Professional Documents
Culture Documents
The Basic Science of Pain Management
The Basic Science of Pain Management
section
1
H
Ch001-W0334.qxd 2/28/06 2:01 PM Page 2
chapter
1
A Conceptual Framework for
Understanding Pain in the Human
Ronald Melzack and Joel Katz
2
Ch001-W0334.qxd 2/28/06 2:01 PM Page 3
C
SENSORY SIGNALLING SYSTEMS ACTION PROGRAMS
Cutaneous, visceral, Involuntary and voluntary
musculoskeletal inputs S action patterns
TIME TIME
FIGURE 1-3 ■ Factors that contribute to the patterns of activity generated by the body-self neuromatrix, which is composed of sensory, affective, and cog-
nitive neuromodules. The output patterns from the neuromatrix produce the multiple dimensions of pain experience, as well as concurrent homeostatic and
behavioral responses. (From Melzack R: Pain and the neuromatrix in the brain. J Dent Educ 65:1378, 2001, with permission.)
part of pain and we need to know more about the mechanisms phantom limb (or other body part) feels so real, it is reason-
of peripheral inflammation, spinal modulation, midbrain able to conclude that the body we normally feel is subserved
descending control, and so forth. But the data on painful phan- by the same neural processes in the brain as the phantom;
toms below the level of total spinal section11,12 indicate that these brain processes are normally activated and modulated
we need to go above the spinal cord and into the brain. by inputs from the body but they can act in the absence of any
Note that we mean more than the spinal projection areas inputs. Second, all the qualities we normally feel from the
in the thalamus and cortex. These areas are important, of body, including pain, are also felt in the absence of inputs
course, but they are only part of the neural processes that from the body; from this we may conclude that the origins of
underlie perception. The cortex, Gybels and Tasker13 made the patterns that underlie the qualities of experience lie in
amply clear, is not the pain center and neither is the thalamus. neural networks in the brain; stimuli may trigger the patterns
The areas of the brain involved in pain experience and behav- but do not produce them. Third, the body is perceived as a
ior must include somatosensory projections as well as the unity and is identified as the “self,” distinct from other people
limbic system. Furthermore, cognitive processes are known and the surrounding world. The experience of a unity of such
to involve widespread areas of the brain. Despite this diverse feelings, including the self as the point of orientation
increased knowledge, we do not have yet an adequate theory in the surrounding environment, is produced by central neural
of how the brain works. processes and cannot derive from the peripheral nervous
Melzack’s12 analysis of phantom limb phenomena, par- system or spinal cord. Fourth, the brain processes that under-
ticularly the astonishing reports of a phantom body and severe lie the body-self are “built-in” by genetic specification,
phantom limb pain in people with a total thoracic spinal cord although this built-in substrate must, of course, be modified
section,10 has led to four conclusions that point to a new by experience. These conclusions provide the basis of the new
H conceptual model of the nervous system. First, because the conceptual model11,12,14 depicted in Figure 1-3.
Ch001-W0334.qxd 2/28/06 2:01 PM Page 5
Outline of the Theory varying patterns riding on the main signature pattern produces
the feelings of the whole body with constantly changing
The anatomic substrate of the body-self, Melzack11,12,14 pro- qualities.
posed, is a large, widespread network of neurons that consists
of loops between the thalamus and cortex as well as between
the cortex and limbic system. He has labeled the entire Conceptual Reasons for a Neuromatrix
network, whose spatial distribution and synaptic links are ini- It is difficult to comprehend how individual bits of informa-
tially determined genetically and are later sculpted by sensory tion from skin, joints, or muscles can all come together to
inputs, as a neuromatrix. The loops diverge to permit parallel produce the experience of a coherent, articulated body. At any
processing in different components of the neuromatrix and instant in time, millions of nerve impulses arrive at the brain
converge repeatedly to permit interactions between the output from all the body’s sensory systems, including the proprio-
products of processing. The repeated cyclical processing and ceptive and vestibular systems. How can all this be integrated
synthesis of nerve impulses through the neuromatrix imparts in a constantly changing unity of experience? Where does it
a characteristic pattern: the neurosignature. The neurosigna- all come together?
ture of the neuromatrix is imparted on all nerve impulse pat- Melzack11,12,14 conceptualized a genetically built-in
terns that flow through it; the neurosignature is produced by neuromatrix for the whole body, producing a characteristic
the patterns of synaptic connections in the entire neuromatrix. neurosignature for the body that carries with it patterns for
All inputs from the body undergo cyclical processing and syn- the myriad qualities we feel. The neuromatrix, as Melzack
thesis so that characteristic patterns are impressed on them in conceived of it, produces a continuous message that repre-
the neuromatrix. Portions of the neuromatrix are specialized sents the whole body in which details are differentiated
to process information related to major sensory events (such within the whole as inputs come into it. We start from the top,
as injury, temperature change, and stimulation of erogenous with the experience of a unity of the body, and look for
tissue) and may be labeled as neuromodules that impress sub- differentiation of detail within the whole. The neuromatrix,
signatures on the larger neurosignature. then, is a template of the whole, which provides the charac-
The neurosignature, which is a continuous output from teristic neural pattern for the whole body (the body’s neuro-
the body-self neuromatrix, is projected to areas in the brain— signature) as well as subsets of signature patterns (from
the sentient neural hub—in which the stream of nerve neuromodules) that relate to events at (or in) different parts
impulses (the neurosignature modulated by ongoing inputs) is of the body.
converted into a continually changing stream of awareness. These views are in sharp contrast to the classical speci-
The neurosignature patterns may also activate a neuromatrix ficity theory in which the qualities of experience are presumed
to produce movement. That is, the signature patterns bifurcate to be inherent in peripheral nerve fibers. Pain is not injury;
so that a pattern proceeds to the sentient neural hub (where the quality of pain experiences must not be confused with the
the pattern is transformed into the experience of movement) physical event of breaking skin or bone. Warmth and cold are
and a similar pattern proceeds through a neuromatrix that not “out there”; temperature changes occur “out there,” but
eventually activates spinal cord neurons to produce muscle the qualities of experience must be generated by structures
patterns for complex actions. in the brain. There are no external equivalents to stinging,
smarting, tickling, itch; the qualities are produced by built-in
The Body-Self Neuromatrix neuromodules whose neurosignatures innately produce the
qualities.
The body is felt as a unity with different qualities at different We do not learn to feel qualities of experience: our brains
times. Melzack11,12,14 proposed that the brain mechanism that are built to produce them. The inadequacy of the traditional
underlies the experience also comprises a unified system that peripheralist view becomes especially evident when we con-
acts as a whole and produces a neurosignature pattern of a sider paraplegics with high-level complete spinal breaks. In
whole body. The conceptualization of this unified brain spite of the absence of inputs from the body, virtually every
mechanism lies at the heart of the new theory, and the word quality of sensation and affect is experienced. It is known that
“neuromatrix” best characterizes it. The neuromatrix (not the the absence of input produces hyperactivity and abnormal
stimulus, peripheral nerves or “brain center”) is the origin of firing patterns in spinal cells above the level of the break.10
the neurosignature; the neurosignature originates and takes But how, from this jumble of activity, do we get the mean-
form in the neuromatrix. Although the neurosignature may be ingful experience of movement, the coordination of limbs
triggered or modulated by input, the input is only a “trigger” with other limbs, cramping pain in specific (nonexistent)
and does not produce the neurosignature itself. The neuro- muscle groups, and so on? This must occur in the brain, in
matrix “casts” its distinctive signature on all inputs (nerve which neurosignatures are produced by neuromatrixes that are
impulse patterns) which flow through it. The array of neurons triggered by the output of hyperactive cells.
in a neuromatrix is genetically programmed to perform the When all sensory systems are intact, inputs modulate the
specific function of producing the signature pattern. The final, continuous neuromatrix output to produce the wide variety
integrated neurosignature pattern for the body-self ultimately of experiences we feel. We may feel position, warmth, and
produces awareness and action. several kinds of pain and pressure all at once. It is a single
The neuromatrix, distributed throughout many areas of unitary feeling just as an orchestra produces a single unitary
the brain, comprises a widespread network of neurons that sound at any moment even though the sound comprises
generates patterns, processes information that flows through violins, cellos, horns, and so forth. Similarly, at a particular
it, and ultimately produces the pattern that is felt as a whole moment in time we feel complex qualities from all of the
body. The stream of neurosignature output with constantly body. In addition, our experience of the body includes visual H
Ch001-W0334.qxd 2/28/06 2:01 PM Page 6
images, affect, “knowledge” of the self (versus not-self) as qualities, affect, and meaning as a dangerous (or potentially
well as the meaning of body parts in terms of social norms dangerous) event to the body.
and values. It is hard to conceive of all of these bits and pieces Melzack11,12,14 proposed that after inputs from the body
coming together to produce a unitary body-self, but we can undergo transformation in the body-neuromatrix, the appro-
visualize a neuromatrix that impresses a characteristic signa- priate action patterns are activated concurrently (or nearly so)
ture on all the inputs that converge on it and thereby produces with the neuromatrix for experience. Thus, in the action-
the never-ending stream of feeling from the body. neuromatrix, cyclical processing and synthesis produces
The experience of the body-self involves multiple dimen- activation of several possible patterns and their successive
sions—sensory, affective, evaluative, postural and many elimination until one particular pattern emerges as the most
others. The sensory dimensions are subserved, in part at least, appropriate for the circumstances at the moment. In this way,
by portions of the neuromatrix that lie in the sensory projec- input and output are synthesized simultaneously, in parallel,
tion areas of the brain; the affective dimensions, Melzack not in series. This permits a smooth, continuous stream of
assumed, are subserved by areas in the brain stem and limbic action patterns.
system. Each major psychological dimension (or quality) of The command, which originates in the brain, to perform
experience, Melzack11,12,14 proposed, is subserved by a partic- a pattern such as running activates the neuromodule which
ular portion of the neuromatrix which contributes a distinct then produces firing in sequences of neurons that send precise
portion of the total neurosignature. To use a musical analogy messages through ventral horn neuron pools to appropriate
once again, it is like the strings, tympani, woodwinds, and sets of muscles. At the same time, the output patterns from
brasses of a symphony orchestra that each compose a part of the body-neuromatrix that engage the neuromodules for par-
the whole; each makes its unique contribution yet each is an ticular actions are also projected to the sentient neural hub and
integral part of a single symphony that varies continually from produce experience. In this way, the brain commands may
beginning to end. produce the experience of movement of phantom limbs even
The neuromatrix resembles Hebb’s “cell assembly” by though there are no limbs to move and no proprioceptive
being a widespread network of cells that subserves a particu- feedback. Indeed, reports by paraplegics of terrible fatigue
lar psychological function. Hebb15 conceived of the cell due to persistent bicycling movements16 and the painful
assembly as a network developed by gradual sensory learn- fatigue in a tightly clenched phantom fist in arm amputees17
ing, whereas Melzack, proposed that the structure of the indicate that feelings of effort and fatigue are produced by the
neuromatrix is predominantly determined by genetic factors, signature of a neuromodule rather than particular input pat-
although its eventual synaptic architecture is influenced by terns from muscles and joints.
sensory inputs. This emphasis on the genetic contribution to The phenomenon of phantom limbs has allowed us to
the brain does not diminish the importance of sensory inputs. examine some fundamental assumptions in psychology. One
The neuromatrix is a psychologically meaningful unit, devel- assumption is that sensations are produced only by stimuli and
oped by both heredity and learning, that represents an entire that perceptions in the absence of stimuli are psychologically
unified entity.11,12,14 abnormal. Yet phantom limbs, as well as phantom seeing,18
indicate this notion is wrong. The brain does more than detect
Action Patterns: The and analyze inputs; it generates perceptual experience even
Action-Neuromatrix when no external inputs occur.
Another entrenched assumption is that perception of
The output of the body neuromatrix, Melzack11,12,14 proposed one’s body results from sensory inputs that leave a memory
is directed at two systems: (1) the neuromatrix that produces in the brain; the total of these signals becomes the body
awareness of the output, and (2) a neuromatrix involved in image. But the existence of phantoms in people born without
overt action patterns. In this discussion, it is important to keep a limb or who have lost a limb at an early age suggests that
in mind that just as there is a steady stream of awareness, there the neural networks for perceiving the body and its parts are
is also a steady output of behavior (including movements built into the brain.11,12,19,20 The absence of inputs does not
during sleep). stop the networks from generating messages about missing
It is important to recognize that behavior occurs only body parts; they continue to produce such messages through-
after the input has been at least partially synthesized and rec- out life. In short, phantom limbs are a mystery only if we
ognized. For example, when we respond to the experience of assume the body sends sensory messages to a passively
pain or itch, it is evident that the experience has been syn- receiving brain. Phantoms become comprehensible once we
thesized by the body-self neuromatrix (or relevant neuro- recognize that the brain generates the experience of the body.
modules) sufficiently for the neuromatrix to have imparted the Sensory inputs merely modulate that experience; they do not
neurosignature patterns that underlie the quality of experi- directly cause it.
ence, affect, and meaning. Apart from a few reflexes (such as
withdrawal of a limb, eye-blink and so on), behavior occurs
only after inputs have been analyzed and synthesized suffi- ■ PAIN AND NEUROPLASTICITY
ciently to produce meaningful experience. When we reach for
an apple, the visual input has clearly been synthesized by a There was no place in the specificity concept of the nervous
neuromatrix so that it has 3-dimensional shape, color, and system for “plasticity,” in which neuronal and synaptic func-
meaning as an edible, desirable object, all of which are pro- tions are capable of being molded or shaped so that they influ-
duced by the brain and are not in the object “out there.” When ence subsequent perceptual experiences. Plasticity related
we respond to pain (by withdrawal or even by telephoning for to pain represents persistent functional changes, or “somatic
H an ambulance), we respond to an experience that has sensory memories,”21,22 produced in the nervous system by injuries or
Ch001-W0334.qxd 2/28/06 2:01 PM Page 7
other pathologic events. The recognition that such changes can represents.31 Nerve section also induces a reduction in the
occur is essential to understanding the chronic pain syndromes, inhibitory effect of A-fiber stimulation on activity in dorsal
such as low back pain and phantom limb pain, that persist and horn neurons.32 Nerve injury affects descending inhibitory
often destroy the lives of the people who suffer them. controls from brain stem nuclei. In the intact nervous system,
stimulation of the locus ceruleus33 or the nucleus raphe
Denervation Hypersensitivity and magnus34 produces an inhibition of dorsal horn neurons. Fol-
Neuronal Hyperactivity lowing dorsal rhizotomy, however, stimulation of these areas
produces excitation, rather than inhibition, in one half of the
Sensory disturbances associated with nerve injury have been cells studied.35
closely linked to alterations in CNS function. Markus and Recent advances in our understanding of the mechanisms
associates23 have demonstrated that the development of that underlie pathologic pain have important implications for
hypersensitivity in a rat’s hindpaw following sciatic nerve the treatment of both acute and chronic pain. Since it has been
section occurs concurrently with the expansion of the saphe- established that intense noxious stimulation produces a sensi-
nous nerve’s somatotopic projection in the spinal cord. Nerve tization of CNS neurons, it is possible to direct treatments not
injury may also lead to the development of increased neuronal only at the site of peripheral tissue damage, but also at the site
activity at various levels of the somatosensory system (see of central changes (see review by Coderre and Katz36). It may
review by Coderre and coworkers24). In addition to sponta- be possible in some instances to prevent the development
neous activity generated from the neuroma, peripheral neurec- of central sensitization which contributes to pathologic pain
tomy also leads to increased spontaneous activity in the dorsal states. The evidence that acute postoperative pain intensity
root ganglion, and spinal cord. Furthermore, after dorsal rhi- and/or the amount of pain medication patients require after
zotomy, there are increases in spontaneous neural activity surgery are reduced by preoperative administration of a
in the dorsal horn, the spinal trigeminal nucleus, and the variety of agents via the epidural37-39 or systemic route40-42 sug-
thalamus. gests that the surgically-induced afferent injury barrage arriv-
Clinical neurosurgery studies reveal a similar relationship ing within the CNS, and the central sensitization it induces,
between denervation and CNS hyperactivity. Neurons in the can be prevented or at least obtunded significantly (see review
somatosensory thalamus of patients with neuropathic pain by Katz43). The reduction in acute pain intensity associated
display high spontaneous firing rates, abnormal bursting with preoperative epidural anesthesia may even translate into
activity, and evoked responses to stimulation of body areas reduced pain44 and pain disability45 weeks after patients have
that normally do not activate these neurons.25,26 The site of left the hospital and returned home.
abnormality in thalamic function appears to be somatotopi- The fact that amputees are more likely to develop
cally related to the painful region. In patients with complete phantom limb pain if there is pain in the limb prior to ampu-
spinal cord transection and dysesthesias referred below the tation22 raises the possibility that the development of longer
level of the break, neuronal hyperactivity was observed in term neuropathic pain also can be prevented by reducing the
thalamic regions that had lost their normal sensory input, but potential for central sensitization at the time of amputation
not in regions with apparently normal afferent input.25 In (see Katz and Melzack46). Whether chronic postoperative
patients with neuropathic pain, electrical stimulation of sub- problems such as painful scars, post-thoracotomy chest-wall
thalamic, thalamic and capsular regions may evoke pain27 and pain, and phantom limb and stump pain can be reduced by
in some instances even reproduce the patient’s pain.28-30 Direct blocking perioperative nociceptive inputs awaits additional
electrical stimulation of spontaneously hyperactive cells well-controlled clinical trials (see Katz47). Furthermore,
evokes pain in some, but not all, pain patients—raising the research is required to determine whether multiple-treatment
possibility that in certain patients the observed changes in approaches (involving local and epidural anesthesia, as well
neuronal activity may contribute to the perception of pain.25 as pretreatment with opiates and anti-inflammatory drugs)
Studies of patients undergoing electrical brain stimulation which produce an effective blockade of afferent input, may
during brain surgery reveal that pain is rarely elicited by test also prevent or relieve other forms of severe chronic pain,
stimuli unless the patient suffers from a chronic pain problem. such as postherpetic neuralgia48 and reflex sympathetic dys-
However, brain stimulation can elicit pain responses in trophy. It is hoped that a combination of new pharmacologic
patients with chronic pain that does not involve extensive developments, careful clinical trials, and an increased under-
nerve injury or deafferentation. Lenz and colleagues29 standing of the contribution and mechanisms of noxious stim-
described the case of a woman with unstable angina who, ulus-induced neuroplasticity, will lead to improved clinical
during electrical stimulation of the thalamus, reported “heart treatment and prevention of pathologic pain.
pain like what I took nitroglycerin for” except that “it starts
and stops suddenly” (p. 121). The possibility that the patient’s
angina was due to myocardial strain, and not the activation of ■ PAIN AND PSYCHOPATHOLOGY
a somatosensory pain memory, was ruled out by demonstrat-
Pains that do not conform to present day anatomic and neuro-
ing that ECG, blood pressure, and cardiac enzymes remained
physiologic knowledge are often attributed to psychological
unchanged over the course of stimulation.
dysfunction.
It is possible that receptive field expansions and sponta-
neous activity generated in the CNS following peripheral There are many pains whose cause is not known. If a
nerve injury are, in part, mediated by alterations in normal diligent search has been made in the periphery and no
inhibitory processes in the dorsal horn. Within 4 days of a cause is found, we have seen that clinicians act as
peripheral nerve section there is a reduction in the dorsal though there was only one alternative. They blame
root potential, and therefore, in the presynaptic inhibition it faulty thinking, which for many classically-thinking H
Ch001-W0334.qxd 2/28/06 2:01 PM Page 8
doctors is the same thing as saying that there is no provider alike; it poisons the patient-provider relationship by
cause and even no disease. They ignore a century’s introducing an element of mutual distrust and implicit (and at
work on disorders of the spinal cord and brain stem times, explicit) blame. It is devastating to the patient who
and target the mind.…These are the doctors who repeat feels at fault, disbelieved, and alone.
again and again to a Second World War amputee in
pain that there is nothing wrong with him and that it is
all in his head.49, p 107 ■ CONCLUSION: THE MULTIPLE
DETERMINANTS OF PAIN
This view of the role of psychological generation in pain
persists to this day—notwithstanding evidence to the contrary. The neuromatrix theory of pain proposes that the neurosig-
Psychopathology has been proposed to underlie phantom nature for pain experience is determined by the synaptic archi-
limb pain,17 dyspareunia,50 orofacial pain,51 and a host of tecture of the neuromatrix, which is produced by genetic
others including pelvic pain, abdominal pain, chest pain, and and sensory influences. The neurosignature pattern is also
headache.52 However, the complexity of the pain transmission modulated by sensory inputs and by cognitive events, such as
circuitry described in the previous sections means that many psychological stress.61 Stressors, physical as well as psycho-
pains that defy our current understanding will ultimately be logical, act on stress-regulation systems, which may produce
explained without having to resort to a psychopathologic lesions of muscle, bone, and nerve tissue, thereby contribut-
etiology. Pain that is “nonanatomic” in distribution, spread of ing to the neurosignature patterns that give rise to chronic
pain to noninjured territory, pain that is said to be out of pro- pain. In short, the neuromatrix, as a result of homeostasis-
portion to the degree of injury, and pain in the absence of regulation patterns that have failed, may produce the destruc-
injury have all, at one time or another, been used as evidence tive conditions that give rise to many of the chronic pains that
to support the idea that psychological disturbance underlies so far have been resistant to treatments developed primarily
the pain. Yet each of these features of supposed psy- to manage pains that are triggered by sensory inputs. The
chopathology can now be explained by neurophysiologic stress-regulation system, with its complex, delicately bal-
mechanisms that involve an interplay between peripheral and anced interactions, is an integral part of the multiple contri-
central neural activity.3,51 butions that give rise to chronic pain.
Recent data linking the immune and central nervous The neuromatrix theory guides us away from the Carte-
systems have provided an explanation for another heretofore sian concept of pain as a sensation produced by injury or other
medically unexplained pain problem. Mirror-image pain or tissue pathology and toward the concept of pain as a multidi-
allochira has puzzled clinicians and basic scientists ever since mensional experience produced by multiple influences. These
it was first documented in the late 1800s.53 Injury to one side influences range from the existing synaptic architecture of the
of the body is experienced as pain at the site of injury as well neuromatrix to influences from within the body and from
as at the contralateral, mirror-image point.54,55 Recent animal other areas in the brain. Genetic influences on synaptic archi-
studies show that induction of a sciatic inflammatory neuritis tecture may determine—or predispose toward—the develop-
by perisciatic microinjection of immune system activators ment of chronic pain syndromes. Figure 1-3 summarizes the
results in both an ipsilateral hyperalgesia and hyperalgesia at factors that contribute to the output pattern from the neuro-
the mirror-image point on the opposite side in the territory of matrix that produce the sensory, affective, and cognitive
the contralateral healthy sciatic nerve.56 Moreover, both the dimensions of pain experience and the resultant behavior.
ipsilateral and contralateral hyperalgesia are prevented or Multiple inputs act on the neuromatrix programs and con-
reversed by intrathecal injection of a variety of proinflamma- tribute to the output neurosignature. They include (1) sensory
tory cytokine antagonists.57 inputs—cutaneous, visceral, and other somatic receptors; (2)
Mirror-image pain is likely not a unitary phenomenon visual and other sensory inputs that influence the cognitive
and other nonimmune mechanisms may also be involved.58 interpretation of the situation; (3) phasic and tonic cognitive
For example, recent human59 and animal evidence60 points to and emotional inputs from other areas of the brain; (4) intrin-
a potential combination of central and peripheral contribu- sic neural inhibitory modulation inherent in all brain function;
tions to mirror-image pain because nerve injury to one side of and (5) the activity of the body’s stress-regulation systems,
the body has been shown to result in a 50% reduction in the including cytokines as well as the endocrine, autonomic,
innervation of the territory of the same nerve on the opposite immune, and opioid systems. We have traveled a long way
side of the body in uninjured skin.60 Interestingly, documented from the psychophysical concept that seeks a simple one-to-
contralateral neurite loss can occur in the absence of con- one relationship between injury and pain. We now have a
tralateral pain or hyperalgesia, whereas pain intensity at the theoretical framework in which a genetically determined tem-
site of the injury correlates significantly with the extent of plate for the body-self is modulated by the powerful stress
contralateral neurite loss.59 This raises the intriguing possibil- system and the cognitive functions of the brain, in addition to
ity that the intensity of pain at the site of an injury may be the traditional sensory inputs.
facilitated by contralateral neurite loss induced by the ipsilat-
eral injury60—a situation that most clinicians would never References
have imagined possible.
Taken together, these novel mechanisms that explain 1. Kuhn TS: The structure of scientific revolutions, 2nd ed. Chicago, Uni-
some of the most puzzling pain symptoms must keep us versity of Chicago Press, 1970.
2. Melzack R, Wall PD: Pain mechanisms: A new theory. Science 150:971,
mindful that emotional distress and psychological disturbance 1965.
in our patients are not at the root of the pain. Attributing pain 3. Melzack R, Wall PD: The challenge of pain, 2nd ed. New York, Basic
H to a psychological disturbance is damaging to the patient and Books, 1996.
Ch001-W0334.qxd 2/28/06 2:01 PM Page 9
4. Goldscheider A: Uber den schmerzes in physiologischer and klinicher 36. Coderre TJ, Katz J: Peripheral and central hyperexcitability: Differential
hinsicht. Berlin, Hirchwald, 1894. signs and symptoms in persistent pain. Behav Brain Sci 20:404, 1997.
5. Livingston WK: Pain Mechanisms. New York, Macmillan, 1943. 37. Katz J, Cohen L, Schmid R, et al: Postoperative morphine use and hyper-
6. Noordenbos W: Pain. Amsterdam, Elsevier, 1959. algesia are reduced by preoperative but not intraoperative epidural anal-
7. Melzack R, Casey KL: Sensory, motivational, and central control deter- gesia: Implications for preemptive analgesia and the prevention of
minants of pain. In Kenshalo D (eds): The skin senses. Springfield, IL, central sensitization. Anesthesiology 98:1449, 2003.
Charles C Thomas, 1968, p 423. 38. Katz J, Clairoux M, Kavanagh BP, et al: Pre-emptive lumbar epidural
8. Melzack R: The McGill Pain Questionnaire: Major properties and anaesthesia reduces postoperative pain and patient-controlled morphine
scoring methods. Pain 1:277, 1975. consumption after lower abdominal surgery. Pain 59:395, 1994.
9. Melzack R: The short-form McGill Pain Questionnaire. Pain 30:191, 39. Katz J, Kavanagh BP, Sandler AN, et al: Preemptive analgesia: Clinical
1987. evidence of neuroplasticity contributing to post-operative pain. Anes-
10. Melzack R, Loeser JD: Phantom body pain in paraplegics: Evidence for thesiology 77:439, 1992.
a central “pattern generating mechanism” for pain. Pain 4:195, 1978. 40. Katz J, Clairoux M, Redahan C, et al: High dose alfentanil pre-empts
11. Melzack R: Phantom limbs and the concept of neuromatrix. Trends pain after abdominal hysterectomy. Pain 68:109, 1996.
Neurosci 13:88, 1990. 41. Katz J, Schmid R, Snijdelaar DG, et al: Pre-emptive analgesia using
12. Melzack R: Phantom limbs, the self, and the brain (The D.O. Hebb intravenous fentanyl plus low-dose ketamine for radical prostatectomy
memorial lecture). Can J Psychol 30:1, 1989. under general anesthesia does not produce short-term or long-term reduc-
13. Gybels JM, Tasker RR: Central neurosurgery. In Wall PD, Melzack R, tions in pain or analgesic use. Pain 110:707, 2004.
(eds): Textbook of pain. Edinburgh, Churchill Livingstone, 1999, p 1307. 42. Snijdelaar DG, Cornelisse HB, Schmid RL, et al: A randomised, con-
14. Melzack R: Pain and the neuromatrix in the brain. J Dent Educ 65:1378, trolled study of peri-operative low dose s(+)-ketamine in combination
2001. with postoperative patient-controlled s(+)-ketamine and morphine after
15. Hebb DO: The organization of behavior. New York, Wiley, 1949. radical prostatectomy. Anaesthesia 59:222, 2004.
16. Conomy JP: Disorders of body image after spinal cord injury. Neurol- 43. Katz J: Timing of treatment and pre-emptive analgesia. In Rowbotham
ogy 23:842, 1973. DJ, Macintyre PE, (eds): Acute pain. London, Arnold Ltd, 2003, p 113.
17. Katz J: Individual differences in the consciousness of phantom limbs. In 44. Gottschalk A, Smith DS, Jobes DR, et al: Preemptive epidural analgesia
Kunzendorf RG, Wallace B (eds): Individual differences in conscious and recovery from radical prostatectomy: A randomized controlled trial.
experience: First-person constraints on theories of consciousness, self- JAMA 279:1076, 1998.
consciousness, and subconsciousness. Amsterdam, John Benjamins, 45. Katz J, Cohen L: Preventive analgesia is associated with reduced pain
2000, p 45. disability three weeks but not six months after abdominal gynecological
18. Schultz G, Melzack R: The Charles Bonnet syndrome: “Phantom visual surgery by laparotomy. Anesthesiology 101:169, 2004.
images.” Perception 20:809, 1991. 46. Katz J, Melzack R: Phantom limb pain. In Grafman J, Robertson IH
19. Melzack R: Phantom limb pain and the brain. In Bromm B, Desmedt JE (eds): Handbook of Neuropsychology, 2nd ed. Oxford, Elsevier, 2003, p
(eds): Pain and the brain. New York, Raven, 1995, p 73. 205.
20. Melzack R, Israel R, Lacroix R, et al: Phantom limbs in people with con- 47. Katz J: Prevention of phantom limb pain by regional anaesthesia. Lancet
genital limb deficiency or amputation in early childhood. Brain 349:519, 1997.
120:1603, 1997. 48. Manabe H, Dan K, Hirata K, et al: Optimum pain relief with continuous
21. Salomons T, Osterman JE, Gagliese L, et al: Pain flashbacks in post- epidural infusion of local anesthestics shortens the duration of zoster-
traumatic stress disorder. Clin J Pain 20:83, 2004. associated pain. Clin J Pain 20:302, 2004.
22. Katz J, Melzack R: Pain “memories” in phantom limbs: Review and clin- 49. Wall PD: Pain: The Science of Suffering. London, Weidenfeld & Nicol-
ical observations. Pain 43:319, 1990. son, 1999.
23. Markus H, Pomeranz B, Krushelnyky D: Spread of saphenous somato- 50. Meana M, Binik YM: Painful coitus: A review of female dyspareunia. J
topic projection map in spinal cord and hypersensitivity of the foot after Nerv Ment Dis 182:264, 1994.
chronic sciatic denervation in adult rat. Brain Res 296:27, 1984. 51. Gagliese L, Katz J: Medically unexplained pain is not caused by psy-
24. Coderre TJ, Katz J, Vaccarino AL, et al: Contribution of central neuro- chopathology. Pain Res Manag 5:251, 2000.
plasticity to pathological pain: Review of clinical and experimental evi- 52. Stoudemire A, Sandhu J: Psychogenic/idiopathic pain syndromes. Gen
dence. Pain 52:259, 1993. Hosp Psychiat 9:79, 1987.
25. Lenz FA, Tasker RR, Dostrovsky JO, et al: Abnormal single-unit activ- 53. Basbaum AI: A new way to lose your nerve. Sci Aging Knowledge
ity recorded in the somatosensory thalamus of a quadriplegic patient with Environ 2004. 2004: pe15.
central pain. Pain 31:225, 1987. 54. Livingston WK: Pain and Suffering. Seattle, IASP Press, 1998.
26. Lenz FA, Kwan HC, Dostrovsky JO, et al: Characteristics of the burst- 55. Maleki J, LeBel AA, Bennett GJ, et al: Patterns of spread in complex
ing pattern of action potential that occurs in the thalamus of patients with regional pain syndrome, type I (reflex sympathetic dystrophy). Pain
central pain. Brain Res 496:357, 1989. 88:259, 2000.
27. Tasker RR: Stereotactic surgery. In Wall PD, Melzack R, (eds): The Text- 56. Chacur M, Milligan ED, Gazda LS, et al: A new model of sciatic inflam-
book of Pain. Edinburgh, Churchill Livingstone, 1989, p 840. matory neuritis (SIN): Induction of unilateral and bilateral mechanical
28. Nathan PW: Pain and nociception in the clinical context. Philos Trans R allodynia following acute unilateral peri-sciatic immune activation in
Soc Lond 308:219, 1985. rats. Pain 94:231, 2001.
29. Lenz FA, Gracely RH, Hope EJ, et al.: The sensation of angina can be 57. Milligan ED, Twining C, Chacur M, et al: Spinal glia and proinflamma-
evoked by stimulation of the human thalamus. Pain 59:119, 1994. tory cytokines mediate mirror-image neuropathic pain in rats. J Neurosci
30. Davis KD, Tasker RR, Kiss ZH, et al: Visceral pain evoked by thalamic 23:1026, 2003.
microstimulation in humans. Neuroreport 6:369, 1995. 58. Koltzenburg M, Wall PD, McMahon SB: Does the right side know what
31. Wall PD, Devor M: The effect of peripheral nerve injury on dorsal root the left is doing? Trends Neurosci 22:122, 1999.
potentials and on transmission of afferent signals into the spinal cord. 59. Oaklander AL, Romans K, Horasek S, et al: Unilateral postherpetic neu-
Brain Res 209:95, 1981. ralgia is associated with bilateral sensory neuron damage. Ann Neurol
32. Woolf CJ, Wall PD: Chronic peripheral nerve section diminishes the 44:789, 1998.
primary afferent A-fibre mediated inhibition of rat dorsal horn neurones. 60. Oaklander AL, Brown JM: Unilateral nerve injury produces bilateral loss
Brain Res 242:77, 1982. of distal innervation. Ann Neurol 55:639, 2004.
33. Segal M, Sandberg D: Analgesia produced by electrical stimulation of 61. Melzack R: From the gate to the neuromatrix. Pain Suppl 6:S121, 1999.
catecholamine nuclei in the rat brain. Brain Res 123:369, 1977. 62. Melzack R: The gate control theory 25 years later: New perspectives on 2
34. Oliveras JL, Guilbaud G, Besson JM: A map of serotoninergic structures phantom limb pain. In Bond MR, Charlton JE, Woolf CJ (eds): Pain
involved in stimulation producing analgesia in unrestrained freely Research and Therapy: Proceedings of the Sixth World Congress on Pain.
moving cats. Brain Res 164:317, 1979. Amsterdam, Elsevier, 1991, p 9.
35. Hodge CJ, Jr., Apkarian AV, Owen MP, et al: Changes in the effects of
stimulation of locus coeruleus and nucleus raphe magnus following
dorsal rhizotomy. Brain Res 288:325, 1983.
H
Au form (WAL1) 2/28/06 2:01 PM Page 1
Dear Author
During the preparation of your manuscript for publication, the questions listed below have arisen. Please attend to these
matters and return this form with your proof.
Many thanks for your assistance.
Query
References Query Remarks
WAL1