AUTHOR AND EDITOR INFORMATION

Section 1 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

INTRODUCTION

Section 2 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Background

Complex regional pain syndrome (CRPS) may develop as a disproportionate consequence of a trauma affecting the limbs without nerve injury (CRPS I, or reflex sympathetic dystrophy [RSD]) or with obvious nerve lesions (CRPS II, or causalgia).

• In the 17th Century, Ambroise Pare presented the earliest description of RSD as severe burning pain following peripheral nerve injury. Pare, a surgeon, treated King Charles IX for smallpox by inducing bleeding with a lancet applied to the arm. After this treatment, the king suffered from persistent pain, muscle contracture, and inability to flex or extend his arm.
• In 1864, Mitchell coined the term causalgia, which means burning pain, to describe persistent symptoms following gunshot wounds to peripheral nerves during the American Civil War.
• In 1900, Sudeck described radiographic spotty osteopenia.
• In 1916, Leriche focused on the sympathetic nervous system.
• In 1943, Livingston expanded the Leriche vicious circle theory that includes the following:
• • Abnormally firing, self-sustaining loops in the dorsal horn
  • Provoked by a small irritation focus in small nerve endings of major nerve trunks
  • Activating central projecting fibers, giving rise to pain

• In 1946, Evans used the term RSD, believing that sympathetic hyperactivity is involved somehow in the abnormal activity in the periphery.
• In 1993, the International Association for the Study of Pain (IASP) held a Special Consensus Conference addressing diagnosis and terminology (endorsing the term CRPS).
• In 1995, Paice wrote that, even after 130 years, there was still no general agreement on what to call RSD, what causes it, or how best to treat it.¹

Pathophysiology

CRPS is a relatively common disabling disorder of unknown pathophysiology.² RSD is a variable symptom complex that probably results from any number of multiple causes through different pathophysiologic mechanisms. Changes in the peripheral and central somatosensory, autonomic, and motor processing and a pathologic interaction of sympathetic and afferent systems are described as underlying mechanisms.

• Several hypotheses exist regarding the mechanism of sympathetically mediated pain and describe central and peripheral components. Wasner and colleagues demonstrated a complete functional loss of cutaneous sympathetic vasoconstrictor activity in an early stage of RSD/CRPS I, with recovery.³ This autonomic dysfunction originates in the central nervous system (CNS).
• Kurvers and colleagues suggested a spinal component to microcirculatory abnormalities at stage 1 of RSD, which appeared to manifest itself through a neural antidromic mechanism.⁴ This spinal component may be evoked by traumatic excitation of a peripheral nerve on the affected side.
• Baron and Janig have proposed a positive feedback circuit, consisting of primary afferent neuron, spinal cord neurons, sympathetic neurons, and a pathological sympathetic coupling.
• The cause of vascular abnormalities is unknown, and debate still surrounds the question of whether the sympathetic nervous system (SNS) is involved in the generation of these changes.
• The old Sudeck concept of an exaggerated regional inflammatory response is supported by new data indicating that, in patients with acute RSD, immunoglobulin G labeled with indium In 111 is concentrated in the affected extremity.
• A study with ³¹P (phosphorus) nuclear magnetic resonance (NMR) spectroscopy showed an impairment of high-energy phosphate metabolism, which explains why these patients are unable, rather than unwilling, to exercise.
• Electron microscope studies of skeletal muscle biopsies showed reduced mitochondrial enzyme activity, vesiculation of mitochondria, disintegration of myofibrils, abnormal depositions of lipofuscin, swelling of endothelial layers, and thickening of the basal membrane, which are all signs of oxidative stress. Oxygen consumption is reduced in limbs affected by RSD, and reduction of pain following treatment with oral vasodilators has been described.
• After a partial nerve lesion, excessive antidromic activation of undamaged afferent C fibers and neuropeptide release, leading to acute vasodilation within the innervation territory of the affected nerve, were demonstrated.
• The frequency of the presence of human lymphocyte antigen-DQ1 (HLA-DQ1) was increased significantly in RSD compared with control frequencies. This association provides an indication of an organic basis.
• Because auto-antibodies against nervous system structures have been described in these patients, Blaes and colleagues suggest an autoimmune etiology.⁵

Frequency

United States

Limited information is available about the epidemiology of CRPS in the United States and internationally. Actual incidence is unknown, as CRPS is often misdiagnosed. Some sources report, the incidence of causalgia (CRPS II) following injury to a peripheral nerve is 1-5%. The incidence of RSD (CRPS I) is 1-2% after various fractures and 2-5% after peripheral nerve injury.

Mortality/Morbidity

RSD has significant morbidity, so raising awareness of this disease is important. According to Murray, earlier recognition and appropriate referral is very important, especially in children. Prompt referral can avoid unnecessary investigations and treatments that may worsen the condition.

Sex

RSD is reported more commonly in women. In a prospective study by Veldman and colleagues, which reviewed 829 patients, 628 patients were female (76%), and 201 were male (24%).⁶

Age

RSD may appear in every age group, but, as widely reported, it is less common in children aged less than 10 years. The lower apparent prevalence in children may be an artifact from underdiagnosis, perhaps due to a milder clinical course or a lower index of suspicion by the treating clinicians. In the Veldman study of 829 patients, age of diagnosis was 9-85 years (median 42 y); only 12 patients were younger than 14 years.⁶

CLINICAL

Section 3 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

History

The typical clinical picture of CRPS consists of disproportionate extremity pain, swelling, and autonomic (sympathetic) and motor symptoms. The condition can affect the upper or lower extremities, but it is slightly more common in the upper extremities.

• Pain
  • Pain is reported in more than 90% of patients.
  • Most patients describe worsening of pain or other symptoms after exercising the affected limb.
• Edema
  • Vascular abnormalities (often abnormal vasodilation and skin warming in the early phase and vasoconstriction in later stages) are characteristic symptoms of RSD/CRPS I.
  • Typically, patients with CRPS I exhibit a warm and vasodilated affected extremity in the early stages and cold and pale skin in the later stages.
• Alteration in motor function
• • Although the IASP did not include motor dysfunction within their formal criteria for diagnosing RSD (because it is not universal), they acknowledged that such dysfunction is common. The abnormal motor symptoms that are reported most classically in RSD include the following:
  • • Inability to initiate movement
    • Weakness
    • Tremor
    • Muscle spasms
    • Dystonia of the affected limb
  • In one study, weakness was reported in 95% of patients, tremor of the affected limb in 49%, and muscular incoordination in 54% of patients. In chronic RSD, severe spasms were present in 25% of patients.
• Alteration in sensory function - Although the IASP also decided not to include sensory dysfunction within their formal criteria for diagnosing RSD (due to variability), such symptoms, including hypo-esthesia, hyperesthesia, and allodynia, may occur.
• Psychological dysfunction - Although psychological dysfunction is often seen in patients with RSD, the IASP decided not to include it within their formal criteria for diagnosing the condition, due to ongoing debate as to whether psychological dysfunction increases the risk of RSD or whether the psychological dysfunction is actually a result of the RSD. Psychological disturbances may include anxiety, hopelessness, and/or depression.

Physical

• The common characteristic features of RSD (CRPS I) are spontaneous pain, hyperalgesia, impairment of motor function, swelling, changes in sweating, and vascular abnormalities in a single extremity. An overt nerve injury is not detectable.
• • Various sensory symptoms have been observed
  • • Allodynia (mechanical and thermal)
    • Hyperalgesia (mechanical and thermal)
    • Hyperpathia
    • Hypo-esthesia
    • Hypothermesthesia
    • Proprioception and anesthesia dolorosa (sensibility to touch is absent, while severe pain is present in the anesthetic area)
    • Dissociated sensory pattern (on rare occasions)
  • In a study by Veldman, discoloration of the skin was reported in 91% of cases, altered skin temperature in 92%, edema in 69%, and limited active range of motion (AROM) in 88% of cases.
  • Hyperhidrosis may be seen in more than 50% of cases (with warm or cold skin temperature).
  • Dystrophic changes may present in skin, subcutaneous tissue, muscles, and bone.
  • Changes in the growth pattern of hair or nails on the affected limb can be commonly observed.
• Complex regional pain syndrome
• • Based on the IASP consensus conference, there are 2 types of CRPS, namely CRPS I (RSD) and CRPS II (causalgia). These 2 types are differentiated mainly based upon whether the inciting incident included a definable nerve injury.
  • CRPS I (RSD) – Occurs after initial noxious event other than a nerve injury
  • CRPS II (causalgia) – Occurs after nerve injury
  • In most other ways, CRPS I and CRPS II are quite similar. Features common to CRPS types I and II include the following:
  • • Pain, whether spontaneous or evoked, may include allodynia (painful response to a stimulus that is not usually painful) and/or hyperalgesia (exaggerated response to a stimulus that is usually only mildly painful).
    • Pain that is disproportionate to the inciting event (eg, years of severe pain after an ankle sprain)
    • Regional pain that is not limited to a single peripheral nerve distribution
    • Evidence of autonomic dysregulation (eg, edema, alteration in blood flow, hyperhidrosis)
    • Diagnosis is excluded if another condition could account for the degree of pain and dysfunction.
  • Typically, CRPS I is subdivided into the following 3 phases:
  • • Acute stage - Usually warm phase of 2-3 months
    • Dystrophic phase - Vasomotor instability for several months
    • Atrophic phase - Usually cold extremity with atrophic changes
  • These stages may be variable and often are not clear cut.
  • In CRPS I, 3 different kinds of spread patterns (ie, contiguous, independent, mirror-image) have been described. According to Maleki and colleagues, CRPS I may be due to aberrant CNS regulation of neurogenic inflammation.⁷

Causes

Various insults that may lead to RSD include the following:

• Trauma (eg, sprain, dislocations, fractures, surgery, burns, crash injury)
• Neurologic disorders (eg, stroke, tumor, syringomyelia)
• Herpes zoster infection
• Myocardial infarction
• Musculoskeletal disorder (shoulder rotator cuff injury)
• Malignancy
• Spontaneous/idiopathic

A study by Veldman and colleagues reported that in 65% of cases, RSD followed trauma (mostly a fracture); in 19% of cases, it followed an operation; and in 2% of cases, it followed an inflammatory process.⁶ In 4% of cases, onset of symptoms followed various other precipitating factors, such as injection, intravenous infusion, or cerebrovascular accident. In 10% of cases, no precipitant could be identified. CRPS II (causalgia) has been reported after automated laser discectomy and cervical epidural injection.

DIFFERENTIALS

Section 4 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Other Problems to Be Considered

Erythromelalgia is a rare and poorly understood clinical syndrome characterized by hot, red, painful extremities. The condition commonly affects the lower extremities. The application of cold or elevation of the extremity may provide pain relief.

The syndrome is classified either as primary (idiopathic) erythromelalgia or as secondary erythromelalgia, which is commonly associated with myeloproliferative, syndrome-related thrombocythemia. Adults with erythromelalgia may get relief with a daily dose of aspirin.

WORKUP

Section 5 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Lab Studies

• No diagnostic criteria have been accepted uniformly for RSD, and no single special investigation has been proven sensitive and specific enough for diagnosing RSD. No criterion standard exists for making this clinical diagnosis, although some tests and findings may contribute to the diagnosis or help to diagnose or exclude other possible medical conditions.
• As required, routine and specific blood tests, as well as other studies, should be performed to identify precipitating causes. The exact tests vary according to the body region involved, as well as according to the findings related to the history and physical examination.

Imaging Studies

• Radiographic films may show patchy peri-articular demineralization within 3-6 weeks. The extent of osteoporosis is more than expected from disuse alone, and it is a common abnormality revealed on radiographs.
• Three-phase bone scan
• • A 3-phase bone scan may be helpful in revealing findings typical for the diagnosis of RSD and in excluding other conditions that could cause the patient's symptoms. A false-negative bone scan is fairly common.
  • The 3-phase bone scan often is considered sensitive and specific, particularly in the early phase (<20 weeks) of the syndrome, but a study by Werner and colleagues reported that the 3-phase bone scan showed a diagnostic sensitivity of only 44%.⁸
  • According to Kozin and co-authors, scintigraphic abnormalities were reported in up to 60% of RSD patients and may be useful in arriving at the diagnosis of RSD, as well as in predicting which patients are likely to respond to systemic steroid therapy.⁹
  • Abnormally increased activity must be diffuse, not focal.
  • The most suggestive and sensitive findings on bone scan include diffuse increased activity, with juxta-articular accentuation uptake on the delayed images (phase 3).
  • Phases 1 and 2 are less sensitive and specific for RSD.
• Imaging studies have shown to not be reliable screening tests in the differentiation between normal posttraumatic changes and those changes seen in CRPS due to a low positive predictive value (17-60%) and a moderate negative predictive value (79-86%).¹⁰

Other Tests

• Skin temperatures - This measurement is simple, but important, to record during examination of the patient with RSD. Skin temperature is measured by (1) tactile perception, (2) surface thermistors, and (3) hand-held infrared thermometers.
• • Vascular changes in RSD
  • • Hyperemic phase - Increase in the temperature of the skin early in the course of RSD
    • Cold limb - Decrease in the temperature of the skin later in the course of RSD
• • Thermography - This test demonstrates limb temperature differences quantitatively, but it is nonspecific. Bruehl and colleagues noted that thermography may be useful in situations in which sensitivity and specificity are equally important; an asymmetry cutoff of 0.6º C appears optimal.¹¹ If specificity is more important, a cutoff of 0.8º C or 1.0º C may be considered.
• Sudomotor function testing - Through the autonomic testing of 396 patients with pain, Chelminsky and colleagues demonstrated that abnormalities in resting sweat output, in resting skin temperature, and in a quantitative sudomotor axon reflex test predicted the diagnosis of CRPS I with 98% specificity.¹²
• • Sweat test - The sympathetic skin response (SSR) provides useful information on sudomotor dysfunction in patients with RSD; however, it is not possible yet to determine the final value of SSR for the diagnosis of RSD.
  • Quantitative sudomotor axon reflex test (QSART)
  • Chemical sweat test - This uses agents such as ninhydrin, cobalt blue, or starch iodine.
  • Testing sweat output - In QSART, the stimulated sweat output is greater and is prolonged when sympathetic hyperfunction is present.
• Electrodiagnostic studies
• • Results of electromyography (EMG) and nerve conduction studies (NCS) typically are within the reference range in RSD. In fact, if the EMG and nerve studies identify a nerve lesion, the condition is not by definition CRPS I but may instead be CRPS II.
  • Single-fiber EMG examination also shows no definite abnormalities.
  • The electrodiagnostic studies may be normal because C-fiber abnormalities cannot be well detected.
  • Patients with allodynia (demonstrating, for example, extreme pain even when clothing touches the involved limb or when a breeze blows across it) may have a difficult time tolerating EMG and NCS.
• Quantitative sensory testing
• • The purpose of quantitative sensory testing (QST) is to quantify perception thresholds objectively.
  • QST uses very precise, reproducible stimuli, allowing comparison of symptomatic areas with asymptomatic areas, comparison with age-matched and sex-matched controls, and changes with time or treatment. This provides the physician with information about the severity and progression of the sensory dysfunction.
  • The standard QST involves determination of vibrotactile detection thresholds (an Ab-fiber–mediated sensation), cool detection thresholds (an Ad-fiber–mediated sensation), and warm thermal thresholds (a C-fiber–mediated sensation) in appropriate areas. Heat and cold pain thresholds also are obtained with the patient's permission and with the patient controlling the amount of stimulus applied.
• Laser Doppler imaging
• • Laser Doppler imaging, with appropriate stressors, provides a simple, fast, noninvasive, and painless method for the study of segmental autonomic function. This type of imaging study provides excellent spatial information, eliminates many sources of artifact, and can be used to rapidly and repeatedly test skin autonomic reflexes bilaterally.
  • Along with baseline images, mild stressors (inspiratory gasp, cold pressor positional dependency) are used to quantify skin vasoconstrictor reflexes (see Image 5). The first author has found these methods to be especially useful in helping to distinguish between sympathetically mediated and sympathetically independent pain conditions.
• Diagnostic sympathetic ganglion block
• • The IASP consensus group did not recognize response to sympathetic ganglion block as part of the diagnostic criteria for CRPS, since such responses, while often dramatic and impressive, are not universal.
  • Further, response to such blocks is more indicative of sympathetically maintained pain, which includes other etiologies in addition to CRPS.

TREATMENT

Section 6 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Rehabilitation Program

Physical Therapy

It is extremely important for patients with RSD to undergo a steady progression from gentle weight bearing to progressive, active weight bearing. Gradual desensitization to increasing sensory stimuli also plays an important role. The altered processing in the CNS is typically reset by a gradual increase in normalized sensation. Other intervention should be offered to enable greater confidence and comfort when patients do not progress in a reasonable amount of time.

Physical therapy (PT), in association with occupational therapy (OT), plays an important role in functional restoration. The goal is to increase strength and flexibility gradually, beginning with gentle gliding exercises. Patients usually are reluctant to participate in PT because of intense pain. A self-directed or therapist-directed PT program is important and should be individualized to each patient's needs and goals.

Patients with CRPS also may have myofascial pain syndrome. A study by Rashiq and Galer found that myofascial pain syndrome can be treated first, and, if it is treated effectively, the entire syndrome may resolve.¹³ Myofascial pain may be treated with modalities and techniques, such as massage and myofascial release.

Occupational Therapy

An analysis by Steverens and colleagues noted that occupational therapists are very important for initiating gentle, active measurements and preliminary desensitization techniques with patients who have RSD.¹⁴

Occupational therapists usually are responsible for introducing and maintaining a stress-loading program for patients with CRPS. This program involves active compression and distraction exercises that provide stimuli to the affected extremity without joint motion. The scrubbing technique requires use of a scrub brush. Scrubbing is performed by gradually increasing the weight on the patient's affected extremity as he/she scrubs in circles. Weight loading of the joints is completed with increasing weight as the scrubbing process continues.

The next part in this program involves a carrying technique. The patient is instructed to carry a weight (bag) in the affected extremity throughout the day, as tolerated. The patient should monitor his/her symptoms and keep a daily record to share with the therapist.

The stress-loading program usually is started as a home exercise program. The patient also can use desensitization techniques (eg, rubbing the skin, massage, tapping, vibration) to reduce sensitivity and pain.

Recreational Therapy

Recreational therapy can help the patient with chronic pain to take part in pleasurable activities that help to decrease pain. The patient finds enjoyment and socialization in previously lost or new recreational activities. Usually, patients with chronic pain are depressed. Recreational therapists may play an important role in the treatment process and enable the patient to become active.

Vocational therapy should be recommended and initiated early for all appropriate patients. Vocational therapy can provide work capacities and targeted work hardening, and the patient may return to gainful employment.

Medical Issues/Complications

Therapeutic strategies include pharmacologic pain relief, sympatholytic interventions, and rehabilitation.

• All treatments should focus primarily on functional restoration. Use of drugs, sympathetic blocks, and psychotherapy helps to achieve good pain control during PT.
• Early intervention is important. The key to successful treatment of RSD is recognition of symptoms in stage I or early in stage II. Physicians should be alert to signs and symptoms of RSD. When RSD is suspected, the treating physician should ensure that that the patient receives evaluation by a pain specialist or other clinician experienced in treating this condition.
• The time between the start of RSD and clinic attendance may vary from several days to years.
• Identifying any underlying disease (eg, fracture, sprain, radiculopathy) and tailoring specific management are important.
• Johnston and Howell reported significant pain improvement after release and anterior transposition of the nerve.¹⁵ Five patients had RSD, 3 cases of which resolved after nerve release. Careful evaluation with diagnostic local nerve blocks and other conservative measures should be tried before surgery is considered.
• Sympathetic or somatic block, if performed, should be integrated into a good rehabilitation program.

See also the following related Medscape topic:
Resource Center Pharmacologic Management of Pain

Surgical Intervention

• Sympathetic blocks
• • For the upper extremity, a stellate (cervicothoracic) ganglion block is recommended. Bupivacaine is preferred over lidocaine because of its longer half-life. Not all patients experience pain relief after blocks.
  • Percutaneous lumbar sympathetic plexus catheter placement usually provides short-term pain relief in most patients and may have some long-term effect.
• Bier block (intravenous regional block)
• • In 1974, the concept of intravenous regional guanethidine was introduced. Block with bretylium or reserpine has less profound effect than it does with guanethidine, which may last for 2-3 days.
  • A double-blind, randomized study was designed to compare the effectiveness of intravenous regional sympatholysis using guanethidine, reserpine, and normal saline; the study reported significant pain relief in all 3 groups. No significant differences were noted among the 3 groups in the degree of pain relief. The saline group's high rate of pain relief could be due partially to a mechanism of tourniquet-induced analgesia.
• Somatic block, consisting of continuous epidural infusion with different variants of brachial plexus blocks, includes an axillary, supraclavicular, or infraclavicular approach that may be useful.
• Dorsal column stimulator
• • Localized extremity pain may be relieved by a dorsal column stimulator.
  • A spinal cord stimulator (SCS) can be an effective treatment for the pain of RSD, including recurrent pain after ablative sympathectomy.
  • Kumar and colleagues note that the low morbidity associated with this procedure and its efficacy in patients with refractory pain related to RSD suggest that SCS is superior to ablative sympathectomy in the management of RSD.¹⁶
  • Careful evaluation is recommended before patient selection
• Intrathecal infusion - Careful selection of patients is needed.
• • Baclofen pump - According to van Hilten and co-authors, an intrathecal (IT) Baclofen pump may be useful for treatment of dystonia in patients with RSD.¹⁷
  • Morphine pump - Intrathecal opioids should be considered carefully for chronic pain of nonmalignant origin.
  • Intrathecal bupivacaine infusion - As noted in a study by Lundborg and colleagues, this approach may alleviate the refractory pain, but it does not affect other associated symptoms or the natural course of CRPS I.¹⁸
• Sympathectomy
• • Radiofrequency or cryoprobe lesioning - If a sympathetic block produces significant pain relief twice, denervation with radio frequency or a cryoprobe could provide long-term relief.
  • Surgical sympathectomy - Endoscopic cervicothoracic sympathectomy could be an effective minimally invasive therapy for upper extremity RSD.
  • Chemical sympathectomy
• Amputations
• • Dielissen and colleagues reviewed cases of 28 patients with RSD who had amputations for intractable pain or recurrent infection, or to improve residual function.¹⁹
  • Only 2 patients were relieved of pain by amputation, and this number could not be predicted.
  • RSD recurred in the stump, especially after amputation at a level that was not free of symptoms.

Consultations

In CRPS, as in other chronic pain conditions, the high incidence of personality pathology, as noted by Monti and co-authors, may represent an exaggeration of maladaptive personality traits and coping styles resulting from chronic, intense pain.²⁰ Such pathology can be addressed with the help of the following:

• Evaluation - An evaluation by a psychologist is appropriate to identify the stressor and to gather information about the distress of the patient. The evaluation should consist of a structural clinical interview and a personality measure (eg, Minnesota Multiphasic Personality Scale, Hopelessness Index).
• Psychotherapist
• Biofeedback and counseling

Other Treatment

• Transcutaneous electrical nerve stimulation (TENS) - According to Hassenbusch and co-authors, peripheral nerve stimulation can provide good relief for RSD when the condition is limited to the distribution of 1 major nerve.²¹
• Ultrasonography
• Superficial hot packs
• A double-blind, prospective, multicenter trial of 416 patients by Zollinger and colleagues has shown that Vitamin C seems to reduce the prevalence of CRPS after wrist fracture. The authors recommended a daily dose of 500 mg for 50 days.²²
• Improvements in pain and bone density following intravenous administration of pamidronate, alendronate, or clodronate have been described in a few patients.

See also the following related Medscape topic:
Resource Center Advanced Approaches to Chronic Pain Management

MEDICATION

Section 7 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Multiple classes of medications have been tried for patients with CRPS, often with variable results and generally with limited published research to help clinicians predict which patients will respond well to a particular medication.

Analgesic drug therapy for CRPS can be divided into the following categories:

Opioid analgesics

• Opioids are used commonly as an analgesic for many pain syndromes.
• Opioid therapy can be a safe and good option in patients with intractable nonmalignant pain and no history of drug abuse.
• Quang-Cantagrel and colleagues reported that failure of one opioid cannot predict the patient's response to another opioid.²³
• High doses of tramadol may provide effective and safe relief in neuropathic pain, including allodynia.

Nonopioid analgesics (eg, NSAIDs, acetaminophen)

• Acetaminophen is a safe choice for treatment of pain during pregnancy and breastfeeding.
• Nonsteroidal anti-inflammatory drugs (NSAIDs) are discussed in further detail within the tables below.

Antidepressants

Antidepressant medications play a major role in treatment of neuropathic pain.

• Tricyclic antidepressants
  • Amitriptyline (Elavil)
  • Imipramine (Tofranil)
  • Doxepin (Sinequan)
  • Clomipramine (Anafranil)
  • Nortriptyline (Pamelor)

• Selective serotonin reuptake inhibitor (SSRI) antidepressants
  • Paroxetine (Paxil)
  • Fluoxetine (Prozac)
  • Sertraline (Zoloft)
  • Escitalopram (Lexapro)

• Other antidepressants
  • Nefazodone (Serzone)
  • Venlafaxine (Effexor)
  • Duloxetine (Cymbalta)
  • Bupropion (Wellbutrin)

Anticonvulsants

• Sodium channel antagonists have been used in the management of neuropathic pain for several years.
• These medications are started slowly and are administered as needed.
• The patient is monitored carefully.
• Use of several anticonvulsant drugs (eg, pregabalin, carbamazepine, phenytoin, sodium valproate, clonazepam, topiramate, lamotrigine) has been tried in the treatment of RSD.
• In studies by Nicholson and by Rowbothan and colleagues, gabapentin has been reported to be effective in the management of chronic neuropathic pain syndromes.²⁴
• Controlled studies for the effect of lamotrigine have not become available yet, but Jain notes that the drug has shown effect in neuropathic pain.
• Ziconotide may be useful in the future for neuropathic pain, as Jain notes that it has a favorable risk/benefit ratio, with advantages over several currently available intrathecal therapies for pain.²⁵

Other adjunct analgesics

• Hewitt states that N-methyl-D-aspartate (NMDA)–receptor antagonists, including ketamine and dextromethorphan, may have potential as co-analgesics when used in combination with opioids. Some studies have shown that ketamine infusion therapy provides effective pain relief and does not have adverse cognitive effects with extended use.^{26, 27}
• Benzodiazepines, baclofen, and tizanidine may be helpful in decreasing spasm and providing pain relief.
• Corticosteroid, mexiletine (orally active class Ib anti-arrhythmic agent), nifedipine (calcium channel blocker), propranolol (beta blocker), phenoxybenzamine (alpha blocker), and clonidine (alpha2-adrenergic agonist) are other alternatives. Some drug trials provided consistent support for analgesia with corticosteroids in the early stage and may have long-term effectiveness.
• Lidoderm 5% patches are sometimes helpful in decreasing allodynia and providing pain relief.
• Although it has not been approved by the Food and Drug Administration (FDA) for this indication, botulinum toxin can be considered for dystonia seen in patients with RSD.

Drug Category: Nonsteroidal anti-inflammatory drugs

These inhibit inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which is responsible for prostaglandin synthesis. NSAIDs may provide pain relief in the early stage of RSD.

Drug Name	Naproxen sodium (Anaprox, Naprelan, Naprosyn)
Description	For relief of mild to moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.
Adult Dose	275 mg PO tid or 550 mg PO bid
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, peptic ulcer disease, recent GI bleeding or perforation, and renal insufficiency
Interactions	Co-administration with aspirin increases risk of inducing serious NSAID-related side effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta blockers; may decrease diuretic effects of furosemide and thiazides; may increase PT when taking anticoagulants (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with pre-existing renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Drug Category: Antidepressants

These drugs increase the synaptic concentration of serotonin and/or norepinephrine in the CNS by inhibiting their re-uptake by the presynaptic neuronal membrane. Similar agents that can be helpful are duloxetine (Cymbalta) and venlafaxine (Effexor).

Drug Name	Amitriptyline (Elavil)
Description	Has demonstrated effectiveness in certain chronic and neuropathic pain.
Adult Dose	25-100 mg PO hs; not to exceed 150 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; patient who has taken MAOIs in past 14 d; history of seizures, cardiac arrhythmias, glaucoma, and urinary retention
Interactions	Phenobarbital may decrease effects; co-administration with CYP2D6 enzyme system inhibitors (eg, cimetidine, quinidine) may increase amitriptyline levels; inhibits hypotensive effects of guanethidine; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Pregnancy	D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions	Caution in cardiac conduction disturbances and history of hyperthyroidism or renal or hepatic impairment; avoid use in elderly patients

Drug Name	Duloxetine (Cymbalta)
Description	Indicated for diabetic peripheral neuropathic pain. Potent inhibitor of neuronal serotonin and norepinephrine reuptake.
Adult Dose	60 mg PO qd; may initiate with lower dose in patient unable to tolerate 60 mg/d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; uncontrolled narrow-angle glaucoma; within 14 d of stopping MAO inhibitor use (do not initiate MAO inhibitors within 5 d of stopping duloxetine)
Interactions	Metabolized by CYP1A2 and CYP2D6; co-administration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase duloxetine blood levels and toxicity; co-administration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase duloxetine blood levels and toxicity; duloxetine moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines [eg, thioridazine], type-1C anti-arrhythmics [eg, propafenone, flecainide]); co-administration with MAO inhibitors or triptans can cause serotonin syndrome consisting of serious, sometimes fatal reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes (including extreme agitation, delirium, and coma) (see contraindications)
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Observe closely for clinical worsening and suicidality when initiating treatment or following dosage change; gradually decrease dose when discontinuing, do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; recommended not to prescribe to patients with substantial alcohol use or evidence of chronic liver disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, dyspepsia, gastritis, loose stools, decreased appetite, fatigue, somnolence and increased sweating; may cause serotonin syndrome (ie, changes in mental status [agitation, hallucinations, coma], autonomic instability [tachycardia, labile blood pressure, hyperthermia], neuromuscular abnormalities [hyperreflexia, incoordination])

Drug Category: Anticonvulsants

Use of certain anti-epileptic drugs, such as the GABA analogue gabapentin (Neurontin), has proven helpful in some cases of neuropathic pain. Other anticonvulsant drugs (eg, carbamazepine, phenytoin, sodium valproate or clonazepam, topiramate, lamotrigine, zonisamide, tiagabine) also have been tried in RSD.

Drug Name	Pregabalin (Lyrica)
Description	Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha2-delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.
Adult Dose	50 mg PO tid initially; if needed, may increase to 100 mg tid within 1 wk
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	May cause additive effects on cognitive and gross motor functioning when co-administered with drugs that cause dizziness or somnolence
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min); angio-edema has been reported during postmarketing surveillance

Drug Category: Opioid analgesics

These commonly used analgesics are employed for many pain syndromes.

Drug Name	Morphine sulfate (MS Contin, Avinza, Kadian, Duramorph, Astramorph)
Description	DOC for analgesia due to reliable and predictable effects, safety profile, and ease of reversibility with naloxone. Various IV doses are used; commonly titrated until desired effect obtained.
Adult Dose	Starting dose: 0.1 mg/kg IV/IM/SC Maintenance dose: 5-20 mg/70 kg IV/IM/SC q4h Relatively hypovolemic patients: Start with 2 mg IV/IM/SC; re-assess hemodynamic effects of dose
Pediatric Dose	Infants and children: 0.1-0.2 mg/kg dose IV/IM/SC q2-4h prn; not to exceed 15 mg/dose; may initiate at 0.05 mg/kg/dose
Contraindications	Documented hypersensitivity; hypotension; potentially compromised airway where establishing rapid airway control would be difficult
Interactions	Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants, MAOIs, and other CNS depressants may potentiate adverse effects of morphine
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in hypotension, respiratory depression, nausea, emesis, constipation, and urinary retention; caution in atrial flutter and other supraventricular tachycardias; has vagolytic action and may increase ventricular response rate

Drug Name	Meperidine (Demerol)
Description	Analgesic with multiple actions similar to those of morphine; may produce less constipation, smooth muscle spasm, and depression of cough reflex than similar analgesic doses of morphine.
Adult Dose	50-150 mg PO/IV/IM/SC q3-4h prn
Pediatric Dose	1-1.8 mg/kg (0.5-0.8 mg/lb) PO/IV/IM/SC q3-4h prn; not to exceed adult dose
Contraindications	Documented hypersensitivity; use of MAOIs; upper airway obstruction or significant respiratory depression; during labor when delivery of premature infant is anticipated
Interactions	Monitor for increased respiratory and CNS depression with co-administration of cimetidine; hydantoins may decrease effects of meperidine; avoid with protease inhibitors
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in patients with head injuries, since meperidine may increase respiratory depression and CSF pressure (use only if absolutely necessary); caution when using postoperatively and with history of pulmonary disease (suppresses cough reflex); substantially increased dose levels, due to tolerance, may aggravate or cause seizures even if no prior history of convulsive disorders; monitor closely for morphine-induced seizure activity if prior seizure history

Drug Name	Fentanyl transdermal patch (Duragesic)
Description	Potent narcotic analgesic with much shorter half-life than morphine sulfate. Excellent choice for pain management and sedation with short duration (30-60 min) and easy to titrate. Easily and quickly reversed by naloxone. When using transdermal dosage form, most patients are controlled with 72 h dosing intervals; however, some patients may require dosing intervals of 48 h.
Adult Dose	12 mcg/h, q48-72h 25 mcg/h (10 cm2), q48-72h 50 mcg/h (20 cm2), q48-72h 75 mcg/h (75 cm2), q48-72h 100 mcg/h (100 cm2), q48-72h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity, hypotension, and potentially compromised airway
Interactions	Phenothiazines may antagonize analgesic effects of opiate agonists; tricyclic antidepressants may potentiate adverse effects of fentanyl when both drugs are used concurrently
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in patients with hypotension, respiratory depression, constipation, nausea, emesis, and urinary retention; idiosyncratic reaction, known as chest wall rigidity syndrome, may require neuromuscular blockade in order to increase ventilation

FOLLOW-UP

Section 8 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Further Inpatient Care

• Hospitalization usually is not required for patients with RSD, but it depends on how invasive the treatment choice is for pain control and the severity of the case. Sometimes, a short hospitalization is necessary for individuals who need a continuous nerve block. Patients with RSD also may have other associated orthopedic conditions that may be amenable to surgery and that require further inpatient care.

Further Outpatient Care

• Patients with RSD generally are treated on an outpatient basis and require a variety of health care professionals to optimally manage their condition. Please refer to the Treatment section for a discussion of proper rehabilitation methods and other treatment options.

Deterrence

• Recognition of RSD at the early stage is very important to achieve the best result and to prevent spread and progression toward the chronic stage (which is usually more difficult to treat).

Complications

• Chronic edema (occasionally chronic lymphedema)
• Chronic relapsing infections and ulcers resistant to treatment
• Brown-gray, scaly pigmentations of the skin
• Recurrent, unexplained, spontaneous hematomas
• Dystonia, tremor, and other movement disorders
• Clubbing of fingers or toes and hourglass nails
• Depression and other psychiatric disorders

Prognosis

• Dumitru's report suggests that, in comparison with adults, children are less disabled from and have more favorable prognoses with RSD.²⁸

Patient Education

• Patient education is very important in the treatment of individuals with RSD. The patient with chronic, debilitating pain usually tries to protect the affected body part and keep it immobile, which leads to further stiffness and a possible frozen joint. The patient's physical and occupational therapists need to educate him/her in the use of the affected extremity through activities of daily living (ADL). Patients with RSD also need to learn about ways to minimize pain. A home exercise program and instruction in the use of a TENS unit may be beneficial. Education and counseling relating to coping with and managing pain are important in patients with RSD, because depression and narcotic dependence can develop.
• For excellent patient education resources, visit eMedicine's Muscle Disorders Center. Also, see eMedicine's patient education article Chronic Pain.

MISCELLANEOUS

Section 9 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Medical/Legal Pitfalls

• Patients with RSD often are labeled psychogenic or malingering if their pain sources are not recognized, which especially may occur in the early stages.
• Recognition and treatment of RSD at the early stages are very important in order to maximize outcome.

Special Concerns

• RSD is rare in childhood, but it has significant morbidity. Therefore, awareness of this disease is important because it allows children with this condition to be recognized earlier and referred for appropriate treatment. As noted by Murray, awareness may avoid unnecessary investigations and treatments that may worsen the condition.
• According to one report on 70 children (<18 y, predominantly girls [59 of 70 patients]) with RSD (lower extremity [61 of 70 patients]), 38 patients had some degree of residual pain and dysfunction after the usual conservative treatment. As in studies in adults, delay in diagnosis was reported (average time from the initial injury to the diagnosis was 1 y).

ACKNOWLEDGMENTS

Section 10 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Debra Ibrahim, 4th year medical student, New York College of Osteopathic Medicine, Class of 2008, assisted with the 2007 revision of this manuscript.

MULTIMEDIA

Section 11 of 12  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Acknowledgments
• Multimedia
• References

Media file 1:  A 29-year-old woman with reflex sympathetic dystrophy in the right foot demonstrates discoloration of the skin and marked allodynia.
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Media file 2:  This photo shows the same patient as in Image 1, following a right lumbar sympathetic block. Marked increase in the temperature of the right foot is noted, with more than 50% pain relief.
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Media file 3:  A 68-year-old woman with complex regional pain syndrome type II (causalgia).
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Media file 4:  A 36-year-old woman with right arm reflex sympathetic dystrophy and dystonic posture (movement disorder).
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Media file 5:  Normal laser Doppler study of the upper extremities. When the patient performs inspiratory gasp repeatedly during laser Doppler image acquisition, the transient capillary flow decreases are displayed easily and dramatically (as dark bands) in the pseudocolor image.
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Media file 6:  Laser Doppler study of the upper extremities in a patient with right hand reflex sympathetic dystrophy.
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Media file 7:  Laser Doppler study of the lower extremities in a 25-year-old woman with reflex sympathetic dystrophy in the right foot.
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Media file 8:  Algorithm for the management of chronic regional pain syndrome (CRPS). Resolution of this syndrome does not commonly occur, and the patient will need chronic pain management.
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REFERENCES

Section 12 of 12