DEFINITION

Complex regional pain syndrome (CRPS) is a pain syndrome that occurs most often in an
extremity in association with abnormal autonomic nervous system activity and trophic changes.
The disorder has both nociceptive and neuropathic features and is characterized by persistent
pain, allodynia or hyperalgesia, edema, alterations in skin blood flow, and sudomotor
dysfunction.[1] In most cases, the syndrome is preceded by an inciting noxious event, trauma, or
immobilization.[2]
The classification of CRPS I versus CRPS II depends on the presence or absence of nerve injury,
as follows: in CRPS I, there is no known nerve lesion; in CRPS II, there is nerve injury.[3]
However, the pain that develops, which is typically severe, deep burning pain, is vastly out of
proportion in duration, distribution, and severity to the pain that is expected from the initiating
injury.[4] When it is left untreated, permanent hair and nail loss, muscle and skin atrophy, and
chronic pain may result. In addition, when it is severe, the disorder may spread to other body
areas, including the contralateral limb.[5]
The incidence of CRPS has been estimated at approximately 5.5 per 100,000.[6] The underlying
pathophysiologic mechanism of the disease remains incompletely understood at this time. An
exaggerated inflammatory response is believed to play a major role, particularly in the early
phases of the disease course.[7] Alternatively, autonomic dysregulation with an overly active
sympathetic nervous system has been thought to account for the ongoing symptoms. In addition,
the site of dysfunction is still unclear, with both central and peripheral mechanisms proposed.[8]
Reflecting this lack of clarity, many terms and definitions have been used to describe the
syndrome since its first report by Silas Weir Mitchell, a Civil War surgeon, from his study of
gunshot wounds. Previous terms include causalgia, shoulder-hand syndrome, and, most
commonly, reflex sympathetic dystrophy. The term sympathetic was more recently thought to be
inaccurate because of lack of response of a significant number of patients to sympathetic
blockade, and the disorder was renamed CRPS by consensus of the International Association for
the Study of Pain in 1994.[9] This terminology is meant to emphasize the complexity of the
disorder in regard to its pathogenesis and manifestations. The International Association for the
Study of Pain established the following four criteria that must be present for a clinical diagnosis
of CRPS to be made[9]:
Preceding noxious event without (CRPS I) or with obvious nerve lesion (CRPS II).

Spontaneous pain or hyperalgesia-hyperesthesia not limited to a single nerve territory and

disproportionate to the inciting event.

Edema, skin blood flow (temperature) or sudomotor abnormalities, motor symptoms, or

trophic changes are present on the affected limb, in particular at distal sites.

Other diagnoses are excluded.

The disorder has been classically divided into three stages, which are useful descriptively.[10]
However, the syndrome may not always follow this stepwise progression. The stages of CRPS
are described as follows:
Stage 1: severe pain; pitting edema; redness; warmth; increased hair and nail growth;
hyperhidrosis may begin; osteoporosis may begin.

Stage 2: continued pain; brawny edema; periarticular thickening; cyanosis or pallor; livedo
reticularis; coolness, hyperhidrosis; increased osteoporosis; ridged nails.

Stage 3: pallor; dry, cool skin; atrophic soft tissue (dystrophy); contracture; extensive
1

osteoporosis.
SYMPTOMS
The hallmarks of CRPS are symptoms, particularly pain, that are disproportionately severe given
the underlying trauma that led to their onset and that tend to spread distally from the site of
original injury in the affected limb.[4] The hand is the most common site of involvement with
spread to the wrist and forearm, followed by the foot and ankle.[11] Further, the symptoms will, by
definition, not be confined to a particular nerve territory. Although there is no obvious nerve
lesion in CRPS I, the symptoms that develop have neuropathic features. Symptoms include
burning spontaneous pain experienced in most of the cases in the deep tissues of the distal part of
the affected limb. The majority will have sensory disturbances in a stocking-glove distribution or
on the palmar surfaces of the hands or feet. The most common description of the pain will be
deep burning, tearing, or stinging that is constant rather than lancinating. Patients with CRPS
will typically experience severe stimulus-evoked pains to deep mechanical pressure, application
of heat or cold, and sharp stimulation. Pain will commonly be elicited with movement of joints,
by wearing of clothes, or with contact of sheets or blankets. Hypoesthesia and hypoalgesia have
been found in 50% of patients with CRPS I, occurring on the entire half of the body or in the
associated quadrant on the same side as the affected limb. In these patients, quantitative sensory
testing has shown that the thresholds to mechanical, cold, warmth, and noxious heat stimuli are
higher on the affected side of the body than on the unaffected side, supporting the clinical finding
of decreased sensation.[12] In some cases, the symptoms of CRPS can spread beyond the initially
affected limb and cause mirror-image pain in the contralateral limb or even spread to affect all
four limbs.
Other common symptoms include proximal muscle pain in the affected limb, often associated
with myofascial dysfunction. Mood disturbance is common in the chronic stages of the illness.
Early in the disease course, patients tend to be euthymic because they expect to get well. From 2
to 6 months of disease progression, patients may begin to become anxious; and by 6 months, all
patients will exhibit varying degrees of depression, sleep disturbance, and anxiety. The key point
is that although mood disturbance is common in CRPS, it does not predate the disease and in fact
can be viewed as an appropriate response to a progressive, unremitting pain disorder.[2]
PHYSICAL EXAMINATION
Although the original International Association for the Study of Pain criteria required only
history and subjective symptoms for a diagnosis of CRPS to be made, recent consensus
guidelines developed by experts have argued for the inclusion of objective physical findings.[2]
Sensory, motor, and autonomic dysfunction should be thoroughly investigated during the
physical examination.
Autonomic disturbances are common; the majority of patients have side-to-side differences in
the temperature of the limbs. Skin temperature of the affected limb will depend on the chronicity,
with temperature increase in acute stages and temperature decrease in chronic stages.
Temperature increase in the acute stages is associated with skin that is white or reddish and with
more swelling; temperature decrease in the chronic stage is associated with cyanotic, bluish skin
and more atrophy.[13] Other findings include sweating abnormalities and trophic changes, with
nail and hair growth in the acute stage and hair loss and nail brittleness in the later stages.
Motor disturbances are often overlooked in CRPS but are a predominant feature. Approximately
70% of patients with CRPS have muscle weakness of the affected limb, exaggerated tendon
2

reflexes or tremor, irregular myoclonic jerks, and dystonic muscle contractions.[14] This muscle
dysfunction is frequently associated with significant loss of range of motion of the distal joints.
In performing the sensory component of the examination for CRPS, special attention should be
focused on the distal extremity. Because of the common finding of regional neuropathic and
motor dysfunction, it is still important to broaden the examination both proximally and
contralaterally.
For proper assessment of the range of presentations in CRPS, light touch, pinprick, temperature,
and vibration sensation should be assessed. Sensory deficits of one modality, such as loss of
pinprick sensation, often accompany exaggerated positive responses to another modality, such as
pain with light touch. To help distinguish symptom amplification from reliable sensory
dysfunction, there should be clear and repeatable findings in the affected area, while the subject
is able to respond normally to examination of an unaffected area. In addition to findings of
allodynia (pain in response to an innocuous stimulus, such as light touch or brush with a cotton
swab) and hyperalgesia (exaggerated pain in response to a painful stimulus, such as pinprick or
deep pressure), signs of cutaneous C-fiber dropout should be sought. This can be accomplished
by applying hot water in a plastic bag over the skin and comparing the time it takes for the
affected limb to be withdrawn with an unaffected area. When loss of C fibers has occurred, the
withdrawal latency will be prolonged. Summation can be assessed by repeated application of the
same pinprick stimulus with equal force and asking the patient to report any change in pain
intensity. The normal nervous system tends to accommodate to repeated painful stimuli, whereas
an individual with a facilitated nervous system may report increasing pain.
Findings of autonomic dysfunction, such as abnormal skin temperature, local areas of cutaneous
trophedema, and hair loss, should be evaluated. In addition to checking for weakness and
difficulty with initiation of motion in the affected limb, regional muscle irritability should be
assessed. Specifically, the examination should look for trigger points, spontaneous muscle
fasciculations, and cramps in the supporting muscles of the limb. Tendon reflexes may be
increased, and presence of a tremor should be noted. Finally, measurement of passive and active
range of motion of the joints in the affected limb is important; this information can be used as
objective findings to be modified with rehabilitation.
Differential Diagnosis
Cellulitis
Lymphedema
Occult or stress fracture
Acute synovitis
Septic arthritis
Septic tenosynovitis
Upper or lower limb venous thrombosis
Scleroderma
Plexitis, peripheral neuropathy
FUNCTIONAL LIMITATIONS
3

Chronic pain leads to the well-known syndrome of deconditioning, sleep disturbance, anxiety,
and depression. With inadequate treatment, all aspects of the patient's life are affected, often with
devastating social, recreational, financial, and vocational consequences. In addition, limb
contracture and loss of strength may lead to difficulty in ambulation and basic and advanced
activities of daily living.
DIAGNOSTIC STUDIES
CRPS is primarily a clinical diagnosis. However, several diagnostic studies may be helpful in its
evaluation and to rule out other pathologic processes. For example, skin temperature can be
measured by Doppler flowmeter and infrared thermography; sweat output can be assessed by
quantitative sudomotor axon reflex testing; cutaneous blood flow can be measured by vital
capillaroscopy; and coexisting nerve injury and muscle fiber loss can be quantified by
electromyography and nerve conduction studies.[15] Imaging has historically been used to exclude
other diagnoses. Plain films are usually normal except in extreme cases, in which
demineralization can occur (Sudeck atrophy). Magnetic resonance imaging may demonstrate
marrow edema, soft tissue swelling, and joint effusion. The classic finding on bone scintigraphy
is increased periarticular activity in the affected limb.[16] The sensitivity and specificity of threephase bone scintigraphy are variable. [17] [18] Although an abnormal finding on bone scan can
confirm the clinical diagnosis of CRPS, the condition cannot be ruled out by a normal study.
A study of brain single-photon emission computed tomography in a small sample of patients with
CRPS revealed increased regional cerebral blood flow in the contralateral thalamus in patients
with acute CRPS and decreased contralateral thalamic regional cerebral blood flow in patients
with chronic CRPS.[19] Further research into the use of nuclear imaging in the evaluation of
CRPS is needed.
TREATMENT
Initial

Early in the disease, treatment should focus on aggressive interventional management to control
pain and to restore function (see the section on procedures).
Medications play an essential role in the treatment of CRPS, in both the acute and the chronic
phases. The following principles should be applied in prescribing drugs for this condition:
Minimize side effects.

Minimize medications that could cause dependency.

Avoid cognitive impairment.

Avoid organ toxicity.

Use rational polypharmacy, when appropriate, directed at different components of the pain.
In choosing medications, the findings of the examination together with a basic understanding of
the mechanisms of actions of the various drugs can provide some structure to treatment.[20] For
example, better medication selection can be made if one can use, within reason, clinical findings
and history to distinguish the underlying physiologic mechanism ( Table 93-1 ).
TABLE 93-1 -- Physical Findings and Associated Underlying Physiologic Mechanism
Physical Finding

Physiologic Mechanism

Hyperalgesia

Sensitized peripheral nociceptor

4

Physical Finding

Physiologic Mechanism

Summation of sensory input

Altered central processing of pain (wind-up)

Allodynia, segmental
widening of pain, or bilateral
findings

Loss of descending pain modulation and loss of inhibitory

neurons in the dorsal horn with C-fiber dropout and phenotypic
switching of A-B fibers

Trophedema, temperature
changes

Altered sympathetic function or responsiveness

With this approach, a patient with signs and symptoms suggestive of a sensitized peripheral
nociceptor may respond better to a topical lidocaine patch, mexiletine, or an anticonvulsant with
known sodium channel blocking properties, such as topiramate or lamotrigine, rather than
gabapentin. In general, most patients with CRPS will have some combination of symptoms and
signs in all four classes; therefore, rational polypharmacy often makes sense.
The tricyclic antidepressants are traditional choices in neuropathic pain disorders with good
evidence to support their use for neuropathic pain.[2] Their sedating side effects are additionally
useful in chronic pain conditions in treatment of associated sleep disturbance. The tricyclic
antidepressants appear to have some efficacy in treatment of CRPS, although they have not been
properly studied in this disorder. A reasonable regimen is to start with amitriptyline at a dose of
10 mg at bedtime with a titration schedule based on patient response up to 75 to 150 mg at
bedtime.
Antiepileptic agents are some of the best-studied agents for neuropathic pain, and strong
evidence demonstrates their effectiveness. These agents appear to be promising in the treatment
of CRPS. Gabapentin has been shown to be effective in large, randomized controlled trials for
other neuropathic pain disorders, and a case series suggests its efficacy in CRPS.[21] Dosing is
typically started at 300 mg at bedtime with gradual titration to a maximum dose of 1200 mg
three times a day (3600 mg daily). Phenytoin and carbamazepine in their usual doses have both
been used in the treatment of CRPS with some success. Lamotrigine has been studied in other
neuropathic pain conditions and may have some usefulness in the treatment of CRPS, but studies
are currently lacking.
Oral corticosteroid agents can be particularly effective early in the disease when significant
inflammation is present, and their use is substantially supported by randomized controlled
clinical trials.[8] A short course of steroids in the acute stage of the disease may be indicated. A
regimen of 30 mg daily tapered during 1 to 2 weeks is reasonable. Longer courses should be
avoided because of significant adverse effects, a questionable risk-benefit ratio, and numerous
contraindications.
Because of the suspected role of increased sympathetic nervous system activity in CRPS, adrenergic antagonists such as phenoxybenzamine and phentolamine have also been used and
may be beneficial in cases of sympathetically maintained pain. Phenoxybenzamine may be
started at a dose of 10 mg two or three times per day and increased by 10 mg every 2 days to a
maximum dose range of 40 to 120 mg daily. The main limiting side effect is postural
hypotension that can be treated with abdominal binders and stockings.
The lidocaine patch, a nonwoven patch containing 5% lidocaine, is used topically to deliver
medication locally to the affected area. It is approved by the U.S. Food and Drug Administration
5

for the treatment of postherpetic neuralgia and has shown some promise for treatment of CRPS.
[22]
In particular, it may be useful in diminishing the allodynia frequently associated with this
disorder.
Opioids may be useful in the acute stages of CRPS for control of pain. However, their use in
chronic pain conditions and conditions with neuropathic features remains controversial. One
randomized controlled trial of controlled-release morphine for the treatment of CRPS reported no
difference in pain reduction compared with placebo after 8 days of use.[23] However, several
studies have suggested the efficacy of opioids for chronic pain.[24] Methadone may be a choice in
cases of severe neuropathic pain because of its N-methyl-d-aspartate (NMDA) receptor
antagonist activity.[25]
Other pharmacologic treatment options include clonidine, nifedipine, calcitonin,
bisphosphonates, nonsteroidal anti-inflammatory drugs, mexiletine, and ketamine, applied
topically or as intravenous infusion. The patient with acute CRPS should have close follow-up
with treatment aggressively aimed at pain and symptom control so that mobilization becomes
possible.
Rehabilitation

The goal of interventional strategies and pharmacologic treatment is to manage pain so that
patients may participate in rehabilitation and begin to mobilize the affected limb as early as
possible. Stress loading and isometric exercise have shown some benefit in CRPS.[26]
Compressive garments are sometimes used to control edema and to desensitize the limb but may
not be tolerated because of pain. Densensitization can sometimes be achieved with contrast
baths, alternating hot (100F, 43C) and cold (65F, 18C) water soaks for several minutes. This
modality can be taught to patients for home use. Transcutaneous electrical nerve stimulation has
been used with mixed results. Paraffin baths or fluidized therapy may be beneficial in the
contractures of late-stage CRPS. For chronic CRPS, interdisciplinary pain programs emphasizing
functional restoration are often necessary for optimal recovery. The treatment team should
consist of medical, psychological, and physical and occupational therapy services.[27] Patients
progress in therapy should be guided by specific functional goals. Inability to progress in therapy
because of pain should be addressed with pharmacotherapy, procedures, or other pain control
modalities. In the setting of such programs, patients may also require medications to control
associated sleep disturbance, anxiety, or depression to progress in an appropriate manner and to
regain function.
Procedures

Sympathetic blocks are the traditional and most common early intervention.[28] However, it has
become clear that patients can be divided by positive or negative response to selective
sympathetic blockade or blockade of the -adrenergic receptors into those with sympathetically
maintained pain and those with sympathetically independent pain.[4] Stellate ganglion blocks for
upper limb and lumbar chain blocks for lower limb symptoms can be done by trained
anesthesiologists or physiatrists. Intrapleural infusion of local anesthetic can alternatively be
used to block the sympathetic chain from T1 to L2. Bier block procedures, involving the
intravenous infusion of pharmacologic substances into a limb after gravitational drainage of the
venous bed, may also be used. Depending on the substance infused, this can accomplish regional
sympathetic blockade with guanethidine, sensorimotor blockade with lidocaine, or a combination
of the two.[29] For those patients with sympathetically independent pain, regional sensorimotor
blockade with lidocaine should be the early intervention of choice. Such procedures have the
possibility of achieving rapid and effective pain relief, allowing more timely progression in
rehabilitation.
6

In addition to the interventional pain control procedures, which should be used aggressively early
in the disease course, spinal cord stimulation has been shown to be effective for treatment of both
CRPS I and CRPS II for which other less invasive treatment strategies have failed.[30]
Surgery

Surgical sympathectomy has been advocated when chemical block is effective but short lasting.
Neurosurgical dorsal root entry zone ablation is another surgical option reserved for chronic
severe cases.[31]
POTENTIAL DISEASE COMPLICATIONS
CRPS can lead to severe chronic pain and its typical sequelae. Limb contracture and muscle
atrophy can result in loss of extremity function and potentially permanent disability.
POTENTIAL TREATMENT COMPLICATIONS
Adverse effects of pharmacotherapy vary according to the medication selected. Because
polypharmacy may be necessary, care should be used in selection of interacting drugs that do not
result in untoward side effects. Long courses of corticosteroids can produce significant
endocrinologic disturbances and should be avoided. Nonsteroidal anti-inflammatory drugs have
well-known adverse effects on the gastric, hepatic, and renal systems. Side effects of opioids
may be an issue when high doses are required to control pain, and tolerance can develop with
chronic use. Potential complications of stellate ganglion block are inadvertent arterial injection
and seizures or recurrent laryngeal nerve injury.[31] Perforation of the aorta, vena cava, or kidney
can occur during lumbar sympathetic block. The most common complications of spinal cord
stimulation include hardware failure, lead migration, infection, and failure to provide pain relief.
[32]

References
1. Ochoa JL, Verdugo RJ: The mythology of reflex sympathetic dystrophy and sympathetically
maintained pains. Phys Med Rehabil Clin North Am 1993; 4:151-163.
2. Harden N: Pharmacotherapy of complex regional pain syndrome. Am J Phys Med
Rehabil 2005; 84:S17-S28.
3. Stanton-Hicks M, Janig W, Hassenbusch S, et al: Reflex sympathetic dystrophy: changing
concepts and taxonomy. Pain 1995; 63:127-133.
4. Janig W, Baron R: Complex regional pain syndrome: mystery explained?. Lancet
Neurol 2003; 2:687-697.
5. Leis S, Weber M, Schmelz M, Birklein F: Facilitated neurogenic inflammation in unaffected
limbs of patients with complex regional pain syndrome. Neurosci Lett 2004; 359:163-166.
6. Sandroni P, Benrud-Larson LM, McClelland RL, Low PA: Complex regional pain syndrome
type I: incidence and prevalence in Olmsted county, a population-based study.
Pain 2003; 103:199-207.
7. Bonica JJ: Causalgia and other reflex sympathetic dystrophies. In: Bonica JJ, ed. Advances
in Pain Research and Therapy, New York: Raven Press; 1979:141-166.
8. Cline M, Ochoa JL, Torebjork E: Chronic hyperalgesia and skin warming caused by sensitized
C nociceptors. Brain 1989; 112:621-647.
9. Birklein F: Complex regional pain syndrome. J Neurol 2005; 252:131-138.
10. Schwartzman RJ, McLellan TL: Reflex sympathetic dystrophy: a review. Arch
Neurol 1987; 44:555-561.
7

11. Anderson DJ, Falat LM: Complex regional pain syndrome of the lower extremity: a
retrospective study of 33 patients. J Foot Ankle Surg 1999; 38:381-387.
12. Rommel O, Malin JP, Zenz M, et al: Quantitative sensory testing, neurophysiological and
psychological examination in patients with complex regional pain syndrome and hemisensory
deficits. Pain 2001; 93:279-293.
13. Birklein F, Riedl B, Sieweke N, et al: Neurological findings in complex regional pain
syndromesanalysis of 145 cases. Acta Neurol Scand 2000; 101:262-269.
14. Van Hilten JJ, Van de Beek WJ, Roep O, et al: Multifocal or generalized tonic dystonia of
complex regional pain syndrome: a distinct clinical entity associated with HLA-DR13. Ann
Neurol 2000; 48:113-116.
15. Law PA, Amadio PC, Wilson PR, et al: Laboratory findings in reflex sympathetic dystrophy:
a preliminary report. Clin J Pain 1994; 10:235-239.
16. Todorovic-Tirnanic M, Obradovic V, Han R, et al: Diagnostic approach to reflex sympathetic
dystrophy after fracture: radiology or bone scintigraphy?. Eur J Nucl Med 1999; 22:1187-1193.
17. Holder LE, Cole LA, Myerson MS: Reflex sympathetic dystrophy in the foot: clinical and
scintigraphic criteria. Radiology 1992; 184:531-535.
18. Intenzo C, Kim S, Millin J, et al: Scintigraphic patterns of the reflex sympathetic dystrophy
syndrome of the lower extremities. Clin Nucl Med 1989; 14:657-661.
19. Intenzo CM, Kim SM, Capuzzi DM: The role of nuclear medicine in the evaluation of
complex regional pain syndrome type I. Clin Nucl Med 2005; 30:400-407.
20. Dworkin RH, Backonja M, Rowbotham MC, et al: Advances in neuropathic pain: diagnosis,
mechanisms, and treatment recommendations. Arch Neurol 2003; 60:1524-1534.
21. Mellick GA, Mellick LB: Reflex sympathetic dystrophy treated with gabapentin. Arch Phys
Med Rehabil 1997; 78:98-105.
22. Devers A, Galer BS: Topical lidocaine patch relieves a variety of neuropathic pain
conditions: an open-label study. Clin J Pain 2000; 16:205-208.
23. Harke H, Gretenkort P, Ladleif HU, et al: The response of neuropathic pain and pain in
complex regional pain syndrome I to carbamazepine and sustained-release morphine in patients
pretreated with spinal cord stimulation: a double-blinded randomized study. Anesth
Analg 2001; 92:488-495.
24. Kalso E, Edwards JE, Moore RA, et al: Opioids in chronic non-cancer pain: systematic
review of efficacy and safety. Pain 2004; 112:372-380.
25. Fishman SM, Wilsey B, Mahajan G, et al: Methadone reincarnated: novel clinical
applications with related concerns. Pain Med 2002; 3:339-348.
26. Carlson LK, Watson HK: Treatment of reflex sympathetic dystrophy using the stress-loading
program. J Hand Ther 1988; 5:149-154.
27. Audette JF, Bailey A: Physiatric treatment of pain. In: Ballantyne JC, ed. The
Massachusetts General Hospital Handbook of Pain Management, 3rd ed,
Philadelphia: Lippincott Williams & Wilkins; 2006:236-247.
28. Cepeda MS, Carr DB, Lau J: Local anesthetic sympathetic blockade for complex regional
pain syndrome. Cochrane Database Syst Rev 2005; 4:CD004598.
29. Paraskevas KI, Michaloglou AA, Briana DD, et al: Treatment of complex regional pain
syndrome type I of the hand with a series of intravenous regional sympathetic blocks with
guanetheidine and lidocaine. Clin Rheumatol 2005; 7:1-7.

30. Taylor RS, Van Buyten JP, Buchser E: Spinal cord stimulation for complex regional pain
syndrome: a systematic review of the clinical and cost-effectiveness literature and assessment of
prognostic factors. Eur J Pain 2006; 10:91-101.
31. Payne R: Neuropathic pain syndromes, with special reference to causalgia and reflex
sympathetic dystrophy. Clin J Pain 1986; 2:59-73.
32. Stojanovic MP: Neuromodulation techniques for the treatment of pain.
In: Ballantyne JC, ed. The Massachusetts General Hospital Handbook of Pain Management, 3rd
ed, Philadelphia: Lippincott Williams & Wilkins; 2006:193-203.