Amg
Reticular area
Figure 166-1. Nociceptive transmission pathways. This schematic
highlights some components of the anterolateral system. Axons
ascending from the dorsal horn target the brainstem (spinoreticular,
spinomesencephalic, and spinoparabrachial), as well as the
spinothalamic tracts: the medial thalamus (M-Thal) and lateral
thalamus (L-Thal). Spinoreticular information can be carried
over multisynaptic pathways to the thalamus (not shown).
Spinoparabrachial information is relayed directly to the amygdala
(Amg) and hypothalamus (Hyp). ACC, anterior cingulate cortex;
PB, parabrachial nuclei; PFC, prefrontal cortex; S-I, somatosensory
cortex; S-II, secondary somatosensory cortex.
SUPRASPINAL NOCICEPTIVE TARGETS
Thalamus
The thalamus was proposed to be involved in pain since as early
as 1911. Indeed, pain was at that time considered uniquely primi-
tive among sensory systems as being perceived at the level of the
thalamus, without important cortical involvement.13 It is now
recognized that reentrant interconnections between different
thalamic nuclei and cortex areas set the stage for conscious per-
ception of pain.14-19
Much of the understanding of the human thalamus is based
on comparative physiology, especially retrograde and anterograde
tracing studies in rats, cats, and nonhuman primates. Naming of
functionally matched areas differs among many species, and there
are significant species-specific differences in structure and orga-
nization, particularly between rodents and primates. In this dis-
cussion, we therefore present data primarily from humans and
nonhuman primates.
In the study of nociception, the thalamus is generally sepa-
rated into medial and lateral aspects. Although this division is
no longer as clear-cut as was once thought, the lateral system is
most strongly linked to the processing of sensory-discriminative
information related to pain, whereas the medial system is more
closely associated with emotional aspects of pain. The lateral
system encompasses the ventral and posterior nuclei of the thala-
mus and their linkages with lateral somatosensory cortices. The
lateral thalamic nuclei receive direct spinothalamic input from
both superficial and deep layers of the dorsal horn.20,21 Thalamic
nuclei assigned to the lateral system include the ventral posterior
medial (VPM) nucleus and the ventral posterior lateral (VPL)
nucleus, as well as the ventral posterior inferior (VPI) nucleus.
Together, the VPM and VPL nuclei in humans are referred to as
the ventrocaudal (Vc) nucleus. Medial and intralaminar nuclei,
along with their targets in the ACC and medial prefrontal corti-
ces, have been considered to constitute the medial pathway. In a
still-controversial remapping of these systems, Dostrovsky and
Craig16 argued that a novel, primate-specific nucleus, the poste-
rior part of the ventromedial nucleus (VMpo) represents the main
thalamic relay for sensory-discriminative information, with the
insula as the principal cortical target. The validity of this frame-
work remains a topic of debate,20-24 and the controversy probably
reflects the somewhat artificial nature of the concept of medial/
lateral pain system. Certainly it should be recognized that these
divisions are not as well demarcated as was once thought,
and overlap and interconnections must exist in function and
structure.
Lateral Thalamic Nuclei
Ventral Caudal Nucleus
The structures of the lateral thalamus primarily associated with
nociception are the three nuclei that make up the Vc nucleus,
also known as the principal sensory nucleus of the thalamus in
humans and as the ventral posterior complex in primates. In both
humans and primates, the constituent nuclei are the VPM and
VPL nuclei, which are functionally matched. Spinothalamic pro-
jections to the VPL nucleus arise from the spinal dorsal horn,
whereas inputs to the VPM nucleus are from the spinal trigemi-
nal nucleus (i.e., the “medullary dorsal horn”).25-27 Spinothalamic/
trigeminothalamic terminations are interdigitated with terminals
of the medial lemniscal pathway, wherein somatotopically orga-
nized tactile information is carried through the dorsal columns
and relayed through the dorsal column nuclei.28,29 The spinotha-
lamic terminations in the VPL nucleus arrive in clusters and are
organized, approximately somatotopically, in concordance with
the same medial-lateral somatotopic organization as the lemnis-
cal pathway.30-32
The outputs of the Vc nucleus are primarily to sensory cortical
areas, most notably to the primary somatosensory cortex (SI).
Using retrograde tracing in the primate, Gingold and associates33
found that Vc nucleus provides the majority of thalamic input to
SI. Of importance is that as many as 90% of identified nociceptive
neurons of the VPL nucleus could be activated antidromically
from the SI.34 Other identified targets of Vc nucleus projections
include the secondary somatosensory cortex (SII), insula, and
posterior parietal cortex.35-38
In addition to anatomic approaches, recording and stimulation
of Vc neurons provide evidence for the involvement of the region
in sensory and discriminative aspects of pain. The majority of
neurons in this region respond to innocuous or low-threshold
mechanical stimuli, but as many as 10% are activated by noxious
stimuli or temperature changes.39-42 Clusters of these nocire-
sponding neurons can be identified most consistently near the
posterior and inferior aspect.28,31,34,43,44 Neurons analogous to the
nociceptive-specific and WDR classes first described in the dorsal
horn can be identified.45 The Vc nucleus receives visceral, as well
as cutaneous, input and neurons in this nucleus have been shown
to respond to noxious visceral stimuli, although the organization
of responsive neurons is not apparently viscerotopic.46,47

Stimulation of Vc neurons in humans most often produces
contralateral, nonpainful paresthesias even at high intensities, at
least in patients without a chronic pain complaint, although tem-
perature and pain sensations can be evoked from some sites at
the lowest stimulus intensity.48,49 In one study, stimulation sites
near the posterior and inferior border were significantly more
likely to evoke painful or thermal sensations than those in the
core region.48 Bagley and associates50 and Lenz and colleagues51
were able to distinguish stimulation sites at which binary sensa-
tions (pain versus no pain) can be elicited and other sites at which
an analogue sensation, in which the sensory magnitude is related
to stimulus intensity, is produced. They suggested that the infor-
mation conveyed at sites associated with binary signaling are
related to an “alarm” aspect of pain processing, whereas process-
ing at analogue signaling sites is more important for coding
stimulus intensity.
The effects of lesions and inactivation of the Vc nucleus
further support the idea that the Vc nucleus is a functional relay
for nociceptive information. Focal application of lidocaine in this
region in nonhuman primates results in reduced detection of
small changes in skin temperature in the noxious range.52 In
humans, lesions of the Vc nucleus and, more broadly, the lateral
thalamus have been attempted for the treatment of neuropathic
pain, with resulting decreases in contralateral detection of thermal
and mechanical pain, as well as in touch and proprioception.53-55
However, such surgeries are necessarily conducted with caution
because of the risk of triggering iatrogenic central pain.56,57
Ventralis Caudalis Parvocellularis
The human ventralis caudalis parvocellularis is thought to be
analogous to the region referred to as the VPI nucleus in the
primate.58 Although not as well studied as the Vc nucleus, this
region is strongly associated with nociception, and one of its
functions is as a relay nucleus for nociceptive signals. Primate
studies show inputs to VPI traveling via the spinothalamic tract,
arising from neurons in laminae I, IV, and V.30,59,60 The VPI differs
from the neighboring ventral posterior complex in that the
former projects primarily to the SII and insular cortex, both of
which are involved in perception of pain.61 Although VPI is ana-
tomically contiguous with the VPL and VPM regions, it is func-
tionally distinct and has been linked to both the sensory and
affective components of pain.62 Recording studies in both humans
and primates have revealed numerous neurons in this region that
respond specifically to the application of noxious stimuli.41,63,64 In
humans, stimulation of the ventralis caudalis parvocellularis
apparently elicits painful sensations more reliably than does stim-
ulation of the Vc nucleus itself.48,65
Posterior Part of the Ventral Medial Nucleus
The VMpo nucleus is the most recently identified of the pain-
related nuclei of the lateral thalamus, and it remains a topic of sig-
nificant debate.21-24 First identified by Craig and colleagues60,66,67
in primates on the basis of direct spinothalamic inputs from
lamina I, the VMpo nucleus is in the caudal aspect of the
thalamus in a location that was formerly considered part of
the posterior complex. A similar region posteromedial to the
Vc nucleus has since been identified in humans.68 No analo-
gous site has been identified in nonprimate species. The VMpo
nucleus projects primarily to the insula, with additional projec-
tions to the SI.60
This area is of particular interest because according to current
evidence, it appears to be a specifically nociceptive region of
the thalamus. In initial recordings of neurons from primate
VMpo nuclei, 97% of the neurons characterized were found to
respond to either thermal or noxious stimuli. Further studies
have confirmed the presence of WDR, nociceptive-specific, and
CHAPTER 166  Anatomy and Physiology of Pain e595
thermoreceptive-specific neurons and the lack of low-threshold
neurons. The recorded neurons have an anterior-posterior topo- 166
graphic organization and small receptive fields.60 Subsequent
electrophysiologic recordings in awake human patients demon-
strated that neurons in a region tentatively identified as the
VMpo nucleus responded to innocuous or noxious cooling of the
skin and that stimulation of the region elicited perception of cold
or cooling.69 These findings suggest that the VMpo nucleus could
be important, not specifically as a nociceptive relay, but rather for
cooling/cold information.
The location, identification, and characterization of the
primate and human VMpo nuclei have become a subject of
debate. Arguments regarding the projection of lamina I neurons
in the VMpo nucleus are based on questions identifying the
terminal versus fibers of passage. Using a different antibody to
the same antigen, another group failed to replicate the staining
results that first identified the VMpo nucleus in primates, and the
human VMpo nucleus was identified primarily on the basis of
antibody staining against the same antigen.21,22,24,58 In a study of
poststroke lesions in humans, Kim and colleagues57 found that
poststroke pain and changes in temperature perception still
occurred in the absence of VMpo damage, although lesions that
did not include a significant part of the Vc nucleus did not cause
these symptoms. Further research is needed to confirm previous
findings on the boundaries and connectivity of the VMpo nucleus
in primates and to characterize the physiology and responsiveness
of VMpo cells in humans and primates.
Medial Thalamic Nuclei
Intralaminar Nuclei
The intralaminar nuclei have long been considered part of a
“nonspecific” medial complex that sends diffuse projections to
the entirety of cerebral cortex.70 Intralaminar nuclei postulated
to be involved in nociception include the central lateral, center
median, and parafascicular nuclei, with the parafascicular and
center median nuclei are sometimes considered together as
the center median–parafascicular complex. Nuclear boundaries
appear to be well matched between species, with only few signifi-
cant differences. One of the primary interspecies differences in
the intralaminar nuclei is in their inputs. In humans, the central
lateral nucleus is the only one of the three nuclei that receives
spinothalamic projections, whereas in primates, there are addi-
tional spinothalamic connections to the center median and para-
fascicular nuclei.26,27,71-73 Inputs to the central lateral nucleus arise
from deeper aspects of the spinal gray matter and laminae V and
VII.25,74,75 Outputs from the intralaminar nuclei go diffusely to
the cortex, including the posterior parietal and motor cortex.
However, organized connections with striatal structures suggest
that these nuclei produce important motor responses to noxious
inputs.76-80
Recordings made in intralaminar nuclei support the idea
that they are involved in processing of nociceptive information,
although their specific role remains unclear. Neurons responding
only to stimuli of noxious intensity have been identified in
humans and primates in all three nuclei and in general have large,
bilateral receptive fields.81,82 Recordings from the center median
and parafascicular nuclei have demonstrated that a large propor-
tion of neurons responded to pinprick or noxious heat, but none
responded to nonnoxious stimuli.83,84
Lesions of the medial thalamus have been created for intrac-
table or neuropathic pain and have produced generally positive
results. In one study of 69 patients with neurogenic pain, medial
thalamotomy was found to relieve the pain for 46 (67%).84,85
Stimulation of the intralaminar nuclei produces pain and thermal
sensation, among unpleasant sensations such as dyspnea and
dizziness.55,86,87
e596 SECTION 6  Pain
Ventral Caudal Part of the Medial Dorsal Nucleus
This area of medial thalamus is often grouped with the intrala-
minar nuclei because of similarities in afferents and physiology,
although the ventral caudal part of the medial dorsal nucleus
(MDvc) has received additional attention as a nociceptive relay
after it was shown to receive a spinothalamic projection from
lamina I of the spinal cord.21,60 The outputs from the MDvc are
argued to be primarily to the ACC and frontal lobe. On the basis
of these projections and the identification of nociceptive-specific
neurons localized to MDvc, this region is proposed to be impor-
tant in the motivational aspects of pain.
Brainstem
The anterolateral system comprises spinoreticular, spinomesen-
cephalic, spinoparabrachial, and spinothalamic pathways; indeed,
the brainstem projections outnumber those going directly from
the dorsal horn to the thalamus.
The spinoreticular pathway arises in deeper laminae of the
dorsal horn and sends projections to medial and lateral brainstem
core areas—including the lateral reticular nucleus, dorsal reticu-
lar nucleus, gigantocellular reticular nucleus, and rostral ventro-
medial medulla—and to the internal parabrachial nucleus (see
Gauriau and Bernard9 for a review). These connections are prob-
ably important in somatomotor integration of nociceptive
responses, recruitment of descending modulatory systems, and
engagement of arousal mechanisms.
The spinoparabrachial pathway, consisting of projections
from lamina I to the lateral parabrachial region, is receiving
increasing attention for its role in pain, especially chronic pain.9
The majority of neurons in the lateral/external parabrachial area
are strongly activated by noxious stimulation over wide areas of
the body. The nociceptive portion of the parabrachial complex
projects heavily to the central nucleus of the amygdala and to the
ventromedial hypothalamus. The connection through the amyg-
dala to the extended amygdala has been implicated in emotional
reactions to painful stimuli, and this input through the spinopara-
brachial system is probably reinforced by direct projections to the
amygdala from deeper spinal laminae that have been demon-
strated in both rodents and primates.88,89 The connection from
the nociceptive parabrachial complex to the hypothalamus seems
more likely to be related to motivated behaviors triggered by
pain, including defensive behaviors, flight, and aggression.
Spinomesencephalic pathways terminate primarily in lateral
and ventrolateral PAG matter, which are thought to be important
in active and passive coping strategies for dealing with escapable
and inescapable pain, respectively.90,91 These inputs presumably
also trigger descending control mechanisms (see “Descending
Modulatory Systems” section).
CORTICAL PROCESSING
There is no specific cortical location in which creating a lesion
eliminates pain. This fact gave rise to an idea that pain was
uniquely primitive among sensory systems in being processed
entirely at subcortical levels.13 However, the advent of functional
imaging approaches reawakened interest in the cortical represen-
tation of pain, and the notion that the cerebral cortex is unin-
volved in detection of noxious stimuli has since been discounted.
It is now appreciated that no single cortical “pain center” medi-
ates all aspects of the complex sensation that is pain. Rather,
a reasonably well-defined cortical network is recruited as a
result of acute noxious stimulation. Although no lesion in a single
site can eliminate the perception of pain, stimulation of any
one of many sites can elicit painful perceptions, in conjunction
with or independent of other somatosensory sensations. Experi-
ments involving such stimulation, along with advances in both
noninvasive and invasive techniques, have shed light on the con-
tributions that the numerous cortical regions make to the “pain
matrix.” Of importance is that the cortical representation of
longstanding chronic pain adds new layers of complexity to this
picture.
The role of five specific cortical areas in nociception is dis-
cussed here: the SI, SII, insula, ACC, and prefrontal cortex. Each
of these regions adds a distinct element to the experience of pain.
The SI has been proposed to be involved in sensory and discrimi-
native aspects of pain, whereas the SII is important in pain learn-
ing and memory. The ACC is involved in the affective aspects of
pain, and the insula is proposed to be a site of integration between
the sensory and affective aspects of pain. The prefrontal cortex,
although not implicated in the direct pain pathways, plays a role
in higher executive functions, attention, and placebo, all of which
can affect the perception of pain and the detection of noxious
stimuli.
Primary Somatosensory Cortex
The SI is part of the anterior parietal lobe and forms the post-
central gyrus. The role of the SI in somatosensory and mecha-
nosensory function is extensively documented.92,93 This region is
thus well suited for the proposed role in nociception of discrimi-
nating location and intensity, although its specific role has been
debated.36,94,95
The primary thalamic input to SI is via the ventral posterior
nuclei of the thalamus, which, as noted previously, receives both
spinothalamic and lemniscal projections. In monkeys, nociceptive
input to the SI has been demonstrated,33 and studies in rats have
also shown clusters of nociceptive neurons in this region of the
cortex.96 Nociceptive neurons in the SI are much rarer in pri-
mates, however, and although some reports have mentioned their
existence, mechanosensory neurons are far more common.97
Nevertheless, subdural and other recording methods in humans
have also shown evidence for neurons specifically activated by
noxious stimuli and specific activation of the SI in pain-related
tasks.98-100
A majority of imaging studies have demonstrated activation of
the SI with experimental noxious stimuli, and SI activation has
been linked specifically to pain intensity.101-103 Interestingly, a
sustained noxious stimulation (immersion of the hand in hot water
for 3 minutes under laboratory conditions) has been reported to
produce a decreased cortical signal in this region.104
Despite the findings of nociceptive neurons and activation of
the SI in imaging studies, stimulation of the SI predominantly
produces contralateral sensations of temperature, paresthesias,
and other innocuous sensations; few, if any, studies have demon-
strated sensations of pain evoked by stimulation of the human
SI.105-107 Studies of surgical and ischemic lesions in the SI and
surrounding areas have also shed light on its role in pain process-
ing. In early reports of SI damage from head trauma, hypoalgesia
and deficits in spatial and temporal discrimination of noxious
stimuli were described.108-110 In a more recent case report of
stroke-related damage to the right SI, the patient was reported
to have difficulty in localizing laser-evoked noxious stimuli on the
left side of the body; this patient was unable to discriminate the
location of the stimuli farther than to a single limb.111 However,
surgical interventions in the SI for pain control have been
reported as generally ineffective.112
Secondary Somatosensory Cortex
The SII is located on the parietal operculum at the superior bank
of the sylvian fissure, and although the functional specifics of pain
processing are still being described, SII has an unambiguous role
in cortically mediated nociception. SII is proposed to be involved
in recognition of painful and thermal stimuli, pain-related

learning, and integration of tactile and nociceptive information.
Thalamic input to the SII comes largely from the VPI.113 Indi-
vidual neurons in the SII may be nociceptive specific and tend
to have large receptive fields, with contralateral or bilateral
activation.114
The SII is consistently activated in imaging studies involving
nociception. Its proximity to the temporal lobe has made it ame-
nable to clinical research involving implantable, intracortical
electrodes in patients with temporal lobe epilepsy, and a wealth
of knowledge about function has been obtained from such studies.
With laser stimuli and implantable electrodes, SII responses were
shown to have gradations with stimulation intensity, from the
lowest sensory threshold to the detection of the stimuli as painful.
Of interest, however, is that the level of SII activation did not
increase with increasing stimulation intensity above the threshold
for detection of pain.115 In another study, Frot and associates,116
using depth electrodes, showed an increased latency in activation
of SII from tactile input in comparison with that from noxious
stimuli, which again supports the idea of SII involvement in
integration and learning. In imaging studies, the SII is activated
concurrently with or even before the SI, which indicates a paral-
lel, rather than serial, relationship between these two regions.117
Stimulation and lesion studies are sparse because of interpre-
tative difficulties related to location and because many ischemic
lesions extend into other areas. Only a few stimulation protocols
have focused specifically on the SII. Ostrowsky and colleagues118,119
reported that stimulation of the SII in humans did not evoke any
painful sensations, although this work was focused primarily on
the insula. In a systematic exploration of stimulation of the SII,
Mazzola and associates107 found the responses to be a mix of
somatosensory, temperature, and pain sensations; the percentage
of evoked pain sensations was the same as that produced by
stimulation of the insula. Difficulties with location have also
inhibited studies of lesions of the SII, although, in general, postle-
sion deficits in the SII support the idea of its direct involvement
in pain processing. In a case involving a pure sensory stroke of
only the SII, the patient showed contralateral restricted deficits
in light touch, pain, and temperature sensation.120 In other
cases involving SII injury, researchers have reported central
pain syndrome, hyperalgesia, and thermal and mechanical defi-
cits; of note, however, is that no such changes are observed with
parietal lesions that do not involve SII.121,122 Despite some imped-
iments to interpreting data related to SII injury, several lines of
research unequivocally indicate the involvement of this region in
pain processing and the integration of tactile and nociceptive
signals.
Insula
When viewed sagittally, the insula is a triangular region of cortex
located fully inside the sylvian sulcus. Before recent advances in
imaging technology, the role of the insula in nociception was
unclear, although now it is considered to be a central structure
in the “pain matrix” and is the site most commonly activated in
cortical imaging studies on pain.14 Many structural subdivisions
of the insula have been proposed, but the system most commonly
used entails divisions are along the anterior-posterior axis. The
anterior or middle/anterior portion of the insula is often impli-
cated in processing of nociceptive information, whereas the
posterior portion of the insula is more involved in tactile
processing.118,119,123 Functional magnetic resonance imaging indi-
cates a somatotopic organization.124,125 Baliki and colleagues126
provided evidence that the insula includes circuits both specific
to pain per se and more generally linked to encoding the intensity
or magnitude of sensory stimuli, including painful stimuli.
Recording and stimulation studies confirm the role of the
insula in nociception and shed light on differences in function
and processing between it and neighboring or functionally similar
CHAPTER 166  Anatomy and Physiology of Pain e597
areas such as the SII. Depth electrodes implanted in humans
reveal activation of insular activity from painful stimuli with 166
slightly longer latency (40 to 60 msec) than similarly activated
suprasylvian areas, which indicates serial rather than parallel pro-
cessing.127 Stimulation of the insula results in a range of somato-
sensory responses (temperature, pain, and paresthesias), as well
as some nonsomatosensory responses, including pharyngolaryn-
geal constriction and interruption of speech. With results of
stimulating the insula, Mazzola and associates107 devised a crude
somatosensory map with much larger areas of sensation, includ-
ing whole body, than is seen with stimulation of the SI or SII. In
previous work, Ostrowsky and colleagues119 devised a somato-
topic pain map that overlapped with a nonpain, somatotopic map,
which supported the idea of integration as a key role of the insula.
In patients with implanted electrodes, a laser was used as the
noxious stimuli to evoke responses within the insula. In contrast
to activation in the SII, cells in the insula did not show activation
until the stimulus reached the threshold for pain. Increasing
intensity above threshold increased the activity of cells, which
indicates that one function of the insula is to code for intensity
of painful stimuli.115 With lesions localized to the insular cortex,
some patients show an increase in pain tolerance or loss of affec-
tive quality of pain while retaining their ability to detect intensity
and heat-pain thresholds.122
Anterior Cingulate Cortex
The ACC commonly is functionally divided into anterior and
posterior segments, and the ACC, which encompasses Brodmann
areas 24 and 32, is further divided into the midcingulate cortex
and the ACC proper. The entire ACC has been specifically impli-
cated in the affective and motivational aspects of pain, although
the region has many other functions, which include overall affect,
response selection, and autonomic control. Activation of the
midcingulate cortex in response to noxious stimuli has been show
to occur with the same latency as that of SII, which suggests that
processing of affective and sensory-discriminative processing
occurs in parallel, rather than serially. The ACC has few afferents,
and most input to the ACC comes from medial thalamic nuclei,
the mediodorsal nuclei, and the parafascicular nuclei.128 In con-
trast, the posterior cingulate cortex receives afferents from ante-
rior thalamic nuclei and numerous other cortical regions and, of
note, also has strong interconnections with the ACC.129
Recordings from neurons in the ACC in rabbits and rats reveal
nociceptive-specific neurons with whole-body receptive fields
and no apparent somatotopic order or mapping.130,131 In psychi-
atric patients awaiting cingulotomy, recordings made from the
ACC show clearly pain-specific neurons that respond to contra-
lateral thermal, noxious thermal, and noxious mechanical stimuli.
Of interest, with excitatory stimulation, even with high-current
stimulation at the site of a nociceptive-specific neuron, painful
sensations were not evoked.132 Earlier findings with stimulation
in the ACC in humans was consistent with these results in that
no painful responses were elicited with stimulation, although
such autonomic signs as changes in blood pressure and heart rate
occurred.133 One explanation of the discrepancy between stimula-
tion and recording results is that ACC requires coactivation of
other pain-related areas to interpret the ACC response as painful,
although an experiment verifying this idea would be very difficult
to conduct.
Lesions and selective modulation of the affective aspect of
pain shed additional light onto the role of the ACC in pain
responses. An imaging study in which the unpleasantness of a
painful stimulus was manipulated through hypnosis revealed con-
sistent correlates of perceived unpleasantness with activation of
only the ACC, which highlights its role in the emotional and
motivational aspects of pain.134 In addition, in a study of 12
patients who underwent therapeutic cingulotomy for intractable
e598 SECTION 6  Pain
pain, pain ratings were improved only modestly, but the pain was
considered less bothersome or distressing. On a long-term basis,
however, the same patients also reported significant deficits in
executive functioning and intention.135
According to imaging studies of activation of the cingulate
cortex in response to noxious stimuli, the primary site of activa-
tion is the rostral ACC or midcingulate area, although different
patterns of activation can occur through modulation of higher
cognitive function.136-138 With anticipation of pain or the early
onset of a painful stimulus, the rostral segment of the ACC is
primarily activated, whereas if the stimulus is maintained, the
caudal ACC may be activated.139 Together, these data indicate that
the ACC is a primary cortical site of the “pain matrix,” but it is
involved in the emotional distress of pain and in selection of
responses to painful stimuli.
Prefrontal Cortex
The prefrontal cortex encompasses a large part of the frontal
cortex just anterior to the motor cortex. Although no evidence
exists for direct nociceptive connections, the area is mentioned
here because of its role in higher cognitive function and endog-
enous modulation of pain. The prefrontal cortex is implicated in
the majority of pain-related imaging studies and is even more
frequently involved during chronic pain.14 The medial prefrontal
cortex and dorsolateral prefrontal cortex are the subdivisions
more commonly activated during pain, and both areas are
involved in executive function, attention, and execution of high-
order tasks. The dorsolateral prefrontal cortex is specifically
involved in the placebo response, in which pain sensations are
modulated by expectation.140
SENSITIZATION OF ASCENDING PAIN
TRANSMISSION PATHWAYS
Stimulation of injured or inflamed tissue is well known to give
rise to exaggerated pain responses, with hyperalgesia (enhanced
pain in response to a normally painful stimulus) and allodynia
(pain produced by a normally innocuous stimulus). Such responses
can be attributed at least in part to a dynamic regulation of the
pain transmission elements in accord with stimulus history, the
state of the tissue (inflamed versus normal), and immune signals.
Plasticity in nociceptive processing has been documented at every
level of processing, so that an increased signal carried by sensi-
tized primary afferents is further amplified at the dorsal horn and
supraspinally. Changes at the dorsal horn are probably the best
studied, and the net effect at this level is often referred to as
central sensitization because molecular, cellular, and circuit-level
changes in the dorsal horn give rise to an increase in sensitivity
of nociceptive neurons, with lowered thresholds, increased
responsiveness, and enlarged receptive fields.141-146 More recently
this concept has been extended to include supraspinal systems,
and there is mounting evidence of reorganization of thalamocor-
tical and subcortical forebrain circuits in chronic pain states, not
all of which may be reversible.147,148
DESCENDING MODULATORY SYSTEMS
The discussion of central nociceptive transmission pathways has
emphasized that afferent input is processed at the level of the
dorsal horn and transmitted over parallel ascending pathways
to the brainstem, thalamus, hypothalamus, and limbic fore-
brain. However, a recurrent theme in clinical and experimental
approaches to pain has been that the relationship between the
presumed stimulus—tissue damage—and the ensuing sensory
experience is rarely straightforward. This is true even in the sim-
plest situation, in which a reasonably uniform sensory experience
(i.e., acute injury to healthy tissue) would be expected.
The variability in pain experience has long been recognized
and frequently underpins a characterization of pain reports as
“subjective” and therefore not to be trusted. One of the first
systematic scientific discussions of the variability of pain and of
the importance of cognitive and emotional factors in pain sensa-
tion was advanced by Beecher,149 who quantified the pain expe-
rienced by wounded soldiers according to the amount of narcotics
they required. He noted that the pain experienced by many of
these soldiers was much less than would have been predicted
on the basis of their injuries, and he argued that the apparent
absence of pain reflected a positive cognitive appraisal of the
injury, which would help remove that soldier from the war, at
least temporarily.
Clinicians now appreciate that cognitive and emotional
factors—including attention, learning, and mood—can all influ-
ence pain perception in situations nowhere nearly as extreme as
the battlefield.150,151 The brain is not a passive receiver of informa-
tion about noxious stimuli, and it actively regulates its own inputs.
Indeed, the coding of afferent information is shaped dynamically
by descending modulatory systems that influence nociceptive
processing at the first central relay, the dorsal horn. These
descending control systems are, in turn, regulated by afferent
sensory input but are also recruited by higher centers to modulate
spinal nociceptive processing in accord with behavioral priorities.
In this section, we consider the organization of the descending
modulatory systems in the central core of the brainstem, with a
particular focus on the PAG/RVM system.
Descending Modulation and the PAG/RVM System
It has been known since the work of Sherrington152 at the begin-
ning of the 20th century that spinal nocifensive reflexes are
altered in the absence of descending influences. However, the
idea that pain modulation is a specific function of the nervous
system is usually traced to a report in the late 1960s that elec-
trical stimulation in the midbrain PAG could produce potent
antinociception in rats.153 These original observations were rela-
tively crude, but subsequent work confirmed the antinociceptive
potency of PAG stimulation in rats154 and extended it to other
species, including humans.155 This phenomenon of “stimulation-
produced analgesia” inspired experimental studies in a number
of laboratories and ultimately led to definition of a brainstem
pain-modulating circuit (Fig. 166-2) with critical links in the
PAG and the RVM. Electrical stimulation at either site resulted
in antinociception, an effect mediated by inhibition of nocicep-
tive activity in the dorsal horn. The anatomic substrate for this
descending control is a significant projection from the PAG to the
RVM, which in turn projects via the dorsolateral funiculus to the
dorsal horn to influence sensory processing. The PAG itself sends
only minor projections to the spinal cord and receives substantial
inputs from limbic forebrain structures, including the ACC, pre-
frontal cortex, insula, amygdala, and hypothalamus. This infor-
mation is integrated and transmitted to the RVM.
Both the RVM and, especially, the PAG also receive significant
nociceptive inputs from the dorsal horn, via the spinoreticular
and spinomesencephalic tracts. On the basis of the connectivity
of this system alone, the PAG/RVM system appears well situated
to integrate higher order influences important in cognition and
emotion with afferent input from the dorsal horn. Other brain-
stem systems, such as the dorsal reticular nucleus in the caudal
medulla (which mediates effects of counterirritation) and the
noradrenergic systems in the dorsolateral pontine tegmentum are
also known to modulate nociceptive transmission, but the PAG/
RVM system is the best studied and probably has the greatest
effect on pain.
Interest in the PAG/RVM system was heightened when it
became clear that it was an important substrate for opioid anal-
gesic drugs.150,156,157 It had long been recognized that morphine

P FC
m-
C
AC
Hyp
PA
Amg
G
RVM
Figure 166-2. Brainstem pain-modulating network with links in
the midbrain periaqueductal gray matter (PAG) and rostral
ventromedial medulla (RVM). The RVM, which includes the nucleus
raphe magnus and adjacent reticular formation, receives a large input
from the PAG. The RVM in turn projects to the dorsal horn, primarily
to the superficial layers and lamina V, where it can facilitate or inhibit
processing of nociceptive information. Significant input to the PAG
from forebrain and hypothalamus provide an anatomic substrate for
top-down control of pain. ACC, anterior cingulate cortex; Amg,
amygdala; Hyp, hypothalamus; m-PFC, medial prefrontal cortex.
and other opioid agents act primarily in the brain. Using micro-
injection mapping to delineate central sites that were directly
sensitive to opioids, Yaksh and Rudy157 found that both the
PAG and RVM could support opioid analgesia and, in fact,
that these regions are required for the analgesic actions of sys-
temically administered opioids. This system also employs endog-
enous opioids as neurotransmitters, and there is evidence that
endogenous opioids in the PAG and RVM contribute to the pain-
modulating function of this system.
Because the direct cellular effects of opioids are inhibitory,158
it may be surprising that focal opioid application and electrical
stimulation in these regions has the same net behavioral effect:
analgesia. However, the answer to this apparent paradox lies in
the circuitry within the PAG and RVM, where the opioids act
directly on inhibitory neurons that normally inhibit the pain-
inhibiting output neurons. Opioids thus activate descending inhi-
bition through disinhibition.159
Bidirectional Control
Along with the evidence that this system mediates the analgesic
actions of exogenous and endogenous opioids, the initial discov-
ery of the PAG/RVM circuit as the basis for stimulation-produced
analgesia led to an early view of this circuit as an “analgesia
system.” This view is now known to be incomplete; that the
brainstem exerts bidirectional control, inhibiting or facilitating
pain under different conditions. The bidirectional nature of
descending modulation is best studied in the RVM. Results of a
number of early behavioral and electrophysiologic studies sug-
gested that electrical stimulation in the RVM could facilitate
pain, depending on the stimulating current and exact location of
the electrode.160 The implications of these observations were
unclear until researchers found evidence that the RVM contrib-
utes to increased pain in a number of paradigms. Thus, for
example, blocking activity in the RVM interferes with secondary
CHAPTER 166  Anatomy and Physiology of Pain e599
166
RVM
ON-cell OFF-cell
(+) Pronocioceptive Antinocioceptive (-)
DRG Anterolateral
C-Nociceptor
Að-Nociceptor system
Pain
behavior
Figure 166-3. Two populations of rostral ventromedial medulla (RVM)
neurons, ON-cells and OFF-cells, provide the neural basis for
bidirectional control of spinal processing by the RVM. DRG, dorsal
root ganglion.
hyperalgesia after inflammation, with nerve-injury pain, and with
hyperalgesia induced by chronic opioid administration (opioid-
induced hyperalgesia).161,162 The current assumption is of a modu-
latory system, rather than an “analgesia system,” with the potential
for bidirectional control.151
Neural Basis for Bidirectional Control
Functional studies thus clearly demonstrate that, as a region, the
RVM exerts bidirectional control of nociceptive processing, with
a net pronociceptive action under some conditions and a net
antinociceptive role in others. The neural basis for the pain-
inhibiting and pain-facilitating influences from the RVM is now
recognized to be two classes of RVM neurons, termed OFF-cells
and ON-cells, respectively (Fig. 166-3).150,163 OFF-cells mediate
the analgesic actions of µ-opioid agents and are probably recruited
in behavioral states associated with decreased pain, such as stress-
induced analgesia. ON-cells are activated as part of positive-
feedback loop that amplifies pain after tissue or nerve injury and
during inflammation. These neurons are also activated by higher
cognitive structures (e.g., hypothalamus) in the absence of noxious
input and could thus account for increased pain sensitivity stimu-
lated by cognitive and emotional processes, as occurs during mild
stress.164,165
Recruitment of the PAG/RVM Modulatory System
The discussion of descending modulatory systems has to this
point focused on anatomic and physiologic delineation of the
PAG/RVM circuitry and the effects of experimental manipula-
tions on dorsal horn processing and nociceptive behavior. This
understanding prompts the question of how these systems come
to be activated in behaving animals. Although the information is
in many ways still incomplete, there is now strong evidence that
the balance between the pain-facilitating and pain-inhibiting
outflow from the RVM is dynamic and allows the organism to
amplify or suppress nociceptive afferent transmission in accord
with behavioral priorities.150,151
e600 SECTION 6  Pain
Activation by Noxious Inputs: A Positive-Feedback Loop
An early view of descending modulatory systems focused on the
phenomenon of counterirritation, in which pain at one site on
the body suppressed inputs from other regions. A reasonable
assumption was that this remote inhibition was mediated by the
PAG/RVM system as part of a negative-feedback loop. However,
negative-feedback processes triggered by noxious input are medi-
ated not by the PAG/RVM system but by the dorsal reticular
nucleus in the caudal medulla.166,167 It can be argued that this
process is important as a contrast mechanism and for integration
of multiple sensory inputs with motor outputs. This negative-
feedback process is in contrast with the PAG/RVM system, which
mediates an acute positive-feedback process. Discrete noxious
stimuli or more prolonged inflammatory events activate ON-cells,
amplifying responses to subsequent inputs.168,169
Stress
A very different approach to the function of the RVM system is
to consider descending modulation within the larger context of
integrating and organizing defensive responses to noxious or
threatening aspects of the environment.150,170,171 The phenome-
non of stress-induced analgesia—which occurs, for example,
upon encounters with biologically relevant threat stimuli, such as
a predator, or during major trauma—is well documented. Stress-
induced analgesia presumably functions to suppress nociception
in situations in which distress or overt behaviors that would
otherwise be evoked by a noxious stimulus might interfere with
effective coping.154,170,172,173 The role of the RVM in stress-induced
analgesia is well documented, and RVM OFF-cells are recruited
in a model of fear-induced analgesia, in which these neurons are
activated through the amygdala.174,175
Stress can also give rise to stress-induced hyperalgesia, an
effect probably more relevant than stress-induced analgesia to
everyday experience and to the clinical environment. In humans,
anxiety or anticipation of pain can be shown to enhance pain
sensitivity,176-180 and stress is often asserted to exacerbate chronic
clinical pain.181-183 Hyperalgesia mediated by activation of RVM
ON-cells has been demonstrated in an animal model of mild or
emotional stress.164,165
Contribution to Chronic Pain States
Descending facilitation from the PAG/RVM system has been
shown to contribute to chronic pain states. Inactivation of the
RVM attenuates or blocks allodynia and hyperalgesia in animal
models of inflammation and nerve-injury pain, which indicates
that this region functions as part of a positive-feedback loop trig-
gered by injury and inflammation.161,184-187 Further evidence indi-
cates that recruitment and sensitization of RVM ON-cells are
important specifically in this positive-feedback process.161,169,188
RVM ON-cells can be engaged by the hypothalamus and preop-
tic areas in models of stress and illness; this observation shows
that pain processing can be facilitated by top-down influences in
the absence of an initial noxious trigger. Such top-down modula-
tion could be relevant to functional pain disorders such as fibro-
myalgia or irritable bowel syndrome.
Descending Modulation in Humans: Evidence from
Imaging Studies
The existence of the brainstem modulatory system in humans was
first demonstrated by the analgesic action of deep brain stimula-
tion in the PAG/periventricular gray area in some forms of clini-
cal pain.155 Functional imaging approaches have increased the
understanding of when brainstem pain-modulating systems are
recruited in humans.103,189,190 Placebo analgesia has probably been
the most intensively studied model, with coactivation of the ACC
and PAG during both opioid- and placebo-induced analge-
sia.140,191,192 Activation of the PAG has also been inversely corre-
lated with pain rating in paradigms associated with increased
pain.193-195 Although correlational, these studies confirm the
recruitment of brainstem core systems in humans by cognitive
and emotional variables.
CONCLUSION
Information about primary afferents and nociceptive signal trans-
duction has burgeoned, but pain as a sensory experience requires
transmission and integration of sensory input within the central
nervous system. It is now recognized that pain reflects activation
of parallel ascending pathways that engage a distributed thalamo-
cortical network, a network sometimes referred to as a “pain
matrix.” This network is not a passive receiver, and input in the
ascending pain system is dynamically regulated in accord with
behavioral priorities by a descending modulatory system. Finally,
there is increasing evidence that as pain becomes chronic, the
systems engaged shift to reflect the growing importance of con-
ditioning and other higher order processes. Understanding and
manipulating these dynamic aspects of pain sensing and modula-
tion will be crucial for future advances in therapeutic approaches
to pain.
Acknowledgments
Mary M. Heinricher’s work is supported by grants from the National
Institute of Neurological Disorder and Stroke (NINDS). We thank Andy
Rekito, MS, for preparation of the artwork for this chapter.
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167 Molecular Basis of Nociception
Susan L. Ingram
This chapter is a review of key molecular mechanisms of pain
transduction and provides several examples of plasticity involved
in peripheral and central sensitization of pain.
Pain (or nociception) is an evolutionally conserved protective
mechanism for detection of a dangerous environment and tissue
damage. The knowledge about cellular mechanisms underlying
the perception of pain and plasticity of pain circuits has increased
exponentially since the 1990s. Acute inflammatory pain after
tissue damage generally plays a protective role for organisms.
Chronic inflammation can induce pain that persists long after the
initial insult. Direct insult to the nerve can induce neuropathic
pain that also may persist after the time of healing. In both
chronic inflammatory and neuropathic conditions, this patho-
logic pain does not appear to be protective; instead, it reflects
activation and plasticity in the central nervous system (CNS). Of
importance is the fact that the central processing of nociceptive
inputs in the spinal cord are subject to modulation by descending
projections from several brain circuits. Thus the “perception” of
tissue damage is rarely a direct reflection of the activated primary
afferents; instead it is a complex output that includes cognitive
and emotional processing by the brain. This critical distinction
demonstrates that the brain plays an important role in the per-
ception of pain and is particularly relevant for considering the
causes of chronic pain.
Sensory neurons that innervate the skin, viscera, deep muscles,
and joints are primary afferents. The soma of each of these
neurons are in the dorsal root or trigeminal ganglia, and their
axons extend bidirectionally into their peripheral targets and cen-
trally into the spinal cord. Primary afferents include neurons that
respond to low-intensity touch stimulation, such as the myelin-
ated A beta fibers (which innervate Pacinian corpuscles) and
Merkel cells (which detect vibration and light pressure). Nocicep-
tive primary afferents respond to high-intensity nociceptive
stimulation and express many chemoreceptors that detect tissue
damage. Nociceptive afferents are classified as two main subtypes:
A delta–fiber and C-fiber afferents. A delta fibers are thin and
myelinated and have faster conduction velocities than C fibers,
which are unmyelinated, and they evoke sharp localized pain
responses. C fiber nociceptors elicit dull, diffuse, burning pain.
The intensity of a painful stimulus is encoded by action potential
frequency. Nociceptive fibers terminate as free nerve endings in
the skin and detect multiple stimuli, including heat, cold, mechan-
ical stimuli, and the myriad of chemicals released with tissue
damage.
Transduction of pain information occurs through direct stim-
ulation of ligand-gated ion channels or indirectly: for example,
through activation of G protein–coupled receptors that are
coupled to ion channels through intracellular signaling mol-
ecules. Activation of these channels leads to the depolarization
of afferent nerve endings. Summation of multiple events leads
to activation of voltage-gated sodium and potassium channels
involved in action potential generation. Action potentials travel
to the spinal cord and stimulate voltage-gated Ca2+ channels
in the central terminals. Influx of calcium initiates release of
neurotransmitters from vesicles. Transduction is modulated by
pronociceptive substances and by immune factors released during
167
tissue damage and the inflammatory process. These substances
modulate pain at all steps in the process, including gating of
channels involved in transduction, propagation of action poten-
tials, and the release of neurotransmitters from central terminals.
PAIN SENSITIZATION
Persistent pain is often caused by direct and long-lasting damage
to peripheral nerve fibers, through either injury or disease states.
Peripheral sensitization is defined as either allodynia, pain initi-
ated by normally innocuous stimuli, or hyperalgesia, an enhanced
response to noxious stimuli. In the periphery, the inflammatory
milieu containing neurotransmitters and peptides (substance P,
calcitonin gene-related peptide [CGRP], bradykinin), prostaglan-
dins, leukotrienes, neurotrophins, cytokines, chemokines, extra-
cellular proteases, and protons can potentiate normal nociceptive
processing. The most common drug targets for peripheral sensi-
tization are cyclooxygenase-1 and cyclooxygenase-2, inhibition of
which reduces synthesis of prostaglandins.
Intense stimulation or persistent injury can cause plasticity of
the central nociceptive circuits, known as central sensitization.
Several molecular mechanisms mediate plasticity of the CNS and
contribute to central sensitization. Plasticity of presynaptic neu-
rotransmitters released from primary afferent terminals and post-
synaptic responses of dorsal horn neurons has been described, as
has plasticity in higher brain centers, all of which contribute to
persistent changes in pain perception. The most well-studied
mechanism is plasticity of glutamatergic signaling on second-
order nociceptive neurons in the dorsal horn of the spinal cord.
N-methyl-d-aspartic acid (NMDA) receptor antagonists have
been developed as potential analgesics, but results from clinical
trials have not been promising because of serious CNS side
effects.
Inhibition of nociceptive circuitry in the dorsal horn plays a
critical role in pain perception. Descending inhibitory serotoner-
gic, noradrenergic, and dopaminergic pathways from the periaq-
ueductal gray matter (PAG), rostral ventral medulla (RVM), locus
coeruleus, and raphe nuclei, as well as local γ-aminobutyric
acid (GABA)– and glycine-containing interneurons, regulate the
excitability of dorsal horn projection neurons. It is clear that
the balance of inhibitory and facilitative control of pain by the
descending pathways is shifted in states of neuropathic or chronic
pain. Descending control of nociception is a primary area of
research because in many clinical trials of drugs that specifically
target peripheral molecules involved in pain transduction, the
results have fallen short of expectations for multiple reasons,
including lack of efficacy and safety, selectivity, and possible issues
with animal model translation. Thus attention is beginning to
turn from a focus on specific molecules to a wider view of pain
circuits and their interactions. Further research with optogenetic
and transgenic techniques to study pain circuits will certainly
advance the understanding of how this balance is modulated at
each level of the pain axis.
Full text of this chapter is available online at ExpertConsult.com
1379
167 Molecular Basis of Nociception
Susan L. Ingram
Pain (or nociception) is an evolutionally conserved protective
mechanism for detection of a dangerous environment and tissue
damage.1 The knowledge of cellular mechanisms underlying the
perception of pain and plasticity of pain circuits has increased
exponentially since the 1990s. Tissue damage causes the release
of myriad substances that activate nociceptive afferents and
recruit immune cells to the area to induce inflammation. Acute
inflammatory pain after tissue damage generally plays a protec-
tive role for organisms. Chronic inflammation can induce pain
that persists long after the initial insult. Direct insult to the nerve
can induce neuropathic pain that also may persist after the time
of healing. In both chronic inflammatory and neuropathic condi-
tions, this pathologic pain does not appear to be protective;
instead, it reflects activation and plasticity in the CNS. Of impor-
tance is that the central processing of nociceptive inputs in the
spinal cord are subject to modulation by descending projections
from several brain circuits. Thus the “perception” of tissue
damage is rarely a direct reflection of the activated primary affer-
ents; instead, it is a complex output that includes cognitive and
emotional processing by the brain. This critical distinction dem-
onstrates that the brain plays an important role in the perception
of pain and is particularly relevant for considering the causes of
chronic pain. This chapter summarizes key molecular mecha-
nisms of pain transduction and several examples of plasticity
involved in peripheral and central sensitization of pain.
ACTIVATION OF PRIMARY AFFERENTS
Sensory neurons that innervate the skin, viscera, deep muscle, and
joints are primary afferents. These neurons have their soma in
the dorsal root or trigeminal ganglia and extend axons bidirec-
tionally, into their peripheral targets and centrally into the spinal
cord. Transduction occurs through direct stimulation of ligand-
gated ion channels or indirectly, for example via activation of
G-protein-coupled receptors that are coupled to ion channels
through intracellular signaling molecules. Activation of these
channels leads to a generator potential or depolarization of
afferent nerve endings and summation of multiple events leads
to activation of voltage-gated sodium and potassium channels
involved in action potential generation.
Primary afferents include neurons that respond to low inten-
sity touch stimulation such as the myelinated A beta fibers that
innervate Pacinian corpuscles and Merkel cells to detect vibration
and light pressure. Nociceptive primary afferents respond to
high-intensity nociceptive stimulation and express many chemo-
receptors that detect tissue damage. Nociceptive afferents are
split into two main subtypes: A delta–fiber and C-fiber afferents.
Thinly myelinated A delta fibers have faster conduction velocities
than unmyelinated C fibers and evoke sharp localized pain
responses as opposed to the dull, diffuse, burning pain elicited by
C-fiber nociceptors. The intensity of a painful stimulus is encoded
by proportional scaling of action potential frequency. Nocicep-
tive fibers terminate as free nerve endings in the skin and detect
multiple stimuli, including heat, cold, mechanical stimuli, or the
myriad of chemicals released with tissue damage.
Pain-Promoting Substances Released with
Tissue Injury
Upon tissue damage, injured cells release large quantities of
adenosine triphosphate (ATP) and glutamate that activate free
167
nerve endings of nociceptive A delta and C fibers in the skin. This
damage sets off a cascade of events that constitute neuroinflam-
mation.2 Activation of nerve endings stimulates the release of
pro-nociceptive substances, including the neuropeptides sub-
stance P, CGRP, and neuropeptide Y that trigger inflammatory
responses. Mast cells are recruited to the site and release a host
of inflammatory mediators including: prostaglandins, bradykinin,
cytokines, serotonin and histamine. Vasodilation and plasma
extravasation also contribute to amplification of the inflammatory
response (Fig. 167-1).
Detection and Transduction of Tissue Injury
The detection of the nociceptive environment and inflammatory
mediators is accomplished through many specialized receptor
proteins that are differentially expressed in primary afferents.
The specificity theory of pain, originating back to the writings
of Descartes, describes specific pain modalities having direct but
separate pathways from the periphery to the brain.3 Considerable
effort has been made to identify different populations of nocicep-
tive afferents on the basis of their sensitivity to painful stimuli and
responses to pain-promoting molecules. C-fiber nociceptors are
loosely categorized as peptidergic and nonpeptidergic subpopula-
tions. Peptidergic C-fiber nociceptors contain and release neuro-
peptides such as substance P and CGRP. These neurons express
the tyrosine kinase A receptor for nerve growth factor (NGF).
Nonpeptidergic nociceptors do not synthesize these peptides but
can be identified by their ability to bind the isolectin GS-IB4
and by their sensitivity to glia-derived neurotrophic factor.
However, neurons within each of these subpopulations respond
to various inflammatory mediators and are generally polymo-
dal, which dramatically increases the complexity of primary
afferents (Fig. 167-2).
Subtypes of C-fiber and A delta–fiber nociceptors express
many specific receptors for endogenous inflammatory mediators,
including bradykinin (both B2 and B1 receptors), serotonin
(5-HT3 receptors), prostaglandin E2 (EP receptors), histamine,
and protons (the acid-sensitive ion channels 1, 2, and 3). ATP
receptors include metabotropic P2Y receptors and P2X2 and
ionotropic P2X3 receptors. Many of the receptor proteins are
activated or modulated, or both, by multiple inflammatory sub-
stances. A prominent example is the family of transient receptor
potential (TRP) channels. TRP channels include several proteins
that are nonselective cation channels that play a role in nocicep-
tive transduction. The first member of this family to be cloned
was TRPV1. TRPV1 is gated by multiple chemical stimuli,
including capsaicin, the active ingredient in hot peppers and
those released during inflammation, as well as by changes in
temperature in the noxious range (>43°C for humans).4-6 Inflam-
matory mediators that sensitize or activate nociceptors can also
modulate or sensitize TRP channels (Fig. 167-3). Metabolites of
12- and 15-lipoxygenase (leukotriene B4 and 15[S]-hydroxyeico-
satrienoic acid), N-arachidonyl dopamine, and protons activate
TRPV1. G protein–coupled receptors (e.g., protease-activated
receptors, bradykinin receptors, P2Y purinergic receptors, pros-
taglandin receptors, metabotropic glutamate receptors) that
couple to phosphatidylinositol 4,5-bisphosphate (PIP2) and phos-
pholipase C strongly sensitize TRPV1-mediated currents. Phos-
phorylation by multiple kinase pathways, including PKC and
PKA, facilitate activation of TRPV1 by different mechanisms.
Thus TRPV1 integrates signals from multiple aspects of the
e605
e606 SECTION 6  Pain

Figure 167-1. Tissue damage sets up an inflammatory cycle. Tissue damage causes release of multiple
substances that excite nociceptive afferents to release neurotransmitters (substance P and calcitonin
gene–related peptide) that in turn recruit immune cells and activate the vasculature to release additional
inflammatory mediators. ATP, adenosine triphosphate; AP, action potential; DRG, dorsal root ganglia;
H+, hydrogen ion; 5-HT, serotonin; NGF, nerve growth factor.

inflammatory cascade and has been shown to be a critical protein

Figure 167-2. Primary afferent nociceptors are heterogeneous
with regard to transduction molecules. Each nociceptor expresses
a unique complement of receptor and ion channels that are sensitive
to pronociceptive stimuli and inflammatory mediators. (From Basbaum
AI, Bautista DM, Scherrer G, et al. Cellular and molecular mechanisms
of pain. Cell. 2009;139:267-284.)
in the development of hyperalgesia.7-9 However, in TRPV1-
deficient mice, heat sensitivity remains intact,10 suggesting that
TRPV1 is not the only molecule involved in heat transduction.
There are several additional subtypes of the TRPV receptors
(TRPV2 to TRPV4). These receptors have slightly different heat
thresholds for activation and are expressed in subpopulations of
primary afferent neurons. TRPV2 has a higher threshold (>52°C)
than TRPV1 and is expressed primarily in A delta–fiber nocicep-
tors. TRPV3 and TRPV4 are expressed in epithelia and have
a narrow activation range, between 25°C and 35°C. These
additional members of the TRP family also respond to mul-
tiple signaling molecules. For example, TRPV4 is activated by
several endogenous chemicals: anandamide, arachidonic acid, and
5′,6′-epoxyeicosatrienoic acid.
Transduction of cold sensation is not as well understood but
probably involves multiple signaling proteins.11 The TRPM8
channel is expressed in a subpopulation of primary afferent A
delta–fiber nociceptors that responds to cold (< 25°C) and is
permeable to calcium ions.12-15 In knockout models of TRPM8,
both normal cold sensation and cold hypersensitivity are defi-
cient,16-18 which indicates that these channels play a primary role
in cold sensation. The TRPM8 channel is sensitive to cooling
agents such as menthol, icilin, and eucalyptol. TRPA1 channels
play an important role in injury-evoked cold hypersensitivity.19-21
TRPA1 channels are also activated by a pungent chemical found
in mustard, wasabi, and allium plants.21-25 Continued research
into these receptor subtypes will further define their roles in pain.
The KCNK family of potassium channels expressed in C-type
nociceptors also plays a role in cold sensation. The TREK-1 (a
“TWIK-related potassium channel,” in which TWIK stands for
“tandem P domain in a weak inward rectifier K+ channel”) and
 CHAPTER 167  Molecular Basis of Nociception e607

167

Figure 167-3. An emerging structure-function map for the capsaicin receptor, TRPV1. Pharmacologic
and mutagenesis studies have identified TRPV1 domains that confer sensitivity to various stimuli or contribute
to physiologic modulation of the channel downstream of metabotropic receptors. These include sites of
action for capsaicin (depicted by the chili pepper) and related vanilloid ligands, extracellular protons (depicted
by the lemon), or peptide toxins from the tarantula (depicted by the spider). Regions implicated in channel
modulation by cellular proteins and cytoplasmic second messengers are also indicated. A, ankyrin
repeats; ATP, adenosine triphosphate; C, carboxy terminus; N, amino terminus; PIP2, phosphatidylinositol
4,5-bisphosphate; PKA, protein kinase A; PKC, protein kinase C; PLC, phospholipase C. (From Julius D. TRP
channels and pain. Annu Rev Cell Dev Biol. 2013;29:355-384.)

TRAAK (TWIK-related arachidonic acid–stimulated K+ channel)
channels are highly mechanosensitive and thermosensitive chan-
nels.26 Of interest is that another member of the family, KCNK18,
is activated by hydroxy-α-sanshool, the active ingredient of the
Szechuan pepper.27
Receptors for mechanical stimuli have long been thought to
be sensitive to stretching or depression of the skin, or both.
Members of the degenerin/epithelial sodium channel family,
including mec-4 and mec-10 of Caenorhabditis elegans, and acid-
sensing ion channels have been proposed as likely candidates for
mechanosensation. However, studies of acid-sensing ion channel
knock-out mice have demonstrated few deficits in mechanosensa-
tion, which indicates that additional molecules will be implicated
in mechanosensation.28 TRP channels have also been implicated
as mechanosensors.29 TRPV2 has been shown to respond to
osmotic stretch,30 and TRPA1 may also detect mechanical stimuli,
inasmuch as selective inhibition of TRPA1 channels reduces
mechanical hypersensitivity associated with inflammation.31,32
Antisense knockdown of TRPV4 channels reduced mechanical
hyperalgesia in several animal models of neuropathy.33 However,
few studies have shown that any of these channels are sufficient
for mechanical transduction in isolated transfection systems; thus
additional proteins or lipid environments may be necessary for
function.
Nociception in Other Tissues
Visceral pain is a prevalent, major clinical problem. The periph-
eral basis of visceral pain differs from that in other body regions.34
Visceral sensory afferents are predominately A delta and C fibers
with diffuse receptive fields, so that pain is less localized. These
visceral afferents travel with sympathetic nerves to the spinal cord
and express transduction channels and receptors similar to those
expressed by somatic primary afferents (see earlier discussion).
Inflammation of the target tissues results in hypersensitivity
of these afferents in association with pain disorders such as
irritable bowel syndrome and other functional gastrointestinal
disorders.35
Muscle pain occurs during sustained muscular contraction and
ischemia, after trauma, or after eccentric exercise.36 The majority
of muscle fiber afferents are low-threshold afferents that transmit
deep pressure. Less than half of the group III and IV fibers in
muscle are thought to be nociceptors. Sensitization of these affer-
ents may play a role in muscle disorders with generalized pain,
such as fibromyalgia.37
Skeletal pain results from activation of terminals ending in
various targets, including joints, the periosteum, and the intra-
medullary space. Nociceptive afferents localized throughout
tissues surrounding joints can be sensitized in osteoarthritis.38,39
Degeneration of cartilage and inflammation within the joint
contribute to the development of chronic pain but the cellular
mechanisms, both peripheral and central, are still being eluci-
dated. Pain caused by tumor metastasis to bone, or other cancer
pain, involves both inflammatory and neuropathic mechanisms.40
Approximately 75% of patients with advanced cancer experience
bone pain that is characterized by dull and continuous background
pain interspersed with spontaneous breakthrough pain.41,42 This
mixture of pain symptoms makes cancer-induced bone pain dif-
ficult to treat successfully, and so considerable effort is being
expended to understand the pathophysiologic mechanisms that
appear to be unique to cancer pain.
Peripheral Sensitization
Persistent pain is often caused by direct and long-lasting
damage to peripheral nerve fibers, either through injury or
through disease states. Peripheral sensitization is defined as
either allodynia (pain initiated by normally innocuous stimuli)
e608 SECTION 6  Pain
or hyperalgesia (an enhanced response to noxious stimuli). In the
periphery, stimulation of the inflammatory cascade and release of
myriad inflammatory substances (the “inflammatory soup”) after
tissue damage initiate gating of ion channels (see Fig. 167-1)
through direct or allosteric binding to the receptor proteins or
through intracellular second messenger signaling. This “inflam-
matory soup” contains neurotransmitters and peptides (substance
P, CGRP, bradykinin), prostaglandins, leukotrienes, neurotroph-
ins, cytokines, chemokines, extracellular proteases, and protons.
The most common drug targets for peripheral sensitization are
cyclooxygenase-1 and cyclooxygenase-2, inhibition of which
reduces synthesis of prostaglandins. NGF is a component of the
“inflammatory soup”43 and contributes to peripheral sensitization
by activation of tyrosine kinase A receptors selectively expressed
by C-fiber nociceptors.44 Tyrosine kinase A receptors modulate
TRPV1 currents45 and induce expression of several pronocicep-
tive proteins, including substance P, TRPV1, and Nav1.8 chan-
nels.44,46 Interesting new therapies for peripheral sensitization
include anti-NGF antibodies and antagonists of TRPV1 and
TRPA1 receptors.21
MODULATION OF PRIMARY AFFERENT FIRING
The frequency of primary afferent firing and the population of
stimulated afferent fibers underlie the encoding of nociception.
Generator potentials summate to depolarize peripheral terminals
and activate voltage-gated sodium, potassium, and calcium chan-
nels to initiate action potential firing. Many subtypes of voltage-
gated sodium channels have been cloned, and these channels
either are blocked by tetrodotoxin (TTX), and are thus termed
TTX-sensitive (Nav1.1, Nav1.6 and Nav1.7), or are TTX-insensitive
channels (Nav1.8 and Nav1.9). Nav1.8 channels are activated by
membrane repolarization and are also called resurgent sodium
channels. Many of these voltage-gated channels involved in action
potential firing are modulated by substances in the “inflammatory
soup”47 and contribute to hyperalgesia and neuropathic pain
states. Expression of the voltage-gated sodium channel Nav1.748,49
is upregulated in inflammatory pain and may exacerbate inflam-
matory pain, but expression of this channel is not changed after
nerve injury.50
Voltage-gated calcium channels involved in release of neu-
rotransmitter from primary afferents are also modulated during
inflammatory or neuropathic pain states. Gabapentin, an anticon-
vulsant drug that targets the auxiliary α2δ subunit of calcium
channels has been used to treat neuropathic pain.51 Finally,
KCNQ channels, which are low-threshold, voltage-activated
potassium channels, do not become inactivated and play a role in
stabilizing membrane potential and decreasing excitability. They
are negatively regulated by G protein–coupled receptors, such as
the bradykinin receptor, so that activation of the bradykinin
receptor increases excitability of primary afferent nociceptors.52
A family of analgesic agents (flupirtine and retigabine) increase
activation of KCNQ channels to reduce excitability of primary
afferents during inflammation.53
TRANSMISSION OF PAIN SIGNALS TO THE CENTRAL
NERVOUS SYSTEM
Action potentials in primary afferents travel from the periphery
to the central terminals in the dorsal horn of the spinal cord. The
majority of lightly myelinated A delta– and unmyelinated C-fiber
axons form a central branch that projects through the dorsal root
to the spinal cord. A subpopulation of these fibers enters via the
ventral roots, but it is not clear whether these fibers carry noci-
ceptive information. As the spinal nerve root approaches the
spinal cord, it splits into smaller rootlets, bifurcates into short
ascending and descending branches that form Lissauer’s tract on
the surface of the dorsal horn, and ultimately synapses with local
interneurons and projection neurons in different laminae of the
dorsal horn. Centrally, primary afferent axons can extend col-
lateral axons into multiple levels of the spinal cord. Communica-
tion between the primary afferent central termini and neurons in
the spinal dorsal horn is predominately glutamatergic but can
include release of various neuropeptides. The dorsal horn con-
sists of secondary projection neurons to the brain and interneu-
rons that can contain GABA, glycine, or glutamate. The dorsal
horn has a complex circuitry and a large capacity to modulate the
nociceptive inputs from primary afferent central terminals.
According to in vivo recordings from neurons in the lamina I
dorsal horn, this population of neurons respond specifically to
nociceptive stimuli and are thus termed nociceptive-specific neurons.
These neurons have small receptive fields and provide informa-
tion as to the localization of the stimuli. In contrast, other neurons
in lamina I respond to multiple inputs and are polymodal noci-
ceptive neurons. The inner lamina II receives thinly myelinated
A delta and unmyelinated C fibers that sense innocuous touch.
Neurons in lamina V respond to nociceptive stimuli, as well as
innocuous stimuli, and have large, complex receptive fields. These
neurons are known as wide dynamic range neurons. Nociceptive
spinal neurons send axons across the midline and ascend to the
brain on the contralateral side of the spinal cord.
Neurotransmitters are released from primary afferent termi-
nals as the action potentials depolarize terminals and activate
voltage-gated calcium channels. As mentioned earlier, inflamma-
tory mediators modulate these channels, and selective inhibition
of calcium channels in nociceptive afferents has been an effective
strategy for relieving inflammatory pain.54 Peripheral inflamma-
tion stimulates a similar inflammatory process centrally, so that
many of the same molecules modulate the flow of information
from central presynaptic terminals of primary afferents to post-
synaptic second-order spinal cord neurons (Fig. 167-4). Thus the
enhanced release of neurotransmitters and peptides from acti-
vated nociceptive primary afferents stimulates vascular responses
and recruitment of immune cells, including microglia, astrocytes,
and T cells, that further contribute to the inflammatory response
by releasing inflammatory mediators. The central neuroinflam-
matory response and neurotransmission is also under control of
descending brain circuits that have been shown to mediate both
inhibition and facilitation of pain transmission.55
Central Mechanisms of Sensitization
Intense stimulation or persistent injury can cause plasticity of the
central nociceptive circuits, which is known as central sensitization.
Plasticity of presynaptic neurotransmitter release from primary
afferent terminals and postsynaptic responses of dorsal horn
neurons has been described, as has plasticity in higher brain
centers, all of which contribute to persistent changes in pain
perception. In some cases, this plasticity leads to abnormal pro-
cessing of information from myelinated A beta touch fibers,
which leads to paraesthesias and dyasthesias, and increased dis-
charge in A delta and C fibers leads to stabbing, burning pain.56
Several molecular mechanisms mediate plasticity of the CNS and
contribute to central sensitization.57,58 Little is known about the
control of vesicle release from primary afferent terminals, but
increased protein kinase G-I and Ca2+ signaling59 has been found
to contribute to an increase in the release probability of C-fiber
afferents impinging on spino-periaqueductal gray projection
neurons. Postsynaptic synaptic plasticity has been studied
more extensively.60 Synaptic plasticity of glutamatergic synapses
involves glutamate activation of metabotropic glutamate recep-
tors and previously silent NMDA receptors similar to long-term
potentiation processes in the brain (Fig. 167-5).61-63 NMDA
receptor antagonists have been developed as potential analgesics,
but results from clinical trials have not been promising because
of serious CNS side effects.64
 CHAPTER 167  Molecular Basis of Nociception e609

167

Figure 167-4. Neuronal activity triggers neurogenic neuroinflammation in the central nervous system
(CNS). Neurogenic neuroinflammation at spinal or trigeminal terminals is illustrated. In the CNS, enhanced
neuronal activity from peripheral sources results in neurogenic neuroinflammation owing to vesicular and
nonvesicular release of neurotransmitters and neuropeptides from the primary afferent fiber (listed in the blue
boxes). This induces concerted and interacting immune responses, vascular responses, and higher order
neuronal network responses in the multipartite synapse. As in the periphery, both proinflammatory and
anti-inflammatory mediators, as well as signaling molecules and forces, can be released from all cell types
(key substances listed in pink boxes for astrocytes, the green box for microglial cells, the lavender box for
mast cells, and the tan box for pericytes) in the multipartite synaptic region to further affect receptors or
channels present on all cell types shown (key substances acting on cells are listed in light yellow boxes).
Signaling from higher order CNS centers (descending neurons) can serve to dampen or aggravate neurogenic
neuroinflammation. ADO, adenosine; ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor;
CB, cannabinoid; CGRP, calcitonin gene-related peptide; DA, dopamine; DAMP, danger-associated molecular
patterns; D-Ser, D-serine; END, endothelin; GABA, γ-aminobutyric acid; Gly, glycine; His, histamine; IgE,
immunoglobulin E; NA, noradrenaline; NGF, nerve growth factor; NO, nitric oxide; NPY, neuropeptide Y; PAF,
platelet activating factor; PG, prostaglandin; SOM, somatostatin; SP, substance P; TRP, tryptase. (From
Xanthos DN, Sandkühler J. Neurogenic neuroinflammation: inflammatory CNS reactions in response to
neuronal activity. Nature Rev. 2014;15:43-53.)
e610 SECTION 6  Pain

Pre-
synapse

Ca2+

IL-1/6

TNF- α
P

mGluR NMDAR AMPAR

BDNF NK1R

NO

ATP
Ca2+
IP3R
2+
Ca
Key: PKA
PKC
Glutamate
CaMKII
SP NOS
Post- MEK/ERK
synapse Nuclear Ca2+,
CREB and DREAM-
dependent gene
transcription

Figure 167-5. Postsynaptic mechanisms of synaptic plasticity. Synaptic potentiation at some synapses
involves Ca2+ influx via N-methyl-D-aspartate (NMDA) receptors (NMDARs) and increased membrane insertion
of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors (AMPARs). Ca2+ influx via ion
channels, as well as Ca2+ release from intracellular stores, brings about sustained plasticity through synapse-
to-nucleus messengers and subsequent gene transcription. Mediators released by microglia further augment
synaptic potentiation. Abbreviations: ATP, adenosine triphosphate; BDNF, brain-derived neurotrophic factor;
CaMKII, calcium/calmodulin-dependent protein kinase II; CREB, cyclic adenosine monophosphate (cAMP)
response element-binding protein; DREAM, downstream regulatory element antagonist modulator; IL,
interleukin; IP3R, inositol-1,4,5- triphosphate receptor; MEK/ERK, mitogen-activated protein kinase kinase/
extracellular signal-regulated kinase; mGluR, metabotropic glutamate receptor; NK1R, neurokinin 1 receptor;
NO, nitric oxide; NOS, nitric oxide synthase; P, phosphorylation site; PKA, protein kinase A; PKC, protein
kinase C; SP, substance P; TNF-α, tumor necrosis factor α. (From Luo C, Kuner T, Kuner R. Synaptic
plasticity in pathological pain. Trends Neurosci. 2014;37:343-355.)

Inhibition of nociceptive circuitry in the dorsal horn plays a
critical role in pain perception. Descending inhibitory serotoner-
gic, noradrenergic, and dopaminergic pathways from the periaq-
ueductal gray matter (PAG), rostral ventral medulla (RVM), locus
caeruleus, and raphe nuclei, as well as by local GABA and glycine-
containing interneurons, regulate the excitability of dorsal horn
projection neurons.65 The inhibitory interneurons also release
endogenous opioid peptides that act at presynaptic terminals to
decrease release probability of pronociceptive neurotransmitters
(substance P and CGRP) and postsynaptically to inhibit lamina
I and V neurons.66 The ability of these interneurons to inhibit
pain transmission is decreased in neuropathic pain,67 but the
mechanism is still under investigation. One potential mechanism
involves activated microglia and astrocytes and release of various
factors from these glial cells. Release of brain-derived neuro-
trophic factor disinhibits lamina I projection neurons leading to
increased responses to pain.68 Other receptors of glia-derived
factors, such as the fractalkine receptor and Toll-like receptors,
have also been implicated in nerve injury.7
Despite the advances in understanding molecular mechanisms
of pain, many clinical trials of drugs that specifically target these
molecules have fallen short of expectations for multiple reasons,
including lack of efficacy and safety, selectivity, and possible issues
with animal model translation.69 Thus attention is beginning to
turn from a focus on specific molecules to a wider view of pain
circuits and their interactions. It is clear that the balance of
inhibitory and facilitative control of pain by the descending path-
ways is shifted in states of neuropathic or chronic pain.70,71
Further research with optogenetic and transgenic techniques to
study pain circuits will certainly advance the understanding of
how this balance is modulated at each level of the pain axis. In
addition, the current intense focus on interactions between
neurons and glia may elucidate novel molecular targets for pain
therapies that are useful in various chronic pain states.

Acknowledgments
The author would like to thank Andy Rekito for assistance with figure
preparation and Dr. Tally Largent-Milnes for providing expert feedback
on the manuscript.
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PART 2 Nonsurgical Therapy
168 Approach to the Patient with Chronic Pain
Joshua M. Rosenow
Evaluating patients with chronic pain can be a challenging
exercise for even the experienced clinician. Many of these
patients have been through numerous previous evaluations and
treatments and have experienced many disappointing outcomes.
Despite this, they may continue to have expectations that are dif-
ficult to meet. This chapter contains an overview of some of the
considerations that need to be taken into account in evaluating
and treating these patients. This process may be time consuming,
but it is time well spent, insofar as a hasty encounter will leave
many issues unresolved on both sides of the physician-patient
relationship.
BEFORE THE PATIENT’S ARRIVAL
Although not an absolute necessity, a letter from the patient’s
referring physician often provides valuable insight into the
patient’s state of mind, as well as the pain complaint. In addition,
this also helps focus the encounter, insofar as the patient may
have numerous somatic complaints. Of importance is that it also
establishes a line of communication with the referring physician
and aids in the coordination of care.
The physician should obtain as complete a record of prior
treatments and outcomes as possible, including operative reports,
psychological reports, results of diagnostic testing (e.g., electro-
myography, discography), imaging studies and reports (before
and after each surgical procedure), specialist consultations, physi-
cal therapy summaries, and relevant office notes. It is also helpful
to know whether the patient has already applied for long-term
worker’s compensation or social security disability, as well as
whether litigation is involved.
Of note, while obtaining comprehensive prior records is
useful, this may result in an overwhelming amount of data. The
neurosurgeon needs to become facile at extracting the key docu-
ments that will provide the highest yield information and retain-
ing the rest as reference material.
Sending the patient a document explaining the policies and
procedures of the clinic before the visit establishes ground rules
on such items as missed appointments, medication prescribing
and refills, general time frame for routine return phone calls, and
paperwork completion.
THE INITIAL VISIT
Understanding the patient’s goals is crucial not just for the initial
encounter but also for the physician-patient relationship. Con-
versely, the patient must understand the capabilities and limits of
the relationship (which parts of care the evaluating physician may
or may not be willing to assume) to avoid future misunderstand-
ings that can erode the patient’s trust in the physician. For
example, a patient may expect the evaluating physician to assume
prescribing responsibility for chronic opioids or to aid in the
patient’s quest for disability benefits.
Patients in pain have already seen numerous physicians, to
whom they have already explained their problems repetitively,
and may become disenchanted or angry at the thought of having
to go through this again. To avoid this, the neurosurgeon should
1380
reassure the patient that obtaining this information is a key part
of determining both why the prior treatments have not succeeded
and whether there are any further surgical treatments that
may provide the desired outcome. However, the neurosurgeon
should also be focused in eliciting these details so as to avoid
wasting time on irrelevant details. Also, the patient should under-
stand that more than a single visit may be necessary for a full
evaluation and to determine a therapeutic course of action.
Further diagnostic testing or other consultative evaluations, such
as psychological or neurophysiologic testing or further imaging,
may also be necessary.
The failure of previous medical or surgical attempts to relieve
pain may be attributable to the failure of the treatment itself, but
it might also be related to a variety of underlying psychosocial
issues. Pain relief that is judged adequate by a previous physician
may not be so according to the patient. Possible reasons for prior
treatment failure are listed in Box 168-1.
Obtaining a History
General Aspects
A detailed history may be the most helpful factor in establishing
a diagnosis and forming a treatment plan. The history provides
important information not only about the possible mechanisms
and pathophysiologic aspects of the patient’s pain but also about
the emotional and psychological status of the patient. As previ-
ously stated, the physician must guide the interview while being
flexible enough to allow the patient to volunteer valuable infor-
mation. Keeping sometimes complex patient histories chrono-
logically organized is helpful.
Prior failures may also have made the patient distrustful of
physicians and suspicious of their motives for suggesting inter-
ventional treatments. Such distrust and suspicion need to be
overcome for the physician-patient relationship to be truly thera-
peutic. Although the patient needs to understand that the neuro-
surgeon must believe the patient, the neurosurgeon should also
listen objectively.
Pain History and Onset
Once an understanding of the current pain situation is
established—including standard factors such as location, quality,
radiation, duration, and exacerbating and alleviating factors—the
pain may be analyzed in relation to the history.
Determining the evolution of the original pain syndrome into
the current one allows the physician to determine whether this
pain represents new pain or a continuation/progression of an
original pain complaint. What prior treatments were used? What
effect on the pain did they have? Were prior therapies inappropri-
ate (possibly guided by the wrong diagnosis), or were they just
not used to their fullest extent?
If the current pain is substantially different from the original
pain, this may imply that a different process may be responsible
for the current pain or that the current pain is the result of a treat-
ment side effect. Patients often undergo misguided treatments for

BOX 168-1  Possible Reasons for Prior Treatment Failure
• Incorrect diagnosis
• Incorrect choice of therapy (medical or surgical)
• Incorrect application of therapy (wrong level, wrong site)
• Failure to apply the therapy to the full extent necessary for
symptomatic relief (i.e., declaring a medication to have failed
before increasing the dose to a sufficient extent; not
sufficiently decompressing a stenotic spine)
• Side effects limiting full application of a treatment
• Treatment-related side effect (e.g., adjacent segment
degeneration)
• Patient factors (health, anatomy, allergies) that prevent full
application of a treatment
• Intraprocedural complication
• Technical failure of procedure (e.g., nonunion)
• Incorrect expectations of outcome (either on the part of the
patient or poor expectation management on the part of the
physician)
• Medicolegal factors
• Occupational factors
• Psychological and social factors
pain syndromes. These treatments can themselves cause further
pain. As previously stated, procedural complications can also
result in pain that is unlike the presenting pain (as with deaf-
ferentation pain). The physician should be cautious in treating
patients whose pain changes significantly in location and charac-
ter after each treatment.
Was an obvious inciting incident associated with the pain?
Was this mechanism consistent with the patient’s original com-
plaints? The location and distribution, quality, intensity or sever-
ity, and duration of the first pain should be ascertained. Were
there any other associated neurological symptoms at the time,
and did any of these develop in a subacute manner? Was any
treatment applied immediately?
Pain that is the result of a workplace-related activity presents
a special challenge because of the complexities unique to worker’s
compensation claims. In such cases, the history needs to be docu-
mented even more fastidiously, including the exact time and date
of the injury. Other information that should be obtained includes
whether the patient continued to work after the injury, when and
to whom the injury was reported, and the response of the patient’s
employer to the injury with regard to the patient’s work status.
The physician should also ascertain the effect of the pain on
the patient’s daily life. To accomplish this, the patient should
provide a timeline of an average day. This provides important
insight into the psychological effects of the pain on the patient’s
life and the level of disability experienced.
Pain Characteristics
The patient should be asked to describe in detail the character-
istics of the pain at the time of evaluation and to indicate whether
these have changed since the onset of the pain syndrome or after
any prior procedures. Factors that have no effect on the pain are
important as well. The neurosurgeon should inquire about such
factors as stress and other emotional disturbances, movement,
pressure, heat or cold, coughing, sneezing, straining, and deep
breathing. The 0-to-10 visual analogue scale (VAS) is the most
commonly used pain rating scale, even if it is not the most robust
measure. It is often more useful to collect the visual analogue
scale by asking the patient to mark the level of pain on an unla-
beled 10-cm line. Physicians should be wary of those patients
CHAPTER 168  Approach to the Patient with Chronic Pain 1381
whose pain either never varies from 10 or is rated as “11” on a
scale of 0 to 10. 168
Pain may be classified as localized, radiating, or referred.
Localized pain continues at the same location as its origination.
This pain may be associated with other anatomic and sensory
changes at the site of pain, such as hyperalgesia, wind-up hyper-
pathia, color change, and trophic changes of the skin. Pain may
also be described as radiating along the distribution of a nerve
root’s dermatome or the innervation of a peripheral nerve. This
is distinct from pain that is referred from a deep visceral structure
to a separate distinct anatomic location. Classic examples of
referred pain are back pain or superficial abdominal pain from
chronic pancreatitis and scapular pain from cholecystitis.
Pain Treatment History
A recounting of past medical and interventional treatments and
the response to each is an invaluable part of the evaluation. A
thorough analysis of this part of the history prevents the clinician
from repeating past failures. Which classes of medications have
been tried? Were the medication trials adequate? Were interven-
tional techniques used appropriately? Did each subsequent treat-
ment follow logically on the basis of past information? Has every
treatment failed to provide any relief? Moreover, this history
helps to ascertain patient compliance and assess for causes of past
treatment failures. The clinician needs to take a very critical view
of this section of the history, always asking why treatments failed
and whether the neurosurgeon can offer anything else to the
patient.
Patients may not recall each treatment and outcome. For
instance, the neurosurgeon should not waste valuable time forcing
a patient to remember the outcome from each of their multitude
of injections if it is clear that all the other similar injections pro-
vided only short-term relief at best.
Medical and Surgical History
Concomitant medical conditions can adversely affect both
medical and surgical treatments. Obesity, diabetes, hypertension,
hypothyroidism, chronic obstructive pulmonary disease, and
inflammatory arthritis can complicate therapy. Patients fre-
quently do not mention conditions they do not consider impor-
tant or omit conditions they consider treated (e.g., not mentioning
hypertension because they are taking medication for it and no
longer consider it an active medical problem). For completeness,
the inquiry should proceed through a comprehensive list of organ
systems.
If the patient has undergone multiple surgical procedures that
failed to ameliorate their pain syndrome, did they also experience
surgical failures for other conditions as well? Intrinsic patient
medical factors, poor surgical techniques, unrealistic expecta-
tions, insistence on unnecessary surgical treatments, and bad
fortune may all reduce the likelihood of a good outcome. It is
important to ascertain whether the patient appears compliant
with their physician instructions for their other ailments. Poor
compliance may also contribute to consistently disappointing
results from health interventions.
Family History
Patterns may be recognized from this effort. Have multiple
family members undergone spinal surgery? Are they all employed
in high-impact professions? Is there is family tendency to develop
spinal degeneration or stenosis? Are multiple family members
receiving disability insurance? Chronic pain behavior may be a
learned trait within families.1 Cohort studies have shown that
a history of child abuse may increase pain and pain-related
behaviors.1-4
1382 SECTION 6  Pain
Social and Psychological History
A complete psychological and psychosocial assessment is crucial
for the overall management of the patient with chronic pain.5-9
The psychological and psychosocial part of the history helps
determine the contribution of affective or environmental factors
to the patient’s pain syndrome. Referral to a psychologist with
special expertise in the evaluation and treatment of patients with
chronic pain is an essential part of the total care of these patients.
At the minimum, this part of the history should include a listing
of current and prior psychological and psychiatric illnesses.
Special attention should be paid to depression, a common condi-
tion in patients with chronic pain. The astute neurosurgeon will
delve deeper into this issue than simply inquire about the patient’s
mood. The patient’s daily schedule provides important data about
depression. Other clues are irritability, insomnia, abulia, weight
gain or loss, and suicidal ideation. The patient’s family may
provide important perspective as well.
The neurosurgeon should also explore the patient’s vocational
status and vocational stressors, including compensation-litigation
issues. These can affect the patient’s motivation and outcome of
treatment.10-13
Although the history should include current prescription
drugs, an appropriately thorough history should also include
over-the-counter and alternative (e.g., herbal) medicines. Infor-
mation about illicit pharmaceutical use (both current and past)
should be elicited by direct questioning, even with specific ques-
tions about the most commonly used abused pharmaceuticals. It
is important to determine not only what the patient is using but
also whether he or she is using it appropriately. For instance, is
the patient using another person’s prescription medication for his
or her own use? Is the patient using medication up earlier than
prescribed? Is he or she obtaining substitutes illicitly? A history
of tobacco and alcohol use, including type and frequency of use
of each, should be included as well. Physical and psychological
dependence on drugs and alcohol is a common impediment to
treatment.
A useful exercise is to conceptualize the patient’s pain syn-
drome into separate components of pain and suffering. Pain is
the purely physical and physiologic component of the syndrome,
whereas suffering includes the individual’s reaction to the pain,
as well the pain’s effect on the rest of the psychological and emo-
tional environment. Suffering includes depression, anxiety, loss of
self-esteem, failure of relationships, past emotional and physical
abuses that shape the pain response, poor coping strategies, and
withdrawal from friends and family. Surgical interventions may
be an excellent method for dealing with the pain, but they are
inadequate at handling an impressive suffering component.
Again, a psychologist skilled at evaluating patients in pain is adept
at determining the balance between the pain and suffering com-
ponents, along with identifying maladaptive coping strategies
and other pitfalls of which the surgeon should be aware before
embarking on a therapeutic relationship with the patient.
Although a small population of individuals have no physical
basis for their pain complaints,14 the majority of patients with
chronic pain have a complex interplay between psychological and
physical components of their pain syndrome in varying propor-
tions. Among the neurosurgeon’s challenges in evaluating and
managing patients with chronic pain are first determining the
relative balance between these factors and then using that estima-
tion to drive the selection of an individualized combination of
medical, interventional, surgical, and psychological treatments
for each patient.
Physical and Neurological Examinations
The examination of the patient with chronic pain is essentially
no different from that of a patient presenting for any other type
of neurosurgical evaluation. The neurosurgeon must still be vigi-
lant for signs such as weakness and pathologic reflexes that may
indicate conditions such as nerve root or spinal cord compression
that could warrant urgent further evaluation or treatment. These
findings should not be discounted or neglected just because the
patient may have already seen other physicians or may have had
other surgical procedures.
The central sensitization that occurs in many patients with
chronic pain can result in certain characteristic exam findings.
Central sensitization affects the wide dynamic range (WDR)
neurons in the dorsal horn of the spinal cord that receive input
from both A beta and C fibers. In neuropathic pain states, A beta
fiber depolarization also results in stimulation of these other
fibers, resulting in allodynia, the perception of pain from light
touch. Patients with chronic pain may exhibit generalized hyper-
pathia (exaggerated and prolonged reactions to painful stimuli).
An example of hyperpathia is the perception that a pinprick is
intensely painful over the entire body. Repetitive stimulation of
C fibers may result in an augmented response to each subsequent
stimulus, a process known as wind-up. Repetitive light stroking of
the painful area is interpreted by the patient as increasingly
painful with each iteration.
Red flags on examination should engender skepticism in the
examiner. These may include Waddell’s signs15-17 for nonphysio-
logic back pain and other inconsistencies on physical and neuro-
logical examination. For instance, does a patient with apparent
ankle dorsiflexor weakness when tested seated have the ability to
heel walk without much difficulty? Do the findings fail to conform
to a peripheral or spinal nerve distribution? Fishbain and col-
leagues18 published a structured review of the medical literature
on the validity of Waddell’s signs and noted that Waddell’s signs
are not reliable as a discriminator of physiologic from nonphysi-
ologic pain.
Formulating a Treatment Plan
The patient with chronic pain requires an individualized treat-
ment plan. First, the treatment team should be able to work in a
cohesive manner and present a united front to the patient. Rep-
resentative members of a pain team are listed in Box 168-2. Lines
of communication among the clinicians involved should be clear
and open. The best method to ensure this is a regularly scheduled
patient management meeting attended by the pain team. A team
consensus may be reached and be discussed with the patient and
family.
Next, in defining a plan, it is important to outline the plan in
as much specificity as possible and then stick to it. The plan
should include steps for dealing with medication-related side
effects and procedural failures. This gives the patient a clear
BOX 168-2  Members of a Pain Team
Surgical specialist(s)
Anesthesia
Neurology
Medical specialists (e.g., internal medicine, oncology)
Physiatry
Pain psychology
Psychiatry
Nursing
Physical therapy
Occupational/vocational therapy
Social work
Addiction medicine

understanding of what steps will be taken and in what order.
Moreover, the patient will understand what the expected out-
comes are for each step and what will be done if the actual
outcome does not meet expectations at each step. As part of
outlining this plan, a treatment contract may be signed by the
patient and clinician.19-21 If a contract is signed, the patient should
have a copy to keep. Contracts should denote the obligations of
both parties, as well as the consequences for violations.
In formulating a plan with the patient, the neurosurgeon may
be requested to prescribe medications (either opioid or other-
wise). This may introduce a complication into an otherwise
straightforward evaluation. As a consultant, the neurosurgeon
may not see his or her role as one of assuming chronic care
of the patient. Moreover, many neurosurgeons are not skilled in
the long-term management of patients on what are often regi-
mens consisting of multiple classes of medications (e.g., opioids,
selective serotonin reuptake inhibitors [SSRIs] or serotonin-
norepinephrine reuptake inhibitors [SNRIs], anticonvulsants,
nonsteroidal anti-inflammatory drugs [NSAIDs], muscle relax-
ants). Even if not requesting that the surgeon manage the entire
pain medication system, the patient may ask the surgeon to pre-
scribe something in addition to the current regimen. In general,
neurosurgeons should be cautious in these situations. It is always
best that the patient’s medication treatment be handled by one
provider so as to avoid inadvertent overdoses, medication interac-
tions, and generalized confusion, as well as to reduce the likeli-
hood of unscrupulous behavior by patients. The surgeon may
state that he or she will communicate and coordinate any medica-
tion changes with the prescribing provider while emphasizing the
importance of the single person to contact for medications. Most
states now have prescription monitoring databases that allow a
clinician to see where, when, and from which physician patients
receive their medications. Neurosurgeons should be familiar with
their own state’s system and how to obtain access to these data.
If there is any concern about the patient’s use of medications, this
database should be consulted and the other providers brought in
to coordinate a response.
Setting expectations of treatment is a crucial part of the overall
plan. In many cases, the patient’s expectations were not met by
past medical and surgical treatments, either because the treat-
ments did not deliver expected results or because the patient’s
expectations were not realistic. Substantial time should be spent
discussing realistic outcomes for each care step, as well as for the
overall plan of care. For instance, it may or may not be realistic
CHAPTER 168  Approach to the Patient with Chronic Pain 1383
for a patient to return to the same line of work after treatment,
but it is critical to understand whether the patient believes that 168
he or she will do so. The clinician’s and patient’s ideas of a “good”
outcome may be divergent, and this disparity needs to be under-
stood and managed.
Goal and expectation setting should include lifestyle modifica-
tion as needed. Smoking and obesity are negative determinants
of outcome,22-24 and the patient’s willingness to resolve these
problems is a good determinant of the patient’s level of motiva-
tion. Return visits may need to be scheduled to evaluate progress
on certain goals or to discuss consultation or imaging results
before the physician agrees to embark on a therapeutic relation-
ship. Return visits also allow the physician to assess the amount
of material internalized by the patient from previous visits.
Written materials given to the patient to read at home may
aid in increasing retention of material discussed during the
office visit.
Some patients may not be accepted for care. A true pain team
is not just a dumping ground for all patients whom other special-
ists do not want to manage. Patients with a significant ongoing
pattern of pharmaceutical misuse, whether legal or illegal, must
first resolve that issue. Moreover, severe overwhelming emotional
and psychological problems also need to be brought under
control, especially before nonurgent surgical procedures.
SUGGESTED READINGS
Burns JW, Sherman ML, Devine J, et al. Association between workers’
compensation and outcome following multidisciplinary treatment for
chronic pain: roles of mediators and moderators. Clin J Pain. 1995;
11(2):94-102.
Doleys DM. Psychologic evaluation for patients undergoing neuroaug-
mentative procedures. Neurosurg Clin N Am. 2003;14(3):409-417.
Doleys DM. Psychological factors in spinal cord stimulation therapy:
brief review and discussion. Neurosurg Focus. 2006;21(6):E1.
Fishbain DA, Cole B, Cutler RB, et al. A structured evidence-based
review on the meaning of nonorganic physical signs: Waddell signs.
Pain Med. 2003;4(2):141-181.
Fishman SM, Mahajan G, Jung SW, et al. The trilateral opioid contract.
Bridging the pain clinic and the primary care physician through the
opioid contract. J Pain Symptom Manage. 2002;24(3):335-344.
Turner JA, Romano JM. Psychological and psychosocial evaluation. In:
Loeser JD, ed. Bonica’s Management of Pain. Philadelphia: Lippincott
Williams & Wilkins; 2001.
See a full reference list on ExpertConsult.com

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2. Koss MP, Heslet L. Somatic consequences of violence against
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169 Pharmacologic Treatment of Pain
Diaa Bahgat, Heather N. Pinckard-Dover, and Erika A. Petersen
Pain—the unpleasant physical and emotional experience associ-
ated with tissue damage, whether impending or actual—involves
sensations transmitted from the periphery to the central nervous
system for processing and perception. The experience of pain,
however, is different for each individual and is influenced by
physical, mental, cultural, and religious factors and by the
individual’s current situation. Because the experience of pain is
diverse, treatment can be difficult. Accurate diagnosis and a thor-
ough understanding of the nature of the pain to be addressed
facilitate appropriate treatment recommendations. Many attempts
have been made to categorize pain. Some systems distinguish
between acute and chronic pain; some are based on the difference
between cancer and noncancer pain causes; some differentiate by
diagnosis; and some are attempts to identify the processes under-
lying the pain.
Acute pain is a reaction to focal peripheral nerve or tissue
injury and usually resolves as tissue heals and inflammation sub-
sides. Chronic pain persists beyond the usual course of injury and
healing and does not respond to routine pain control measures.1
Pain directly related to cancer can be caused by multiple pro-
cesses, including vertebral involvement, and can take the form of
referred pain. Certain pain conditions such as trigeminal neural-
gia and diabetic neuropathy have been shown to respond better
to specific medications; therefore, appropriate diagnosis governs
treatment strategy.
On the basis of underlying characteristics, pain can be catego-
rized as nociceptive, neuropathic, or inflammatory. Nociceptive
pain is usually acute and comparable to the degree of damage to
tissue. Neuropathic pain is caused by nerve dysfunction related
to injury or inappropriate signaling. Usually chronic and the
most resistant to treatment, neuropathic pain is described as
burning or lancinating. Inflammatory pain results from release
of inflammatory mediators and hypersensitization of nerve
endings to innocuous stimulus, and its degree can differ between
patients.2 Regardless of the system used to approach each case,
it is important for the physician to understand the basic patho-
physiologic process behind pain, the subjective influences on
pain, and the various tools designed to relieve pain and how
they work.
PATHOPHYSIOLOGY
The exact mechanisms involved in pain signaling and perception
are not known, but research has led to improved understanding
of a few of the underlying processes, which allows drug therapies
to be more targeted. Nociceptive neurons are now known to be
responsible for the conversion of mechanical, chemical, or
thermal stimuli to electrical signals, which is the process of trans-
duction. Nociceptive neurons are usually bipolar and can be
either myelinated or unmyelinated. The myelinated A delta–fiber
nociceptive neurons transmit their signals rapidly, whereas
the unmyelinated C-fiber nociceptive neurons transmit their
signal more slowly. Both types propagate the signals through
voltage-gated sodium channels, which are the target of multiple
medications. When tissue damage ensues, multiple inflammatory
mediators are released, including histamine, serotonin, bradyki-
nin, substance P, leukotrienes, cytokines, neurotropic factors, and
prostaglandins. These mediators upregulate voltage-gated sodium
1384
channels, cause conformational changes in transducer proteins,
and increase calcium influx in second-messenger systems, all
leading to sensitization of already activated nociceptors and the
activation of dormant ones.
Nociceptive neurons transmit their signal to the dorsal horn
of the spinal cord, where the signal is modified by inhibitory and
excitatory interneurons and by descending inhibitory neurons
from the central nervous system. If this inhibition is lost, it can
lead to peripheral sensitization. The C fibers are temporally sum-
mated in the dorsal horn, and the combined effects of the fiber
signal, interneurons, and descending input result in a new signal
that is transmitted from the dorsal horn to the thalamus through
the spinothalamic tract.
The thalamus is not the only location where pain is processed.
Pain signals are also received by the periaqueductal gray matter
in the midbrain, somatosensory cortex, periventricular gray
matter, ventral medulla, nucleus raphe magnus, limbic system,
and insula. The importance of the pain signal is perceived through
a pathway involving the insula, striatum, parietal association
cortex, and lateral prefrontal cortex. The perception of pain can
be suppressed by supratentorial structures that release endor-
phins, enkephalins, dynorphins, norepinepherine, γ-aminobutyric
acid (GABA), and serotonin. All of these neurotransmitters
are also the targets for specific medications in the treatment
of pain.3,4
PHARMACOLOGIC TREATMENT OF PAIN
As knowledge about the underlying mechanisms of pain increases,
so has the ability to apply medications to target these mechanisms.
The main classes of treatment currently include nonsteroidal
anti-inflammatory drugs (NSAIDs), acetaminophen, antidepres-
sants, ion channel blockers, and opioids. These medications can
be delivered through multiple routes of administration. Their
effectiveness, dosing, and tolerability often vary with the route
of administration.
Nonsteroidal Anti-inflammatory Drugs
NSAIDs are a large group of medications that have antipyretic,
analgesic, and anti-inflammatory effects. They are divided into
selective cyclooxygenase-2 (COX-2) inhibitors and nonselective
cyclooxygenase (COX) inhibitors. COX is an enzyme responsible
for prostaglandin synthesis from arachidonic acid. Inhibition of
COX results in downregulation of the synthesis of prostaglan-
din and thromboxane. Common nonselective COX inhibitors
include aspirin (acetylsalicylic acid), ibuprofen, and naproxen.
Common selective COX-2 inhibitors include diclofenac and
ketorolac.
NSAIDs interfere with the inflammatory response to tissue
damage and thus are best used for acute nociceptive, neuro-
pathic, or inflammatory pain. They are generally well tolerated
but can have some gastrointestinal side effects nonselective COX
inhibitors have more pronounced gastrointestinal side effects
than do selective COX-2 inhibitors. Some manufacturers have
started combining NSAIDs with proton pump inhibitor or his-
tamine blockers in an aim to offset these side effects. Because of
NSAIDs’ effect on thromboxane A (an enzyme that plays a

key role in the aggregation of platelets), NSAIDs should be
prescribed with special caution in the preoperative period.
There are reported drug-drug interactions between NSAIDs
and angiotensin-converting enzyme inhibitors, corticosteroids,
warfarin, sulfonylurea, and methotrexate. Combining these medi-
cations causes a risk of bradycardia and gastrointestinal ulceration
and increases the risk of bleeding.
Acetaminophen
Like NSAIDs, acetaminophen (paracetamol) has antipyretic and
analgesic effects. It does not, however, have any anti-inflammatory
effects. The mechanism of action of acetaminophen is poorly
understood, but it is believed to reduce the oxidized form of COX
and selectively inhibit prostaglandin H2 synthase. Its metabolites
may also block the uptake of anandamide, therefore inhibiting
vanilloid receptor activation in nociceptors. There is also evi-
dence that acetaminophen decreases prostaglandin E2 synthesis
in the brain by COX-3 inhibition. It is generally well tolerated,
the most noted side effects being allergic reactions and effects on
renal function. Acetaminophen causes minimal inhibition of
platelet aggregation. It does, however, carry risk of hepatotoxicity
when taken in large quantities, as in overdose; therefore, the daily
dose should be less than 4 g.
Antidepressants
Three main classes of antidepressants are used for the
treatment of pain: tricyclic antidepressants (TCAs), serotonin-
norepinephrine reuptake inhibitors (SNRIs), and selective sero-
tonin reuptake inhibitors (SSRIs). These drugs primarily increase
the serotonin and norepinephrine available in the synaptic cleft,
thereby reinforcing the descending inhibitory pathways from
the central nervous system to nociceptive neurons in the dorsal
horn.5 They may also act by decreasing central prostaglandin
E2 and tumor necrosis factor α production, activating µ and δ
opioid receptors, increasing GABA type B receptor function,
increasing adenosine availability and activating α1 receptors,
blocking calcium and voltage-gated sodium channels, activat-
ing potassium channels, and inhibiting N-methyl-d-aspartate
(NMDA) receptors.5,6 The best analgesic effects are achieved by
medications with primarily norepinephrine or mixed receptor
activity.5,7,8
There is a high correlation between pain and depression. In
fact, in an epidemiologic study, Tunks and colleagues9 showed
that the presence of pain doubled, and in some cases almost
tripled, the likelihood of having depression, dysthymia, anxiety
disorder, agoraphobia or panic disorder, and social phobia.5
Because of their analgesic effects, prescription of antidepres-
sants is not limited to individuals with depression or other psy-
chological issues. Instead, the analgesic effect has been found to
be independent of the antidepressant effect and typically occurs
at lower dosages than those required for antidepressant
effect.5,10-12
TCAs such as amitriptyline and nortriptyline have become the
“gold standard” of antidepressants for treating neuropathic
pain.5,13,14 Level 1 evidence supports the use of amitriptyline for
postherpetic neuralgia and polyneuropathy.5,14 Level 2 evidence
supports the use of TCAs in the treatment of central neuropathic
pain caused by stroke, spinal cord injury, or multiple sclerosis.15
Other studies have shown that TCAs are helpful in the treatment
of fibromyalgia, although they showed greater effects on the sleep
disorders and fatigue than on pain ratings in this population.
TCAs have also been found to be as effective as NSAIDs in the
treatment of low back pain.16 They have been found to have weak
analgesic effects in patients with rheumatoid arthritis.17 Amitrip-
tyline, but not other TCAs, has been shown effective in the
treatment of pain, fatigue, and sleep disorder related to
CHAPTER 169  Pharmacologic Treatment of Pain 1385
ankylosing spondylitis. Patients with headaches showed the
greatest response to TCAs among classes of antidepressants.17 169
Despite their usefulness in multiple pain disorders, TCAs have
not been found useful in the treatment of neuropathy related to
human immunodeficiency virus (HIV) infection, cisplatin-related
neuropathy, neuropathic cancer pain, phantom limb pain, or
chronic lumbar root pain.17
TCAs have multiple side effects, and patients taking them
must be monitored closely. Before starting TCAs, patients
should complete a cardiac workup, including orthostatic blood
pressure measurements and electrocardiography for measure-
ment of the corrected QT (QTc) interval. TCA therapy should
always be started at a low dosage and titrated upward every 3 to
7 days. An adequate trial requires 6 weeks of therapy with 1 to
2 weeks at the maximum tolerated dosage. Patients’ serum
drug concentrations should be monitored, and routine electro-
cardiograms to monitor the QTc interval may be obtained.
Side effects to watch for include sedation, dry mouth, blurred
vision, weight gain, urinary retention, sinus tachycardia and ven-
tricular ectopy, and QTc interval prolongation. The medications
can also potentiate the actions of cytochrome P-450, and so
the patient’s other medications must be checked for interactions
with TCAs.
Like TCAs, venlafaxine (an SNRI) is effective in treating neu-
ropathic pain; however, it is more tolerable and has fewer side
effects. Venlafaxine and other SNRIs have been found to be effec-
tive in the treatment of fibromyalgia. They also improve the poor
sleep and fatigue associated with fibromyalgia.18,19 There are no
studies to support the use of SNRIs in low back pain. Venlafaxine,
however, has been show to be just as effective as amitriptyline for
migraine prophylaxis. The most common side effects experienced
with SNRIs including nausea, vomiting, constipation, somno-
lence, dry mouth, hyperhidrosis, anorexia, weakness, agitation,
diarrhea, hypertension, and hyponatremia. Venlafaxine has been
associated with increased liver enzyme levels, and therefore liver
function must be monitored. Because of the serotonergic effects
of SNRIs, there is a slight risk of serotonin syndrome: headache,
agitation, mental confusion, sweating, hyperthermia, hyperten-
sion, tachycardia, diarrhea, myoclonus, tremor, hallucinations,
and coma.
Although studies have shown that SSRIs are superior to
placebo in the treatment of neuropathic pain and fibromyalgia,
they are less effective than TCAs.11 They are, however, better
tolerated; side effects include nausea, vomiting, anorexia, diar-
rhea, decreased libido, delayed orgasm, hyperhidrosis, somno-
lence, insomnia, drowsiness, fatigue, weight gain, increased risk
of bleeding, and syndrome of inappropriate diuretic hormone
secretion. There is a small risk of serotonin syndrome. Unlike
TCAs and SNRIs, SSRIs are not effective in the treatment of
headache, low back pain, or rheumatoid arthritis.5
Antiepileptics
Antiepileptics with varying mechanisms of action are commonly
used for the treatment of neuropathic pain. Some antiepileptics
work by blocking calcium channels on the nerve terminal, thereby
preventing release of neurotransmitters into the synaptic cleft.
Others target sodium channels to suppress ectopic discharges
while preserving normal nerve conduction.
Calcium channel blockers include zonisamide, ziconotide,
levetiracetam, gabapentin, and pregabalin. Zonisamide is an anti-
epileptic used in the treatment of diabetic neuropathy,20,21 post-
stroke central pain,20,22 and migraine prophylaxis.23 Because it is
usually a component of multidrug regimens, its individual effi-
cacy and tolerability are not well known. Zonisamide is believed
to act by blocking both voltage-gated and N-type calcium chan-
nels, reducing monoamine release. It has also been shown to work
as a free radical scavenger. Ziconotide is a synthetic peptide
1386 SECTION 6  Pain
analogue of ω-conotoxin from marine snails that selectively
blocks N-type voltage-sensitive calcium channels. It is given
intrathecally and has been approved by the U.S. Food and Drug
Administration for use in only patients with chronic severe pain
refractory to other therapies, including intrathecal morphine. It
has been used to treat complex regional pain syndrome, chronic
pain from cancer and acquired immunodeficiency syndrome
(AIDS), and trigeminal neuralgia.20,24,25
Levetiracetam’s mechanism of action is not well known, but
it has been shown to target N-type voltage-sensitive calcium
channels and to modulate the dopaminergic, GABAergic, and
glutamatergic systems. Studies have shown it to be effective in
the treatment of neoplastic plexopathies, peripheral neuropathy,
and postherpetic neuralgia and to be useful in migraine prophy-
laxis.20,26 It is generally well tolerated; most common side effects
are fatigue, dry eyes, and dizziness.
Both gabapentin and pregabalin work through binding the
α2δ subunit of voltage-gated calcium channels, decreasing the
release of excitatory neurotransmitters such as glutamate, sub-
stance P, and calcitonin gene–related peptide. Their side effect
profiles and time to effectiveness differ; this is believed to be
attributable to pregabalin’s higher affinity for the α2δ subunit.
Both medications are useful in the treatment of diabetic neuropa-
thy, peripheral neuropathy after spinal cord injury, and posther-
petic neuralgia.20 Gabapentin has also been shown effective in
the treatment of trigeminal neuralgia, HIV neuropathy, cancer-
related neuropathy, multiple sclerosis, complex regional pain syn-
drome, Eagle’s syndrome, and glossopharyngeal neuralgia.20
There are also data to support its use in treating postoperative
pain. Gabapentin is usually well tolerated, but patients may expe-
rience dizziness and diarrhea, which typically subsides in 7 to
10 days and can usually be prevented with slow tapering up of
medication. Pregabalin is also well tolerated; common side effects
are dizziness, somnolence, and mild to moderate peripheral
edema. Pregabalin tends to have a quicker onset of action, and
sometimes a patient may experience pain relief from the first
doses. It has been shown to be effective in treatment of fibromy-
algia, facial neuropathic pain, and neuropathic pain refractory to
gabapentin.20
Antiepileptics that treat pain by sodium channel blockade
include lamotrigine, carbamazepine, oxcarbazepine, and topira-
mate. Lamotrigine works by blocking voltage-gated sodium
channels, as well as suppressing calcium influx to the nerve
terminal and therefore decreasing excitatory neurotransmitter
release. It is used in the treatment of trigeminal neuralgia,27
peripheral nerve or spinal cord injury,28,29 and HIV neuropa-
thy.20,30 Lamotrigine can have severe side effects, such as rash
and Stevens-Johnson syndrome. It can also cause dizziness, som-
nolence, nausea, and constipation. It is very important to start
with a low dosage, titrate up over 2 to 3 weeks, and monitor for
side effects. Carbamazepine also has rare severe side effects,
including aplastic anemia and agranulocytosis, and can have
significant drug-drug interactions and central nervous system
effects.
With the development of the better tolerated carbamazepine
analogue oxcarbazepine, carbamazepine is no longer the first-line
medication for trigeminal neuralgia. Oxcarbazepine, a sodium
channel blocker and neuronal membrane stabilizer, has the same
efficacy as carbamazepine for the treatment of trigeminal neural-
gia but with fewer serious side effects.20,31 It has also been shown
effective in the treatment of diabetic neuropathy, postherpetic
neuralgia, and complex regional pain syndrome. Although more
tolerable than carbamazepine, oxcarbazepine can nonetheless
cause dizziness, drowsiness, hypotension, nausea, and hyponatre-
mia; therefore, it also must be started at a low dosage and titrated
up over a couple of weeks, and sodium levels must be monitored.
Topiramate has side effects similar to those of oxcarbazepine;
however, it can also cause weight loss, which can be beneficial in
some clinical scenarios. It has been effective in the treatment of
diabetic neuropathy, sleep disorders, and tension, cluster, and
migraine headaches.20,32,33 Its effectiveness in other neuropathic
disorders is unclear.
Two other medications work by blocking voltage-gated
sodium channels but are not antiepileptics: lidocaine and mexi-
letine. Lidocaine is a local anesthetic and an antiarrhythmic
drug that has been used diagnostically for neuropathic pain.
Petersen and associates34 showed that 78% of pain cases have
good responses to intravenous lidocaine but that this treatment
did not provide long-term relief. Topical formulations, including
patches and creams, have been used. They have good effect
locally but little to no systemic effect. They are beneficial in
the treatment of diabetic neuropathy, postherpetic neuralgia,
other peripheral neuropathies, and chronic low back pain.34
The patches can cause local irritation and rash, which is why it
is recommended that patients wear patches for only 12 hours of
the day and rotate location with each application. Mexiletine is
an oral form of lidocaine that allows more prolonged pain relief
in patients who have a positive response to the intravenous lido-
caine test. It is useful in the treatment of diabetic neuropathy,
phantom pain, fibromyalgia, myofascial pain, and spinal cord
injury.20
Opioids
Probably the most well-known and controversial class of analge-
sic medications is that of the opioids. These medications activate
µ receptors on the primary afferent nerves, dorsal horn neurons,
and supraspinal pain centers. µ Receptors are located on both
sides of a synapse. At presynaptic µ receptors, opioids act to
decrease neurotransmitter release; at postsynaptic µ receptors,
they act to hyperpolarize the neuron by increasing potassium
conductance. Studies have shown than in patients with chronic
central pain, pain intensity scores were significantly lower after
opioid administration than with placebo. There is some evidence
of efficacy in the use of opioids for neuropathic pain, but the
evidence is inconclusive because of small study size, bias, and
duration.35 Although opioids are best suited for the treatment of
acute nociceptive and inflammatory pain for short durations,
their long-term use has not been studied adequately, but it has
become common practice.1,36 The use of opioids is cultural: in
some nations, such as Japan, there are very few prescriptions for
opioids37; although the United States has 4.6% of the world’s
population, more than 80% of the world’s oxycodone and hydro-
codone was consumed in the United States in 2007.1 This trend
has continued: According to the International Narcotics Control
Board (INCB), the United States consumed over six times the
global mean of oxycodone in 2013.37a The most common opioids
are morphine, codeine, oxycodone, hydrocodone, fentanyl,
meperidine, methadone, hydromorphone, propoxyphene, and
alfentanil. Opioids and their morphine equivalents are listed in
Table 169-1.
Opioids have a wide range of frequent side effects, including
nausea, vomiting, constipation, and sedation. Other effects
include perceptual distortion, urinary retention, anorexia, dry
mouth, and respiratory depression. Addiction, habituation, and
hyperalgesia may occur with long-term use of opioids. Both the
magnitude of the side effects and how well they are tolerated vary
among patients; they also vary among different opioids and
depending on the mode of delivery of the medication. Transder-
mal fentanyl, for example, has been shown to produce less
constipation than do other opioids, including oxycodone and
morphine.38-40 Long-term intrathecal morphine has been shown
to cause hypogonadotropic hypogonadism and other hormonal
disturbances.41
Managing the side effects of opioids is vital for adequate pain
control; this can be done by symptomatic treatment, such as use
 CHAPTER 169  Pharmacologic Treatment of Pain 1387

TABLE 169-1  Parenteral-Oral Opioid Equianalgesia Conversion

8 169
Duration Equianalgesic
Medication of Action Half-Life Dosage
7
Morphine 3-7 hr 1.5-2 hr 10 mg IM or IV
30 mg PO
Morphine, sustained 8-12 hr NA 30 mg PO 6
release
Oxycodone 4-6 hr NA 20 mg PO 5
Oxycodone, 8-12 hr NA 20 mg PO
controlled release

Rate
Fentanyl 1-2 hr 1.5-6 hr 100 µg IV or IM 4
15 µg transdermal
Hydromorphone 4-5 hr 2-3 hr 1.5 mg IV or IM 3
7.5 mg PO
Methadone 4-6 hr 2-3 hr 5 mg IM or IV
2
10-20 mg PO
Codeine 4-6 hr 3 hr 120 mg IM or IV
200 mg PO 1
Hydrocodone 4-8 hr 3.3-4.5 hr 30 mg PO
Meperidine 2-4 hr 3-4 hr 75 mg IM
0
300 mg PO
1999 2001 2003 2005 2007 2009
Propoxyphene 4-6 hr 6-12 hr 130-200 mg PO
The following dosages are equianalgesic but not standard dosing. Year
Tramadol 4-6 hr NA 300 mg PO OPR deaths/100,000 Treatment
Ketorolac 6 hr NA 10-30 mg IV or IM admissions/10,000
10 mg PO OPR sales kg/10,000
Ibuprofen 6-8 hr NA 1300 mg PO
Acetaminophen 4 hr NA 3900 mg PO
Aspirin 4 hr NA 3900 mg PO Figure 169-1. Rates of opioid pain reliever (OPR)–related
overdose deaths and treatment admissions and kilograms of
IM, intramuscularly; IV, intravenously; NA, not applicable; PO, orally.
OPR sold: United States, 1999-2010. Rates are age adjusted per
100,000 population for OPR-related deaths, per 10,000 population for
admissions for treatment of OPR abuse, and per 10,000 population
for kilograms of OPR sold. (From Paulozzi L, Jones C, Mack K, et al;
Centers for Disease Control and Prevention. Vital signs: overdoses of
of laxative for constipation, antihistamines for itching, and anti- prescription opioid analgesics—United States, 1999-2008. MMWR
emetics for nausea and vomiting. Another approach is titration Morb Mortal Wkly Rep. 2011;60[43]:1487-1492.)
of dosage and opioid rotation, which involves the switch from
one opioid to another in an effort to improve pain control and
reduce side effects.42 When opioids are rotated, it is important to TABLE 169-2  Mortality and ED Visits Related to Use of Prescription
use equivalent dosages, as well as provide breakthrough doses, Medication in 2010
which are generally 5% to 15% of the total daily dose.43 The most
effective way to minimize side effects is to treat with the lowest Prescription No. of Medication-
Medication Related Deaths No. of ED Visits†
possible effective dosage.
Opioid 16,651 420,000
Current Practices with Opioids and Their Consequences.  Benzodiazepine 6,497 425,000
The use of opioids has increased five times since the 1990s (Fig. Antidepressants* 3,889 NA
169-1),44 and these increases are reflected across all age groups Data from Behavioral Health Coordinating Committee, Prescription
and both genders (Fig. 169-2).45 Between 2007 and 2010, opioids Drug Abuse Subcommittee, U.S. Department of Health and Human
were prescribed in 2.6% of clinic visits.46 There has been an Services. Addressing Prescription Drug Abuse in the United States:
increase in mortality and morbidity with this rise in consumption; Current Activities and Future Opportunities. Atlanta: Centers for
according to statistics from 2011, more than 1.4 million deaths Disease Control and Prevention; 2013.
and emergency room visits were related to pharmaceutical misuse ED, emergency department; NA, not available.
*Usually associated with other medication.
or abuse (Table 169-2).47,48 The rapid increases in opioid prescrib- †
Alcohol was included in 18% of cases.
ing and associated opioid-related mortality have led to increased
awareness of tolerance, dependence, and addiction. It is of para-
mount importance to be able to differentiate between these
problems. attributed to activation of NMDA receptors and increased spinal
In clinical tolerance, increased dosages are needed to achieve dynorphin levels.52,53
adequate pain relief49; however, clinicians should bear in mind Dependence, on the other hand, presents with symptoms
that other factors, such as disease progression and depression, and sign of withdrawal: fatigue, diaphoresis, pupillary dilation,
may also lead to increased dosage requirements. Understanding anxiety, diarrhea, tachycardia, abdominal cramps, lacrimation,
the underlying cause of poor pain control will help guide therapy. and increased pain. These symptoms may be subtle, and their
Pain caused by disease progression may be better controlled with peak varies according to the type of opioid used. With long-
disease-modifying agents, and psychological problems may be acting opioids, withdrawal symptoms occur after 48 to 72 hours,
better managed with antidepressants or anxiolytics. Also, it is whereas with short-acting opioids, withdrawal symptoms peak at
important to distinguish tolerance from hyperalgesia, which is 6 to 12 hours.49 The patient must restart the prior medication
usually a more diffuse pain, less defined in quality. In hyperalge- dosages, and symptomatic control is needed once symptoms are
sia, the pain threshold decreases, and an increased dose of opioids noticed. Clonidine, an α2 agonist, can be used to help control
will cause an increase in the pain.50,51 Hyperalgesia has been symptoms (Table 169-3).
1388 SECTION 6  Pain
Nonmedical Use of Opioids in the
United States
6
5 6
Percentage of population
4 5
3
2
1
0 0
All ages Male Female
2002-2003 2009-2010
Figure 169-2. Percentage of population using prescription opioids for chronic nonmedical reasons.47
Chronic is defined here as more than 200 days.
TABLE 169-3  Management of Tolerance, Hyperalgesia, and Dependence
Tolerance
• Increase the opioid dosage by 15%-20%.
• Rotate opioids.
• Add NMDA receptor antagonist to regimen.
• Prescribe adjuvant medications to target
analgesia at different pain mechanisms.
NMDA, N-methyl-D-aspartate.
Understanding how long-term opioid use leads to tolerance
and dependence is crucial in the perioperative management of
patients receiving long-term opioid therapy. Postoperative pain
often becomes a major problem and a source of frustration
for the patient and the surgeon. The use of short-acting analge-
sics, such as remifentanil, has been shown to increase hyperalge-
sia.54 Longer acting opioids, such as fentanyl or sufentanil,
have been shown to be more effective.55 Other options include
ketamine56 and COX inhibitors, which act on NMDA receptors
to reduce hyperalgesia.57 Scheduled medication provides better
pain control than does as-needed dosing. Knowledge of prior
home medication dosage and calculating equivalent dosage
also help in avoiding withdrawal symptoms and suboptimal pain
control.55
Addiction remains a major problem with opioid prescription:
the number of people addicted to prescription medication is
higher than the numbers heroin and cocaine addicts combined.
In a review on opioid use, the American Society of Interventional
Pain Physicians (ASIPP) found a pattern of extensive nonmedical
Nonmedical Use of Opioids in the United States by Age
8
7
Percentage of population
4
3
2
1
12-17 18-25 26-34 34-49 50 and above
Age group
2002-2003 2009-2010
Hyperalgesia Withdrawal
• Taper dosage slowly until pain control • Restart opioids at prior dosage.
is achieved. • Taper dosage slowly and gradually.
• Rotate opioids. • Prescribe symptomatic treatment, including
• Prescribe adjuvant pain medications. clonidine.
• Prescribe NMDA receptor antagonists. • Instruct patient to avoid sudden discontinuation
of opioids and to avoid simultaneous use of
agonists and antagonists.
use of opioids in the United States. Of patients with chronic pain
who are receiving opioids, one third are not taking them as pre-
scribed or are abusing them. Further ASIPP investigation into
the practice patterns of physicians who prescribe opioid medica-
tion revealed that most patients taking opioids receive both long-
acting and short-acting opioids for more than 3 months and
prescribed by a physician who is not a pain specialist. Patients
receiving combined long- and short-acting opioids account for a
significant proportion of the fatalities associated with opioid use.
Of opioid-related fatalities, 60% occur in patients taking medica-
tion prescribed within the current guidelines. In view of these
findings and the dearth of studies on the effectiveness of long-
term opioid use, it is important for physicians to weigh all benefits
and risks when prescribing these medications for long-term use.
There is evidence to support the use of urine drug tests to identify
patients who are noncompliant or abusing their medications.
Furthermore, prescription drug monitoring programs may
reduce abuse and “doctor shopping.” An ASIPP-developed set
of guidelines related to opioid prescribing intended to guide

TABLE 169-4  Classification of Pain and Characteristics
Pain Type Description Onset and Course
Nociceptive Sharp; may be dull if Correlated with injury
not severe
Inflammatory Aching, dull, stabbing Progressive; affected by activity
Neuropathic Burning, shooting, Insidious, usually progressive,
squeezing, numb and possibly lasting for years
physicians in patient management can be used as a reference
point, but clinical management should be tailored to each indi-
vidual case.24,33
Mechanistic Approach to Pain
With different pharmacologic agents available for pain treat-
ment, it is important to match the patient with the appropriate
medication. Clinicians must understand that certain classes of
medication are most effective for certain broad classes of pain,
depending on the pathophysiologic mechanisms of the pain
process. However, depending solely on this approach is not
always effective, and other factors such as pain intensity, toler-
ability, safety, use of disease-modifying agents, compliance, and
cost have to be considered.
Because of the extensive controversy over the categorization
of pain, a broad classification may be more applicable for clinical
purposes. Pain can be categorized as nociceptive, which is a
response to injury; inflammatory, which results from upregulation
of inflammatory mediators; and neuropathic, which is caused by
nerve injury. Pain should also be characterized as either acute or
chronic. With either system, clinicians can classify pain by obtain-
ing a careful history and performing a thorough examination on
the patient in which the qualities and characteristics of the pain
are assessed. Some diagnoses are associated with specific types of
pain; others can manifest with multiple types of pain that syner-
gistically affect the patient (Table 169-4). Certain diagnoses tran-
scend this classification system, lending themselves to specific
treatment; for example, trigeminal neuralgia is best treated with
oxcarbazepine.
Medication Selection
Once the type of pain is established, the class of pharmacologic
agents can be established. The challenge lies in appropriately
adjusting medications according to the pain intensity, efficacy of
the drug, and side effects. At times, multiple lines of therapy are
needed for synergistic effects, to reduce side effects, and to
promote safety. This is possible when more than one pain modal-
ity is involved, as in the case of prolapsed lumbar disk, whereby
the disk releases inflammatory mediators that cause inflammatory
pain and may also physically compress the nerve and thus causes
neuropathic pain. In this situation, it is important to remember
that some medications can be used for multiple types of pain; for
example, NSAIDs can be used for both nociceptive and inflam-
matory pain. Drug-drug interactions should always be assessed
when a polypharmacy approach is considered.
Neuropathic Pain
In general, neuropathic pain results from neural dysfunction or
damage to the somatosensory pathway; unlike nociceptive pain,
neuropathic pain has no functional or protective benefit.58 Neu-
ropathic pain has been defined by the International Association
CHAPTER 169  Pharmacologic Treatment of Pain 1389
169
Distribution Intensity
Related to area of injury or trauma Varies widely between individuals
Localized to the body part that is Is variable and can affect functioning
inflamed or infected
Radiating both proximally and Varies widely between individuals
distally from the site of nerve Is usually intense and profound
damage
for the Study of Pain (IASP) as “pain initiated or caused by a
primary lesion, or dysfunction of the nervous system.”59 Neuro-
pathic pain often exceeds the severity of the injury leading to the
pain. It can be described as burning, lancinating, cramping, or
electric, and it tends to be more diffuse and less focal. It can also
be more intense distally, increase at night, and be aggravated by
factors such as cold, touch, and movement.60,61
It remains important to identify the cause of the pain as much
as possible because this can direct the therapy. Causes of neuro-
pathic pain can be from trauma, nerve avulsion injury, polyneu-
ropathy (as in diabetes), postherpetic pain, phantom pain, or
complex regional pain syndrome.
Current therapies for neuropathic pain aim at regulating the
action of neurotransmitters, receptors, and ion channels. Antide-
pressants and antiepileptics remain the first choices for pain
control and can be used in combination. Although opioids are
more effective in treating nociceptive pain, opioid use has been
shown to have synergistic value in select refractory cases of neu-
ropathic pain. Methadone, for example, acts as an NMDA recep-
tor antagonist and inhibits serotonin and norepinephrine uptake,
which helps with neuropathic pain control.62 Other alternatives
include local anesthetics, capsaicin, clonidine, and baclofen
(Tables 169-5 and 169-6).
Acute Pain
Acute pain results from direct injury and trauma. The most
common occurrence of acute pain in neurosurgical practice is
postoperative pain. The main processes involved in acute pain are
inflammatory and nociceptive. NSAIDs can be used to disrupt
the inflammatory process and opioids to further diminish the
pain. Other options aim to interrupt signal conduction and
transmission from the peripheral nervous system to the central
nervous system. These options include local anesthetics that
block voltage-gated ion channels, as well as epidural and intrathe-
cal opioids and anesthetics.
Patient-controlled analgesia has been shown to be effective
against postoperative pain. The use of multimodal therapy and a
stepladder approach can help with better control and reduce side
effects. The control of postoperative pain starts in the preopera-
tive period with patient education and shaping expectations.
This can be applied to both the adult and pediatric populations
(Table 169-7).
Acute Pain in Children.  Identifying pain in children can be
challenging because children often cannot express their pain and
cannot describe its severity or character. Therefore, it remains
the charge of the physician to identify subtle signs such as irrita-
bility, crying, guarding, and apathy as signs of pain. It is also useful
to listen to the parents and addressing their concern because they
are likely to know how their child responds when in pain or
discomfort.
Pain control can start before a procedure with the use of
long-lasting local anesthetics, lidocaine and prilocaine (EMLA)
1390 SECTION 6  Pain

TABLE 169-5  First-Line Medications for Neuropathic Pain

Duration of
Medication Beginning Dosage Titration Maximum Dosage Adequate Trial
CALCIUM CHANNEL α2δ LIGANDS
Gabapentin 100-300 mg every Increase by 100-300 mg for 3600 mg/day (1200 mg three 3-8 wk for titration plus
night or 100-300 mg three times daily dosing times daily); reduce if 1-2 wk at maximum
three times daily every 1-7 days as tolerated creatinine clearance is low tolerated dosage
Pregabalin 50 mg three times daily Increase to 300 mg daily after 600 mg daily (200 mg three 4 wk
or 75 mg twice daily 3-7 days, then by 150 mg/ times daily or 300 mg twice
day every 3-7 days as daily); reduce dosage if renal
tolerated function is impaired
Topical 5% lidocaine Maximum of 3 patches None needed Maximum of three patches daily 3 wk
patch daily for a maximum for a maximum of 12 hr
of 12 hr
OPIOIDS
Morphine 5-15 mg every 4 hr as After 1-2 wk, convert total daily No maximum with careful 4-6 wk
needed dosage to long-acting opioid titration; consider evaluation
analgesic and continue by pain specialist at dosages
short-acting medication as exceeding 120-180 mg/day
needed
Tramadol hydrochloride 50 mg once or twice Increase by 50-100 mg/day in 400 mg/day (100 mg four times 4 wk
daily divided doses every 3-7 days daily); in patients older than
as tolerated 75 years, 300 mg/day in
divided doses
TRICYCLIC ANTIDEPRESSANTS
Nortriptyline hydrochloride 10-25 mg every night Increase by 10-25 mg/day 75-150 mg/day; if blood level of 6-8 wk, with at least
or desipramine every 3-7 days as tolerated active drug and its metabolite 1-2 wk at maximum
hydrochloride is <100 ng/mL, continue tolerated
titration with caution
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSNRIS)
Duloxetine 30 mg once daily Increase to 60 mg once daily 60 mg twice daily 4 wk
after 1 wk
Venlafaxine 37.5 mg once or twice Increase by 75 mg each wk 225 mg daily 4-6 wk
daily
Modified from Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain.
2007;132:237-251.

TABLE 169-6  Treatment Effectiveness in Neuropathic Pain anxiolytic medication. In children, dosing is based primarily on
weight, and thus it is very important to verify dosages carefully
Neuropathic Pain Medication Class Number Needed to Treat*
(Table 169-8).
Tricyclic antidepressants 2.4 Different nonmedical interventions have been shown to
Carbamazepine 2.5 reduce pain and anxiety and shorten hospital stays. These tech-
Tramadol 3.5 niques aim to distract the patient from pain; examples include
Gabapentin 3.7 playing games, muscular relaxation, guided imagination, hypno-
Selective serotonin reuptake inhibitor 6.7
sis, and massage. Other alternatives include acupuncture, bio-
Dextromethorphan 1.9
Levodopa 3.4 feedback, art therapy, music therapy, herbal medicine, and
Capsaicin 5.9 chiropractic care. Reductions in the duration of the procedure,
Mexiletine 38 preoperative delay, waiting time, and noise level can reduce the
child’s anxiety level and enable better pain control.
*Number needed to treat is an epidemiologic calculation of treatment
effectiveness, defined as the number of patients who need to be
treated in order to achieve benefit from the treatment in one patient. CONCLUSION
Pharmacologic treatment of pain has become increasingly
complex with the growing understanding of pain mechanisms
cream, and topical agents. In general, the use of a scheduled and the development of medications targeting these mechanisms.
pain regimen is preferred over as-needed dosing. Oral and intra- Multiple drug classes for the management of pain can be used
venous acetaminophen and NSAIDs remain the cornerstone of individually or in combination to provide synergistic effects.
pharmacologic agents for control of mild and moderate pain Management techniques vary: some therapies are chosen accord-
because of their analgesic and anti-inflammatory properties. If ing to type of pain and underlying mechanism of action, whereas
pain is not controlled, opioids can be added to the regimen, with others are selected on the basis of the diagnosis. Either way, it is
caution because of the potential side effects of sedation, respira- important to consider the mechanism of action, side effects,
tory depression, nausea, and vomiting. The use of opioids dosing, drug-drug interactions, and the individual patient in
in mechanically ventilated patients can have good results, but determining the appropriate therapies. When prescribing opioids,
with prolonged treatment, patients may develop dependence clinicians must also be vigilant for abuse and counsel patients on
and will need to be weaned off them. Other options include the appropriate use of the medication.
1392 SECTION 6  Pain
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of diabetic neuropathy. Diabetes Care. 2005;28(2):485-487.
PART 3 Treatment of Trigeminal Neuralgia
170 ofEvidence-Based
Facial Pain
Approach to the Treatment
Turo J. Nurmikko and Francis O’Neill
The evolution of the surgical management of pain has been
shaped by shared clinical experience and observation, with limited
effect from well-designed clinical trials. The common successful
scenario follows a typical path: an innovative novel procedure,
supported by a single or very few successful case series, is pro-
posed; it is followed by further case reports by interested sur-
geons; interest becomes more widespread; the procedure is
gradually adopted into general surgical practice; and finally it
becomes the “gold standard.” In many cases, however, the early
success is not repeated in other centers, and interest in the inno-
vation wanes. Even procedures that become established may face
rejection if in popular use they are shown to be associated with
excessive risk or poor tolerability or are simply perceived as less
effective than an alternative intervention. In the process, many
patients will have been subjected to surgical interventions that
have limited value. Although multiple mechanisms are necessary
to dictate the fate of a particular intervention, an important role
is played by key opinion leaders whose views remain unchal-
lenged because of the lack of objective evidence to the contrary.
This scenario was played out in the 20th century in the surgi-
cal management of trigeminal neuralgia. The notable limitations
of pharmacologic treatment paved the way to the evolution of
surgical methods ranging from division of the trigeminal nerve
to alcohol injections, neurectomy, radiofrequency rhizotomy,
glycerol rhizotomy, and balloon microcompression. By the 1970s
the ganglion-level minimally invasive neuroablative procedures
(NAPs) had become the surgical “gold standard.” Coincidentally
with the development of the operative microscope, microvascular
decompression (MVD) became a therapeutic option.1 After Peter
Janetta reintroduced Walter Dandy’s original proposal of MVD
from 1932 and converted it into a procedure in 1967, it was slowly
adopted into the neurosurgeon’s armamentarium over the follow-
ing two decades.2-4 Both enthusiasm and criticism accompanied
its early adoption; opponents and proponents substantiated their
views on the basis of their own experience rather than well-
designed studies. MVD is now the commonest operation for
trigeminal neuralgia in the United States.5,6
MVD has reached this status by common surgical consensus.
It is easy to understand why: it is an elegant way of removing a
cause that can be visualized on magnetic resonance imaging
(MRI); it avoids injury to the nerve and, in contrast, restores its
function; patients find the concept easy to understand; the pro-
cedure is among the safest of intracranial operations; it is well
tolerated by the majority of patients who undergo it; and the
early and long-term results are excellent. In contrast, NAPs—
that is, radiofrequency rhizotomy, balloon microcompression
of the gasserian ganglion, glycerol rhizotomy, and stereotactic
radiosurgery—do not treat the cause, are associated with inten-
tional injury to the nerve, yield poorer long-term results, and are
associated with side effects that include annoying paresthesias
and frank anesthesia dolorosa.7,8
Many of the reasons to perform MVD are less compelling if
subjected to scrutiny. First, vascular compression or contact
cannot be the primary cause because (1) it is common in asymp-
170
tomatic people9; (2) in up to 28% of patients with classic trigemi-
nal neuralgia, no compression can be found10; and (3) trigeminal
neuralgia does recur over the years in 25% of affected patients
without evidence of a new compression.11-13 A more plausible
explanation is that compression is only one (albeit perhaps the
most common) cause of alterations in anatomy and physiology of
the nerve and its central connections.14-16 Although decompres-
sion undoubtedly improves nerve function significantly,17 it has
not been shown that such change is needed to render the condi-
tion asymptomatic.
Second, MVD is less effective in patients with atypical tri-
geminal neuralgia who have concomitant multiple sclerosis
and when the compression is caused by a vein13,18-21 (but see
Sindou and associates22). The reason may be that the pathophysi-
ologic process affecting the trigeminal system remains unaffected
by MVD.
Third, repeated MVD usually provides no better outcome
than less invasive percutaneous procedures.23 As a result, most
neurosurgeons favor the latter in cases of recurrent pain after
initial MVD.8
Fourth, the risks of MVD, including hearing loss, brainstem
infarction, and mortality, are marginally higher than with other
procedures.1
Because the primary aim in the management of trigeminal
neuralgia is pain relief, all procedures that sufficiently alter the
pathophysiologic process may be clinically useful. As described
elsewhere in this book (Chapter 172), minimally invasive NAPs—
currently in widespread use—have a respectable record for com-
plete or near-complete control of the pain, with an excellent
safety profile. When the surgeon discusses the advantages and
disadvantages of various procedures with the patient, results from
comparative trials showing superiority of a given procedure over
the others would be helpful; however, there are none.1,8 There-
fore, the surgeon must extrapolate from published outcomes of a
large number of observational studies and adapt the conclusions
to the individual needs of the patient.
Observational studies, however, have been conducted with
clear patient selection, careful data collection, independent asses-
sors, and actuarial outcome presentation.7,8,22,24 There are ample
published clinical data that allow the surgeon to describe what a
given patient may expect from a particular procedure. However,
it does not answer the question of whether in a particular case
the chosen method is optimal.
The currently available procedures are, without doubt,
extraordinarily effective in treating trigeminal neuralgia. In a
patient with refractory trigeminal neuralgia, the remarkable
outcome of postoperative freedom of pain for several years is
evidence enough.8,24-26 It is obvious that subjecting both MVD
and ganglion-level NAPs to efficacy trials against sham treatment
is meaningless.27 In fact, considering the very large effect size and
a substantial number of patients in prospective case series with
independent assessors, the level of evidence from them, if assessed
according to Grades of Recommendation, Assessment, Develop-
ment, and Evaluation (GRADE) criteria, would be considered
1393
1394 SECTION 6  Pain
high.28 The neurosurgical literature contains sparse preoperative
pain data; when such data are available, however, the effect sizes
calculated from them are extremely high, between 2 and 3, after
radiofrequency rhizotomy at 3 years and MVD at 2 years, respec-
tively.29,30 Because of these large effect sizes that characterize both
MVD and all NAPs, comparative trials are necessary that focus
on the balance between benefit on the one hand and safety and
tolerability on the other.
Unfortunately, only low-quality comparative studies to that
effect have been published. They are mostly single-center retro-
spective assessments of outcomes from two or more procedures
with inconstant follow-up (for reviews, see Pollock1; Tatli and
associates11; and Zakrzewska and colleagues31). The picture
emerging is confusing. As the first operation, MVD in most
comparisons emerges superior in long-term effectiveness over
NAPs.2,3,32-34 However, some authors either claim better effective-
ness with NAPs35 or point to the associated risks of mortality and
morbidity and the marginal difference between the procedures’
effectiveness and therefore favor radiofrequency rhizotomy.26 In
a valiant attempt to resolve the question, Tatli and associates11
evaluated data from approximately 5000 patients in studies pub-
lished between 1970 and 2005 and concluded that although the
quality of many of the studies was not high, the overall picture
emerging was that of considerable success in controlling the pain
in nearly 40%, more or less permanently, with any intervention.
Of importance is that after 20 years, there was little difference
between those undergoing MVD and those undergoing NAPs.
Practically all authors acknowledge greater effectiveness of
MVD over stereotactic radiosurgery, but the benefits of the latter
are also promoted.36,37 Comparisons between various NAPs yield
variable results; no single procedure is clearly superior when the
outcome is based on recurrence rate, morbidity (especially
sensory loss), and patient satisfaction.8,38 In systematic reviews of
better quality prospective case series with actuarial outcome
reporting, authors could not find a real difference between
these procedures.7 In a situation in which preoperative three-
dimensional MRI reconstruction fails to show vascular compres-
sion, the choice of the operation probably represents the personal
preference of the surgeon.
The uncertainty over the best method becomes even greater
if the clinician wishes to establish which approach is best for
subgoups of patients with trigeminal neuralgia associated with
multiple sclerosis, trigeminal neuralgia with atypical features, and
trigeminal neuralgia that recurs after an earlier operation. Advo-
cates and opponents of MVD report completely different results
in patients with multiple sclerosis–associated trigeminal neural-
gia.18,39 In most case series, patients with atypical trigeminal neu-
ralgia have a poorer response to any procedure than do patients
with typical trigeminal neuralgia4,12,19,40; however, whether MVD
or any other intervention is superior in this subgroup of patients
remains unclear.
The failure of any of the comparative studies published so far
to identify a superior treatment results from their inherent biases.
The major bias concerns the difference between compared
patient groups because of lack of randomization. The groups tend
to differ in previous treatment received, duration of trigeminal
neuralgia, associated disability, clinical features (especially those
of atypical trigeminal neuralgia), and previous responses to
therapy. There is an inherent bias in the operator’s choice of the
procedure and patient’s preference, which is based on informa-
tion that he or she has received, which itself may be inaccurate.
In addition, because of the high attrition rate in long-term studies
and the general tendency not to use an independent party for
outcome assessment, the risk of overall bias is too high for
conclusions.
It is intriguing that despite the obvious lack of evidence for
the optimal intervention in trigeminal neuralgia, the popularity
of MVD over radiofrequency rhizotomy and other NAPs is
steadily growing in the United States.6 Not only that, NAPs are
being performed less frequently than before, which suggests that
the overall demand for operative treatment of trigeminal neural-
gia is mostly satisfied. The very significant difference in cost has
not stifled this trend.5
Trigeminal neuralgia is by no means the only example of facial
pain in which evidence of efficacy of surgical interventions is
conspicuously lacking. The surgical options available for chronic
cluster headache are limited. We carried out a systematic review
of publications from 1980 to 2013 and found 14 procedures that
were advocated by various authors. Practically all material was
based on uncontrolled case series (eTable 170-1). Of interest was
that no intervention was superior to the rest in efficacy or safety.
None yielded such poor results that it would be rejected outright.
The relative similarity of benefit across all reported methods
reveals the same problem as in the surgical management of tri-
geminal neuralgia: for the surgeon, the choice of the best method
for the patient remains arbitrary.
THE BENEFIT OF EVIDENCE-BASED MEDICINE
In the 1970s, physicians realized that treatment decisions must
not be based on evidence that is derived from clinical practice
alone and that any treatment must undergo rigorous scientific
evaluation. This led to the development of evidence-based medi-
cine (EBM), which is now an integral part of pharmacologic
medicine and should be essential for all new surgical procedures
and some in common use now. EBM aims to ensure that a given
treatment is as accurate, effective, and unbiased as possible. By
definition, EBM is the conscientious, explicit, and judicious use
of current best evidence in making decisions about the care of
individual patients.41 In the previously described examples of tri-
geminal neuralgia and chronic cluster headache, clinical trials
with rigorous scientific methods stand the best chance of identi-
fying the preferred treatment for a given patient.
It is widely accepted that the strongest evidence comes from
randomized controlled trials (RCTs) that are adequately powered
and whose design limits bias and ensures that the outcome will
be measured objectively.28,42,43 The weakest evidence comes from
uncontrolled case series, case reports, and expert opinion.43 Criti-
cal EBM appraisal is increasingly applied to novel diagnostic
techniques, drugs, and noninterventional treatments, and there
are ever stronger calls for its application to surgery. However,
implementation of EBM in surgery is not as straightforward as
it is in other areas of medicine, and it is not surprising that the
surgical community approaches the idea with circumspection and
reservation.44
We posit that there are particular reasons for application of
EBM in the surgical management of chronic pain. First, chronic
pain is subjective, and its intensity notoriously fluctuates over
time; some conditions are even known to go into long spontane-
ous remissions. Second, for chronic pain, there are many treat-
ments easily accessed by patients, seemingly similar in outcome,
which enhances the risk of bias from patients. Third, the placebo
reaction is greater in chronic pain than in any other condition,
except depression, and accounts for up to 44% of the treatment
response.45 The resulting risk of bias may be high enough to
question the very foundation of a standard treatment. Indeed,
when RCTs were conducted to evaluate the efficacy of arthroscopic
débridement or partial meniscectomy for symptom relief in
degenerative knee pain or adhesiolysis in abdominal pain, no
difference was found between the outcomes of the active and
sham treatments.46-48
The two critical aspects of studies that determine the strength
of evidence are randomization and control. Random assignment
of patients to two or more treatment conditions provides the best
protection against a wide array of confounding factors that are
either unknown or unavoidable and will inevitably influence the
 CHAPTER 170  Evidence-Based Approach to the Treatment of Facial Pain 1394.e1

eTABLE 170-1  Reported Interventions with Outcomes for the Management of Chronic Cluster Headache, 1980 to 2013
170
Total No. Duration of Good-to-Excellent
Intervention No. Trials Publication Years Patients Follow-up Long-Term Response
Sphenopalatine ganglion blocks 2 2006-2010 36 8-28 mo 5/36
Sphenopalatine ganglion RFL 4 1987-2012 35 6-34 mo 15/35
Sphenopalatine ganglion pulsed RFL 2 2005-2011 10 4-52 mo 2/3 (other data N/A)
Sphenopalatine ganglion stimulation 1 2013 28 3-8 wk N/A
Vagus nerve stimulation 3 2005-2013 11 N/A 8/11
Occipital nerve stimulation 6 2007-2011 56 3-64 mo 29/56
Supraorbital nerve stimulation 2 2007-2012 5 16-36 mo 4/5
Cervical cord stimulation 1 2011 7 3-78 mo 4/7
Trigeminal glycerol rhizotomy 3 1985-2000 29 9-78 mo 11/29
Trigeminal RFR 4 1982-1995 55 7 mo–20 yr 35/55
Stereotactic radiosurgery 4 1998-2011 29 5-88 mo 7/29
Trigeminal open rhizotomy 2 1983-2003 25 1 mo–19 yr 17/25
Microvascular decompression 1 1998 28 12-144 mo 9/28
Deep brain stimulation 7 2005-2013 55 9-144 mo 25/55
N/A, not available; RFL, radiofrequency lesioning; RFR, radiofrequency rhizotomy.
 CHAPTER 170  Evidence-Based Approach to the Treatment of Facial Pain 1395

outcome. Comparison of a novel treatment with sham treatment
will show whether the novel treatment has some efficacy in a
given condition and, in most cases, the magnitude of the effect.
Comparison of a novel treatment with an established treatment
(e.g., the “gold standard”) will allow clinicians to judge whether
the efficacy of the novel treatment is similar to that of the estab-
lished treatment and how the two compare in terms of patient
preference, safety, and cost. In contrast, studies that lack random-
ization and control yield results applicable only to that particular
study population, and generalizability is limited. With few excep-
tions, such studies fail to address the very essence of the matter:
whether a particular treatment is superior to an alternative treat-
ment or sham treatment.
IMPLEMENTATION OF EVIDENCE-BASED MEDICINE
IN SURGERY FOR FACIAL PAIN
There are increasing calls from study reviewers and authors
themselves for controlled studies. In cluster headache, both indi-
vidual experts and the Task Force of the European Headache
Society emphasize the need for adequately powered controlled
trials before treatment recommendations can be formulated.49,50
In accordance with this, a protocol for a multicenter study to start
in Europe has been published in which researchers will compare
low- and high-amplitude stimulation of the occipital nerves in
144 patients.51 Low stimulation for the control was chosen over
nonstimulation to maintain blinded conditions. For treatment of
attacks, another multicenter study focused on the efficacy of
sphenopalatine ganglion stimulation versus control for 15 minutes
before use of acute medication. The latter trial builds on the first
RCT in which such stimulation was found to be effective.52 Of
interest, a sham-controlled study design was implemented in a
small study of patients treated with deep brain stimulation.53
Because of the nature of deep brain stimulation, a genuine sham
control condition was possible during the trial period. Although
the results were negative, they reflected the practicalities of the
study rather than its design.
These trials are examples that should allay the concern some
surgeons have expressed for EBM.44 The results will not be
known for years, but they are likely to end the 30 or more years
of uncertainty about interventional treatment of cluster head-
ache. One caveat has to be pointed out in this development:
if the new neuromodulation studies based on RCT methods show
efficacy in attack prophylaxis, it may lead to their adoption into
clinical practice without comparison of neuroablative methods
for which a similar level of evidence is not available. Unless the
effect sizes are substantial, this would not be in the interest of
therapeutic evolution. Rather, a further step would be a compara-
tive trial between balloon microcompression of the gasserian 170
ganglion or radiofrequency lesioning of the sphenopalatine/
trigeminal ganglion for both efficacy and cost effectiveness.
As discussed previously, in trigeminal neuralgia little benefit
is expected from any sham-controlled efficacy studies, now that
case series in large patient populations have shown a substantial
effect size. However, comparative studies involving subgroups
of patients with trigeminal neuralgia are clearly needed and
have significant potential in providing clinically meaningful
information.54 We suggest that in patients with either multiple
sclerosis or atypical trigeminal neuralgia shown to have vascular
compression on preoperative MRI, noninferiority trials could be
carried out between a NAP (e.g., balloon compression) and
MVD. Patients with recurrent trigeminal neuralgia in which the
shooting pain typical of classic trigeminal neuralgia remains pre-
dominant, posterior fossa exploration could be compared with a
NAP. This idea is based on reports of relative success both
from posterior fossa exploration and balloon compression and
radiofrequency rhizotomy.23,55,56 Table 170-1 contains more
recommendations.
One should not be reluctant to conduct such studies because
of the difficulties that they entail, but without them (or similar
controlled trials), a large percentage of patients with trigeminal
neuralgia remain in danger of receiving inferior care. For novel
interventions, which are likely to be less invasive than MVD, the
appropriate approach is to first conduct a sham-controlled effi-
cacy study and then conduct a controlled comparison with a
NAP; patients should be chosen because of lack of vascular
contact on MRI or because of their inability or unwillingness to
undergo MVD.
OTHER TRIAL OPTIONS
Not all surgery is suited to clinical trial methods. Clearly,
blind conditions may be impossible or must be compromised
to an unsatisfactory degree. Many surgeons are uncomfortable
with the concept of equipoise. Research by its very nature is
time consuming and expensive. These issues, however, are not
insurmountable, and alternative trial designs can be used to
address them.
The Idea, Development, Exploration, Assessment, Long-term
follow-up (IDEAL) collaboration (http://www.ideal-collaboration
.net) is an international network of researchers, surgeons, and
methodologists formed to address issues of experimental design
in surgery and other areas of complex interventions. It has devel-
oped a framework for describing the stages of development in

TABLE 170-1  Trigeminal Neuralgia: Some Unanswered Questions Benefiting from Further Research
Research Question Justification for Trial Possible Trial Designs
If trigeminal neuralgia pain recurs after a No controlled trials; inconsistent results from 1. Following MVD: RCT of PFE vs. BC/RFR/GKS
remission period, what is the best case series with preferred option status 2. Following NAP: same or alternative NAP
intervention? claimed for PFE, RFR,BC,GSK
What is the preferred first-line intervention All procedures less effective than in classic 1. If vascular contact on MRI: RCT of MVD vs. BC/GKS
for atypical trigeminal neuralgia (TN2)? trigeminal neuralgia (TN1) 2. If no vascular contact: RCT of BC vs. GSK
What is the preferred first-line intervention Dual mechanism of trigeminal neuralgia16; 1. RCT of MVD vs. NAP (noninferiority trial)
for MS-related trigeminal neuralgia conflicting outcomes from case series18,39 2. RCT of MVD vs. NAP (superiority trial)
with MRI confirmed vascular
compression of V nerve?
In patients >80 yr, does MVD offer any All interventions tolerated by the elderly. Given 1. Noninferiority RCT of MVD vs. NAP
advantage over NAP? length of life expectancy, NAPs (repeated if 2. Cost effectiveness of MVD vs. NAP
necessary) may provide same level of pain (Consider lowering the age limit to 75 yr)
relief/satisfaction than MVD.
BC, balloon compression of the gasserian ganglion; GR, glycerol rhizotomy; GSK, Gamma Knife surgery; MS, multiple sclerosis; MVD, microvascular
decompression; NAP, neuroablative procedure; PFE, posterior fossa exploration; RFR, radiofrequency rhizotomy.
1396 SECTION 6  Pain
surgery and innovation and for issuing recommendations for how
research at each of these different stages can be optimized.
Among these recommendations are suggestions for modifica-
tions and additions to the standard RCT design, as well as alter-
natives to RCT design that are appropriate for some surgical
questions (i.e., case-matching studies, controlled interrupted time
series, and step-wedge study designs). When a stringent RCT
design is not possible, then full description of the design with
minimalization and explanation of confounders will allow more
realistic interpretation of results.57
Although modern health care is increasingly based on evi-
dence that confirms the efficacy and cost effectiveness of surgical
procedures, observational studies still have their role. They are
appropriate when used to test early innovative ideas and when
researchers gather data to allow sample size estimates for pivotal
controlled trials. The mistake in the past was to assume that
observational data per se suffice to prove a hypothesis, which is
not the case. Scientifically robust methods to assess the value of
a new intervention should be rigorously employed.
Trials such as the ones just proposed would undoubtedly add
to clinical practice but are costly and time consuming. They
require multicenter and even international collaborations to be
adequately powered, with added attention to standardization of
surgical procedures and patient selection. In an effort to encour-
age greater engagement, groups such as the NeuroPoint Alliance
(http://www.neuropoint.org/index.html) have been developed by
the American Association of Neurological Surgeons to collect,
analyze, and report nationwide clinical data.58 This alliance also
provides clinical trial management, study design, and survey
facilitation.
CONCLUSION
Surgical management of facial pain is based almost exclusively on
observational data, and controlled studies are all but lacking. In
the case of trigeminal neuralgia, substantial effect sizes in large
patient populations undergoing MVD or NAPs are sufficient to
provide solid evidence of their efficacy. Trigeminal neuralgia sub-
types, in contrast, have not been rigorously assessed in this regard,
and there are no reliable data to be used for treatment recom-
mendations. In chronic cluster headache, the emergence of novel
neurostimulation methods is welcome, but their value remains
uncertain as long as adequately powered RCTs have not been
conducted.
SUGGESTED READINGS
Asher AL, McCormick PC, Selden NR, et al. The National Neurosur-
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nale, development, and implementation. Neurosurg Focus. 2013;34:E2.
Balshem H, Helfand M, Schunemann HJ, et al. GRADE guidelines: 3.
Rating the quality of evidence. J Clin Epidemiol. 2011;64:401-406.
Glasziou P, Chalmers I, Rawlins M, et al. When are randomised con-
trolled trials unnecessary? Picking signals from noise. BMJ. 2007;334:
349-351.
Haines SJ. Evidence-based neurosurgery. Neurosurgery. 2003;52:36-47.
Jurgens TP, May A. Role of sphenopalatine ganglion stimulation in
cluster headache. Curr Pain Headache Rep. 2014;18:433.
McCulloch P, Altman DG, Campbell WB, et al. No surgical innovation
without evaluation: the IDEAL recommendations. Lancet. 2009;374:
1105-1112.
Sackett DL, Rosenberg WM, Gray JA, et al. Evidence-based medicine:
what it is and what it isn’t. BMJ. 1996;312:71-72.
Sivakanthan S, van Gompel JJ, Alikhani P, et al. Surgical management of
trigeminal neuralgia: use and cost-effectiveness from an analysis of the
Medicare Claims Database. Neurosurgery. 2014;75:220-226.
Truini A, Galeotti F, Cruccu G. New insight into trigeminal neuralgia.
J Headache Pain. 2005;6:237-239.
Zakrzewska JM, Akram H. Neurosurgical interventions for the treatment
of classical trigeminal neuralgia. Cochrane Database Syst Rev. 2011;(9):
CD007312, doi:10.1002/14651858.CD007312.pub2.
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outcome of microvascular decompression for trigeminal neuralgia. N 170
Engl J Med. 1996;334:1077-1083.
26. Taha JM, Tew JM Jr. Comparison of surgical treatments for trigemi-
nal neuralgia: re-evaluation of radiofrequency rhizotomy. Neurosur-
gery. 1996;38:865-871.
27. Glasziou P, Chalmers I, Rawlins M, et al. When are randomised
controlled trials unnecessary? Picking signals from noise. BMJ.
2007;334:349-351.
28. Balshem H, Helfand M, Schunemann HJ, et al. GRADE guide-
lines: 3. Rating the quality of evidence. J Clin Epidemiol. 2011;64:
401-406.
29. Reddy VK, Parker SL, Lockney DT, et al. Percutaneous stereotactic
radiofrequency lesioning for trigeminal neuralgia: determination of
minimum clinically important difference in pain improvement for
patient-reported outcomes. Neurosurgery. 2014;74:262-266.
30. Reddy VK, Parker SL, Patrawala SA, et al. Microvascular decom-
pression for classic trigeminal neuralgia: determination of minimum
clinically important difference in pain improvement for patient-
reported outcomes. Neurosurgery. 2013;72:749-754.
31. Zakrzewska JM, Akram H. Neurosurgical interventions for the treat-
ment of classical trigeminal neuralgia. Cochrane Database Syst Rev.
2011;(9):CD007312, doi:10.1002/14651858.CD007312.pub2.
32. Meglio M, Cioni B, Moles A, et al. Microvascular decompression
versus percutaneous procedures for typical trigeminal neural-
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76-79.
33. Zakrzewska JM, Lopez BC, Kim SE, et al. Patient reports of satis-
faction after microvascular decompression and partial sensory rhi-
zotomy for trigeminal neuralgia. Neurosurgery. 2005;56:1304-1311.
34. Degn J, Brennum J. Surgical treatment of trigeminal neuralgia.
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sion, and rhizotomia. Acta Neurochir (Wien). 2010;152:2125-2132.
35. Chen J-F, Lee S-T. Comparison of percutaneous trigeminal gan-
glion compression and microvascular decompression for the man-
agement of trigeminal neuralgia. Clin Neurol Neurosurg. 2003;105:
203-208.
36. Dhople AA, Adams JR, Maggio WW, et al. Long-term outcomes of
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37. Regis J, Tuleasca C. Fifteen years of Gamma Knife surgery for tri-
geminal neuralgia in the Journal of Neurosurgery: history of a revolu-
tion in functional neurosurgery. J Neurosurg. 2011;115:205.
38. Parmar M, Sharma N, Modgill V, et al. Comparative evaluation of
surgical procedures for trigeminal neuralgia. J Maxillofac Oral Surg.
2013;12:400-409.
39. Eldridge PR, Sinha AK, Javadpour M, et al. Microvascular decom-
pression for trigeminal neuralgia in patients with multiple sclerosis.
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40. Pollock BE. Percutaneous retrogasserian glycerol rhizotomy for
patients with idiopathic trigeminal neuralgia: a prospective analysis
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47. Sihvonen R, Paavola M, Malmivaara A, et al. Arthroscopic partial
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171 Nonoperative
Trigeminal Neuralgia: Diagnosis and
Management
Mark E. Linskey
According to the Headache Classification Committee of the
International Headache Society (IHS), trigeminal neuralgia (TN)
is a disorder characterized by recurrent unilateral brief, electric,
shock-like pains, abrupt in onset and termination, limited to the
distribution of one or more divisions of the trigeminal nerve,
often triggered by innocuous trigeminal tactile stimuli.1 It may
develop without apparent cause (classic or typical TN) or may be
a result of another diagnosed disorder (secondary or symptomatic
TN).2-4 Other diagnosed disorders that can lead to secondary TN
include intrinsic brainstem pathology with trigeminal nerve,
nuclei, or tract involvement (e.g., multiple sclerosis [MS] or
lacunar infarction), or extrinsic cerebellopontine angle pathology
(e.g., neoplasms, benign or malignant or nonneoplastic cysts such
as epidermoid, dermoid, or arachnoid cysts or vascular lesions
such as aneurysms or arteriovenous malformations). In addition,
there may or may not be persistent background facial pain of
moderate intensity, usually comprising less than 50% of the
overall syndrome (classic TN with concomitant persistent facial
pain, sometimes called atypical TN).1-5
Considerable progress has occurred in determining the etiol-
ogy of TN. In the majority of patients with classic TN, the pain
is generated because of compression of the trigeminal nerve at
the root entry zone (point in the proximal nerve root central
oligodendrocyte myelin persists and has not yet given way to
peripheral Schwann cell myelin). The plaques of demyelination
that occur lead to hyperexcitability of exposed and potentially
injured afferents, which results in afterdischarges large enough
to cause a nonnociceptive signal being perceived as pain.5 Cur-
rently, the most widely accepted theory to explain TN is the one
proposed by Devor—the ignition theory.6 It is likely that both
central nervous system and nerve root changes occur over time,
which would account for why not all patients get permanent relief
after relief of vascular compression of the nerve root.
There may also be genetic and/or myelin biologic predisposi-
tions, given that rare reports of genetic and familial associations
do exist.7-15 However, at least one fascinating study suggests that
environmental factors may also play a role. Hemminki and col-
leagues constructed a nationwide neurological database from the
Swedish multigenerational register on 0- to 69-year-old siblings
that was linked to the hospital discharge register for the 15-year
period 1987 to 2001.12 They found that if one sibling had TN,
the standardized risk ratio for another sibling having TN was
2.36 (95% confidence interval [CI], 0.85-5.99), confirming a
familial tendency. However, in an interesting environmental
control analysis, they showed that if a wife had TN, the standard-
ized risk ratio for development of TN in her spouse was 2.21
(95% CI, 1.10-3.97), and if a husband had TN, the standardized
risk ratio for development of TN in his spouse was 1.62 (95%
CI, 0.69-3.21)—suggesting that common familial environmental
exposures could account for a significant portion of this familial
association.12
HISTORICAL PERSPECTIVE
One of the earliest known descriptions of paroxysmal facial pain
was by the Arab physician Jurjani in the 11th century. He
171
described “a type of pain which affects the teeth on one side and
the whole of the jaw on the side which is painful”.16 The 17th
century physician John Locke described the symptoms of TN in
the wife of the English ambassador to France. Faced with limited
treatment options for the patient’s excruciating pain, the physi-
cian opted for eight rounds of cleansing of the gastrointestinal
tract, which reportedly resulted in remission of symptoms.17
An important breakthrough in the management of TN
occurred fortuitously in 1942 when Bergouignan administered
his patients the new anticonvulsant diphenylhydantoin (phenyt-
oin).18 Before this, the condition had been referred to as neuralgia
epileptiform because of a prior hypothesis by Trousseau in 1853
that TN, being paroxysmal, was related to abnormal impulse
conduction, analogous to epilepsy.19 When carbamazepine, a new
medication for epilepsy, was introduced in 1962, it was soon
found to be useful in patients with TN.20,21 It had greater efficacy
and less toxicity than the hydantoins and remains to this day the
mainstay of medical therapy.4
EPIDEMIOLOGY
In the United States the annual incidence of TN (age adjusted
to the 1980 age distribution of the United States) is 5.9 per
100,000 women and 3.4 per 100,000 men.22 The incidence tends
to be slightly higher in women at all ages, and increases with age.
Peak incidence is between ages 50 and 60. Point prevalence has
been estimated to be 0.001.2 A retrospective cohort study in
U.K. primary care, with a very loose definition of TN that
likely included many patients with other forms of facial pain,
reported a higher incidence of 26.8 per 100,000 person-years.23
A similar primary care study carried out in Holland reported an
incidence of 12.5 per 100,000 person-years (95% CI, 10.4-14.9)
when trained neurologists reviewed the data.24 A population-
based study in Germany reported a lifetime prevalence of
0.3% (95% CI, 0.1% to 0.5%).25 Pediatric TN does exist, but is
even more rare and is estimated to represent less than 1.5% of
all TN cases.26-28
Bilateral involvement is present in only 5% of cases. In a
retrospective study by Pollack and colleagues, patients with bilat-
eral TN were more commonly females (74% versus 58%, P < .1),
had a higher rate of “familial” TN (17% versus 4.1%, P < .001),
and had a greater increased incidence of additional cranial nerve
dysfunction (17% versus 6.6%, P < .05) and hypertension (34%
versus 19%, P < .05).13
RISK FACTORS
The major risk factor for TN is MS (for unilateral TN—risk ratio
[RR], 20.0; 95% CI, 4.1-59.0).29 Despite this risk factor, less than
5% of patients with unilateral TN will be found to have MS.
Conversely, less than 2% of patients with MS will eventually
develop TN, and in approximately 85% of patients the diagnosis
of MS will already have been made based on the basis of other
symptoms, imaging, or laboratory findings before TN develops.30
With MS-associated TN, the demyelination plaque is character-
istically located either in the nerve root entry zone itself or in the
1397
1398 SECTION 6  Pain
intrapontine fascicular fibers of the trigeminal nerve, sometimes
also including the trigeminal nucleus sensorius principalis or the
trigeminal nucleus spinalis.31 In patients with bilateral TN, the
incidence of MS is much higher (>18%), and bilateral TN, espe-
cially in a younger patient (<40 years old), should trigger consid-
eration of MS as an underlying cause.5,30,32
Hypertension is a risk factor in women (RR, 2.1; 95% CI,
1.2-3.4), but the evidence is less clear for men (RR, 1.53; 95%
CI, 0.30-4.50).29 A history of TN in a first-degree relative is also
a minor risk factor.7-15
DIAGNOSIS
TN is a characteristic pain in the distribution of one or more
branches of the fifth cranial nerve (Fig. 171-1). In the majority
of cases the pain begins in the second or third divisions of the
trigeminal nerve (V2 and V3, respectively). With time it can
spread to other divisions including the first division (V1).
However, TN involves V1 in isolation in only 5% of cases.2-5,29
Isolated V1 involvement should lead to careful consideration of
differential diagnoses.3,4
The diagnosis is made on the history alone, based on charac-
teristic features of the pain.1-5 It occurs in sudden paroxysms, with
each pain lasting a few seconds to several minutes. The pain is
characteristically so severe that it is “arresting.” Whatever the
patient is doing is immediately stopped, and the patient usually
either is frozen in position or contortion or suddenly reaches
up to grab the face. The pain is usually described as sharp, stab-
bing, electric, or shock-like. It characteristically resolves as sud-
denly as it started. The first time the pain is experienced is usually
memorable. Patients may not be able to name a date or time,
but they can usually describe the circumstances and exactly
what they were doing when it first occurred. Typically, the pain
can be triggered by light touch on any area innervated by the
trigeminal nerve, including such things as wind, chewing, talking,
washing the face, applying or removing makeup, shaving, or
cleaning the teeth.
The frequency of paroxysms is highly variable, ranging from
hundreds of attacks a day to long periods of remission that can
Shooting, sharp
Terrifying, exhausting Character
Unbearable
Clinical features of
Moderate to severe Severity
trigeminal neuralgia
Right up to 60% Trigeminal nerve
Site
First division rare
Unilateral 97%
Associated
Figure 171-1. Major clinical features of trigeminal neuralgia. (From Zakrzewska JM, Linskey ME. Trigeminal
neuralgia. In: Zakrzewska JM, ed. Orofacial Pain. New York: Oxford University Press; 2008:119-134.)
last years. Between paroxysms, the person is asymptomatic.
Although the attacks last only seconds to minutes (Fig. 171-2),
they can cluster together in “tetanic bursts” that can last minutes
to hours. In some cases the bursts are individual shocks with reso-
lution between the shocks (Fig. 171-3A). In others, the bursts
have incomplete resolution between the shocks (Fig. 171-3B). A
pain that is continuous and unvarying for many minutes to hours
(Fig. 171-3C and D) should lead to consideration of differential
diagnoses.3,4
Although approximately 10% of TN patients do not respond
to antiepileptic drug (AED) treatment, up to 90% of TN patients
do, at least initially.33 Thus a trial of appropriate AED treatment
can be used as both a therapeutic option and as a diagnostic chal-
lenge, as long as it is not considered to be an absolute criterion
or pathognomonic.
Despite the exclusion of patients with evidence of sensory
deficit from the IHS definition of TN,1 abundant evidence sug-
gests that a subset of TN patients have subtle sensory deficits that
can be picked up by either careful and thorough neurological
examination34-36 or by trigeminal sensory evoked potential
study.37,38 In one TN experience looking mostly at patients who
had had the syndrome for many years, subtle sensory deficits were
detectable in the medial aspect of the V2 or less commonly the
V3 division in up to 30% of cases.3 Nevertheless, early, signifi-
cant, and nonsurgical sensory loss, in addition to bilateral involve-
ment, should trigger a thorough investigation for symptomatic
(i.e., secondary) TN.
There is growing evidence to suggest that classic TN with no
pain between episodes evolves over time into a syndrome in
which a minor component of constant background trigeminal
pain (<50% of the overall facial pain syndrome) can develop while
the syndrome remains dominated by intermittent sudden sharp,
stabbing, electric, shock-like episodes.39
The condition can impair activities of daily living, impair job
performance and/or professional advancement, and lead to social
withdrawal and/or depression.5 Before the discovery of AEDs,
patients occasionally resorted to suicide to escape the fear of
severe and unpredictable attacks.17 It was during this period that
TN developed the moniker of “the suicide disease.”
Seconds, no afterpain
Attacks Seconds, dull afterpain
for minutes
Timing
Periods of complete remission
weeks, months
Eating
Light touch
Provoking Talking
Spontaneous
Washing
Sometimes sleep
Relieving
Drugs
Trigger points
May be sensory change
 CHAPTER 171  Trigeminal Neuralgia: Diagnosis and Nonoperative Management 1399

171

Pain intensity
Pain intensity
Pain intensity

A Time B Time C Time

Figure 171-2. Pictogram describing the typical time onset, resolution, and severity early in the course of the
syndrome (A) and later in the course as the pain frequency and severity increase (B). The pain is
characteristically sudden in onset and resolution without pain between episodes and lasts only seconds to a
few minutes. With chronicity, a constant persisting background dull, aching, or burning pain may develop (C),
but this component is usually minor in comparison to the characteristic episodes from the patient perspective.

Minutes-to-hours Minutes-to-hours Minutes-to-hours Minutes-to-hours

Pain intensity

Pain intensity

Pain intensity

Pain intensity
A Time B Time C Time D Time

Figure 171-3. Pictogram demonstrating how short bursts of episodic pain can be interpreted by trigeminal
neuralgia (TN) patients as lasting many minutes or even a few hours. If the transient spikes cluster in tetanic
bursts, the patient may time the length of the cluster rather than the component episodes, and the clinician
may be fooled into discounting the syndrome as TN. These bursts may cluster with either complete (A) or
partial (B) resolution between spikes. In our experience, patients who describe a sudden onset of pain that
lasts many minutes to hours and remains at the same intensity level until sudden (C) or gradual (D) resolution
are not likely to have TN.

Certainly, before the AED treatment era, patients with TN
were so desperate for relief that they were willing to undergo
brain surgery at a time when the risk of brain surgery mortality
was still relatively high. As a result, TN surgery became strongly
associated with early neurosurgery pioneers and neurosurgical
technical developments.40-43
Differential Diagnosis
Common conditions that mimic TN as well as their presenting
features are listed in Table 171-1. Continuous trigeminal pain, if
the dominant complaint (>50% of the overall orofacial pain syn-
drome), is usually a sign of a disorder other than TN and should
trigger an appropriate differential work-up.
Isolated V1 involvement occurs in less than 5% of TN
patients and should trigger additional work-up to rule out other
conditions such as temporal arteritis, herpes zoster, ocular
migraine, paroxysmal hemicranias, cluster headache syndrome,
short-lasting unilateral neuralgiform headaches with conjuncti-
val injection and tearing (SUNCT), or short-lasting unilateral
neuralgiform headaches with cranial autonomic symptoms
(SUNA). In a study of V1 division neuralgic pain TN patients, a
median pain episode duration of 4 seconds (range, 2-32 seconds)
was found, compared with 40 seconds (range, 5-250 seconds) for
SUNCT syndrome patients, 10 minutes (range, 3-46 minutes)
for chronic paroxysmal hemicrania patients, and 38 minutes
(range, 8-238 minutes) for cluster headache patients.44
Association of trigeminal pain with autonomic symptoms
including dermatomal flushing, ptosis, conjunctival injection,
tearing, or rhinitis should trigger additional work-up to rule out
other conditions such as cluster headache syndrome, SUNCT,
SUNA, or chronic regional pain syndrome (CRPS), formerly
known as reflex sympathetic dystrophy.3-5
Less than 5% of TN patients have bilateral involvement. If
present, it overwhelmingly manifests as first unilateral involve-
ment, to be later followed by contralateral involvement. A diag-
nosis of bilateral TN, particularly developing in a patient younger
than age 40, should lead to a very careful investigation into the
possibility of MS. Simultaneous onset of bilateral involvement
should trigger work-up for a broader orofacial pain differential
diagnosis.3-5 Bilateral TN occurs in 11% to 30% of MS TN
patients versus 3% to 10% of non-MS TN patients.32,45 Patients
1402 SECTION 6  Pain

with MS-associated TN have a younger median age of onset
(45 years) compared with their non-MS–associated TN counter-
parts (54 years).30
In the absence of prior surgery for TN, demonstrable trigemi-
nal hypesthesia and/or hypalgesia are rare and is usually present
only in patients with chronic TN. Presence in a newly diagnosed
patient should trigger work-up for diseases other than TN, par-
ticularly for lesions such as cavernous sinus or cerebellopontine
angle masses, or perineural spread of head and neck cancer
(including cutaneous malignancy and adenoid cystic carcinoma).
Magnetic resonance imaging (MRI) with and without contrast is
very useful for ruling out structural, nonvascular, compressive
causes of TN or other orofacial pain syndromes.3-5 In patients
with trigeminal sensory loss studied with MRI, MS, infarct, and
glioma are the most common abnormalities found in the brain-
stem; acoustic and trigeminal schwannomas, meningiomas, epi-
dermoid cysts, lipomas, and metastases are the most common
abnormalities identified in the cistern; meningiomas, trigeminal
schwannomas, epidermoid cysts, metastases, pituitary adenomas,
and aneurysms are the most common abnormalities identified in
Meckel’s cave and the cavernous sinus; and malignant tumors,
which may demonstrate perineural tumor spread, are the most
common extracranial abnormality identified.46
NONOPERATIVE MANAGEMENT
The first-line treatment for TN is medical or pharmacologic
(Table 171-2). Although phenytoin was the first AED ever shown
to be effective for TN,18 it has not been tested in a prospective
randomized clinical trial and has been largely bypassed for
chronic therapy owing to its relatively high toxicity profile.
However, it is still useful in emergency room, acute extremis situ-
ations because it can be rapidly loaded to full therapeutic dose by
intravenous bolus.
Carbamazepine is considered the most proven, first-line treat-
ment for TN. In the United Kingdom, this position has now been
formally codified by the National Institute for Health and Care
Excellence (NICE), which advocates that carbamazepine should
be offered as the initial treatment for patients with TN.47
Carbamazepine is associated with a very rare risk of poten-
tially life-threatening skin reactions including Stevens-Johnson
syndrome. However, the risk of this condition is markedly
increased in people with the allele HLA-B*1502. The frequency
of this allele varies worldwide and is highest in some Asian popu-
lations. Individuals of Han Chinese, Hong Kong Chinese, or
Thai origin should be screened for HLA-B*1502 before starting
treatment with carbamazepine.48
Carbamazepine is an enzyme inducer and interacts with the
renal distal tubule antidiuretic hormone receptor, which can lead
to hyponatremia. A full blood count; measurements of electro-
lytes, liver enzymes, and vitamin D levels; and other tests of bone
metabolism (e.g., serum calcium and alkaline phosphatase) should
be performed before and a few weeks after the start of carbam-
azepine therapy and then every 2 to 5 years.49 Clinicians should
start or stop treatment by changing the dose in increments over
several days to reduce common adverse effects. After treatment

TABLE 171-2  Common Drugs Used for the Medical Management of Trigeminal Neuralgia (TN)
Drug Level of Evidence Effect Adverse Effects Suggested Dose Comment
Carbamazepine Systematic review NNT for pain Drowsiness, ataxia, 100 mg twice daily; Dose may need to be
(the only of four relief is 1.9; nausea, increase as necessary adjusted after 3 weeks
first-line randomized 72% of constipation by 50-100 mg every because of enzyme
agent) controlled trials patients had (minor); NNT, 3.7 3-4 days; target range induction.
(n = 160) excellent or 400-1000 mg/day
good response
Baclofen One controlled trial 7/10 improved Drowsiness, 10 mg three times daily; May be useful in patients
compared with baclofen; hypotonia; avoid increase as necessary with multiple sclerosis, in
baclofen with 0/10 improved abrupt by 10 mg/day; target whom its antispasticity
placebo (n = 10) with placebo withdrawal dose 50-60 mg daily effects can be harnessed.
(P = .05)
Gabapentin Five uncontrolled Good to excellent Drowsiness, ataxia, 300 mg once daily; Widely used for TN although
studies (n = 123) pain relief in diarrhea (minor); increase as necessary evidence is weak;
40%; any pain NNT, 2.5 by 300 mg every 3 evidence base in other
relief in 53% days in divided doses types of neuropathic
(three times daily); pains much stronger.
target dose
900-2400 mg daily
Lamotrigine One randomized 10/13 improved Drowsiness, 25 mg twice daily; Probably better tolerated
controlled trial on lamotrigine; dizziness, increase by 50 mg than carbamazepine but
with lamotrigine 8/14 improved constipation, weekly; target dose needs slow titration; may
as add-on to on placebo; ns nausea; no 200-600 mg daily therefore have a role in
carbamazepine different from the elderly or patients with
or phenytoin placebo multiple sclerosis who
(n = 14) have less severe disease.
Oxcarbazepine Two uncontrolled Pain relief in all Dizziness, fatigue, 300 mg twice daily; Evidence weak; structurally
studies (n = 21) 21 patients rash, and increase by 600 mg similar to carbamazepine,
hyponatremia weekly; target dose although probably better
600-2400 mg daily tolerated.
Phenytoin Three uncontrolled 77% of patients Drowsiness, ataxia, 300 mg/day; dose First drug used in the
studies (n = 30) reported some dizziness, gum altered to achieve successful management
pain relief hypertrophy therapeutic plasma of TN; little evidence but
concentration rapid dose titration and
once-daily administration
are advantages.
Modified from Zakrzewska JM, Linskey M. Trigeminal neuralgia. In: Zakrzewska JM, ed. Orofacial Pain. London: Oxford University Press; 2009:119-134.
NNT, number needed to treat; ns, not statistically significant.
 CHAPTER 171  Trigeminal Neuralgia: Diagnosis and Nonoperative Management 1403
is started, a dose adjustment is often necessary at about 3 weeks
owing to induction of liver enzymes.
On the basis of observational studies, including a 15-year
prospective cohort study,50 oxcarbazepine has also been shown to
be effective for treating patients with TN. It is the first-line treat-
ment for TN in Scandinavian countries and second-line treat-
ment after carbamazepine in North America.5 One nonsystematic
review (three randomized clinical trials totaling 130 people)51
found that oxcarbazepine and carbamazepine were associated
with similar reductions in attacks (pain, global symptoms) of TN.
Although oxcarbazepine has not demonstrated superiority over
carbamazepine for pain control, and is more expensive in coun-
tries where it is still under patent, many clinicians prefer it for its
lower toxicity profile.5
Although gabapentin has been shown to be effective in treat-
ing some neuropathic pain conditions,52 particularly MS,53 evi-
dence for its use in TN is weak. One randomized controlled trial
showed that gabapentin plus ropivacaine compared with gaba­
pentin alone can improve pain and functional health status in TN
with few or no side effects.54 Pregabalin is another anticonvulsant
in the same family as gabapentin that is used for patients with
TN with little published evidence to date to support it. Anecdot-
ally, both gabapentin and pregabalin are often used for patients
with MS, patients with a “burning” component to their pain, or
as an add-on agent for patients already taking carbamazepine or
oxcarbazepine.
Baclofen is also used for patients with TN, despite very weak
evidence in the literature supporting its use.5 Consensus suggests
that it may be useful in people with MS who develop TN. These
patients are often taking baclofen already, and may achieve
control of symptoms without having to add carbamazepine.
Lamotrigine is also used for patients with TN, despite very
weak evidence in the literature supporting its use. Consensus
suggests that it may be useful in people who cannot tolerate or
are allergic to carbamazepine, or as an add-on agent augmenting
either carbamazepine or oxcarbazepine as their effectiveness
wains.5
CNV1014802 is a novel new sodium channel blocker that has
selectivity for the NaV 1.7 sodium channel and is being assessed
in the treatment of TN.55 Initial reports presented June 8, 2015
at the IHS International Headache Congress suggested promis-
ing initial results with the 31 patients randomized, with
CNV1014802 therapy failing in only 33% of patients (defined as
≥50% of the original pain frequency and severity returning)
versus a 64% failure rate in patients taking placebo over the
course of the study.56 While still early in development and assess-
ment, CNV1014802 is significant as the first pharmacologic
agent being specifically developed to treat TN.
Side effects of treatment with AEDs are quite common, and
their frequency and impact are usually underestimated by clini-
cians treating TN patients.57 Drowsiness and cognitive impair-
ment are the side effects most disliked by patients.57 These side
effects are often dose related and therefore worsen as the syn-
drome progresses and AED doses increase.
PROGNOSIS
Consensus experience suggests that TN is a progressive syn-
drome with progression rates that vary widely, patient-to-patient.
Life table analytic methods demonstrate that 65% of newly diag-
nosed TN patients will have a second episode within 5 years, and
77% within 10 years.29 Fifty percent of TN patients will experi-
ence remissions of at least 6 months’ duration.58
The main problem with treating TN patients with AEDs,
even if they are tolerated initially, is that the treatment does not
address the vascular compression cause present in 95% of patients,
nor the fact that TN is a progressive syndrome. Therefore the
usual result is that, over time, patients require a higher and higher
medication dose to achieve the same degree of pain relief, until
a point is reached at which either the medication no longer con- 171
trols the syndrome or the patient can no longer tolerate the
medication side effects.
Although adding medications in combinations can be consid-
ered, there is no good evidence that patients will achieve signifi-
cantly durable pain control once an adequate trial of a single
first-line agent (such as carbamazepine or oxcarbazepine) has
failed at the maximum tolerable dose. Consideration should be
given to surgical consultation at that point. For carbamazepine,
maximum tolerable doses are usually 800 to 1200 mg/day, but
elderly patients may reach tolerance limits at even lower doses.
TIMING OF SURGICAL CONSULTATION
AND INTERVENTION
Unfortunately, many practitioners currently wait too long to
refer patients for surgery. In one postoperative survey of patients
who underwent surgery for their TN, approximately 70% wished
that they had had their surgery earlier.59 In our practice, although
there are certainly exceptions wherein patients reach tolerance
sooner or tolerate the medications longer, the large majority of
patients referred for surgical intervention have reached medica-
tion intolerance or ineffectiveness somewhere between 5 and 10
years after symptom onset.
Patients with TN are best managed by a coordinated multi-
disciplinary approach. This approach includes early referral to a
surgeon experienced and skilled in TN surgery for initial consul-
tation and counseling. This should ideally be done well before
the nonsurgical members of the team feel that a patient actually
needs surgery. It is neither fair to the patient nor likely best
practice to have the patient be seen by the surgeon only when
medical therapy has failed. Under these circumstances, the patient
is usually in very severe pain to the point of desperation and will
likely agree to anything offered to help. He or she is also likely
to be taking high doses of AEDs, which can impair focus, con-
centration, memory, and ability to learn and to make decisions.
The time to learn about surgical options, their relative pros
and cons, and the providers available to deliver these options is
in the “cool of the moment” when patients are neither desperate
from pain nor relatively incapacitated by high doses of medica-
tions. Patients may also have their own ideas about optimal
timing for their lives for moving on to a surgical treatment once
they understand the prognosis, the procedures, and their relative
success rates. Contingency plans for surgery are best made well
in advance, just as one would do for a trust fund or a will. These
plans can then be implemented with confidence once the appro-
priate agreed-on trigger point is reached.
The paradigm of pursuing surgical intervention for patients
with TN only after medical therapy has failed is in most need
of rethinking with younger adult patients and especially
pediatric patients.60,61 For patients in the United States, a general
idea of median life expectancy for any given patient can be deter-
mined by going to the Social Security Administration life expec-
tancy calculator website (https://www.ssa.gov/oact/population/
longevity.html) and entering in the patient’s sex and date of birth.
This will give the clinician some idea of the timeline for necessary
pain control in any given TN patient. If the median life expec-
tancy for a given patient is longer than 20 years (currently age
<63.5 for men and <66 for women), then it is not very likely that
a strategy consisting solely of medical therapy is likely to be
effective in the long run. Surgical intervention should probably
be considered before conditions develop with age that might
make general anesthesia or surgical intervention excessively risky.
Unfortunately, AEDs are not selective. They have general
electrical suppressive effects throughout the brain. In children
the brain is still developing, and the effects of these drugs at these
doses are potentially much more severe than in adults. These
1404 SECTION 6  Pain
drugs at TN doses interfere with learning and memory during
the key learning period in life. This interferes with the child’s
grades and impairs competitiveness for higher educational and
career opportunities. AEDs are general suppressants, and they
interfere with successful peer socialization and interaction at a
time when adolescents are developing their social self-confidence
and a feel for their place in society. If the child is young enough,
he or she may even be erroneously diagnosed with attention-
deficit/hyperactivity disorder (ADHD).60,61
Even the syndrome of TN by itself is potentially devastating
for adolescents from a socialization perspective. Imagine being
afraid to have someone touch your face or kiss you if you are an
adolescent (especially girls) and the effect that would have on
you socially at this vulnerable time. Many even withdraw and
become almost reclusive. Getting them off these medications and
pain free, allowing them to learn, compete, develop profession-
ally, socialize, and gain personal self-confidence is crucial. In
these patients, early surgical intervention should probably be
considered.60,61
SUGGESTED READINGS
Headache Classification Committee of the International Headache
Society (IHS). The International Classification of Headache Disor-
ders, 3rd ed (beta version). Cephalalgia. 2013;33:629-808.
Linskey ME. Trigeminal neuralgia. American College of Physicians (ACP)
Smart Medicine. <http://pier.acponline.org/physicians/diseases/d625/
d625-pdf.htnl> <http://smartmedicine.acponline.org/content.aspx?gb
osid=299>.
Linskey ME, Zakrzewska JM Trigeminal neuralgia. BMJ Talk Medicine.
April 2015 <https://soundcloud.com/bmjpodcasts> or via <http://
journals.bmj.com/site/podcasts/>.
Zakrzewska JM, Linskey M. Trigeminal neuralgia. In: Zakrzewska JM, ed.
Orofacial Pain. London: Oxford University Press; 2009:119-134.
Zakrzewska JM, Linskey ME. Trigeminal neuralgia. BMJ. 2015;350:h1238.
doi:10.1136/bmj.h1238; PMID:2576710.
See a full reference list on ExpertConsult.com
 CHAPTER 171  Trigeminal Neuralgia: Diagnosis and Nonoperative Management 1404.e1
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55. Zakrzewska JM, Palmer J, Ettlin DA, et al. Novel design for a phase
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172 Percutaneous Procedures for Trigeminal Neuralgia
Andrew L. Ko and Kim J. Burchiel
HISTORICAL DEVELOPMENT OF PERCUTANEOUS
PROCEDURES FOR TRIGEMINAL NEURALGIA
Percutaneous procedures for treatment of trigeminal neuralgia
were first introduced in 1853 by Patruban, who divided the maxil-
lary nerve behind the orbit by passing a tenotome along the floor
of the orbit and cutting the nerve as far back as possible.1 In 1910,
Harris applied a lateral approach to reach the foramen ovale and
inject alcohol.2 In 1914, Härtel modified the approach to an
anterior one similar to that currently practiced,3,4 and in 1930,
Irger used an inferior approach (both approaches used alcohol
injection).4,5 It was Rethi who first introduced the use of electro-
lytic techniques for treatment of trigeminal neuralgia.6 In 1960,
radiofrequency (RF) lesioning was introduced by Sweet, and it
was applied to the treatment of trigeminal neuralgia in 1974.7,8
Serendipity led to the application of glycerol to treat trigeminal
neuralgia. In 1981, Häkanson,9 used glycerol as a medium to
introduce tantalum dust into the trigeminal cistern as part of a
stereotactic radiosurgical technique for the treatment of trigemi-
nal neuralgia. He noticed that patients became pain free imme-
diately. Later, he used glycerol alone and confirmed the pain relief
effect. By applying Taarnhøj and Shelden’s10-12 principle of inter-
nal neurolysis of the root of the trigeminal nerve in the dural
canal over the margin of the petrous ridge, Mullan and Lichtor,13,14
in 1983, introduced the technique of percutaneous balloon com-
pression of the gasserian ganglion.
The development of procedural safety was necessary for the
widespread adoption of percutaneous techniques for treatment of
trigeminal neuralgia. Visualization of needle placement to avoid
extratrigeminal injury was first addressed in 1916 by Pollock and
Potter15 in cadaveric studies, in which the needle site during
alcohol injection was confirmed using radiography. It was not
until 1936 that Putnam and Hampton applied this procedure to
patients, with good results.10,16 Another important development
involved the use of electrophysiology to confirm needle place-
ment and ensure adequate neurolysis, while avoiding excessive
damage. To this end, in 1955, Silverstone designed an insulated
needle with an exposed tip used as a nerve stimulator.10,17 Later,
motor and sensory evoked potential monitoring was used in tri-
geminal destructive procedures by Karol and colleagues,18 and
this was adopted by Sindou and others.19-21 Most recently, neu-
ronavigation has been used to assist with percutaneous trigeminal
neurolysis.22-24
TRIGEMINAL ANATOMY
Percutaneous procedures in general aim to reach the trigeminal
nerve ganglion or sensory root through the foramen ovale. An
understanding of the relationship among the foramen, the third
division of the nerve (mandibular), and surrounding structures is
vital to avoid injury to the neighboring nervous system structures
and vasculature.
The foramen ovale is situated in the anterior part of the sphe-
noid bone. It lies lateral to the foramen lacerum, which is occluded
at its base only by cartilage. It is also near the posterior margin
of the lateral pterygoid plate. Posterolaterally lies the foramen
spinosum, which transmits the middle meningeal artery and men-
ingeal branch of the mandibular nerve. Rarely, the foramen spi-
nosum and ovale may be confluent. Posteroinferiorly lies the
jugular foramen, and posterolaterally, the carotid canal.25 The
172
shape of the foramen ovale is typically oval, yet it can be almond
shaped, round, or slit-like. The average length and width are
7.46 mm ± 1.41 mm and 3.21 mm ± 1.02 mm, respectively.26 The
foramen may be divided into two or three components in 4.5%
of cases.27
Several nerves, arteries, and veins pass through the foramen
ovale: the mandibular nerve, lesser superficial petrosal nerve,
accessory meningeal artery, and emissary veins (from the cavern-
ous sinus to the pterygoid plexus). The optic ganglion is situated
directly under the foramen but may also pass through the foramen
ovale.25
The gasserian ganglion originates from the cranial neural
crest and the overlying thickened ectoderm. The three processes
of the ganglion can be identified at 6 weeks’ gestation; the oph-
thalmic division develops first, followed by the maxillary and
mandibular divisions. Meckel’s cave attains its final shape at 12
weeks’ gestation, with the arachnoid ending around the ganglia.28
The gasserian ganglion is a sensory ganglion of the trigeminal
nerve; it is crescent shaped with convexity directed forward. It is
located at the apex of the petrous portion of the temporal bone
and may extend to the foramen lacerum, or the posterior lip or
floor of the foramen ovale. The mean distance from the foramen
ovale to the gasserian ganglion is 6 mm (range, 5.8 to 6.3 mm).29
The anterior border of the ganglion is usually within 2 mm in
front of, or behind, the posterior lip of the foramen ovale. The
ganglion’s dural covering forms Meckel’s cave and, medially, the
cavernous sinus.30
Meckel’s cave is confined between the outer and inner layers
of the dura but also contains a separate sleeve of meningeal dura
formed by extension of the posterior fossa dura into the middle
fossa. Surfaces are concave inferiorly and medially and more flat
superiorly. The sensory branches of the trigeminal nerve and
partially the gasserian ganglion and its three divisions occupy
Meckel’s cave. The subarachnoid space within Meckel’s cave
extends an average of 4.9 mm medially and 1.7 mm laterally
beyond the posterior edge of the gasserian ganglion. This space
may extend over the divisions of the trigeminal nerve. The mean
length of Meckel’s cave ranges from 6 to 16 mm.31 The gasserian
ganglion measures 4 to 5 mm wide and 15 to 25 mm long. The
length of the sensory root varies from 5 to 15 mm; the length of
the mandibular nerve from the anterosuperior margin of the
foramen ovale to the gasserian ganglion is 0 to 10 mm.30-32
The ganglion has a posterior sensory root, which joins the
brainstem about halfway between the lower and upper borders
of the pons. It starts with an oblique run upward from the lateral
part of the pons toward the petrous apex, exits the posterior fossa,
enters the middle cranial fossa by passing forward beneath the
tentorial attachment, and enters Meckel’s cave to join the gan-
glion through a deep hilum on its posterior aspect. The motor
branch of the trigeminal nerve runs in front of and medial to the
sensory root and passes beneath the ganglion, leaving the skull
through the foramen ovale and, immediately below this foramen,
joining the mandibular nerve.33
The sensory rootlets, between the gasserian ganglion and the
root in the cerebellopontine angle, form a plexus at its entry into
the ganglion. This retrogasserian triangular area has been named
the triangular plexus and has been identified as the best place to
create a lesion for the treatment of trigeminal neuralgia.34
The trigeminal ganglion is formed by union of the three divi-
sions of the trigeminal nerve: the mandibular nerve, maxillary
1405
1406 SECTION 6  Pain
nerve, and ophthalmic nerve, also known as V3, V2, and V1,
respectively. The ophthalmic nerve is the smallest of the three
trigeminal divisions. It inclines upward as it passes forward near
the medial surface of the dura, forming the lower part of the
lateral wall of the cavernous sinus and reaching the superior
orbital fissure. The maxillary nerve takes a more direct course
and enters the foramen rotundum. The mandibular nerve occu-
pies most of the gasserian ganglion and takes a caudolateral
course from the ganglion and enters the foramen ovale.33,35
DIAGNOSIS
The first known references to what is believed to be trigeminal
neuralgia were by Aretaeus of Cappadocia36 and later by Avi-
cenna, who described trigeminal neuralgia in his text Canon
Medicinx.37,38 The International Association for the Study of Pain
defined the essential features of idiopathic trigeminal neuralgia
as “sudden, transient, intense bouts of superficially located pain,
strictly confined to the distribution of one or more divisions of
the trigeminal nerve usually precipitated by light mechanical
activation of a trigger point or area.”39 Penman, in a detailed
description of trigeminal neuralgia, stated that the only constant
feature is the symptom of pain that is unilateral, trigeminal,
severe, paroxysmal, and precipitated.40
A diagnosis of trigeminal neuralgia is dependent on the
patient’s history and analysis of the patient’s complaint. Pain is
usually described as spreading outward from the trigger point to
cover an area that roughly approximates the territory of distribu-
tion of one (or more) of the trigeminal divisions.41 Usually, there
is no clinically evident sensory deficit, yet quantitative and quali-
tative tests have demonstrated deficits for tactile and warm sensa-
tions in the affected area, with no deficit for heat pain or for
pinprick.41-44 There is also an absolute, followed by a relative,
refractory period after an attack, during which further paroxysms
cannot be elicited by trigger-point stimulation,45 a phenomenon
confirmed by microelectrode recordings obtained during percu-
taneous RF ablation of the ganglion for trigeminal neuralgia.46
A differential diagnosis of trigeminal neuralgia includes a large
array of facial pains. Trigeminal neuralgia itself may be due to
multiple causes and pathologic processes, which influence the
mode of treatment and outcome. To assist in diagnosis and treat-
ment of trigeminal neuralgia, a facial pain classification system
has been proposed by Burchiel (Table 172-1).47-49
Diagnostic Tools
Trigeminal neuralgia is a purely clinical diagnosis; there is no
confirmatory laboratory or imaging study for this disease.
However, there are electrophysiologic and imaging studies that
may be useful as an adjunct to clinical acumen. Trigeminal evoked
potentials and electrophysiologic studies are not widely used
but are complementary diagnostic tools.50,51 Magnetic resonance
TABLE 172-1  Burchiel Classification of Facial Pain
Diagnosis History
Spontaneous onset
Trigeminal neuralgia, type 1   >50% episodic pain
Trigeminal neuralgia, type 2   >50% constant pain
Trigeminal injury
Trigeminal neuropathic pain   Unintentional, incidental trauma
Trigeminal deafferentation pain   Intentional deafferentation
Symptomatic trigeminal neuralgia Multiple sclerosis, tumor
Post-herpetic neuralgia Trigeminal herpes zoster outbreak
Atypical facial pain* Somatoform pain disorder
*Cannot be diagnosed by history alone.
imaging (MRI) and magnetic resonance angiography processed
as three-dimensional images have been used to verify vascular
compression.52-54 MRI may not be necessary in cases managed
purely by a percutaneous procedure.
SURGICAL TREATMENT
There are no specific surgery guidelines for patient selection or
guidelines for which surgical method to select. A report by
Gronseth and colleagues details the diagnostic evaluation and
treatment of trigeminal neuralgia as an evidence-based review
and makes some recommendations.55
Surgery is generally offered to patients who fail medical treat-
ment, have only partial relief of pain after 1 year, or, according
to Garvan and Siegfried,56 still require medication after consump-
tion of more than 3000 tablets of a single drug. Microvascular
decompression (MVD) remains the surgical option of choice for
trigeminal neuralgia, with percutaneous procedures generally
reserved for patients who experience recurrent pain after MVD
or are a high surgical risk owing to medical comorbidity. The
less invasive percutaneous procedures are more often employed
in patients older than 65 to 70 years of age, although outcomes
from MVD in this population are similar to those in younger
patients.57,58 In the case of suspected symptomatic trigeminal neu-
ralgia caused by multiple sclerosis (MS), further evaluation may
be needed for surgical planning and prognostication. Percutane-
ous procedures are usually offered to patients with MS.59-61
Although neurovascular compression may be seen in patients
with MS, surgical outcomes tend to be less satisfactory than in
cases of idiopathic trigeminal neuralgia.62,63
PERCUTANEOUS PREOPERATIVE CARE
All percutaneous procedures for the management of trigeminal
neuralgia involve producing some injury to trigeminal afferents.
This is achieved by using heat in the case of RF rhizotomy,
chemical neurolysis in the case of glycerol rhizotomy, mechanical
neurolysis in the case of balloon compression rhizotomy, and
radiation-induced neural injury in the case of stereotactic radio-
surgery (SRS). That so many percutaneous procedures are avail-
able points to the fact that none has proved ideal. That is, no
one percutaneous procedure is applicable in all cases with a uni-
formly high rate of long-term success and with minimal possibil-
ity of complication or recurrence. RF rhizotomy is perhaps the
most commonly used procedure, and long-term case results are
available.61,64,65
Patient Selection
Percutaneous procedures are usually offered to patients with tri-
geminal neuralgia who have failed medical management or have
developed complications or side effects of medical management
and either have already had or are not suitable candidates for
MVD. Although there are no surgical age guidelines or limits,
age older than 65 years can often lead to exclusion of an otherwise
eligible patient from the benefits of MVD. Some surgeons prefer
percutaneous procedures for patients older than 65 years of age.66
One could argue that it is prudent to offer MVD to the most
eligible patients: those who demonstrate vascular impingement
of the trigeminal root on the affected side and are otherwise
fit to undergo the procedure. However, a recent study indicates
that patients without neurovascular compression who undergo
posterior fossa exploration and internal neurolysis have outcomes
comparable to those undergoing MVD.67 Patients with MS,
pontine infarction that affects the trigeminal root entry zone, or
brainstem white matter lesions without MS and those who have
previously failed MVD should initially be considered for a per-
cutaneous procedure.64,68,69
 CHAPTER 172  Percutaneous Procedures for Trigeminal Neuralgia 1407
Preoperative Patient Preparation
We recommend preoperative MRI for all trigeminal neuralgia
patients, with the exception of those with a confirmed MS diag-
nosis. Patients with trigeminal schwannoma and epidermoid
tumor have been described as presenting with trigeminal pain,
but this is not usually considered typical trigeminal neuralgia.
MRI serves to begin to address primary pathology and to poten-
tially exclude such patients from percutaneous procedures.70-73
Also, when a vascular compression is in doubt, high-resolution,
three-dimensional, time-of-flight magnetic resonance angiogra-
phy may be performed to assess and demonstrate vascular
impingement (if present) with greater than 90% accuracy.74,75
Patients are advised that, although most percutaneous proce-
dures can be performed as day surgery, they may be required to
stay overnight in the hospital if circumstances dictate. Anticoagu-
lant and antiplatelet medications should be stopped before
surgery, and patients are advised to continue taking any antihy-
pertensive medications throughout the perioperative period.
Patients are advised to take nothing by mouth on the day of the
procedure.
PERCUTANEOUS SURGICAL PROCEDURES
Radiofrequency Rhizotomy
RF rhizotomy was popularized by Sweet and Wepsic, as reported
in 1974.76 The concept behind the technique is to use RF stimula-
tion (alternating electrical field with an oscillating frequency of
500,000 Hz) to cause a thermal lesion in the retrogasserian root,
or ganglion.77 In an animal study, RF heating was reported to
cause selective injury to small myelinated and unmyelinated
fibers78; however, a subsequent neuropathologic clinical model
study failed to substantiate this.79 It is now generally believed that
RF heating causes a nonselective destruction of axons, regardless
of fiber size.80
In the operating suite, the patient is placed supine on the
operating table. Intravenous access is secured. The patient is then
placed with the head extended to about 30 degrees to obtain a
clear submental-vertex view of the foramina ovale and spinosum,
located on the greater wing of the sphenoid bone, of the affected
side. Biplanar fluoroscopy can be used if available. Usually a
portable C-arm digital fluoroscope is sufficient. Magnification
(2×) of the fluoroscopic image may be required to visualize the
foramen clearly.
Anesthesia is induced using a short-acting agent, such as pro-
pofol. The goal is to reach plane 1 of stage III anesthesia, with
loss of eyelash reflex but without abolition of laryngeal reflexes.
Bolus dosing (usually 40 mg of propofol) is most effective. Ben-
zodiazepines should be avoided because they prolong awakening
time. Anticholinergics (usually 0.2 mg of glycopyrrolate) may be
given to minimize oral secretions and blunt the vasovagal response
during penetration of the needle through the foramen ovale.
Some surgeons prefer to watch for the vagal response as a guide
while engaging the foramen ovale and may not use preoperative
anticholinergics. If anticholinergics are not used, an external
pacemaker strapped to the chest wall, set to deliver 45 beats/min
should bradycardia occur during electrode insertion or during
stimulation, may be used.80
The skin of the cheek and perioral region on the ipsilateral
side is painted with antimicrobial solution after the required
depth of anesthesia has been obtained (eyelash reflex is lost). A
nasal cannula or trumpet may assist in the maintenance of the
airway. The surgeon stands on the same side as the patient’s pain,
and cannulation of the foramen proceeds under fluoroscopic
guidance using the Härtel technique with the RF electrode
trochar.3 The needle enters the cheek through a point 2.5 cm
lateral to the corner of the mouth and 1 cm inferior to the
172
3 cm Midpupil
2.5 cm
1 cm
Trajectory
Figure 172-1. The radiofrequency needle is inserted into the cheek at
a point 2.5 cm from the corner of the mouth, 1 cm below the occlusal
plane. The trajectory is the intersection of two planes: one directed to
the midpupil and the other to a point 3 cm anterior to the tragus.
During needle insertion, the surgeon’s index finger is inserted into the
patient’s mouth lateral to the teeth to prevent intraoral penetration and
to ensure that the needle is not directed lateral to the maxilla.
occlusal plane and advances through the cheek in the submucosal
layer, between the pterygoid bone and the angle of the mandible,
guided by the surgeon’s index finger of the other hand within the
patient’s mouth (Fig. 172-1). The needle is directed along a line
representing the intersection of a vertical plane passing through
the medial aspect of the ipsilateral pupil and a horizontal plane
passing through a point 3 cm anterior to the external auditory
meatus along the inferior border of the zygoma. The needle
engages the foramen ovale about 6 to 8 cm from the skin surface.
This can usually be evidenced by a contraction of the masseter
muscle manifested as jaw jerk (see Fig. 172-1).
Lateral fluoroscopy is used thereafter, and the needle is
advanced to a point just superior to the intersection of the petrous
part of the temporal bone and the clivus on a true lateral view.
The needle trajectory should be at 45 degrees to the planum
sphenoidale on this view. The patient is now awakened from
anesthesia, and the stylet of the trochar is withdrawn and replaced
with the RF electrode. The RF generator should report the
patient’s temperature accurately. Electrode impedance within the
ganglion is usually 150 to 350 ohm. These readings are helpful
to confirm that the RF generator is functioning and that the
electrode is within the ganglion rather than in cerebrospinal fluid
(CSF). A curved-tip (Tew) electrode may be necessary to target
V1 and V2, but typically a straight electrode suffices to produce
a lesion in V3 (Fig. 172-2).
Once the patient is adequately awake, test stimulation of the
target is achieved using a square wave stimulus at 50 Hz, using a
1-millisecond pulse duration, to evoke paresthesias in the stimu-
lated division. This is usually obtained at an amplitude of 0.05 to
0.15 volts, although a somewhat higher threshold of stimulation
1408 SECTION 6  Pain
Figure 172-2. On lateral fluoroscopy, the needle is seen entering the foramen ovale, directed to a region
that is just anterior to the intersection of the petrous bone and clivus. For V3, the needle is directed at
the 10-o’clock position, and for V2 and/or V1, the needle is directed more superiorly toward the 11- or
12-o’clock position. The latter approach will require a somewhat lower and more lateral entry point on the
cheek.
may be required in patients who have had a previous lesioning
procedure. When the electrode location has been confirmed, the
patient is again anesthetized. Lesion creation is achieved by
heating the electrode up to 75° to 80° C for 90 seconds. For
lesions in the V1 segment, a duration of 60 seconds may be used.
The initial lesion may be bracketed by making a lesion on either
side by moving the electrode 2 mm proximally and distally from
the initial position. After neurolysis is complete, the patient is
again awakened from anesthesia to test the procedure efficacy.
The end point of this procedure is slight hypoesthesia, such that
the patient is able to feel touch in the affected area but cannot
differentiate between the sharp and blunt ends of a safety pin.
When the desired end point has been achieved, the needle is
withdrawn with the electrode, and the entry point is checked for
bleeding. Rarely, pressure application may be required in the
presence of bleeding to preempt the formation of a hematoma.
The patient is then transferred to the recovery room and is kept
under observation for a few hours. Typically, the patient can
return home the same day.
In 98% to 99% of the patients, pain relief is obtained imme-
diately after surgery.81,82 A recurrence rate of 20% at 9 years has
been described, with an incidence of 9% for mild dysesthesia, 2%
for major dysesthesia, and 0.2% for anesthesia dolorosa.81 Because
hypoesthesia is the end point of the procedure, numbness is
present in 100% of patients after surgery.81 Other studies show a
higher pain recurrence rate associated with lower rate of dyses-
thesia and anesthesia dolorosa.83 It is generally accepted that a
denser lesion results in longer pain relief at the cost of a higher
sensory complication rate. The irreversible loss of long-latency
trigeminal root evoked potentials has been documented as a
means of objective assessment of the effects of the rhizotomy,84
and a newer multiarray electrode method for mapping the tri-
geminal nerve may help in producing more selective lesions.85
Glycerol Rhizotomy
The procedure for injecting anhydrous glycerol (99.5%), a mild
neurolytic, can be performed both in an operating room with
fluoroscopic facilities and in a radiology suite setting with anes-
thetic support.86 Because the procedure is largely anatomic (does
 
not require intraoperative patient response to guide the surgeon
during the lesioning), the patient can be sedated throughout
the procedure, although some surgeons prefer that the patient
be awakened after the needle has been placed through the
foramen ovale. Patients often receive a short-acting barbiturate,
such as methohexital, or another short-acting agent, such as
propofol.
The patient is positioned supine with the neck extended,
similar to the RF procedure, and a 20-gauge, 3.5-inch spinal
needle is inserted into the foramen ovale using the Härtel tech-
nique, as described earlier. To ensure access to the trigeminal
cistern, the foramen ovale should be entered through the medial
third. The position of the needle is confirmed by fluoroscopy and
is manipulated, usually in 1-mm increments under guidance, to
obtain a free flow of CSF on removing the stylet. When a free
flow of CSF is obtained on removing the stylet, the stylet is
reinserted into the needle, and the patient is carefully moved into
a sitting position with the neck flexed forward such that the
orbital-meatal line is past horizontal. A cisternogram is then per-
formed using a water-soluble contrast medium such as iohexol
(Omnipaque; GE Healthcare AS, Oslo, Norway). Using a tuber-
culin syringe, the contrast medium is injected in 0.05-mL boluses
and, under continuous lateral fluoroscopy, the filling of the tri-
geminal cistern is noted. A typical pear-shaped appearance of the
cistern is visualized. The volume of the cistern is recorded as
the amount of contrast required to fill up the cistern, and then
the contrast is allowed to drain out either through the needle by
removing the syringe or into the posterior fossa by tilting the
head backward. The average volume of the cistern is 0.25 to 0.30
mL, and it uncommonly exceeds 0.5 mL (range, 0.1 to 1 mL).82,87
Some surgeons have reported successful procedures without
using the cisternogram for localization, instead relying on fluo-
roscopy and CSF backflow,88 although this introduces an element
of uncertainty as to the destination of the injected glycerol.
Glycerol is then slowly injected into the trigeminal cistern in
a similar manner, under continuous fluoroscopy, with the patient
sitting upright and the head flexed forward. Although many sur-
geons simply fill the cistern with glycerol,89 others attempt to
produce a more selective lesion.80 Calculating the volume of
glycerol required for a more “selective” neurolytic effect relies on
 CHAPTER 172  Percutaneous Procedures for Trigeminal Neuralgia 1409
the “floating glycerol” technique, which depends on the assump-
tion that glycerol has a lower specific gravity than the contrast
medium and therefore floats on its surface. The ratio of glycerol
to contrast medium can be varied for directing treatment against
specific targeted fibers; ratios of 30:70 for V1, 50:50 for V2, and
70:30 for V3 are used to achieve the purpose. The emphasis is
that it is more important to drain the cistern completely of con-
trast medium before injecting glycerol in the case of V3 pain than
in the case of V1 pain.
Another technique for injecting glycerol is that of varying the
amounts of glycerol used to fill the trigeminal cistern, subsequent
to drainage of all the contrast medium after cisternography. One
half of the cistern is filled in cases of V3 pain, two thirds in cases
of V2 pain, and the whole cistern in cases of V1 pain or for pain
in multiple trigeminal divisions.
After withdrawal of the spinal needle, the glycerol should be
kept in contact with the nerve for at least 1 hour (up to 2 hours
has been recommended), by keeping the patient in a sitting posi-
tion with the head flexed.80,86,87,90 The patient may then be dis-
charged home.
Most patients experience relief immediately or within 1 to 2
days after surgery, although it can take up to 2 weeks to achieve
pain relief in some cases.89 Liu and Apfelbaum have recom-
mended a repeat procedure if pain relief does not occur within 7
days of surgery.86
Sensory loss after glycerol retrogasserian rhizotomy is variable
and may present as a mild numbness, usually in the perioral
region; however, profound sensory loss may occur. Corneal hypo-
esthesia may occur in a few patients when the V1 division or all
the fibers are targeted, and these patients need to be advised to
check their eyes daily for signs of irritation.
Balloon Compression
Percutaneous balloon microcompression of the trigeminal gan-
glion using a balloon catheter was introduced by Mullan and
Lichtor.13 This technique was purportedly derived from the open
technique of mechanical injury to the trigeminal ganglion per-
formed through temporal craniotomy by Shelden and Pudenz in
1955.91,92 Skirving and Dan have reported performing a similar
technique since 1980,93 following an introduction to the method
by Mullan and before the detailed method published by Mullan
and Lichtor in 1983.13 Based on a rabbit experimental study,
Brown and colleagues have postulated that balloon compression
has the advantage of selectively avoiding injury to the small,
unmyelinated fibers that mediate corneal reflex, providing rela-
tive protection of the corneal sensation.60 Microcompression of
the trigeminal ganglion takes place during the procedure; it has
also been documented in anatomic study on cadavers that, when
the balloon is fully inflated, there is stretching of the dura, reliev-
ing what is called the dural compression of the trigeminal ganglion
and its root.94 This lends some support to the hypothesis of
Taarnhøj, who postulated that trigeminal neuralgia may, in part,
be caused by the compression and angulation of the nerve root
where it crosses the apex of the petrous ridge.95,96
Balloon microcompression does not require the patient to be
awake during surgery and can thus be performed under general
anesthesia, thereby limiting the anxiety and discomfort of the
patient. The procedure is performed in a surgical suite with fluo-
roscopic facilities. General anesthesia is administered, and either
premedication with an anticholinergic, such as glycopyrrolate, is
administered, or an external pacemaker is placed to mitigate
bradycardia that may occur during insertion of the needle through
the foramen ovale or during balloon compression of the trigemi-
nal ganglion. A combination of both precautions against bradyar-
rythmia is advisable.
The patient is positioned supine with the head extended
about 15 degrees. Using fluoroscopic guidance and the Härtel
technique, as discussed in the “Radiofrequency Rhizotomy”
section earlier, a 14-gauge needle with a blunt obturator is intro- 172
duced into the foramen ovale of the affected side.3 When the
cannula has engaged the foramen ovale, the blunt obturator is
removed, and a straight guiding stylet is inserted. Under fluoro-
scopic guidance, the stylet is then directed toward the porus
trigeminus (proximal entrance to Meckel’s cave), radiographically
denoted by the medial dip in the petrous bone on an anteropos-
terior image (with the petrous ridge positioned in the radio-
graphic center of the orbital cavity). This brings the tip of the
stylet between 17 and 22 mm beyond the foramen ovale, within
5 mm beyond the clival line. In this location, the tip of the stylet
abuts the maxillary fibers. Manipulations (1 mm) of the stylet
medially or laterally bring the tip closer to V1 or V3 fibers,
respectively.
A No. 4 Fogarty balloon catheter is test-inflated with contrast,
and all air should be excluded from the balloon. The stylet is
withdrawn, and the balloon with inner stylet is introduced. This
is the standard apparatus used for this procedure, although the
use of variably sized balloon catheters has also been reported.97
A pressure transducer attached to an insufflation syringe or a
tuberculin syringe is screwed to the proximal end of the catheter
using a three-way stopcock. The balloon is then inflated using
about 1 mL of contrast agent. If accurately positioned, the balloon
assumes a pear shape on lateral fluoroscopy. The thin neck of the
pear is the portion of the balloon within the porus trigeminus.
Adequate compression can be verified by measuring the intralu-
minal pressure changes and is limited by lifting the dura off
the trigeminal ganglion. An intraluminal pressure of 1200 to
1500 mm Hg (1.3 to 1.5 atm) is considered adequate, signifying
a resultant tissue compression pressure of 650 to 950 mm Hg.80,98
The balloon is kept inflated for 1 to 1.5 minutes if it is a first
surgery and for 1.5 to 2 minutes in cases of recurrent pain to
minimize the risk for dysesthesia. Compression times of up to 10
minutes have been reported.93,99 Limiting the compression time
to less than 2 minutes has resulted in reduction of the incidence
of masseter muscle weakness and severe numbness.98 After com-
pression is completed, the balloon is deflated, and the balloon and
catheter are removed, with pressure applied to the cheek for
about 5 minutes to prevent hematoma formation. The patient can
be discharged home after about 4 hours of observation. Most
patients obtain pain relief immediately after surgery. The remain-
ing patients experience pain relief by postoperative day 2.
Postoperative Management
After all percutaneous procedures, the entry point on the cheek
is cleaned and dressed, if necessary. Corneal sensation should be
tested, and the patient should be counseled as to how to recognize
signs of corneal irritation. If substantial loss of corneal sensation
occurs or corneal irritation occurs, artificial tears may be advised
for use every 2 to 4 hours, and an ophthalmologic evaluation may
be warranted. Dietary restrictions are not necessary; however,
many patients prefer to restrict their intake to soft foods for a
few days. Jaw opening exercises may be necessary, especially in
patients undergoing the balloon compression procedure. The
inner cheek on the affected side may feel numb, and the patient
should be advised to avoid biting the tongue and cheek on that
side. Some patients may develop a maceration of the buccal
mucosa, requiring irrigation of the mouth with warm saline solu-
tion every 4 hours. Some patients may develop herpes simplex
type 1 lesions a few days after surgery, which can be treated with
a topical application of acyclovir.80 In cases of headache after
glycerol rhizotomy, it is necessary to differentiate between chem-
ical meningitis, which will resolve over time, and infective
meningitis. Anticonvulsant medications need to be continued
immediately after surgery but can be tapered off and discontinued
depending on the degree of pain relief obtained.
1410 SECTION 6  Pain
RADIOSURGERY
SRS was first used by Leksell for the treatment of trigeminal
neuralgia in 1971.100 Since then, several groups have demon-
strated the efficacy of various radiosurgical techniques in the
management of the condition.101-105 The mechanism of action of
radiosurgery is presumed to be axonal degeneration as result of
radiation. This was postulated by Kondziolka and colleagues
from their work on a primate model106 and was later confirmed
by histologic analysis of the cisternal segment of the trigeminal
nerve in a patient with recurrent trigeminal neuralgia who under-
went partial sectioning of the nerve.107 Arteriolar thickening that
occurs after radiation insult to the vessel in contact with the nerve
has been postulated to have a possible therapeutic effect.108
The procedure is indicated in selected patients of advanced
age or poor medical condition, patients who are on anticoagu-
lants, and those who are reluctant to pursue other forms of
therapy.
The procedure involves placing a stereotactic head frame on
a patient who is under local anesthesia or with the help of a brief
general anesthetic. Thin-section (1- to 1.4-mm) axial MRI is
obtained. Constructive interference in steady state images are of
great value in identifying the nerve as it passes through the tri-
geminal cistern. Various radiosurgical targets, including the gas-
serian ganglion, the root entry zone at the pons, and the
retrogasserian portion of the nerve (4 to 6 mm long, 2 to 3 mm
anterior to the root entry zone), have been used. Most centers
now employ the posterior target (root entry zone).86,109-112 The
patient is positioned in the radiosurgery device (linear particle
accelerator or Leksell Gamma Knife [Elekta AB, Stockholm,
Sweden]), and the target is irradiated using a small collimator
(4 mm) at a maximal dose of between 60 and 90 Gy for initial
treatment and of about 50 Gy in cases undergoing repeat treat-
ment. A 50% isodose line is used at the nerve boundary.
On completion of the radiosurgical procedure, the stereotactic
frame is removed, and the patient can be prepared for discharge
home. Patients should be advised to continue taking their pain
relief medications because radiosurgery may take up to 4 to 6
weeks to relieve pain. Depending on the degree of pain relief
achieved, patients may slowly taper off pain relief medications.
RESULTS AND COMPLICATIONS
Of the available percutaneous procedures for trigeminal neural-
gia, RF rhizotomy has been reported to provide the highest rate
of pain relief. In some series, results are comparable to those of
MVD.80 Long-term pain relief (average, 6 years; range, 1 to 9
years) has been reported in 75% of patients (range, 63% to 89%)
after RF rhizotomy.80 Pain relief after glycerol rhizotomy (average,
3 years; range, 0.5 to 5.5 years) has been reported in 55% of
patients (range, 22% to 70%),80 whereas in the case of balloon
compression, pain relief was reported in 73% of patients (range,
62% to 83%) at 4 years’ follow-up (range, 0.5 to 10.7 years).80
Pain relief obtained after SRS has been reported to be as high as
83.1% after the first year,113 with a decrease to 55.8% (complete
or partial pain relief) at 5 years.114
Although graded lesions involving the different trigeminal
nerve distributions are best obtained using RF rhizotomy, in the
case of trigeminal neuralgia affecting the V1 segment, corneal
hypoesthesia is a significant complication in up to 16% of cases.115
The initial theory that glycerol could relieve neuralgia without
causing sensory loss has largely been disproved. Sensory loss and
dysesthesia continue to be significant complications of the
procedure.116-118 Damage to the motor rootlets affects the results
of balloon compression and has been shown to occur in up to
12% of cases.119
The most common complications of RF rhizotomy are severe
dysesthesia in 6% to 9% of cases, corneal hypoesthesia in 1% to
17% (average, 6%), and transient motor weakness in about
19%.82 After glycerol rhizotomy, the most common complica-
tions are corneal hypoesthesia in about 5% (range, 0% to 10%)
of cases and significant dysesthesia in about 4% (range, 0% to
13%).80 Although permanent motor root weakness is a major
complication of balloon rhizotomy, occurring in 3% of cases
(range, 0% to 12%), significant dysesthesia is also common,
occurring in about 5% (range, 0% to 10.6%).80 The most signifi-
cant complication of SRS is numbness, which has been reported
to occur in up to 21% of cases and is considered as bothersome
or painful in 5% to 10% of patients.113,120 Significant dysesthesia
has been reported in about 3.2% of patients after radiosurgery
for trigeminal neuralgia.121
Other potential, but rare, complications resulting from percu-
taneous needle procedures through the foramen ovale include the
risks for stroke, hemorrhage, pseudomeningocele, permanent
hearing loss or facial weakness, diplopia resulting from trochlear
nerve or abducens nerve palsy, and CSF rhinorrhea.80,122-125
SPECIAL CONSIDERATIONS
Multiple Sclerosis
About 2% of patients with MS suffer from trigeminal neural-
gia.126 Although the possibility of concomitant vascular impinge-
ment on the trigeminal nerve in cases of MS with trigeminal
neuralgia has been well documented63 and anecdotal reports of
treatment with decompression published,127 the procedure of
MVD is not routinely recommended for such cases even by the
staunchest of advocates,128,129 primarily because of a high failure
rate. In this instance, failures may be due to MS patients having
extension of demyelination into the brainstem, central to the area
generally treated by MVD.130,131 MS patients generally present at
a younger age and are somewhat more likely to have bilateral
facial pain.59,130 Percutaneous techniques, including glycerol rhi-
zotomy, RF lesioning, and radiosurgery, have been advocated for
management.64,132,133 Treatment failure occurs in MS-related tri-
geminal neuralgia independently of the type of treatment modal-
ity, but recent work indicates that balloon compression may have
the highest initial pain-free response rates and longest pain-free
intervals when compared to glycerol rhizotomy, SRS, RF lesion-
ing, or MVD.134
Recurrent Treatment
In patients in whom pain has returned after MVD, a second
MVD procedure is unlikely to be of any benefit unless the offend-
ing vessels from the first MVD were reported to be veins.135,136
In recurrent cases, glycerol rhizotomy or RF rhizotomy has been
advocated as the procedure of choice.137 Because the trigeminal
cistern may become scarred after a prior glycerol rhizotomy,
a repeat glycerol injection has a higher chance of technical
failure.138 It may be prudent in such cases to undertake an RF
procedure. There is no evidence that RF rhizotomy and balloon
compression are associated with greater technical failure rates
when repeated.80
CONCLUSION
Percutaneous procedures for trigeminal neuralgia involve pene-
tration of the foramen ovale with a cannula and then creation of
a destructive lesion either on the trigeminal ganglion or root.
This can be accomplished by thermal injury through RF, chemi-
cal injury by injection of glycerol, or mechanical compression by
balloon inflation in Meckel’s cave.
Currently, there are no evidence-based guidelines for when to
apply these procedures or which one to choose. The general
consensus has been to reserve percutaneous procedures for older
 CHAPTER 172  Percutaneous Procedures for Trigeminal Neuralgia 1411
patients, for those not able to tolerate MVD, for patients with
trigeminal neuralgia caused by MS, and for recurrent disease.
The overall trend in the United States has been a dramatic
decline in the use of percutaneous procedures for the treatment
of trigeminal neuralgia.139
As a group, about 90% of patients with trigeminal neuralgia
attain immediate pain relief from a percutaneous procedure.
Most postoperative pain recurrences occur within the first 2
years, after which the recurrence rate decreases, with a more
than 50% recurrence after 5 years. Sensory loss after these per-
cutaneous procedures occurs in almost half of patients and varies
from slight hypoesthesia to troublesome dysesthesia. Other com-
plications include anesthesia dolorosa, corneal numbness, and
motor weakness. A low pain recurrence rate is clearly associated
with more sensory loss, but complications of deafferentation,
such as anesthesia dolorosa and its more minor variants, also
increase in parallel with numbness. The surgeon must balance
adequate and sustained pain relief with unwanted sensory com-
plications. These procedures provide a good alternative for man-
agement of trigeminal neuralgia as an initial modality, in recurrent
cases, and in patients with symptomatic trigeminal neuralgia sec-
ondary to MS.
At present, there is no ideal surgical procedure for trigeminal
neuralgia—one that is minimally invasive, uniformly effective,
lacking complications, and without failures or recurrences. MVD
still remains the standard by which all other contemporary pro-
cedures are measured. MVD provides the longest pain-free inter-
val, yet it is not free of morbidity and mortality. SRS provides a
reasonable noninvasive option, but it has delayed onset of relief
and a recurrence interval comparable to other percutaneous pro-
cedures. Finding an answer to what procedure to use, and when
to use it, is difficult because there is no class I or II evidence, in
part owing to a lack of uniformity in terms of both the outcome
measures and the reporting methods used by most reported case
series.140,141 Clearly, randomized controlled studies are needed
that employ standardized outcomes measures to answer these
questions.140,142-144 172
SUGGESTED READINGS
Bowsher D. Trigeminal neuralgia: an anatomically oriented review. Clin
Anat. 1997;10:409-415.
Burchiel K, ed. Surgical Management of Pain. 2nd ed. New York: Thieme;
2002.
Burchiel KJ. A new classification for facial pain. Neurosurgery. 2003;53:
1164-1166.
Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines on tri-
geminal neuralgia management. Eur J Neurol. 2008;15:1013-1028.
Hakanson S. Trigeminal neuralgia treated by the injection of glycerol into
the trigeminal cistern. Neurosurgery. 1981;9:638-646.
Kanpolat Y, Berk C, Savas A, et al. Percutaneous controlled radiofre-
quency rhizotomy in the management of patients with trigeminal neu-
ralgia due to multiple sclerosis. Acta Neurochir (Wien). 2000;142:685-689,
discussion 689-690.
Leksell L. Sterotaxic radiosurgery in trigeminal neuralgia. Acta Chir
Scand. 1971;137:311-314.
Lopez BC, Hamlyn PJ, Zakrzewska JM. Systematic review of ablative
neurosurgical techniques for the treatment of trigeminal neuralgia.
Neurosurgery. 2004;54:973-982.
Mullan S, Lichtor T. Percutaneous microcompression of the trigeminal
ganglion for trigeminal neuralgia. J Neurosurg. 1983;59:1007-1012.
Resnick DK, Jannetta PJ, Lunsford LD, et al. Microvascular decompres-
sion for trigeminal neuralgia in patients with multiple sclerosis. Surg
Neurol. 1996;46:358-361, discussion 361-362.
Sweet WH, Wepsic JG. Controlled thermocoagulation of trigeminal gan-
glion and rootlets for differential destruction of pain fibers. 1. Trigemi-
nal neuralgia. J Neurosurg. 1974;40:143-156.
Taha J. Trigeminal neuralgia: percutaneous procedures. Semin Neurosurg.
2004;15:115-134.
Tatli M, Satici O, Kanpolat Y, et al. Various surgical modalities for tri-
geminal neuralgia: literature study of respective long-term outcomes.
Acta Neurochir (Wien). 2008;150:243-255.
See a full reference list on ExpertConsult.com
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129. Eldridge PR, Sinha AK, Javadpour M, et al. Microvascular decom-
pression for trigeminal neuralgia in patients with multiple sclerosis.
Stereotact Funct Neurosurg. 2003;81(1–4):57-64.
130. Hooge JP, Redekop WK. Trigeminal neuralgia in multiple sclerosis.
Neurology. 1995;45:1294-1296.
131. Kondziolka D, Lunsford LD, Bissonette DJ. Long-term results after
glycerol rhizotomy for multiple sclerosis-related trigeminal neural-
gia. Can J Neurol Sci. 1994;21:137-140.
132. Huang E, Teh BS, Zeck O, et al. Gamma knife radiosurgery for
treatment of trigeminal neuralgia in multiple sclerosis patients. Ste-
reotact Funct Neurosurg. 2002;79:44-50.
133. Cheng JS, Sanchez-Mejia RO, Limbo M, et al. Management of
medically refractory trigeminal neuralgia in patients with multiple
sclerosis. Neurosurg Focus. 2005;18(5):e13.
134. Mohammad-Mohammadi A, Recinos PF, Lee JH, et al. Surgical
outcomes of trigeminal neuralgia in patients with multiple sclerosis.
Neurosurgery. 2013;73:941-950, discussion 950.
135. Yamaki T, Hashi K, Niwa J, et al. Results of reoperation for failed
microvascular decompression. Acta Neurochir (Wien). 1992;115:
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136. Lee SH, Levy EI, Scarrow AM, et al. Recurrent trigeminal neural-
gia attributable to veins after microvascular decompression. Neuro-
surgery. 2000;46:356-361, discussion 361-362.
137. Rath SA, Klein HJ, Richter HP. Findings and long-term results
of subsequent operations after failed microvascular decompression
for trigeminal neuralgia. Neurosurgery. 1996;39:933-938, discussion
938-940.
138. Rappaport ZH, Gomori JM. Recurrent trigeminal cistern glyc-
erol injections for tic douloureux. Acta Neurochir (Wien). 1988;90:
31-34.
139. Wang DD, Ouyang D, Englot DJ, et al. Trends in surgical treatment
for trigeminal neuralgia in the United States of America from 1988
to 2008. J Clin Neurosci. 2013;20:1538-1545.
140. Lopez BC, Hamlyn PJ, Zakrzewska JM. Systematic review of abla-
tive neurosurgical techniques for the treatment of trigeminal neu-
ralgia. Neurosurgery. 2004;54:973-982, discussion 982-983.
141. Zakrzewska JM, Akram H. Neurosurgical interventions for the
treatment of classical trigeminal neuralgia. Cochrane Database Syst
Rev. 2011;(9):CD007312.
142. Cruccu G, Gronseth G, Alksne J, et al. AAN-EFNS guidelines
on trigeminal neuralgia management. Eur J Neurol. 2008;15:
1013-1028.
143. Tatli M, Satici O, Kanpolat Y, et al. Various surgical modalities for
trigeminal neuralgia: literature study of respective long-term out-
comes. Acta Neurochir (Wien). 2008;150:243-255.
144. Akram H, Mirza B, Kitchen N, et al. Proposal for evaluating
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Neurosurg Focus. 2013;35(3):E3.
173 Stereotactic Radiosurgery for Trigeminal Neuralgia
Zhiyuan Xu and Jason P. Sheehan
“Tic douloureux” or trigeminal neuralgia (TN) was described by
the French surgeon Nicholas André in 1756.1 TN is character-
ized by a temporary paroxysmal, lancinating or electric shock–
like neuropathic pain in the trigeminal nerve (TGN) distribution
and typically confined to one side of the face, but the pain may
be bilateral in rare cases. Pain-free intervals are common and vary
in length from weeks to decades. The prevalence of TN is 4 to
5 per 100,000.2 First-line treatment for TN is medical. Agents
typically employed include carbamazepine, gabapentin, pregaba-
lin, and baclofen. In particular, response to carbamazepine may
help differentiate TN from other orofacial pain syndromes. Dif-
ferent kinds of facial pain, broadly called “atypical” TN, may
occur with deafferentation, trauma, multiple sclerosis (MS),
somatoform pain disorders, and herpes zoster; more appropriate
classification schemes exist.3 Nonetheless, treatment options for
these types of facial pain are fairly similar to those used for TN
but the treatment options are generally less effective.
Because most patients with TN present in their 50s or 60s,
they typically have a life expectancy greater than 10 years for
which the TN must be managed. Over time, it is not uncommon
for a patient’s TN to become refractory to the medications.
Those with medically refractory TN go on to neurosurgical
treatment. The widely accepted cause of TN is demyelination
resulting from compression of the nerve by a vascular structure.
The first microvascular decompression (MVD) procedure was
described by Taarnhoj4,5 in 1952 and later refined by Barker and
colleagues.6 MVD is the only nonablative surgical procedure.
Ablative neurosurgical procedures treated through percutaneous
techniques (e.g., glycerol injection, thermocoagulation, radiofre-
quency rhizotomy) produce lesioning to the TGN and may
afford pain relief. The concept of stereotactic radiosurgery for
TN was introduced as a minimally invasive option, but this
approach necessitates a lesion of the TGN at least to some
degree.
HISTORICAL PERSPECTIVE OF GAMMA KNIFE
RADIOSURGERY IN TRIGEMINAL NEURALGIA
The initial interest in Gamma Knife radiosurgery (GKRS) for
TN arose from Lars Leksell’s interest in using radiosurgery for
the treatment of pain syndromes.7 Twenty years before building
the Gamma Knife, Leksell used an orthovoltage stereotactic
technique to treat patients with TN and achieved some relief of
symptoms.8
Leksell also described the use of Gamma-thalamotomies,
which were used not only for tremor but also for intracta-
ble pain.9 The gasserian ganglion was irradiated for TN and
Gamma-capsulotomies were performed to interrupt fronto-
limbic connections in the treatment of intractable anxiety and
obsessive-compulsive disorders.10,11 Leksell’s first patient was
treated through an x-ray tube attached to a stereotactically cen-
tered device, and in some patients, Leksell achieved pain relief for
up to 17 years after treatment. The major challenge in targeting
TN at that time was the limited visualization of the gasserian
ganglion on plain radiographs. This hurdle combined with the
introduction of new drugs and the emergence of nonablative
methods caused a decline in the use of GKRS for TN through
the 1970s and early 1980s. However, with the introduction of
high-quality magnetic resonance imaging (MRI), which permitted
1412
high-resolution imaging of TGN and its root entry zone, interest
was renewed in the radiosurgical approach.
RATIONALE FOR RADIOSURGERY IN TRIGEMINAL
NEURALGIA AND FACTORS RELATED TO
FAVORABLE OUTCOMES
As early as 1941, Olivecrona12 described that mechanical pressure
along the root or at the level of the Gasserian ganglion could be
the cause of TN. In their pioneering work 3 years later, Granit
and Skoglund13 demonstrated that local pressure on nerve fibers
could result in painful afferent discharges from the injured neural
segment,3 evidence that has been supported by more contempo-
rary work from Jannetta and colleagues, who have suggested that
vascular compression of the TGN may be a causal agent in
TN.6,14,15 In spite of these hypotheses, however, the fact that
balloon compression of the TGN can lead to symptomatic
improvement in some patients with TN underscores the void in
our understanding of the pathophysiology of this disease entity.16,17
Radiosurgery appears to be more effective when used as the
initial modality than as a salvage treatment for patients with
TN.18-22 Maesawa and colleagues20 demonstrated that patients
who underwent radiosurgery after failed MVD had high rates of
recurrence, with only 60% maintaining complete pain relief at 1
year, 53% at 2 years, and 33% at 5 years. Régis and colleagues21
have reported that the probability of pain relief at 1 year in
patients without previous surgery was 88%, compared with 82%,
80%, and 75% in patients with one, two or three prior surgical
interventions, respectively.
However, all secondary treatments for TN are associated with
poorer results than those after the first procedure, a factor related
to the fact that patients who need re-treatments (or alternative
treatments) have more severe disease.23,24 Also, for image-guided
surgery, prior procedures such as MVD that disturb the pristine
anatomy of the cisternal segment of the trigeminal nerve result
in more difficult targeting during radiosurgery. Such targeting
difficulty may translate to a slight reduction in overall efficacy
and an increase in complication rate for those undergoing a
salvage procedure such as radiosurgery.
Among patients who have not undergone previous surgery for
TN, those in whom high-resolution MRI has visualized contact
between a blood vessel and the TGN have a particularly favorable
response to radiosurgery.25 In addition to these factors, Pollock
and associates19 demonstrated that younger patient age and
longer TGN segment irradiated were related to improved radio-
surgical outcomes. In contrast, Régis and colleagues26 noted that
the probability of being pain-free was lower in patients younger
than 60 years (56%, compared with 91% in older patients).
The presence of atypical facial pain (such as tingling or
burning) has also been reported to have a poorer prognosis when
radiosurgical treatment is used, with only 44% improvement of
symptoms in this group, compared with 84% improvement in
patients with typical pain, according to Maesawa and coworkers.20
Patients with atypical facial pain frequently have different types
of underlying disease (e.g., post-herpetic neuralgia, pain follow-
ing sinus surgery, pain from facial trauma). The efficacy of
GKRS for relief of atypical facial pain is not well defined by the
literature, in part owing to the heterogeneity of this patient popu-
lation. Nevertheless, it is safe to conclude that the outcome of
 CHAPTER 173  Stereotactic Radiosurgery for Trigeminal Neuralgia 1412.e1

KEY WORDS:
173
trigeminal neuralgia
facial pain
stereotactic radiosurgery
Gamma Knife
 CHAPTER 173  Stereotactic Radiosurgery for Trigeminal Neuralgia 1413
radiosurgical treatment for atypical facial pain is less favorable
than for traditional TN.27
Treatment with GKRS in the setting of MS has been per-
formed in small series,21,28-32 because the clinical outcomes of
MVD and percutaneous glycerol or radiofrequency rhizotomy
provide a lower rate of response and durability of pain relief in
this cohort of patients.31,33,34 TN develops in approximately 2%
of patients with MS, and this incidence is 20 times that in the
general population.35 No consensus has been reached regarding
the best surgical treatment modality, owing to the lack of pro-
spective studies.36 Rogers and colleagues30 achieved a high level
of success with GRKS in a study of 15 patients with MS-associated
TN. At a mean follow-up of 17 months, 80% of patients had
experienced relief from the use of an initial dose of 70 to 90 gray
(Gy). Five patients underwent repeat GKRS to the same treat-
ment area with a mean maximum dose of 48 Gy. All 5 patients
attained some pain relief, and 60% were able to discontinue their
TN pain medication. Weller and associates37 reported the clinical
outcomes in a series of 35 patients with MS-related TN treated
with GKRS with a median maximum dose of 90 Gy. At a median
follow-up of 39 months, 88% of patients had either complete
pain relief or reasonable pain control (grade I to III on the
Barrow Neurological Institute [BNI] facial pain intensity grading
system; see later discussion of postoperative pain control) at 3
months after GKRS, and the actuarial rates of freedom from
relapse of BNI IV or V pain were 57%, 57%, and 52% at 1, 2,
and 5 years, respectively. “Non-bothersome” facial numbness sec-
ondary to GKRS developed in 39% of patients. To date, one of
the largest series, published by the University of Pittsburgh
group, involved 37 patients, in 78% of whom previous surgery
had failed; 23 patients experienced complete pain relief (BNI I),
and 36 patients (97%) had reasonable pain control (BNI I-IIIb)
at a median follow-up of 57 months.38 Reasonable pain relief was
maintained in 83%, 74%, and 54% of patients at 1, 3, and 5 years,
respectively, following GKRS. Nondisabling paresthesias devel-
oped in 5.4% of patients. Although more investigation is required
to assess the long-term success and toxicity (in particular the
development of troublesome facial numbness) of GKRS, this
treatment proves to be effective and safe owing to a reasonably
favorable complication profile.
RADIOSURGICAL TARGETING
Accurate targeting is critical to the success of radiosurgery, and
for the indication of trigeminal neuralgia, it is usually performed
with stereotactic MRI (Video 173-1). The MRI is typically per-
formed with at least a 1.5-tesla (1.5 T) field strength (Fig. 173-
1A); 3 T imaging during GKRS may offer better resolution.39,40
Localization is performed using T1-weighted and fast spin echo,
constructive interference in steady state (CISS) axial images along
with coronal images of the nerve (Fig. 173-1B). The axial volume
acquisition matrices are then divided into sections of 1 mm
without gaps. In many centers, further T1-weighted images are
obtained after administration of gadolinium. Three-dimensional
(3D) reconstructions are also routinely performed. When MRI is
not feasible (i.e., in patients with pacemakers), computed tomog-
raphy (CT) may be used for targeting,27,41,42 although it is not
ideal. CT cisternography can be used to improve delineation of
the radiosurgical target.43
With radiosurgery, the initial target for treating TN is the
TGN’s root entry zone (REZ) at the level of the pons. Different
locations along the affected nerve have been targeted in clinical
practice. Varying lengths of the cisternal segment of the TGN
can affect radiosurgical targeting. Longer segments of the nerve
allow for placement of a single isocenter with minimal to no
blocking yet delivery of a still tolerable dose to the brainstem. In
a patient with a shorter trigeminal nerve cisternal segment, block-
ing or beam shaping may be needed to reduce dose to the
brainstem (Fig. 173-2). Using a Gamma Knife angle of 110
degrees frequently facilitates alignment of the isocenter with the 173
axis of the trigeminal nerve. However, a study performed by Xue
and colleagues,44 demonstrated that by virtue of the steep falloff
of the radiation dose, the brainstem may be capable of receiving
an increased dose without significant toxicity.
Much has been written about whether or not the TGN should
be targeted more proximally or more distally (see Fig. 173-1).45-48
Régis and coworkers,26 who irradiated the cisternal (retrogasse-
rian) portion of the trigeminal root in their patients, reported a
high rate of effective pain control, with an 87% rate of excellent
outcome and a 10% rate of painful relapse. Use of this more
anterior target choice involved fewer complications even with a
maximum dose of 90 Gy. Nicol and colleagues49 and Pollock and
associates19 targeted the trigeminal REZ with a dose of 90 Gy
and reported a higher rate of pain control, along with a higher
rate of complications in comparison with use of lower doses.
Massager and coworkers47 reported a higher pain control rate
with use of the plexus triangularis as the target. However, the
length of the nerve targeted in this study was significantly
increased than in other reports, and as a result, the rate of TGN
injury (38%) was higher than that reported by Régis and Pollock’s
groups. Our group has analyzed 99 patients with idiopathic TN
treated with GKRS using a 80-Gy maximum dose and found that
proximal targeting provided significantly longer pain relief (BNI
grade I or BNI I to IIIa), although some facial numbness was
present in approximately 56% in this group compared with 27%
in the group with more anterior targeting.50 These findings reca-
pitulate that long-term pain relief is achievable using appropriate
targeting of GKRS; however, there is an acceptable tradeoff
between the pain relief and the risk of facial numbness, particu-
larly for patients who have severe facial pain that multiple surgical
procedures have failed to relieve. Interestingly, Gorgulho and
colleagues51 demonstrated that gadolinium-induced enhance-
ment of the brainstem at the REZ rather than of the TGN on
MRI correlated with favorable pain relief and a higher incidence
of facial numbness.51 This finding further underscores that
patients with TN may benefit from proximal targeting, as evi-
denced by the enhancement of the brainstem rather than distal
targeting.
Length of the irradiated TGN is another contentious topic in
relation to pain relief and complications. A randomized clinical
trial has proved that no treatment difference, other than more
severe complications including facial paresthesias, was obtained
when the length of TGN irradiated was increased by the use of
two adjacent 4-mm isocenters instead of a single 4-mm isocen-
ter.52 In addition, the Cleveland Clinic group explored the effec-
tiveness and safety of the combined use of 4- and 8-mm
collimators, which results in a larger target volume.53 No evi-
dence indicated that patients with TN treated with the combined
concentric collimators at a maximum of 75 Gy fared better than
those treated with a single 4-mm collimator.
Dose selection for TN has also been studied extensively. Most
centers utilize a maximum dose of 70 to 85 Gy.18,22,27,32,54-58 Several
investigators have demonstrated a significant improvement in
the rate of pain cessation and a reduction of recurrence rate when
an elevated maximum dose is employed. Brisman and Mooij59
reported that treatments in which the brainstem received 20%
or more of the maximum radiation dose to a volume of 20 mm3
had better pain control than those in which smaller regions were
targeted with lower doses. In cases in which higher doses are
required, the isocenter is usually placed away from the brainstem
to avoid injury. Because doses higher than 90 Gy have been
associated with an increased risk of postradiosurgery complica-
tions,60 most radiosurgical teams tend to limit the maximum dose
to 90 Gy or less.48,57,61
Also important during planning is to ensure that the steepest
gradient index of the dose distribution (between the 50% and
1414 SECTION 6  Pain

Figure 173-1. Accurate magnetic

resonance imaging (MRI) for radiosurgical
treatment. A, T1-weighted axial (top) and
corresponding sagittal and coronal (bottom)
unenhanced MR images demonstrating a
Gamma Knife radiosurgical plan for trigeminal
neuralgia. B, Constructive interference in
A B
steady state (CISS) sequence, axial (top) and
corresponding coronal and sagittal (bottom)
images. The nerve is targeted with a single
unblocked isocenter. Yellow circles indicate
the 50% isodose line, which is receiving 40
Gy); green circles represent the 90% isodose
line. C, Proximal targeting: Axial (top) and
corresponding sagittal and coronal (bottom)
1-mm T1-weighted MR images obtained
during the procedure, illustrating the location
of 50% isodose lines (yellow circles) relative to
the trigeminal nerve root entry zone into the
pons. The green circles stand for the 90%
isodose line. D, Distal targeting: Axial (top)
and corresponding coronal and saggital
(bottom) 1-mm T1-weighted MR images
obtained during the procedure, illustrating the
location of a 20% isodose line (green circles)
touching the emergence of the pons. The
yellow circles represent the 50% isodose line,
C D
which was prescribed 40 Gy.

A B
Figure 173-2. Blocking or beam shaping to reduce brainstem radiation dose. A, T1-weighted axial (top)
and corresponding sagittal and coronal (bottom) magnetic resonance images. B, Constructive interference in
steady state (CISS) axial (top) and corresponding coronal and sagittal (bottom) images. The 50% isodose line
is depicted in yellow and the 20% isodose line in green. The isocenter has been blocked so as to alter the
normal spherical shape to a more elliptical one. This change helps decrease the brainstem dose in patients
who are undergoing re-treatment or in in whom the cisternal segment of the trigeminal nerve is short.
 CHAPTER 173  Stereotactic Radiosurgery for Trigeminal Neuralgia 1415
70% isodose lines) coincides with the periphery of tissue being
treated. This goal may require several overlapping fields of radia-
tion, each using a different collimator size and a separate stereo-
tactic focal point. Changing the relative time of radiation at each
target may also change the isodose distribution. Finally, the radia-
tion field may be altered by blocking some of the radiation
sources, also known as “plugging” or shielding. However, con-
flicting reports exist regarding the benefit of blocking or shield-
ing because some clinicians contend that blocking the nerve root
might not be beneficial.60,62
CLINICAL FOLLOW-UP
Generally patients should be followed up at 3- to 6-month inter-
vals, and new MRI studies should be obtained 6 to 9 months
postoperatively. In patients who have new-onset neurological
symptoms, an MRI can be performed earlier. In addition to
imaging studies, follow-up examination should include a full neu-
rological assessment, examination of cranial nerve function, and
full ophthalmologic examination as needed.
The TGN function in particular may have significant correla-
tion to patient prognosis. Pollock and associates19 reported a
strong correlation between the development of new facial sensory
loss and the achievement and maintenance of pain relief after
radiosurgery, with patients who have new trigeminal deficits
being 4.5 times more likely to have excellent pain relief than
patients who have normal postradiosurgery TGN function.
Experimental models of radiosurgical treatment have confirmed
that the etiology for this difference may lie in a nonselective
destruction of myelinated and unmyelinated sensory fibers,
including afferent nociceptive fibers.63 This finding remains con-
troversial because it is not confirmed in the newest large series—
that is, the large series found no correlation between the long-term
pain control and TGN dysfunction.21,24,64
Some have suggested that enhancement of the TGN on post-
radiosurgery MRI may correlate with the radiation dose used and
thus may be related to the accuracy of targeting.65 In clinical
practice, however, TGN enhancement has not routinely corre-
lated with better clinical outcomes.51,66
PAIN CONTROL AFTER RADIOSURGERY FOR
TRIGEMINAL NEURALGIA: A REVIEW OF
THE LITERATURE
Although MVD remains the neurosurgical treatment of choice
for TN, GKRS offers a reasonable alternative in patients who are
either unwilling to undergo surgery or who are not ideal surgical
candidates. A summary of major series on stereotactic radiosur-
gery for TN is presented in Table 173-1.21,23,24,54,55,60,61,64,67-74 The
majority of studies have utilized the BNI intensity grading
system75,76 or the Marseille pain grading system with modifica-
tions.21 To date, however, no standardized grading system is avail-
able, rendering comparison of various TN studies difficult or
impossible. Owing to variations in data presentation, not all data
are available for every series, although every effort has been made
to present a homogenous data set in Table 173-1 to allow direct
comparison of a wide variety of studies. Prior to 2006, very few
papers used Kaplan-Meier methodology to indicate the durability
of pain relief in response to stereotactic radiosurgery77; the
majority of papers documented the percentage of pain response
at the last follow-up. Currently the wide use of the Kaplan-Meier
model allows us to appreciate the maintenance of failure-free
treatment status given that facial pain is a time-to-event variable
similar to cancer survival.78
The effects of radiation depend on both acute and delayed
changes in the target tissue, so there is a latency interval for the
expected response, as in all radiosurgical procedures.79 In all of
the series presented in Table 173-1, pain relief was typically
achieved within the first several weeks after the procedure. Régis
and associates21 achieved a high rate of initial pain control, with 173
94% of their patients having either excellent or good response
within 10 days. Pollock and associates19 reported that 75% of
their patients experienced complete pain relief at some point after
radiosurgery. Dhople and colleagues24 reviewed 112 patients with
typical TN for a median follow-up of 5.6 years. The median time
to response to treatment was 2 weeks with a range of 0 to
12 weeks. Among those patients with a response to treatment,
40% experienced pain relief within 1 week. Fountas and cowork-
ers69 reported that a majority of patients with no previous surgery
responded within 4 weeks after treatment. Pollock and associ-
ates19 found a comparable mean latency period of about 3 weeks.
In other large series, however, the latency has been noted to be
as long as 1 year following GKRS.20,64
According to the University of Pittsburgh group,64 the major-
ity (89%) of patients with TN had response to GKRS within 6
months of treatment, with a median of 1 month, achieving pain
relief grades BNI I to IIIb. Initial complete pain relief (BNI I)
was achieved in 40% of patients, with a range between 1 day and
1 year. The 11% of patients who did not experience pain control
within a year also had no clinical improvement following radio-
surgery, indicating that 1 year may be the optimal time to judge
the true effectiveness of radiosurgery in patients with TN.
From 1996 to 2003, 151 patients with TN were treated with
the GKRS at the University of Virginia and had evaluable
follow-up.55 Radiosurgery was performed once in 136 patients,
twice in 14 patients, and three times in 1 patient. One hundred
twenty-two patients presented with typical TN, 3 with atypical
TN, 4 with MS-associated TN, and 7 with TN secondary to a
cavernous sinus tumor. In each case, the chosen radiosurgical
target was located 2 to 4 mm anterior to the surface of the pons.
The maximum radiation doses ranged from 50 to 90 Gy. The
mean time to relief of pain was 24 days (range, 1-180 days). Forty-
seven percent, 45%, and 34% of patients were pain free without
medication at the 1-, 2-, and 3-year follow-up, respectively.
Ninety percent, 77%, and 70% of patients experienced some
improvement in pain at 1-, 2-, and 3-year follow-up, respectively.
Twelve patients (9%) suffered the onset of new facial numbness
after treatment.
Currently the most commonly used classification systems, the
modified Marseille scale and BNI pain intensity score, remain
less than ideal with respect to medication usage. Therefore,
quality of life (QOL) is a very important issue in assessing the
clinical results. In practice, many patients are hesitant to discon-
tinue or taper off the pain medications in fear of possible pain
recurrence, further suggesting that the BNI pain intensity score
may underestimate the actual rate at which BNI I pain status is
achieved.24,32,60
The TN pain can be debilitating to those affected, and pain
control itself may not be the only QOL measure that is related
to patient outcomes. Petit and colleagues56 investigated QOL
associated with GKRS for TN. Even with partial pain relief,
patients reported a median of 80% improvement in QOL, with
65% believing that their GKRS was successful. Patients in whom
pain relief was maintained at the time of analysis reported a
median 100% improvement in their QOL, with a 100% success
rate. Even the patients with temporary treatment responses (pain
recurrence after a median of 8.5 months) described a median 80%
improvement in QOL with an associated 60% rate of treatment
success. These findings suggest that temporary pain relief coupled
with a low incidence of treatment morbidity is a worthwhile
treatment outcome for most patients. Pan and associates80
explored the changes in QOL after GKRS in 52 patients with
TN whose median age was 71 years and who had remarkably
various comorbidities, including cardiovascular disease, liver cir-
rhosis, and coagulopathy. Pain relief significantly contributed to
the improvement in QOL during the follow-up of more than 4
 CHAPTER 173  Stereotactic Radiosurgery for Trigeminal Neuralgia 1417

years. The improved aspects of QOL included physical function,
role limitation due to a physical problem, bodily pain, general
health, vitality, social function, role limitation due to an emo-
tional problem, and mental health.80
RECURRENCE AND RE-TREATMENT
Reported rates of recurrence following radiosurgery for TN have
ranged from 5% to 43%, and recurrence is likely related to
incomplete radiation effects on the targeted tissues.a Given the
low risk profile of GKRS, some patients may benefit from a
second GKRS procedure, in particular in those for whom mul-
tiple surgical interventions failed prior to the initial GKRS.
Pollock and associates,28 Maesawa and associates,20 Herman and
associates,88 and Park and associates89 recommend re-treatment
with radiosurgery in patients if they experienced a significant
reduction in pain after initial GKRS. Eight of 10 patients in the
initial study by Pollock and associates90 were pain-free after initial
radiosurgery, and all of these patients had complete pain relief
with a second GKRS procedure. These findings suggest that the
response to initial GKRS may be used by physicians to predict
the response to a second procedure. Other investigators have
observed that patients who have longer remission after radiosur-
gery tend to have better results from re-treatment.88 The Uni-
versity of Pittsburgh group found that approximately 43% of
patients had pain recurrence at a median of 4 years after the initial
GKRS.64 Subsequently, the investigators reviewed data from 119
patients who underwent a second GKRS procedure with a median
follow-up of 4 years. As with the initial GKRS, 87% of patients
achieved initial pain relief (BNI I-IIIb) and actuarial pain relief
rate was 44% at 5 years. Facial sensory dysfunction developed in
21% of patients within 18 months of the second GKRS proce-
dure, much higher than the 10.5% rate in patients after the initial
procedure.64 Nevertheless, a second GKRS procedure for recur-
rent TN is regarded as safe and effective.89
The precise location to target during re-treatment is contro-
versial. Generally speaking, re-treatment involves the delivery of
radiation at91 or anterior to (Fig. 173-3)88,89,92,93 the previously
treated site. Hasegawa and colleagues94 positioned a single 4-mm
a
References 2, 3, 19, 20, 26, 47, 49, 57, 59, 66, 81-87.
collimator anterior to the portion of the TGN originally targeted
so that there was a 50% overlap in the two radiosurgical volumes 173
(compared with 100% overlap in most other studies). The ratio-
nale for this strategy is to reduce the radiation dose to the brain-
stem while increasing the dose to the length of trigeminal nerve
root. Kimball and associates93 have reported using a single 4-mm
collimator isocenter targeted 4 to 5 mm anterior to the initial
50% isocenter and a lower maximum dose of 70 Gy. They used
a modified Marseille pain scale in which favorable pain control
was set as more than 50% improvement with or without pain
medications; TN pain was controlled in 70% of their patients at
1 year, in 50% at 3 years, and in 50% at 5 years. In addition, there
was a correlation between newly developed facial numbness and
better pain relief. However, rates of other complications after the
second GKRS increased, including dry eye in 10.9% of patients,
taste change in 8.7%, jaw weakness in 2.2%, and bothersome
facial numbness in 8.7%.
In an attempt to balance the benefits and risks, other clinicians
consider total radiation dose important in terms of efficacy and
complications. Generally, the maximum dose of the second
GKRS is identical to or slightly lower than the first dose.88,89,91-93
Some neurosurgeons recommend that the cumulative dose be
kept within a range of 120 to 170 Gy.89 Dvorak and coworkers95
determined, from their data and analysis of data from seven other
studies, that a cumulative radiation dose lower than 140 Gy was
appropriate. Zhang and colleagues46 used a lower dose of 75 Gy
in the initial GKRS and 40 Gy in the second procedure. They
also treated at the 40% isodose line tangential to the brainstem
surface. Both the lower isodose and the lower total dose would
seem to confer a lower chance of pain control from the radiosur-
gery. In a total of 40 patients with a median follow-up of 28
months, 11 patients had complete pain relief, 7 had nearly com-
plete relief (≥ 90%), 8 had partial relief (≥ 50%), and 14 had
minimal or no relief.46 Ultimately, a prospective dose planning
study will be required to determine which technique is preferred
for re-treatment.
In our experience, the side effects of repeat GKRS are more
common but occur at an acceptable rate when compared with
that after the initial procedure, with new facial numbness being
the most common complication reported. New-onset or wors-
ened facial numbness, including mild to moderate trigeminal

A B
Figure 173-3. Repeat Gamma Knife radiosurgery for recurrent trigeminal neuralgia. A, T1-weighted
axial (top) and corresponding sagittal and coronal (bottom) magnetic resonance images. B, Constructive
interference in steady state (CISS) axial (top) and corresponding coronal and sagittal (bottom) images. The
50% isodose line, shown in in yellow, was prescribed anterior to the previously delivered 50% isodose line,
shown in blue.
1418 SECTION 6  Pain
dysfunction, can be found in 11% to 70% of patients after second
treatments.2,20,21,92 The overall effectiveness of repeat radiosur-
gery is similar to that of the initial procedure, with rates of
complete or partial pain relief ranging from 72% to 85%,28,49,89,91,94
although fewer patients undergoing re-treatment have enough
pain relief to completely discontinue their pain medications.
COMPLICATIONS FROM RADIOSURGERY
Although stereotactic radiosurgery is not associated with some of
the immediate risks of open surgical procedures, it nonetheless
has risks. Potential complications after radiosurgery include
radiation-induced parenchymal changes (only some of which are
reversible), radiation-induced neoplasia, and vascular injury.96,97 A
noteworthy complication in the treatment of trigeminal pain is
facial numbness or dysesthesias, with anesthesia dolorosa being
the most dreaded one. The incidence of new-onset trigeminal
dysfunction varies from 6% to 66%.22-24,45,55-57,64 In general, the
placement of the isocenter proximal to the brainstem or increased
radiation dose is correlated with a higher risk of newly developed
facial numbness. Pollock and colleagues57 reported an association
between higher radiation doses and the risk of TGN dysfunction.
In that study, 54% of patients treated with 90 Gy experienced
facial numbness, whereas only 15% of patients treated with 70
Gy experienced a similar problem.57 In our series, new facial
numbness developed in 12 out of 136 patients (9%) following
GKRS.55 Only 1 patient had received a dose of 90 Gy, and no
facial numbness was noted in this case. Our later study comparing
the proximal and the distal targeting locations indicated that with
the same 80 Gy maximum dose, targeting to the proximal loca-
tion achieved longer facial pain relief than targeting to the distal
location (56% vs. 25%).50 Fortunately, cases of anesthesia dolo-
rosa and absence of the corneal reflex following radiosurgery are
quite rare. The risk of anesthesia dolorosa secondary to GKRS
is claimed to be less than 1%, and only a few cases have been
reported.23,61,64
COMPARISON OF RADIOSURGERY AND OPEN
SURGERY FOR TRIGEMINAL NEURALGIA
MVD is the only nonablative treatment modality for TN that
addresses the underlying pathophysiology of the disease, making
it the well-established gold standard. Barker and colleagues6
reported that 70% of patients who underwent MVD had com-
plete pain relief 10-years postoperatively. Likewise, Olson and
associates98 reported in a retrospective study that 74% of patients
were pain free at 10 years after treatment in a total of 156 patients
with TN. Pain recurred in 18% of patients over a 25-year
follow-up. Although this type of follow-up and sustained pain
relief are lacking in the radiosurgical literature, GKRS provides
similar favorable pain response and exceedingly low rates of com-
plications except facial numbness.64 In patients without previous
surgery, Pollock and coworkers99 observed a 67% rate of com-
plete pain relief at 1 and 3 years, whereas Maesawa and col-
leagues20 observed a 70% rate of complete pain relief at 9 months
and 5 years. Given these results, radiosurgery as a primary treat-
ment appears to provide a rate of pain control comparable to that
of open surgery.
The major disadvantages of radiosurgery are the higher rate
of recurrence and the delay in onset of pain relief in comparison
with MVD. As described in the previous section, only 27% of
patients in the Pollock series were pain free without medication
at the time of latest follow-up.99 Therefore, it is generally accepted
that, particularly in patients who are young and have less signifi-
cant comorbidities, MVD should (at least for now) remain the
first-line treatment for those who can tolerate the operation
because of the durability of pain relief.50,64 In patients who cannot
tolerate a surgical procedure, those in whom a vascular etiology
cannot be identified as the cause of symptoms, or those unwilling
to undergo open surgery, radiosurgery is an appropriate alterna-
tive. The risks of repeat MVD are also known to be significantly
higher than after the first procedure,6 and thus patients who have
recurrence following failed MVD may also be considered candi-
dates for radiosurgery albeit with a lower chance of successful
remission. Nevertheless, patients treated with GKRS are gener-
ally one decade older than those who underwent MVD in prior
publications, making the comparison less equivalent.98,100
CONCLUSION
Although MVD remains the treatment of choice for patients with
TN, stereotactic radiosurgery is an effective treatment for those
unwilling or unable to undergo an MVD. Stereotactic radiosur-
gery is also a reasonable treatment option for patients with recur-
rent TN after previous invasive surgical intervention. More than
50% of patients with typical facial pain have relief following
radiosurgery, although a lower proportion of patients with atypi-
cal pain do so. Optimal target selection and radiation dose remain
the subjects of ongoing debate within the neurosurgical com-
munity. Long-term follow-up for recurrence as well as for
radiation-induced complications is required in all patients.
SUGGESTED READINGS
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Brisman R, Mooij R. Gamma knife radiosurgery for trigeminal neuralgia:
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Eller JL, Raslan AM, Burchiel KJ. Trigeminal neuralgia: definition and
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tory trigeminal neuralgia. Neurosurgery. 2002;50:494-500.
Kondziolka D, Lacomis D, Niranjan A, et al. Histological effects of tri-
geminal nerve radiosurgery in a primate model: implications for tri-
geminal neuralgia radiosurgery. Neurosurgery. 2000;46:971-976.
Kondziolka D, Lunsford LD, Flickinger JC, et al. Stereotactic radiosur-
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gamma unit. J Neurosurg. 1996;84:940-945.
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reotactic radiosurgery for idiopathic trigeminal neuralgia. J Neurosurg.
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597-605.
Merrison AF, Fuller G. Treatment options for trigeminal neuralgia. BMJ.
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Nicol B, Regine WF, Courtney C, et al. Gamma knife radiosurgery
using 90 Gy for trigeminal neuralgia. J Neurosurg. 2000;93(suppl 3):
152-154.
Petit JH, Herman JM, Nagda S, et al. Radiosurgical treatment of trigemi-
nal neuralgia: evaluating quality of life and treatment outcomes. Int J
Radiat Oncol Biol Phys. 2003;56:1147-1153.
Pollock BE, Foote RL, Stafford SL, et al. Results of repeated Gamma
Knife radiosurgery for medically unresponsive trigeminal neuralgia.
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2006;104:913-924.
 CHAPTER 173  Stereotactic Radiosurgery for Trigeminal Neuralgia 1419
Richards GM, Bradley KA, Tomé WA, et al. Linear accelerator radiosur-
gery for trigeminal neuralgia. Neurosurgery. 2005;57:1193-1200.
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2002;18:42-47.
78. Régis J, Tuleasca C. Fifteen years of Gamma Knife surgery for
trigeminal neuralgia in the Journal of Neurosurgery: history of a
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2-7.
79. Jagannathan J, Sherman JH, Mehta GU, et al. Radiobiology of brain
metastasis: applications in stereotactic radiosurgery. Neurosurg Focus.
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80. Pan HC, Sheehan J, Huang CF, et al. Quality-of-life outcomes after
Gamma Knife surgery for trigeminal neuralgia. J Neurosurg. 2010;
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81. Flannery TW, Suntharalingam M, Kwok Y, et al. Gamma Knife
stereotactic radiosurgery for synchronous versus metachronous
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82. Levivier M, Lorenzoni J, Massager N, et al. Use of the Leksell
Gamma Knife C with automatic positioning system for the treat-
ment of meningioma and vestibular schwannoma. Neurosurg Focus.
2003;14:e8.
83. Levivier M, Massager N, Wikler D, et al. Use of stereotactic PET
images in dosimetry planning of radiosurgery for brain tumors:
clinical experience and proposed classification. J Nucl Med. 2004;45:
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84. Levivier M, Wikler D Jr, Massager N, et al. The integration of
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gery: a review. J Neurosurg. 2002;97(suppl):542-550.
85. Lorenzoni J, Devriendt D, Massager N, et al. Radiosurgery for
treatment of brain metastases: estimation of patient eligibility using
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86. Lorenzoni JG, Massager N, David P, et al. Neurovascular compres-
sion anatomy and pain outcome in patients with classic trigeminal
neuralgia treated by radiosurgery. Neurosurgery. 2008;62:368-375,
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87. Massager N, Lorenzoni J, Devriendt D, et al. Radiosurgery for
trigeminal neuralgia. Prog Neurol Surg. 2007;20:235-243.
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89. Park KJ, Kondziolka D, Berkowitz O, et al. Repeat Gamma Knife
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90. Pollock BE, Foote RL, Link MJ, et al. Repeat radiosurgery for
idiopathic trigeminal neuralgia. Int J Radiat Oncol Biol Phys. 2005;
61:192-195.
91. Gellner V, Kurschel S, Kreil W, et al. Recurrent trigeminal neural-
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 CHAPTER 173  Stereotactic Radiosurgery for Trigeminal Neuralgia 1419.e3

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174 Trigeminal
Microvascular Decompression for
Neuralgia
Jonathan P. Miller and Kim J. Burchiel
Trigeminal neuralgia (TN) is a syndrome of neuropathic pain
characterized by severe paroxysmal lancinating pain in one or
more distributions of the trigeminal nerve. Vascular compression
of the trigeminal nerve at the point of entrance into the brainstem
has been associated with this syndrome, and surgical separation
of the vessel from the nerve is helpful for many patients. This is
usually done by a retrosigmoid craniotomy or craniectomy using
intraoperative microscopic or endoscopic assistance.
HISTORY
TN has been known since ancient times. Two thousand years
ago, Aretaeus of Cappadocia referred to headache with “spasm
and distortion of countenance,” and Persian scholar Avicenna
described a similar syndrome of facial pain in the 10th century.1
In the 17th century, Fehr described the syndrome in a eulogy.2
John Locke described facial pain of the Countess of Northum-
berland, wife of the English Ambassador to France, as a “fit of
such violent and exquisite torment that it forced her to … cries
and shrieks … which extended itself all over the right side of her
face and mouth.”1 In 1756, Nicolas Andre coined the term tic
douloureux, describing it as “a cruel and obscure illness, which
causes … in the face some violent motions, some hideous gri-
maces which are an insurmountable obstacle to the reception of
food, [and] which put off sleep.”3 The first comprehensive clinical
description occurred in 1773 when John Fothergill wrote to the
medical society of London about 14 patients with TN, and his
descriptions of triggerable lancinating pain are still considered
accurate.4
Early surgical treatments for TN involved intentional lesion-
ing of the trigeminal nerve. In 1934, Walter Dandy described the
retrosigmoid approach to the trigeminal nerve and noted fre-
quent vascular contact in patients with TN. He wrote, “In many
instances the nerve is grooved or bent in an angle by the artery.
This I believe is the cause of tic douloureux.”5 Despite his insight,
Dandy did not attempt to decompress the nerve, believing the
pathologic process to be irreversible. Microvascular decompres-
sion (MVD) was first performed by W. James Gardner in 1959,
who described mobilizing a vessel from the trigeminal nerve and
placing a piece of absorbable gelatin sponge (Gelfoam) between
them without any intentional damage to the nerve itself.6 The
procedure was subsequently refined and popularized by Peter
Jannetta, who, with the aid of the operating microscope, per-
formed thousands of MVD operations and demonstrated that
long-term relief of pain is possible in most patients with appro-
priate selection.7-9 MVD has been the most common procedure
for TN every year since 1992 and currently accounts for more
than 90% of surgical procedures performed for neuropathic
facial pain.10
PATHOPHYSIOLOGY
The etiology of TN is believed to be related to abnormal conduc-
tion within the trigeminal nerve possibly due to changes in
myelin induced by pulsatile mechanical trauma from an adjacent
vessel. At the point just before it enters the brainstem, there is
a short segment where nerve axons are still ensheathed in
central myelin (produced by oligodendrocytes), but after a few
1420
millimeters, there is a transition to peripheral myelin (produced
by Schwann cells). The region of this transition is called the
Obersteiner-Redlich zone. It is thought that the area of the nerve
containing the central form of myelin is especially susceptible to
pathologic changes from vascular contact that result in demyelin-
ation and altered conduction. Pathologic studies from patients
with TN have demonstrated severe damage to myelin as well as
axon loss within the nerve adjacent to the site of compression.11
The resulting conduction abnormality may lead to nerve hyper-
activity owing to ectopic impulse discharge, spontaneous and
triggered after discharge, and cross-excitation among neighbor-
ing afferent fibers (ephaptic transmission).11,12
Separation of the nerve from the offending vessel appears to
immediately reverse many of the physiologic changes. In Leandri
and colleagues’13 study of 10 patients undergoing MVD who
underwent nerve root and scalp electrode recordings, 7 showed
signs of immediate improvement in neurophysiologic parameters
after decompression. Other investigators have reported improve-
ment in sensory thresholds for touch, pinprick, and temperature
sensations after MVD14 as well as resolution of asymmetric jaw
motion.15,16 These findings suggest that the changes associated
with neurovascular compression are likely to be reversible if the
nerve is decompressed, at least in the early stages.
Radiographic and anatomic studies have demonstrated that
vascular contact with the trigeminal nerve is common even in
asymptomatic individuals but tends to be more severe and more
proximal on the nerve ipsilateral to TN symptoms.17,18 Patients
with TN are more likely to have contralateral arterial compres-
sion than asymptomatic people even though bilateral TN is
distinctly rare.17,19 Symptomatic and asymptomatic arterial com-
pression of the trigeminal nerve increases with age because of
elongation of cisternal arteries, explaining why it is primarily a
disease of older adults.17 However, trigeminal neuralgia can occur
in the absence of neurovascular compression; in one study of 184
patients with TN, 28.8% had no evidence of vascular compres-
sion.20 Because most individuals with neurovascular compression
do not have TN and many with TN do not have neurovascular
compression, it is probable that factors other than neurovascular
conflict are responsible for development of TN.
ALTERNATIVE TREATMENTS
TN symptoms often improve with medications that exert a sta-
bilizing effect on neural conduction, such as antiepileptics. Medi-
cations that have been successfully used include carbamazepine,
phenytoin, valproate, gabapentin, pregabalin, baclofen, and clon-
azepam. Most patients obtain good pain control initially,21,22 but
the effect tends to diminish over time, and after 10 years about
half no longer have a response.23 Because the clinical and patho-
logic changes associated with TN may be progressive over time,
initial failure of pharmacologic therapy may represent an indica-
tion to proceed with more aggressive treatment.24 Nevertheless,
medical therapy is recommended as a first-line treatment for
patients with TN because some patients require no further
treatment.
Surgical treatments for TN other than MVD generally involve
intentional production of a lesion within the trigeminal nerve.
Many commonly performed procedures consist of percutaneous
 CHAPTER 174  Microvascular Decompression for Trigeminal Neuralgia 1421
access to the nerve through a needle advanced through the face
followed by direct creation of a lesion using a radiofrequency
generator, glycerol injection, or balloon compression. Stereotac-
tic radiosurgery targeting the nerve root entry zone is also effec-
tive, although pain relief is delayed by months, and complete
elimination of pain may occur less frequently than with other
methods. In general, the success of each of these lesioning tech-
niques requires some degree of facial numbness, with greater
numbness associated with a higher rate of pain control but also
greater likelihood of complications such as facial dysesthesia and
anesthesia dolorosa. Also, all these procedures are associated with
a high recurrence rate after a few years as facial sensation returns,
suggesting that they work primarily by blocking triggering
impulses rather than by treating the cause of the pain itself.
MVD differs from the other treatments in that it treats the
primary cause of TN so that long-term pain relief is possible.
Also, because there is no intentional damage to the nerve, facial
dysesthesia and numbness are rare with MVD. Although it is the
most invasive and expensive treatment, MVD is associated with
the lowest rate of pain recurrence and the highest rate of patient
satisfaction among all surgical treatments for TN.25 MVD can
also be safely performed after a lesioning procedure and appears
to be no less effective so long as there is no evidence of trigeminal
neuropathy.26
PATIENT SELECTION AND CLASSIFICATION
OF FACIAL PAIN
MVD is ideal for young healthy patients with TN because no
other treatment offers a significant likelihood of long-term pain
relief.27 However, advanced age is not by itself a contraindication
because there is no difference in complication rate or outcome
in elderly patients.28-30 The operation is in fact technically easier
in older patients, in whom cerebellar atrophy leads to less need
for retraction and less risk for cerebellar swelling. If life expec-
tancy is very short or general anesthesia cannot be tolerated, a
less invasive destructive procedure may be more appropriate.31,32
A careful history is essential during preoperative evaluation.
Patients generally report intense stabbing or electric shock–like
sensation, although there may be an overlying constant pain that
may be more severe than the stabbing pain. Pain in any distribu-
tion within the trigeminal nerve innervation territory may be
observed. Cranial nerve (CN) V2 and V3 branches of the trigemi-
nal nerve are more common sources of pain,7 especially radiating
out from near the mouth. V1 symptoms are sometimes associated
with decreased corneal sensation. The pain is often worse during
the day and may be positional, with relief with a supine position,
with the affected side up, or during sleep. Trigger points are
present in most patients and are activated by light cutaneous
stimuli such as wind, eating, talking, and shaving. Often, the trig-
gers lead to guarding of the face and refusal to be touched, wash,
apply makeup, shave, or brush the teeth because of fear of an
attack. Pain-free intervals lasting weeks to months are common
at first but become rare as the syndrome progresses. Initial onset
of pain is frequently quite memorable. Many patients undergo
dental procedures without relief before a diagnosis is made. If the
patient is given antiepileptic medication, pain usually improves
dramatically. Physical findings are usually normal, although about
one third of patients have some degree of sensory loss in the
affected area.
In the evaluation of a patient for surgery, it is helpful to classify
facial pain according to the classification scheme reported by
Burchiel.33 Patients with TN type 1 have predominantly shock-
like pain, whereas patients with TN type 2 report that at least 50%
is constant pain, although there still may be a component of
lancinating pain. Pain relief after MVD is more strongly corre-
lated with the lancinating pain component than with any other
symptom, so although most patients with either type have
long-term pain control, patients with TN type 1 are more likely
to do well than those with TN type 2.34,35 Facial pain diagnoses 174
other than TN are unlikely to improve after MVD. TN with a
history of multiple sclerosis (MS) is called symptomatic trigeminal
neuralgia (STN). MS is present in 1% to 3% patients with TN,
and 2% to 4% of patients with MS have TN, probably because
of intrinsic demyelination within the nerve or increased sensitiv-
ity to vascular trauma.36,37 Although patients with MS sometimes
improve after MVD, the recurrence rate is higher, and long-term
elimination of pain is rare,38-40 so destructive procedures may be
more appropriate for these patients.41 Sensory loss with burning
pain is a sign of trigeminal neuropathic pain (TNP); if it occurs
after a previous destructive procedure, this is called trigeminal
deafferentation pain (TDP). Allodynia and dysesthesia with a
history of herpes zoster suggest postherpetic neuralgia (PHN).
MVD is not a good option for patients with any of these disor-
ders. Atypical facial pain (AFP), which refers to pain of psychologi-
cal onset, requires neuropsychological testing for the diagnosis
and is unlikely to improve after MVD.
Pain outside the trigeminal nerve distribution is not TN,
although other vascular compression syndromes may be present
with throat pain (glossopharyngeal neuralgia) or pain deep in the
ear (nervus intermedius neuralgia). Other causes of facial pain are
dental disease, orbital disease, sinusitis, cluster headache, tem-
poromandibular joint disease, temporal arteritis, and posttrau-
matic neuralgias. None of these has the clinical characteristics of
TN, nor does any respond to MVD of the trigeminal nerve.
PREOPERATIVE IMAGING
All patients should undergo magnetic resonance imaging (MRI)
before MVD to verify that there is no intracranial mass lesion
that may be responsible for the pain, such as a tumor, cyst, aneu-
rysm, or arteriovenous malformation. MRI also can identify evi-
dence of demyelinating disease or inflammatory changes and may
reveal anatomic characteristics that would make MVD techni-
cally problematic, such as an ectopic basilar artery or bony abnor-
malities. Atrophy of the affected trigeminal nerve is also frequently
seen in patients with trigeminal neuralgia and is associated with
good prognosis after MVD.42 High-resolution MRI using steady-
state precession images can be used to identify neurovascular
compression preoperatively with a high degree of accuracy, and
fusion of these images with those from magnetic resonance angi-
ography followed by three-dimensional reconstruction can be
used to simulate the intraoperative view for surgical planning
(Fig. 174-1).43
OPERATIVE TECHNIQUE
Standard neuroanesthetic techniques are used, with chemical
paralysis and controlled ventilation to prevent motion in the field.
Use of diuresis or spinal drainage for brain relaxation is generally
not necessary because release of cerebrospinal fluid (CSF) from
the trigeminal cistern relaxes the cerebellum enough to allow
adequate retraction. Intraoperative monitoring is helpful to
prevent injury to the brainstem and cranial nerves. Brainstem
auditory evoked potentials are very sensitive to stretch-induced
injury to the eighth cranial nerve, and a delay in comparison with
baseline readings of more than 20% or a shift in interpeak latency
of more than 1.5 to 2 milliseconds requires loosening of cerebel-
lar retraction until the signals normalize. Facial nerve monitoring
may also be used but is less helpful.
A cranial fixation device such as the three-pin Mayfield head
holder is applied before positioning. There are several options
for patient positioning for MVD. The simplest option is to place
the patient in a flat supine position with the head rotated and
flexed to the side opposite the affected side (Video 174-1). Ideally,
no shoulder roll should be used so that the ipsilateral shoulder
1422 SECTION 6  Pain

A B

C D
Figure 174-1. Preoperative magnetic resonance imaging to identify arterial compression of the
trigeminal nerve before microvascular decompression. Steady-state precession imaging demonstrates
contact of a vessel with the nerve (A), and magnetic resonance angiography reveals that the vessel is an
artery (B). Fusion and three-dimensional reconstruction of these sequences produce an image (C) that
corresponds well with intraoperative findings (D). (Modified from Miller J, Acar F, Hamilton B, et al.
Preoperative visualization of neurovascular anatomy in trigeminal neuralgia. J Neurosurg. 2008;108:477-482.)

does not obscure the operative approach. This position requires
a flexible neck and may not work for obese or short-necked
patients. Another option is the lateral decubitus or three-quarter
prone position with the shoulder taped caudally and the neck
flexed, ensuring the chin is at least two fingerbreadths from the
sternum. Regardless of the position chosen, it is generally best to
place the vertex parallel to the floor so that the seventh and eighth
cranial nerves are inferior in relation to the trigeminal nerve,
simplifying the approach.44 All pressure points are padded, and
an axillary roll is used if necessary. The sitting position can also
be used, although it is associated with complications such as air
embolism and subdural hematoma.
Preoperative MRI is used to evaluate the anatomy of the
sinuses, cerebellum, and any anomalous veins. A small posterior
fossa or Chiari malformation may necessitate alteration of surgi-
cal technique. The position of the transverse and sigmoid sinuses
may be estimated from bony landmarks. The transverse sinus
generally runs along a line connecting the inion to the external
auditory meatus, parallel and posterior to the zygomatic arch.
The sigmoid sinus runs along the digastric groove posterior to
the mastoid eminence. Alternatively, frameless stereotaxy may be
used to accurately define the position of the sinuses. Hair is
clipped from the surgical site, and the scalp is sterilized and then
infiltrated with local anesthetic with epinephrine to reduce bleed-
ing. The linear incision runs longitudinally two fingerbreadths
behind the ear (5 mm behind the hairline) and extends 3 to
5 cm, with one fourth of the incision above the iniomeatal line.
Monopolar electrocautery is used to dissect and clear muscle and
soft tissue until the bone of the mastoid eminence and digastric
groove is seen. The occipital artery is often encountered in the
muscular tissue and sacrificed. A large mastoid emissary vein is
usually seen at this point, which represents an important land-
mark because it overlies the junction of the transverse and
sigmoid sinuses. The bony exposure is extended to the curving
portion of the suboccipital bone at the floor of the posterior fossa.
The wound is held open with a self-retaining retractor or with
sutures. A dural graft is generally not necessary, but if desired, the
periosteum along the superior nuchal line may be harvested, or
fascia may be collected if a C-shaped incision was used.
Bone removal is performed with a high-speed drill or perfora-
tor, starting at the mastoid emissary vein, which exits the bone
just inferior and posterior to the transverse sinus–sigmoid sinus
junction. If there is any doubt about the location of the sinuses,
it is always better to start more inferior and posterior to avoid
unintentional damage to the sinuses. A craniectomy is safe and
well tolerated if the defect is filled with artificial bone material at
the end of the procedure. Alternatively, some surgeons advocate
elevation of a craniotomy flap inferior and posterior to the initial
bur hole that can be replaced after the dura is closed. With a drill
and a periosteal elevator to carefully elevate the dura, the crani-
ectomy is expanded until the junction of the transverse and
sigmoid sinuses can be seen. The sigmoid sinus is especially sus-
ceptible to injury because of its thin outer wall and curved bony
groove. In older patients, the lateral wall of the sinus is adherent
 CHAPTER 174  Microvascular Decompression for Trigeminal Neuralgia 1423
to the mastoid bone and may be damaged if not carefully sepa-
rated from the bone before the craniectomy. Small injuries to the
sinus are managed with oxidized cellulose or absorbable gelatin
sponge and tack-up sutures, but large rents may require further
bony exposure with a dural patch graft because packing with a
large amount of hemostatic material may lead to venous obstruc-
tion. The mastoid air cells are visible at the lateral margin of the
bony opening and should be carefully waxed. Hemostasis is
important at this point to prevent entry of blood into the sub-
arachnoid space.
The dura is opened in an inverted L shape, parallel to and 3
to 5 mm from the transverse and sigmoid sinuses. A C- or
T-shaped incision can be used as well, with T-shaped relaxing
incisions as needed, although it should be remembered that
watertight closure is desired at the end of the procedure. If neces-
sary, the dura next to the sigmoid sinus is tacked laterally to
slightly rotate the sigmoid sinus and expose the lateral surface of
the cerebellum. CSF is then allowed to drain through gentle
retraction on the cerebellum with a cotton neurosurgical patty
(Cottonoid; Codman Neuro, Raynham, MA). Any adhesions or
bridging veins along the superior margin of the cerebellum along
the transverse sinus are coagulated and sharply divided.
At this point, the microscope is brought into the field, and the
self-retaining retractor system is set up. A flexible self-retaining
brain retractor is placed over a neurosurgical cotton patty to
gently retract the cerebellum up and medially and slightly ele-
vated toward the surgeon. This retraction allows for penetration
of the trigeminal cistern and further drainage of CSF, greatly
reducing the need for medial cerebellar retraction for exposure
of the trigeminal nerve. Superficial cerebellar veins draining into
the tentorial sinus and the superior petrosal vein are easy to tear
even with gentle retraction, so the cerebellum should first be
retracted medially (as though approaching the seventh and eighth
cranial nerves), then inferiorly under direct vision once its lateral
extent of the cerebellum. The angle of approach is changed to
follow the petrous bone anteriorly, keeping the retractor blade
close to the tentorium along the superior surface of the cerebel-
lum to avoid injury to the seventh and eighth cranial nerves. If
bleeding is encountered during retraction, a dorsal bridging vein
may have been torn, requiring removal of the retractor and gentle
depression of the cerebellum to identify and coagulate the vein.
As the retractor is advanced, the petrosal vein complex is
encountered, often appearing as an inverted Y that drains into
the superior petrosal sinus. This vein is usually two thirds of the
way from the dura to the trigeminal nerve, but there is great
variability: the vein may be completely absent or it may lie on
the nerve itself, producing venous compression. The petrosal vein
is divided sharply after thorough coagulation. It is prudent not
to coagulate the nerve or to divide it all the way to the point of
its entry into the bone, because it tends to retract with cautery
and is difficult to control if it retracts into the petrous bone. Some
surgeons recommend preserving all or at least the superior part
of the petrosal venous complex if the veins do not obstruct the
nerve or are easily mobilizable, but their presence usually pre-
vents full exploration of the nerve, and they can nearly always be
taken with impunity.
The arachnoid membrane over the nerve is carefully removed
to allow complete inspection of the nerve. Thin, translucent
membrane can be teased off, but thick, opaque bands must be
sharply dissected to avoid injury to the trigeminal nerve, the
trochlear nerve (a thin, delicate structure in the arachnoid above
the trigeminal nerve), or small vascular branches in the subarach-
noid space. Vascular compression is usually seen close to the
brainstem, often anterior to the nerve. The site of compression
may vary according to symptoms, with symptoms closer to CN
V1 associated with compression of more caudolateral portions of
the nerve. The arachnoid membrane anterior to the nerve must
be dissected to allow decompression. Endoscopic assistance has
been advocated as a method of very thorough evaluation of the
nerve with minimal cerebellar retraction.45-48 Some advocate use 174
of a small mirror to visualize behind the nerve.
The artery that most frequently produces compression is the
superior cerebellar artery (SCA), which often compresses the
nerve anteromedially from within the axilla. Decompression
requires elevation of the artery into a horizontal rather than verti-
cal orientation, displacing it upward and away from the nerve.
SCA often divides into two branches as it courses around
the midbrain, either or both of which may compress the nerve.
The anterior inferior cerebellar artery (AICA) may compress the
nerve from below, requiring displacement more inferiorly away
from the nerve. Sometimes both the SCA and AICA are involved,
surrounding the nerve like a pincer, in which case both must be
mobilized and decompressed. Less commonly, the vertebral or
basilar artery contacts the nerve, usually in hypertensive, elderly,
and male patients.7 Small arterioles may be seen, more often in
younger patients. Compression by a persistent trigeminal artery
has also been described.49
Any arterial loops producing compression are carefully dis-
sected, with kinking of arteries avoided at all times. Shredded
polytetrafluoroethylene (Teflon) is created by grasping and
tearing a piece of the material to create a soft substance resem-
bling a cotton ball. This material is then placed between the
vessel and nerve in a proximal-to-distal manner; it is held in place
by the tension between the artery and nerve root and reinforced
if necessary with absorbable gelatin sponge or fibrin glue. The
vessel is flipped onto the dorsal aspect of the nerve with the
polytetrafluoroethylene separating the nerve from the vessel. If
small vessels are pushed into the nerve by the polytetrafluoroeth-
ylene, it must be replaced. Multiple pieces of polytetrafluoroeth-
ylene can be used to decompress multiple arteries or looping
arteries affecting more than one side of the nerve. If the artery
passes through the nerve, careful dissection can be used to sepa-
rate the vessel from the nerve, although there is a greater risk of
sensory loss with any nerve manipulation.50 Small veins may be
coagulated, but arteries should always be preserved. The nerve
must be explored along its entire length, because the root entry
zone may extend many millimeters from the brainstem and even
very small vessels may cause compression.
Venous contact is frequently seen, often concomitantly with
arterial compression. The vein may be anterior (transverse
pontine vein), posterior (petrosal vein), or distal at the entrance
to Meckel’s cave (trigeminal vein); frequently, compression is
caused by one of the many unnamed veins that run along the
brainstem.51,52 Posterior venous compression may be obscured by
the ridge of the petrous bone. Compression from draining veins
from a venous angioma or arteriovenous malformation is some-
times observed. If venous compression is identified, the vein is
carefully dissected from the nerve and coagulated with low-
voltage small bipolar forceps to prevent spread of current into
the adjacent nerve, after which the vein is coagulated and divided.
It is uncommon to find no evidence of compression whatso-
ever, but if after thorough exploration no compression is found,
the nerve may be gently manipulated to produce a lesion or the
nerve partially sectioned along the anteroinferior aspect. Gentle
compression of the nerve virtually always produces immediate
pain relief, although relapse rates are high.53 Alternatively, the
patient may be treated with a subsequent destructive procedure
such as radiofrequency rhizolysis or stereotactic radiosurgery.
After decompression, the vessels are carefully observed, and
topical papaverine–soaked absorbable gelatin sponge is used if
there is any evidence of vasospasm. The operative field is liberally
irrigated, retractors are removed, and a Valsalva-like maneuver is
performed with the ventilator by the anesthesiologist to ensure
there is no bleeding. The dura is closed in a watertight manner
with continuous or interrupted braided 4-0 sutures to prevent
subsequent leakage of CSF. It is usually possible to close the dura
1424 SECTION 6  Pain

A B C

D E F
Figure 174-2. Right-sided retromastoid craniotomy. A, The patient is positioned supine with
the head turned 90 degrees toward the opposite shoulder, slightly flexed, and slightly bent
toward the floor. The Mayfield head holder apparatus is visible on the extreme upper right and
left of the figure, and the right ear has been taped forward (visible to the right of the incision).
The 5-cm incision extends just above the iniomeatal line. B, The bone is removed with high-
speed drill and rongeurs, starting at the emissary vein and extending anterior and superior to
the junction of the transverse and sigmoid sinuses. C, The dura is opened, and a neurosurgical
cotton patty is placed in the trigeminal cistern to facilitate drainage of cerebrospinal fluid. D, The
petrosal vein is visualized and divided after coagulation. E, After dissection of the arachnoid, the
right trigeminal nerve is seen to be compressed by a branch of the superior cerebellar artery.
G F, The artery is decompressed with polytetrafluoroethylene. G, The dura is closed, and the bony
defect is filled with artificial bone material; the wound is then closed in layers.

primarily, but if necessary, a graft of cadaveric, synthetic, or

autogenous tissue may be used. Fibrin dural sealant is helpful,
especially in reoperations. A piece of absorbable gelatin sponge
is placed over the dura, and a cranioplasty of wire mesh and
artificial bone material is fashioned, or the bone is replaced if a
craniotomy was performed (Fig. 174-2). The fascia, subcutaneous
tissue, and skin are closed in standard fashion with absorbable
sutures.
POSTOPERATIVE CARE
After the operation, the patient must be observed overnight in
the intensive care unit or stepdown unit.54 Blood pressure is
monitored with an arterial line, and an antihypertensive (labet-
alol or hydralazine) is administered if systolic blood pressure
exceeds 160 mm Hg. Mild narcotics may be used for headache,
which may persist for several weeks. Severe bifrontal headache
warrants computed tomography (CT) to rule out posterior fossa
hemorrhage, but postoperative imaging is otherwise not neces-
sary. Nausea is common and usually responds to antiemetics.
Steroids are not helpful. The patient is transferred to the general
medical/surgical floor on the first postoperative day, and diet and
activity are gradually increased. Patients are generally discharged
by the third postoperative day. After discharge, activity is gradu-
ally increased over a week, and most patients are able to return
to work within 2 to 4 weeks. Half of all patients undergoing
MVD return to baseline activity within 1 month, and 90% by
3 months.55
COMPLICATIONS
Complications from MVD are rare when it is performed by
experienced hands,7,27 and morbidity is lowest at high-volume
centers.56 Cranial nerve damage is rare, and such complications as
facial dysesthesia and anesthesia dolorosa are much less common
than with the lesioning procedures. Many patients have a tran-
sient conductive hearing loss due to tracking of fluid from the
mastoid bone into the middle ear that clears spontaneously within
a few weeks. Sensorineural hearing loss tends to be permanent
but can be prevented by gentle retraction, careful technique, and
treatment of any AICA vasospasm that occurs. Brainstem audi-
tory evoked potential monitoring is very helpful in preventing
this complication and has diminished its incidence from 1.3% to
0.6%.44 Prolonged postoperative vertigo or tinnitus is reported in
about 2% of patients,57 and some facial nerve palsy occurs in up to
5% of patients.7 Both these complications tend to improve spon-
taneously over a few weeks. Injury to the fourth cranial nerve pro-
duces a trochlear palsy that usually subsides after a few months.
CSF rhinorrhea, which occurs in 1.5% of cases,7 is caused by
leakage of CSF through the dural opening, into the mastoid air
cells, and through the pharyngotympanic tube into the nasophar-
ynx. This complication occurs more often with reoperations and
may be prevented by meticulous waxing of the mastoid process,
careful dural closure, and application of fibrin glue. CSF rhinor-
rhea is often successfully treated with 3 days of CSF drainage
through a lumbar drain. If leakage continues, reexploration of the
wound and direct fistula closure may be needed.
 CHAPTER 174  Microvascular Decompression for Trigeminal Neuralgia 1425
Aseptic meningitis with headache and sterile CSF pleocytosis
may occur in response to artificial materials such as the polytet-
rafluoroethylene pledget used or todural graft material. It is
usually self-limited but often responds to steroids or lumbar
puncture to remove CSF. Wound infection, which manifests as
swelling of the wound, fever, and purulent drainage, requires
reoperation with removal of all foreign materials and 4 to 6 weeks
of intravenous antibiotics.
Cerebellar contusion may be caused during the opening and
initial retraction and is prevented by avoidance of aggressive
cerebellar retraction, initial lateral retraction, and early drainage
of CSF. Cerebellar hemorrhagic infarction may occur from arte-
rial damage but more often results from venous insufficiency, so
it is important to minimize the number of veins sacrificed. Pos-
terior fossa hemorrhage occurs early in the postoperative course
and usually requires immediate evacuation.
RESULTS
Multiple investigators have found MVD to be an effective treat-
ment for TN. In one study of 1204 patients, 75% had complete
relief and 9% had partial relief after 1 year. After 10 years, 64%
had complete relief, and 4% had partial relief. The annual rate
of recurrence was less than 2% by 5 years and less than 1% by
10 years.7 Although initial results are similar, MVD offers a much
higher likelihood than destructive procedures for a long-term
cure. In one study comparing 378 MVD recipients with 316
radiofrequency (RF) rhizotomy recipients over 20 years, patients
undergoing RF rhizotomy had a 75% chance of pain recurrence
in the first 5 years. By contrast, 63% of patients undergoing
MVD were pain free at 20 years.57
As mentioned previously, the most significant predictor of
outcome after MVD appears to be type of TN pain. Patients with
TN type 1 (mostly episodic, lancinating pain) tend to have much
better immediate and long-term results than those with TN type
2 (mostly constant pain). This effect appears to be proportional
to the amount of lancinating pain, so that a higher amount of
lancinating pain leads to a better outcome.58 TN type is more
predictive of outcome than any other clinical feature of TN,
including duration of symptoms, presence of trigger points,
response to antiepileptics, and type of compression (arterial
versus venous) found at surgery.58 In one large study, 80% of
patients with TN type 1 had some degree of pain relief at 5 years,
compared with 51% of those with TN type 2.59 However,
although outcomes for patients with TN type 2 are less satisfac-
tory than for those with TN type 1, MVD still benefits most
patients, and no alternative interventions appear to offer a better
chance of long-term relief.
Venous compression appears to predict worse outcome, pos-
sibly because of regrowth of veins. In one study of 393 patients
treated by MVD for venous compression, the 1-year recurrence
rate was 31%, and 28 of 32 undergoing reexploration had evi-
dence of recurrent venous contact.51 Venous compression is also
more common in pediatric patients with TN. In one study,
venous contact was found in 86% of pediatric patients with TN
undergoing MVD, and a vein was the sole offending vessel in
18%. These findings may explain why pediatric patients with TN
have worse results after MVD, with 10-year recurrence rates as
high as 43%.60 Other predictors of recurrence include female
gender, prolonged preoperative symptoms (>8 years), and failure
of immediate postoperative relief.7,61-67 Severity of compression
and focal arachnoiditis have also been associated with worse
outcome.68 In general, the best results occur when TN is caused
by severe compression by a single artery.69
It is unclear whether MVD for recurrent TN after a previous
destructive procedure is associated with a worse prognosis. The
likelihood of pain relief appears to be similar,26 but patients who
have undergone a lesioning procedure before MVD have a higher
likelihood of postoperative trigeminal neuropathic symptoms
(burning, aching pain).7 Some investigators have noted that 174
lesioning procedures before an initial MVD may increase the
likelihood of negative exploration during subsequent MVD oper-
ations for recurrent TN.70
Recurrent disease after a prolonged postoperative pain-free
interval may be effectively treated with medication, but repeat
MVD has also been advocated, even though it is associated with
a much higher rate of negative exploration. Reoperations are
technically more difficult, and if the first MVD was unsuccessful
for technical reasons, it is unlikely that repeating the operation
will yield better results. When neurovascular compression is seen
during a repeat MVD, it is nearly always because of growth of
veins or expansion of arteries rather than dislodging of the
polytetrafluoroethylene ball placed during the first operation,
although scarring produced by the ball can produce neural com-
pression. Reports of operative findings during repeat MVD vary
widely; most investigators report recurrent vascular compression
in about half of patients.71,72 Outcome after the second operation
is generally good.62
OTHER NEUROVASCULAR FACIAL PAIN SYNDROMES
Glossopharyngeal Neuralgia
Glossopharyngeal neuralgia manifests as sharp severe pain in the
throat or neck, sometimes radiating to or from the upper neck
or ear. It is much less common than TN and more likely to be
bilateral.73 Vagal involvement can lead to bradycardia, syncope,
and even asystole. Like TN, it may be triggerable, and common
triggers include cold beverages, yawning, chewing, coughing,
sneezing, and touching the tragus. Because the lower cranial
nerves exit the brainstem as a series of rootlets, attempted decom-
pression with polytetrafluoroethylene may lead only to worsen-
ing of the compression. Instead, the nerve is exposed through a
retrosigmoid craniectomy (as with MVD for TN), and the glos-
sopharyngeal nerve and the upper few fascicles of the vagus nerve
are sectioned. Patients should be warned that postoperative tem-
porary dysphagia is often seen. Potential complications include
permanently diminished gag reflex and vocal cord paralysis.
There are few long-term studies, but most reports indicate suc-
cessful long-term outcome in most patients.74,75 In one study,
58% of patients had complete relief of symptoms, and another
18% had some relief, after a mean follow-up time of 4 years.54
Isolated throat pain appears to predict a greater likelihood of
postoperative success.
Geniculate Neuralgia (Nervus
Intermedius Neuralgia)
The nervus intermedius is a small branch of the facial nerve that
carries the sensory and parasympathetic fibers of the facial nerve.
Within the cerebellopontine angle, the nervus intermedius runs
between the motor component of the facial nerve and the ves-
tibulocochlear nerve branches before joining the facial nerve in
the internal acoustic meatus. Nervus intermedius neuralgia is
associated with sharp shooting pain deep in the ear that may
radiate to the temple or face. Parasympathetic facial nerve func-
tion (tearing) may be affected, but patients seldom complain of
this. This condition may be treated by cutting of the nerve. After
exposure of the seventh and eighth nerves by a retrosigmoid
approach, the facial nerve is gently retracted to expose and mobi-
lize the nervus intermedius, which is then cut.
CONCLUSION
TN is associated with and is likely to be caused by pulsatile
mechanical compression of the trigeminal nerve by a blood vessel
1426 SECTION 6  Pain
near the dorsal root entry zone. MVD differs from other treat-
ments because it fixes the underlying cause to produce long-term
relief of symptoms. Careful patient selection is the most impor-
tant determinant of outcome, and morbidity is rare when the
procedure is performed by an experienced surgeon.
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neuralgia. A five-year follow-up study. Surg Neurol. 1984;22:235.
66. Puca A, Meglio M, Cioni B, et al. Microvascular decompression for
trigeminal neuralgia: prognostic factors. Acta Neurochir Suppl. 1993;
58:165.
67. Sun T, Saito S, Nakai O, et al. Long-term results of microvascular
decompression for trigeminal neuralgia with reference to probability
of recurrence. Acta Neurochir. 1994;126:144.
68. Sindou M, Leston J, Decullier E, et al. Microvascular decompression
for primary trigeminal neuralgia: long-term effectiveness and prog-
nostic factors in a series of 362 consecutive patients with clear-cut
neurovascular conflicts who underwent pure decompression. J Neu-
rosurg. 2007;107:1144.
69. Jo KW, Kong DS, Hong KS, et al. Long-term prognostic factors for
microvascular decompression for trigeminal neuralgia. J Clin Neuro-
sci. 2013;20(3):440.
70. Rath SA, Klein HJ, Richter HP. Findings and long-term results of
subsequent operations after failed microvascular decompression for
trigeminal neuralgia. Neurosurgery. 1996;39:933.
71. Cho DY, Chang CG, Wang YC, et al. Repeat operations in failed
microvascular decompression for trigeminal neuralgia. Neurosurgery.
1994;35:665.
72. Liao JJ, Cheng WC, Chang CN, et al. Reoperation for recurrent
trigeminal neuralgia after microvascular decompression. Surg Neurol.
1997;47:562.
73. Patel NK, Aquilina K, Clarke Y, et al. How accurate is magnetic
resonance angiography in predicting neurovascular compression in
patients with trigeminal neuralgia? A prospective, single-blinded
comparative study. Br J Neurosurg. 2003;17:60.
74. Kondo A. Follow-up results of using microvascular decompression
for treatment of glossopharyngeal neuralgia. J Neurosurg. 1998;
88:221.
75. Resnick DK, Jannetta PJ, Bissonnette D, et al. Microvascular decom-
pression for glossopharyngeal neuralgia. Neurosurgery. 1995;36:64.
PART 4 Surgical Procedures for Nontrigeminal Pain
175 Neurosurgical Management of Intractable Pain
William S. Rosenberg, Richard B. North, and Kenneth A. Follett
Neurosurgeons have a long history of accomplishments in the
field of pain management, and neurosurgery, as a specialty, holds
an important position within this discipline. The development of
neuroablative pain therapies, which were the mainstay of the
surgical treatment of intractable pain for many years, was facili-
tated by neurosurgeons’ understanding of the physiology and
anatomy of nociception and their ability to access the peripheral
and central nervous systems surgically. During the past two to
three decades, the treatment of intractable pain has undergone
evolutionary change as neuromodulatory therapies, such as spinal
cord stimulation (SCS), peripheral nerve stimulation (PNS), and
intrathecal drug delivery (IDD), have augmented neuroablative
therapies. Neurosurgeons have had significant roles in guiding
this change.
Neurosurgeons are unique among health care providers in the
field of pain care by virtue of their training, expertise in neuro-
logical differential diagnosis, and ability to provide patients the
full range of neuromodulatory and neuroablative therapies as well
as anatomic, reconstructive procedures to address the underlying
condition causing the pain, as appropriate. Neurosurgeons should
take advantage of this special position but must recognize that
successful treatment of intractable pain requires more than surgi-
cal skill—it requires the ability to properly select specific treat-
ments for patients and manage them throughout the course
of therapy. The neurosurgeon is an important and integral
member of the pain care team, ideally establishing collaborative
relationships with physicians who coordinate the long-term care
of patients with complex pain problems. This multidisciplinary
interaction can help the neurosurgeon better understand how the
treatments provided fit within the context of the patient’s clinical
and psychosocial needs and promote good long-term outcomes.
PRELUDE TO SURGICAL TREATMENT
The fundamental requirement for successful pain management,
whether the treatment is surgical or nonsurgical, is an under-
standing of the nature of the pain being treated. Different types
of pain respond differently to treatment; thus, the etiology and
characteristics of a patient’s pain must be understood in order for
a rational treatment plan to be developed. In general, pain can be
classified as acute or chronic and nociceptive or neuropathic.
Classification of a pain complaint into these simple categories
facilitates formulation of a proper treatment scheme.
Acute pain is a signal of actual or impending tissue injury and
is generated by activation of nociceptors in tissue that has sus-
tained an injury or insult. This type of pain resolves as injured
tissue heals. Chronic pain, on the other hand, outlasts the typical
period required for healing of an acute injury. Some definitions
of chronic pain are based on the duration of pain (e.g., pain that
lasts longer than 3 or 6 months). This is an arbitrary distinction,
however, because different types of acute injury require differing
lengths of time for healing, and the transition of acute pain to
chronic pain can vary according to the nature of the injury.1
The distinction between acute pain and chronic pain is some-
times difficult to make but important. The goal of acute pain
treatment should be to provide pain relief while promoting tissue
healing. Such treatment might include rest or immobilization,
175
analgesics, and passive physical therapy.2 In contrast, chronic pain
does not serve a useful physiologic purpose (unless tissue injury
is ongoing). In some cases, chronic pain is no longer a symptom
of disease, but instead is a disease itself.3 Physical deconditioning
also commonly accompanies a number of chronic pain disorders,
such as failed back surgery syndrome (FBSS). Thus, many patients
with chronic pain require physical reactivation and rehabilitation,
rather than the rest and relaxation recommended for the treat-
ment of acute pain. This distinction between acute pain and
chronic pain is critical, because treating chronic pain as acute pain
only promotes further disuse and deconditioning.2 The differen-
tiation between acute pain and chronic pain is also important
because psychological and social factors that can complicate a
pain complaint are often more common in patients with chronic
pain than in those with acute pain. In fact, in some cases, psycho-
social factors can perpetuate or even cause chronic pain. Thus,
current clinical practice emphasizes the biopsychosocial model of
chronic pain.4
The distinction between nociceptive pain and neuropathic
pain is also important, because each type of pain usually responds
differently to specific treatments. Nociceptive pain occurs when
tissue injury or disease (e.g., a broken arm or cancer with local
tissue invasion) initiates signals that are transferred through
peripheral nerves to the brain via the spinal cord. Such pain, which
patients commonly describe as “throbbing,” “aching,” or “dull,”5
is a normal, protective response of the nociceptive systems. In
contrast, neuropathic pain is the result of a pathologic process
(injury or disease) affecting the peripheral or central nervous
system. Such neurological pathophysiology leads to abnormal
neuronal excitability, spontaneous discharges, and ephaptic trans-
mission, which might, in turn, lead to generation of pain with or
without peripheral, let alone nociceptive, input. Thus, in contrast
to nociceptive pain, neuropathic pain reflects abnormal neuronal
activity. Neuropathic pain, which patients commonly describe as
“burning,” “shooting,” “tingling,” or “shock-like,”5 can be con-
tinuous or paroxysmal (lancinating). Whereas nociceptive pain
often responds to opioids (e.g., the pain of a broken arm can be
treated with morphine), neuropathic pain tends to resist opioid
treatment (at least at typical doses) and frequently requires treat-
ment with non-opioid medications or other modalities.
Pain can also be classified according to its association with
cancer or lack thereof. This classification can be useful because
each of these types of pain (cancer vs. noncancer) might respond
differently to specific interventions. In addition, the etiology of
cancer-related pain can be very complex, with simultaneous noci-
ceptive and neuropathic components and causes ranging from
tumor expansion into soft tissue and/or nerves to iatrogenic
(i.e., associated with surgery, chemotherapy, radiotherapy). In
evaluating such a patient, the neurosurgeon must consider the
entire spectrum of factors, including the continuation and objec-
tives of ongoing oncologic treatment as well as the patient’s
psychosocial support system, personal goals, and reasonable life
expectancy. It is important that these factors be considered in
addition to the source of the patient’s pain in the development of
a treatment plan.
Unless a correctible anatomic problem causing pain can be
diagnosed with confidence, surgical treatment of intractable pain
1427
1428 SECTION 6  Pain
is not usually a first-line approach. As a general principle, treat-
ment of intractable pain should follow a rational process that both
considers the least disruptive therapy with a reasonable chance
of success and is sensitive to the patient who is in pain. Placing
the needs of the patient at the center of decision making can help
achieve the desired balance between avoiding unnecessary risk
and exploring all options with significant probability of success,
all evaluated through the lens of the urgency, needs, and circum-
stances of the patient. The overly dogmatic approach of formally
exploring treatments with little chance of success for the sole
reason that they are “less invasive” is rarely in the best interest of
the patient. As Hippocrates said, “Timidity betrays a want of
powers, and audacity a want of skill.”6 The World Health Orga-
nization proposed a simple, stepwise system for pain control
designed for ease of implementation.7 There is much to recom-
mend this approach, as each step in the ladder represents a more
invasive approach with presumably more risk. Although it is
useful, however, there is growing evidence that such a linear
system is less than optimal.8-12
Medical therapy, beginning typically with non-opioid agents
(e.g., nonsteroidal anti-inflammatory medications) in conjunc-
tion with adjuvant therapies when appropriate, should generally
precede surgical intervention. If adequate pain control is not
obtained with non-opioid agents, mild opioids might be con-
sidered, to be replaced by strong opioids if appropriate. In most
cases, pain relief is most readily achieved with scheduled rather
than “as needed” (prn) analgesic dosing.13,14 Neuropathic pain
frequently requires treatment with non-opioid medication,
although opioids can be helpful for some patients. For continu-
ous neuropathic pain (e.g., constant burning, dysesthetic pain),
useful adjuvant medications include antidepressants (e.g., tricy-
clic antidepressants, serotonin-norepinephrine reuptake inhibi-
tors), clonidine, local anesthetics (e.g., mexiletine), and capsaicin
cream.14 Paroxysmal, lancinating, or evoked neuropathic pain
might improve with anticonvulsants (e.g., carbamazepine, phe-
nytoin, gabapentin) or baclofen.14 Nonpharmacologic adjuvant
therapy, including psychologic support, relaxation therapies,
coping strategies, passive physical therapy (e.g., massage, heat/
cold), transcutaneous electrical nerve stimulation, and ortho-
ses,13,14 can be useful in the treatment of nociceptive or neuro-
pathic pain.
Simple interventional therapies (e.g., nerve blocks, peripheral
nerve ablations) might be useful supplements to medical manage-
ment. Neuromodulatory therapies (e.g., SCS and neuraxial anal-
gesic infusion) are typically the next step, followed by neuroablative
therapies if the former approaches are unsuccessful or inappro-
priate. An element of flexibility should be maintained in the
approach to patients with pain, however, and treatment should
be tailored to meet individual needs. For example, dorsal root
entry zone (DREZ) lesioning can relieve pain associated with
spinal nerve root avulsion and, in some cases, is preferable to
neuroaugmentative techniques. In addition, a patient with intrac-
table pain related to late-stage cancer might be treated more
appropriately with cordotomy than with implantation of an intra-
thecal drug infusion system.
PATIENT SELECTION FOR SURGICAL
PAIN THERAPIES
In most cases, surgical intervention is reserved for patients in
whom nonsurgical therapies do not provide adequate pain relief
or are associated with unacceptable side effects or risks, no abso-
lute contradictions to surgery exist, and treatment of the underly-
ing cause of pain is not possible, practical, or appropriate.5,15 For
example, radicular leg pain from lumbar spinal stenosis can be
treated with decompressive lumbar laminectomy; however, if a
patient also has severe coronary artery disease that increases
operative risk or has had prior spinal surgery that reduces the
potential benefit of subsequent surgery, SCS might be the safest
and most appropriate treatment.15,16
It is important to determine a likely organic basis for the pain,
especially for patients with chronic pain of nonmalignant origin,
and to identify any comorbid psychologic dysfunction, which can
have a negative impact on outcomes for any treatment plan. Thus,
formal psychologic evaluation might be appropriate for many (or
most) patients being considered for surgical treatment of intrac-
table pain. Contraindications to surgical intervention include
overt psychologic dysfunction, such as active psychosis, suicidal
or homicidal behavior, major uncontrolled depression or anxiety,
serious alcohol or drug abuse, and serious cognitive deficits.
Other psychologic problems that may be viewed as “risk factors”
include somatization disorder, personality disorders (e.g., border-
line or antisocial), history of serious abuse, major issues of sec-
ondary gain, non-organic signs on physical examination, unusual
pain ratings (e.g., 12 on a 10-point scale), inadequate social
support, unrealistic outcome expectations, and, in the case of
implantable augmentative devices, an inability to understand the
purpose of a device or its use. Patients with psychologic risk
factors are not necessarily precluded from surgical treatment, but
the treatment program should incorporate management of the
psychologic issues to facilitate a good outcome.17
NEUROSURGICAL THERAPIES
FOR INTRACTABLE PAIN
Neurosurgeons can use anatomic, neuromodulatory, and neu-
roablative therapies (Table 175-1).18 The treatment offered
should be tailored to meet the needs of each individual patient
and the skills of the treating physician. Specific interventions vary
in their appropriateness as treatment for pain in specific body
regions (Boxes 175-1 through 175-4). Patient-related factors that
must be taken into consideration in the selection of a therapy
include the etiology, distribution, and characteristics (nociceptive
or neuropathic) of the pain; life expectancy; and psychological,
social, and economic issues relevant to the pain complaint. The
relative advantages and disadvantages of anatomic, augmentative,
and ablative therapies should be weighed in view of these factors,
and a choice among these three general approaches should be
made before a specific intervention is chosen. Selecting the right
TABLE 175-1  Neurosurgical Pain Therapies
Anatomic Correction of structural deformity
Augmentative Stimulation:
Peripheral nerve
Spinal cord
Deep brain structures
Motor cortex
Neuraxial/drug infusion:
Intrathecal/epidural
Intraventricular
Ablative Neurectomy
Sympathectomy
Ganglionectomy
Rhizotomy
Spinal DREZ lesion
Cordotomy
Myelotomy
Nucleus caudalis DREZ lesion
Trigeminal tractotomy
Mesencephalotomy
Thalamotomy
Cingulotomy
Hypophysectomy
DREZ, dorsal root entry zone.
Modified from North RB. Neurosurgical procedures for chronic pain:
general neurosurgical practice. Clin Neurosurg. 1992;40:182-196.
 CHAPTER 175  Neurosurgical Management of Intractable Pain 1429

BOX 175-1  Neurosurgical Procedures for Treatment of BOX 175-4  Neurosurgical Procedures for Treatment of 175
Head/Neck Pain Diffuse Pain
AUGMENTATIVE AUGMENTATIVE
Peripheral nerve stimulation Intraspinal/intraventricular analgesic administration
Intraventricular analgesic administration ABLATIVE
Deep brain/motor cortex stimulation
Thalamotomy
ABLATIVE Cingulotomy
Cranial/cervical rhizotomy/ganglionectomy Hypophysectomy
Caudalis dorsal root entry zone lesion
Trigeminal tractotomy
Mesencephalotomy
Medial thalamotomy techniques as procedures of choice for pain management, are
Cingulotomy often preferred as initial surgical treatments because of their rela-
tive safety and reversibility and the availability of a specific prog-
nostic trial.
Ablative therapies, however, have a role in the treatment of
certain pain syndromes19,20 and can target almost every level of
BOX 175-2  Neurosurgical Procedures for Treatment of Upper the peripheral and central nervous systems. Thus, ablative thera-
Trunk/Shoulder/Arm Pain pies can be directed at preventing transmission of nociceptive
information into the central nervous system at the level of periph-
AUGMENTATIVE eral nerves (neurectomy, neurotomy), roots (ganglionectomy,
Peripheral nerve stimulation rhizotomy), and the spinal cord dorsal horn (DREZ, including
Spinal cord stimulation nucleus caudalis DREZ). Ascending nociceptive pathways can
Intraspinal/intraventricular analgesic administration be disrupted at the level of the spinal cord or brainstem (cor-
Deep brain/motor cortex stimulation dotomy, myelotomy, tractotomy) or within the brain (thalamot-
ABLATIVE omy, cingulotomy).
Sympathectomy Augmentative and ablative therapies are reviewed briefly here
Neurectomy to provide a broad perspective about the applications of neuro-
Ganglionectomy/rhizotomy surgical pain therapies. A detailed discussion of indications for,
Spinal dorsal root entry zone lesion techniques of, and outcomes of many of these techniques is avail-
Mesencephalotomy able in other chapters. Outcomes of most interventional pain
Thalamotomy therapies have been studied mainly via case series. Few therapies
Cingulotomy have been studied in rigorous fashion, so data regarding efficacy
Hypophysectomy and complications should be interpreted cautiously.

Augmentative Therapies
Augmentative therapies offer the advantages of relative safety,
BOX 175-3  Neurosurgical Procedures for Treatment of Lower reversibility, and scalability. For example, intraspinal analgesic
Trunk/Leg Pain infusion can be adjusted to meet the changing needs of a patient
who has worsening cancer pain. On the other hand, augmentative
AUGMENTATIVE therapies are generally more expensive than ablative therapies
Peripheral nerve stimulation owing to initial device cost and upkeep, require maintenance
Spinal cord stimulation (e.g., refilling of infusion pumps, device replacement because of
Intraspinal/intraventricular analgesic administration battery depletion), and have the potential for device-related com-
Deep brain/motor cortex stimulation plications. Thus, cost-effective care mandates the consideration
ABLATIVE of such factors as life expectancy in the evaluation of the appro-
Sympathectomy priateness of certain neuroaugmentative therapies.
Neurectomy Stimulation therapies approved for pain management in the
Ganglionectomy/rhizotomy United States include SCS and PNS. In general, the highest yield
Spinal dorsal root entry zone lesion for SCS is for relatively focal (e.g., localized to one or two
Cordotomy extremities or focal on the trunk) and static neuropathic pain, but
Myelotomy individual responses are highly variable, and in general, a thera-
Thalamotomy peutic trial of SCS is relatively simple. Common applications
Cingulotomy include treatment of persistent radicular pain associated with
Hypophysectomy FBSS15,16,21-26 or neuropathic pain related to complex regional
pain syndrome (“reflex sympathetic dystrophy”).27-29 In patients
with FBSS, the success rate (defined typically as 50% or greater
reduction in pain) is approximately 60% at 5 years.15,22,23 Patients
treatment for the right patient at the right time increases the with complex regional pain syndromes have similar outcomes,
likelihood of a successful outcome. although success rates as high as 70% to 100% have been
Neuromodulatory therapies fall into the following two cate- reported.28,30 SCS also can be effective for neuropathic pain
gories: neurostimulation (SCS, PNS, deep brain stimulation affecting the trunk (e.g., postherpetic neuralgia and some types
[DBS], and motor cortex stimulation [MCS]) and targeted drug of postthoracotomy pain) and for extremity pain due to periph-
delivery (intrathecal and intraventricular). These neuromodula- eral neuropathy,31 root injury, phantom limb and postamputation
tion therapies, which have frequently supplanted neuroablative stump pain, and peripheral vascular disease.26,31,32 SCS is widely
1430 SECTION 6  Pain
used in Europe as a successful treatment for refractory angina
pectoris,33,34 but this indication does not have specific U.S. Food
and Drug Administration (FDA) approval.
SCS and PNS parameters in use since the 1960s, in particular
“frequencies” (pulse repetition rates) in 10s to 100s per second
(Hz), produce paresthesias, but “burst” protocols35 and higher
frequencies (up to 10 kHz)36 have been reported to relieve pain
without producing paresthesias. Results reportedly have been
superior to those of conventional SCS, and different subgroups
of patients (e.g., those with axial low back pain or nociceptive
pain) might experience responses. Furthermore, whereas concor-
dance of paresthesia with areas of pain has been necessary for
pain relief using conventional stimulation,37 requiring careful
electrode placement and postoperative adjustment in the awake
patient, such requirements might not be necessary for high-
frequency stimulation. These novel protocols (not yet FDA
approved) add treatment possibilities—indeed, some patients
with conventional SCS systems that have lost efficacy have
reported restored pain relief with high-frequency stimulation.
The traditional goal of achieving paresthesias concordant with
areas of pain continues to inspire new devices with growing
numbers of independent contacts.37 Slender insulated “paddle”
electrodes, which can be introduced percutaneously, have been
developed to the same end.38,39 Future devices should continue to
address this technical goal, so that conventional as well as high-
frequency stimulation can be delivered using the same electrode(s).
Another new approach, “peripheral nerve field stimulation”
via subcutaneous electrodes, has been combined with SCS and
appears to be a useful adjunct for pain control, although it is not
yet FDA approved.40 The subcutaneous electrodes target an area
of pain rather than specific peripheral nerves.
The indications for conventional PNS (i.e., the stimulation of
a specific, named peripheral nerve) are similar to those for SCS,
except that the distribution of pain should be able to be covered
by the stimulation of discrete peripheral nerves.41 Overlap exists
between the applications of SCS and PNS. Extremity pain that
might be appropriate for PNS can sometimes be treated equally
well with SCS, and many surgeons find it easier to implant a
percutaneous SCS electrode than to implant a PNS electrode
(which usually requires an open procedure, although ultrasound-
based percutaneous techniques are being developed).42,43 Con-
versely, some clinical scenarios (e.g., pain in the distal leg and
foot) may benefit from stimulation of the peripheral nerve, with
little neuroplasticity or anatomic opportunity for variation over
time, rather than the spinal cord. Some situations (e.g., treatment
of occipital neuralgia or cranial postherpetic neuralgia) clearly
require PNS rather than SCS.44 High-frequency stimulation (in
the kHz range) has been demonstrated experimentally to achieve
pain relief through conduction block; it is under development for
eventual clinical use.45
Stimulation of the dorsal root ganglion has been facilitated by
new electrode technology, and it has also become a discrete
target. Its advantages over SCS have been reported for specific,
mostly focal pain syndromes, although this technique remains
under investigation.46
Intracranial stimulation therapies include DBS of the
somatosensory thalamus, hypothalamus, and periventricular-
periaqueductal gray (PVG-PAG)47-54 and MCS.55-58 These thera-
pies are used primarily for treating pain of nonmalignant origin,
such as pain associated with FBSS, neuropathic pain following
central or peripheral nervous system injury, trigeminal pain, and
cluster headache. Neither DBS nor MCS is approved by the FDA
for the treatment of pain, although DBS has been used for more
than three decades.
Targets for focal electrical stimulation of the brain include
the ventrocaudal nucleus (nucleus ventroposterolateralis for body
and nucleus ventroposteromedialis for face) and the PVG-PAG.
Stimulation sites for DBS are generally determined on the basis
of pain characteristics. Nociceptive pain and paroxysmal, lanci-
nating, or evoked neuropathic pain (e.g., allodynia, hyperpathia)
tend to respond to PVG-PAG stimulation, which might acti-
vate endogenous opioid systems. Continuous neuropathic pain
responds most consistently to paresthesia-producing stimulation
of the sensory thalamus (nucleus ventrocaudalis).50 The affective
component of pain may respond to stimulation of the anterior
cingulate gyrus.59 Because many pain syndromes (e.g., cancer
pain, FBSS) have components of both nociceptive pain and neu-
ropathic pain, some physicians offer the patient a screening trial
using electrodes in both regions to determine which provides
the best pain relief. Patients might also be given a morphine-
naloxone test to clarify the extent of nociceptive and neuropathic
pain components and to facilitate selection of the best stimulation
target.48
DBS success rates for the treatment of intractable pain are
difficult to determine because patient selection, surgical tech-
niques, and measurement of outcomes vary substantially among
studies. Approximately 60% to 80% of patients undergoing a
screening trial with DBS have pain relief sufficient to warrant
implantation of a permanent stimulation system. Of those who
receive a permanent stimulation system, 25% to 80% (typically
50-60%)47 have been reported to gain acceptable long-term pain
relief.47-51 Patients with cancer pain,50 FBSS, peripheral neuropa-
thy, and trigeminal neuropathy (not anesthesia dolorosa)47,48,50
tend to show more favorable response to DBS than patients with
central pain syndromes (e.g., thalamic pain, spinal cord injury
pain, anesthesia dolorosa, postherpetic neuralgia, or phantom
limb pain).47,48,50 The incidence of serious complications related
to DBS is low, but the combined incidences of morbidity, mortal-
ity, and technical complications can approach 25% to 30%.47,50 A
retrospective series involved 85 patients who were treated with
DBS for a variety of etiologies; with a mean follow-up of almost
20 months, 66% reported good relief of pain.60
MCS has received attention as an alternative to thalamic and
PAG-PVG stimulation.55-58 MCS is used primarily for treatment
of neuropathic pain syndromes and might be particularly effec-
tive for certain varieties of intractable facial pain (e.g., trigeminal
neuropathic pain).56 Approximately 50% of patients undergoing
MCS have good long-term pain relief. As with DBS, MCS
appears most effective when there is no anesthesia in the distribu-
tion of pain being treated. The overall clinical efficacy of MCS
is similar to that of DBS, but the complications associated with
MCS might be less serious because the electrode is placed epidur-
ally, rather than directly on or within the brain parenchyma.
Because of the somatotopic distribution of leg sensation in the
interhemispheric fissure, MCS is usually restricted to face and/
or arm pain. MCS is a promising therapy the long-term efficacy
of which is under active investigation at several centers.
Neuraxial drug infusion has become a popular interventional
treatment for intractable pain,61-66 especially for pain with a sig-
nificant nociceptive component,67-69 and can be cost effective
compared to treatment with more conservative measures.70 Intra-
thecal analgesics for the treatment of cancer pain is well accepted.71
In contrast, the use of this therapy for chronic nonmalignant pain
has been controversial,66 reflecting concern that neuropathic pain
(common in chronic nonmalignant pain syndromes) does not
respond adequately to opioids and that the efficacy and cost
effectiveness of neuraxial drug infusion for neuropathic pain have
not been determined in controlled trials. Despite these concerns,
intrathecal analgesic therapy has been used to treat neuropathic
pain conditions with favorable results,62,63,65,72 and the most
common indication for intrathecal analgesic administration is
FBSS, which typically has components of nociceptive (low back)
and neuropathic (extremity) pain.
The key advantage of neuraxial analgesic administration is its
versatility, which allows it to be applied to a wide range of indica-
tions, including nociceptive and mixed nociceptive/neuropathic
 CHAPTER 175  Neurosurgical Management of Intractable Pain 1431
pain syndromes. It can be used to treat focal or diffuse axial and/
or extremity pain. Neuraxial analgesia is commonly used to treat
pain below cervical levels but can be effective for head and neck
pain, especially if analgesic agents are delivered intraventricularly
or within the foramen magnum.73,74 Neuraxial analgesics can also
treat changing pain (e.g., in a patient with progressive cancer).
Significant disadvantages of neuraxial analgesics include the high
cost of the device and medication and the need for maintenance
(e.g., refilling and, in the case of programmable pumps, replace-
ment of depleted batteries). Approximately 50% to 80% of
patients with neuraxial analgesics achieve good long-term relief
of pain, and outcomes (i.e., extent of pain relief, patient satisfac-
tion, and dose requirements) are similar in patients with cancer
and noncancer pain.61,62,67-69 Serious complications of the therapy
are uncommon. Some patients, particularly those with neuro-
pathic pain syndromes, may need intrathecal “polyanalgesia.”38
The cost is higher with polyanalgesia but may be offset by a
greater likelihood of pain relief.75
Neuroablative Therapies
Although neuromodulatory pain therapies are becoming increas-
ingly common, neuroablative procedures maintain a role in the
treatment of intractable pain. Neuroablative therapy is often con-
sidered the treatment of “last resort,” but in some cases it may be
the procedure of choice. For example, a patient with cancer pain
who has a short life expectancy might be treated more appropri-
ately with cordotomy than with an implanted intrathecal analge-
sic infusion system. In such cases, as in every case, pain therapy
must be tailored to meet the needs of individual patients.
Neuroablative therapies include peripheral techniques that
interrupt or alter nociceptive input into the spinal cord (e.g.,
sympathectomy, neurectomy, ganglionectomy, rhizotomy), spinal
interventions that alter afferent input or rostral transmission of
nociceptive information (e.g., DREZ lesioning, cordotomy,
myelotomy), and supraspinal intracranial procedures that inter-
fere with transmission of nociceptive information (e.g., mesen-
cephalotomy, thalamotomy) or the affective perception of painful
stimuli (e.g., cingulotomy). As with neuromodulatory techniques,
a successful outcome requires appropriate patient and interven-
tion selection. Neuroablative therapies are more successful in the
treatment of nociceptive pain than of neuropathic pain; when
neuropathic pain is treated with neuroablative therapies, improve-
ment is primarily limited to intermittent, paroxysmal, or evoked
(allodynia, hyperpathia) pain, whereas continuous pain remains
relatively unchanged.76
Peripheral Procedures
Sympathectomy has been reported to alleviate visceral pain asso-
ciated with certain cancers77,78 and might also be an effective
treatment for noncancer pain, such as pain associated with vaso-
spastic disorders or sympathetically maintained pain (in which
sympathetic blocks reliably relieve the pain). Sympathectomy,
however, has fallen into disfavor as a treatment for intractable
pain of nonmalignant origin because of inconsistent results and
concerns about complication rates.77-81 Furthermore, research
suggests that SCS, which has the advantage of reversibility, pro-
vides a better long-term outcome with lower morbidity than
sympathectomy and thus might become the treatment of choice
for sympathetically maintained noncancer pain.26
Neurectomy might be a useful treatment for some patients in
whom pain develops following peripheral nerve injury, including
that associated with limb amputation or neuroma.82 However,
neurectomy is not useful for treatment of nonspecific stump pain
after amputation, nor is it generally useful for the treatment of
other nonmalignant peripheral pain syndromes. The utility of
neurectomy is limited because pain arising from a pure sensory
nerve is uncommon, and mixed sensory-motor nerves cannot be
sectioned without risk of functional impairment. Some specific 175
exceptions to this general observation exist; for example, section
of the lateral femoral cutaneous nerve might provide long-lasting
relief of meralgia paresthetica,83 and section of the ilioinguinal
and/or genitofemoral nerves might relieve some inguinal pain
syndromes (e.g., post-herniorrhaphy pain) in properly selected
patients.84,85 However, in these situations in which pain originates
from a specific peripheral nerve, as in the sympathetically medi-
ated pain described previously, neurostimulation of that specific
nerve is often less invasive, is reversible and, therefore, is prefer-
able to neurectomy.86-88 Radiofrequency facet denervation might
provide substantial relief of neck or back pain, albeit with signifi-
cant rates of recurrence after 2 to 3 years.89
Dorsal rhizotomy and ganglionectomy serve similar purposes
in denervating somatic and/or visceral tissues, but ganglionec-
tomy might produce more complete denervation than can be
accomplished by dorsal rhizotomy, which does not affect the
afferent fibers that enter the spinal cord through the ventral
root.90 In contrast, ganglionectomy effectively eliminates input
from ventral root afferent fibers by removing their cell bodies,
which are located within the dorsal root ganglion. Rhizotomy and
ganglionectomy can be used to treat pain in the neck, trunk, or
abdomen. Neither procedure is useful for the treatment of pain
in the extremities unless extremity function is already lost,
because denervation removes proprioceptive as well as nocicep-
tive input, resulting in a functionless limb. Limited denervation
does not provide adequate pain relief, probably because of the
dermatomal overlap of segmental innervation. These procedures
are most appropriate for the treatment of cancer pain and do not
consistently result in long-term improvement of noncancer
pain,91,92 although both dorsal rhizotomy93,94 and ganglionec-
tomy95 have been used successfully to treat occipital neuralgia.
Temporary relief by “diagnostic” blocks is nonspecific96 and
might not predict success. In patients with cancer, rhizotomy and
ganglionectomy might be useful for thoracic or abdominal wall
pain; for perineal pain in patients with impaired bladder, bowel,
and sex function97; or for the treatment of pain in a functionless
extremity.98 Multiple sacral rhizotomies can be performed (e.g.,
to treat pelvic pain from cancer) by passing a ligature around the
thecal sac below S1.99 Alternatively, intrathecal alcohol neurolysis
can be performed percutaneously.100 Rhizotomy might be useful
for treatment of craniofacial pain101 of nontrigeminal origin as
well as for classic trigeminal neuralgia.
Spinal Procedures
DREZ lesioning of the spinal cord (for trunk or extremity
pain)102-106 or of the nucleus caudalis (for facial pain)103,106-108 can
provide significant pain relief with proper selection, with improve-
ment in pain reported in 60% 80% of patients. These techniques,
however, are best reserved for localized pain. Certain types of
cancer pain can be treated effectively with DREZ lesioning (e.g.,
neuropathic arm pain associated with Pancoast tumor), but the
most successful applications are related to treatment of neuro-
pathic pain arising from root avulsion (cervical or lumbosacral)
and “end-zone” or “boundary” pain following spinal cord injury.
These pain syndromes sometimes respond adequately to SCS or
intrathecal drug infusion, but DREZ lesioning might provide a
similar result without the need for long-term maintenance of an
augmentative device. DREZ lesioning has been used for the
treatment of other neuropathic pain syndromes (e.g., post-
herpetic neuralgia) but does not consistently result in good pain
relief. Nucleus caudalis lesioning seems most useful for deaffer-
entation pain affecting the face (including post-herpetic neural-
gia) and less helpful for facial pain of peripheral origin (e.g.,
traumatic trigeminal neuropathy); it can also be effectively
employed for cancer pain.106,109 A CT-guided percutaneous
1432 SECTION 6  Pain
Figure 175-1. Axial computed tomography myelogram at the
foramen magnum with the patient facing to the reader’s left. The
tip of the radiofrequency electrode is seen in the brainstem in the
region of the nucleus caudalis. A second needle has been placed   less frequently to manage noncancer pain but a risk-benefit analy-
in the thecal sac from directly posterior (right) through which an
endoscope has been placed. Inset: Screen capture of the endoscopic
view of the thin-walled, 20-gauge needle (silver with bevel) from which
the radiofrequency electrode (black) is seen exiting and entering the
brainstem. The inferior edge of the cerebellum can be seen just to the
right of the needle.
technique for nucleotractotomy has been developed with the
addition of endoscopic observation (Fig. 175-1).110 As with other
ablative procedures, DREZ lesioning is most effective for reliev-
ing paroxysmal rather than continuous pain.104
Cordotomy is a valuable procedure for pain management,
especially for cancer pain, even though it has been largely replaced
by intrathecal analgesic administration. Cordotomy offers several
advantages and is one of the most clinically useful neuroablative
techniques.111 Although cordotomy can be performed as an
open procedure,112,113 the most common modern technique is
CT-guided and percutaneous, often with use of local anesthesia
(Fig. 175-2). In addition to requiring no long-term follow-up or
maintenance, percutaneous cordotomy allows for intervention
without interruption of chemotherapy, and only very brief cessa-
tion of anticoagulation therapy is necessary. Percutaneous cor-
dotomy, with its attendant real-time patient feedback, seems to
be much safer than the open procedure,114 resulting in a general
reconsideration of its place in the pain care algorithm. It is likely
that the risks and efficacy of the open procedure112,113 are not
relevant to percutaneous cordotomy; outcome studies of the
newer procedure are necessary. Moreover, the very low cost of
cordotomy relative to more expensive, implanted technologies
should be considered.
Cordotomy is used most commonly for the treatment of
cancer-related pain below mid- to low-cervical dermatomes that
Figure 175-2. Axial computed tomography myelogram image
through C1-C2. A thin-walled, 20-gauge needle enters from the left.
A small radiofrequency electrode passes through the needle and  
into the anterolateral quadrant of the spinal cord—the lateral
spinothalamic tract.
is lateralizing opposite the side of the cordotomy.112-117 It is used
sis of the newer percutaneous cordotomy for this indication has
yet to be performed.
Cordotomy can improve both lancinating, paroxysmal neu-
ropathic pain that sometimes arises from spinal cord injury and
evoked (allodynic or hyperpathic) pain associated with periph-
eral neuropathic pain syndromes, but it is not an effective
treatment for continuous neuropathic pain.117 Cordotomy pro-
vides good pain relief in approximately 60% to 90% of studied
patients.114,117,118 Although some data suggest a significant inci-
dence of recurrent pain following cordotomy,98,118,119 an observa-
tion used to suggest the procedure be reserved for patients with
limited life expectancy, there have also been case reports of pain
relief lasting years to decades.120,121
Historically, open cordotomy has been associated with
impaired respiratory function. For example, bilateral open cor-
dotomy has been linked to Ondine’s curse (potentially fatal loss
of respiratory drive during sleep).112,117 However, it is unclear
whether the same is true for the percutaneous procedure. A
review of 35 patients undergoing percutaneous cordotomy did
not demonstrate respiratory dysfunction,122 and in a later series
of 207 cordotomies, 12 of which were bilateral, there were no
instances of Ondine’s curse or other severe complication.114 Some
neurosurgeons have advocated using a CT-guided transdiscal
approach for the contralateral cordotomy to allow for placement
at different spinal cord levels, thereby mitigating the risk of
adverse outcome.123 An alternative approach is to perform a uni-
lateral high cervical percutaneous procedure followed by a con-
tralateral open low cervical or thoracic cordotomy.112,115
Like sympathectomy, myelotomy fell into disuse with the
advent of intrathecal drug infusion therapy, but it can provide
significant pain relief in properly selected patients, including
some who fail treatment with intrathecal analgesics.124 Commis-
sural myelotomy was developed to provide the benefits of
 CHAPTER 175  Neurosurgical Management of Intractable Pain 1433
Figure 175-3. Operating microscope image of midline myelotomy
through a T8-T9 laminectomy. The dura is tented open and the pia
has been incised in the midline. A blunt micro-instrument (right) is
creating the myelotomy up to the commissure. (A previously placed
intrathecal drug delivery catheter can be seen below the pial opening.)
bilateral cordotomy without the inherent risks associated with
lesioning both anterior quadrants of the spinal cord.124-127 It is
accomplished by sectioning spinothalamic tract fibers as they
decussate in the anterior commissure. Subsequently, it was
observed that a limited midline myelotomy (Fig. 175-3)128 or high
cervical myelotomy125,129,130 could be equally effective. Identifica-
tion of a dorsal column visceral pain pathway has led to the
development of punctate midline myelotomy.129,131
A myelotomy is indicated primarily for the treatment of
cancer pain, generally in the abdomen (visceral), pelvis, perineum,
or sacrum. It is most effective for nociceptive rather than neuro-
pathic pain and should be of particular utility to most neurosur-
geons because the various techniques are straightforward and the
anatomy is familiar. Early complete pain relief is achieved in more
than 90% of patients, but pain tends to recur over time; neverthe-
less, approximately 50% to 60% of patients experience long-term
pain relief.116,130 The risk of bladder, bowel, and sexual dysfunc-
tion is less than that associated with bilateral cordotomy but
remains sufficiently high, so the use of myelotomy procedures is
typically restricted to patients with cancer pain who have preex-
isting dysfunction.98 Recently, myelotomy has been performed as
a percutaneous, CT-guided outpatient technique with good
results (Fig. 175-4).132,133
Supraspinal Intracranial Techniques
Ablative neurosurgical procedures directed at the brainstem are
not widely used, in part because relatively few patients require
such interventions and because relatively few neurosurgeons have
the expertise to perform them. However, as with other ablative
procedures, they can provide significant benefit in carefully
selected cases. Mesencephalotomy, which is indicated for the
treatment of intractable pain involving the head, neck, shoulder,
and arm,76,134,135 can be viewed as a supraspinal version of cor-
dotomy.76 Mesencephalotomy is used for the treatment of cancer
pain and results in long-term pain relief in 85% of patients.130
This procedure, however, does not provide consistent long-term
relief of central neuropathic pain129 and is associated with fre-
quent side effects and complications, especially oculomotor dys-
function.76,129,130 The utility of mesencephalotomy has diminished
subsequent to the advent of neuraxial analgesic administration,
such as intraventricular morphine infusion, which can provide
175
Figure 175-4. Axial computed tomography myelogram just caudal
to the foramen magnum. The patient is prone. A thin-walled,
20-gauge needle enters thecal sac from directly posterior, through
which a radiofrequency electrode passes into the parenchyma of the
spinal cord between the dorsal columns.
good pain relief with a lower incidence of complications. Mesen-
cephalotomy, however, might be the preferred therapy for some
patients, for example, those with short life expectancies or for
whom the cost of the long-term follow-up required with neur-
axial analgesic administration becomes burdensome.
Thalamotomy has been used for the treatment of cancer
and noncancer pain and can be accomplished via stereotactic
radiofrequency,76,130,135-137 radiosurgery,138,139 or magnetic reso-
nance imaging (MRI)–guided, focused ultrasound.140 As a cancer
pain treatment, thalamotomy is most appropriate for patients
who have widespread pain (e.g., from diffuse metastatic disease)
or midline, bilateral, or head/neck pain for which other proce-
dures might not provide relief.108 Thalamotomy can be useful
for patients who are not candidates for cordotomy, for example,
those with pain above the C5 dermatome.137 Thalamotomy is
slightly less effective than mesencephalotomy but is associated
with fewer complications.137 The lateral thalamus (nucleus ven-
trocaudalis) is not considered an acceptable target for ablation
owing to the risk of dysesthesia and sensory loss,76 but the sub-
jacent parvicellular ventrocaudal nucleus, which is thought to
be a relay site for spinothalamic afferents, has been used as a
target. Results of thalamotomy directed to this structure might be
similar to those achieved with cordotomy.135 Medial thalamotomy
appears to be most effective for treating nociceptive pain (e.g.,
cancer pain), with acceptable long-term pain relief obtained in
approximately 30% to 50% of patients.76,118,136,139 Compared with
nociceptive pain, neuropathic pain responds less consistently to
thalamotomy, with only about one third of recipients achieving
long-term improvement.76,136 Patients with paroxysmal, lancinat-
ing neuropathic pain or neuropathic pain with elements of allo-
dynia and hyperpathia might experience significant improvement
after thalamotomy, whereas those with continuous neuropathic
pain tend not to benefit.76
Cingulotomy is used to treat cancer pain and has also been
used to treat noncancer pain; however, it is most commonly used
for management of psychiatric disorders.41,128,141-143 Approxi-
mately 50% to 75% of patients with cancer pain benefit from the
procedure, at least in the short term. In these patients, pain relief
is generally maintained for at least 3 months. The efficacy of
1434 SECTION 6  Pain
cingulotomy for chronic noncancer pain is less clear; some inves-
tigators report relatively good long-lasting pain relief,130,141,143 but
others indicate only 20% long-term success.134 Cingulotomy
might be a reasonable option for patients, especially those with
cancer pain, in whom other treatments have not worked. One
report suggests that the procedure may also effectively treat the
symptom of air hunger.144 The ability to perform a cingulotomy
using a noninvasive radiosurgical technique may make it more
attractive as an alternative for the fragile patients in whom it is
most often used.145 Because cingulotomy is performed for treat-
ment of psychiatric disease and carries the stigma of “psychosur-
gery,” formal review by institutional ethics committees might be
warranted if this procedure is being considered as a treatment for
intractable pain.
Hypophysectomy (surgical, chemical, or radiosurgical) can
provide good relief of cancer pain and is thought by some to be
most effective for hormone-responsive cancers (e.g., prostate,
breast), but seems to relieve pain related to other tumors as well.
Hypophysectomy is most appropriate for patients with wide-
spread disease and diffuse pain, especially pain associated with
diffuse bony metastases. Pain is alleviated in 45% to 95% of
patients independent of tumor regression; the specific mecha-
nism of pain relief is unknown.130,135,146-148
CONCLUSION
Successful treatment of intractable pain requires that the right
therapy be offered to the right patient at the right time. Candi-
dates for neurosurgical treatment must be identified carefully,
with full recognition of chronic pain as a biopsychosocial disor-
der. Undue emphasis on “pain generators” without consideration
of the psychosocial factors that contribute to the pain complaint
will predispose to treatment failure. Any recommendation must
be tailored to the clinical diagnosis, the emotional needs of the
patient, and his or her relevant social circumstances. Outcomes
of neuromodulatory therapies after proper patient selection are
good, and the risk of serious or permanent complications is low,
factors that must be carefully considered in the recommending
of first-line neurosurgical treatment of pain. These techniques,
especially the neurostimulation therapies, are superior to neu-
roablative techniques for the treatment of neuropathic pain with
a continuous, dysesthetic component. Neuroablation, however,
might be appropriate for other patients, including those with
cancer pain and a short life expectancy, those with predominantly
nociceptive pain, and those with neuropathic pain with paroxys-
mal or evoked components.
Neurosurgeons are unique within the discipline of pain
medicine by virtue of their diagnostic knowledge, technical
skills, and access to the nervous system. These attributes enable
neurosurgeons to provide pain treatments chosen from the entire
spectrum of pain therapies, including neuromodulation and
neuroablative techniques. As more attention is focused on neu-
romodulation for the treatment of intractable pain, ablative
strategies that might be appropriate for some patients may be
overlooked, especially by nonsurgical specialists unfamiliar with
the role of such neurosurgical therapies in the management of
intractable pain. Neurosurgeons should remain knowledgeable
about pain therapies and should remain actively involved in the
field of pain medicine to ensure the continued availability of the
entire spectrum of pain therapies. By accepting this responsibility,
neurosurgeons will continue to fulfill their important role in the
management of intractable pain.
Acknowledgment
The authors gratefully acknowledge the editorial assistance provided by
Keren Price.
SUGGESTED READINGS
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brain stimulation for neuropathic pain. Neurosurgery. 2013;72(2):221-
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Deer TR, Leong MS, eds. Comprehensive Treatment of Chronic Pain by
Medical, Interventional, and Integrative approaches. New York: Springer;
2013.
Deer TR, Levy R, Prager J, et al. Polyanalgesic consensus conference–
2012: Recommendations to reduce morbidity and mortality in intra-
thecal drug delivery in the treatment of chronic pain. Neuromodulation.
2012;15(5):467-482, discussion 482.
Deer TR, Mekhail N, Provenzano D, et al. The appropriate use of neuro-
stimulation of the spinal cord and peripheral nervous system for the
treatment of chronic pain and ischemic diseases: The Neuromodula-
tion Appropriateness Consensus Committee. Neuromodulation. 2014;
17(6):515-550, discussion 550.
Deer TR, Mekhail N, Provenzano D, et al. The appropriate use of neuro-
stimulation: Avoidance and treatment of complications of neurostimu-
lation therapies for the treatment of chronic pain. Neuromodulation.
2014;17(6):571-597, discussion 597-8.
Deer TR, Prager J, Levy R, et al. Polyanalgesic consensus conference–
2012: Recommendations on trialing for intrathecal (intraspinal) drug
delivery: Report of an interdisciplinary expert panel. Neuromodulation.
2012;15(5):420-435, discussion 435.
Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference
2012: Recommendations for the management of pain by intrathecal
(intraspinal) drug delivery: Report of an interdisciplinary expert panel.
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Deer TR, Prager J, Levy R, et al. Polyanalgesic Consensus Conference–
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Kanpolat Y. Percutaneous destructive pain procedures on the upper spinal
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Prager J, Deer T, Levy R, et al. Best practices for intrathecal drug delivery
for pain. Neuromodulation. 2014;17(4):354-372, discussion 372.
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control of cancer pain: The case for cordotomy. J Neurosurg. 2011;
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1434.e2 SECTION 6  Pain
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 Neuromodulation
176 Evidence-Based Neurostimulation for Pain
Feridun Acar, Athanasios K. Zisakis, and Selçuk Göçmen
Chronic pain is a major cause of physical and emotional suffering.
The medical treatment of patients with chronic pain is rather
challenging because serious side effects frequently complicate the
course of medical treatment. Neurostimulation is an intervention
that has become increasingly popular lately. However, patient
selection is of utmost importance to outcomes, and neuromodu-
lation does have recognized risks and complications, although
complications very rarely result in long-term morbidity or mor-
tality. First, neuromodulation aims to address the neuroanatomic
substrates thought to play a role in the propensity for pain.
Second, neuromodulation offers the ability to titrate the stimula-
tion parameters. Third, the nondestructive effect of neuromodu-
lation is important in minimizing the potential side effects of the
surgical procedure. Several new therapies and neuroanatomic
targets have been developed. They include stimulation of the
central nervous system through intracranial deep brain stimula-
tion (DBS), spinal cord stimulation (SCS), and peripheral nerve
stimulation (PNS).
Determination of the appropriateness of using neurostimula-
tion devices for pain is an ongoing and rather evolving process
that is often clouded by poor data, inaccurate patient selection,
and difficulty in understanding treatment goals. The Interna-
tional Neuromodulation Society (INS) has identified the need
for better definition of the appropriate application of the use of
these advanced tools for disease and pain, which has led to the
formation of the Neuromodulation Appropriateness Consensus
Committee (NACC) to evaluate the current literature and best
practices and to form an expert opinion on this topic. Thus, this
chapter focuses on evidence-based neurostimulation in the treat-
ment of pain.
INTRACRANIAL NEUROSTIMULATION
Intracranial neurostimulation for pain relief has been used effec-
tively in the algorithmic treatment of primary chronic headache
symptoms by stimulating the motor cortex, the sensory thalamus,
or the periaqueductal and periventricular gray matter. The stimu-
lation of these sites through motor cortex stimulation (MCS) and
DBS has proved effective for treating a number of neuropathic
and nociceptive pain states that are not responsive or amenable
to other therapies or types of neurostimulation. MCS has shown
particular promise in the treatment of trigeminal neuropathic
pain and central pain syndromes such as thalamic pain syndrome.
On the other hand, DBS may be employed for a number of
nociceptive and neuropathic pain states, including cluster head-
aches, failed back surgery syndrome, peripheral neuropathic pain,
facial differentiation pain, and pain secondary to brachial plexus
avulsion. Additionally, SCS in the high cervical (C1-C2) region
has been shown also to impact both headache and facial pain
syndromes.
Deep Brain Stimulation
DBS has been performed successfully to treat a variety of neuro-
pathic and nociceptive pain states that are not responsive to
other neuromodulation techniques, including cluster headaches,
failed back surgery syndrome, peripheral neuropathic pain, facial
176
deafferentation pain, and pain that is secondary to brachial plexus
avulsion.
It is extremely important to select a correct nuclear
target for satisfactory outcomes. Stimulation sites included
the periventricular/periaqueductal gray matter (PVG/PAG), the
internal capsule, the sensory thalamus, and the posterior hypo-
thalamus. It is important to note that benefit varies depending on
the etiology, length of follow-up, definition of adequate pain
relief, and the site of stimulation.
Levy and colleagues4 concluded that DBS has had its best
success in treating cluster headaches and nociceptive syndromes
such as chronic low back pain. Thalamic pain syndrome (prob-
ably owing to the frequent loss of the target cells for stimulation),
postherpetic neuralgia, and pain due to spinal cord injury are not
well treated with DBS. DBS continues to play a role in the treat-
ment of chronic pain when other less invasive treatment modali-
ties have been exhausted.
Motor Cortex Stimulation
Patient selection and target criteria are essential for MCS in
patients with refractory neuropathic pain and central pain. MCS
is a promising therapy for the treatment of trigeminal neuro-
pathic pain and central pain syndromes. Long-term stimulation
of the precentral cortex for the treatment of pain was first
reported by Tsubokawa and colleagues41 in 1991. MCS is more
commonly used than DBS because it is more easily performed.
Occipital Nerve Stimulation
Occipital nerve stimulation (ONS) is being investigated as a less
invasive and less risky alternative to deep brain intracranial stimu-
lation. Studies have reported promising results in small groups of
patients with cluster headaches. Some patients became pain-free,
but others had reduced frequency of headache attacks.
ONS is the most studied neuromodulation technique for
primary headaches. The overall efficacy of this procedure is
59%, and it has been effective in a variety of primary headache
conditions. The conclusion from these studies is that peripheral
neurostimulation techniques carry an advantage over central
neuromodulation.
Spinal Cord Stimulation
Spinal cord stimulation modifies the perception of pain by stimu-
lating the dorsal columns of the spinal cord and may relieve
neuropathic or ischemic pain.72 Relief of pain from failed back
surgery syndrome (FBSS) appears to respond best to SCS. SCS
was found to be superior to conventional medical management
and reoperation.
A study by Song and associates75 demonstrated that SCS is
significantly superior to conservative medical management and
reoperation for dealing with pain from FBSS. Clinical benefit was
also conclusively shown for complex regional pain syndrome,
critical limb ischemia, and refractory angina pectoris. Percutane-
ous hybrid paddle leads, peripheral nerve field stimulation,
nerve root stimulation, dorsal root ganglion, and high-frequency
1435
1436 SECTION 6  Pain
stimulation are actively being refined to address axial low back
pain and foot pain. High-frequency stimulation is unique in pro-
viding paresthesia-free analgesia by stimulating beyond the phys-
iologic frequency range. However, large randomized control
trials demonstrating clear clinical benefit are needed to gain
evidence-based support for the use of these newer treatments and
approaches.
Peripheral Nerve Stimulation
Peripheral nerve stimulation targets the peripheral nervous
system for the control of pain through either surgical placement
of electrodes directly over a peripheral nerve or percutaneous
placement of the electrodes sufficiently near the nerve to provide
an effective neuromodulating waveform.
Some observational studies showed that the peripheral nerve
stimulation and peripheral nerve field stimulation, two newer
types of neurostimulation, may be combined with SCS to improve
the outcomes of patients with low back pain.
CONCLUSION
In areas such as spinal cord stimulation for the treatment of pain,
there clearly is strong evidence for positive results. The large
number of evidence-based studies at level I support the use of
SCS as a basic method for treatment of pain from FBSS.
Results of studies of PNS and ONS do not reveal strong
evidence-based support of their use as methods for treating pain.
Still, the existing literature in PNS and ONS focuses on level III
evidence-based studies, so there is more to be done before con-
clusions can be drawn about their efficacy in treatment of pain.
On the other hand, however, the studies of DBS and MCS for
treating pain are far from achieving unambiguous evidence for
their use as treatment methods. Mainly the studies in these two
methods are at level III and thus cannot be considered the ideal
techniques for treating chronic pain.
From the literature on neurostimulation as a treatment of
pain, it can be concluded that there are data and studies support-
ing the use of neurostimulation as a treatment method in special
cases of pain but that further studies are needed to support an
epistemologic and clear conclusion concerning the efficacy and
importance of neurostimulation as a treatment method in pain.
Full text of this chapter is available online at ExpertConsult.com
 Neuromodulation
176 Evidence-Based Neurostimulation for Pain
Feridun Acar, Athanasios K. Zisakis, and Selçuk Göçmen
Chronic pain is a major cause of physical and emotional suffering.
The medical treatment of patients with chronic pain is rather
challenging because serious side effects frequently complicate the
course of medical treatment and some cases may be even intrac-
table to medical treatment.1 There is a long history to nerve
stimulation application, a process known as neurostimulation.
Neurostimulation is an intervention that has become increasingly
popular lately owing to the growing body of literature showing
its effectiveness in treating pain and the reversible nature of the
treatment with implant removal. However, patient selection is
of utmost importance to outcomes, and neuromodulation does
have recognized risks and complications, although complications
very rarely result in long-term morbidity or mortality.2 Neuro-
modulation systems are unique, and it is their treatment effective-
ness that is the major advantage for patients treated with them.
First, neuromodulation aims to address the neuroanatomic sub-
strates thought to play a role in the propensity for pain. Second,
neuromodulation offers the ability to control the strength of
the stimulation parameters for each case, potentially providing
improved benefit with minimal side effects. Third, the nonde-
structive effect of neuromodulation is important in minimizing
the potential side effects of the surgical procedure. Neuromodu-
lation has proved to be very well tolerated by patients. If adverse
effects occur, stimulation parameters may be changed, such as
decreases in intensity or frequency, and changing the stimulated
contacts. Another advantage is that there is no deterioration of
neurologic function. The neuroanatomic targets for these tech-
niques vary.
Several new therapies and neuroanatomic targets have been
developed. They include stimulation of the central nervous
system through intracranial deep brain stimulation (DBS), spinal
cord stimulation (SCS), and peripheral nerve stimulation (PNS).
Many studies, mostly in the form of retrospective case series
and a few prospective series, have consistently shown the benefits
of neurostimulation therapy in treating intractable chronic pain.1
Determination of the appropriateness of using neurostimula-
tion devices for pain is an ongoing and rather evolving process
that is often clouded by poor data, inaccurate patient selection,
and difficulty in understanding treatment goals. Lately, the Inter-
national Neuromodulation Society (INS) has identified the need
for better definition of appropriate application of these advanced
tools for disease and pain, which has led to the formation of
the Neuromodulation Appropriateness Consensus Committee
(NACC) to evaluate the current literature and best practices and
to form an expert opinion on this topic.3 According to their
conclusions, neurostimulation is rather safe. The reason is that
the procedure is minimally invasive and has reversible character-
istics. It is relatively difficult to compare with medical manage-
ment, because conservative management has already failed the
patients considered for neurostimulation. Unlike alternative
therapies, neurostimulation is not associated with medication-
related side effects and has an enduring effect. However, device-
related complications are still not uncommon. The incidence of
complications is dropping as technology progresses and surgical
skills improve. Randomized controlled studies on spinal cord
stimulation support its efficacy in treating failed back surgery
syndrome and complex regional pain syndrome.3 Analogous
176
studies of neurostimulation for peripheral neuropathic pain, post-
amputation pain, postherpetic neuralgia, and other causes of
nerve injury are needed to extend the support of neumodulation
as chronic pain treatment.3 International guidelines recommend
neuromodulation, and specifically spinal cord stimulation, as
treatment for refractory angina and other indications, such as
congestive heart failure. However, these indications are still
under investigation. Thus, this chapter focuses on evidence-based
neurostimulation in the treatment of pain.
INTRACRANIAL NEUROSTIMULATION
Intracranial neurostimulation for pain relief has been used effec-
tively in the algorithmic treatment of primary chronic headache
symptoms by stimulating the motor cortex, the sensory thalamus,
or the periaqueductal and periventricular gray matter. The stimu-
lation of these sites through motor cortex stimulation (MCS) and
DBS has proved effective for treating a number of neuropathic
and nociceptive pain states that are not responsive or amenable
to other therapies or types of neurostimulation.4 DBS and MCS,
techniques of intracranial neurostimulation, are commonly used
to control pain.
MCS has shown particular promise in the treatment of tri-
geminal neuropathic pain and central pain syndromes such as
thalamic pain syndrome. On the other hand, DBS may be
employed for a number of nociceptive and neuropathic pain
states, including cluster headaches, failed back surgery syndrome
(FBSS), peripheral neuropathic pain, facial differentiation pain,
and pain secondary to brachial plexus avulsion.4 Additionally, SCS
in the high cervical (C1-C2) region has been shown also to
impact both headache and facial pain syndromes.2,3,5,6
DEEP BRAIN STIMULATION
DBS has been performed successfully to treat a variety of neuro-
pathic and nociceptive pain states that are not responsive to other
neuromodulation techniques, including cluster headaches, FBSS,
peripheral neuropathic pain, facial deafferentation pain, and pain
secondary to brachial plexus avulsion.
It is extremely important to select a correct nuclear target for
satisfactory outcomes. Stimulation sites include the periventricular/
periaqueductal gray matter (PVG/PAG), the internal capsule, the
sensory thalamus, and the posterior hypothalamus.7 The use of
PVG/PAG stimulation is generally recommended for nociceptive
pain, and that of sensory thalamus DBS for deafferentation pain,
whereas DBS of the posterior hypothalamus is an effective
approach to treat refractory chronic cluster headache.7 It is
important to note that benefit varies depending on the etiology,
length of follow-up, definition of adequate pain relief, and the
site of stimulation.8
Long-term follow-up results of DBS for a number of indica-
tions have been reported by large studies.4,9-32 Katayama and
associates31 reviewed the effects of DBS and MCS treatments in
patients with pain after cerebrovascular accidents. DBS of the
thalamic nuclei ventralis oralis posterior et intermedius proved
to be useful in more than 70% of patients who had suffered with
poststroke involuntary movements.31 However, the results of
e613
e614 SECTION 6  Pain
DBS of the thalamic nucleus ventralis caudalis or internal capsule
for poststroke pain were disappointing.31
A meta-analysis performed to determine the long-term effi-
ciency of DBS for chronic pain found that the success rates varied
by diagnosis.8 This study showed that in periaqueductal gray
matter (PAG), rate of long-term pain alleviation was highest with
DBS of the PVG/PAG (79%) or of the PVG/PAG plus the
sensory thalamus/internal capsule (87%). Stimulation of the
sensory thalamus alone was proven less effective (58% long-term
success rate) (P < .05). DBS was more effective, however, for
nociceptive pain than for deafferentation pain (63% versus 47%
long-term success rates, respectively; P < .01). Long-term success
was attained in more than 80% of patients with intractable low
back pain (FBSS) following successful trial stimulation. Trial
stimulation was also successful in approximately 50% of those
with poststroke pain, and 58% of patients who received perma-
nent stimulation implants achieved ongoing pain relief.
Levy and colleagues34 performed a meta-analysis to determine
the efficacy of DBS for the treatment of chronic pain. They
evaluated 13 series with long-term outcome reports for a total of
1114 patients.15,26-28,30-37 Of these patients, 561 (50%) had long-
term successful pain relief with DBS. The rates of long-term
success ranged from 19% to 79%, and it appears that there is a
falloff in success as the length of follow-up increases. Overall, 711
patients had neuropathic pain, of whom 296 (42%) were without
pain at long-term follow-up. Of the 443 patients with nociceptive
pain, 272 (61%) experienced long-term pain relief. Of 409
patients in whom the ventral posterolateral nucleus of thalamus
(VPL) was stimulated for neuropathic pain, 228 patients had
long-term pain relief (56%), but none of the 51 patients in whom
sensory thalamic stimulation was used for nociceptive pain did
so. A total of 35 out of 155 patients (23%) experienced long-term
pain relief when the PVG was stimulated for neuropathic pain,
whereas 172 out of 291 patients (59%) did so when the same site
was used to treat nociceptive pain. These results support the
hypothesis that PVG stimulation is the preferred site for nocicep-
tive pain states and that sensory thalamic stimulation is preferable
for neuropathic pain treatment.
Levy and colleagues4 concluded that DBS appears to be
more effective for certain pain states than others. Long-term
success was achieved more frequently for pain resulting from
cervical or brachial avulsion, pain due to peripheral neuropathy,
and pain in FBSS. DBS, however, appears to be less effective
for the treatment of thalamic pain syndrome and paraplegia
pain. For other pain states, outcomes reported in the literature
are mixed.
Martelletti and associates,1 reviewing more than 60 articles
about patients undergoing hypothalamic implantation of elec-
trodes for cluster headache and other types of trigeminal auto-
nomic cephalalgia for the European Headache Foundation,
found the overall success rate (patients pain-free or with 50% or
more improvement) was found to be around 50% to 60%; accu-
mulated follow-up data made it possible to better understand the
advantages and limitations of the procedure.1
Levy and colleagues4 concluded that intracranial stimulation
should be considered only after more conservative therapies,
including less invasive neurostimulation methods, have failed.
Like other pain treatments, MCS or DBS must be employed in
light of the circumstances of individual cases and the morbidity
associated with alternative treatments, particularly the long-term
use of opioids. MCS appears to be an appropriate treatment for
neuropathic facial pain, poststroke pain, and chronic pain condi-
tions that do not respond to other types of neurostimulation.
However, there may be cases in which MCS is indicated without
being preceded by such neurostimulation, as is the case in patients
with complete deafferentation conditions. There is no compel-
ling evidence that MCS is less effective than DBS for treating
chronic pain.
Owing to the poor overall results reported by several investi-
gators, DBS is not highly recommended for thalamic pain syn-
drome, postherpetic neuralgia, or pain due to spinal cord injury.4
Implantation of two leads, one in the PAG/PVG and the other
in the sensory thalamus, may optimize the chances of achieving
satisfactory pain relief.
An uncritical review of the literature indicates that DBS
appears to be more effective for certain pain states than others.5
For example, previous studies have concluded that DBS can be
successful in treating specific conditions such as cluster headaches
and nociceptive syndromes such as chronic low back pain.38-40
Long-term success also appears to be achieved more frequently
for pain resulting from cervical or brachial avulsion, peripheral
neuropathy, and FBSS. In contrast, the literature indicates that
DBS appears to be less effective for the treatment of thalamic pain
syndrome and paraplegia pain. Almost all of the evidence to
support the use of DBS is derived from uncontrolled, unblinded
case series, so this evidence must be interpreted with considerable
caution.
In 2013, Martelletti and associates1 reviewed and analyzed any
currently existing method of neuromodulation for chronic head-
ache if at least two case series had been published for it. This
paper was therefore not a conventional guideline but an interna-
tional expert recommendation based strictly on published evi-
dence. Their conclusions are summarized below:
• General recommendations:
• From a medical standpoint, neurostimulators should be
considered only when all appropriate alternative drug and
behavioral therapies as recommended by international
guidelines have failed and medication overuse headache is
excluded.
• The patient has to be considered to have chronic headache,
following the current International Headache Society
(IHS) definition and the evaluation has to be done by a
tertiary care headache center.
• The patient’s headache has to be medically intractable as
defined by international consensus.
• Procedural recommendations:
• Hypothalamic stimulation (HS) as a treatment for chronic
cluster headache (CCH) is invasive and expensive, and
should be employed with caution.
• Occipital nerve stimulation (ONS) is also an expensive and
invasive technique. ONS may prevent CCH but has no
acute effect on CCH.
• Sphenopalatine ganglion stimulation should be considered
experimental because there is only one placebo-controlled
study in the literature. It may be worthwhile to use this
method for episodic cluster headaches, given the contribu-
tion of the parasympathetic system to the origin of cluster
headaches.
• Vagal nerve stimulation (VNS) may be employed for
chronic headache treatment but only in the context of a
randomized placebo-controlled trial.
• Transcranial direct current stimulation (TDS) may also be
a candidate for a controlled trial.
• Transcranial magnetic stimulation (TMS) appears to be
safe, but further study is necessary to determine whether
it is potentially effective for chronic migraine. However,
further studies are important to assess factors underlying
its therapeutic effect.
• Spinal cord stimulation should be avoided in patients with
primary headache syndrome.
Subsequently, in 2014, Deer and coworkers2 reported on a
further consensus statement on the clinical use of neuromodula-
tion in chronic pain based on theoretical background, clinical
data, and side effect of each method.

MOTOR CORTEX STIMULATION
Patient selection and target criteria are essential for MCS in
patients with refractory neuropathic pain and central pain. MCS
is a promising therapy for the treatment of trigeminal neuro-
pathic pain and central pain syndromes. Long-term stimulation
of the precentral cortex for the treatment of pain was first
reported by Tsubokawa and colleagues41 in 1991.41,42 MCS is
more commonly used than DBS because it is more easily
performed.2,3,5,6,43
Previous studies involving MCS have focused on its use in
poststroke and trigeminal neuropathic pain, for which there are
few other treatments.4,41-51 Poststroke pain responds well to
MCS, with approximately two thirds of patients experiencing
adequate relief. Some studies have shown that 75% to 100% of
patients with trigeminal neuropathic pain have excellent pain
relief.43,52-56
OCCIPITAL NERVE STIMULATION
Occipital nerve stimulation (ONS) is being investigated as a less
invasive and less risky alternative to deep brain intracranial stimu-
lation. Studies have reported promising results in small groups of
patients with cluster headaches.60 Some patients became pain-
free, whereas others had reduced frequency of headache attacks.
Burns and associates60 in 2009 presented a study on ONS in
14 patients with intractable chronic cluster headache. At a median
follow-up of 17.5 months (range of follow-up 4-35 months), 10
of the 14 patients reported improvement. Three patients had
improvement of more than 90%, three of them had moderate
improvement (40%-60%), and four patients had mild improve-
ment (20%-30%).
ONS implantations for 15 patients with intractable CCH
were prospectively monitored for up to 5 years (mean 36.8
months)61. The device was infected in one patient. Of the remain-
ing 14 patients, nearly 80% had a 90% or greater reduction in
attack frequency and 60% remained pain-free during long periods
(months to years), results that are consistent with those of other
studies, indicating that ONS demonstrates rather promising
results.1,62 Furthermore, a prospective trial of ONS in 13 patients
demonstrated that the mean attack frequency and intensity
decreased by 68% and 49%, respectively.1,63 That study showed
that 8 of the 13 patients were able to reduce or even stop their
preventive medications. Burns and colleagues64 performed ONS
in 6 patients with hemicrania continua (range of application was
6 to 21 months)64 and reported that 4 of them experienced pain
reduction exceeding 80%. In two reports of the use of ONS in a
total of 9 patients with drug-resistant short-lasting unilateral
neuralgiform headache attacks with conjunctival injection and
tearing (SUNCT) and 3 with short-lasting unilateral neuralgi-
form headache attacks with autonomic symptoms (SUNA),
the patients experienced at least 50% relief after ONS, and 4
patients were nearly pain-free after approximately 14 months of
follow-up.65,66
Only three randomized controlled trials (RCTs) of ONS in
chronic migraine have been published since 2009, and their out-
comes overall were disappointing. In the Precision Implanted
Stimulator for Migraine (PRISM) trial, patients with drug-
refractory chronic migraine were treated with ONS or sham
therapy without any significant improvement.67 In the ONSTIM
trial, 39% of 66 patients treated with active ONS over 3 months
had at least 50% reduction in headache frequency and/or a
3-point decrease in intensity scale score, while there was no
improvement in the nonstimulated group or in those having
preset rather than adjustable stimulation.68 Finally, in a trial
involving 157 patients, the percentage of “responders” did not
significantly differ between active (17.1%) and control (13.5%)
groups (primary end point).69 However, the number of headache
CHAPTER 176  Evidence-Based Neurostimulation for Pain e615
days was significantly lower in the ONS group than in the sham
therapy population (−27.2% vs. −14.9%, respectively). A decrease 176
in migraine-related disability with the application of ONS was
also found. Interestingly, the combination of occipital and supra-
orbital neurostimulation in an uncontrolled series of 7 patients
with chronic migraine produced a headache frequency improve-
ment greater than 90% in all patients, but there was no significant
response to either stimulation alone.1
ONS has also been used in drug-refractory chronic cluster
headache (dCCH), but only open studies have been performed
and in smaller groups of patients than for chronic migraine. In
the three main trials treating a range of 13 to 15 patients, the
success rate was slightly more than 60%.1
Jenkins and colleagues70,71 systematically reviewed the avail-
able data on neurostimulation for primary headache conditions.
Their first review dealt with the pathophysiology, relative
anatomy, theoretical mechanisms, and history of neurostimula-
tion; and the second review focused on central stimulation
and contained an overall analysis of efficacy, safety, cost, patient
selection, and suggestions for further study based on available
evidence. In their review of 154 articles and abstracts, the inves-
tigators found that ONS is the most studied neuromodulation
technique for primary headaches. The overall efficacy of this
procedure is 59%, and it has been effective in a variety of primary
headache conditions. The investigators concluded that peripheral
neurostimulation techniques carry an advantage over central
neuromodulation.
SPINAL CORD STIMULATION
Spinal cord stimulation modifies the perception of pain by stimu-
lating the dorsal columns of the spinal cord, and may relieve
neuropathic or ischemic pain.72 Pain from FBSS appears to
respond best to SCS. SCS was found to be superior to conven-
tional medical management (CMM) and reoperation.73-75
Liem and associates,58 in a multicenter, prospective, open-
label, observational study, reported 50% reduction in back, leg,
and foot pain in 57%, 70%, and 89% of patients, respectively,
with use of dorsal root ganglion stimulation. Simpson and
coworkers72 performed a systematic review and economic evalu-
ation of SCS using 6000 studies. Eleven RCTs were included in
the clinical effectiveness: three of neuropathic pain and eight of
ischemic pain. These reviewers suggested that SCS was more
effective than CMM or reoperation in reducing pain, as shown
in the study by Song and associates.75 The main limitation of the
ischemic pain trials was the small sample sizes, suggesting that
most of the trials may not have been adequately powered to
detect clinically meaningful differences. Trial evidence failed to
demonstrate that pain relief in critical limb ischemia (CLI) was
better for SCS than for CMM.72 Simpson and coworkers72 con-
cluded that SCS was effective in reducing the chronic neuro-
pathic pain of FBSS and complex regional pain syndrome (CRPS)
type I. In the ischemic pain disorders, development of selection
criteria may be required for CLI, and SCS may have clinical
benefit for refractory angina in the short term.72
The favorable outcome of SCS was also presented in another
study of 83 patients in whom high-frequency (10-kHz) SCS
(HF10) was used.76 The good results in 6 weeks of follow-up were
sustained at the 24-month follow-up.77 However, without a sepa-
rate comparator, the placebo effect could not be discounted.76,77
Another double-blinded study (N = 40) reported that there was
no difference between HF5 SCS (5 kHz stimulation) and sham
control after 2 weeks of stimulation.75,78 Sham control (no stimu-
lation after paresthesia-free stimulation was achieved) was the
control. Assessing the results from these two studies (HF10 SCS
and HF5 SCS), one can conclude that different frequencies may
have different effects. Furthermore, the study using HF10 SCS
looked at 6-month and 24-month results, but the HF5 SCS study
e616 SECTION 6  Pain
looked only at 2-week results, making comparisons between the
two studies more challenging. HF10 SCS is in phase 3 trials in
the United States and a multicenter, prospective, RCT is under
way; the results may shed further light on the future of paresthesia-
free, high-frequency analgesia.
Sears and colleagues102 reported better results for SCS, with
only 50% or greater pain relief in 50% of the patients with CRPS,
at a mean follow-up of 4.4 years. However, Kemler and associ-
ates79,80 did report that 95% of the patients implanted with an
SCS device for RSD/CRPS reported that they would undergo
the treatment again. Ultimately, however, a higher-powered RCT
may be needed to resolve whether SCS is a reasonable approach
to patients with CRPS, in the long term.
Furthermore, SCS for treatment of critical limb ischemia
appears to have mixed results for pain relief and limb salvage;
however, a meta-analysis of several RCTs demonstrated clear
benefit of SCS in limb salvage.81 SCS was reported to be superior
to conservative management for refractory angina pectoris but
equivalent to coronary artery bypass graft surgery (CABG).82-85
Poor patient selection and indiscriminate use of SCS for a variety
of pain conditions were identified as accounting for the low effi-
cacy rates (<25%) in early SCS studies.57 Later RCTs have dem-
onstrated that with careful patient selection, SCS can be clinically
efficacious and cost effective in FBSS, CRPS, refractory angina,
and critical limb ischemia.33,73,74,80-89 The disciplined pain physi-
cian generally selects SCS for the patient in whom conservative
treatment has failed and has the patient undergo psychological
evaluation prior to performing a SCS trial.90
Satisfactory pain relief after SCS therapy is supported also by
a randomized, controlled study (N = 50) that compared the clini-
cal outcomes of SCS and repeated back operations.74 In the trial,
patients in whom results of the randomly assigned treatment
were unsatisfactory could “cross over” to undergo the other treat-
ment. It was found that patients treated with SCS reported better
pain relief and higher satisfaction levels than those treated with
surgical reoperations, and when given the choice, many patients
who received reoperations would have chosen SCS over reopera-
tion.74,90 Among the 45 patients (90%) available for follow-up,
SCS was more successful than reoperation (9 of 19 patients versus
3 of 26 patients; P < .01). Patients who initially were randomly
allocated to undergo SCS were significantly less likely to cross
over than were those allocated to reoperation (5 of 24 patients
versus 14 of 26 patients; P = .02). Also, patients undergoing
reoperation required increased opiate analgesics significantly
more often than those undergoing SCS (P < .025).74
Another study compared the outcomes of CMM alone with
CMM plus SCS in 100 patients with FBSS and predominantly
radicular leg pain.73 In the intention-to-treat analysis at 6 months,
the primary outcome (50% or more pain relief in the legs) was
achieved in 24 of the 50 patients in the CMM + SCS group (48%)
and 4 of the 50 in the CMM alone group (9%) (P < .001).
Between 6 and 12 months, 5 patients in the CMM + SCS group
crossed over to CMM alone, and 32 patients in the CMM alone
group crossed over to CMM + SCS. At 12 months, 27 patients
in the CMM + SCS group (32%) had experienced device-related
complications. The investigators concluded that CMM plus SCS
provides better pain relief and improves health-related quality of
life and functional capacity in comparison with CMM alone in
selected patients with FBSS.73,90
A study by Song and associates75 demonstrated that SCS is
significantly superior to conservative medical management and
reoperation in patients with pain from FBSS. Clinical benefit was
also conclusively shown for complex regional pain syndrome,
critical limb ischemia, and refractory angina pectoris. Percutane-
ous hybrid paddle leads, peripheral nerve field stimulation, nerve
root stimulation, dorsal root ganglion, and high-frequency stimu-
lation are actively being refined to address axial low back pain
and foot pain. High-frequency stimulation is unique in providing
paresthesia-free analgesia by stimulating beyond the physiologic
frequency range. However, large RCTs demonstrating clear
clinical benefit are needed to gain evidence-based support for
their use.
PERIPHERAL NERVE STIMULATION
Peripheral nerve stimulation targets the peripheral nervous
system for the control of pain through either surgical placement
of electrodes directly over a peripheral nerve91 or percutaneous
placement of the electrodes sufficiently near the nerve92 to
provide an effective neuromodulating waveform.5
Some observational studies showed that PNS and peripheral
nerve field stimulation (PNfS), two newer types of neurostimula-
tion, may be combined with SCS to improve the outcomes of
patients with low back pain.75,93-96 In these observational studies,
baseline VAS was used as the internal control, adding the possibil-
ity, as previously suggested, that the placebo effect was a con-
founding variable.75
The larger area of analgesia provided by PNfS may be due to
inter-lead stimulation (“cross-talk”) between the two separate
subcutaneous leads, as demonstrated in cadavers by Falco and
colleagues.93 The mechanism for PNfS is unknown but is specu-
lated to be similar to that for SCS.75
DISCUSSION
Evidence-based medicine aims to optimize decision making by
emphasizing the use of evidence from well-designed and well-
conducted research. Although all medicine based on science has
some degree of empirical support, evidence-based medicine goes
further, classifying evidence by its epistemologic strength and
requiring that only the strongest evidence (coming from meta-
analyses, systemic reviews, and randomized controlled trials) can
yield strong recommendations; weaker evidence (such as from
case-control studies) can yield only weak recommendations.
Evidence quality can be assessed according to the source type
as well as other factors, including statistical validity, clinical rel-
evance, currency, and peer-reviewed acceptance. Evidence-based
medicine categorizes different types of clinical evidence and rates
or grades them according to the strength of their freedom from
the various biases that beset medical research.
Several organizations have developed grading systems for
assessing the quality of evidence. This chapter used the grading
system of the U.S Preventive Services Task Force (USPSTF),
which defines the grades or levels as follows103:
• Level I: Evidence obtained from at least one properly designed
randomized controlled trial.
• Level II-1: Evidence obtained from well-designed controlled
trials without randomization.
• Level II-2: Evidence obtained from well-designed cohort or
case-control analytic studies, preferably from more than one
center or research group.
• Level II-3: Evidence obtained from multiple time series designs
with or without the intervention. Dramatic results in uncon-
trolled trials might also be regarded as this type of evidence.
• Level III: Opinions of respected authorities, based on
clinical experience, descriptive studies, or reports of expert
committees.
Intracranial Stimulation
For general studies on intracranial stimulation, five studies were
examined, of which four can be assigned level I for quality of
evidence,2,3,5,6 and the fifth, level II-3.4,34 It could be said that there
is strong support for the efficacy of neurostimulation for the
treatment of the pain, because the studies are mainly level I.

Deep Brain Stimulation
Of the studies examining the effect of DBS in the treatment
of pain, we found 3 with level I quality of evidence,3,6,8 3 with
level II-3,1,4,8 and 34 with level III.9-28,30-33,36-40,45,46,73,97,98 So it is
obvious that in this area, because there are only a few evidence
level I studies and mainly level III studies, the support for
the efficacy of DBS as treatment method for pain is not strong.
DBS for the treatment of chronic pain is a technique that evolved
more than 35 years ago, at a time when the level and quality
of medical evidence to support a procedure were not as objective
as they are currently. As a result, effectively no level I studies
have been performed on these procedures. Thus, we must rely
on meta-analyses and systematic reviews as the underpinnings
of our conclusions about the effectiveness of DBS as a pain
treatment.
Motor Cortex Stimulation
A similar pattern of studies was found in the case of MCS. There
were 23 studies. Three studies were level I,2,5,6 1 was level II-1,58
1 was level II-2,59 and two were level II-34,57; the remaining 16
were level III.41-45,47-52,54,56,99,100 Strong support cannot be given to
MCS as a method of treating pain because most of the evidence
is level III quality.
Occipital Nerve Stimulation
In the treatment of pain by ONS, however, there were three
studies with level I evidence,67-69 two with level II-2,64,70 three with
level II-31,65,66 and four with level III.60-63 The majority of the
studies were level III and there are few level I and level II studies,
so it could be said that ONS as treatment of pain has stronger
support than MCS, suggesting the role of ONS as a rather effec-
tive pain treatment.
Spinal Cord Stimulation
Examining the studies on SCS shows that this method is clearly
effective in the treatment of pain. Out of 21 studies, 10 were level
I in quality of evidence,73,74,78,79,81-84,86,87 2 were level II-1,58,101 4
were level II-2,75-77,85 2 were level II-3,57,88 and 3 were level
III.80,90,102 These studies support SCS as an important way of
treating pain.
Peripheral Nerve Stimulation
Finally in the area of PNS there were eight studies. Two were
level I in quality of evidence,6,95 two were level II-2,75,96 and four
were level III,91-94 again showing rather good support for the
efficacy of PNS in pain treatment.
CONCLUSION
It can be concluded that in areas such as spinal cord stimulation
for the treatment of pain, there clearly is strong evidence for
positive results. The large number of evidence-based studies at
level I support the use of SCS as a basic method for treatment of
pain from FBSS.
Results of studies of PNS and ONS do not reveal a strong
evidence-based support for their use as methods for treating pain.
Still, the existing literature in PNS and ONS focuses on level
III evidence–based studies, and thus there is more to be done
before conclusions can be drawn about their efficacy in treatment
of pain.
Studies of DBS and MCS for treating pain have not been
conducted by evidentiary standards that stand up to contempo-
rary scrutiny. Therefore, until such data is available, these
CHAPTER 176  Evidence-Based Neurostimulation for Pain e617
procedures cannot be recommended as other than an option for
patients with chronic pain. 176
Taking into account the studies on neurostimulation as a treat-
ment for pain, we can conclude that there are data and studies
supporting the use of neurostimulation as a treatment method
in special cases of pain but that further studies are needed
to support an epistemologic and clear conclusion concerning
the efficacy and importance of neurostimulation as a treatment
method for pain.
SUGGESTED READINGS
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neurostimulation: new and evolving neurostimulation therapies and
applicable treatment for chronic pain and selected disease states. Neu-
romodulation. 2014;17:599-615.
Deer TR, Mekhail N, Petersen E, et al. The appropriate use of neuro-
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head for chronic pain. Neuromodulation. 2014;17:551-570.
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177 Peripheral Nerve Stimulation for Neuropathic Pain
Cristian Gragnaniello, Angela Li Ching Ng, and Andrew C. Zacest
Peripheral nerve stimulation (PNS) involves passing electrical
current through peripheral nerve fibers to cause paresthesias in
the distribution of that nerve to alleviate neuropathic pain, based
on the gate-control theory of pain, suggested by Melzack and
Wall.1,2 The concept was initially instigated from an observation
made by Scribonius Largius that electric shocks sent by sea crea-
tures such as the torpedo fish or Mediterranean ray could attenu-
ate pain in patients with gout and headaches.3,4
The first reports of PNS with implantable devices are even
older than those of spinal cord stimulation (SCS) in 1966 and
1967. Wall and Sweet stimulated patients with neuropathic pain,
achieving pain suppression while the stimulator was in function.5
Around the same time, Shelden implanted PNS electrodes with
14,000-Hz stimulation, achieving temporary pain relief.6
THEORY AND APPLICATION
According to the gate-control theory of pain, large A delta and
small C nerve fibers carry normal and painful sensations, respec-
tively, to the substantia gelatinosa, where stimulatory and inhibi-
tory neurons are activated to transmit sensory messages to the
brain. Pain perception is allowed to pass through this gate only
when small nerve fibers are triggered; stimulation by signals from
both types of fibers suppresses the nociceptive input at the spinal
cord level and reduces the signals to the sensory cortex.
Wall and Street later tested this theory on themselves by
inserting electrodes in their own infraorbital foramina to stimu-
late A delta fibers and found that they had pinprick sensation in
the area stimulated, followed by numbness or paresthesia. Shortly
after this, the first surgical implantation of electrodes was per-
formed around the ulnar and median nerves of a patient with
complex regional pain syndrome.5
Surgical exposure of nerves for implantation of electrodes has
been a source of major delays in popularizing PNS surgery, and
only when Weiner and Reed developed the percutaneous inser-
tion of electrodes for occipital neuralgia and migraines did PNS
start to become more accepted and widely performed.7-13 Since
then, the technique has been used for treatment of occipital
headaches, migraines, trigeminal nerve pain, truncal pain and
autonomic disruption (as in diaphragmatic palsy), complex pain
syndrome, back pain, and sacroiliac pain and fibromyalgia.12,14-20
Supraorbital PNS has been used for postherpetic neuralgia and
trigeminal neuralgia.21,22
INDICATIONS
Patient selection is crucial for success of PNS. The primary
indication is a description of neuropathic pain by the patient, with
the classic symptoms of hyperalgesia, hyperpathia, hyperesthesia,
and allodynia.23-25 The patient’s pain should also have been refrac-
tory to previous conservative treatment. The area of pain
described should correspond to nerve root distribution and neu-
ropathy confirmed via electromyography (EMG) and somatosen-
sory evoked potentials. A psychological and cognitive assessment
should also be conducted. A test trial is also often performed 7
to 10 days before implantation of the device to determine the
likely response to PNS. Patients who benefit from PNS usually
experience at least 50% improvement after trial of a temporary
device.26 A good response to transcutaneous electrical nerve stim-
ulation (TENS) may also be a good indicator of benefit.
177
Contraindications include patients on anticoagulants, active
infection at the site of electrode insertion, and major cognitive
problems such as refractory depression or major personality
disorder.
TECHNIQUE
The PNS device is made up of electrodes inserted along the
desired peripheral nerve and a generator system that is buried
subcutaneously some distance away. PNS is composed of two
different phases—an initial trial followed by a permanent implant.
Electrodes can be placed in an open fashion or percutaneously.
Before the development of a percutaneous technique, direct
nerve exposure and placement of the peripheral nerve electrode
over the nerve was performed under radiologic guidance.
In open surgery the nerve is exposed and a plate-type elec-
trode is placed next to the nerve, surrounded by fascia. Major
peripheral nerves are exposed at their traditional exposure sites
(Table 177-1 and Fig. 177-1).
The leads for the first part of the procedure are usually kept
for 2 days, and a chart of pain scores at different stimulation
intensities is maintained.
At present the procedure is truly minimally invasive, with a
sedated patient. A Tuohy needle is used to insert the percutaneous
leads subcutaneously perpendicularly to the nerve from medial
to lateral or vice versa, and the electrode is guided over the region
of maximal pain. An ultrasound probe can be used for peripheral
nerves that are difficult to locate.
Over the years, delivery of electrical stimuli has improved
while safety has been maintained. Initially, electrodes were
paddle-like or cylindrical in shape, but these were changed to
button electrodes or fascial padding after a high rate of fibrosis
was noted after use in surgically exposed nerves. Moreover, the
newer electrodes are designed to cover wider surface area of
stimulation and are better insulated for patient safety. They have
also proven to have a lower risk of migration when anchored to
the skin and produce more targeted stimulation of the required
nerve if the nerve is below or between two electrodes. With the
invention of percutaneous PNS the electrodes can be quadripolar
or octapolar.
The implantable generators can have a primary cell or be
rechargeable. Although rechargeable batteries last longer, they
are usually more expensive and should be inserted only in patients
able to recharge them frequently. Combinations of different leads
and generators are available to suit stimulation requirements.
After the electrode is implanted, it is tunneled out to connect to
the external generator. The device can be tested intraoperatively
and the generator is buried subcutaneously, often in the gluteus
region, abdominal wall or infraclavicular region, away from joints
and locations that may reduce mobility. They should also be
inserted deep enough to reduce the risk of pressure sores in bed-
bound patients.
OUTCOME
Although studies of PNS for various peripheral nerve locations
remain small, there is evidence to show that in select groups of
patients, PNS can have major effects in reducing neuropathic
pain. In a study of PNS with suboccipital stimulators in chronic
migraine by Matharu and colleagues, 50% of patients had
1437
1438 SECTION 6  Pain

3 Lead
4 2
Medial intermuscular Ulnar n.
5
septum
Brachialis m.

C7 Subclavicular
pouch
C8 Struther’s (IPG)
C6 arcade
Skin incision
Ulnar nerve
Medial epicondyle
Arcuate 2 Subcutaneous
C6 1 Cubital Suture tunnel
C8 ligament
tunnel Lead extension in
subcutaneous tunnel to IPG
Ulnar n.
C5 Lead

T1 Ulnar nerve

Lead
A B 3 C
Figure 177-1. Ulnar nerve stimulation. A, Distribution of the ulnar nerve in the right forearm and hand.
B, Surgical anatomy of the approach and placement of the ulnar nerve stimulator. 1, Skin incision, with
musculature, ligaments, and tendons shown. 2, The ulnar nerve is mobilized in the usual fashion and the lead
placed beneath it. 3, The lead is anchored to prevent its mobilization. C, Subcutaneous pacemaker placed
under the right clavicle and with a cord tunneled to the lead at the elbow. IPG, implantable pulse generator.

TABLE 177-1  Major Peripheral Nerves Are Exposed at Their
Traditional Exposure Sites
Nerve Exposure
Median and ulnar Brachial groove
Radial Spiral groove
Common peroneal Deep to the biceps femoris cranial to
the popliteal space
Posterior tibial Proximal to the medial malleolus
Sciatic nerve Sciatic notch
excellent response, with headaches being completely suppressed
with rare occasions of breakthrough headaches; 25% had good
response with headaches completely suppressed most of the time
with a pain reduction of 50% to 75% at follow-up of up to 3
years.20 In 30 patients craniofacial pain, including supraorbital,
occipital, and infraorbital pain, Slavin and colleagues showed that
16 (53%) experienced more than 50% improvement in pain
intensity; three patients (10%) had less than 50% pain improve-
ment, and three (10%) had complications from their devices
including loss of effect or infection.16 Johnson and colleagues
revealed some successful treatment of trigeminal neuralgia after
postherpetic neuralgia and facial trauma—at least 50% reduction
in pain in 7 of 10 patients, as well as decrease in medication use.21
In a long-term study of PNS in 30 patients with reflex sympa-
thetic dystrophy, 60% experienced good or fair relief and there
was an overall 60.9% pain reduction after electrode implantation
in the ulnar, median, radial, and superficial peroneal nerves. In
case reports of three patients with intractable postoperative
inguinal pain, all patients had 75% to 100% pain relief up to 12
months after implantation. Paicius and colleagues27 reported on
six patients with chronic low back pain treated with PNS; in this
cohort, all patients had less pain and better quality of life. Finally,
in a 100-patient case study of PNS in chronic pain including
craniofacial, thorax, lumbosacral, abdominal, pelvic, and groin
pain conditions, the authors showed an average pain reduction of
4.2 ± 2.5 pain scale points on an 11-point scale after PNS and an
overall reduction in analgesic use at follow-up 1 to 23 months
later.28
Individual complications after PNS in the aforementioned
studies included electrode migration, breakage of parts, skin
infection, and muscle spasm that could have required removal and
replacement of the apparatus; but in general, rates of complica-
tions are low.
FUTURE
There is a lot of positive outcome to gain from PNS in neuro-
pathic pain. There are still unanswered questions on the way PNS
works to cause analgesia. More studies should be guided toward
patient selection, and more long-term follow-up studies should
be conducted to expand the range of conditions that can be
managed by this noninvasive treatment. Another field of expan-
sion is the devices used; there is increased interest in new elec-
trodes and the nerves’ response to electrode type and positioning.
There are still devices that are not approved for clinical use, and
we should invest in further research to make these pieces of
hardware safe for clinical use.
SUGGESTED READINGS
Eisenberg E, Waisbrod H, Gerbeshagen HU. Long term peripheral nerve
stimulation for painful nerve injuries. Clin J Pain. 2004;20:143-146.
Freitas TD, Paiva AV, Ogliari KC, et al. Peripheral nerve stimulation to
treat chronic painful syndromes. Rev Dor. 2013;14:315-319.
Johnson MD, Burchiel KJ. Peripheral stimulation for treatment of tri-
geminal postherpetic neuralgia and trigeminal posttraumatic neuro-
pathic pain: a pilot study. Neurosurgery. 2004;55:135-142.
Slavin KV. History of peripheral nerve stimulation. Prog Neurol Surg.
2011;24:1-15.
Wall PD, Sweet WH. Temporary abolition of pain in man. Science.
1967;155:108-109.
White JC, Sweet WH. Pain and the Neurosurgeon. A Forty-Year Experience.
Springfield, IL: Thomas; 1969:894-899.
See a full reference list on ExpertConsult.com
 CHAPTER 177  Peripheral Nerve Stimulation for Neuropathic Pain 1438.e1
REFERENCES
1. White JC, Sweet WH. Pain and the Neurosurgeon. A Forty-Year Expe-
rience. Springfield, IL: Thomas; 1969:894-899.
2. Melzack R, Wall PD. Pain mechanisms: a new theory. Science. 1965;
150:971-979.
3. Rode J. Scribonius (Largus), Compositiones Medicae. Padua. 1655;
23-24.
4. Kellaway P. The part played by electric fish in the early history of
bioelectricity and electrotherapy. Bull Hist Med. 1946;20:112-137.
5. Wall PD, Sweet WH. Temporary abolition of pain in man. Science.
1967;155:108-109.
6. Shelden CH, Paul F, Jacques DB, et al. Electrical stimulation of the
nervous system. Surg Neurol. 1975;4:127-132.
7. Sweet WH, Wepsic JG. Treatment of chronic pain by stimulation
of fibers of primary afferent neuron. Trans Am Neurol Assoc. 1968;
93:103-107.
8. Shealy CN, Mortimer JT, Reswick JB. Electrical inhibition of pain
by stimulation of the dorsal columns: preliminary clinical report.
Anesth Analg. 1967;46:489-491.
9. Slavin KV. History of peripheral nerve stimulation. Prog Neurol
Surg. 2011;24:1-15.
10. Hanai F. Effect of electrical stimulation of peripheral nerves on
neuropathic pain. Spine. 2000;25:1886-1892.
11. Ignelzi RJ, Nyquist JK. Direct effect of electrical stimulation on
peripheral nerve evoked activity: implications in pain relief. J Neu-
rosurg. 1976;45:159-165.
12. Weiner RL, Reed KL. Peripheral neurostimulation for control of
intractable occipital neuralgia. Neuromodulation. 1999;2:217-221.
13. Stanton-Hicks M, Salamon J. Stimulation of the central and periph-
eral nervous system for the control of pain. J Clin Neurophysiol.
1997;14:46-62.
14. Dunteman E. Peripheral nerve stimulation for unremitting oph-
thalmic postherpetic neuralgia. Neuromodulation. 2002;5:32-37.
15. Stinson LW Jr, Roderer GT, Cross NE, et al. Peripheral subcuta-
neous electrostimulation for control of intractable post-operative
inguinal pain: a case report series. Neuromodulation. 2001;4:99-104.
16. Slavin KV, Burchiel KJ. Use of long-term nerve stimulation with
implanted electrodes in the treatment of intractable craniofacial 177
pain. J Neurosurg. 2000;92:576.
17. Freitas TD, Paiva AV, Ogliari KC, et al. Peripheral nerve stimula-
tion to treat chronic painful syndromes. Rev Dor. 2013;14:315-319.
18. Hassenbusch SJ, Stanton-Hicks M, Schoppa D, et al. Long-term
results of peripheral nerve stimulation for reflex sympathetic dys-
trophy. J Neurosurg. 1996;84:415-423.
19. Thimineur M, De Ridder D. C2 area neurostimulation: a surgical
treatment for fibromyalgia. Pain Med. 2007;8:639-646.
20. Matharu MS, Bartsch T, Ward N, et al. Central neuromodulation
in chronic migraine patients with suboccipital stimulators: a PET
study. Brain. 2004;127:220-230.
21. Johnson MD, Burchiel KJ. Peripheral stimulation for treatment of
trigeminal postherpetic neuralgia and trigeminal posttraumatic
neuropathic pain: a pilot study. Neurosurgery. 2004;55:135-141.
22. Palmer SC, Jimenez AA. Peripheral nerve stimulation for treatment
of postherpetic neuralgia: a case report. Acta Med Acad. 2011;40:
187-191.
23. Dworkin RH, Backonja M, Rowbotham MC, et al. Advances in
neuropathic pain: diagnosis, mechanisms, and treatment recom-
mendations. Arch Neurol. 2003;60:1524-1534.
24. Heavner JE, Racz G, Diede JM. Peripheral nerve stimulation:
current concepts. In: Waldman SD, Winnie AP, eds. Interventional
pain management. Philadelphia: Saunders; 1996:423-425.
25. Slavin KV. Peripheral nerve stimulation for neuropathic pain. Neu-
rotherapeutics. 2008;5:100-106.
26. Eisenberg E, Waisbrod H, Gerbeshagen HU. Long term peripheral
nerve stimulation for painful nerve injuries. Clin J Pain. 2004;20:
143-146.
27. Paicius RM, Bernstein CA, Lempert-Cohen C. Peripheral nerve
field stimulation for the treatment of chronic low back pain: pre-
liminary results of long-term follow-up: a case series. Neuromodula-
tion. 2007;10:279-290.
28. Verrills P, Vivian D, Mitchell B, et al. Peripheral nerve field stimula-
tion for chronic pain: 100 cases and review of the literature. Pain
Med. 2011;12:1395-1405.
178 Spinal Cord Stimulation
Oren Sagher and Emily Lehmann Levin
Since its development more than 40 years ago, spinal cord stimu-
lation (SCS) has been increasingly utilized to treat chronic pain.
In one of the early examples of “bench-to-bedside” research
translation, the gate control theory of pain transmission was first
put to use by the development of SCS by Shealy and collegues1,2
in 1967, a mere 2 years after it was proposed. However, pain relief
through the use of electrical stimulation had not been an entirely
novel idea. For centuries eels, as biologic sources of electrical
current, have been used as analgesic aids. This effect was largely
written off as magical until the work of Melzack and Wall offered
a reasonable explanation. The ensuing clinical experience and
accumulated body of knowledge constitute one of the most suc-
cessful examples of useful, translational research in the history of
neurosurgery. This chapter outlines the proposed mechanisms by
which spinal cord stimulation works and discusses contemporary
issues and clinical uses of this technology.
MECHANISM OF ACTION
Gate Theory
The gate control theory of pain transmission proposed by
Melzack and Wall3 in 1965 describes a balance between small and
large sensory fibers, with positive and negative feedback loops
controlling the activity of the dorsal horn cells of the spinal cord.
The theory postulates that a predominance of small-diameter
sensory fiber activity opens “gates” within the dorsal horn of the
spinal cord and that predominance of large-diameter fiber activ-
ity closes them. Shealy and associates1,2 reasoned that because
large fibers have a lower threshold for depolarization by an elec-
trical field applied to a peripheral nerve, they may be recruited
selectively by an externally applied field. Moreover, because
large-diameter sensory fibers within peripheral nerves are segre-
gated into the dorsal columns, they may be more selectively
activated by electrical stimulation of the dorsal aspect of the
spinal cord. It is for this reason that the primary electrical effect
of spinal cord stimulation has been assumed to be mediated by
the dorsal columns.
As elegant as it is, the gate control theory alone does not fully
explain the clinical effect of spinal cord stimulation. For example,
many pain conditions are not effectively treated by SCS, includ-
ing the pain of acute injury.4 On the other hand, SCS is effective
at treating hyperalgesia, which is signaled by large fibers. This
feature may indicate that relief of pain by electrical stimulation
is due to frequency-related conduction block acting at primary
afferent branch points where dorsal column fibers and dorsal
horn collaterals diverge.5 If so, other mechanisms involving inter-
neurons in the dorsal horn or involving descending fibers or
sympathetic mechanisms may exist.6
One of the major limitations in our understanding of the
mechanisms underlying spinal cord stimulation has been the
paucity of animal models that reproduce the human chronic pain
condition. Initial animal models utilizing acute tissue injury have
given way to those employing peripheral nerve injury, in an effort
to create a reliable chronic pain model. However, it has been
difficult to develop a rat model of chronic pain, because rats
generally recover from painful insults without long-term pain.5
Even in humans, peripheral nerve injury does not reliably result
in neuropathic pain, and objective assessment of pain in the rat
relies on behavioral changes. We therefore rely largely on the
178
data accumulated over the last three decades of the use of SCS
in humans to further elucidate a possible mechanism.
Neurotransmitters
In order to better clarify the mechanism of action of SCS,
investigators have also examined the role of local neurotransmit-
ters within the spinal cord in pain conduction. Early studies
explored opioid receptors as the conventional model of pharma-
cologic analgesia. It was found that administration of the narcotic
antagonist naloxone had no effect on the relief of pain by
SCS.7 Other studies showed that substance P is increased in the
cerebrospinal fluid (CSF) following SCS. It has also been noted
that SCS causes a decrease in the release of excitatory amino
acids, such as glutamate and aspartate, while also increasing
the release of γ-aminobutyric acid (GABA).6 This finding sug-
gests that neuropathic pain may be a state of imbalance between
excitatory and inhibitory neurotransmitters and that SCS may
restore that balance (Fig. 178-1).5 These data are further cor-
roborated by studies that show that the GABA agonist baclofen
improves the effect of SCS and that GABA antagonists inhibit its
effect.8 These lines of research offer the possibility of adjunctive
pharmacotherapy.
Summary
The mechanisms underlying SCS-induced analgesia are still open
to question. However, it is clear that the effect is related to modu-
lation of signals mediated by dorsally located fibers within the
spinal cord. Neurohumoral changes in the spinal cord may be
secondary to such activity modulation and may explain post-
stimulation analgesia, which is quite prominent in some patients.9
INDICATIONS AND OUTCOMES
Early uses of SCS spanned the gamut of chronic pain etiologies,
and outcomes were decidedly mixed. Clinicians soon learned that
electrical stimulation was well-suited for the treatment of certain
diagnoses, whereas its use in others yielded disappointing results.
With this fact in mind, prior to implantation of a spinal cord
stimulator, one should establish the cause of the patient’s pain.
There should be appropriate, objective evidence of a pain disor-
der for which spinal cord stimulation has been shown to have
efficacy. In general terms, SCS has had the most favorable track
record for pain conditions marked by nerve injury (so-called
neuropathic pain). For an exhaustive description of indications
for and outcomes of SCS, the reader is referred to Krames’s10
1999 paper. In this section, we highlight a few of the most
common diagnoses treated with spinal cord stimulation.
Failed Back Surgery Syndrome
Chronic neuropathic pain is most commonly located in the back
and legs. Of patients undergoing lumbosacral spine surgery for
treatment of this pain, 10% to 40% eventually have persistent or
recurrent pain.11 This postoperative pain is often referred to as
failed back surgery syndrome (FBSS). Patients commonly have com-
plaints of axial low back pain and lower extremity pain. Tradition-
ally, SCS has been indicated in patients with FBSS in whom the
radicular leg symptoms are more severe than the component of
1439
1440 SECTION 6  Pain

GABA GABA
neuron neuron
Afferent Afferent

Ca2+

AM
DA PA Ca2+ Ca2+
NM
A Normal B Peripheral nerve injury

SCS GABA
neuron
Afferent
1

C D SCS

Figure 178-1. Schematic illustration of the postulated effect of spinal cord stimulation (SCS). A, Dorsal
horn neurons under normal conditions. Afferent inputs release excitatory neurotransmitters into the synaptic
cleft. Simultaneously, γ-aminobutyric acid (GABA) neurons are activated exerting both presynaptic and
postsynaptic inhibition, balancing the state of excitation. AMPA, α-amino-3-hydroxy-5-methyl-4-
isoxazolepropionic acid; NMDA, N-methyl-D-aspartate. B, After peripheral nerve injury, GABAergic activity is
reduced and excitatory neurotransmission is enhanced. These changes can give rise to allodynia and
hyperalgesia. C, SCS activates dorsal column fibers, and the resulting nerve activity is antidromically (2)
mediated to neurons in the dorsal horn superficial laminae (3). The paresthesias experienced during SCS are
due to orthodromic activation of the dorsal columns (1). D, SCS-evoked nerve activity induces the release of
GABA from dorsal horn interneurons, reducing hyperexcitability. (Modified from Cui JG, O’Connor WT,
Ungerstedt U, et al. Spinal cord stimulation attenuates augmented dorsal horn release of excitatory amino
acids in mononeuropathy via a GABAergic mechanism. Pain. 1997;73:87.)

axial back pain. Objective evidence for a source of their neuro-
pathic pain should be sought, including radiographic evidence of
an anatomically successful procedure for herniated disk with an
appropriate radiculopathy, matching the pain complaint.
Failed back surgery syndrome is the most common indication
for SCS and has the most evidence supporting its use. The Pro-
spective, Randomized, Controlled, Multicenter Study of Patients
with Failed Back Surgery Syndrome (PROCESS trial), a large,
multicenter, randomized controlled trial of spinal cord stimula-
tion, has provided some of the best evidence for the use of spinal
cord stimulation in failed back surgery syndrome.12-14 The data
emerging from this ongoing trial, first presented in 2005, reflect
pain relief after and cost-effectiveness of SCS in comparison with
conventional medical management. Pain relief was significantly
better in patients treated with spinal cord stimulators than in
those managed conventionally.13 Patients also reported signifi-
cant improvement in health care–related quality of life. However,
the latest data from this trial shows that, at 6 months, health care
costs were significantly higher in the SCS group, likely in relation
to the costs of the device and implantation. Longer follow-up of
these patients is required to assess the true cost of this therapy.
The role of SCS in the management of recurrent back and leg
pain following spine surgery has been examined in a randomized
controlled trial comparing this therapy with repeat lumbar
spine surgery.16 In this series of 42 patients with operable spinal
pathology, SCS proved more effective than repeat spine surgery.
Moreover, a significant proportion of patients who had been
randomly allocated to spine surgery and had not benefited from
it subsequently had good results with SCS. Finally, the cost of
therapy with SCS proved lower than that of repeat lumbar spine
surgery, despite the significant cost of the hardware utilized in
the former.17
The latest outcomes data evaluate patients with FBSS involved
in workers’ compensation claims. In this challenging population,

spinal cord stimulation decreased leg pain but failed to reduce
opioid dependence or improve disability.18 It is likely that factors
affecting medication use and disability in patients with chronic
pain who are involved in worker’s compensation claims are far
more complex and multifactorial than can be accounted for by
the addition of a surgical procedure like SCS.
Complex Regional Pain Syndrome
Spinal cord stimulation has been in use for the treatment of
complex regional pain syndrome (CPRS). Also known as reflex
sympathetic dystrophy, CPRS is a condition for which there are
few effective treatment options. The pathophysiology is unclear,
with pain, dysfunction, and trophic changes occurring in an
affected limb after trauma or surgery to that limb.19 Kemler and
associates20 have published 5-year follow-up results of a random-
ized, controlled trial comparing SCS and physical therapy with
physical therapy alone. They found significantly better relief of
symptoms in patients undergoing SCS than in those conserva-
tively managed during the first 3 years. However, a spontaneous
improvement in the control group seems to gradually diminish
the effect of SCS over longer periods, with no statistical differ-
ence between the groups at 5 years. Despite these results, 95%
of patients with SCS reported that they would undergo implanta-
tion again.
Ischemic Pain
It has been noted that spinal cord stimulation may alter vascular
tone and improve tissue perfusion. SCS is thought to dilate
peripheral vasculature through a combination of sympathetic
outflow modulation and antidromic activation of sensory fibers.21
The use of SCS in the treatment of peripheral vascular disease
was first proposed in the 1970s.22 Subsequently, placement of the
stimulator in the low thoracic or lumbar region of the spine has
been shown to be effective in the treatment of pain caused by
lower extremity peripheral artery occlusive disease.21,23,24 Place-
ment of the stimulator electrode at higher thoracic levels has
been used in the treatment of intractable angina, with studies
showing better exercise tolerance and fewer ST-segment changes
with SCS treatment.21 In addition, the effect of cervical SCS on
the cerebral vasculature has been explored, with focus on cerebral
vasospasm following subarachnoid hemorrhage.25 Although there
is evidence that SCS in the setting of subarachnoid hemorrhage
is safe, the growing use of endovascular therapies for ruptured
aneurysms has complicated this practice, likely owing to the fre-
quent use of systemic anticoagulation in affected patients.26,27
Psychological Screening
One of the practical issues in spinal cord stimulation is the
screening of patients. Clearly, not every pain syndrome responds
equally well to SCS. In the same vein, not every patient with
chronic pain responds well to this therapy. In an effort to sort
out who will respond well to SCS, many practitioners have turned
to psychological screening. Aside from its ability to identify
patients with major psychiatric morbidity, psychological screen-
ing has been reported to have some predictive value in identifying
patients who would benefit from the therapy.28 Some studies have
found that it is important to assess the psychological profile of
the patient in order to determine the suitability of SCS for treat-
ment of the pain. In particular, pre-implantation screening pro-
tocols have examined the patient’s overall stability, defensiveness,
self-confidence, and self-efficacy. Other aspects examined are the
response to and concern about the illness and the ability to cope
with setbacks. Family support and a willingness to be an active
participant in his or her care are also important.29 However, the
utility of psychological screening is not uniformly accepted; there
CHAPTER 178  Spinal Cord Stimulation 1441
are also data suggesting that the predictive value of psychological
testing is low.30 In summary, evidence regarding the usefulness of 178
psychological screening of patients prior to spinal cord stimula-
tion is mixed. Nevertheless, this type of screening continues to
be widely practiced.
Early Lead Configurations
The initial foray into spinal cord stimulation utilized a small
laminectomy for placement of the stimulating electrode into the
epidural, endodural, or subarachnoid space. The placement of the
electrode with a laminectomy under local anesthesia provided
limited access to different levels of the spinal cord, yielding little
intraoperative flexibility in tailoring the stimulation field to the
patient’s pain. The advent in the 1970s of slender electrodes that
may be inserted percutaneously through a Tuohy needle improved
the maneuverability of the electrode longitudinally along the
spinal canal. This development, in turn, has allowed for improved
ability to determine the optimal level for electrode placement,
maximizing stimulation in affected areas.
MODERN-DAY LEAD TYPES
Contemporary stimulator lead types consist of either insulated
wires containing anywhere from one to eight contacts at their
tips in a linear array, or paddle-shaped electrodes with two or
three columns of disk-shaped electrodes (Fig 178-2). The con-
tacts are composed of a nonferromagnetic alloy such as platinum-
iridium. In general, the insulating material is Silastic (Dow
Corning Corp., Carrollton, KY) based in order to maintain
flexibility and durability. The percutaneous, wire-shaped elec-
trodes can be placed through a needle under fluoroscopic guid-
ance, giving the surgeon broad access to multiple levels of the
spinal cord in a minimally invasive fashion. However, by virtue
of their cylindrical shape, these contacts radiate current in all
directions, requiring more energy and potentially stimulating
dorsally located nerve fibers in addition to the ventrally located
spinal cord. The paddle-shaped leads allow for more focused
dispersion of current but require a more invasive implantation
procedure.31
Figure 178-2. Electrode arrays and generators in contemporary
use for spinal cord stimulation. The linear arrays on the left may be
placed through a Tuohy needle, whereas the flat, paddle-shaped
electrodes (center) require open surgery for placement. Several
implantable generators made by the various manufacturers are
pictured on the right.
1442 SECTION 6  Pain

The percutaneous technique was initially used for temporary Surrounding layer Dorsal
trials of stimulation prior to laminectomy and placement of a Vertebral bone
permanent lead. However, the percutaneous leads have since
Lead material Electrode
become popular for long-term use, owing to ease of placement.
The earliest percutaneous electrode had a single contact and
required the placement of multiple leads to achieve bipolar stim- Epidural fat
ulation. In the 1980s, leads were developed with increasing Cerebrospinal fluid Dura
numbers of contacts, providing more maneuverability in stimula- Dorsal mater
tion. Earlier lead designs incorporated large contacts with long columns
intercontact spacing, which were believed to broaden the effect
of stimulation. However, more contemporary lead designs utilize Dorsal
Gray matter
smaller contacts with narrow intercontact spacing. Work with root
finite element modeling of the spinal canal has demonstrated that
this narrow intercontact spacing provides superior targeting of
the dorsal columns of the spinal cord (Fig. 178-3).32 In addition,
it appears that a transverse orientation of anode and cathode
minimizes uncomfortable radicular stimulation and maximizes Vertebral bone
stimulation of the dorsal columns. The “transverse tripole,” Ventral 5 mm
which involves a negative terminal flanked transversely by two A
positive terminals, is currently believed to provide for optimal
stimulation characteristics.33 Accomplishing a transverse orienta-
tion requires that multiple percutaneous leads be placed parallel
to one another or, alternatively, requires the placement of a
paddle electrode with multiple linear electrode arrays.

LAMINECTOMY VERSUS
PERCUTANEOUS PLACEMENT
The ability to implant leads for spinal cord stimulation via a
minimally invasive, percutaneous technique has resulted in a pro-
found rise in the popularity of this therapy over the last 20 years.
However, over the last decade a number of reports have surfaced
suggesting that leads implanted via laminectomy may deliver
better results than those placed percutaneously.31,34 In the early
2000s, a randomized prospective controlled trial was conducted
in order to compare both the technical and clinical results associ-
ated with the percutaneous and laminectomy lead placements. B
Initial technical data, published in 2002, touted the greater insu-
Dorsal
lation of the paddle-style electrodes for longer battery life and
the ability to use lower stimulation amplitudes.31 All patients
participating in the trial initially underwent temporary percuta-
neous lead implantation, followed by random allocation to
permanent implantation of either percutaneously placed or
laminectomy-placed leads. Patients who were able to compare
the two types of leads reported better ratings of paresthesia
coverage of pain as well as improved low back coverage with Spinal
laminectomy-placed electrodes. Clinical data, published in 2005, cord
revealed that this advantage was durable to a follow-up point of
2 years, but the statistical significance disappeared at a mean of
2.9 years of follow-up. The evidence therefore does not clearly
support the theoretical and anecdotal reports of superiority of CSF
laminectomy-placed leads.34 Still, laminectomy placement is
clearly indicated in patients in whom percutaneous implantation
cannot be accomplished because of epidural adhesions and in
patients who have experienced repeated migration of percutane- Ventral
ously placed leads. C
Figure 178-3. A, Transverse section of cervical three-dimensional
GENERATORS model of the spinal canal and surrounding tissues; the cathode is
centered at this section, and dorsal roots are not included in the
Advances in the miniaturization of electronics and battery tech- model. B, Iso-potential lines in unipolar stimulation. C, Iso-current
nology have provided significant improvement in the flexibility of density lines in unipolar stimulation. CSF, cerebrospinal fluid. (Modified
SCS systems. The earliest generators employed radiofrequency from Holsheimer J. Computer modelling of spinal cord stimulation and
transmitters worn externally to energize the stimulator electrode. its contribution to therapeutic efficacy. Spinal Cord. 1998;36:53.)
These have no implanted battery that would require replacement,
and revisions were rarely required. The major disadvantage of
such systems is the need for the patient to wear an external power-
transmitting device, which may have variable communication
with the internal component, altering the perceived stimulation

amplitude. Radiofrequency-coupled devices are therefore used
infrequently, but are still employed in selected patients with very
high energy requirements.
Implantable pulse generators became available in the 1980s
with the advent of lithium ion battery technology (see Fig.
178-2). These have the obvious advantage of providing more
convenience and a better cosmetic result. Battery life in older
models is limited, however, and requires balancing stimulation
parameters with battery life to achieve the best result. The patient
must undergo surgical replacement of the implanted generator
when the battery has been exhausted.
Although fully implanted pulse generators now make up
the lion’s share of systems in clinical use, a new generation
of rechargeable generators has entered the marketplace. These
devices allow patients to enjoy the convenience of an internalized
power source, without the need for frequent surgical procedures
to replace the generator. In order to recharge these generators,
the patient wears a radiofrequency-coupled external recharging
device periodically for several hours. Unfortunately, compliance
with recharging these devices is very important; if completely
depleted, the rechargeable generator may be irreversibly damaged
and require surgical replacement. The price of rechargeability
therefore appears to be more significant than patient compliance
in a regular maintenance schedule, interfering with the conve-
nience of this device.35 Therefore, the new, rechargeable genera-
tors do not necessarily replace the primary-cell, implantable
generators that have dominated this clinical arena.
CONSTANT CURRENT VERSUS CONSTANT VOLTAGE
The first stimulators to come on the market employed constant-
voltage circuitry to provide stimulation. In this configuration,
current amplitude may vary depending on changes of impedance
of the surrounding tissues, such as may happen with changes of
position or the development of scar tissue.36 This variation has
been implicated in the unpredictability of stimulation efficacy and
paresthesias.
Stimulation efficacy is directly related to current density at the
excited tissue. With constant-voltage technology, current peaks
early and decays rapidly in the stimulus pulse, leaving less effec-
tive time per cycle than with constant-current technology.37
Thus, constant-current stimulation provides more effective exci-
tation of tissues.
Animal models have demonstrated greater efficacy of constant-
current stimulation than with constant-voltage stimulation.38 A
randomized, double-blind trial found that patients prefer the
sensation and pain relief obtained with constant-current pro-
gramming.39 Although both treatment conditions led to improve-
ment, this study demonstrated significantly lower pain scores and
better quality of life with constant-current stimulation than with
in constant-voltage stimulation.
PATIENT PROGRAMMERS
One of the advantages enjoyed by SCS users is their ability to
interact with their therapy. Patient programmers allow the user
to modify the stimulation characteristics to optimize pain man-
agement. Over the years, the programmers have become more
sophisticated. Initially, patients were given a magnet that simply
turned the generator on or off. Contemporary programmers are
considerably more sophisticated, enabling the patient to adjust
amplitude, frequency, pulse width, and contact polarities. Some
programmers allow patients to experience multiple stimulation
programs that alternate with one another on a millisecond basis,
essentially becoming simultaneous in their effects. Certain gen-
erators now have the capability to sense patient position and alter
the program to provide ideal coverage. Such advanced program-
ming options have not been shown to be superior to traditional
CHAPTER 178  Spinal Cord Stimulation 1443
stimulation programs but do offer a glimpse into the possibilities
offered by advances in electrical engineering. Time will tell 178
whether these devices will improve the efficacy of spinal cord
stimulators.
STIMULATION PARAMETERS
The intensity of stimulation has been shown to improve efficacy
in animal models of neuropathic pain.40,41 Intensity may be
varied through changes in amplitude or frequency. Traditionally,
spinal cord stimulation frequency has been relatively low, in
the range of 40 to 60 Hz.5 However, exploration of higher-
frequency stimulation has shown promise. Observational trials
of stimulation at 10 kHz has been shown to be effective in provid-
ing pain relief in patients with FBSS.42 In this series, high-
frequency SCS appeared to provide better treatment of low back
pain, which has historically been difficult to treat with conven-
tional SCS.
Unlike conventional SCS, high-frequency stimulation does
not cause paresthesias, which some patients find uncomfortable.
This lack of paresthesias allowed for a double-blinded, random-
ized, controlled trial comparing high-frequency SCS with sham
stimulation.43 This trial was conducted in a group of patients with
a history of FBSS. All had previously been successfully treated
with conventional spinal cord stimulation. The primary outcome
measured in this study compared current pain control with pain
control through conventional SCS. Although it was important as
one of the first blinded trials of SCS, each phase of sham or
stimulation lasted only 2 weeks, and there was no interval between
treatments to allow for washout of the effect. Perhaps a longer
period of evaluation may show a greater difference between the
two SCS methods.
SURGICAL TECHNIQUE
Electrode Placement
Placement of epidural stimulation electrodes may be accom-
plished in a number of ways. In the simplest technique, the
electrode may be placed percutaneously through a Tuohy needle,
with the leads connected to external a generator that may be
either external (temporary) or implanted. At the other end of the
range, a single-level laminectomy may be performed for place-
ment of a paddle-style electrode. All of these procedures are
traditionally performed in a conscious patient, with use of local
anesthetics and mild sedation to allow the patient to assist in
optimal placement of the stimulating electrode.
A trial of stimulation prior to permanent implantation is
usually performed to ensure that the effects of spinal cord stimu-
lation are therapeutic. This trial involves an initial lead placement
with connection to an external generator, allowing for evaluation
of the treatment for several days. The electrodes may then be
used permanently or changed at that time.
Determination of the spinal level for electrode insertion and
placement is key to successful stimulation. The location of pain
treated and the type of electrode being placed guide the level of
insertion. Needle-type electrodes have more flexibility, in that
they may be advanced a number of levels cranially through the
epidural space to ensure the best stimulation coverage. On the
other hand, paddle-type electrodes may generally be placed only
one to two levels cranial to the location of the laminectomy. For
upper extremity symptoms, cervical placement is required. One
should be mindful of the cervical cord enlargement, and percu-
taneous electrode insertion should ideally be performed below
the T1-T2 level. A practical rule of thumb is to insert the elec-
trode at T2-T3 or T3-T4 for upper extremity pathology and at
L1-L2 or L2-L3 for lower extremity targets. The target level for
the electrical contacts varies by patient and the pain region being
1444 SECTION 6  Pain
treated. Common target levels for lower extremity coverage
range from T8 through T12, spanning the lumbar enlargement
of the cord. Similarly, common levels for upper extremity symp-
toms range from C3 to C6, covering the cervical enlargement.
Placement where the spinal cord is of small caliber may result in
unpleasant local segmental effects. Barolat’s group has published
an exhaustive review of stimulation levels and their physiologic
correlates.44,45
Percutaneous placement of spinal cord stimulator electrodes
is an attractive option, especially for temporary trial of stimula-
tion. The patient is placed in the prone position and biplanar
fluoroscopy is established. Several centimeters of the lead should
lie in the epidural space to stabilize the electrode and minimize
migration. This is best accomplished by entry into the spine at
least two segments below the target stimulation level. The tech-
nique for insertion utilizes a Tuohy needle to gain access to the
epidural space.
The epidural space may be identified through the loss-of-
resistance method. Identification of subarachnoid placement of
the needle versus epidural placement is important and may be
accomplished in a number of ways. Of course, the appearance of
CSF will indicate violation of the dura. In the absence of CSF
flow, insertion if a guidewire or the electrode has been inserted
in the subarachnoid space, it will glide more easily and the wire
may be seen to “float” in the CSF on fluoroscopy. Finally, elec-
tronic stimulation within the subarachnoid space elicits stimula-
tion response at extremely low thresholds.
When the epidural space has been identified, the electrode
may be advanced through the Tuohy needle to the appropriate
stimulation position. Care should be taken to recognize ventral
migration of the electrode, which will be indicated on AP fluo-
roscopy by slight lateral deviation followed by medial curvature.
Lateral imaging may be useful in determining this issue as well.
The electrode should be secured with multiple points of fixa-
tion to reduce the chance of dislodgement. Strain-relief loops
may be utilized around the insertion site to deflect tension away
from the trajectory of the electrode. Anchors and nonabsorbable
suture are used to fix the electrode to the interspinous ligaments
and to the fascia prior to tunneling toward the generator.
Similarly, the paddle electrode is placed with the patient in the
prone position (Videos 178-1 through 178-5). A fluoroscope is
positioned anteroposteriorly, and the vertebral level is identified.
Following generous administration of local anesthetic, a midline
incision is made over the interspace through which the electrode
will be placed. Unlike in the percutaneous technique, the level of
entry in paddle electrode placement is usually only one or two
segments below the level of planned stimulation. The paraspi-
nous muscles are cleared from the spinous processes and lamina
bilaterally, the inferior portion of the cranial lamina is resected,
and the ligamentum flavum is carefully removed. The epidural
space is explored cranially to ensure there are no adhesions, and
the electrode is placed under visual and anteroposterior fluoro-
scopic guidance. With the advent of minimally invasive spine
surgery techniques,46,47 some writers have advocated their use for
electrode placement to decrease postoperative surgical pain and
recovery time.48
Often at this point, a trial of stimulation is performed to
ensure good coverage of the patient’s pain. Once final placement
is determined, the leads are secured to the interspinous ligament
and the fascia is closed. Much as with percutaneous leads, strain-
relief loops are made in the subcutaneous space, and the leads are
tightly secured to the fascia.
Awake versus Asleep Placement
Debate has emerged about whether electrodes are best placed
intraoperatively with awake examination of the patient or with the
use of general anesthesia and neuromonitoring.49,50 Awake place-
ment allows for direct confirmation in the operating room that
the paresthesias cover the region of the patient’s pain. Surgeons
who advocate for placement with general anesthesia argue that
certain patients have physical and mental comorbidities that pre-
clude awake surgery. With trial fluoroscopy to guide localization,
electromyography and somatosensory evoked potentials are used
to tailor placement. Testing is performed as in the awake patient,
with a standard screener box, but a significantly lower frequency,
in the 5- to 10-Hz range.49 Each column of the lead is activated
independently, and the electromyography response pattern is
evaluated visually for symmetry. Some published reports show
efficacy of placement with the patient asleep to be equal, and
perhaps superior, to that of awake placement.49,50 One potential
drawback of this method is the lack of ability to detect unpleasant
radicular stimulation when the patient is asleep. Unintended
radicular stimulation, which is frequently the amplitude-limiting
factor in SCS, is typically detectable when the patient is awake
during surgery and can report it, allowing for repositioning of the
electrode. Use of general anesthesia prevents this adjustment.
Generator Placement
Internal pulse generators are implanted in a subcutaneous pocket
in a position where they will not interfere with bony promi-
nences. Two common locations are the lower quadrant of the
abdomen and the buttock. It is important to consider the ease of
the patient to access the generator for routine programming.
Also, care should be taken to avoid placing the generator where
undue pressure would be placed on it, causing skin breakdown
from clothing waistbands or sitting. Some practitioners advocate
placing a generator in the region of the buttock, because it is
more convenient surgically and is cosmetically acceptable to most
patients. However, some are data show that such generator place-
ment increases the strain on the leads, raising the propensity for
lead migration or fracture.51
In preparation for tunneling and generator placement, it has
been our practice to close the midline spinal incision and put the
patient in the lateral position under general anesthesia. Any trial
leads exiting the skin are disconnected from the external genera-
tor and are cut close to the skin. The site is surgically prepared
and draped and the subcutaneous pocket is created. The back
incision is then reopened and an extension lead is tunneled sub-
cutaneously between the two incisions (Videos 178-6 through
178-11).
COMPLICATIONS
Spinal cord stimulation has proven to be a safe technique for the
management of chronic neuropathic pain. The incidence of life-
threatening infection is low; the most severe complications
require repeat operation, whereas others may simply affect pain
relief.51,52 Complications may be divided into two categories:
technical and biologic. Technical complications relate to both the
implantation technique and long-term durability of the hardware.
A review of literature found that one of the most frequent com-
plications is electrode migration. Percutaneously placed elec-
trodes are more susceptible to migration than paddle electrodes.
Paralysis has been reported rarely, usually in relation to the devel-
opment of epidural abscess.53
CAUTIONS AND CONTRAINDICATIONS
The presence of an implanted neurostimulator device warrants
special consideration in medical and day-to-day situations. The
manufacturers of these devices and the U.S. Food and Drug
Administration (FDA) recommend caution with any sources of
electrical or magnetic energy, because they may cause uncon-
trolled heating of the electrode, leading to tissue damage. Obvious

sources include surgical electrocautery and magnetic resonance
imaging (MRI). Although most practitioners advocate avoiding
monopolar cautery in the presence of spinal cord stimulators, it
appears that this type of cautery in the operating room may be
used safely; it use requires placing the grounding pad to direct
the current field away from the electronic device and keeping
the amplitude of electrocautery current at the lowest usable
settings.
Compatibility with Magnetic Resonance Imaging
Concerns about device failure and uncontrolled electrode heating
has also prompted practitioners to avoid MRI, which has not been
recommended for patients with any neurostimulator device. A
study published in 2007, however, cited no adverse events in a
series of 31 patients scanned in a 1.5-T MRI machine.54 Device
manufacturers have made significant efforts to improve MRI
safety and compatibility. A new generation of radiofrequency-
shielded stimulator leads has been introduced, promising to allow
whole-body MRI.55 These leads, currently available in limited
configurations, hold considerable promise for clinical use, espe-
cially in cases in which routine MRI is required for disease
surveillance.
Other sources of radiofrequency energy may occasionally be
encountered outside the operating room or imaging suite. For
example, diathermy is a commonly used method of generating
tissue heat, usually in coordination with physical therapy. This
modality involves depositing significant energy in soft tissue,
energy that may be transmitted to electrical devices, causing
uncontrolled heating at the electrical contacts. There have been
no reports of injury in patients with SCS undergoing diathermy.
However, there have been a number of reports of diathermy
injury to patients with deep brain stimulators.56,57 Nonmedical
use of radiofrequency energy may also affect spinal neurostimula-
tors; patients have been reported to experience alteration in
stimulation while passing through antitheft devices, and a single
death has been reported under this circumstance.55 It is therefore
recommended that patients avoid lingering near these antitheft
devices.
NEW DIRECTIONS
The ability to modulate nervous system impulses with the use of
electrical stimulation is an exciting development that has already
resulted in a highly effective treatment modality for many patients
with chronic pain. Present-day systems provide patients with the
ability to modulate their therapy on the basis of their activity and
their perceived analgesia in increasingly sophisticated ways.
However, these systems lack real-time feedback that can sense
activity or position, both of which affect stimulation parameters.
Future iterations of generators may incorporate such closed-loop
systems, already found in cardiac pacemakers, to sense patient
activity or perhaps even neural signals characteristic of neuro-
pathic pain and then adjust stimulation parameters accordingly.
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1445.e2 SECTION 6  Pain
in the midcervical and midthoracic vertebral levels. Stereotact Funct
Neurosurg. 1993;61:146-155.
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 Destructive Procedures
179 Evidence Base for Destructive Procedures
Justin S. Cetas, Amr AlBakry, Ahmed M. Raslan, and Kim J. Burchiel
The surgical treatment of pain has been an integral part of neu-
rosurgery since the early 20th century, when Harvey Cushing
pioneered the ganglionectomy for trigeminal neuralgia (TN).
Over the ensuing years as anatomic and physiologic knowledge
of pain systems grew, new techniques aimed at new targets were
developed for an array of pain conditions.1-4 Targets have included
the anterolateral quadrant of the spinal cord, the sensory and
sympathetic ganglia, the dorsal and ventral spinal roots, the dorsal
root entry zone (DREZ) and decussating extralemniscal fibers,
the hypophysis, the thalamus, and the cingulate gyrus. Careful
detailed descriptions of these techniques and their purported
efficacy from pioneers in the field established the importance of
surgery for the treatment of pain. The invasive nature of these
techniques and associated comorbidities, as well as the high
degree of technical skill required for their use, led to the develop-
ment and widespread adoption of newer pharmaceuticals and
nondestructive treatments. As a result, the use of destructive tech-
niques in the surgical treatment of pain has dramatically declined
over the last few decades. They are being or have been replaced
with nondestructive techniques and devices, such as spinal cord
stimulation (SCS), intrathecal opiate pumps, newer medications,
and high-dose opiates. However, it is becoming increasingly
apparent that none of these techniques is free from its own set of
detriments. For example, the long-term administration of opioids
is associated with addiction, opioid-induced hyperalgesia, cogni-
tive disorders, high costs, and the suppression of the immune and
reproductive systems.5,6 Furthermore, it has yet to be proven that
the long-term use of opioids improves such outcomes as pain
relief, functional capacity, and health-related quality of life.7,8
Neurostimulation and intrathecal drug administration are
expensive and require ongoing battery and catheter maintenance
and pump refills.9 Despite their widespread use and study, their
clinical efficacy has not been demonstrated according to modern
standards of evidence-based medicine.10
Given that all three broad approaches to the treatment of pain
(destructive, nondestructive, and medical) have “matured” and
the initial wide-eyed enthusiasm of their introduction is over, it
now seems timely to revisit the existing literature and see how
the older destructive techniques compare. By so doing we can
develop and implement those techniques that are effective and
relegate to history those that are not.
In this chapter we summarize the published data on destruc-
tive procedures for both malignant and nonmalignant causes of
pain in order to determine the level of evidence supporting con-
tinued use and help define areas that warrant further study.
Therefore we reviewed human clinical studies that reported out-
comes for destructive techniques used in the treatment of non-
malignant pain conditions. Reviewed studies were grouped
according to the surgical target, beginning with peripheral or
“first-order neuron” targets.11
METHODS
In the sixth edition of this book, we reviewed peer-reviewed
English literature that encompassed January1954 to July 200812
applied to both malignant and nonmalignant pain etiologies.13
1446
Evidence was classified according to the hierarchy of clinical
research design and the grading system used by the U.S. Preven-
tive Services Task Force,14 as follows:
I: Evidence obtained from at least one properly randomized con-
trolled trial.
II-I: Evidence obtained from well-designed controlled trials
without randomization.
II-2: Evidence obtained from well-designed cohort or case-
control analytic studies, preferably from more than one center
or research group.
II-3: Evidence obtained from multiple time series with or without
intervention, comparisons between times or places with or
without the intervention. Dramatic results in uncontrolled
experiments (such as the results of treatment with penicillin
in the 1940s) could also be included in this category.
III: Opinions of respected authorities, based on clinical experi-
ence, descriptive studies, or reports of expert committees.
In this edition, we also review later peer-reviewed English litera-
ture from January 2009 to December 2014 for both malignant
and nonmalignant pain etiologies. Additional studies have been
cataloged and the data added to tables.
RESULTS
In total, 182 papers on noncancer pain and 135 papers on cancer
pain were reviewed; few articles were included in both noncancer
and cancer pain reviews. The large majority of studies constituted
class III evidence. Only 25 class I or class II studies were found.
Seventeen of these studies evaluated radiofrequency (RF) rhi-
zotomies for different pain etiologies, such as lumbar facet syn-
drome, cervical facet pain, and type I (typical) TN, whereas three
examined ganglionectomies for either lumbar or cervical pain.
Three studies, two class I and one class II, evaluated and sup-
ported sympathectomy of visceral cancer pain. One evaluated the
use of cordotomy in malignant cancer states, and one evaluated
DREZotomy technique in the management of intractable bra-
chial plexus avulsion pain.
Rhizotomy
Our database search and secondary review of references
located 56 rhizotomy studies that generally concerned spinal
or facet pain and facial pain syndromes (eTables 179-1A
through F), and 11 papers that addressed cancer pain (eTable
179-1G). The majority of the studies (43/56) reported data
relevant to either trigeminal neuralgia (eTable 179-1A, 33
studies15-46) or lumbar facet syndrome (eTable 179-1B, 15
studies47-61), whereas the remainder evaluated the effects of rhi-
zotomy on a variety of truncal and extremity neuralgias (eTable
179-1C, 1 study62), cervical pain (eTable 179-1D, 9 studies63-71),
cluster headaches (eTable 179-1E, 3 studies72-74), vagoglossopha-
ryngeal neuralgia (eTable 179-1F, 1study75), or cancer pain of
various etiologies (eTable 179-1G76-84).

Rhizotomy for Truncal or Extremity Neuralgias and
Lumbar Facet Syndrome
In the studies on rhizotomy for truncal or extremity neuralgias
and lumbar faced syndrome, success rates were initially around
60% but declined on long-term follow-up. Despite the variability
in treated pain syndromes, number of sectioned roots, outcome
measures, and follow-up, the results were discouraging enough
that the procedure was relatively abandoned and replaced with
modified rhizotomies directed at facet denervation for the treat-
ment of lumbar facet syndrome.52
Four randomized, blinded controlled trials compared RF rhi-
zotomies of the medial branch of the dorsal root with a sham
procedure (3 studies) or intrafacetal with extrafacetal rhizotomy
(1 study). Outcome measures and patient selection differed
between the groups sufficiently to preclude a meta-analysis.85
Modest long-term improvement in pain scores in the treated
group was observed in all three studies comparing rhizotomy
with a sham procedure. In the last study, intrafacetal rhizotomy
was found to be superior to extrafacetal rhizotomy. Complica-
tions were minimal in all four studies. Of the remaining 15
papers, 5 are prospective in nature. Proportions of patients with
“good outcomes” varied from 41% to 75% in long-term
follow-up. The remaining 7 series are classified as class III studies
and reported long-term success rates of 40% to 60%. (See eTable
179-1B, 14 studies.47-61)
Rhizotomy for Chronic Discogenic Back Pain
One randomized controlled trial62 (see eTable 179-1C) evaluated
the effects of RF lesions of the ramus communicans for treatment
of single-level chronic discogenic back pain. All selected patients
had previously undergone a failed intradiscal electrothermal
(IDET) procedure and had a good response to local nerve block-
ade of the ramus communicans. At 1 month and 4 months of
follow-up, the treated group showed significant improvement in
Visual Analog Scale (VAS) and Medical Outcomes Study (MOS)
Short Form Health Survey (SF-36) scores.
Rhizotomy for Cervical Pain
RF rhizotomies were compared with sham procedures for the
treatment of cervical pain or cervicogenic headache68 in three
randomized control trials (RCTs).65,68,69 One prospective class II
clinical trial64 and four case series also addressed rhizotomies for
cervical pain. The number of patients in each RCT was small,
ranging from 12 to 24.65 Two of the RCTs demonstrated a sig-
nificant treatment effect of RF lesions,65,69 although one did not
(was an underpowered study).68 The class II study also reported
durable reduction in validated pain scores.64 Both studies with
long-term follow-up demonstrated similar median-time to recur-
rence.64,65 (See eTable 179-1D, 9 studies.63-71)
Rhizotomy for Trigeminal Neuralgia
We located no controlled trials that reviewed the treatment
of TN by rhizotomy. The best evidence consisted of two class II
and four class III studies that prospectively followed patients
with TN who were treated with RF rhizotomy or glycerol rhi-
zolysis, as well as a large (1600-patient) case series.33 In a large
comparative study using glycerol and RF in multiple sclerosis–
related TN and idiopathic TN, both procedures were effective,
with a mean duration to recurrence of 26 months for idiopathic
TN and 20 months for multiple sclerosis–related TN.37 Three
studies evaluated pain recurrence rates with life-table analy-
ses,22,33,74 and two of these studies prospectively compared sepa-
rate cohorts of patients defined by symptomatology31 or treatment
protocol.24
CHAPTER 179  Evidence Base for Destructive Procedures 1447
Overall, these studies demonstrate a significant long-term
benefit of rhizotomy for TN. Reported recurrence rates con- 179
curred, ranging from 40% to 60% at 5 years. Several investigators
have suggested that patients with facial pain other than typical or
type I TN86 had higher recurrence rates or poorer patient satis-
faction.22,23,31 (See eTable 179-1A, 20 studies.15-31,33-46,87)
Neurectomy for Trigeminal Neuralgia
Five additional case series concerning the treatment of TN15-19
were found with the search word “neurectomy”; they are sum-
marized in eTable 179-1A.15-19
Rhizotomy and Neurectomy for Cluster Headache
and Facial Pain
Two retrospective studies (19 patients)72,74 and one prospective
study (18 patients) on the use of rhizotomy and neurectomy for
cluster headache or facial pain were reviewed. In the prospective
study,73 83% of patients had immediate pain relief but also dem-
onstrated a 39% recurrence rate at long-term follow-up. (See
eTable 179-1E, 3 studies.72-74)
Rhizotomy for Cancer Pain
Ten case series studying the use of rhizotomy for cancer pain
were identified, the majority of which evaluated the effects of
dorsal root rhizotomy for malignant pain of the extremities. The
largest series contained 71 patients and was one of the earliest
papers.52 Reported outcomes generally were favorable initially
but faded quickly with time. The open nature of the procedure,
the fading effect, and the presence of more effective procedures
all contributed to the abandonment of this procedure. One case
report was available for the management of facial pain secondary
to squamous cell carcinoma of the tongue. (See eTable 179-1F,
11 studies.76-84,88)
Ganglionectomy
A total of 20 articles on the use of ganglionectomy for treatment
of pain were found that met the selection criteria previously
indicated. All studies addressed benign pain conditions. Three
were randomized controlled trials: one compared RF lumbar
ganglionectomies with sham surgery for sciatica,89 the second
compared RF lesions made at two different temperatures,90 and
the third compared dorsal root ganglion destruction by doxoru-
bicin (Adriamycin) with injection in management of postherpetic
neuralgia.91 The remaining articles were case series ranging in
size from 3 to 102 patients. (See eTable 179-2, 17 studies.55,89-106)
Ganglionectomy for Lumbar and Cervical Radicular Pain
In 2003, Geurts and colleagues89 reported on their study, which
randomly assigned 83 patients to either RF lesioning (45 patients)
or needle placement without RF lesion (38 patients) of selected
lumbar ganglion. Evaluators and patients were blinded to the
protocol used. Despite adequate power, this study found no sta-
tistical difference between the groups.
Slappendel and associates,90 reported in 1997 that they found
no difference in outcome between patients receiving RF lesions
at 60°C and those receiving lesions at 40°C for cervicobrachial-
gia. In another study, a case series of 61 patients with sciatica,
59% of patients had “markedly reduced” postoperative pain at
follow-up ranging between 1 month and 15 years.103 Definite
conclusions concerning long-term outcomes are difficult given
the variability in follow-up data. The remaining studies were
small and inconsistent.
eTABLE 179-2  Ganglionectomy

Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome

Dubuisson92 1995 Case series Occipital neuralgia 11 Unclear 71% likelihood of improvement
Fedder93 1990 Case report Minor causalgia 4 6-12 mo All had pain relief and decrease in narcotic dosage
Geurts et al89 2003 Multicenter, Chronic lumbosacral 83: 45 patients had 3 mo At 3 mo, treatment was successful in 16% treated patients and 25%
randomized, radicular pain radiofrequency lesioning, 38 control patients; lumbosacral radiofrequency lesioning of dorsal root
double-blind, patients had control treatment ganglia failed to show advantage over control treatment
controlled trial (local anesthetics)
Hosobuchi94 1980 Case series Intractable chest pain 3 3 yr Total anesthesia, including loss of dysesthesia, hyperesthesia, and
original pain, occurred in 2 of the 3 patients
Jansen95 2000 Case series Cervicogenic headache 102 Unclear 80% of patients experienced improvement
Kato et al96 1990 Case report Neuropathic pain 3 1 mo-2 yr, 1 patient had complete pain relief, 2 partial pain relief
8 mo
Lozano et al97 1998 Case series Medically refractory 39 19-48 mo 19 patients had excellent results; patients who had pain from trauma or
chronic occipital described their pain as “shocklike, electric, shooting, jabbing,
pain stabbing, sharp, or exploding” (group I) had better response to
ganglionectomy (80% good or excellent response); patients who had
nontraumatic pain or described their pain as “dull, pounding, aching,
throbbing, or pressurelike” (group II) did not have a good response
Murphy98 1969 Case series Occipital neuralgia of 30 <1 yr-5 yr 18 patients had excellent results, 7 good results, 3 fair results, and 2
various etiologies poor results; it was not clear what criteria were used to determined
outcome measurements
North et al99 1991 Case series Failed back surgery 13 Mean 5.5 yr Treatment “success” found in 2 patients at 2 yr postoperatively but in 0
syndrome at 5.5 yr; “equivocal success” found in 1 patient at 2 yr
postoperatively and in 2 at 5.5 yr
Osgood 1976 Case series Lumbosacral pain, 18 Mean 7 mo 10 patients had “good” results and 4 “fair” results
et al100 brachial plexus
avulsion, amputation
Sanders and 1997 Case series CHA 66 Mean 29 mo 60.7% had complete relief of intermittent CHA; 30% (3 patients) had
Zuurmond55 (group A) or complete relief of chronic CHA
24.1 mo
(group B)
Slappendel 1997 Prospective Cervicobrachialgia 32 patients received RF lesion at 3 mo Identical outcomes in the two groups
et al90 randomized 67°C; 29 patients received RF
double-blind lesion at 40°C (control group)
study
Smith102 1970 Case series Post-thoracotomy, 10 nonmalignant, 12 total Unclear “All had some degree of relief”
herpes
Stechison and 1994 Case series Greater occipital 5 Mean 24 mo All had immediate postoperative relief of pain; 1 had recurrence of pain
Mullin107 neuralgia at 26 mo and underwent ganglionectomy; all experienced nausea
and dizziness postoperatively, and 1 had a cerebrospinal fluid leak
Taub et al103 1995 Case series Sciatica 61 <1 yr-15 yr In 59%, pain was markedly reduced or eliminated
Wetzel et al105 1997 Case series Post-surgical chronic 51 6 mo, 2 yr At 6 mo, 55% had good or excellent outcome, the rest poor outcome
lumbar radiculopathy or treatment failure; at final follow-up (2 yr? 37 patients?), 19% had
good or excellent results
Wilkinson and 2001 Retrospective Various etiologies 19 Mean 22 mo 74% reported >50% reduction; only 1 pain free
Chan106 chart review
Pisapia et al101 2012 Retrospective Occipital neuralgia 10 patients underwent C2 24 mo Mean pain reduction (on a 1-10 scale) was 4.5 ± 4.1
case series ganglionectomy (4 unilateral
and 6 bilateral)
Chun-jing 2012 Randomized Postherpetic neuralgia 36 patients treated with dorsal 6 mo Patients showed excellent or good relief of pain without any adverse
et al91 controlled trial root ganglia destruction by reactions or serious complications
Adriamycin
Weigel et al104 2012 Case series Segmental neuropathic 7 Mean 24 mo All patients had good outcome in regard to pain relief; only 3 required
pain a second procedure
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J Neurosurg. 2008;109:389-404.
CHAPTER 179  Evidence Base for Destructive Procedures 1447.e1

CHA, cluster headache; RF, radiofrequency.

179
1448 SECTION 6  Pain
Ganglionectomy for Occipital Neuralgia
The largest case series evaluated the efficacy of C2 ganglionec-
tomies for occipital neuralgia.95 The investigators found that 80%
of patients had significant relief from symptoms. Unfortunately,
long-term follow-up data were unclear, rendering any conclu-
sions difficult. The second largest series of patients with occipital
neuralgia compared ganglionectomies performed in patients with
occipital pain described as either “sharp, burning, jabbing, electri-
cal, or exploding” (group I) or “dull, aching, throbbing, or
pressure-like” (group II).97 Patients in group I tended to have a
higher prevalence of a traumatic history (74%) and had the better
response, nearly 80%. Overall, group II patients had a poor
response. Follow-up ranged from 19 to 48 months. Other pub-
lished series on ganglionectomy performed for occipital neuralgia
were small and without standardized follow-up data.
One retrospective paper evaluated the effects of occipital neu-
rectomy for the treatment of occipital neuralgia of various
causes.98
Ganglionectomy for Pain of Other Etiologies
One study evaluated sphenopalantine ganglionectomies for
cluster headache55 and found that patients with intermittent
headache had a 67% response rate but those with chronic, con-
tinuous headache had only a 24% response. Mean follow-up
times were 24 and 29 months, respectively.
Two small series, one with 4 patients93 and another with 10
patients,102 reported on patients treated with thoracic ganglionec-
tomies for a variety of symptoms. Both claimed some success.
(See eTable 179-2, 16 articles.55,89,90,92-97,99,100,102,103,105-107)
DREZ Lesions
A total of 31 (26 noncancer pain, 5 cancer pain) case series were
obtained for DREZ lesions. No class I or II studies were found.
These reports consisted of between 3 and 124 patients with a
wide range of follow-up time points. For noncancer pain, all
studies reported a greater than 50% relief in pain in a majority
of patients, and these results tended to be durable.108 Patients
with brachial plexus avulsion (BPA) injuries and traumatic spinal
cord injuries tended to have the best responses to DREZ lesions
in studies that compared different presenting etiologies directly,
whereas patients with postherpetic neuralgia and peripheral neu-
ropathies had the worst.109-111 Outcomes for patients with BPA
injuries were quite consistent across series, with more than 50%
reduction in reported pain levels in from 54% to 86% of patients.
(See eTable 179-3A, 26 articles.108-134)
Since 2008, 10 studies involving DREZ lesions for manage-
ment of noncancer pain were published: three case reports, six
case series, and one comparative study (eTables 179-3A and
179-3B).135-144
Only four papers were identified that address the use of DREZ
lesions for cancer pain (eTables 179-3C and 179-3D).145-148 Two
were case series that claimed long-lasting pain relief in patients
with mixed cancer pain etiologies. Specific follow-ups and
outcome measures were not reported. For facial pain from cra-
niofacial malignancies, three of the four papers were small case
series papers reported some benefit from DREZ of the nucleus
caudalis.145-147
Trigeminal Tractotomy for Facial Pain
Nine pertinent articles were found for the use of tractotomy in
noncancer pain, including the oldest article retrieved for this
review.149 No class I data was found for this topic. Instead, all
papers were case series. The largest case series was reported in
1975 by Schvarcz,150 who found that excellent pain relief was
obtained in 16 of 17 patients. Interestingly, all case series reported
good to excellent results even in patients with postherpetic neu-
ralgia. In one series, for example, deep pain was eliminated or
significantly decreased in all of six patients with postherpetic
craniofacial dysesthesia.151 (See eTable 179-4A, eight case series
and one case report.149-157)
Seven papers were found for tractotomy in cancer facial pain
(eTable 179-4B).150,152,158-162 All were cases series with one excep-
tion,162 an open-label prospective study. In this prospective class
II study, a standardized outcomes measure (Visual Analog Scale
[VAS]), Karnofsky performance score, activities of daily living,
and sleep duration were assessed at 6 months. The researchers
reported sustained pain relief in 80% of patients at 6 months.
Though the study was classified as class II, the number of trac-
totomy recipients included was limited (10 patients). We did not
consider this number sufficient to assign it class II evidence for
the efficacy of tractotomy in cancer facial pain. Current literature
supports only class III evidence for tractotomy for cancer pain.
Cordotomy
A review of cordotomy studies in patients with noncancer pain
produced 12 case series, published between 1958 and 1990, and
two case reports, published in 2012.163,164 No class I or II studies
were found. The number of patients in these case series ranged
from 1 to 72, and follow-up was between 1 month and 41 years.
Outcome data from these studies generally demonstrated an
overall improvement in postoperative patient-reported pain over
preoperative values.
In general, for studies with long-term follow-up, surgical ben-
efits declined with time. However, determining the statistical
significance of these findings was difficult as neither outcome
nor follow-up was standardized in the studies. Furthermore,
outcome measures were inconsistent among studies, complicat-
ing any attempts to make generalized recommendations. (See
eTable 179-5A, 12 case series.132,165-175)
The longest follow-up was in a case report for a period of 41
years; the patient was completely pain free for 35 years, after
which he started to experience slowly progressive aching pain.163
For cancer pain, cordotomy is the invasive procedure most
often reported in the literature. Eighty-four papers qualified
under our search criteria (eTable 179-5B).79,162,166,169,173,174,176-222
Many reports included more than 100 patients, and many had
long-term follow-up. A surge in publications followed the intro-
duction of percutaneous cordotomy in the mid-1960s, followed
by a gradual decline in published reports and number of patients
treated in the late 1990s. The introduction of computed tomog-
raphy (CT) guidance for percutaneous cordotomy by Kanpolat
in the late 1980s, was considered a major contribution to the field
of pain surgery. However, use of intrathecal opioids was also
introduced at around the same time and gained widespread
popularity.
Two prospective trials on cordotomy were identified. One of
them used a standardized outcome measure (VAS), Karnofsky
performance score, activities of daily living, and total sleeping
hours, and there was a statistically significant improvement in all
outcomes measures over baseline pain levels.162 The other trial
showed average pain scores (numeric rating scale) immediate pre-
operatively, 2 days postoperatively, and 28 days postoperatively
to be 7, 0, and 0, respectively.221 Three papers were retrospective
cohort studies with survival analysis of pain relief of the whole
cohort until death.84,189,190 Five papers were retrospective cohort
studies with large numbers (>100) of patients and 6 months of
follow-up.185,192,206,211,212 There were no randomized controlled
trials. Three case reports were found in the literature, in which
all patients had complete pain relief postoperatively.216,218,220
Only one systematic review, by France and associates,219 con-
cluded that cordotomy might be safe and effective in treatment

of cancer pain but that more reliable evidence is needed to aid in
decision making.
Despite the heterogeneity of outcome measures, the vast
majority of studies reported excellent lasting relief after cordot-
omy within the context of cancer longevity. Reported cordotomy
outcomes in patients with cancer pain contrasts with outcomes
in those with noncancer pain, in whom pain relief was moderate,
short-lived, and often complicated with dysesthesias.
Within the medical literature, there is limited class II evidence
for cordotomy as an effective treatment modality in cancer pain
patients.
Myelotomy
Three articles examining the use of myelotomy in noncancer pain
were found. These were small case series (3 to 14 patients) with
variable follow-up periods and pain etiologies. The largest series
reported that 64% of patients experienced a complete or marked
reduction in deep “background” pain.223 (See eTable 179-6A,
three case series.223-225)
For cancer pain, 20 papers were identified (eTable 179-
6B).133,153,225-242 These articles were all case series and included
papers about commissural as well as extraleminiscal myelotomy,
both open and percutaneous. With the exception of two papers,
most reports involved a small number (<20) of patients.133,224,232,239
Outcome measures and follow-up periods were heterogeneous.
In general, reported outcomes after myelotomy were less favor-
able than those after cordotomy. However, a consistent observa-
tion was that myelotomy was most effective in treating midline
visceral cancer pain syndromes, that is, pain from cervical, pan-
creatic, or gastric cancer.
The current literature supports only class III evidence for
myelotomy for pain relief.
Mesencephalotomy
Using the criteria described, we reviewed nine relevant articles
concerning the use of mesencephalotomy for noncancer pain. All
of these articles were case series, and most had relatively small
numbers of patients. The latest publication reported the effects
of lesions made in one of two locations in 27 patients with central
pain following a stroke.243 Long-term pain relief was produced in
75% of patients with lesions created at the level of the superior
colliculus, although with significant ocular side effects. These side
effects were reduced with lesions adjacent to the inferior collicu-
lus; long-term pain relief was achieved in 58% of patients who
received the adjacent lesions. Follow-up was between 3 months
and 5 years. In a separate study, good pain relief was produced in
23 patients (67%) with thalamic syndrome and tabes dorsalis,
followed for 3 to 70 months.244 (See eTable 179-7A, nine case
series.243-251)
Mesencephalotomy and pontine tractotomy for cancer
pain were reported in seven papers ( eTables 179-7B and
179-7C).250,252-257All were case series, with variable outcome mea-
sures and follow-up. Outcome varied from extreme success (in
92% of patients until death)257 to very poor success (lasting pain
relief in 1 of 12 patients).250 There was agreement on frequency
of side effects, specifically those related to ocular mobility.
Thalamotomy
All published articles describing thalamotomy for pain were
limited to small case series with heterogeneous patient popula-
tions. The largest case series (n = 85) was published not in a peer-
reviewed article but in book format,258 and so is not included here;
however, the investigators did describe a subset of patients from
this series in an earlier report.259 Follow-up, outcome measures,
target site, and pain etiology were inconsistent within or among
CHAPTER 179  Evidence Base for Destructive Procedures 1449
series, making definite conclusions difficult. Dougherty and col-
leagues260 and Tasker261 have provided thorough discussions of 179
thalamotomy. (See eTable 179-8A, 13 case series.165,251,259,262-271)
Sixteen papers on thalamotomy in cancer pain were found
(eTable 179-8B),165,251,262,263,266,272-282 (some articles are included in
the noncancer pain tables). All were case series with variable
outcome measures and follow-up. Most reported lasting benefits
in more than 50% of patients. In some instances bilateral pain
relief was obtained with unilateral thalamotomy. Effects tended
to fade with time and were often accompanied by persistent
psychiatric complications.278
Cingulotomy
A total of 14 original case series focusing on cingulotomy for
noncancer pain were identified on the basis of the inclusion cri-
teria (eTable 179-9A). Because the largest case series described
in the literature (n = 133) was not published as a peer-reviewed
article, it is not included in our analysis.283 No class I or class II
studies were identified. Reported case series were small, the
largest one describing 36 patients. Overall, only two papers used
a validated outcome measure such as the VAS,284,285 and only two
papers had a common diagnosis for the series.286,287 Different
follow-up periods and variable outcome measures were used,
making comparisons difficult, and for most series, reported out-
comes were also variable. Also, the majority of the reports were
published before 1980. Abdelaziz and Cosgrove133 provide a
detailed description and summary of published case series. (See
eTable 179-9A, 14 case series.251,284-296).
After elimination of redundancy, seven papers qualified for the
criteria of this review and addressed cingulotomy for cancer pain
(eTable 179-9B).251,285,289,291,293,297All were case series, with small
numbers and heterogeneous patient selection. In a later report,
50% of patients had some pain relief for up to 6 months.285
Results in the other papers were variable, ranging from 10%
to 50%.
Sympathectomy
A Cochrane systematic review on sympathectomy for nonmalig-
nant pain syndromes; specifically for neuropathic pain syndrome,
was published in 2003.298 The review criteria the investigators
used included all randomized clinical trials, controlled clinical
trials, observational studies (cohorts and case-control studies),
and relevant retrospective reviews of patient charts, for a total of
223 titles and abstracts. Only surgical sympathectomy (cervico-
thoracic or lumbar sympathetic chain ablation or coagulation by
open, endoscopic, laser, or radiofrequency) or chemical sympa-
thectomy (phenol or alcohol solution injection of cervicothoracic
or lumbar sympathetic chain) were included. The review showed
that treating neuropathic pain with sympathectomy is based on
very limited evidence. An additional publication, published in
2012, reported on sympathectomy for complex regional pain
syndrome (CRPS) and described achieving adequate pain relief
for a mean duration of 3.2 years.299
As to sympathectomy for malignant pain, our search identified
much the same information. A meta-analysis of neurolytic celiac
block (the most common form of sympathectomy performed for
cancer pain) was identified,300 along with seven additional papers
(eTable 179-10299,301-306) addressing either celiac block (published
in subsequent years after the meta-analysis data) or other forms
of sympathectomy. These studies generally focused on patients
with midline pain from visceral malignancies. The meta-analysis
identified two class I RCTs demonstrating the efficacy and safety
of celiac block in treatment of pancreatic as well as upper abdomi-
nal visceral malignancies. Of the other seven papers, one was a
class I RCT for sympathectomy for inoperable cancer pain in
which excellent pain relief was achieved for up to 3 months. Two
eTABLE 179-6A  Myelotomy for Pain*
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
224
Broager 1974 Case series Unbearable pain in lower 3 with nonmalignant 3 wk-18 mo Permanent excellent results
half of body pain causes, 34 in 16, temporary excellent
total in 9, permanent good in
3, continuous poor in 5; 1 179
death
Schvarcz223 1978 Case series Pain of central origin 14 6 mo-4 yr Abolition of hyperpathia and
disappearance of, or
marked reduction in, deep
background pain achieved
in 64% cases overall
Sourek225 1969 Case series Arachnoiditis, multiple 6 Long-term follow-up not 2 patients had no recurrence
sclerosis, or unknown carried out due to of pain
bad general health;
6-36 mo in 3 patients
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J Neurosurg.
2008;109:389-404.
*No publications after 2008.

eTABLE 179-6B  Myelotomy for Cancer Pain

Authors Year Study Design Diagnosis Patient No. Follow-up Outcome
Hwang et al233 2004 Case series Cancer pain 6 2-18 wk Moderate pain relief, at 3 mo
according to Visual Analog Scale
score
Becker et al226 2002 Case report Cancer pain 1 5 wk Complete pain relief; patient died at
5 wk
VilelaFilho et al240 2001 Case report Cancer pain 2 Short Safe techniques achieved effective
pain relief
Nauta et al237 2000 Case series Cancer pain 6 3-31 mo Significant pain reduction
Kim and Kwon235 2000 Case series Cancer pain 8 Short Adequate pain relief in 5 patients
Watling et al241 1996 Case series Cancer pain 2 Patients died after 4 Commisural myelotomy reported;
and 6 wk good pain relief prior to death
Kanpolat et al234 1997 Case series Cancer pain 14 3-6 mo 8 of 14 patients had no pain or
satisfactory pain relief
Gildenberg and 1984 Case series Cancer pain 14 2-13 mo 91% experienced total pain relief till
Hirshberg230 death
Schvarcz239 1976 Case series Cancer pain 35 with cancer pain, 45 6 mo-4 yr 30 had pain relief initially, and 25 had
total persistent pain relief
Papo and 1976 Case series Cancer pain 9 with cancer pain, 10 Till death, 1 yr Only 3 patients experienced pain relief;
Luongo238 total commissural myelotomy was
performed
Hitchcock232 1974 Case series Cancer pain 21 with cancer pain. Till death (a few 9 had no pain, and 5 had good pain
Twenty-six procedures weeks to 1 yr) relief
in 26 patients;
procedure abandoned
in 5 cases; 2 patients
lost to follow up; 19
patients with follow-up
data
Broager224 1974 Case series Cancer pain 31 with cancer pain, 34 3 wk-18 mo Permanent excellent results in 16,
total temporary excellent in 9, permanent
good in 3, and continuous poor in
5; there was 1 death
Cook et al227 1977 Case series Cancer pain 16 with cancer pain, 24 A few weeks to Of the 16 cancer patients, 11, 3, and
total months 2 had good, fair, and poor
immediate pain relief, respectively;
in late follow up, 11 died, 2 had
good pain relief, and 1 had fair pain
relief; 1 was lost to follow up
Sourek225 1969 Case series Cancer pain 19 with cancer pain, 25 Unclear 17 had good pain control
total
236
Lippert et al 1974 Case series Cancer pain 11 with cancer pain,16 A few days to 7 mo Most had good pain relief
total
Eiras et al228 1980 Case series Cancer pain 12 3-14 mo 7 had total alleviation of pain, 3 were
lost to follow-up, and few survived
>6 mo
Fascendini 1979 Case series Cancer pain 6 3 mo Initial pain relief, but pain recurred in
et al229 all patients who survived; 2 had
neurological deficits
Goedhart et al231 1984 Case series Cancer pain 10 Up to 3 yr Not clear; pain relief did not last, and
complication rate high
Hosobuchi and 1971 Case series Mixed 4 with cancer pain, 6 4-12 mo Good
Rutkin153 total
Viswanathan 2010 Retrospective Intractable 11 Median postoperative 5 patients had excellent outcomes, 3
et al242 case series malignancy- survival was 43 patients good, and 2 fair, and 1
induced days (range 11 had a poor outcome
visceral pain days-39 mo)
1449.e2 SECTION 6  Pain

eTABLE 179-7A  Mesencephalotomy for Pain*

Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Amano 1986 Case series Thalamic syndrome 27 with pain of nonmalignant 3-70 mo Overall effectiveness: good pain
et al244 and tabes dorsalis causes, 34 total relief in 23 patients (67%)
Helfant 1965 Case series Herpes zoster, 3 60 mo; lost to Low-grade pain 3 mo
et al245 thalamic follow-up; postoperatively; unchanged;
syndrome, otitic 30 mo left-sided pain and
herpes zoster paresthesias 1.5 mo
postoperatively
Liberson 1970 Case series Intractable pain of 5 with pain of nonmalignant Not stated Improvement in all cases
et al246 face, upper or causes, 6 total
lower extremities
Shieff and 1988 Case series Pain of central origin 27; lesions at original target 3 mo-5 yr 75% with long-term pain relief
Nashold243 after stroke adjacent to superior in first group; 58% with
colliculus made in 14 long-term pain relief in
patients and surgery at second group
revised target at level of
inferior colliculus in 13
patients
Spiegel and 1953 Case series Intractable facial pain 6 6.5 wk-4.5 yr Improvement in all cases,
Wycis247 ranging from no recurrence
of pain to little facial pain
Voris and 1975 Case series Intractable pain 13 with pain of nonmalignant >3 yr 0 patients with no pain relief; 8
Whisler251 causes, 58 total patients with 1-12 mo of
pain relief; 2 patients with
1-3 yr of pain relief; 3
patients with >3 yr of pain
relief; combined procedures
not included in this paper
Wycis et al248 1958 Case series Postherpetic 4 3-6 yr Mesencephalotomy alone (3
trigeminal patients) or combined with
neuralgia mesencephalothalamotomy
(1 patient) used: 3 patients
had at least partial relief of
facial pain
Wycis and 1962 Case series Mixed 42 with pain of nonmalignant Up to 13 yr 72% had immediate relief, and
Spiegel249 causes, 54 total 31% complete or partial
permanent relief
Zapletal250 1969 Case series Mixed 4 with pain of nonmalignant Unclear 1 patient had lasting relief
causes, 18 total
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J Neurosurg.
2008;109:389-404.
*No publications after 2008.

eTABLE 179-7B  Mesencephalotomy for Cancer Pain*

Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
253
Bosch 1991 Case series Cancer pain 40 Long term Effective in nociceptive pain relief
Frank et al254 1989 Case series Cancer pain 202 >6 mo 81% persistent pain relief
Barbera et al252 1979 Case series Cancer pain 6 Short All patients had pain relief in
neck and upper extremities
Zalpetal250 1969 Case series Cancer pain 12 with cancer Unclear 1 patient with lasting pain relief
pain, 16 total
Whisler and 1978 Case series Cancer pain 38 Till death; most patients survived 92% had pain relief till death
Voris257 1-6 mo, only 3 living >1 yr
Nashold256 1972 Case series Cancer pain 8 9.5 mo average All patients had pain relief, and
all had side effects
From Raslan AM, Cetas JS, McCartney S, et al. Destructive procedures for control of cancer pain: the case for cordotomy. J Neurosurg. 2011;114:
155-170. Published online with permission from the American Association of Neurological Surgeons Journal of Neurosurgery.
*No publications after 2008.

eTABLE 179-7C  Pontine Tractotomy for Cancer Pain*

Authors Year Study Design Diagnosis Patient No. Follow-up Outcome
255
Hitchcock et al 1985 Small case series Cancer pain of only 6 Till death 100% had pain relief; 4 patients died less
neck and upper body than 3 mo after surgery, and 2 survived
more than 3 mo
*No publications after 2008.
 CHAPTER 179  Evidence Base for Destructive Procedures 1449.e3

eTABLE 179-8A  Thalamotomy for Pain

179
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Amano 1976 Case series Intractable pain of mixed 33 with pain of 1-24 mo Good pain relief for thalamic pain or
et al165 etiology nonmalignant causes, causalgia
47 total
Choi and 1977 Case series Intractable pain 7 with pain of Not stated 91% of all patients had excellent or
Umbach262 nonmalignant causes, good results
37 total
Hitchcock 1981 Case series Mixed 29 with pain of Up to 10 yr Bilateral center-median thalamotomy
and nonmalignant causes, is superior to basal thalamotomy
Teixeira263 43 total
Jeanmonod 1993 Case series Chronic therapy-resistant 45 Mean 14 mo VAS used; 67% of all patients
et al259 neurogenic pain; gained 50%-100% relief, and
various lesions 29% had complete relief
Kudo et al270 1968 Case series Cerebrovascular accident, 8 with pain of Up to 2 yr Complete relief of pain without
atypical facial pain, nonmalignant causes, appreciable sensory loss in 10
trigeminal neuralgia 17 total patients, fairly good effects of
pain relief in 7
Lende et al264 1971 Case series Facial pain from stroke or 2 14-20 mo Relief of pain
trigeminal neuralgia
Niizuma 1982 Case series Central pain from 18 9 mo-6 yr 56% effective, but longest duration
et al265 cerebrovascular disease of pain relief was about 6 mo
Obrador and 1960 Case series Atypical facial pain and 3 Not stated Patient with trigeminal neuralgia had
Bravo269 trigeminal neuralgia no improvement; those with
atypical facial pain had less
intense pain postoperatively
Richardson266 1967 Case series Mixed ? with pain of nonmalignant Up to 5 mo Favorable results
causes, 38 total
Shieff and 1987 Case series Central pain from 24 reviewed; 27 total 3 mo-5 yr 66.7% had long-term relief
Nashold267 cerebrovascular
accident
Voris and 1975 Case series Intractable pain 23 with pain of >3 yr 4 patients had no pain relief; 12 had
Whisler251 nonmalignant causes, 1-12 mo of pain relief, 2 patients
58 total had 1-3 yr, and 5 had >3 yr;
combined procedures were not
included in this paper
Young et al315 1995 Case series Chronic intractable pain of 19 1-22 mo 15 patients were followed for
mixed etiology >3 mo; 4 patients (27%) were
pain free and 5 patients (33%)
achieved >50% pain relief;
therefore 9/15 patients (60%) had
worthwhile benefit from medial
thalamotomy with Gamma Knife
Jeanmonod 2012 Case series Chronic therapy-resistant 11 patients, but the 1 yr Preoperative mean VAS score was
et al271 neuropathic pain outcomes of only 9 59.5/100; significant pain relief
patients were used in (mean group value 55%) was
the analysis as the reported during and at the end of
lesion made in the the procedure; mean VAS was
posterior part of 34.3/100 at 3 mo and 35.3/100
the thalamic central at 1 yr
lateral nucleus
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review.
J Neurosurg. 2008;109:389-404.
VAS, Visual Analog Scale.
1449.e4 SECTION 6  Pain

eTABLE 179-8B  Thalamotomy for Cancer Pain*

Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Whittle and 1995 Case series Cancer pain 2 Patients died 6 wk and Adequate pain relief till death
Jenkinson282 3 mo postoperatively
Steiner et al279 1980 Case series Cancer pain 52 Few mo 8 had excellent pain relief, 18 with
moderate pain relief
Hitchcock and 1981 Case series Mixed 16 with cancer Up to 10 yr Bilateral center-median is superior
Teixeira263 pain, 43 total to basal thalamotomy
Fairman and 1973 Case series Cancer pain 165 2-12 mo 70% had no or satisfactory pain
Llavallol273 relief
Richardson266 1967 Case series Mixed 38 total Up to 5 mo Favorable outcome
Richardson276 1974 Case series Mixed 24 total 2-12 mo Mixed results, but return of chronic
pain occurred in all patients
Uematsu et al281 1974 Case series Cancer pain 17 Till death; average 6 mo 3 excellent, 7 good, 3 no benefit
Sugita et al280 1972 Case series Cancer pain 44 with cancer Up to 18 mo; most had 85% had excellent or satisfactory
pain, 60 total 1-yr follow-up; patients pain relief initially; generally good
with cancer mostly did results in patients with cancer
not survive to 1 yr pain
Leksell et al274 1972 Case series Cancer pain 25 Up to 1 yr; most patients 6 were pain free and 4 had
died before 1 yr moderate pain relief; effect
noticed after 3 wk
Shimizu et al278 1968 Case series Cancer pain 8 with cancer 23 days-14 mo 6 had complete pain relief till death
pain, 17 total (3 died <1 mo postprocedure), 2
had adequate pain relief;
psychological disturbances were
common but resolved 4-20 days
after surgery
Fairman272 1967 Case series Cancer pain 15 with cancer 2-12 mo 80% had bilateral pain relief
pain, 53 total
Ramamurthi and 1966 Case series Cancer pain 7 Short All had reasonable pain relief
Kalyanaraman275
Sano et al277 1966 Case series Mixed 10 total 2 mo-2.5 yr Lasting effect in 8 patients
Amano et al165 1976 Case series Mixed 14 with cancer 1-24 mo Good pain relief only in patients
pain, 47 total with thalamic pain or causalgia
Choi and Umbach262 1977 Case series Mixed 30 with cancer Unclear 91% of all patients had excellent or
pain, 37 total good results
Voris and Whisler251 1975 Case series Mixed 35 with cancer >3 yr Pain relief in most patients; few had
pain, 58 total long-lasting pain relief
From Raslan AM, Cetas JS, McCartney S, et al. Destructive procedures for control of cancer pain: the case for cordotomy. J Neurosurg. 2011;114:
155-170. Published online with permission from the American Association of Neurological Surgeons Journal of Neurosurgery.
*No publications after 2008.
 CHAPTER 179  Evidence Base for Destructive Procedures 1449.e5

eTABLE 179-9A  Cingulotomy for Pain*

179
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Broager and 1972 Case series Benign and 17 3-13 yr 14 had good or excellent results
Olesen288 psychogenic pain (combined)
Faillace et al289 1971 Case series Benign pain 2 Unclear Pain improved in 1
Foltz and White290 1968 Case series Benign and 24 1-9 yr 18 had excellent or good results
psychogenic pain
Hurt and 1974 Case series Benign 36 1-21 yr 8 had marked to complete pain relief
Ballantine291
Laitinen and 1972 Case series Intractable phantom 3 Unclear Poor in all 3
Vilkki287 limb pain
Le Beau292 1954 Case series Intractable benign pain 5 Unclear Poor
and depression
Pillay and 1992 Case series Benign 2 1 yr 1 had excellent results
Hassenbusch293
Sharma294 1974 Case series Intractable pain 3 <1 yr All 3 patients stopped craving opiates
Turnbull295 1972 Case series Benign 13 Unclear 4 had good or excellent results
(combined)
Voris and Whisler251 1975 Case series Intractable pain 11 with pain of >3 yr 3 patients had no pain relief; 6
nonmalignant patients had 1-12 mo of pain
causes, 58 total relief, 1 had 1-3 yr, and 1 patient
had >3 yr; combined procedures
not included in this paper
Wilkinson et al284 1999 Case series Benign 23 1-15 yr 18 responded to a follow-up
questionnaire; 72% reported
5-point reduction or more on VAS
Wilson and 1974 Case series Benign 4 1-55 mo Poor in all 4
Chang296
Yen et al285 2005 Case series Benign 7 1 yr 4 had significant pain relief as
demonstrated by VAS score
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review.
J Neurosurg. 2008;109:389-404.
*No publications beyond 2008.
VAS, Visual Analog Scale.

eTABLE 179-9B  Cingulotomy for Cancer Pain*

Authors Year Study Design Diagnosis Patient No. Follow-up Outcome
Yen et al285 2005 Case series Cancer pain 15 6 mo 50% had pain relief at 6 mo
Wong et al 316 1997 Case series Cancer pain 3 Not reported Adequate pain relief but with personality
changes and delusions in 1 patient
Pillay and Hassenbusch293 1992 Case series Cancer pain 8 6 mo 50% had excellent results, 25% poor
Hurt and Ballantine291 1974 case series Mixed 32 with cancer 4 days-6 yr Helpful in 12 patients
pain, 68 total
Foltz297 1968 Case series Cancer pain 11 Unclear Helpful in 9 patients
Faillace et al289 1971 Case series Mixed 9 with cancer Unclear Helpful in 1 patient
pain, 11 total
Voris and Whisler251 1972 Case series Mixed 7 with cancer 1 mo-3 yr Helpful in 5 patients
pain, 29 total
From Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J Neurosurg.
2008;109:389-404. Published online with permission from the American Association of Neurological Surgeons Journal of Neurosurgery.
*No publications after 2008.
1449.e6 SECTION 6  Pain

eTABLE 179-10  Sympathectomy for Cancer Pain

Authors Year Study Design Diagnosis Patient No. Follow-up Outcome
Happak et al299 2012 Case series Complex regional 16 3.2 ± 0.4 yr Twelve patients (75%) demonstrated a
pain syndrome significant decrease in their pain scores
type II after the surgery. The mean score on
the VAS was 8.8 before the operation
and 2.7 after the operation.
Functional improvement of the limbs was
reported by 15 (94%) of the 16 patients.
Kang et al303 2007 Case series Cancer pain 21 Short Significant improvement in (Verbal)
Numerical Rating Scale, percutaneous
sympathectomy
Gunaratnam et al302 2001 Prospective Cancer pain 58 6 mo Significant reduction of VAS score for up to
open-label 6 mo, percutaneous sympathectomy
Lin et al305 1994 Case series Cancer pain 14 Short Good immediate pain relief
Fujita301 1994 Case series Cancer pain 27 Short Complete pain relief in 20 of 21 patients
who received successful bilateral
splanchnic nerve neurolysis
Lillemoe et al304 1993 Prospective Cancer pain 65 Short Significant pain relief
randomized
Eisenberg et al300 1995 Meta-analysis Cancer pain Only for celiac plexus block, which was
found effective; included many papers
Erdek et al306 2010 Retrospective case Visceral cancer 50 1 mo 28 patients showed pain relief >50% for
series pain for which >1 mo
conservative
treatment failed
Wyse et al317 2011 Randomized Painful inoperable 98 3 mo Pain scores decreased significantly at 1 mo
controlled pancreatic after endoscopic ultrasound-guided
double-blind trial cancer celiac plexus neurolysis, with a further
decrease at 3 mo
VAS, Visual Analog Scale.
1450 SECTION 6  Pain
others—a class II “prospective randomized trial” involving 65
patients and a prospective open-label “class II” study involving
58 patients—both demonstrated statistically significant pain
relief at 6-month follow-up (P < .05) in patients with pancreatic
cancer.302,304
DISCUSSION
Numerous studies have been published on destructive techniques
for the treatment of pain, many dating from the beginnings of
modern neurosurgery. Few, however, have detailed descriptions
of long-term outcomes using validated outcome measures and
standardized follow-up. The vast majority of published articles
constitute case series and uncontrolled chart reviews. Heteroge-
neous populations of patients, inconsistent follow-up, hugely
variable study groups, vastly different treatment techniques, and
lack of either concurrent or historical controls are endemic to the
majority of the reviewed studies. As accepted methods of clinical
reporting have evolved, investigators have made significant
efforts to incorporate modern standards of evidence, but the
absolute number of studies with such standards in the field of
ablative surgery for pain remains limited.
The few studies that can be classified as class I,10,14 in general,
are from the anesthesia literature and address percutaneous
methods for the treatment of facet or radicular pain. The results
of these studies are overall mixed, highlighting the difficulty in
extrapolating efficacy from earlier, uncontrolled studies.
In many instances in the literature on neuroablation, for both
malignant and nonmalignant pain etiologies, repeated observa-
tions have been made across different studies, writers, and institu-
tions that, given their consistency, should be further explored. For
example, better outcomes for DREZ lesions were reported for
the treatment of patients with BPA than for those with posther-
petic neuralgia.109-111 Although the observations were made in
uncontrolled studies, expectation and observer bias were likely
consistent throughout the groups. DREZ lesions may provide
considerable benefit to patients with BPA. Denervation pain from
BPA historically has been difficult to treat despite the treatment
modality.2,108 The efficacy of DREZ lesions in BPA should be
studied in a well-controlled and sufficiently powered study. Simi-
larly, consistent beneficial long-term outcomes with similar rates
of recurrence for TN treated with rhizotomies have been reported
in several large case series.22,31,33 There is strong anecdotal evi-
dence for a significant treatment effect. However, considerable
controversy remains regarding patient selection, timing,86 and the
place of DREZ lesioning in light of other efficacious, nondestruc-
tive treatments, such as microvascular decompression.
In studies of cancer pain two consistent observations stand
out. First commissural myelotomy and extralemniscal myelotomy
may be effective treatments for visceral cancer pain states and
should be studied directly. Second, a large number of studies as
well as one class II study support the use of cordotomy for the
treatment of cancer pain states, reporting sustained relief for up
to 2 years. In this regard, cordotomy is unique among invasive
procedures for the treatment of cancer pain. The procedure fell
out of favor largely because of strong competition from intrathe-
cal opioid treatment. Now that the side effects and cost of long-
term intrathecal opioid use are better appreciated, it is time to
revisit cordotomy by means of modern, well-designed studies for
the treatment of certain cases of cancer pain.
Important observations have also been made throughout dif-
ferent treatment modalities and etiologies that may contribute to
a deeper understanding of the underlying pathophysiology of
different pain states. Independently, different writers reporting
on ablative techniques for the treatment of various pain etiolo-
gies, ranging from spinal cord injury to TN, have observed that
pains described as electrical, intermittent, and stabbing were
more successfully treated by ablative procedures than pains
described as steady and/or aching.22,31,97,108,132 This observation
suggests that there may be an underlying difference between
these two types of pain that may require distinct interventions.
These observations regarding BPA, TN, pain symptomology,
visceral cancer pain, and cordotomy are just a few of the issues
in the published literature that warrant further study and assess-
ment through focused, well-designed trials. The value of such
studies could potentially lead to improvements in patient selec-
tion and surgical outcomes as well as to new understandings of
the pathophysiology of different pain states.
Anyone designing appropriate modern studies must under-
stand that clinical trials for pain treatment are especially prone
to such confounding factors as reporting and observer bias,10
owing to the subjective nature of pain and the complete absence
of an objective or treatment effect marker. The value of validated
outcome measures, such as the VAS, as surrogates for more objec-
tive measures, is now well recognized, and such measures must
be employed in modern studies. Care must also be taken to limit
such confounders as expectation by the patient and the physician
that the treated pain will improve. In fact, it has been well-
documented not only that invasive procedures tend to have a
greater placebo effect on patients’ symptoms than noninvasive
treatments but also that the effect decays with time.308 In patients
treated for cancer pain, however, this pattern might also represent
the limited survival in terminally ill patients and may mask a real
therapeutic effect. In addition, different pain states are now
known to have different underlying pathophysiologies. Modern
studies should not group all patients together and potentially miss
treatable subgroups of patients. However, identifying subgroups
of patients make it even more difficult for single centers to main-
tain sufficient volume for a particular procedure to adequately
power a valid outcome study. Collaboration among institutions
and countries is imperative. The accurate evaluation of surgical
pain procedures is a difficult task owing to the subjective nature
of pain and the additional challenges in blinding patients and
evaluators to the procedure performed. Although sham surgery
has been performed in a neurosurgical clinical trial for the treat-
ment of Parkinson’s disease,309 such practice is highly controver-
sial.310 More realistically, it should be recognized that useful and
meaningful information can be obtained from well-designed
studies that incorporate as many of the elements of a class I study
as possible.10,311 Modern observational studies using case controls
and modern statistics may still demonstrate treatment effects
within the confidence intervals of RCTs.311,312 Important ele-
ments include investigator equipoise, blinded or at least impartial
evaluators, long follow-up times with intention-to-treat type
analyses, validated outcome measures, controls, uniform diagno-
ses, and uniform surgical techniques. With appropriate and well-
designed studies, large numbers of patients may not be needed
to begin to answer fundamental questions in the surgical treat-
ment of pain.
The field of pain surgery has suffered from a general pattern
of early enthusiasm for new techniques followed by a shift to even
newer approaches without adequate establishment of indications
and efficacy data for existing procedures. A large paradigm shift
occurred that favored neuromodulation over neuroablation. This
shift represented a more modern perspective, in which pain is
viewed as a primitive but fundamental protective mechanism of
the entire organism. Pain is the result of a distributed network
rather than simple afferent inputs that can be removed. However,
neuromodulation as well as modern pharmaceuticals have also
failed to be all things to all patients. By the time that the surgical
community realized the limitations of the new paradigm, it was
too late to revive many of the older and potentially efficacious
ablative techniques. In fact, very few practicing neurosurgeons
are either trained in or actively perform many of the more inva-
sive ablative techniques. If neurosurgery is to maintain a leader-
ship role in the treatment of pain, we must come together to first

determine and then promote and teach those techniques that
hold promise for patients with pain.
Finally, it should be noted that the studies reviewed were
limited to peer-reviewed journals using the criteria outlined in
our methodology. As eloquently stated by two statesmen in the
field, “much information about lesioning surgery in the nervous
system for pain relief can be found in textbooks devoted to
surgery for pain.”313 For new ideas, read old books (after Pavlov).
CONCLUSION
Destructive techniques for the treatment of pain have a long and
important history within the field of neurosurgery, but their effi-
cacy has not been well established through the use of contempo-
rary standards. This comprehensive review of the existing
literature on ablative techniques for pain was aimed at summariz-
ing the extent and quality of support for these techniques. With
very few exceptions, there is limited evidence of their efficacy.
Modern studies are needed to define appropriate indications and
methodologies in the treatment of noncancer chronic pain.
Acknowledgments
The authors would like to express their appreciation and thanks to Robert
J. Coffey, M.D., and Shirley McCartney, Ph.D., for contributions to this
chapter.
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1451.e6 SECTION 6  Pain
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CHAPTER 179  Evidence Base for Destructive Procedures 1451.e7
315. Young RF, Jacques DS, Rand RW, et al. Technique of stereotactic
medial thalamotomy with the Leksell Gamma Knife for treatment 179
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eTABLE 179-3A  Dorsal Root Entry Zone Lesioning for Pain—cont’d
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Tomas and 2005 Case series BPA 2; group 1 (localization of DREZ Mean 44.1 mo All patients: 62% had good results, 38% fair, and 0% poor; group
Haninec125 by evoked potentials was not 1: 33% had good results, 67% fair, and 0% poor; group 2: 83%
performed), 9 patients; group had good results, 17% fair, and 0% poor
2 (direct spinal cord bipolar
stimulation and registration
with the goal to localize
DREZ), 12 patients
Young126 1990 Case series Deafferentation pain 78 Up to 5 yr 61.5% had satisfactory results
1448.e2 SECTION 6  Pain

(mixed)
Kanpolat et al222 2013 Case report Complex regional pain 2 1 case followed up The first patient experienced postoperative ataxia, with recovery
syndrome for 60 mo, the after 2 mo, and was followed up for 60 mo without any
other 33 mo recurrence or complications; the second patient experienced
ataxia that improved after 3 mo, was pain free for 6 mo then
had a recurrence, received psychiatric consultation reassurance
and antidepressants, and then was followed up for 33 mo with
partial satisfactory pain relief
Aichaoui et al135 2011 Prospective Pain following BPA 29 Mean 60 mo (range On discharge: 23 patients showed excellent global pain relief, and
case series 10-122) for 26 the other 6 showed good pain relief with the residual pain
patients controlled by class 1 analgesics and/or anticonvulsants or
antidepressants; at the first outpatient visit 3 mo later: 21 had
excellent pain relief, 7 good, and 1 poor; at last evaluation: 14
had excellent pain relief, 6 good, and 6 poor
Ruiz-Juretschke 2011 Case series Neuropathic 18 Mean 28 mo (range Mean level of pain decreased according to VAS score, which fell
et al140 deafferentiation pain 6-108) from 8.6 significantly to 2.9; at last f/u the mean VAS score was
syndromes 4.7
Chun et al137 2011 Retrospective Refractory neuropathic 38 Mean 42 mo (range Good pain relief was achieved in 30 patients (79%), fair in 4
case series pain following SCI 19-84) (10.5%), and poor in 4 (10.5%)
Tomycz and 2011 Case report BPA and phantom 1 26 yr The patient had significant relief of phantom limb pain and no
Moossy142 limb pain recurrence for 26 yr
Ali et al136 2011 Comparative Intractable BPA pain 15 patients, of whom 7 Of the EMCS patients EMCS: the percentage of patients with favorable outcomes (>50%
study underwent DREZotomy 7 were followed for reduction in VAS score) was higher for those with continuous
alone, 4 underwent EMCS average of 47 mo. pain than for those with paroxysmal pain, both during the trial
alone, and 4 underwent both Of the DREZ patients and with long-term stimulation; during the trial, 4 of 8 patients
procedures 10 were followed (50%) with continuous pain had favorable outcomes, compared
for an average of with 2 of 6 patients (33%) with paroxysmal pain; at the latest f/u,
31 mo (range 3 of 7 patients (42%) with continuous pain had favorable
12-61) outcomes, compared with 0 of the 5 patients (0%) with
paroxysmal pain, and the mean percentage of VAS reduction
was greater in those with continuous pain than in those with
paroxysmal pain (28% vs. 7%)
DREZotomy: in immediate postoperative period, 10 of 11 patients
(91%) with paroxysmal pain had favorable outcomes compared
with 8 of 11 patients (72%) with continuous pain; at the latest
follow-up, 7 of 10 patients (70%) with paroxysmal pain had
favorable outcomes compared with 2 of 10 patients (20%) with
continuous pain, and the mean percentage of VAS reduction
was greater in those with paroxysmal pain than in those with
continuous pain (63% vs. 26%)
Tao et al144 2014 Retrospective Intractable chronic 35 Mean 36.1 yr in 33 At 36.1 mo follow up, excellent pain relief was reported in 24
case series neuropathic pain patients (range patients (69%), good results in 6 patients (17%), and poor
due to SCI and/or 1-6 yr) results in 5 patients (14%)
cauda equina injury
Dong et al138 2012 Case series Pain after BPA 7 12 mo All patients showed good pain relief postoperatively as follows:
mean ± SD VAS pain scores were 8.9 ± 0.9 preoperatively and
0.9 ± 0.7 at 12 mo postoperatively
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J Neurosurg. 2008;109:389-404.
BPA, brachial plexus avulsion; DREZ, dorsal root entry zone; EMCS, electric motor cortex stimulation; f/u, follow-up; SCI, spinal cord injury; SD, standard deviation; VAS, Visual Analog Scale.
 CHAPTER 179  Evidence Base for Destructive Procedures 1448.e3

eTABLE 179-3B  Dorsal Root Entry Zone Lesioning for Facial Pain
179
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Sandwell and 2013 Case report Anesthesia 1 1 yr Immediate postoperatively the patient
El-Naggar141 dolorosa was free of facial pain, and at 7th
postoperative week he stopped
medication completely
Park et al143 2010 Retrospective Refractory 39 patients; 16 Mean 26.1 mo 15 (93.8%) RGZ patients and 20 (87.0%)
case series trigeminal underwent GKRS (range 12-53 mo) DREZ patients experienced treatment
neuralgia to the RGZ, and success (BNI score I-IIIb); 7 (43.8%)
23 underwent RGZ patients and 4 (17.4%) DREZ
GKRS to the DREZ patients reported complete pain relief
without medications (BNI score I)
BNI (score), Barrow Neurological Institute Pain Intensity (score); DREZ, dorsal root entry zone; GKRS, gamma knife radiosurgery; RGZ, retrogasserian
zone.

eTABLE 179-3C  Dorsal Root Entry Zone Lesioning for Cancer Pain*
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Sindou148 1995 Case series Cancer pain 81 Long ?
Kanpolat et al146 2008 Case series cancer pain 7 Long Significant pain relief
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review.
J Neurosurg. 2008;109:389-404.
*No publications after 2008.

eTABLE 179-3D  Caudalis Dorsal Root Entry Zone Lesioning for Cancer Pain*
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Bullard and 1997 Case series Cancer pain among 1/25 Unclear in the cancer No definitive f/u time, no outcome for the
Nashold145 noncancer facial pain patient cancer patient; yet initially 24/25 had
pain pain relief, but only 67% did so at 1 yr
Kanpolat et al146 2008 Case series Cancer pain 3 Long Significant pain relief
Rossitch et al147 1989 Case series Cancer pain 5 Mean 14.4 mo 3 patients had significant improvement
From Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review. J Neurosurg.
2008;109:389-404. Published online with permission from the American Association of Neurological Surgeons Journal of Neurosurgery.
*No publications after 2008.

eTABLE 179-4A  Tractotomy for Pain

Study
Authors Year Design Diagnosis Patient No. Follow-up Outcome
Brodal149 1947 Case series Facial pain 4 Unclear Good pain relief
Crue et al152 1972 Case series Trigeminal neuralgia 4 with pain of Unclear Unclear
nonmalignant
causes, 12 total
Hitchcock and 1972 Case series Postherpetic facial pain 3 >1 yr Good
Schvarcz156
Hosobuchi and 1971 Case series Intractable facial pain of different 2 with pain of 4-12 mo Good
Rutkin153 etiologies nonmalignant
causes, 6 total
Kanpolat et al154 1998 Case series Idiopathic vagoglossopharyngeal 9 2-24 mo Excellent in 6, good in 3
neuralgia and geniculate neuralgia
Kunc155 1965 Case series Cranial nerve IX essential neuralgia 15 Unclear Reported case histories
of last 6 patients with
“successful” operations
Schvarcz150 1975 Case series Mixed 17 with pain of 4-18 mo Excellent in 16
nonmalignant
causes, 25 total
Thompson et al157 2013 Case report Postherpetic neuralgia and 2 3 and 6 mo Both patients described
postoperative hemicranial excellent pain relief
neuralgia postoperatively
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review.
J Neurosurg. 2008;109:389-404.
1448.e4 SECTION 6  Pain

eTABLE 179-4B  Trigeminal Tractotomy for Cancer Pain*

Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
Raslan162 2008 Prospective Cancer pain 10 6 mo Significant improvement in Visual Analog Scale
open-label score, Karnofsky performance score,
activities of daily living, sleeping hours
Kanpolat et al160 1995 Case series Cancer pain 5 6 mo Satisfactory pain relief
Plangger et al161 1987 Case series Cancer pain 6 ? 50% had complete pain relief and 50% had
excellent pain control
Schvarcz150 1975 Case series Cancer pain 8 of 25 treated for 4-18 mo Excellent in all 8 cases
neoplasms
158
Fox 1971 Case series Cancer pain 8 of 12 treated for pain Unclear 6 had excellent pain relief, 1 had 50% relief,
and 1 had no relief
Hitchcock159 1970 Case series Cancer pain 5 of 7 treated for pain 6-8 mo 3 had complete pain relief, 2 partial relief
Crue et al152 1972 Case series Cancer pain 8 of 12 treated for pain Till death 6 of the 8 had excellent or good pain relief
From Raslan AM, Cetas JS, McCartney S, et al. Destructive procedures for control of cancer pain: the case for cordotomy. J Neurosurg. 2011;114:
155-170. Published online with permission from the American Association of Neurological Surgeons Journal of Neurosurgery.
*No publications after 2008.

eTABLE 179-5A  Cordotomy for Pain

Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
165
Amano et al 1976 Case series Intractable pain of 4 with pain of nonmalignant 2 wk Reduced pain without medication
mixed etiology causes, 30 total in 2 patients, persistent pain
with medication in 2 patients
Cowie and 1982 Case series Neuropathic pain of 13 with pain of nonmalignant >3 yr 85% relief at 6 mo, 35% at 1 yr,
Hitchcock166 various etiologies causes, 56 total 20% at 3 yr
Diemath et al167 1961 Case series Neuropathic pain of 33 with pain of nonmalignant >2 yr 67% complete relief immediately
various etiologies causes, 121 total postoperatively, 58% complete
relief at 2 yr
Frankel and 1961 Case series Neuropathic pain of 16 with pain of nonmalignant Up to 31% (non)complete relief
Prokop168 various etiologies causes, 75 total 10 yr
French 1974 Case series Neuropathic pain of 22 with pain of nonmalignant >6 mo Not stated for patients with pain of
various etiologies causes, 185 total nonmalignant causes
Grant and 1957 Case series Neuropathic pain of 72 with pain of nonmalignant >1 mo 32/72 complete relief, 52/72 at
Wood170 various etiologies causes, 312 total least partial relief
Porter et al171 1966 Case series Cauda equina injury 34 >18 mo 61.7% good or fair results
Probst172 1990 Case series Epidural/intradural 22 6-132 mo 65% good long-term results
fibrosis (complete and partial pain relief)
Raskind173 1969 Case series Neuropathic pain of 30 with pain of nonmalignant Not stated 60% good, not requiring narcotics
various etiologies causes, 237 total
Rosomoff174 1969 Case series Pain of various 29 with pain of nonmalignant ≥2 yr 10/17 or 60% of survivors at 2 yr
etiologies causes, 100 total with satisfactory results; unclear
how many survivors had pain of
nonmalignant causes
Tasker et al132 1992 Case series Pain due to spinal 34 underwent cordotomy, Not stated 54% for cordotomy and 60% for
cord injury of and 12 cordectomy cordectomy in patients whose
various etiologies pain had been intermittent or
evoked
Lewin et al164 2012 Case report Low back pain, 1 11 mo Patient was free of pain from
right hip and immediately postoperatively until
buttock pain his death 11 mo later
Collins et al163 2012 Case report Pain in the left leg, 1 41 yr Patient remained completely free
calf, and foot of pain for 35 yr then started to
following pelvic experience slowly progressive
bullet injury and descending recurrence of
aching pain in the left subcostal
region
Modified from Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment of nonmalignant pain: a structured literature review.
J Neurosurg. 2008;109:389-404.
eTABLE 179-5B  Cordotomy for Cancer Pain—cont’d
Author(s) Year Study Design Diagnosis Patient No. Follow-up Outcome
189
Ischia et al 1984 Retrospective cohort Cancer pain 36 Till death Bilateral cases only; 47% had complete pain relief
of prospectively and 12.5% partial pain relief; patients might be
collected data included in other Ischia studies cited in table
Cowie and 1982 Case series Cancer pain 33 Up to 1 yr 95%, 73%, and 55% of patients had pain relief
Hitchcock166 immediately postoperatively, at 6 mo, and at 1 yr,
1448.e6 SECTION 6  Pain

respectively
Meglio and 1981 Case series Cancer pain 52 15 wk 73% and 63% of patients had excellent results after
Cioni199 1 wk and 15 wk, respectively
Lipton S197 1978 Case series Cancer pain 650 Till death 95% of patients had initial pain relief, but only 75%
near death; 6.2% mortality
207
Rothbard et al 1972 Case series Cancer pain (gynecologic) 10 Up to 3 yr Pain-free interval 6-29 mo
Batzdorf and 1970 Case series Cancer pain 41 with cancer pain, 47 Up to 12 mo 27 had excellent or good pain relief, and 11 fair pain
Weingarten178 total relief
O’Connell202 1969 Case series Cancer pain (rectal) 56 6 wk-2 yr 63% had complete pain relief till death
French169 1974 Case series Cancer pain 177 with cancer pain, 200 Up to 1 yr 90.6% had no pain or good pain relief for up to
total, underwent open >1 yr, open surgical cordotomy
surgical cordotomy
Rosomoff174 1969 Case series Cancer pain 71 with cancer pain, 100 Till death Initial 93% pain relief that faded to about 60%
total, underwent based on survival at 2 yr; patients were followed
bilateral cordotomy up till death
Lin et al196 1966 Case series Cancer pain 38 2 wk-7 mo 74%-86% had adequate results (no pain or good
pain relief), depending on whether approach was
anterior or posterior
Mullan et al200 1965 Case series Cancer pain 47 Short 36 had good outcome; 1 death
Esposito et al79 1985 Case series Cancer pain 8 6 mo Cordotomy worked for 2-3 mo only
Grote et al186 1978 Case series Cancer pain 138 Unclear Initial relief in 114 (106 complete, 8 partial),
dysesthesia in 9, anesthesia dolorosa in 1
Tasker212 1976 Case series Mostly cancer pain 264 mixed Unclear Initial results, 96% and 83% pain relief with unilateral
and bilateral, respectively; 89% and 66%,
respectively, at the time of latest follow-up; 3%
permanent complications
Crue and 1974 Case series Mixed 29 with cancer pain, 48 Short 31% pain relief even in the short term
Felsoory179 total
Fox183 1973 Case series Mixed 14 with cancer pain, 18 Unclear 11 had adequate pain relief
total
Tasker and 1973 Case series Mixed, mostly cancer pain 78 Till death; survival 84% had pain relief till death
Organ213 generally 3-6 mo
Smith210 1972 Case series Mixed, mostly cancer pain 19 Around 6 mo 100% of patients with cancer pain had complete or
satisfactory pain relief
Foer182 1971 Case series Cancer pain 21 with cancer pain, 30 Unclear 90% had partial to complete pain relief; 1 death
total
Salmon208 1969 Case series Mixed 34 Unclear 25 of 34 had good pain relief, 3 had minor transient
ataxia; no deaths
Fox184 1969 Case series Mixed 50 Not reported Not reported
Uihlein et al214 1969 Case series Cancer pain 45 with cancer pain, 50 Unclear 80% complete pain relief, 52% satisfactory pain
total relief, and 28% persistent pain relief
Acosta and 1969 Case series Cancer pain 12 with cancer pain,15 3 mo-2 yr Adequate pain relief in all patients; 2 required repeat
Grossman176 total procedure
Kelly and 1966 Case series Cancer pain 14 with cancer pain, 17 1-10 mo 13 had pain relief
Alexander193 total
180 Dorsal Rhizotomy and Dorsal Root Ganglionectomy
Feridun Acar, Selçuk Göçmen, and Athanasios K. Zisakis
The treatment of pain remains a major interest of neurosurgery.
Since the beginning of 20th century, destructive procedures tar-
geting different locations on the pain pathway have been used
widely.1,2 As a result of new neuromodulation techniques and
medications, there is a tendency to abandon the use of destructive
procedures such as dorsal rhizotomy and dorsal root ganglionec-
tomy despite their value and efficacy. However, in some cases, the
modern modalities lack the sufficiency to control pain, and more-
over these modalities are expensive and need maintenance. With
this perspective, a pain surgeon should know the indications
for destructive procedures and have the skills to perform these
procedures.3,4
INDICATIONS FOR DORSAL RHIZOTOMY
AND GANGLIONECTOMY
The indications for dorsal rhizotomy and ganglionectomy can
be reviewed under two major pain groups: cancer pain and
noncancer pain. The determination of level can vary from a
single root or ganglion to multilevel surgery. The level of surgery
also depends on intradural root anastomosis, rich anastomoses
of the sympathetic system, and ventral root sensory fibers
(Fig. 180-1).
Local preoperative blocks for testing can help to determine
the levels of surgery. However, diagnostic blocks can also be
misleading because of inappropriate application or a placebo
effect. Placebo control is important, and the blocks can be
repeated. The determination, however, should always be a clinical
decision, and the outcome of diagnostic blocks cannot be used as
a sole and major factor on the way to surgery.
Cancer Pain
In patients with malignancies involving the brachial plexus, such
as invasive breast carcinoma, multilevel cervical dorsal rhizotomy
to denervate a functionally impaired limb can be successful in
controlling pain.5 In patients with an intact upper extremity
motor function, this procedure can result in severe function loss
of the involved limb.
In patients with malignancies of the thorax and chest wall,
thoracic ganglionectomy with rhizotomy can be a good surgical
option.5 There is a segmental overlap of dermatomes in the tho-
racic area, which leads to the need for multilevel surgeries in
these patients. A three- to five-level ganglionectomy with or
without rhizotomy should be considered.
The most important disadvantage of this surgery is the
destruction of S2 and S3 sensory innervation, which will result
in neurogenic bladder, neurogenic bowel, and impotence.
Noncancer Pain
The most common indication for ganglionectomy and rhizotomy
in noncancer pain is the treatment of occipital neuralgia.6-8
Occipital neuralgia can be successfully treated with C2 and C3
ganglionectomies.6-8 C2 and C3 ganglionectomies can also be
considered for medically resistant cervicogenic headache.
1452
SURGERY
Cervical Ganglionectomy and Rhizotomy
For C2 ganglionectomy, the C2 ganglion is exposed through a
midline incision between the inion and the transverse process of
C3 and dissection of the paravertebral musculature to expose the
C1-2 interspace.9 The venous complex is cauterized using bipolar
electrocautery. The root exiting from the C2 space is identified
and followed in both directions, and the ganglion is identified.
The nerve should be cut just proximal to the ganglion, allowing
it to retract slightly, and the proximal stump is cauterized to
prevent bleeding. The nerve is then followed distally, and the end
is cut distal to the ganglion and again cauterized while maintain-
ing hemostasis (Fig. 180-2). The C3 ganglionectomy is per-
formed in a similar fashion with the addition of a foraminotomy
to expose the C3 nerve root and ganglion (Fig. 180-3). When the
ganglion is identified, it is cut and removed as in C2 surgery.
Thoracic Ganglionectomy and Rhizotomy
The dorsal rhizotomy is performed similar to cervical rhizotomy.
The feeding segmental arteries that can enter along the posterior
roots must be protected.10 Dorsal rhizotomy is performed
through an intradural or extradural approach. A multilevel lami-
nectomy is a standard for intradural rhizotomy. In general, the
roots of at least two segments should be destroyed to accom-
modate overlap innervations.11 In this approach, the correct
sensory roots are identified by opening dura at their respective
intervertebral foramina. They then are cut after coagulating. The
procedure for extradural rhizotomy is comparable to that of
extradural ganglionectomy without resection of ganglion.
A posterior paraspinal approach is used for a radiofrequency
rhizotomy in the thoracic region. The theory behind radiofre-
quency lesions of the dorsal roots and dorsal root ganglia was
developed by Letcher and Goldring,12 who noted that the action
potentials of nociceptive fibers (A delta and C fibers) are blocked
at lower temperatures than those of the larger tactile fibers (A
alpha and A-beta fibers). In the thoracic region, a posterior
approach is performed percutaneously, and intravenous sedation
and local anesthesia are given to the patient. With fluoroscopic
guidance, a 2-mm uninsulated-tip electrode is placed within the
neural foramen. Proper placement is confirmed, and sensory
stimulation is then performed at less than 1 V, with 50-Hz stimu-
lation to ascertain paresthesia in the region of patient’s pain.
Motor stimulation is then tested at 2 Hz to elicit contraction in
the paraspinal muscles. A test lesion is made at 42 degrees for 15
seconds. A permanent radiofrequency lesioning is performed at
65 to 90 degrees for 60 to 90 seconds.5
Lumbar Ganglionectomy and Rhizotomy
For L5 ganglionectomy, the L5 ganglion is exposed within the
intervertebral foramen. However, S1 ganglion usually lies within
spinal canal.13 The resection of the lateral margin of the facet
joint and a little bit of the inferolateral margin of the pars
 CHAPTER 180  Dorsal Rhizotomy and Dorsal Root Ganglionectomy 1453

180

Figure 180-1. The anatomic organization of the spinal nerve. Each spinal nerve is attached to the spinal
medulla by two roots: posterior (afferent) and anterior (efferent). The afferent fibers carry the sensory input and
efferent fibers innervate the skeletal muscles. (From Acar F, Göçmen S. Dorsal rhizotomy and dorsal root
ganglionectomy. In: Burchiel KJ, ed. Surgical Management of Pain. 2nd ed. New York: Thieme; 2015.)

A B C
Figure 180-2. Illustration of C2 ganglion. A-C, No foraminotomy is needed to expose ganglion. Note that
the ganglion is covered by venous plexus. (From Acar F, Göçmen S. Dorsal rhizotomy and dorsal root
ganglionectomy. In: Burchiel KJ, ed. Surgical Management of Pain. 2nd ed. New York: Thieme; 2015.)

interarticularis is required. For S1 ganglionectomy, the standard

B The rhizotomy is performed in a similar manner to cervical
A C
Figure 180-3. Illustration of C3 ganglion. A-C, Note that a
foraminotomy is needed to expose the ganglion. This ganglion is also
covered by venous plexus. Careful coagulation is necessary before
the ganglion excision. (From Acar F, Göçmen S. Dorsal rhizotomy and
dorsal root ganglionectomy. In: Burchiel KJ, ed. Surgical Management
of Pain. 2nd ed. New York: Thieme; 2015.)
L5-S1 hemilaminectomy and foraminotomy are performed. After
the dural sheath of the S1 root is identified and longitudinally
incised, the dorsal root is sectioned proximal and distal to the
ganglion. The ganglion is elevated and bluntly dissected off the
fibrous septum, which separates it from the ventral motor root.
Finally, the ganglion is cut distally after coagulating and proxi-
mally ligaturing its distal connection to the spinal nerve.
rhizotomy. Crue and Todd described the technique of extradural
rhizotomy in the sacral region.14 In brief, the S1 and S2 roots are
exposed after a bilateral upper sacral laminectomy. The thecal sac
is then ligated with 0-silk suture. One tie is passed around the
thecal sac just caudal to the S1 nerve root axilla, and a second tie
is passed around the thecal sac just rostral to the S2 nerve root
axilla. The thecal sac is sharply cut with its contents between the
two ties, preserving the S1 nerve roots.
CONCLUSION
Patients with intractable pain are difficult to treat. Destructive
surgeries such as ganglionectomy and rhizotomy still have an
important role in the treatment of some pain syndromes men-
tioned in this chapter. Destructive procedures for the treatment
of pain have played an important role in the history of neurosur-
gery, but their efficacy has not been well established based on
contemporary standards.
1454 SECTION 6  Pain
How should future studies be designed and conducted if they
have to determine accurately and reliably the effectiveness of
these surgical procedures in the treatment of pain? The answer
is easy: double-blinded random controlled trials in patients with
standardized and well-documented diagnoses without ethical,
financial, and practical considerations. However, it is almost
impossible to do such trials on destructive procedures for pain
because many of the earlier studies have failed to distinguish
between different pain states and a single-center rarely has suf-
ficient volume of a particular procedure to power a valid outcome
study adequately. The last one is the accurate evaluation of surgi-
cal pain relief procedures. Well-designed studies with appropriate
control groups will answer fundamental questions in the surgical
treatment of pain.
SUGGESTED READINGS
Arguelles J, Burchiel K. Ablative neurosurgical procedures for the treat-
ment of pain: peripheral. In: Tindall G, ed. The Practice of Neurosurgery.
Baltimore: Williams & Wilkins; 1996:3153-3175.
Cetas JS, Saedi T, Burchiel KJ. Destructive procedures for the treatment
of nonmalignant pain: a structured literature review. J Neurosurg.
2008;109:389-404.
Gallagher J, Petriccione di Vadi PL, Wedley JR, et al. Radiofrequency
facet joint denervation in the treatment of low back pain: a prospective
controlled double-blind study to assess its efficacy. Pain Clin. 1994;7:
193-198.
Oh WS, Shim JC. A randomized controlled trial of radiofrequency dener-
vation of the ramus communicans nerve for chronic discogenic low
back pain. Clin J Pain. 2004;20:55-60.
Oh WS, Shim JC. A randomized controlled trial of radiofrequency dener-
vation of the ramus communicans nerve for chronic discogenic low
back pain. Clin J Pain. 2004;20:55-60.
Taha JM. Dorsal root ganglionectomy and dorsal rhizotomy. In: Burchiel
KJ, ed. Surgical Management of Pain. New York: Thieme; 2002:
677-685.
Young RF. Dorsal rhizotomy and dorsal root ganglionectomy. In: Youmans
JR, ed. Neurological Surgery, Vol. 6. 3rd ed. Philadelphia: WB Saunders;
1990:4026-4035.
See a full reference list on ExpertConsult.com
 CHAPTER 180  Dorsal Rhizotomy and Dorsal Root Ganglionectomy 1454.e1
REFERENCES
1. Bell C. Idea of a New Anatomy of the Brain. London: Strahan &
Preston; 1811:17-19.
2. Abbe R. Intradural section of the spinal nerves for neuralgia. Boston
Med Surg J. 1896;135:329-335.
3. Harris AB. Dorsal rhizotomy for pain relief. In: Tindall G, ed.
The Practice of Neurosurgery. Baltimore: Williams and Wilkins; 1996:
4029-4032.
4. White JC, Kjellberg RN. Posterior spinal rhizotomy: a substitute for
cordotomy in the relief of localized pain in patients with normal life
expectancy. Neurochirurgia (Stuttg). 1973;16:141-170.
5. Taha JM. Dorsal root ganglionectomy and dorsal rhizotomy. In:
Burchiel KJ, ed. Surgical Management of Pain. New York: Thieme;
2002:677-685.
6. Dubuisson D. Treatment of occipital neuralgia by partial posterior
rhizotomy at C1-3. J Neurosurg. 1995;82:581-586.
7. Stechison MT, Mullin BB. Surgical treatment of greater occipital
neuralgia: an appraisal of strategies. Acta Neurochir (Wien). 1994;131:
236-240.
8. Arguelles J, Burchiel K. Ablative neurosurgical procedures for the
treatment of pain: peripheral. In: Tindall G, ed. The Practice of Neu- 180
rosurgery. Baltimore: Williams & Wilkins; 1996:3153-3175.
9. Acar F, Miller J, Golshani KJ, et al. Pain relief after cervical ganglio-
nectomy (C2 and C3) for the treatment of medically intractable
occipital neuralgia. Stereotact Funct Neurosurg. 2008;86:106-112.
10. Loeser JD, Sweet WH, Tew JM, et al. Neurosurgical operations
involving peripheral nerves. In: Bonica JJ, ed. The Management of
Pain. Philadelphia: Lea & Febiger; 1990:2044-2066.
11. Loeser JD. Dorsal rhizotomy for the relief of chronic pain. J Neuro-
surg. 1972;36:745-750.
12. Letcher FS, Goldring S. The effect of radiofrequency current and
heat on peripheral nerve action potential in the cat. J Neurosurg.
1968;29:42-47.
13. Hasue M, Kunogi J, Konno S, et al. Classification by position
of dorsal root ganglia in the lumbosacral region. Spine. 1989;14:
1261-1264.
14. Crue BL, Todd EM. A simplified technique of sacral rhizotomy for
pelvic pain. J Neurosurg. 1964;21:835-837.
181 Diagnosis and Management of Painful Neuromas
Brett E. Youngerman, Taylor B. Nelp, Deepa Danan, and Christopher J. Winfree
PATHOPHYSIOLOGY
The capacity of peripheral nerves to regenerate following injury
enables functional recovery in many cases. Unfortunately, this
regenerative capability, when it goes awry, can produce a painful
scar at the site of injury. Neuromas can affect any nerve: large,
small, or microscopic. The key process that contributes to
neuroma formation is the regrowth of injured axons into impen-
etrable scar. A traumatic neuroma is a dense, minimally vascular
fibrous mass containing many small nerve fibers originating from
an otherwise functional nerve.1 The fibrous connective tissue that
comprises the outer layer of the neuroma is continuous with the
perineurium of the involved nerve.2
There are two categories of neuromas: terminal neuromas and
spindle neuromas. Terminal neuromas typically form after neu-
rotmesis, or complete severing of the nerve, such as occurs in
laceration injuries.3 In neurotmesis, the severed ends often retract
apart. While the distal axons undergo wallerian degeneration and
the nerve withers into scar, the proximal end may form a bulbous
neuroma as axons regenerate haphazardly without finding the
fibronectin and laminin in the basal lamina of the distal segment
epineurium (Fig. 181-1). Because the cut ends are physically
separate, without repair or conduit, the probability of meaningful
recovery of axons across the injured segment is vanishingly low.4
Spindle neuromas, or neuromas-in-continuity, typically form
after axonotmesis, injury of axons with intact epineurium.3 Axo-
notmesis may follow injuries related to compression, stretch, or
gunshot wounds, which most commonly cause injury through
shock waves. A fusiform neuroma may form along the injured
segment as axons regenerate and local scar tissue forms (Fig.
181-2). Because the epineurium is intact, meaningful recovery of
axons across the injured segment often occurs, leading to a regen-
erating neuroma-in-continuity.5 The presence of scar, however,
may prevent recovery in some cases, leading to a nonconducting
neuroma-in-continuity. These forms are distinguished most reli-
ably by using intraoperative nerve action potential recordings.
Recovering nerve action potentials are seen with a conducting
neuroma-in-continuity, but not with a nonconducting neuroma-
in-continuity (Fig. 181-3).
Pain in neuromas relates to compression, traction, and isch-
emia of nerve fibers by scar tissue. Spontaneous firing of nocicep-
tors sending impulses centrally may lead to neuropathic pain.6
Additionally, nerve fibers in close proximity to each other may
stimulate impulse transmission in the absence of a synapse by
ephatic transmission.7 Further stimulation may occur through the
abnormal release of chemical pain mediators.8 More recent find-
ings suggest that upregulation of ion channels (with ectopic foci),
nerve growth factor, and receptors (TRPA1, CGRP, alpha1C) con-
tribute to neuropathic pain in neuromas.9
CLINICAL PRESENTATION
Neuromas form after nerve trauma. Often the patient is able to
give a clear history of the traumatic event. In many cases, the
nerve injury is obvious. Sometimes neuromas form unexpectedly
after surgery following an unrecognized nerve injury. In other
cases, neuromas form following a prolonged period of mild,
repetitive injury. At times, a large, named nerve is injured, and in
other cases, a small, unnamed sensory nerve forms the neuroma.
181
When a nerve is acutely injured, it may be sensitive to touch or
pressure immediately after injury. Sometimes this sensitivity per-
sists until a neuroma forms. Sometimes nerves are not particu-
larly painful in the early period after injury but become sensitive
later when the neuroma forms.
Traumatic neuromas are firm, slow-growing, and sometimes
palpable nodules that can be associated with pain and paresthesias
in the affected area. The hallmark finding for a painful neuroma
is an exquisitely sensitive, focal area along the course of a previ-
ously injured nerve. Pain is evoked by palpation of the region and
may remain local or radiate along the course of the peripheral
nerve sensory distribution, a positive Tinel’s sign.7 Patients can
also have tenderness and hypersensitivity to normal tactile
stimuli2 and temperature sensitivity, more commonly cold intol-
erance, in the surrounding regions.10 If the injured nerve is non-
functional, there will often be loss of sensation in the distribution
of that nerve.
DIAGNOSIS
The diagnosis of a neuroma can be made clinically: pain in the
region of a scar, altered sensation in the distribution of the
affected nerve, and a Tinel’s sign. Confirmatory testing may
include injection of local anesthetic into the vicinity of the
neuroma11 or more proximally along the course of the affected
nerve.12 The presence of temporary pain relief helps make the
diagnosis of a painful neuroma and additionally may help
to identify the exact nerve involved. This may be helpful if mul-
tiple candidate nerves are in the vicinity, such as in the inguinal
region. Some practitioners use control injections of saline or local
anesthetics of differing durations, one long-acting and one short-
acting, in an effort to increase reliability of this diagnostic modal-
ity. Such a strategy may help reduce unwanted placebo effects,
which can complicate the treatment of any pain disorder.
Imaging may be used to identify larger neuromas. Magnetic
resonance imaging and magnetic resonance neurography may
delineate the neuroma quite clearly in some cases but are perhaps
most useful for excluding other pathology.13 Ultrasonography is
also used routinely to diagnosis and localize neuromas.14,15 It can
be used in in real time to guide anesthetic injections as well. A
method for electrophysiologic testing has also been described as
an alternative to imaging in patients with Morton’s neuroma.16
Perhaps the most reliable way to identify a neuroma is with
surgical exploration in the awake patient. After external neuroly-
sis of the neuroma, when palpation of the neuroma reproduces
the patient’s exact pain, little diagnostic uncertainty remains. This
strategy is essentially identical, in theory, to the conscious pain-
mapping procedures used by gynecologists during laparoscopic
procedures used to identify pelvic pain generators.17
TREATMENT
After a painful neuroma is diagnosed, a comprehensive, pain
management−oriented approach may be helpful. Initial efforts
may involve over-the-counter pain medications and protecting
the painful area from additional trauma. Anticonvulsant18 and
antidepressant19 medications may provide relief for neuropathic
pain; however, opiates are often used clinically,20 and a study in
a rat model comparing morphine, pregabalin, gabapentin, and
1455
 CHAPTER 181  Diagnosis and Management of Painful Neuromas 1455.e1

ABSTRACT KEY WORDS:

181
Painful neuroma formation is a complex and frustrating problem
nerve injection
for physicians and patients. These neuromas may appear after
obvious injuries to nerves, or they may appear quite unexpectedly nerve injury
after procedures varying from nerve biopsies and limb amputa- neuroma
tions to tooth extractions. As the nerve regenerates, sprouting peripheral nerve
neural fibers and connective tissue may develop haphazardly,
forming neuromas and potentially producing severe neuropathic
pain. The reported incidence of neuropathic pain resulting from
traumatic neuromas ranges from 20% to 30%. The pain caused
by traumatic neuromas may be vexingly resistant to pharmaco-
logic treatments, including those typically used for neuropathic
pain, such as anticonvulsants and antidepressants. When such
pain occurs after an otherwise unremarkable surgical procedure,
patients and physicians alike may experience significant distress.
Although there is no single best treatment for the pain caused by
traumatic neuromas, invasive procedures have been developed to
help treat this condition. Refractory cases may be amenable to
treatment with neurostimulation.
1456 SECTION 6  Pain

duloxetine showed that only morphine was effective.21 Comple-

P When these noninvasive efforts are insufficient, a more
D
Figure 181-1. Intraoperative photograph taken after exposure of
a median neuroma at a midhumeral level. This patient sustained a
median nerve transection by glass from a broken window 5 months
previously. The proximal nerve stump (P) has formed a bulbous
neuroma, whereas the distal end (D) has thinned and scarred down to
adjacent tissues. Note the significant retraction that has occurred,
producing a substantial gap between the proximal and distal ends.
mentary and alternative therapies such as acupuncture may be
useful.22
aggressive strategy may be required. Steroid injections, some-
times coupled with a local anesthetic, may provide temporary
and, in some cases, durable pain relief.23 Ablative techniques such
as radiofrequency ablation, pulsed radiofrequency ablation,
chemical neurectomy,24 or cryoneurolysis25 may destroy the asso-
ciated nerve or neuroma, providing the necessary pain relief.
There are a paucity of high-quality clinical data supporting the
use of these techniques.
Surgical neurectomy is considered after noninvasive treat-
ment measures fail and percutaneous ablative techniques are
deemed ineffective or inappropriate. For superficial neuromas
along named peripheral nerves, an attempt is made in the mildly
sedated patient to subject the nerve to an external neurolysis and
definitively identify the nerve. Palpation of the suspected neuroma
should reproduce the patient’s pain (Fig. 181-4). When located,
the nerve is sectioned proximal to the neuroma, and the neuroma
is removed.
For superficial neuromas along unnamed, cutaneous sensory
nerves, a conscious pain-mapping procedure is used. First, the
painful area is marked in the preoperative area with the patient
fully awake. In the operating room, an incision is made over the
painful area using local anesthetic in the skin. Progressively
deeper dissection through nonanesthetized tissues enables iden-
tification of the discrete painful area in the awake patient. The
tissue is excised with the patient temporarily rendered uncon-
scious by the anesthesiologist. Repeat probing of the surrounding
tissues is performed with the patient awake to find and remove
any additional painful areas, which presumably contain the
responsible mechanosensitive tissue.

Figure 181-2. Intraoperative photograph taken after excision of a

sural neuroma at a midcalf level. This patient underwent a
PREVENTION OF SECONDARY NEUROMA
partial-thickness sural nerve biopsy 1 year previously. A fusiform A major problem in neuroma excision is the recurrence of the
neuroma has formed at the biopsy site, leaving the nerve in-continuity. neuroma, and prevention of growth of a secondary neuroma is a

Tibial S NAP

Peroneal

S NAP

Figure 181-3. Intraoperative photograph taken after external neurolysis of a sciatic nerve that
sustained a blunt injury several months previously. The nerve has been subjected to an internal neurolysis
as well, dividing it into its tibial and peroneal divisions. Hook electrodes are applied proximally and distally to
the injured area, a stimulus (S) is applied, and intraoperative nerve action potential recordings (NAP) are
obtained. The tibial division (top) shows a recovering nerve action potential, indicative of a conducting
neuroma-in-continuity, whereas the peroneal division (bottom) shows a flat tracing, indicative of a
nonconducting neuroma-in-continuity.
 CHAPTER 181  Diagnosis and Management of Painful Neuromas 1457
B the site of nerve transection. B shows the result after neuroma
Figure 181-4. Intraoperative photographs taken during surgical
excision of a painful sensory neuroma that formed along the
iliohypogastric nerve following a laparoscopic procedure. With the
patient under mild sedation, a conscious pain-mapping procedure is
performed. Local anesthetic is infiltrated into the skin only. Palpation
of the deeper tissues reveals the painful area, subjacent to the fascia,
which is marked with an X (A). After the fascia is opened, the nerve
and a fusiform neuroma become apparent (B). Pinching the neuroma
with forceps reproduces the patient’s pain exactly. With the nerve
under traction, the nerve is transected proximal to the neuroma, and
the proximal end of the nerve is allowed to retract into the muscle
belly. This reduces the likelihood of neuroma recurrence. The distal
end is then cut, enabling excision of the entire neuroma. The distal
side is cut second so that the patient only experiences a single nerve
transection sensation.
key part of surgical treatment. In the past, treatment of neuromas
involved neuroma excision followed by capping the nerve with
many substances, including silicone and surplus epineurium, to
prevent new neuroma formation.26 Additionally, chemical treat-
ment of the cut proximal end of the nerve has been used.27 One
study reported that oblique transection of peripheral nerves, as
opposed to perpendicular transection, greatly reduces the rate of
classical neuroma development.28 Additionally, this method of
oblique transection was thought to significantly reduce neuro-
pathic pain compared with that following the traditional form of
nerve transection.
A different surgical strategy emphasizes placement of the cut
end of nerve into an appropriate environment and does not
attempt to physically restrain axonal outgrowth.29 In cases in
which the nerve arises from muscle proximally, including the
plantar digital nerves, the lateral femoral cutaneous nerve, or the
abdominal nerves such as the iliohypogastric and ilioinguinal,
sectioning the nerve under tension allows it to retract into the
muscle. If the nerve does not arise from nearby muscle, the nerve
181
N
B
Figure 181-5. Intraoperative photographs of a patient who
sustained an iatrogenic injury to the superficial radial sensory
nerve during an orthopedic surgical procedure a few months
previously. A shows a typical bulbous sensory neuroma (N) at
excision and implantation (I) of the distal end of the nerve into the
brachioradialis muscle. The sutures anchor the nerve into the muscle
to prevent pull-out with arm movement during the postoperative
period.
may be transposed to a nearby muscle, implanted through a small
incision in the muscle belly, and sutured into place (Fig. 181-5).
When in muscle, the likelihood of neuroma recurrence is
reduced. In a primate model of neuroma, transection of the radial
sensory nerve at the wrist, followed by turning the sensory nerves
proximally and implanting them into a forearm muscle, effec-
tively prevented classical neuroma formation. Specifically, the
sensory nerve showed no signs of regeneration when implanted
into the muscle.12 Meyer and colleagues produced superficial
radial nerve neuromas in a group of baboons and found that
neuromas produce spontaneous activity of pain fibers and are
sensitive to mechanical stimulation.30 Thus muscle reimplanta-
tion may also reduce pain caused by mechanohypersensitivity by
decreasing the mechanical stimulation encountered by the
neuroma.31 In a study by Burchiel and colleagues of 18 patients
with distal sensory neuromas, reimplantation of nerve endings
showed a success rate of 44%, and an average drop in Visual
Analog Scale–registered pain of 32%.32 Dellon and associates
found that 80% of patients had excellent pain relief after neuroma
resection and reimplantation into muscle.33 They suggest that the
nerve must be directed into muscle without tension in a distal-
to-proximal direction to accommodate the minimal amount of
nerve regeneration that will inevitably occur and that it should
be implanted in muscles with minimal excursion to keep the
implanted nerve in place. Additionally, if the nerve is implanted
near the deep surface of the muscle, regeneration into the overly-
ing skin is prevented, thus reducing mechanical stimulation of
the nerve.34
In addition to muscle, nerve implantation in veins, artificial
conduits, and autologous fat grafts have yielded positive results.
In a randomized controlled trial of 20 subjects, Balcin and col-
leagues reported a statistically significant greater reduction in
1458 SECTION 6  Pain
pain when the nerve end was implanted in vein compared with
muscle.35 Multiple retrospective case series also demonstrated
pain relief in patients who underwent nerve resection with
the use of collagen conduits.36,37 In a retrospective study of 30
patients, Gould and associates found that 43% of patients treated
with a collagen conduit during neuroma resection (“graft to
nowhere”) reported no pain at follow-up, 33% reported pain
scores of 1 to 4 (on a scale from 1 to 10), while 15% reported
pain scores of 8 to 10.36 Autologous fat grafting is another tech-
nique that has yielded positive results in small case series.38,39
Baptista and colleagues report reduction of pain in 9 of 11
patients.38
POOR SURGICAL CANDIDATES
The practicing neurosurgeon may encounter cases in which
neuroma excision surgery is inappropriate. For example, patients
who have already undergone one or more failed neuroma excision
surgeries, in our experience, do not experience pain relief with
additional neurectomy surgery. We can only speculate as to the
reason at this point, but centralization of the pain generators and
psychological factors may play a role. Postamputation neuromas
of large, mixed nerves such as the sciatic nerve may be especially
problematic for the surgeon. Wound healing in these regions may
be fraught with difficulties. In most cases, unless there is a clear
structural abnormality in a stump, such as a sharp end of bone
cutting into the nerve, local excision surgery should probably be
avoided.40
When surgical excision of neuromas is thought to be inap-
propriate, and patients have failed less invasive measures, then
interventional pain management techniques may be used. Specifi-
cally, neurostimulation can be quite helpful, depending on the
distribution of pain.41 Neuroma pain in the extremities can gener-
ally be treated with spinal cord stimulation. Spinal nerve root
stimulation, which targets pain-relieving stimulation paresthesias
into the distribution of single or multiple nerve roots, may
provide relief to patients with pain in the hands, feet, inguinal
regions, pelvic regions, and intercostal distributions.42 These
areas are often unreachable with spinal cord stimulation. Periph-
eral nerve stimulation may be used to treat pain confined to the
distribution of the stimulated nerve. Small regions of neuroma
pain, inaccessible to other forms of neurostimulation, may be
targeted effectively with subcutaneous peripheral nerve stimula-
tion,43 in which the electrodes are placed under the skin at the
site of pain (Fig. 181-6). Transcutaneous magnetic stimulation44
and extracorporeal shock-wave therapy45 have also been used
successfully to reduce neuroma-related pain.
FUTURE DIRECTIONS
Currently the surgical treatment of painful neuromas remains
crude, and the field has been advanced little in recent years
regarding definitive treatments. The most notable advancements
have been in the field of neurostimulation, with novel applica-
tions of electrical stimulation targeting pain relief to specific
painful areas and limiting unwanted paresthesias in adjacent, non-
painful areas. Future studies will hopefully establish whether
these less invasive techniques, as well as the percutaneous ablative
techniques such as radiofrequency ablation, are effective. Robotic
techniques have been described and may help to reduce the size
Figure 181-6. Intraoperative photograph of a patient who
developed a sensory neuroma near her incision following a hip
replacement. Her painful area was marked (hatched area) using a
conscious pain-mapping procedure intraoperatively. Two
subcutaneous stimulator electrodes were placed within the painful
region. Intraoperative testing revealed good overlap of the stimulation
paresthesias with her painful area. During her 1-week external trial,
she experienced significant pain relief, and she later underwent
permanent placement of the stimulator system.
of the exposure and effect on surrounding nerves in some cases,46
but a clear role remains to be established.
Ultimately, prevention of neuroma formation by inhibiting
axonal growth into the nerve scar would be ideal. Perhaps nerve
growth inhibitors could be injected into injured nerves before
neuroma formation, or perhaps a method of pharmacologically
silencing mechanosensitive nerves subsequent to neuroma for-
mation would be a comparably effective strategy. The role of
conduits in prevention of primary and secondary neuroma forma-
tion remains to be further elucidated.
SUGGESTED READINGS
Burchiel KJ, Johans TJ, Ochoa J. The surgical treatment of painful trau-
matic neuromas. J Neurosurg. 1993;78:714-719.
Dellon AL, Mackinnon SE. Treatment of the painful neuroma by neuroma
resection and muscle implantation. Plast Reconstr Surg. 1986;77:
427-438.
Gould JS, Naranje SM, McGwin G Jr, et al. Use of collagen conduits in
management of painful neuromas of the foot and ankle. Foot Ankle Int.
2013;34:932-940.
Mackinnon SE. Evaluation and treatment of the painful neuroma. Tech
Hand Up Extrem Surg. 1997;1:195-212.
Mackinnon SE, Dellon AL, Hudson AR, et al. Alteration of neuroma
formation by manipulation of its microenvironment. Plast Reconstr
Surg. 1985;76:345-353.
Seddon HJ. Three types of nerve injury. Brain. 1943;66:236-288.
Stuart RM, Winfree CJ. Neurostimulation techniques for painful periph-
eral nerve disorders. Neurosurg Clin N Am. 2009;20:111-120, vii-viii.
See a full reference list on ExpertConsult.com
 CHAPTER 181  Diagnosis and Management of Painful Neuromas 1458.e1
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182 Dorsal Root Entry Zone Lesions for Pain
Marc Sindou, Andrei Brînzeu, and Kim J. Burchiel
Integration of sensory information is a multistage process leading
to perception with several levels of modulation along pathways.
The first level of modulation, located at the entry into the central
nervous system, is the dorsal root entry zone (DREZ) and dorsal
horn (DH). The role of this region was popularized in 1965 in
the gate-control theory by Melzack and Wall.1,2
DREZ was defined as an entity including the central portion
of the dorsal rootlet, the medial part of the tract of Lissauer, and
layers I to V of the DH in which the afferent fibers terminate
and synapse3,4 (Fig. 182-1).
At the level of the DREZ, dysfunction or failure of modulation
or spontaneous generation of pain signals can occur as a result
of pathologic lesions, especially those leading to the loss of affer-
ent stimuli, damage to neurons, or gliosis formation.5,6 This
makes the DREZ a logical surgical target for treating some types
of intractable pain, either by modulating pain processes with
methods such as spinal cord stimulation7 or by creating surgical
lesions in the nociceptive system that limit signal transmission or
destroy pain generators located at the DREZ.5,8-9
Attempts at DREZ surgery were first made in 1972 at Lyon
University by Sindou.4,10 The technique of microcoagulation
of the dorsal rootlets entry was successfully used in a patient
with Pancoast’s syndrome. Further attempts were successful
for neuropathic pain after spinal cord injury (SCI) in Decem-
ber 1972, amputation of limb in July 1973, and brachial plexus
avulsion (BPA) in January 1974, all performed in Lyon. Sub-
sequently, lesions at the DREZ were made by Nashold and
colleagues in 1974 using radiofrequency (RF) thermocoagula-
tion.11-13 They coined the term DREZ operation and championed
its merits. Later, lesions were made with the laser beam by
Levy and coworkers, Powers and associates, and Young and col-
leagues14-18 and with the ultrasonic probe by Dreval and Kandel
and associates.19,20 In recent years, Spaic and coauthors designed
a microsurgical technique of incising the dorsolateral sulcus and
suctioning the DH.21,22
RATIONALE
The DREZ serves as the interface between the peripheral nervous
system and the central nervous system at the level of the spinal
cord. Although in the peripheral nerves afferent fibers are ran-
domly organized, at the level of the DREZ they become segre-
gated according to size and destination. The small myelinated
and unmyelinated fibers carrying nociceptive impulses course to
the lateral side, which makes them appropriately situated to enter
into the tract of Lissauer, where they run for one or two segments
before penetrating the gray matter of the spinal cord. The large
myelinated fibers course medially to enter directly into the dorsal
column.3,4
The second neuron in the nociceptive pathway is located in
the DH both superficially (Rexed laminae I and the substantia
gelatinosa), receiving afferences from unmyelinated fibers, and
deep in the DH (Rexed laminae V) for small myelinated fibers of
the A delta type.23,24 These will project through the spinothalamic
tracts to the third neuron situated in the thalamus.
Activity of the second neuron is influenced both by upper
levels and by peripheral afferents. Collaterals of large myelinated
fibers of the dorsal columns give inhibitory inputs that modulate
the passage of pain stimuli at the level of the DH.2,25 This has
been popularized as the gate-control of Melzack and Wall.1
182
When lesions occur at the level of the DREZ, several pro-
cesses can develop that upset the normal balance between inhibi-
tory and excitatory controls exerted on the second-order neurons
situated in the DH. Lesions and deafferentation can occur as a
result of a number of pathologic processes. These may lead to
scar formation within the DREZ, and/or interruption of first-
neuron afferents with dendritic sprouting at the level of the
second neuron, and thus complete interruption of inputs such as
in root avulsion lesions.
In patients with lesions of the DREZ, microelectrode record-
ings of the DH have been performed showing spontaneous
paroxystic activity at the level of DH neurons. This suggests that
one of the pain generators in such patients is at the level of the
DREZ.9,26
The microanatomy of the DREZ (see Fig. 182-1), with the
pain fibers situated laterally and the localization of pain genera-
tors at the level of the DH, makes the DREZ a target for lesion-
ing in an attempt to control pain. The procedure intends to
preferentially interrupt the (nociceptive) fibers grouped in the
lateral bundle of the dorsal rootlet and the (excitatory) medial
part of the tract of Lissauer. The dorsalmost layers of the DH,
which harbor hyperactive neurons in the cases with deafferenta-
tion (Fig. 182-2), are destroyed if microcoagulations are per-
formed deeply inside the DH. The procedure is presumed to
partially preserve the (inhibitory) medially located structures of
the DREZ, namely the fibers reaching the dorsal column and
their recurrent collaterals to the DH. Microsurgical DREZot-
omy (MDT) was conceived to avoid total abolition of tactile and
proprioceptive sensations when preoperatively present, as well as
further deafferentation.27 The depth and extent of the lesion are
tailored depending on the degree of the desired therapeutic
effects and on the patient’s preoperative sensory and functional
status.28,29
INDICATIONS
Cancer Pain
The first use of DREZ lesioning for control of pain was to the
benefit of a patient with a neoplastic lesion, namely a Pancoast-
Tobias tumor invading the brachial plexus.30,31 The procedure was
greatly effective in controlling the pain of the patient, and it has
been used since in a number of patients with pain related to
cancer.32
It is estimated that 75% of patients with advanced cancer
suffer from chronic pain. Intricate mechanisms can lead to severe
refractory pain. Somatogenic pain due to cancer invasion is
certainly an important component; however, neurogenic pain
linked to compression and destruction of neural structures or
iatrogenic pain (after surgery or radiation treatment) can often
be encountered.
In recent years, progress in oncology has greatly prolonged
survival of patients with cancer, and the long-term use of opioids
can, even when administered intraspinally, have side effects
infringing on the quality of life. The use of ablative procedures
may be considered, therefore, in patients with refractory pain
and in those requiring high doses of morphine. Options are spi-
nothalamic tractotomy, open high cervical anterolateral cordot-
omy, percutaneous computed tomography−guided cordotomy or
1459
1460 SECTION 6  Pain
Cervical
DC T L
I
II
III
Thoracic
IV-VII
IN
MN
Lumbar
A B Sacral
Figure 182-1. Anatomy of the dorsal root entry zone (DREZ).
A, Organization of fibers on transverse section. Most of the fine
(nociceptive) afferents, which convey excitatory input, enter the
dorsolateral sulcus as a lateral bundle of the DREZ, then penetrate the
dorsal horn (DH) ventrolaterally through the medial part of the tract of
Lissauer (TL) and the dorsal aspect of the substantia gelatinosa (SG).
The Ramón y Cajal’s recurrent collaterals of the large primary afferent
fibers25 approach the DH through the ventromedial aspect of the SG
to exert inhibitory effects on the DH neurons.24 Because a number of
dendrites of the cells of origin of the spinoreticulothalamic tract, which
will form the contralateral anterolateral pathways, make synaptic
connections with the primary afferents inside the SG layers, the SG
exerts a strong segmental modulating effect on the nociceptive
input.23 Large pink arrowhead: The microsurgical DREZotomy (MDT)
target includes the lateral bundle of the (nociceptive) fine fibers, the
medial (excitatory) part of the TL, and the five dorsalmost layers of the
DH where the primary afferents terminate and whose neurons become
hyperactive if deafferentated. MDT attempts to spare the maximum
number of the large fibers of the medial bundle that reach the DC.
B, Variations of shape, width, and depth of the DREZ area according
to spinal cord level (from top to bottom, seventh cervical, fifth
thoracic, fourth lumbar, and third sacral medullary segments).
Note how at the thoracic level, the TL is narrow and the DH is
deep, so DREZ lesioning, especially at that level, can be dangerous
for the corticospinal tract and the dorsal column. IN, interneurons;
MN, motorneurons.
midline myelotomy, and DREZ lesioning, which is particularly
adapted when the topography of the pain is limited.33,34
Situations in which DREZ lesioning could be useful are pul-
monary apex tumors with invasion of the brachial plexus, thoracic
tumors with invasion of the wall nerves, and pelvic tumors with
invasion of the perineum and parietal nerves. Principles for indi-
cations are a limited, controlled cancer in a patient with good
enough general status to withstand major surgery and well-
identified and well-characterized pain due to a clearly defined
lesion. An early surgical decision can be made with benefit to the
patient when it provides the possibility to avoid extremely dis-
turbing and heavy pain medication.
Gadgil and Viswanathan recently reviewed results of DREZ
lesioning in cancer pain.32 The largest series, to our knowledge,
is the one published by Sindou in 1995 describing results in 367
patients in whom DREZ lesioning was performed.28 In 81
patients, the pain was a consequence of a neoplasm. The follow-up
was from 1 month to 4 years, with a mean survival of 13 months.
For surgeries performed in the cervicothoracic region, control of
pain was good in 87% of patients; and for surgeries performed
in the lumbosacral region, control of pain was good in 78%.
Complication rates remained similar to those for DREZ per-
formed for other types of pain; however, the authors reported
that in 2 patients, the procedure may have precipitated death.
Other series report a relatively small number of patients, and
results are somewhat heterogeneous.12,32,35-41 A composite of all
series can be found in Table 182-1.
Neuropathic Pain
Root Avulsion Pain (Brachial and Lumbosacral Plexus)
Brachial plexus injuries occur after major trauma, typically
motorcycle crashes in young adults. Trauma results in stretching
of the roots up to their complete avulsion from the spinal cord.
Pain occurs in 30% to 90% of patients, and its incidence is related
to the localization of the lesion.42 Preganglionic lesions with true
deafferentation lead to severe chronic pain in 90% of patients,
whereas only 33% of patients with postganglionic lesions develop
chronic neuropathic pain.43
Description of the pain is quite stereotypical: continuous
background pain described as burning or throbbing, associated
to paroxysms of shooting electrical pain. Both pain components
are described by two thirds of patients; only the background pain
is noted in 20%, and solely paroxysms appear in only 10%. Most
frequently, the distal part of the limb (hand and forearm) is con-
cerned. Sensory deficits are the rule; they are complete in two
thirds of patients. Major motor deficits are usually associated and
more often situated on the C7 to C8 territories.44
Pain is constantly described as unbearable and resistant to
various types of medication, including opioids and antiepileptics.
Its onset can be immediately after the trauma or delayed even
years after the initial event. In the period following the avulsion,
most patients underwent direct nerve suturing, grafting, or neu-
rotization, all theoretically known to prevent the installation of
chronic pain. For these patients facing severe uncontrollable pain,
various surgical techniques have been tried with limited effect.
Spinal cord stimulation is generally ineffective as a result of fiber
degeneration up to the brainstem.45 Trials of deep brain stimula-
tion and motor cortex stimulation were revealed to be scarcely
successful.46 The several other lesional techniques—anterolateral
cordotomy, spinothalamic tractotomy, medial thalamotomy—
when tried, were not only ineffective but also accompanied by
serious harmful side effects.
DREZ lesioning was first attempted for the control of BPA
pain, in 1974 in Lyon, using the MDT technique.3,29,47 Soon after,
Nashold used RF thermocoagulation as the lesion maker11,12;
and later on, laser14-17 and ultrasound18,19 were also used.12,29
The efficacy of DREZ lesioning in controlling BPA pain has
made it a recognized technique, and several case series have
been published, although no randomized controlled trial was ever
attempted.
Preoperative evaluation must include magnetic resonance
imaging (MRI) of the cervical spinal cord. Fine images are able
to show the extent of the avulsions. Root meningocele is generally
associated with root avulsion, but avulsion can be present even in
the absence of meningocele. In addition, MRI can show associ-
ated lesions of the spinal cord as well as eventually its rotation
because of arachnoiditis. This information can be useful for the
identification of the dorsolateral sulcus when attempting DREZ
surgery.44
Findings during surgery include the avulsion of the ventral
and dorsal rootlets, which can be partial or complete. Several
levels are usually affected, but all roots of the brachial plexus are
avulsed in about 40% of patients. Scarring of the dorsolateral
 CHAPTER 182  Dorsal Root Entry Zone Lesions for Pain 1461

182

A B

Figure 182-2. Microsurgical

DREZotomy (MDT) for brachial C D
plexus avulsion (BPA). MDT at the
cervical level for C6 to T1 brachial
plexus avulsion on the left side.
A-B, T2-weighted magnetic
resonance imaging shows complete
avulsion of both ventral and dorsal
roots and also of part of the lateral
cord (A), and a pseudomeningocele
at the lower cervical spine on the left
side with a hyperintensity of the
ipsilateral dorsal column subsequent
to the trauma and the stretching
with avulsion of the dorsal root
(B). C, Schematic drawing of the
floating microelectrode (arrow)
implanted into the dorsal horn
following its axis. D, Trace of the
dorsal horn microelectrode recording
E F
of so-called deafferentation
hyperactivity, manifested by
spontaneous regular high-frequency
discharges after BPA. E-H, Operative
views (rostral at bottom, caudal at
top) show total avulsion of cervical
roots on the left side. The
dorsolateral sulcus can be easily
identified in this case (E); incision into
the dorsolateral sulcus is made with
a microknife (F); the dorsolateral
sulcus is opened (G); and dotted
microcoagulations into the dorsal
horn, which has a gliotic aspect, are
performed 3 to 5 mm deep at a
35-degree angle inside the sulcus
with a specially designed, graduated G H
bipolar microforceps (H).
1462 SECTION 6  Pain

TABLE 182-1  Dorsal Root Entry Zone Lesioning Studies and Outcomes
Follow-Up in Years: Results: Percentage of Patients
Technique References No. of Patients Range (mean) Having >75% Relief (mean)
CANCER PAIN
Microsurgery Sindou unpublished data 94 0.1-4 78-90
RF-Th 10, 13, 31, 34, 36-38, 40, 41 37 0.1-4 33-100
BRACHIAL PLEXUS AVULSION
Microsurgery 44, 48, 51, 56; Taira personal 198 1-27 (4.47) 65-82.4 (77.01)
communication
RF-Th 10, 36, 38, 49-50, 52-55, 57-60 290 1-18 (5.67) 42, 7-87, 4 (70.64)
Ultrasound 20 124 1-5 (4) 87
CO2 laser 17 4 1-5 (4) 50
SPINAL CORD INJURY
Microsurgery 65, 67, 71, 73 112 0.5-20 (4.15) Segmental 68-100 (79.8); below lesion, 0
RF-Th 17, 34, 62, 63, 69, 70, 74 261 0.1-13 (3.11) 20-92; segmental, 78
PERIPHERAL NERVE PATHOLOGIES AND COMPLEX REGIONAL PAIN SYNDROME
Microsurgery Taira personal communication 7 (complex regional >1 57
pain syndrome)
Microsurgery Sindou 42 1 to 15 Paroxysmal, allodynic: good outcome
Continuous, deep: poor outcome
POST-HERPETIC PAIN
Microsurgery Sindou; Taira personal communication 6 1 to 3 50-66
RF-Th 34, 61, 77 20 0.5-5 14-67
POSTAMPUTATION PAIN
Microsurgery Sindou; Taira personal communication 14 1-15 Paroxysmal, allodynic: good outcome
Continuous, deep: poor outcome
RF-Th 34, 74, 75 45 0.5-6 25-100
RF-Th, radiofrequency thermocoagulation.

sulcus is often evident and is considered a major factor in pain
generation. Arachnoiditis, atrophy, and rotation of the spinal cord
are also often seen. Absence of rootlets and major scarring make
identification of the sulcus difficult. It is therefore essential to
expose at least one level above and one level below the avulsion
to identify the sulcus in a healthy region.44
Multiple groups have reported extensive series with long-term
results and with different types of lesion makers. Regardless of
the technique, immediate and short-term results are often spec-
tacular, with major improvement in up to 86% to 96% of patients.
However, relapses are not a rarity. A summary of all published
series, including DREZ lesioning for BPA pain, is presented in
Table 182-1.10,16,19,36,38,44,48-60
Sindou reported several series with long-term follow-up to 28
years. Two thirds of patients had good (no more opioids) to excel-
lent (no pain, no medication) outcome, and 71% noticed improve-
ment in their daily activities at a mean follow-up of 6 years. At
12 years, the Kaplan-Meyer statistic for excellent outcome (no
pain, no medication) was 59.8%, testifying to the efficacy of
MDT for BPA pain44; moreover, another 25% of patients had a
significant decrease in pain, and the result was considered good
(no use of opioids). Noteworthy in another series of 29 patients
operated by Sindou’s team, the results of MDT on the two com-
ponents of pain were analyzed. Kaplan-Meyer statistics at 10
years showed complete relief in 76.2% of the patients for the
paroxysmal pain and 43.1% for the background pain; this was
statistically significant.48
Although less frequent than brachial plexus injuries, lumbosa-
cral injuries with avulsion of the roots at the conus medullaris
level should be searched and documented by MRI in patients
with severe pelvic dislocation fractures. MDT is similarly effec-
tive for controlling pain in these cases.61-63
Spinal Cord Injury Pain
Chronic pain after SCI is frequent and can be of many types;
it may have a mechanical origin related to the fractures and
irritative free bony fragments or to the fixation devices.64 Fre-
quently observed (up to 30%) at the conus medullaris and cauda
equina level, an important component of pain is neuropathic,
described as being of two types: segmental (at the level of the
injury) and infralesional (below the level of neural structure
damage). Distinction between the two types is of importance for
establishing an appropriate treatment strategy.65
The segmental pain resides in the territories corresponding
to the injury but can extend to several adjacent levels. It is pre-
dominantly characterized as sharp electrical paroxystic attacks
lasting several minutes confined to dermatomes corresponding to
the lesional level. Mechanisms are related to the contusion of the
spinal cord and of the nerve roots, with local changes leading to
entrapment and scarring. Intraoperative recordings have shown
paroxystic hyperactivity in the DH neurons.8 Adjacent, especially
rostral, levels can be involved because the scarring usually extends
to levels above the level of injury and the distribution of pain
fibers after their entry into the spinal cord is over several levels
(Fig. 182-3).
The infralesional pain is usually burning, continuous pain in
the anesthetic territory below the injury level. Several mecha-
nisms have been described, but for practical purposes one should
assume that the principal one is deafferentation of the third-order
neurons due to interruption of spinothalamic tracts. This locates
the most probable pain generator above the spinal cord, leading
to the gross inefficacy of procedures targeted at the spinal cord.
The two types of pain are often present together in a hetero-
geneous mix. In a series of 44 patients reported by Sindou
and colleagues,65,66 mostly affected at the conus medullaris level,
the pain was segmental in 84% and infralesional in 16%. In a
more recent series of 38 patients reported by Chun and associ-
ates, the distribution of pain was 60% segmental and 40%
infralesional.67
Neuropathic pain after SCI is notoriously difficult to treat.
Spinal neuromodulation techniques can be useful only in the
situation of partial lesions when sensory loss is incomplete. Func-
tional integrity of the dorsal columns must be checked before

C2
C3+C2
C4
C5
T2
T2
T4
T5
T6
T1 T7
7
–C
T10
C5
T12
T1
L1
+
C8
7
+C
Cyst L2
C6
L3
L4
L5+S1
L5
A L5
B C
Figure 182-3. Microsurgical DREZotomy (MDT) for spinal cord and cauda equina injury. MDT is
performed bilaterally in a paraplegic patient after spinal cord injury at the conus medullaris (A), with a crush of
T12 to L4 spinal segments presenting with “segmental pain” in the corresponding territory (C). The drawing
(B) illustrates the intraoperative findings: myelomalacic cavity and gliosis in the conus medullaris. MDT will be
performed at the T12 to L4 spinal cord segments, bilaterally. The operative view (D) shows fibrotic arachnoids
surrounding the conus medullaris and cauda equina roots as well as the contused spinal cord. Arrowheads
designate the dorsolateral sulcus, which was difficult to identify within the fibrotic arachnoid and gliotic cord.
implantation.45 The use of intrathecal opioids in SCI patients
brings all the disadvantages of long-term morphine use, with
frequent hyperpathy and therefore low efficacy in the long-term.
Other intrathecal analgesics, such as ziconontide,68 have yet to be
proved effective; intrathecal therapy faces the challenge of drug
delivery in patients with extensive arachnoiditis and poor cere-
brospinal fluid (CSF) circulation.
Segmental pain is likely to be sensitive to DREZ lesioning,
whereas pain below the injury level would probably be refractory
to the lesion. This has been verified in practice, and in the now
classic series of Sindou and colleagues, patients with mostly
infralesional, burning, continuous pain had no benefit from the
procedure at long-term follow-up, whereas segmental pain was
cured in two thirds of patients.65
Preoperative assessment should therefore focus on the types
of pain, the residual functions below the level of injury that would
be at risk during the procedure, and evaluation of recent imaging
studies.
Technically, delivering lesioning in the DREZ of an SCI is
generally demanding because the morphology of the spinal cord
is most often greatly altered, which makes it difficult to identify
the dorsolateral sulcus. Stepwise the procedure must expose the
appropriate bony levels that need to be identified, sometimes
through complex fixation devices and reossification. Dural expo-
sure is rendered difficult and often bloody by local fibrosis. Intra-
durally, arachnoiditis and intrinsic lesions make it difficult to
identify and liberate the rootlets. Surgeries performed in two
sittings have been described, the first being the approach up to
liberation of the rootlets. Whatever exposure not only the injured
segments but also of the rostral healthy levels is most useful to
identify the sulcus. The classical MDT technique for SCI seg-
mental pain implies a lesion from one level above and to one level
below the pain levels. The method thus far used for SCI DREZ
lesioning has been either microsurgery with microcoagulations
or RF thermocoagulation.16,38,55,62,63,66,67,69-72
Mehta and colleagues have recently systematically reviewed
results of DREZ lesions for SCI injury.64 They concluded that
this type of procedure is effective for control of especially
CHAPTER 182  Dorsal Root Entry Zone Lesions for Pain 1463
C3 182
C4
C4
T2
C5
T4
T5
T6
T7 T1
C5 –
T10
C7
T12
C6+
C8+
S4+S5
C7
T1
S3 L2
L3
S2
L4 S1
S1
D
neuropathic pain. Overall results are summarized in Table 182-1.
Again, segmental pain was shown to be responsive to DREZ
lesions, whereas infralesional pain tends to be resistant. Other
positive prognostic factors are the paroxystic character of the
pain, conus lesions, and incomplete lesions. Recently, a modified
MDT procedure has been proposed by Chun and associates,67
with the aim of controlling infralesional pain; some results,
however, remain unverified.
Other Pain Indications
More rarely, DREZ lesioning has been applied to some other
indications, such as complex regional pain syndrome (CRPS),
peripheral nerve injury, postamputation pain, occipital neuralgia,
post-herpetic neuralgia, and radiation-induced plexopathy, when
pain did not respond to spinal cord stimulation. Published series
are short and results mitigated over the long-term; therefore,
DREZ lesioning cannot be considered a first-line indication in
these pathologies.
CRPS is most often responsive to spinal cord stimulation, and
ablative surgery is rarely indicated. DREZ lesioning can be con-
sidered in disabling and refractory forms.28
For pain after peripheral nerve injuries or for postamputation
pain, the first option is spinal cord stimulation. DREZ lesioning
may be considered when the predominant component of pain
is of the paroxysmal type (electrical flashes) or corresponds
to severe allodynia and hyperalgesia. Saris and Nashold reported
good pain relief in short-term follow-up, but good pain relief
persisted in long-term follow-up in only 25% of patients.11,75
Severe refractory occipital neuralgia can be effectively
treated by MDT at the C2 to C3 level performed through a
hemilaminectomy.76
For post-herpetic pain, there is a general agreement that
DREZ surgery may alleviate paroxysmal and allodynic compo-
nents, but the deep aching pain is not as well relieved and may
even be aggravated. Because herpes zoster neuralgias occur
mostly at the thoracic level, the procedure entails a significant
risk for neurological complications.38,61,62,77
1464 SECTION 6  Pain
Hyperspastic States with Pain
DREZ lesions have been noted to diminish muscle tone in
the corresponding territory. This is explained by the fact that
MDT interrupts the afferents of both the myotactic and the
nociceptive reflexes and thus deprives the somatosensory relays
of the ventral horn from most of their excitatory inputs (see
Fig. 182-1).
Hyperspastic states with pain can be encountered in the lower
limbs of paraplegic patients and even more in the upper limb
of hemiplegic patients. Besides neuropathic components, pain
in these hyperspastic states can be due primarily to severe
tendon and muscle contractures and joint deformities. Also, asso-
ciated algodystrophic reflex mechanisms may lead to so-called
CRPS.
DREZ lesioning is used to reduce the excess of spasticity and
related painful manifestations. Technique and indications are
described in Chapter 103.72 For hemiplegic patients with severe
spasticity in the upper limb, MDT is performed from C5 to T1
segments through a C3 to C7 hemilaminectomy. For patients
presenting with hyperspastic paraplegia, MDT is performed
bilaterally through a T11 to L1 laminectomy from L2 down to
S2, and additionally down to S5 when there is a hyperactive
bladder with urine leakage around the catheter.
TECHNIQUE
Several methods for creating DREZ lesions have been
described. Bipolar coagulation under direct vision of the DH
was described by Sindou in 1972 and is commonly referred to as
MDT.3,10 Nashold and coworkers described in 1974 the use
of RF current delivered through a needle electrode piercing
the dorsolateral sulcus.12 In 1983, Levy and colleagues intro-
duced the use of carbon dioxide laser as the lesion generator in
an attempt to increase precision of the lesion.14,15,82,83 Dreval and
associates reported in 1993 on the use of ultrasound19,20 for the
same purpose, and finally Spaic and colleagues described direct
aspiration of the DH in 2005.21,22,71,72
Regardless of the method for creating the lesion, the key to
the surgery is accurate identification of the appropriate levels to
be targeted. This has to take into account the localization of the
pain but also its nature and etiology in the context of the patient.
In patients with complete loss of function at and below the levels
concerned, lesions can be extended in terms of levels and depth
of lesioning. As an example, in SCI pain after trauma to the conus,
many metameres might be concerned and therefore targeted. On
the other hand, in delicate regions, such as the thoracic cord
where the DREZ area is narrow and deep, lesioning must be kept
to a minimum.
When taking decision the most likely location of the pain
generators should be kept in mind and pain that is not likely
generated in the DH should not be targeted; DREZ lesions
mostly work for paroxystic shooting pain and only to a lesser
extent for continuous burning pain.
Patients are operated on under general anesthesia; muscle
relaxants are used only at the induction of surgery, which allows
for electromyographic monitoring and, if necessary, motor
evoked potentials monitoring throughout the surgery. Monitor-
ing sensory evoked potentials may be useful for intraoperative
identification of the metameric levels and sometimes determining
the extent and depth of the lesion.84 Positioning should take into
account the CSF loss that can be important in long surgeries, and
therefore the dural opening should be kept higher than the head
of the patient.
Identification of levels is of paramount importance and
requires identification of the vertebrae, after which intraoperative
stimulation of the anterior roots with electromyographic moni-
toring of corresponding muscles will be used.85
Exposure should allow access to the targeted levels and also
the adjacent ones not only because of the necessity to extend
the lesion to them but also for accurate identification of normal
levels as help for precise lesion placement. A hemilaminectomy
with conservation of the spinous processes, if transversally
large enough, is sufficient when surgery is performed unilaterally.
With proper rongeuring underneath the base of the spinous
process the roots and dorsolateral sulcus on the other side
are visible. After dural incision is made, the dura should be sus-
pended in order to keep the intradural space clean of blood
contamination.
Working in the DREZ requires knowledge of microsurgical
anatomy of the spinal roots and cord29,30 as well as of the internal
morphology of the cord to avoid damaging the neighboring ana-
tomic structures79-81 (Fig. 182-4).
For MDT, access to the dorsolateral sulcus should be per-
formed ventrolaterally to the dorsal rootlet entry after the dorsal
rootlets are displaced dorsally and medially (see Fig. 182-4). Then
the sulcus is opened using a microknife of the ophthalmology
type, until the pink-gray color of the DH can be seen (see Figs.
182-1 and 182-4). Coagulation is performed using a fine-tipped
bipolar forceps with millimetric graduations. Coagulations are
performed at an angle depending on the level of the spinal cord:
35 degrees at the cervical level and 45 degrees at the lumbosacral
level (see Fig. 182-1), at a depth of approximately 3 to 5 mm. We
perform continuous coagulations along the dorsolateral sulcus at
every selected root. The objective of a DREZ lesion is to coagu-
late strictly within the DH, down to the level of the nucleus
proprius (laminae IV to V included). Accurate placement of the
lesion is critical to avoid injury to the dorsal column medially and
the corticospinal tract laterally.
For RF thermocoagulation lesioning, detailed technique can
be found in the 2009 article by El-Naggar and colleagues.82 A
specially designed electrode is in use (Cosman Medical Inc., Bur-
lington, MA). This has a lesion tip of 2 mm and a diameter of
0.25 mm. The electrode is inserted into the dorsolateral sulcus
at millimetric intervals, an the RF lesion is made with a current
strength of 35 to 40 mA at a temperature of less than 75 degrees
for 15 seconds. The lesion usually extends 1 to 2 mm beyond the
tip of the electrode. Nashold and associates also recommended
measuring impedance during surgery after they determined that
the impedance of damaged spinal cord was less than 1200 Ω,
whereas that of a normal spinal cord reaches 1500 Ω.
Carbon dioxide, argon, and neodymium:yttrium aluminum
garnet (Nd-YAG) lasers have all been used to create DREZ
lesions.14,15,18 Levy and colleagues advocated a pulse duration of
0.1 second, 20-W power, and one to two pulses to create a 2-mm
deep lesion at an angle of 45 degrees to the DREZ.18 For SCI
pain, Stranjalis and Torrens used an Nd:YAG laser to create
lesions at 1-mm intervals to a depth of 2 mm at a power output
of 10 W/sec, with the lesions extending 3 cm above and below
the involved segment.18 In his analysis of lesions made by RF and
lasers, Young reported that lasers produced a V-shaped lesion,
whereas RF lesions were mostly spherical.16 Young also noted that
RF resulted in better pain control, but at the cost of a higher
complication rate.
Dreval, at the Moscow Central Institute, reported on the use
of ultrasound at 44 KHz and an amplitude of 15 to 50 µm to
create a “sulcomyelotomy” along the dorsolateral sulcus at an
angle of projection of 25 degrees medially and ventrally.19 This
procedure keeps vessels crossing the sulcus intact.
Spaic and coauthors reported a technique of microsurgical
suctioning of the DH in place of the coagulation procedure.72
They advocated use of a 0.8-mm suction tip to suction the DH
under microscopic visualization after opening the dorsolateral
sulcus. According to these authors, the DH can be visualized at
20 times magnification as a band of gray substance that gradually
reaches the massive central gray matter of the cord.
 CHAPTER 182  Dorsal Root Entry Zone Lesions for Pain 1465

182

A B D

E F G
Figure 182-4. Microsurgical DREZotomy (MDT) for cancer pain caused by a pulmonary tumor invading
the right brachial plexus. Positron emission tomography in coronal (A), sagittal (B), and axial (C) planes
showing a well-limited tumor at the right pulmonary apex. T1-weighted magnetic resonance imaging with
gadolinium in axial section (D) shows invasion of spine and roots at the cervicothoracic junction. The patient
presented with complete functional loss of the upper limb, shooting pain along the arm down to the hand,
and allodynia and dysesthesia distributed from the shoulder down to T4 territory. The prone position with the
head and neck flexed in the Concorde position with three-pin head holder has the advantage of avoiding
brain collapse caused by cerebrospinal fluid depletion. The level of laminectomy is determined after
identification of the prominent spinous process of C2 by palpation. For unilateral dorsal root entry zone
operation, a hemilaminectomy with preservation of the spinous processes is sufficient to access the
dorsolateral aspect of the spinal cord. After opening the dura and arachnoid, identification of roots can be
verified by electrical stimulation at their corresponding foramen and their functional value checked. Stimulated
ventral roots have a motor threshold at least 3 times lower than the dorsal roots. Responses are in the
diaphragm for C4 (the response is palpable below the lower ribs), in the shoulder abductors for C5, in the
elbow flexors for C6, in the elbow and wrist extensors for C7, and in the muscles intrinsic of the hand for C8
and T1. Microsurgical lesioning is performed at the selected levels according to the preoperative program. As
shown in E and F, the dorsal rootlets are displaced dorsally and medially with a hook or a microsucker to
access to the ventrolateral aspect of the dorsolateral sulcus. Then an incision, 2 mm in depth at a 35-degree
angle, is made with a microknife, currently an ophthalmologic microscalpel, at the ventrolateral border of the
dorsolateral sulcus (F). Microcoagulations are made in a “chain” (i.e., dotted manner), 3 to 5 mm deep into
the dorsal horn (G). Each microcoagulation is performed, under direct magnified vision, by short-duration (a
few seconds), low-intensity, bipolar electrocoagulation, with a specially designed graduated sharp bipolar
forceps incremented in millimeters (graduated bipolar forceps ref: 12-30179, DREZotomy Set, Stryker
Leibinger GmbH & Co. KG, Freiburg, Germany]. The depth and extent of the lesion depend on the desired
therapeutic effect and the preoperative functional status of the limb. If the laxity of the root is sufficient, the
incision is performed, continuously, in the dorsolateral sulcus, thus accomplishing a sulcomyelotomy. If not,
successive incisions are made ventrolaterally at entry of each of the rootlets of the root after the surgeon has
isolated each one by separating the tiny arachnoid membranes that hold them together.
1466 SECTION 6  Pain
HOW TO AVOID COMPLICATIONS
Avoiding complications while achieving maximal results is a key
balance problem as for all functional neurosurgical procedures.
Although local or general complications are of the usual type
for a spine surgery (CSF leaks, hematoma, infection, thrombosis),
their frequency may be higher in some groups of patients, such
as those with cancer or SCI, in whom status can be greatly
altered.
Neurological complications occur as a result of the extension
of the surgical lesion to structures adjacent to the DH, namely
the ipsilateral dorsal column or pyramidal tract or tracts impli-
cated in visceral function. Cited complications are dysesthesia,
hypoesthesia, ataxia, motor weakness, and urogenital dysfunction,
all of which may be either temporary or permanent.
Typically, patients in whom the cervical cord is operated on
are at risk for ipsilateral lower limb ataxia, and this has been
described in 4% to 25% of patients according to series. Although
the depth of the lesion is a factor, its trajectory has, in our view,
a more important role, and in this aspect, MDT has an advantage
because it implies opening the dorsolateral sulcus and controlling
the lesion through direct magnified vision of the DH and adja-
cent tracts.
DREZ lesioning in the conus medullaris entails a higher risk
for sphincter dysfunction in cases of preserved function and for
disturbances of automatism in cases of complete lesions. Also,
coagulation of vessels in the dorsolateral sulcus, known to harbor
important arteries, may be the cause of uncontrolled extension of
the lesion volume, with subsequent deficits.
Lesions performed in the thoracic cord are at a higher risk for
neurological complications because of the narrowness of the DH
(see Fig. 182-1).
DREZ surgery may generate new pain at the borders of the
operated territory. When reported, such pain was most often
considered bearable compared with the original pain that led to
the surgical indication. Mechanisms remain putative and may
include unmasking of previous pain or damage to the DH cells
at the origin of the spinoreticulothalamic tract.
Direct comparisons between the different techniques have not
been made in terms of their complications, with the exception of
those by Young and colleagues, who found more deficits with RF
when performed on an area of 0.5 × 2 mm than with laser or RF
on an area of 0.25 × 2 mm.16,17 MDT performed under direct
vision of the intramedullary structures seems to generate less
severe neurological side effects.
CONCLUSION
DREZ lesioning can be helpful to relieve pain in strictly selected
patients, especially those in whom pain generators are likely to
be at the level of the DH, the more so because in such situations
other methods are not generally effective. Surgery in the DREZ
requires training in microsurgical techniques for safety and accu-
racy. Indications should be discussed within the framework a
multidisciplinary team to choose the most appropriate method
among the wide neurosurgical armamentarium.33
SUGGESTED READINGS
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56. Prestor B. Microsurgical junctional DREZ-coagulation for treat-
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183 Tractotomy-Nucleotomy
Percutaneous Cordotomy and Trigeminal
Ahmed M. Raslan
HISTORY
Spinal ablation to control pain is not a new concept. In general,
physicians have been progressively moving away from procedures
that cause irreversible neural tissue destruction for pain control,
albeit with a few exceptions. Cordotomy and trigeminal tractot-
omy are two such procedure exceptions.
The underlying principle is the creation of a discrete lesion
in a rather compact bundle of nerve fibers or cell bodies that
transmit or process pain from a defined area of the body. This is
usually undertaken in cases of intractable pain with or without a
terminal or debilitating condition when other methods have
failed or survival time is not sufficient to offer the luxury of
testing alternatives. Cordotomy and trigeminal tractotomy pro-
cedures share a common history that historically represents pain
surgery itself.
Early procedures were open and involved a knife section of
either the anterolateral cord or a transverse stab incision dorsal
to the olive, which afforded a high-risk status with associated
morbidity and mortality.1,2
In the 1960s, a second iteration of these procedures was intro-
duced in two different places; a common thread was that they
were both percutaneous. Cordotomy was made percutaneous
through the pioneering efforts of Mullan3 and Rosomoff,4
whereas trigeminal tractotomy was made percutaneous by Hitch-
cock,5 who developed a stereotactic apparatus specifically for
trigeminal tractotomy and myelotomy. A third iteration was
introduced by Kanpolat, who introduced computed tomography
(CT) guidance to both procedures. This latest procedural itera-
tion is performed using intraoperative CT guidance with neuro-
monitoring and possibly general anesthesia.
CORDOTOMY
Cordotomy is essentially a lateral spinothalamic tractotomy; the
spinothalamic tract carries nociceptive signals, temperature, and
nondiscriminative touch from the contralateral side of the body.
There is somatotopic organization of axons within the spinotha-
lamic tract; fibers entering from rostral and caudal segments are
located in the medial and lateral parts of the tract, respectively.
The spinothalamic tract terminates mainly in the ventral poste-
rior lateral nucleus, ventral posterior medial nucleus, intralaminar
nuclei (mainly the central lateral nucleus), and posterior complex.
The corticospinal tract lies posterior to the lateral spinothalamic
tract (LST), with white matter (the safety zone) in between. The
ventral spinocerebellar tract overlies the LST, and a lesion that
eliminates the spinocerebellar tract may cause ipsilateral ataxia
of the arm. Human autonomic pathways for vasomotor and geni-
tourinary control, in addition to the reticulospinal tract that
controls ipsilateral automatic respiration, are also part of the
anterolateral quadrant of the spinal cord. Therefore, sleep apnea
(Ondine’s curse), incontinence, and hypotension are possible
undesirable cordotomy side effects (Fig. 183-1).6
Indications
Patient candidacy for cordotomy has evolved over time: origi-
nally it was widely used for chronic noncancerous pain, then it
183
was used for both cancerous and noncancerous pain, and finally it
settled as a procedure that is mostly used for cancer-related pain.
The ideal candidate is a cancer patient with unilateral somatic
pain and a life expectancy of approximately 1 year. However,
extreme cases of frail patients with intractable noncancerous pain
can be treated by cordotomy. Bilateral pain is much more difficult
to treat, and midline pain is not a candidate for cordotomy. Pain
above the dermatome of C5 is generally not managed by cordot-
omy. Pulmonary function test results higher than 50% in forced
expiratory volume and forced vital capacity in 1 second are gener-
ally the minimal cutoffs for cordotomy candidacy.6
Mesothelioma is a particularly attractive malignancy to treat
using cordotomy given its unilateral nature and somatic type of
pain resulting from involvement of the pleura and ribs, together
with late involvement of pulmonary parenchyma to the point of
reduction of pulmonary functions beyond the minimal cutoff for
cordotomy.7
Technique
Equipment
An LCE kit for CT-guided spinal cord radiofrequency lesioning
by (Cosman Medical, Burlington, MA) is used to perform the
procedure. A radiofrequency lesion generator that is capable of
stimulation and impedance monitoring is needed and is manu-
factured by multiple companies.
The procedure is typically performed in the CT scanner in a
radiology suite; however, with the recent availability of wide-bore
mobile intraoperative CT scanners, the procedure could be done
in the operating room.
Procedure
Thirty minutes before the procedure, a lumbar injection of
12 mL of Omnipaque 300 mg/mL solution is performed, and the
patient is kept in the Trendelenburg position to allow contrast to
diffuse up to the cervical region.
Cordotomy is performed in a supine position, and the head is
immobilized by taping to the CT gantry. Maintenance of an
orthogonal neutral position to help the three-dimensional orien-
tation during needle placement is critical. The shoulders are
pulled down to ensure adequate access to the side of the neck to
allow placement of the electrodes. The area around the mastoid
tip is prepared and draped.
Parallel, preferably zero gantry angle, 1- to 1.25-mm cuts are
scanned spanning the foramen magnum down to the bottom of
C2, with a wide field of view to allow imaging of the skin. The
field of view can be adjusted to avoid denture artifact. The slice
of choice to perform the procedure is between C1 and C2, where
there is a lateral space between C1 and C2 to allow introduction
of the needle. The laser beam of the scanner is used to guide the
entry point into the skin.
The skin dura thickness and anteroposterior and lateral diam-
eters of the cord are determined from the slice through which
skin entry will be done.
After local infiltration with 2% lidocaine, the LCE cannula is
introduced through the skin to a length that is shorter than the
1467
1468 SECTION 6  Pain
Posterior
funiculus
Posterior column
Lateral
Lateral corticospinal
funiculus tract
Spinothalamic
tract
Anterior funiculus
Figure 183-1. Schematic representation of somatotopic organization
of spinothalamic and corticospinal tracts in the cervical spinal cord.
A B
C D
Figure 183-2. A, Computed tomographic myelography reveals the
dentate ligament and the upper cervical spinal cord, the cord
diameter, and skin dura thickness. B, The needle is introduced to a
trajectory anterior to the cord. C, The needle trajectory is adjusted to
proper targeting of the anterolateral quadrant. D, The electrode is
inserted through the needle into the spinal cord.
skin dura thickness in a direction mostly perpendicular to the skin
in the level of the mastoid tip in the anteroposterior plane. With
frequent CT checks, the position of the cannula is adjusted until
the dura is punctured. Before puncture of the dura, 2 mL of 2%
lidocaine can be injected to avoid pain due to contact with C2
ganglion and the sensitive dura. After free flow of cerebrospinal
fluid is obtained, a CT check is always performed, then according
to the previously known lateral diameter of the cord, the length
of exposed tip of the electrode is adjusted on the hub of the
electrode and the electrode introduced through the cannula.
Cord penetration is known when there is a rapid rise of the
impedance from cerebrospinal fluid values, which are between
400 and 1000 Ω; also either mild pain or electric sensation is
experienced by the patient.
A low transdiscal route for cordotomy below C4 had been
described by Raslan elsewhere to avoid sleep apnea (Fig. 183-2).8
Target Verification
Radiologic.  Frequent CT checks on the position of the elec-
trode in relation to the geometry of the cord (the opposite
anterolateral quadrant of the cord in relation to the side of pain)
and also in relation to the area of maximal pain intensity and the
somatotopic arrangement of pain fiber within the spinothalamic
tract (more anteromedial = more toward the arm side; more
posterolateral = more toward the leg side) is required.
Clinical.  Usually, cord penetration produces pain in the area
supposed to be ablated of pain sensation if a lesion is made in
that particular target; also, electric stimulation confirms this
phenomenon.
Electrophysiologic
Impedance Monitoring.  Impedance monitoring is mainly
beneficial in identifying cord penetration but is of very limited
significance in regard to verification of the target inside the cord.
Macrostimulation.  The electrodes used for lesioning allow
stimulation of the spinothalamic tract (the target) in both sensory
and motor frequencies to verify the target.
All patients are stimulated with a sensory frequency (100 Hz),
as well as motor frequency (2 Hz); pulse duration of both fre-
quencies is 0.1 msec. The expected response to sensory stimula-
tion is a painful or hot temperature sensation in the contralateral
half of the body, preferably covering the painful area at a thresh-
old not exceeding 0.15 V. The motor stimulation should be
carried out with no motor response in the ipsilateral side of the
body up to 1.0 V with exception of neck muscle response, which
could result from C2 anterior horn cell activation. If both condi-
tions are met, lesioning could be carried out; if not, then elec-
trode position needs to be adjusted.
The procedure begins with one test lesion of 60 seconds’
duration at 60° C; the other half of the body is then tested for
hypothesia and pain relief. The ipsilateral leg of the patient is
elevated to detect any subtle change of motor power during
lesioning. If adequate hypothesia or pain relief is not obtained,
which is the case in most patients, a second lesion of 75° C
for 90 seconds is performed. The benchmark of successful lesion-
ing is abolishment of the distinction between sharp pinprick
and dull sensation. The cannula is removed from the patient,
and the puncture site is sterilized and covered. Overnight obser-
vation with continuous pulse oximetry is needed for cordotomy
patients to monitor for possible sleep apnea. Generally speaking,
weaning off opioids could be started the next day after cordot-
omy, but in most cases, it is delayed for about 1 week after the
procedure.
Results and Complications
Most cordotomy case results pertain to cancer pain only, and
results of cordotomy in noncancer pain are from relatively older
studies; a recent review of all destructive procedures for noncan-
cer pain lists the results of all cases series since 1966.9 However,
this general perception had been challenged by case reports of
prolonged pain relief after cordotomy for nonmalignant pain.10
CT-guided cordotomy is categorically different from fluoro-
scopic cordotomy in that it allows direct visualization of the
target-electrode relationship, leading to higher safety and preci-
sion. In a series of 41 patients,11 the immediate postoperative
results of CT-guided cordotomy ranged from 92% to 98% pain
relief or satisfactory pain relief, which declined to 80% at 6
months, with a persistent clinically and statistically significant
reduction of Visual Analog Scale (Fig. 183-3). Kanpolat reported
initial success of 97%, which declined to 84% at 6 months’
follow-up.12
Cordotomy stands alone among all other ablative procedures
in that it is the procedure most often performed and is associated
with a great degree of confidence in results despite a lack of high
level of evidence. In a recent structured review of all ablative
procedures, cordotomy was graded as 1C using the Grading of
Recommendations Assessment, Development and Evaluation
(GRADE) system,13 which equates to a strong recommendation
of use based on low-level quality evidence.14
 CHAPTER 183  Percutaneous Cordotomy and Trigeminal Tractotomy-Nucleotomy 1469
Visual Analog Scale
7
6 device−spinal cord relationship.18
Mean
5 TRIGEMINAL TRACTOTOMY-NUCLEOTOMY
4 Intractable facial pain can be one of the most devastating pains
3 cranial nerves V, VII, IX, and X, are carried by the trigeminal tract
2
1 carried by the trigeminal tract made it an ideal target for surgical
0 1937 when Sjogvist surgically severed the tract through a trans-
VASpre VASpost VAS1 VAS3 VAS6
Figure 183-3. Persistence of statistically and clinically significant
reduction in a Visual Analog Scale (VAS) after cordotomy at 6 months.
CT-guided cordotomy is a safe procedure, and there are no
reposted mortalities in the literature. This compares with a
6.25% mortality rate reported for the older fluoroscopic cor-
dotomy technique.15
The famous Ondine’s curse is an epitome of cordotomy risk.
A true Ondine’s curse is universally fatal; however, no cases
of Ondine’s curse have been reported so far using CT-guided
cordotomy.11,12
Postcordotomy painful sensory loss (dysthesia) affects 5% of
patients. This can develop immediately but commonly develops
in long-term survivors who had a significant component of neu-
ropathic pain and had received a large lesion.15,16
With direct visualization of the electrode in the spinal cord
and proper electrophysiologic verification, ipsilateral weakness,
ataxia, and urinary incontinence are very rare occurrences.
One rare troubling and unpredictable consequence of cor-
dotomy is what is called mirror pain, which could be due either
to a bilateral pain syndrome that is masked by marked severity
on one side or to bilateral projection of dorsal roots in the both
spinothalamic tracts.
Unintentional injection of local anesthetic in the cerebrospi-
nal fluid could lead to respiratory cessation, especially if a cister-
nal injection is contemplated, and therefore clearly marking the
injection syringes and completely discarding local anesthetics
from the field are necessary.
Future Directions
Cordotomy is poised to be used once again as part of the neuro-
surgical armamentarium, essentially returning full circle, for
several reasons: (1) costs to maintain and manage the complica-
tions of intrathecal opioid systems are increasing; (2) pharmaco-
logic neuromodulation is not always practically reversible; (3)
recognition of opioid-induced hyperalgesia is increased; (4)
development of cost-effective procedures is needed throughout
society; and (5) there is the potential for increased safety, accu-
racy, and precision of a cordotomy procedure using modern tech-
nology, such as intraoperative monitoring and neuronavigation.
The use of intraoperative imaging in cordotomy is a recent
technical addition. A report of O-arm−guided cordotomy was
published in 2013.10 Burchiel and associates reported use of intra-
operative CereTom (NeuroLogica, Danvers, MA) in CT-guided
tractotomy and myelotomy, and with wider bore intraoperative
CT scanners, cordotomy will move back to the surgical suite
rather than the radiology suite.17 183
Endoscopic cordotomy was introduced in 2010 and presents
the potential for improved visualization of the lesioning
in human experience. Sensory input from the head, through
to the spinal nucleus of the trigeminal nerve.
The compact sensory information from the head and face
interruption. This kind of surgical interruption dates back to
verse incision in the dorsal medulla.1 The immediate juxtaposi-
tion of the trigeminal nucleus to the trigeminal tract would
render any trigeminal tractotomy an effective tractotomy and
nucleotomy, hence the name trigeminal tractotomy-nucleotomy
(TR-NC) (Fig. 183-4).
Percutaneous rhizotomy of the gasserian ganglion was subse-
quently used primarily for facial pain treatment along with open
rhizotomies to treat “typical” trigeminal neuralgia. Trigeminal
tractotomy was reserved for intractable terminal pain and because
of the extreme morbidity of the open procedures; therefore, it
was not used often.19
When Crue and Hitchcock developed a stereotactic technique
and device to lesion the trigeminal tract percutaneously, the pro-
cedure realized resurrection in the late 1960s.5,20,21
The invention by Hitchcock in the 1960s5 is what led to the
present-day version of the TR-NC, which was introduced by
Kanpolat in the early1990s. Kanpolat described and performed a
CT- guided TR-NC, which allowed a direct visualization of the
electrode-target relationship.22
Simultaneously, Nashold described and performed an open
procedure to destroy the nucleus caudalis dorsal root entry zone
(DREZ) for deafferentation facial pain23; the TR-NC is a minia-
ture of the caudalis DREZ operation.
Indications
Trigeminal neuropathic pain with varying degrees of trigeminal
nerve damage and neuropathy are the main candidates for
TR-NC. Conditions such as traumatic trigeminal neuropathy,
post-herpetic neuralgia, cancer pain of the head or face, glosso-
pharyngeal or geniculate neuralgia, bilateral trigeminal neuralgia,
and possibly anesthesia dolorosa are the typical indications for
TR-NC.24
Technique
Equipment
The needle, stylet, and electrode are from the LCE kit provided
for CT-guided spinal cord radiofrequency lesioning.
The procedure is generally performed in the CT scanner
in the radiology suite, but with the recent availability of wide-
bore mobile intraoperative CT scanners, the procedure could
be undertaken in the operative suite. To use an intraoperative
scanner for TR-NC, a wide-bore aperture of the CT scan is
recommended to allow for scanning while the needle and elec-
trode are in place to target in prone position without collision
of the electrode with the CT scanner. In my experience, a switch
to general anesthesia, given the difficulty of maintaining the
prone position for patients with sensitive facial pain, is preferred
for this procedure. Other neurosurgeons perform the proce-
dure in a lateral position to circumvent this problem (personal
1470 SECTION 6  Pain

Figure 183-4. Diagrammatic representation of the trigeminal tractotomy electrode in position between C0 and
C1 and on axial between the dorsal column tract and nuclei medially and the spinocerebellar tract laterally.

communication). When general anesthesia is used, muscle relax-

ants should be withheld to allow for motor stimulation and elec-
trophysiologic verification of target.

Preoperative Preparation
Patients are usually admitted the day of surgery. The use of anti-
coagulants and antiplatelets is stopped at least 1 week before the
procedure. Thirty minutes before the procedure, a lumbar injec-
tion of 12 mL of Omnipaque 300 mg/mL solution is performed,
and the patient is kept in the Trendelenburg position.

Surgical Positioning
TR-NC is performed in the prone or lateral position, and the
head is immobilized by taping to the CT gantry. It is important
to maintain the head in an orthogonal position to help the three-
dimensional orientation during needle placement. If an intraop-
erative CT scan is used, a three-pin head holder is often used.17
Figure 183-5. Computed tomographic myelography showing the
Adequate flexion of the head to allow opening the space between
needle in final position for trigeminal tractotomy.
C0 and C1 is critical.

Imaging and Data Acquisition
Parallel, preferably zero gantry angle, 1- to 1.25-mm cuts are
scanned spanning the foramen magnum down to the top of C2,
with a wide field of view to allow of imaging the skin. The field
of view and the gantry angle are adjusted to avoid dentures arti-
fact. The axial slice of choice to perform TR-NC is between C0
and C1. The laser beam of the scanner is used to guide the entry
point into the skin.
The skin dura thickness, anteroposterior diameter, and lateral
diameter of the cord are determined from the slice through which
skin entry will be done.
Needle Placement
The technique is similar to cordotomy with a difference in the
skin entry point and the target. The entry point is usually 2 to
3 cm off the midline ipsilateral to the side of lesion at the axial
level determined by the laser beam of the skin corresponding
to the level of the space between C0 and C1; the target is the
posterolateral sulcus on the spinomedullary junction approxi-
mately midway between the midline and the equator of the cord
dorsally. Note that the medial displacement of the target will
lead to lesioning of the gracile or cuneate tracts, whereas ventral
displacement risks missing the tract. Because of the proximity
of the spinocerebellar tract to the trigeminal tract, ipsilateral
upper extremity ataxis is almost unavoidable after this procedure;
however, it is almost always mild or temporary, or both.
Target Verification
Radiologic.  The position of the electrode is confirmed by CT
checking of the position of the electrode in relation to the geom-
etry of the cord. Figures 183-4 and 183-5 show the final position
of the electrode and depict its relationship to surrounding tracts.
Clinical.  Usually, cord penetration produces pain in the area
supposed to be ablated of pain sensation if the lesion is made in
that particular target; also, electric stimulation confirms this
 CHAPTER 183  Percutaneous Cordotomy and Trigeminal Tractotomy-Nucleotomy 1471
phenomenon. However, this is only relevant in awake patients,
and when general anesthesia is used, there is no clinical verifica-
tion of the target.
Electrophysiologic
Impedance Monitoring.  Impedance monitoring is mainly
beneficial in identifying cord penetration; however, it was of very
limited significance in regard to verification of the target inside
the cord.
Macrostimulation.  The electrodes used for lesioning allow
one to stimulate the spinothalamic tract (the target) in both
sensory and motor frequencies to verify the target.
All patients are stimulated with 100 Hz, with a pulse duration
0.1 msec as a sensory frequency, and no lesion is made except
after obtaining a sense of temperature change or painful sensation
in the face. That verification is only possible in awake patients,
and it should be noted that stimulation of the trigeminal tract of
the nucleus is extremely painful. Motor stimulation at 2 Hz, with
a pulse duration 0.1 msec, is then performed up to 1 V. There
should be no motor response in the extremities to stimulation,
this part done irrespective of anesthesia used to rule out proxim-
ity to motor tracts.
Lesion Making
If patients are awake, creation of the lesion is painful, and lower
temperatures over longer periods have been advocated by Kan-
polat. The author is performing the procedure with patients
asleep, and TR-NC lesions are created using 75°C for 90 seconds,
two lesions usually suffice.
Postoperative care is very similar to cordotomy.
Results and Complications
When patients are adequately selected, adequate pain control
rates exceed 90% for follow-up reported up to 4 years. Complica-
tions and side effects include ipsilateral upper extremity ataxia,
which is usually mild but common, cerebrospinal fluid leak, men- 183
ingitis, and persistence of pain.24
CONCLUSION
Neuroablation of the spinothalamic tract or the trigeminal tract
is an effective method for control of intractable pain. These
procedures should not be considered first-line management but
can be an effective strategy in the right context for severe, refrac-
tory pain. There is a renewed interest in these procedures, owing
to technologic advances and the emergence of new indications
for patients who fail neuromodulation therapy.
SUGGESTED READINGS
Collins KL, Patil PG. Flat-panel fluoroscopy O-arm-guided percutane-
ous radiofrequency cordotomy: a new technique for the treatment of
unilateral cancer pain. Neurosurgery. 2013;72(1 suppl Operative):27-34,
discussion 34.
Kanpolat Y, Deda H, Akyar S, et al. CT-guided trigeminal tractotomy.
Acta Neurochir (Wien). 1989;100(3–4):112-114.
Kanpolat Y, Ugur HC, Ayten M, et al. Computed tomography-guided
percutaneous cordotomy for intractable pain in malignancy. Neurosur-
gery. 2009;64(3 suppl):ons187-193, discussion ons193-194.
Raslan AM. Percutaneous computed tomography-guided radiofrequency
ablation of upper spinal cord pain pathways for cancer-related pain.
Neurosurgery. 2008;62(3 suppl 1):226-233, discussion 233-224.
Raslan AM, Cetas JS, McCartney S, et al. Destructive procedures for
control of cancer pain: the case for cordotomy. J Neurosurg. 2011;
114(1):155-170.
Thompson EM, Burchiel KJ, Raslan AM. Percutaneous trigeminal
tractotomy-nucleotomy with use of intraoperative computed tomog-
raphy and general anesthesia: report of 2 cases. Neurosurg Focus. 2013;
35(3):E5.
See a full reference list on ExpertConsult.com
 CHAPTER 183  Percutaneous Cordotomy and Trigeminal Tractotomy-Nucleotomy 1471.e1
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