Current Pain and Headache Reports (2018) 22:26

https://doi.org/10.1007/s11916-018-0680-x

OTHER PAIN (A KAYE AND N VADIVELU, SECTION EDITORS)

Spinal Cord Stimulation, MILD Procedure, and Regenerative Medicine,

Novel Interventional Nonopioid Therapies in Chronic Pain
Ken P. Ehrhardt Jr 1 & Susan M. Mothersele 1 & Andrew J. Brunk 1 & Jeremy B. Green 1 & Mark R. Jones 2 & Craig B. Billeaud 1 &
Alan David Kaye 1,3

# Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract
Purpose of Review Chronic pain is a highly prevalent condition affecting millions of individuals.
Recent Findings In recent years, newer treatments have emerged that are changing the way clinicians treat pain pathogenesis,
including novel nonopioid strategies. In this regard, spinal cord stimulation, the MILD procedure, and regenerative medicine
have shown promise. This review summarizes recent literature on these three emerging treatment strategies.
Summary The results of this review suggest that under certain conditions, spinal cord stimulation, the MILD procedure, and
regenerative medicine can be effective treatment modalities.

Keywords Spinal cord stimulation . MILD procedure . Regenerative medicine . Pain . Ligamentum flavum hypertrophy . Lumbar
stenosis

Introduction
Spinal cord stimulation is a therapy that blocks nerves causing
pain and discomfort by stimulating larger nerves directly in
the spinal cord. By placing electrodes into the epidural space
either percutaneous or surgically, spinal cord stimulation has
proven to be a minimally invasive method of treating other-
wise chronic debilitating pain. Since 1967, its use has helped
treat painful conditions that otherwise caused decreased func-
tion and livelihood in patients [1].
According to the 1965 “gate control” theory of Melzack
and Wall, spinal cord stimulation was thought to relieve pain
by stimulating large myelinated nerve fibers such as the dorsal
This article is part of the Topical Collection on Other Pain
* Alan David Kaye
alankaye44@hotmail.com
1
Department of Anesthesiology and Pain Medicine, LSU Health
Science Center, Louisiana State University School of Medicine, 1542
Tulane Avenue, Room 659, New Orleans, LA, USA
2
Beth Israel Deaconess Medical Center, Department of
Anesthesiology, Critical Care and Pain Medicine, Harvard Medical
School, Boston, MA, USA
3
Department of Pharmacology, LSU School of Medicine, New
Orleans, LA, USA
columns which in turn would block or gate off the painful
small unmyelinated nerve fibers leading to pain reduction
[2]. While this in part may be true, we have come to learn that
the spinal cord stimulation pain relieving mechanism is more
complex. It is thought to work by the reduction of wide dy-
namic range neurons at the dorsal horn as well as diminishing
GABAergic interneurons [3].
A spinal cord stimulator can only be chosen for patients
with chronic pain that suffer from specific pathologic condi-
tions. The patient must have been unsuccessful in all other
conservative measures such as physical therapy, non-
steroidal medications, and other non-invasive measures.
Spinal cord stimulation has only been proven to be effective
in certain disease states such as complex regional pain syn-
drome (CRPS). CRPS is a neuropathic syndrome causing au-
tonomic dysfunction, edema, pain out of proportion to initial
injury, and changes in skin color. Spinal cord stimulation has
been shown to decrease pain and increase functionality in
patients suffering with CRPS. It has been shown to improve
function in affected limbs of patients and is suggested as an
early treatment if conservative treatments fail to resolve CRPS
[1]. Another condition that is effective with spinal cord stim-
ulation treatment is failed back surgery syndrome (FBSS) or
post-laminectomy syndrome. FBSS is a state of lower back
and sometimes leg pain that has not been relieved by surgery
and in some cases pain worsened by surgery [4]. When
26 Page 2 of 7
conservative measures have failed patients suffering from
FBSS, spinal cord stimulation has proven to be effective.
Evidence has shown long-term opioid use as well as repeat
surgery to be ineffective treatments for these patients. Spinal
cord stimulation helps patients suffering from FBSS regain
functionality and acquire pain relief [4]. Spinal cord stimula-
tors have been shown to be effective in treating other pain
conditions such as peripheral artery disease, intractable angi-
na, and diabetic neuropathy.
Ever since the first spinal cord stimulator was developed in
1967, new and more effective spinal cord stimulators have been
produced based off of innovative technology. Spinal cord stim-
ulators are made up of an implantable pulse generator that is
battery operated along with a stimulation lead. Implantable im-
pulse generators can be controlled by changing the frequency,
width, and amplitude of the electrical impulse to provide a
maximal decrease in pain. Before a spinal cord stimulator is
permanently placed, a trial is performed on the patient to see
what settings provide the patient with maximal benefits of pain
relief. Temporary leads are placed during the trial and then
removed and the spinal cord stimulator is normally placed per-
manently at a later time using the information gained from the
trial [5]. Traditional spinal cord stimulators have involved low-
frequency stimulation, which had side effects such as paresthe-
sias and tolerance of stimulation. Newer high-frequency stim-
ulators have recently shown promising evidence to spare pa-
tients from these traditional side effects [4].
Numerous rare complications can arise from spinal cord
stimulators and prior to placing one, a recent MRI of the spine
is required to ensure safe placement. Every provider should be
familiar with potential placement obstacles, minimize the like-
lihood of these complications, and identify and treat them
immediately when they include serious complications such
as paralysis or infection. One of the more common complica-
tions is lead migration. Lead migration is not a life-threatening
or fatal complication, but it is the most likely a reason for a
patient to not receive pain relief in the long term from a spinal
cord stimulator [5]. Stimulators placed percutaneously have a
higher risk of becoming misplaced compared to placement by
laminectomy. Lead migration is detected normally by either
the patient abruptly receiving appropriate pain relief or the
patient feeling stimulation across a different dermatome.
Lead breakage is rare at about 9.1% seen in one literature
review and is most commonly seen in patients with active
lifestyles that perform motions that require frequent spinal
movements [5]. Infection is a rare but possibly serious com-
plication of spinal cord stimulator implantation. Cameron
et al.’s review found infection occurring in 3.4% of about
3000 patients [5]. Infections can be both prevented and treated
with appropriate antibiotics. Physicians should have a low
threshold to remove hardware if they have a suspicion that it
is infected [6]. The most life-threatening complication is a
spinal epidural hematoma. This problem is very rare and more
Curr Pain Headache Rep (2018) 22:26
likely in patients with bleeding or coagulation disorders.
Much caution should be placed when placing a spinal cord
stimulator in patients on anticoagulants or antiplatelets as they
are at increased risk for spinal epidural hematomas [7].
Neurologic deficits in a patient’s lower extremities or new-
onset lower back pain may be the first sign of this complica-
tion either hours, days, or weeks after spinal cord stimulator
placement [7].
Spinal cord stimulators are a minimally invasive treatment
for patients with chronic pain and have proven to be an effec-
tive treatment for multiple types of chronic pain syndromes.
After a successful trial is completed, a permanent spinal cord
stimulator can be placed to treat the patient’s pain in the long
term.
In summary, spinal cord stimulation initially consisted of
monopolar leads connected to external generators to create an
electric field around the spinal cord for the treatment of chron-
ic pain. Currently, technology has allowed us to have expan-
sion to fully implanted rechargeable batteries and leads have
progressed from monopolar plates to multiple leads with mul-
tiple contacts allowing for up to 32 contacts. Further, each
contact has individual power sources to maximize precise
targeting of pain.
Although there have been many advances in the technolo-
gy, relatively little has changed with the stimulation parame-
ters until recently. In general, conventional spinal cord stimu-
lation characteristics include frequency of stimulation ranging
from 40 to 120 Hz, pulse duration from 0.1–0.3 ms, and cur-
rent applied at 60–80% of motor threshold which varies per
patient. Patients vary significantly in what parameters of stim-
ulation they prefer and resultant perceived paresthesia tolerat-
ed to achieve maximal analgesia. The parameters determine
energy usage by the battery and allow for estimation when a
battery will need recharging. Recharging is currently done by
using an external radiofrequency unit to charge the implant-
able pulse generator.
The field of spinal cord stimulation has expanded from stim-
ulating only the spinal cord to also being applied to regions of
the brain, now called deep brain stimulation, as well as periph-
eral nerve stimulation being applied to more peripheral struc-
tures like the dorsal root ganglia. New and innovative types of
spinal cord stimulators are being trialed and placed in patients
on a regular basis. The future of spinal cord stimulators appears
to be very promising for many debilitating pain states.
MILD Procedure: A Review of Current
Literature
Background
Lumbar spinal stenosis, narrowing of the spinal canal, is a
significant contributor to chronic pain. Found in over 19%
Curr Pain Headache Rep (2018) 22:26
of sexagenarians, it is associated with a threefold increase in
low back pain [8]. Treatment options include physical therapy,
analgesic medications, epidural steroid injections, and surgical
interventions. Laminectomy has been performed for over a
century with proven efficacy; however, it is not without draw-
backs that accompany a more extensive surgical procedure.
The MILD procedure is a relatively new, minimally invasive
option for decompression of spinal stenosis.
The MILD Procedure: An Overview
The procedure has previously been described in detail by Deer
and Kapural. The patient is positioned prone, and with the
guidance of epidurography and fluoroscopy, the interlaminar
space is accessed via a six-gauge port. The superior and infe-
rior laminas are sculpted to allow a specialized instrument
adequate space to perform resection of the hypertrophic
ligamentum flavum. Decompression is confirmed by re-
imaging [9••].
The procedure offers decompression that can only be ob-
tained through surgical intervention, while minimizing tissue
trauma associated with traditional laminectomy. Furthermore,
the procedure is normally performed using sedation and local
anesthesia, eliminating some of the risks that accompany gen-
eral anesthesia.
Early Experiences
Numerous early studies showed MILD to be an effective treat-
ment option for patient with lumbar spinal stenosis. These
early studies used one or more of the following outcome mea-
sures: visual analog score (VAS), Oswestry Disability Index
(ODI), and Zurich Claudication Questionnaire (ZCQ). Some
studies incorporated other measures as well.
In 2011, a meta-analysis of four clinical patient series found
3-month improvement in VAS and ODI scores of 3.5 points
and 17.1 points, respectively. The authors of this study also
compared MILD to epidural steroid injection (ESI) therapy,
showing similar efficacy at 3 months [10]. Subsequently, Basu
published a prospective study showing reduction in pain at
6 months post-procedure when compared to pre-procedure
status, with statistically significant VAS improvement of 5.2,
and ODI improvement of 24 [11]. A separate prospective
study showed VAS improvement of 2.9 and ODI improve-
ment of 11.9 at 12 months following MILD [12]. Published
in 2013, Chopko describes persistent statistically significant
improvement in pain and function per VAS, ODI, and ZCQ in
this cohort at 2 years [13]. A review of the MILD procedure
literature published through May 2013 acknowledged the con-
sistent statistically significant improvement in pain and func-
tion but rated the overall body of literature as low quality [14].
More recent publications allow us a better understanding of
the value of MILD.
Page 3 of 7 26
Recent Reports
The MiDAS ENCORE trial is a prospective multicenter, ran-
domized, controlled clinical trial (RCT) of patients with neu-
rogenic claudication and ligamentum flavum hypertrophy at
26 interventional pain management centers across the USA.
This large RCT raises the quality of evidence available for
assessment of the MILD procedure. In 2016, 6-month results
were published. The authors identified a statistically signifi-
cant symptomatic improvement in patients undergoing MILD
when compared to epidural steroid injection (ESI). They also
found no difference in the safety profile of the two treatment
options [15]. A subsequent report from the MiDAS ENCORE
trial published in 2016 supported the initial findings, with
statistically significant improvements in pain at 1-year post-
procedure [16]. Furthermore, at 1 year, patients who
underwent MILD had significantly improved functionality
as measured by ODI and ZCQ Physical function. Two patients
from the MILD arm experienced adverse events, including a
non-serious procedural hemorrhage; however, the safety pro-
file was similar to that of the comparison ESI group.
Outcomes for the MILD group at later post-procedure times
will be reported and will allow an analysis of the durability of
positive early reports.
Whereas the MiDAS ENCORE trial contributes a well-
designed RCT to the literature, an article by Giannadakis
et al. seeks to evaluate MILD with greater applicability to
the population as a whole undergoing the procedure. This
prospective study using data from the Norwegian Spine
Registry limited exclusion criteria to patients undergoing
discectomy and those with certain associated spinal conditions
and used diagnosis of central lumbar spinal stenosis, undergo-
ing one or two level microsurgical decompression and inclu-
sion in the registry as the only inclusion criteria. Mean ODI
score improvement for the population was a statistically sig-
nificant 16.9 points [17].
While the current literature seems to paint an overall favor-
able picture of the MILD procedure, there are certain circum-
stances in which MILD may not be the optimal treatment. One
study compared MILD to another approach less invasive than
traditional laminectomy, unilateral laminectomy for bilateral
decompression (ULBD). Use of the VAS and Japanese
Orthopedic Association scoring system identified a favorable
response following MILD at 2 years, and the results were
comparable to ULBD. The subgroup of patients undergoing
multilevel decompression, however, had better pain and func-
tional responses to ULBD than to MILD [18].
In addition to studies evaluating clinical outcomes, the
MILD procedure has been studied from a radiologic perspec-
tive. A 2017 study showed that signs of paravertebral muscle
inflammation and edema were evident on MRI at 3 months
post-procedure; however, at 12–18 months, those findings had
returned to their pre-procedure levels. Furthermore, the
26 Page 4 of 7
authors found the rate of paravertebral muscle atrophy to be
only 4% versus the 4–23.9% comparison rate they cite for
alternative surgical approaches. Two seemingly reasonable
explanations offered by the authors are that MILD procedure
causes less trauma to paravertebral muscles and allows sooner
return to rehabilitation and exercise, minimizing damage and
subsequent atrophy [19].
An important aspect of any medical treatment is cost-effec-
tiveness. Given there are numerous approaches to treating
lumbar spinal stenosis, a very common condition, it follows
that cost-effectiveness should play some role in selecting the
proper treatment given the heavily burdened nature of our
healthcare system. One study compared the cost-
effectiveness of laminectomy, MILD, and epidural steroid in-
jections at 2 years post-procedure. The cost per quality-
adjusted life year (QALY) suggested that MILD is the most
cost-effective option. While clearly ESI is a less costly proce-
dure than MILD, this study assumed that ESI did not have as
positive an effect on QALY and pointed out that most patients
with severe lumbar spinal stenosis require multiple rounds of
ESI [20].
To summarize, recent publications have bettered our under-
standing of the role of the MILD procedure in treating patients
with lumbar spinal stenosis. As with any relatively new treat-
ment, further research is needed. Additional randomized con-
trolled trials comparing MILD to alternative treatments will
bolster the quality of evidence and further inform clinicians.
Reports of patient outcomes at greater post-procedure time
points will also help in valuation of the MILD procedure.
Regenerative Medicine
Regenerative medicine is a term used for innovative tech-
niques used in the management of chronic pain that aim at
allowing the body to repair, to replace, to restore, and to re-
generate damaged or diseased cells, tissues, or organs. Various
substances have been used in regenerative medicine, includ-
ing stem cells, platelet-rich plasma, and amniotic fluid.
Regenerative medicine has implications in treating joint pain,
disc and other spinal structural disease, and ligamentous inju-
ry. Pharmacologic treatments of chronic and neuropathic pain
have varying results and also result in tolerance with long-
term use. Regenerative medicine serves as a potential pain
reliever and disease modifier which could be used as an ad-
junct to current management of pain.
Stem cells are cells that have the capacity to divide both
symmetrically, increasing their numbers, and asymmetrically
to differentiated progeny that can self-renew. This ability al-
lows the cells to have many potential uses in the treatment of
chronic pain and other chronic diseases. Transplantation of
stem cells has been shown to slow or even block disease and
have shown promise in the treatment of a variety of nervous
system injuries [21••]. There are multiple types of stem cells
Curr Pain Headache Rep (2018) 22:26
including germ cells, embryonic stem cells, mesenchymal
stem cells, and induced pluripotent stem cells [22]. Germ cells
are the most primitive stem cells. They are pluripotent and can
give rise to identical cells while also producing differentiated
cell lines. Embryonic stem cells are derived from the fetus.
These cells are also pluripotent and can differentiate into any
cell line. They are derived from an aborted human embryo or
left over from in vitro fertilization. They also contain different
DNA than the host which can lead to formation of teratomas
or the risk of transplant rejection. Related to their source,
embryonic stem cells have been morally and ethically contro-
versial. Induced pluripotent stem cells are derived from non-
pluripotent somatic cells such as dermal fibroblasts, which are
then transformed and genetically engineered into a pluripotent
state.
Mesenchymal stem cells are derived from adult bone mar-
row aspirate, adipose tissue, amnion, cord blood/placenta,
periosteum, synovial membrane, or dental pulp. These stem
cells have not generated controversy in that patients can use
their own supply of stem cells for treatment and therapy, and
the supply is potentially limitless. Bone marrow or adipose
tissue can be aspirated and then mesenchymal stem cells can
be isolated and transplanted to the area in need.
Each of these stem cell lines may provide potential thera-
pies for chronic pain. Estimates by the WHO indicate that as
many as 116 million people in the USA in 2011 suffered with
chronic pain [23]. This number is estimated to have grown
over the years and does not include those suffering with acute
pain or children. In a recent study, mesenchymal stem cells
were found to reduce opioid tolerance and opioid-induced
hyperalgesia caused by daily morphine injections in rats
[24]. The researchers also found that opioid tolerance was
reversed with the use of stem cells. This could prove to be
an effective way to help treat chronic pain and combat the
growing opioid epidemic. In a study looking at the use of stem
cells in nervous system injury, marrow transplantation was
performed in rats with chronic constriction of their sciatic
nerve. Comparing this to rats who did not receive transplan-
tation, they found shorter latency periods to withdrawal indic-
ative of continuing pain in the control group [25].
Stem cell implantation has shown promise in improvement
after spinal cord injury as they have the ability to incorporate
and differentiate to improve locomotor recovery [26]. Stem
cells transplanted following spinal cord injury have been shown
to improve functional recovery and decrease allodynia by dif-
ferentiating into oligodendrocytes [27]. Hyperexcitability from
spinal cord injury has been reduced by the use of serotonergic
neural precursor cell grafts [28]. In this way, stem cell trans-
plantation has shown to have many potential benefits in the
treatment of chronic pain and neuropathic pain. The effect of
stem cells on pain modulation and relief may be related to their
ability to symptomatically control pain as well as modify dis-
ease progression [21••]. Research is still lacking and clinical
Curr Pain Headache Rep (2018) 22:26
considerations need to be addressed in order to begin to imple-
ment stem cell therapy successfully. Some considerations in-
clude classification of cells, their efficacy and potency, their
mode of administration, their dosage and their source, together
with the final goal of the analysis, and the tracking of the stem
cell [29].
Novel Interventional Nonopioid Therapies:
Platelet-Rich Plasma
Platelet-rich plasma (PRP) is another treatment rapidly
gaining interest in the field of regenerative medicine.
Originally used in the 1950s in dermatology and oral maxil-
lofacial surgery, the use of PRPs has grown exponentially,
particularly in the fields of sports medicine and orthopedics,
as clinicians attempt to find novel therapies that are both effi-
cacious and safe [30••].
What Is PRP
Fundamentally, PRP is a concentrate of proteins derived from
autologous blood that is rich in growth factors and cytokines
that are involved in wound healing and tissue repair [31–34].
The process of obtaining PRP involves multiple rounds of
centrifugation of a patient’s whole blood. The first round of
centrifugation yields two layers in which the plasma and plate-
lets are separated from the reticulocytes and leukocytes. An
additional round of centrifugation will yield platelet-rich and
platelet-poor plasma fractions [35, 36]. Although there exists
some variation and heterogeneity among differing PRP sys-
tems, PRP can be expected to contain a platelet concentration
of up to five times greater than normal physiologic platelet
concentrations (150,000–450,000 per microliter) [37].
Current Uses of PRP
Despite a paucity of randomized, double-blind clinical studies
confirming the efficacy of PRP, its use continues to expand,
particularly in the realm of musculoskeletal related injuries,
with many non-randomized studies and case reports suggest-
ing beneficial effects in regard to pain and healing [38–41].
Most commonly, PRP is used in the treatment of chronic ten-
dinitis, osteoarthritis, and plastic surgery, with increasing re-
search focusing on the potential benefits in the treatment of
chronic neuropathic pain.
Clinical Validity of PRP
Multiple studies have shown promise in regard to the use of
PRP in osteoarthritis as compared to controls and convention-
al treatments. One prospective, double-blind, randomized
control trial showed better outcomes at 24 weeks in the PRP
group as compared to those receiving an injection of
Page 5 of 7 26
hyaluronic acid (HA) [42]. Two similar studies showed sig-
nificant clinical improvement in the PRP groups at 6 months
vs saline control [43], and at 1 year, although the latter was not
a significant difference compared to the HA group [44]. A
2015 meta-analysis identified 9 acceptable studies out of over
500 studies on the use of PRP in the osteoarthritic knee.
Improved functional outcomes were shown over the short
term (<1 year) as compared to placebo and HA, with no sta-
tistically significant difference in adverse events [45]. While
there are multiple studies that suggest a benefit in the use of
PRP injections for OA, continued research is needed to quan-
tify the long-term benefits in the setting of arthritis.
The use of PRP is also popular in the treatment of chronic
tendinopathies, most notably lateral epicondylitis (Tennis
Elbow), patellar tendinitis, and Achilles tendinopathy. A
double-blinded RCT with over 100 patients showed statisti-
cally and clinically significant improvements in quality of life
pain scores in the PRP injection group as compared to the
conventional treatment of corticosteroid injections [46]. Two
limited studies looking at the use of PRP in chronic patellar
tendinitis showed significant improvement in activity level
[47] and in pain [48] in the injection group as compared to
physiotherapy only group. Conflicting data does exist in re-
gard to the use of PRP for chronic tendinopathy. A 2010
randomized, double-blind, placebo-controlled study pub-
lished in JAMA studying the treatment of chronic Achilles
tendinopathy showed no significant improvement in the PRP
injection group as compared to the saline control [49].
PRP in Chronic Pain
While a majority of the studies on PRP involve the treatment
of musculoskeletal disease, there is growing interest in the
potential for treatment of neuropathic pain. Multiple promis-
ing animal studies have shown the potential for axonal regen-
eration in the presence of PRP and neural-induced human
mesenchymal stem cells [50–53]. A small clinical study per-
formed on humans with previous nerve damage showed ex-
tensive axonal regeneration and a significant reduction in
chronic pain after treatment with PRP [54].
One of the most common sources of chronic pain, low back
pain secondary to intervertebral disk degeneration, is also be-
ing treated with PRP injections. A recent meta-analysis of 11
animal studies found significant differences in the PRP treat-
ment group, with increased disc height, improved MRI sig-
naling, and decreased degeneration in the PRP group [55].
Several in vivo studies echoed similar results, with increased
disc height, nucleus pulposus regeneration [56] and increased
accumulation of type II collagen [57] after injections of PRP.
In contrast to corticosteroid injections which provide only
short-term symptomatic relief, PRP injections are targeted at
potentially reversing the underlying pathophysiology of
discogenic back pain.
26 Page 6 of 7
Future Direction
Interest in PRP as a treatment modality for musculoskeletal
disease and chronic pain has never been higher, with over 80
active or upcoming studies on clinicaltrials.gov involving
treatment with PRP. Future studies will need to continue to
evaluate the efficacy and safety of PRP as compared to
conventional treatments, as well as identify optimal dosing,
as well as optimal preparation of platelet-rich plasma.
Compliance with Ethical Standards
Conflict of Interest Ken P. Ehrhardt Jr., Susan M. Mothersele, Andrew J.
Brunk, Jeremy B. Green, Mark R. Jones, Craig B. Billeaud, and Alan
David Kaye declare no conflict of interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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Papers of particular interest, published recently, have been
highlighted as:
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