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Advances in treatment of complex regional pain syndrome:
recent insights on a perplexing disease
Amit Sharmaa, Kayode Williamsb and Srinivasa N. Rajab
Purpose of review
The paper is a critical appraisal of recent advances in the
treatment of complex regional pain syndrome. Rapidly
changing concepts related to the pathophysiology of this
disease has transformed its current management and
necessitates an updated review of the literature.
Recent findings
Chronic regional pain syndrome is a perplexing disease
that continues to challenge researchers with respect to its
cause and treatment. Recent modification to diagnostic
criteria has enabled clinicians to diagnose this disease in a
more consistent fashion. Emerging data indicate a possible
role of inflammation in the overall pathophysiology and have
led to treatment trials with newer anti-inflammatory
medications. Certain ‘conventional’ interventional
techniques have been recently scrutinized. A few novel
therapeutic options like graded imagery are also outlined.
Summary
Enhanced insight into the pathophysiology of chronic
regional pain syndrome has modified current clinical
practice and the focus of research. Certain ‘standard’
therapeutic options for chronic regional pain syndrome have
failed the test of time while others have prevailed. New
options have recently been evaluated and have shown
promising early results. Knowledge of recent advances in
chronic regional pain syndrome will help pain physicians
provide optimal care to these patients.
Keywords
complex regional pain syndrome, neuropathic pain, reflex
sympathetic dystrophy, shoulder–hand syndrome,
treatment advances
Abbreviations
CRPS
IRSB
LASB
SCS
complex regional pain syndrome
intravenous regional sympathetic blockade
local anesthetic sympathetic blockade
spinal cord stimulation
ß 2006 Lippincott Williams & Wilkins
0952-7907
Introduction
Complex regional pain syndrome (CRPS) has been
extensively studied over the past few decades and significant insight has been gained into its pathophysiology.
More precise diagnostic criteria with improved sensitivity
and specificity have also been proposed [1]. These dynamic
changes have introduced a new era of clinical research in
CRPS. This review provides the reader with a concise
update on the treatment of CRPS, highlighting recent
reports. Available treatment options can be discussed in
three broad categories: pharmacotherapy, interventional
techniques, and miscellaneous therapeutic options.
Pharmacotherapy
Innumerable drugs have been tried in CRPS and many
are still being investigated. There is a paucity of controlled studies investigating the efficacy of drugs in CRPS
patients prior to 1996. This might stem, in part, from the
fact that clear diagnostic criteria were proposed by the
International Association for Study of Pain only in 1994.
Moreover, the sensitivity and specificity of the initial
criteria have been questioned [2].
Anti-inflammatory drugs
Curr Opin Anaesthesiol 19:566–572. ß 2006 Lippincott Williams & Wilkins.
a
Division of Pain Medicine, Department of Anesthesiology, College of Physicians
and Surgeons of Columbia University, New York, New York and bDivision of Pain
Medicine, Department of Anesthesiology and Critical Care, The Johns Hopkins
University, Baltimore, Maryland, USA
Correspondence to Amit Sharma, MD, Assistant Professor, Division of Pain
Medicine, Department of Anesthesiology, College of Physicians and Surgeons of
Columbia University, 622 West 168th Street, PH 5, Room 500, New York,
NY 10032, USA
Tel: +212 305 7812; fax: +212 305 8883; e-mail: [email protected]
Current Opinion in Anaesthesiology 2006, 19:566–572
Historically, CRPS has been considered as an epitome of
neuropathic pain. Certain features characterizing the
acute phase of the disease, such as swelling, erythema,
and warmth, point towards an inflammatory cause [3].
Numerous clinical and experimental investigations add
to the growing consensus that CRPS may have an inflammatory cause, at least during its acute phase [4]. The
clinical picture of CRPS may represent an exaggerated
local inflammatory response (medicated via cytokines
such as interleukins, free oxygen radicals, and tumor
necrosis factor-a) [5–7] as well as ‘neurogenic inflammation’ (mediated via neuropeptides such as calcitonin
gene-related peptide or substance P) [7–10]. It is not
surprising, therefore, that symptomatic improvement
is seen in patients with CRPS after treatment with
nonsteroidal anti-inflammatory drugs [11], corticosteroids
566
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Complex regional pain syndrome Sharma et al. 567
[12,13], free radical scavengers, [6,14,15] and anti-tumor
necrosis factor agents [16].
The efficacy of free radical scavengers such as topical
50% dimethylsulfoxide (DMSO) and N-acetylcysteine
(NAC) has been shown in a large multicenter, doubleblind trial [15], in which 146 patients were randomly
treated with either 50% topical DMSO cream five times a
day or given 600-mg NAC tablets three times a day for
17 weeks. Both therapies were generally equally effective
in the treatment of CRPS type I.
Neuropathic drugs
Neuropathic medications are commonly used for treating
patients with CRPS. Most clinical trials reporting the
efficacy of these medications in neuropathic pain have
been conducted on patients with painful diabetic neuropathy and postherpetic neuralgia. These results have
been extrapolated to patients with CRPS. In a recent
evidence-based review, Beniczky et al. [17] opined that
the classification of neuropathic pain medications based
on their original therapeutic class is misleading. For
instance, medications such as gabapentin, carbamazepine, and pregabalin are categorized as ‘antiepileptic
drugs’, possibly giving a false impression that these drugs
are effective for all neuropathic pain states, which is
clearly not the case. The authors propose four distinct
etiologic groups for therapeutic management: peripheral
neuropathic pain, CRPS, trigeminal neuralgia, and
central neuropathic pain. Furthermore, most ‘standard’
neuropathic pain medications are discussed under the
umbrella of ‘peripheral neuropathic pain’. CRPS is,
indeed, more complex than merely a peripheral neuropathic pain state, but a lack of evidence for conventional
neuropathic medications (such as tricyclic antidepressants) should not be accepted as lack of efficacy. In the
past, researchers avoided inclusion of patients with CRPS
in the efficacy trials of neuropathic medication due to the
lack of precise ‘diagnostic’ criteria for this disease. Other
authors have acknowledged the importance of these
medications in clinical practice [18].
The neuropathic pain medications that are commonly
used in the treatment of patients with CRPS include
tricyclic antidepressants, antiseizure medications such
as gabapentin and pregabalin, centrally acting medications
such as tramadol, opioids, and topical local anesthetics such
as lidocaine or clonidine. With the acceptance of the
revised diagnostic criteria [1] for CRPS, additional studies
need to be conducted to examine the usefulness of these
individual drugs for patients with CRPS.
Calcitonin
Calcitonin is a hormone secreted by the parafollicular cells
of the thyroid gland. It acts on bone and kidneys causing
inhibition of osteoclastic bone resorption that results in
reduction in serum calcium and phosphates. Thus, it has
been introduced as a useful therapeutic agent in the
treatment of Paget’s disease, hypercalcemia, and osteoporosis. The antinociceptive effects of calcitonin have not
been clearly elucidated. Numerous explanations have
been proposed including serotoninergic and catecholaminergic mechanisms, Ca2þ fluxes, protein phosphorylation,
endorphin production, cyclooxygenase inhibition [19,20],
and possibly actions on opioid receptors [21].
Since salmon calcitonin has a longer half-life and a reduced
metabolic clearance in comparison with human calcitonin,
it has become a therapeutic agent of choice. It is commercially available in the form of nasal spray. Side effects
include rhinitis, nasal itching, headache, epistaxis, and
arthralgias. It is metabolized primarily by kidneys and to
a certain extent by peripheral tissues. Most of the drug is
cleared by the kidneys, with its half life being 43 minutes
[22]. Although calcitonin is considered a valuable addition
to the existing therapeutic alternatives for patients with
CRPS, the results of a few randomized controlled trials
have been controversial (Table 1) [23,24–27].
Bisphosphonates
The bisphosphonates are pyrophosphate analogues that
have recently been promoted as effective agents in the
treatment of CRPS. Clodronate, pamidronate, and alendronate have specifically been tested in recent randomized controlled clinical trials (Table 2) [28–31] and have
shown promising results. The bisphosphonates also
selectively inhibit bone resorption and hence are commonly used in the treatment of osteoporosis or Paget’s
disease. They reduce the formation and dissolution of
hydroxyapatite crystals within and outside the skeletal
system. Like calcitonin, the exact analgesic mechanism
of bisphosphonates in patients with CRPS is unclear.
Although patients with CRPS do manifest some degree of
regional osteoporosis in the involved extremity, the
assumption that the antinociceptive effect of bisphosphonates is primarily due to their capacity to inactivate
osteoclasts and antagonize osteoclastogenesis may be
simplistic. They inhibit prostaglandin E2, proteolytic
enzymes, and lactic acid [18,32] but not proinflammatory
cytokines [33] as was previously believed.
Alendronate, given in oral doses of 40 mg daily for 8
weeks, has shown benefits in improving pain, pressure
tolerance, and joint mobility in patients with CRPS [28].
Bioavailability of most bisphosphonates after oral intake
is less than 10% and is even less when they are taken with
food. These drugs are thus often given on an empty
stomach or via an intravenous route (pamidronate). Side
effects include nausea, dyspepsia, constipation or diarrhea, musculoskeletal pain, fever, and even esophageal
erosion or ulcers. Esophageal irritation can be reduced by
taking the drug with plenty of water and remaining
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568 Pain medicine
Table 1 Randomized controlled trials for efficacy of calcitonin in complex regional pain syndrome
Patients (n) and
duration of follow-up
Study
Dose
Type of study
Sahin et al.,
2006 [23]
Salmon calcitonin,
200 IU intranasal per day
RCT,
single blind
35 patients
(17 paracetamol,
18 drug), 2 months
Hamamci et al.,
1996 [24]
Salmon calcitonin,
100 IU intramuscular
Controlled trial
Gobelet et al.,
1992 [25]
Salmon calcitonin,
100 IU 3 times a day for
3 weeks with or without
physical therapy
RCT,
double blind
41 patients
(16 placebo, 25 drug),
4 weeks
66 patients
(33 placebo, 33 drug),
8 weeks
Bickerstaff
and Kanis,
1991 [26]
Salmon calcitonin,
100 IU each nostril twice
a day (400 IU total) for
4 weeks
Salmon calcitonin, 100 IU,
3 times a day for 3 weeks
with or without physical
therapy
RCT,
double blind
40 patients, 4 weeks
RCT
24 patients, 4 weeks
Gobelet et al.,
1986 [27]
Results
Pain, allodynia, hyperalgesia, trophic
changes, and ROM improved in
both groups, with no statistical
significance
Significant reduction in pain scores and
improvement in ROM
Significant improvement in pain and ROM,
significant improvement in ability to work
in upper-extremity CRPS patients (81.2%
versus 50%), no difference in level of
edema, no difference in ability to work in
lower-extremity CRPS patients (47%
versus 40%)
No difference in improvement in pain
scores, stiffness, swelling, and
vascular instability
Improvement in pain scores at 1 week
RCT, randomized controlled trial; ROM, range of motion.
upright for 30 minutes [22]. Contraindications to use of
bisphosphonates include decreased renal function, esophageal motility disorders, and peptic ulcer disease.
Other bisphosphonates such as residronate and ibandronate can also be administered orally, although they have
not yet been explored in the treatment of patients
with CRPS.
Interventional therapeutic techniques
The interventional therapies are technically demanding.
They can prove beneficial when used in a multidisciplinary setting with a clear understanding that the primary
goal of these therapies is to help decrease the pain and
facilitate functional rehabilitation.
Intravenous regional sympathetic blockade
In 1908, August Bier described a technique involving
injection of a local anesthetic solution in a limb isolated
by tourniquet (intravenous regional anesthesia). Hannington-Kiff [34] proposed the use of intravenous regional
sympathetic blockade (IRSB) in patients with CRPS, with
guanethidine being delivered by a similar method. A host
of other medications have been subsequently used, including sympatholytics such as reserpine, bretylium, and
Table 2 Randomized controlled trials for efficacy of bisphosphonates in patients with complex regional pain syndrome
Patients (n) and
duration of follow-up
Study
Drug studied
Type of study
Manicourt et al.,
2004 [28]
Alendronate 40 mg
oral every day for
8 weeks
RCT, double blind,
placebo controlled
40 patients 12 weeks
Optional open trial at
12 weeks for 8 weeks
RCT, double blind,
placebo controlled
12 patients from each
group opted
27 patients (13 placebo,
14 drug), 3 months
RCT
32 patients (17 placebo,
15 drug) 40 days
Open trial at 40 days
All 32 patients received
drug and followed for
another 120 days
20 patients (10 placebo,
10 drug) 2 weeks
Robinson et al.,
2004 [29]
Pamidronate 60 mg IV,
one time
Varenna et al.,
2000 [30]
Clodronate 300 mg IV for
10 days
Adami et al.,
1997 [31]
Alendronate IV infusion
(7.5 mg in 250 ml saline)
every day for 3 days
RCT, placebo controlled
Open trial at 2 weeks
20 patients, 2 weeks
Results
Improvement in spontaneous pain,
pressure tolerance, and joint mobility
Improvement in pain score, global
assessment of disease severity score,
and physical function
Improvement in pain score and clinical
global assessment in clodronate group
at 40 days
Overall reduction in VAS of 93% 15%
Significant reduction in spontaneous
pain, tenderness, and swelling along
with improvement in motion of
involved extremity at 2 and 4 weeks
Similar response in all patients
RCT, randomized controlled trial; IV, intravenous; VAS, Visual Analogue Pain Scale.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Complex regional pain syndrome Sharma et al. 569
clonidine; local anesthetics such as prilocaine or lidocaine;
and others such as ketanserin (serotonin antagonist),
methylprednisolone, and droperidol.
Barring a few isolated studies, the long-term advantages
of IRSB in patients with CRPS are questionable. A
systematic review of studies on the effects of IRSB with
guanethidine in CRPS failed to demonstrate beneficial
effects [35]. One study each with ketanserin and bretylium showed potentially beneficial effects [19]. IRSB
with lidocaine and steroids have been studied, but the
results are inconsistent. Two previous controlled trials
[36,37] showed positive long-term benefits (28 and
12 months of follow-up, respectively); however, a more
recent study [38] failed to replicate these observations.
Local anesthetic sympathetic blockade
A local anesthetic solution can be injected by placing a
needle tip in the proximity of sympathetic structures such
as the stellate ganglion or lumbar sympathetic chain
(LASB) under fluoroscopic or computed tomographic guidance. Although complications have been reported in the
literature, these techniques are safe in experienced hands.
For decades these techniques were considered a ‘gold
standard’ in the treatment of patients with CRPS. Unfortunately, only a few controlled trials have been conducted
to assess the usefulness of sympathetic blockade in
patients with CRPS. Moreover, almost all these trials have
been done in mixed CRPS patient populations that
include both sympathetically maintained and sympathetically independent states, which may bias the results.
Cepeda et al. [39] attempted a systematic review of
randomized controlled trials to examine the benefits of
LASB in patients with CRPS (not sympathetically maintained pain). Significant differences in study design
precluded sensible pooling of data. The authors then
reviewed nonrandomized controlled studies, case series,
and randomized controlled trials with acceptable
designs, published in English-language peer-reviewed
journals from 1916 through 1999. Pooled data from these
studies (454 patients) showed that 29% patients undergoing LASB obtained full pain relief (>75% improvement) while 41% obtained partial relief (25–75%
improvement). The authors concluded that a less than
one-third positive response (‘full’ pain relief) is consistent
with the placebo effect and that the efficacy of sympathetic blocks for treatment of CRPS is inconclusive. Many
of these 14 studies were published prior to 1960 and only
two identified technical success of block and pain scores.
Cepeda et al. [40] recently performed another systemic
review to assess the short-term (30-minute to 2-hour) and
long term (48-hour or later) analgesic effects of LASB.
Only two randomized double-blind controlled studies
(with a total of 23 subjects) were eventually selected
based on the inclusion criteria, but no conclusions could
be drawn. The authors called for further trials to address
the value of sympathetic blockade with local anesthetic
for the treatment of CRPS. At present, short duration of
pain relief and reduction in vasomotor symptoms, as often
achieved by LASB, should be used to improve mobility,
range of motion, and motor strength by physiotherapy.
Repeated blocks are beneficial in selected patients to
help facilitate participation in physiotherapy, particularly
when signs of continued improvement are observed.
Spinal cord stimulation
Spinal cord stimulation (SCS) is the newest therapeutic
modality to gain acceptance for a wide variety of neuropathic pain syndromes, including CRPS. The mechanisms of the analgesic effects of neuromodulation are
unclear. Neuromodulation may act to restore normal
gamma g-aminobutyric acid levels in the dorsal horn
and affect the release of adenosine, thus reducing neuropathic pain [41]. In a recent systematic review of the
literature and metaregression, Taylor et al. [42] reported
a statistically significant 2-point mean reduction in Visual
Analogue Pain Scale pain ratings in patients with CRPS
type I at 24 months’ follow-up along with a lifetime cost
saving of approximately US$60 000. The pooled data
from case series [42] showed that almost two-thirds
of both type I and type II CRPS patients reported at
least 50% improvement in their pain scores over a median
follow-up period of 33 months.
Although Taylor et al. [42] failed to isolate statistically
significant predictors of pain relief, studies suggest that
patients with good response to sympathetic blocks
respond better to neurostimulation [43]. A controlled
trial on 29 patients to evaluate the long-term effect of
SCS on the improvement of functional status in sympathetically maintained CRPS type I (positive response
to sympathetic nerve block) showed that SCS reduced
deep pain and allodynia [44]. Considerable improvement
in activities of daily living (based on pain disability index)
and a reduction in analgesic requirement were observed.
Almost 77% (20/26) patients showed significant improvement in their motor strength over an average follow-up
period of about 3 years. In view of the abovementioned
clinical and financial benefits, it is not surprising that
many pain physicians have started recommending this
therapy even in the early phases of the disease.
Neuraxial techniques
Continuous epidural infusions of local anesthetics, clonidine, or opioids have been studied in the management
of CRPS. Epidural clonidine has shown some benefit in a
randomized trial [45]. Use of these agents has significantly decreased over the past decade, as other less
demanding therapies have been explored. Besides, efficacy of intrathecal medications (morphine, bupivacaine,
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
570 Pain medicine
clonidine, baclofen, or ziconotide) via an implanted
pump has shown positive results in case reports and
case series. These interventions are considered only as
a last resort in complicated and resistant cases of CRPS.
Sympathetic denervation
Patients who show good response to initial sympathetic
blocks were subjected in the past to radiofrequency
denervation, chemical neurolytic destruction of the sympathetic innervation, or surgical sympathectomy in the
hope of achieving prolonged benefits. Indeed, almost
90% partial or complete evidence of sympathectomy
had been reported even 2 years after these procedures
[46], but their analgesic benefits often do not persist that
long. Most authors report sustained pain relief in less than
two-thirds of patients at 2 years and in about one-third at
5 years. In a systematic review of the effects of percutaneous neurodestructive procedures for neuropathic
pain, Mailis et al. [47] concluded that the practice of
surgical and chemical sympathectomy is based on poorquality evidence, uncontrolled studies, and personal
experience.
Surgical sympathectomy has also been advocated as an
alternative in the past for patients who achieve good pain
relief with a series of sympathetic block. Videoscopic
lumbar sympathectomy has been proven to be as effective as an open surgical intervention [48] and is less
aggressive. In a case series with 73 patients with CRPS
who underwent video-assisted sympathectomy, Bandyk
et al. [49] showed significant improvement (pain severity
score <3) in 25% and a moderate improvement in an
additional 50% of patients at 1-year follow-up. The most
important independent factor in determining a positive
outcome of sympathectomy is an interval of less than 12
months between the inciting event and sympathectomy
[50].
Complications of all these neurodestructive procedures
include postsympathectomy sympathalgia, compensatory
hyperhidrosis, Horner’s syndrome, wound infection,
and spinal cord injury. Although lower complication rates
and postprocedure morbidity are expected following
percutaneous techniques, surgical sympathectomy (both
videoscopic and open) might achieve better (or more
precise) neurodestruction. The accuracy of this presumption remains speculative.
Miscellaneous therapeutic options
In a large, prospective, randomized controlled trial [51],
physical therapy has been proved to reduce the pain and
improve active mobility in patients with CRPS I of less
than 1 year’s duration. In addition, the benefits of behavioral and psychological interventions have also been
shown in numerous case series. At present, all these
modalities should be considered an integral component
of any therapeutic plan and their importance cannot
be overemphasized.
The discussion of current advances in therapy for CRPS
would be incomplete without the mention of certain novel
options. Alternatives that are being explored include
graded imagery, repetitive transcranial magnetic simulation [52], hyperbaric oxygen [53], intravenous infusion
of iloprost (a prostacyclin analogue) [54] and immunoglobulin [55], as well as subanesthetic infusion of ketamine
[56,57]. Of these options, graded motor imagery has shown
benefit in a randomized controlled trial [58] consisting of
13 patients with CRPS who were given 2 weeks each of a
hand laterality recognition task, imagined hand movements, and mirror therapy. The 12-week follow-up showed
an almost 25-point reduction on the neuropathic pain
scale. Last but not least, there has been a valuable recent
trend to investigate the factors that might prevent the
occurrence or recurrence of CRPS. Reuben et al. [59]
have recently shown that the incidence of CRPS is
significantly reduced following fasciectomy for Dupuytren’s contracture with preoperative use of axillary block
or intravenous regional anesthesia with clonidine (and
lidocaine). These encouraging results have added a new
dimension to the enduring efforts to minimize the incidence and prevalence of this dreadful disease.
Conclusion
Current knowledge about the pathophysiology of CRPS
is rapidly expanding. Recent modifications in the diagnostic criteria have improved identification of this disease
with more conviction. These ‘winds of change’ have
certainly guided researchers in the right direction. Over
the past decade or so, many traditional treatment modalities have been scrutinized and some unique therapeutic options have been explored. At present diverse
recommendations exist as the ‘treatment of choice’ in a
given stage of the disease. Physicians are advised to adopt
an individualized, multidisciplinary approach for the
optimum care of their patients. Although the dream of
conquering this perplexing disease is still far fetched, the
future certainly looks bright.
References and recommended reading
Papers of particular interest, published within the annual period of review, have
been highlighted as:
of special interest
of outstanding interest
Additional references related to this topic can also be found in the Current
World Literature section in this issue (pp. 586–587).
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.