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Complex regional pain syndrome in adults: Treatment, prognosis, and prevention

Complex regional pain syndrome in adults: Treatment, prognosis, and prevention
Literature review current through: Jan 2024.
This topic last updated: Jan 19, 2023.

INTRODUCTION — Complex regional pain syndrome (CRPS) remains a relatively mysterious chronic pain disorder, usually affecting a single limb and characterized by pain in an area of the limb or limbs that is disproportionate in time or degree to the usual course of any known trauma or other lesion. The pain is not restricted to a specific nerve territory or dermatome and usually has a distal predominance of abnormal sensory, motor, sudomotor, vasomotor, and/or trophic findings. The syndrome shows variable progression over time.

The prevention and management of CRPS will be reviewed here. Other aspects of CRPS in adults and children are presented separately. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis" and "Complex regional pain syndrome in children" and "Approach to the management of chronic non-cancer pain in adults".)

GENERAL PRINCIPLES

Goals of therapy — A multidisciplinary approach is suggested for the management of CRPS [1,2]. The goals of therapy are to restore function to the affected limb, decrease pain and disability, and improve quality of life while minimizing medication side effects and toxicities. Clinical experience suggests that treatment is more effective when begun early in the course of the disease, ideally as soon as the diagnosis is established and before radiographic changes appear. (See "Complex regional pain syndrome in adults: Pathogenesis, clinical manifestations, and diagnosis", section on 'Clinical manifestations'.)

When to refer to pain specialist — Referral to a pain management specialist with experience in management of CRPS is appropriate for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to the initial measures outlined below, as well as for patients with severe or chronic CRPS.

It is uncertain whether immediate referral to a specialist in pain management results in better outcomes than early physical therapy (PT) and occupational therapy (OT) for protective and assisted mobilization of the affected limb within pain limits, supplemented by conservative pharmacologic interventions, and followed by referral to a pain management specialist if the patient does not improve. On the other hand, early referral to an interventional pain specialist for appropriate nerve block may reduce pain and enable patients with CRPS to tolerate aggressive PT and OT.

INITIAL MANAGEMENT — Interventions that are appropriate for all patients with CRPS include the following:

Patient education (see 'Patient education' below)

Physical therapy (PT) and occupational therapy (OT), initiated as quickly as is practical following diagnosis of CRPS (see 'Physical and occupational therapy' below)

Psychosocial assessment to determine whether psychosocial and behavioral management strategies may be of benefit (see 'Psychosocial and behavioral therapy' below)

Symptomatic pain management, typically beginning with low-risk pharmacotherapy selected based on consideration of patient age, comorbidities, concurrent medications, drug interactions, and side effects (see 'Approach to pharmacotherapy' below)

Patient education — Patient participation in PT and OT may be facilitated by an explanation that the pain associated with CRPS, which is presumably related to neuropathic and central mechanisms, does not indicate tissue damage in the hyperalgesic region but arises from an unknown cause. Prior to a referral to a specialist in rehabilitation or to a physical or occupational therapist, the clinician should stress the importance of working to regain use of the affected limb while recognizing the difficulty of doing so in the face of ongoing pain.

A consumer education and support group available for patients and caregivers in the United States is the Reflex Sympathetic Dystrophy Syndrome Association (RSDSA).

Physical and occupational therapy — PT and OT are considered first-line treatments for CRPS [1,3,4], though most of the relevant studies are limited by methodologic problems, including but not limited to variable treatment modalities used, lack of control groups, and small patient numbers [5,6]. Aside from cost and inconvenience, there is little downside to PT and OT for patients with CRPS.

We suggest referral to an appropriate therapist immediately after the diagnosis is established. PT, which can be performed twice daily at home for patients in all stages of disease, should ideally begin before limitation of movement occurs in order to maintain range of motion and prevent contractures. Resting splints for the affected limb are sometimes used with a goal of preventing progressive joint contractures. However, the effectiveness of splinting is uncertain.

A number of general therapeutic methods of PT and OT have been used to treat CRPS, including but not limited to the following list [7]:

General exercises and strengthening

Functional activities

Gait retraining

Transcutaneous electrical nerve stimulation (TENS)

Postural control

Pacing, prioritizing, and planning activities

Goal setting

Relaxation techniques

Coping skills

Hydrotherapy

Sleep hygiene

Edema control strategies

Vocational support

Facilitating self-management of condition

Splinting

There is no definitive evidence in favor of any of these methods [8]. Other rehabilitation techniques that have been developed in centers with particular CRPS expertise include [7]:

Graded motor imagery [9-11]

Pain-exposure PT [12] and graded exposure in vivo [13] to reduce pain-avoidance behaviors

Self-administered tactile and thermal desensitization with the aim of normalizing touch perception [14]

Mirror visual feedback and immersive virtual reality [15-19]

Functional movement techniques to improve motor control and awareness of affected limb position [20]

Principles of stress loading [21]

Conflict allodynia re-education to reduce fear of physical contact with others in community settings [22]

Among these techniques, perhaps the strongest evidence is for graded motor imagery, which led to significant reductions in pain and swelling in patients with CRPS in three small single-center randomized controlled trials [9-11]. A 2023 meta-analysis that included 33 trials on conservative treatment for CRPS found low-quality evidence supporting the benefits of mirror therapy, graded motor imagery, pain exposure therapy, and aerobic exercise [23]. However, a prospective observational study from two centers with a special interest in CRPS found no improvement in pain despite the use of graded motor imaging [24], suggesting it does not translate well into clinical practice [25].

Psychosocial and behavioral therapy — Patients with CRPS who have preexisting or suspected psychologic or psychiatric issues and those who have insufficient improvement with physical, pharmacologic, or interventional therapies may benefit from psychosocial and behavioral management.

We suggest consulting a pain management clinical psychologist with training in treating CRPS if any of the following are present:

CRPS of more than two months' duration at presentation

Insufficient response to treatment

Suspected comorbid psychologic or psychiatric disorder

The goals of psychosocial and behavioral management include the following [7,26]:

Identify any psychologic factors contributing to pain and disability

Treat anxiety and depression

Identify, explore, and proactively address any internal factors (eg, counter-productive behavior patterns) or external influences (eg, perverse incentives, family dynamics, etc) that may perpetuate disability or dependency

Consider needs of family and caregivers and provide psychologic intervention and counseling where appropriate

Provide a practical problem-solving, goal-orientated approach (involving both the patient and their family) to reduce barriers and promote healthy functioning

Although psychologic assessment and therapy have not been well studied in patients with CRPS, their usefulness in other chronic painful disorders suggests that this approach may be beneficial to those with CRPS. Patients with severe or chronic CRPS may benefit from cognitive behavioral therapy [26]. (See "Approach to the management of chronic non-cancer pain in adults", section on 'Psychological therapy'.)

Case reports and personal experience suggest that a skilled hypnotherapist can be helpful for patients with heightened arousal, manifested by features of fear, anxiety, excessive sweating, and weakness, and in whom exercise is otherwise impossible [27,28]. Hypnosis allowed PT to progress in some patients with otherwise intractable disease.

Approach to pharmacotherapy — The goals of pain management in patients with CRPS are to allow active participation in a rehabilitation regimen and to restore movement and strength of the affected limb. Multiple treatment modalities are available to provide pain relief in patients with CRPS. The key to success is to use analgesics to reduce pain so that patients can tolerate PT, always balancing efficacy with safety.

Both pharmacologic and interventional procedures for pain control are used in an escalating fashion, beginning with those that are relatively safe and for which there is some evidence of effectiveness, and progressing to more risky interventions if a desired response is not achieved after a few weeks of therapeutic trial. Absent high-quality data for any individual drug or class of drugs and lacking comparative data, pharmacologic therapy is individualized based on consideration of patient age, comorbidities, concurrent medications, drug interactions, and side effects. For patients with early CRPS, this approach generally encompasses one or more of the following agents:

A nonsteroidal anti-inflammatory drug (NSAID). A typical initial regimen is ibuprofen 400 to 800 mg three times a day or naproxen 250 to 500 mg twice daily. Dose adjustments must be made for older adult patients. (See 'Nonopioid oral analgesics' below.)

An adjunctive medication for neuropathic pain, such as gabapentin, pregabalin, or a tricyclic antidepressant. (See 'Adjuvant medications for neuropathic pain' below.)

A course of bisphosphonate treatment in patients with CRPS and evidence of abnormal uptake on bone scan. (See 'Bisphosphonates' below.)

Topical lidocaine cream (2 to 5%) or topical capsaicin cream (0.025 to 0.075%), which may be discontinued if it is too irritating or if there is no benefit after three to five days of use. The author prefers topical lidocaine instead of capsaicin for most patients. (See 'Topical creams' below.)

The duration of therapy is also individualized. For all medications except bisphosphonates (which, if used, are given as a discrete course), therapy is generally continued as long as the patient has significant symptom burden, benefits are evident, and side effects are tolerable. Once symptoms improve, medications can be gradually tapered.

Nonopioid oral analgesics — NSAIDs are often used in the initial treatment of CRPS, and some experts find them effective for some patients [1], but they are not well studied for this condition [29,30]. A typical initial regimen is ibuprofen 400 to 800 mg three times a day or naproxen 250 to 500 mg twice daily for two to four weeks, after which time it should be clear whether the medication has improved pain or not.

Continuous long-term use of NSAIDs at these doses is not practical or advised, and therefore NSAIDs are generally combined with any of the other agents listed below so that NSAIDs can be tapered or eliminated over time. For patients who cannot tolerate nonselective NSAIDs, a selective cyclooxygenase 2 (COX-2) inhibitor is an alternative option, although direct data in CRPS are lacking.

Adjuvant medications for neuropathic pain — Although the pathogenesis of CRPS is not well established, neurogenic inflammation and changes in central pain perception have been suspected to play a role, thereby providing rationale for use of medications with some evidence of benefit in other neuropathic pain conditions [29].

Anticonvulsants – Although unproven in CRPS, the author's clinical experience suggests that anticonvulsants such as gabapentin and pregabalin may be useful for pain management. However, other experts believe that these medications have only a marginal and clinically unimportant benefit for CRPS [31], and there is growing awareness of the potential for misuse and abuse of these drugs [32] as well as risk of respiratory dysfunction when used in combination with other central nervous system depressants [33].

When used, these medications should be started at low doses and titrated gradually as needed and tolerated. For gabapentin, we use a starting dose of 100 mg at bedtime for older adults and 300 mg at bedtime for most other patients. Both drugs may cause dose-dependent dizziness and sedation that can be reduced by starting with lower doses and titrating cautiously. Dosing and administration of gabapentin and pregabalin for chronic pain are reviewed in more detail separately. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antiseizure medications'.)

Supporting data for the efficacy of adjunctive anticonvulsants in CRPS are limited or absent [8,32]. In one randomized cross-over trial of 58 patients with CRPS, gabapentin (titrated to maximum of 1800 mg daily) was associated with a small reduction in pain scores at three weeks that was not statistically significant [34]. A 2021 systematic review found that gabapentin was associated with improvement in pain in three studies but the available data were insufficient to recommend its use [35]. Pregabalin has not been studied directly in CRPS.

Antidepressants – Though not specifically studied in CRPS, certain antidepressant medications can be effective in reducing neuropathic pain [29]. The author's clinical experience suggests that tricyclic antidepressants reduce pain and are a valuable addition to PT for patients with CRPS. A typical starting dose of amitriptyline or nortriptyline can be used (10 to 25 mg at bedtime or earlier in the evening if morning drowsiness occurs), followed by gradual increase in the dose, as tolerated.

Other tricyclic antidepressants and dual uptake inhibitors that are indicated for treatment of neuropathic pain are alternatives to amitriptyline and nortriptyline. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Antidepressants'.)

Bisphosphonates — A course of bisphosphonate therapy can be considered for pain reduction in patients with early CRPS who have abnormal uptake on bone scan, based on evidence from several small randomized trials [8,36]. The mechanism of analgesic effect in CRPS is uncertain but is probably not related to the antiresorptive properties of bisphosphonates. Proposed mechanisms include decreased proton concentration in the bone microenvironment, altering pain signal transduction via acid-sensitive ion channels, and decreased production of tumor necrosis factor and other proinflammatory mediators [37-40].

The author's experience with bisphosphonates in CRPS is limited, and choice of drug and dosing should be informed by the trials reviewed below. Supporting evidence comes from several small placebo-controlled randomized trials, including trials of alendronate, intravenous neridronate (not available in the United States), intravenous pamidronate, and intravenous clodronate (available in Canada) [30,41-45]. Four of these trials enrolled only patients who had evidence of osteopenic or osteoporotic changes in the affected limb [41-43,45]. Illustrative trials include the following:

The largest trial enrolled 82 subjects with CRPS of the hand or foot who had a disease duration of four months or less and abnormal uptake in early and late phases of three-phase bone scintigraphy [43]. The trial participants were randomly assigned to intravenous neridronate (100 mg given four times over 10 days) or placebo. At the end of the double-blind phase, 40 days after the first infusion, there was a significantly greater decrease in the visual analog pain scale for the neridronate treatment group compared with the placebo group (-47 mm versus -22.6 mm). Neridronate also led to improvement on several secondary outcomes including indices of quality of life. The most common adverse events were acute-phase reactions (polyarthralgia and fever) with bisphosphonate administration; no serious adverse events were reported.

Oral alendronate at a dose of 40 mg daily for eight weeks (extrapolated from dosing used in Paget disease) was compared with placebo in 40 patients with traumatic CRPS of the lower extremity who had evidence of regional osteoporosis on bone radiographs and an abnormal bone scan [42]. At both 8 and 12 weeks, visual analog pain scores, pressure tolerance, and mobility scores were better with alendronate than placebo. At study end, pain scores in the alendronate group were approximately one-third of those in the placebo group on a 100 mm visual scale. One patient discontinued alendronate after two weeks due to gastrointestinal intolerance.

Another trial randomly assigned 32 patients with early CRPS either to 300 mg of intravenous clodronate given daily for 10 days or to placebo [45]. After 40 days, pain decreased by a mean of 36 and 6 mm (on a 100 mm visual analog pain scale) in the clodronate and placebo groups, respectively, a difference that was statistically significant. The only side effect of active therapy was asymptomatic hypocalcemia in three patients.

Adverse effects of bisphosphonates are uncommon and include transient hypocalcemia, flu-like symptoms (for intravenous infusions), musculoskeletal pain, renal toxicity, and ocular side effects. When bisphosphonates are used for osteoporosis, supplemental calcium and vitamin D are typically provided concurrently. (See "Risks of bisphosphonate therapy in patients with osteoporosis".)

Serious adverse effects of bisphosphonates include esophageal ulceration with oral use and osteonecrosis of the jaw. Patients who have difficulty swallowing, those with disordered esophageal motility, and those who cannot sit or stand for 30 minutes should not receive oral bisphosphonate therapy. Most reported cases of osteonecrosis have been in patients with malignant disease receiving potent intravenous bisphosphonates. However, osteonecrosis has been reported in some patients receiving oral bisphosphonates for benign disorders. (See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy", section on 'Osteonecrosis of the jaw' and "Clinical manifestations and diagnosis of osteonecrosis (avascular necrosis of bone)", section on 'Medications and drugs'.)

Topical creams — Topical application of lidocaine or capsaicin cream is used for treating neuropathic pain, but only limited data suggest efficacy in CRPS [29,46]. They are probably best suited for patients with early CRPS and mild to moderate pain despite the use of anticonvulsants, antidepressants, and/or NSAIDs. A treatment trial of three to five days may suffice to assess effectiveness and tolerability of these agents.

By analogy with treatment of painful diabetic neuropathy, lidocaine or capsaicin cream may be applied topically three to four times daily over painful areas. Local burning and skin irritation that occur with capsaicin limit its widespread use, even though this may become less of a problem with continued use. (See "Management of diabetic neuropathy", section on 'Topical therapies or neuromodulation'.)

Some practitioners use compound cream (formulated mixture of local anesthetics, antidepressants, and/or anticonvulsants) based on efficacy for constituent agents [47]. However, there is no compelling data to support the efficacy of these formulations.

Less favorable risk:benefit ratio — In patients with progressive CRPS who are unwilling to consider interventional procedures, sequential addition of pharmacologic agents with either lower-quality evidence or higher risk can be considered. Among these options, calcitonin and oral glucocorticoids are the most reasonable to consider.

Calcitonin – Considering weak evidence for efficacy in CRPS yet low risk associated with its use, calcitonin is an option in combination with PT for patients who have mild or moderate symptoms despite the use of the agents discussed above. The rationale for use in CRPS involves the ability of calcitonin to retard bone resorption and a putative analgesic effect. The mechanism responsible for analgesia is uncertain. (See "Calcitonin in the prevention and treatment of osteoporosis".)

The optimal dose and duration of calcitonin treatment in CRPS is uncertain. A dose of 300 international units daily was used in the one positive randomized trial [48]. If pain and/or function improve during a two- to four-week trial period, it can be continued for up to three months; the safety of more prolonged use is not established.

There is conflicting evidence regarding the benefit of calcitonin for CRPS [8,30,36]. Calcitonin has been evaluated in three small placebo-controlled randomized trials for the treatment of CRPS, including two of nasal calcitonin [48,49] and one of subcutaneous calcitonin [50]. However, only one of these three trials detected benefit [48].

Glucocorticoids – Supporting evidence for the use of oral glucocorticoids in CRPS is very weak, and the risk of side effects and long-term toxicities outweighs potential benefits in most cases.

Oral glucocorticoids (eg, divided doses of prednisone, 30 to 80 mg/day) have been studied for early CRPS, but there is only low-quality evidence from small randomized trials with substantial methodologic limitations [8,30]. The findings of one small trial suggested that oral glucocorticoids are more effective than NSAIDs [51]. The trial randomly assigned 60 patients with CRPS following stroke to prednisolone (40 mg daily) or piroxicam (20 mg daily) for one month. At one month, a significantly greater proportion of patients in the prednisolone group than those receiving piroxicam met criteria for improvement (83 versus 17 percent, respectively). Patients with chronic CRPS usually do not respond to glucocorticoids.

Alpha-adrenergic antagonists and agonists – Sympathetically maintained pain may respond to the addition of an alpha-1 adrenoceptor antagonist, which is supported by the clinical experience of the author and other experts [52]. The author has noted apparent benefit in some patients with the use of either prazosin (1 to 6 mg/day as tolerated) or phenoxybenzamine (10 to 30 mg/day as tolerated). Hypotension can be a limiting side effect of alpha-adrenergic blockers. The author has also treated patients using a clonidine patch (0.1 mg), which is changed every seven days, usually in combination with anticonvulsants and/or antidepressants; this approach has generally not resulted in significant side effects.

Ketamine infusion – Systematic reviews have found that there is only low- to moderate-quality evidence supporting the use of subanesthetic doses of ketamine for CRPS [8,30,53-55]. In one of the higher-quality randomized trials, ketamine infusion was compared with placebo in 60 patients with type I CRPS [56]. Patients assigned to five-day ketamine infusions had a statistically significant decline in pain scores from weeks 1 through 11 of follow-up compared with the placebo group, but the reduction was no longer statistically significant by week 12. Frequent side effects of ketamine in this trial included psychomimetic symptoms (eg, hallucinations, delirium), nausea, and vomiting.

Dosing and delivery methods are not standardized, and there is a need for further research and validation [57]. In the author's practice, ketamine infusion is a last option after trying sympathetic blocks and/or pharmacologic treatment using traditional neuropathic pain medications. A treatment plan is individualized, taking into consideration age, comorbidities, severity of pain, where the infusion will be administered, and the availability of monitoring and skilled personnel. The author typically uses an initial dose of 0.25 to 0.5 mg/kg diluted in 100 mL solution, infused over one to four hours. A bolus dose of intravenous midazolam (eg, 0.5 to 2 mg) is used for premedication to prevent acute side effects from ketamine. Some patients may require antinausea medication before or during the procedure. Patients are observed in a postanesthesia recovery room prior to discharge to home. In patients who respond to ketamine infusion, the effect usually lasts for 4 to 12 weeks. The author recommends against use of oral ketamine based on safety concerns and risk of abuse or diversion. (See "Pharmacologic management of chronic non-cancer pain in adults", section on 'Ketamine'.)

Opioids – The use of opioids for chronic noncancer pain is controversial, and there is a paucity of high-quality data supporting their efficacy for CRPS [29,58]. Based on the author's clinical experience, there are patients who can benefit from a small dose of opioids in combination with other drugs for neuropathic pain described above. Other experts recommend against use of opioids in this setting. If opioids are used in patients with CRPS, escalating the dose can result in the risk outweighing the benefit. Response to treatment and quality of life need to be regularly evaluated during follow-up visits. Prescribing clinicians must be prepared to follow safe prescribing practices, including an evaluation of risk prior to initiating therapy and setting patient responsibilities, expectations, and treatment goals. (See "Use of opioids in the management of chronic non-cancer pain".)

Ineffective therapies — Intravenous immune globulin (IVIG) does not appear to be beneficial for CRPS, despite promising preliminary studies. A single-center randomized trial involving 13 patients with CRPS found that low-dose IVIG reduced pain at 6 to 19 days following infusion by a modest degree compared with normal saline [59]. However, in a later multicenter randomized trial of 111 patients with chronic CRPS of one to five years duration, low-dose IVIG given for six weeks was not effective for pain reduction compared with placebo [60].

INTERVENTIONAL OPTIONS FOR REFRACTORY PAIN — Referral to a pain management specialist with experience in management of CRPS is appropriate for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to the measures outlined above, as well as for patients with severe or chronic CRPS.

Procedure selection and rationale — Interventional procedures for the treatment of pain related to CRPS include trigger/tender point injections, regional sympathetic nerve block, spinal cord stimulation, epidural clonidine, and chemical or mechanical sympathectomy, among others. The published evidence for these methods, though generally limited and of low quality, does not support their efficacy. However, in the author's clinical experience, a number of patients derive meaningful benefit from these interventional procedures.

Patients receiving noninvasive therapy who are not improving are candidates for increasingly invasive interventions, allowing two weeks for improvement before moving on to the next type of treatment. In some tertiary centers, spinal cord stimulation, arguably the most invasive therapy, would be considered by 12 to 16 weeks from the time therapy for CRPS is initiated [61]. The author prefers to begin with sympathetic nerve blocks and reserves the use of spinal cord stimulation for willing patients who do not respond to sympathetic nerve blocks.

Trigger point/tender point injections — Trigger/tender points may be found about the shoulder girdle when CRPS is limited to the upper limb. These trigger/tender points are located in the trapezius and suprascapular muscles in most patients. If unilateral involvement occurs, the other side can be used for comparison. The author's clinical experience is that trigger/tender point injections are sometimes effective and are safer than other treatment modalities. Injection of each trigger/tender point with local anesthetics with or without glucocorticoids is used for patients with early CRPS, before proceeding to more invasive and risky procedures.

Sympathetic nerve blocks — Sympathetic nerve block is an option at centers with expertise in this technique for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to standard pharmacologic treatment. Temporary regional sympathetic nerve block usually involves infiltration of a local anesthetic (eg, lidocaine, bupivacaine) into the region of the relevant sympathetic ganglia (ie, stellate ganglion for CRPS of the upper extremity, lumbar sympathetic ganglion for CRPS of the lower extremity), under fluoroscopic or ultrasound guidance. Alternatively, sympathetic blockade can be achieved by slow intravenous injection of an antiadrenergic drug (eg, guanethidine) into the vein of the affected extremity with a tourniquet applied to the extremity to occlude circulation (ie, Bier block).

However, the limited evidence base for sympathetic block as a treatment for CRPS is conflicting. Small trials comparing nerve block with sham/placebo or other active comparators have failed to show a difference in short-term pain reduction [62], but other studies have suggested benefit in selected patients [63,64]. Despite weak supporting evidence in the literature, it is the author's experience, and that of many interventional pain clinicians, that the aforementioned procedures could be beneficial for many patients and life changing for some. The range of evidence includes the following:

A systematic review updated in 2016 identified 12 randomized trials with a total of 461 participants that evaluated the effect of local anesthetic sympathetic block in children or adults with CRPS [62]. All the included trials were considered to have a high or unclear risk of bias. The following observations were noted:

Two small trials compared regional local anesthetic sympathetic nerve block with sham or placebo and found no difference for short-term pain reduction.

Two trials investigated regional local anesthetic sympathetic nerve block as an addition to rehabilitation treatment; only one of these reported pain outcomes and found no additional benefit from regional sympathetic nerve block.

Eight small trials compared local anesthetic sympathetic blockade with a different active intervention. In most of these reports, there was no difference between sympathetic block and other active treatments for pain outcomes.

A retrospective review identified 318 patients who underwent successful sympathetic blocks for CRPS (80 percent) or other painful conditions at an academic tertiary care pain management center in the United States [63]. Blocks included lumbar sympathetic (83 percent), stellate ganglion (16 percent), and thoracic sympathetic (<1 percent). Patients who received an unsuccessful block (defined by authors as a postprocedure temperature rise <1.5°C) were excluded from the study (n = 166); other notable exclusions were patients for whom preprocedure temperature or pain evaluations were missing (n = 125). Pain relief (>50 percent) was reported by 68 percent of patients, of whom the majority endorsed pain relief for one to four weeks (71 percent) or longer (14 percent). Limitations of the study include the selected nature of the analyzed cohort and the inability to exclude placebo effect.

A 2010 guideline noted that intravenous sympathetic blockade with guanethidine for CRPS, as evaluated in eight small studies, had no added value for pain reduction compared with placebo [29].

Implanted devices

Spinal cord and peripheral nerve stimulation — Spinal cord stimulation (SCS; also termed "dorsal column stimulation") and peripheral nerve stimulation (PNS) are invasive neuromodulation strategies, which may be helpful if traditional therapeutic modalities fail [31], particularly in patients with disease limited to one extremity.

SCS plus PT reduced pain and improved health-related quality of life more than PT alone for up to two years in a study of 36 patients and 18 controls but did not improve functional outcome measures [65,66]. No difference in pain was present during the period from three to five years following implantation [67]. Methodologic limitations of this trial include lack of sham intervention for control group and unblinded outcome assessment [68]. In another small trial of 31 patients with CRPS, tonic SCS improved sensory thresholds and reduced pain, allodynia, and hyperalgesia at three-month follow-up [69].

PNS was associated with improved function and reduced long-term pain in 240 patients with CRPS from a single center assessed a median of 74 months after PNS implantation [70]. In addition, a small study reported that direct sciatic nerve electrical stimulation helped to control disabling foot pain, dystonia, and autonomic features in CRPS I, some of whom failed SCS [71].

Complications of neuromodulation techniques are mostly associated with improper positioning of the electrode. This technique should only be attempted at expert centers [31]. (See "Spinal cord stimulation: Placement and management".)

Dorsal root ganglia stimulation — With advances in neuromodulation technology, some interventional pain centers are using dorsal root ganglia (DRG) stimulation either as the first choice of neuromodulation or in cases where SCS and/or PNS has failed. Some data suggest that DRG stimulation might have better outcomes than SCS [72-74]. Risks and complications are similar to those of SCS. (See "Spinal cord stimulation: Placement and management".)

Other modalities

Epidural clonidineClonidine administered by epidural injection or infusion may reduce the pain of CRPS, but side effects such as hypotension and sedation can occur depending upon the dose [75,76]. Potential complications of epidural injection have limited study of this treatment to patients with severe refractory CRPS.

We suggest that epidural clonidine be used only for patients refractory to other, less invasive approaches. The author has experience in using clonidine in combination with local anesthetics for stellate ganglion and lumbar sympathetic nerve blocks successfully, but its value needs to be systematically studied.

In one trial, 26 patients with severe chronic CRPS that was unresponsive to sympathetic blocks were randomly assigned to epidural clonidine (300 or 700 microgram bolus injection) or to placebo and were assessed for up to six hours [76]. Epidural clonidine provided greater pain relief than placebo injections. Pain relief was similar with both doses of epidural clonidine, though numeric pain scores were not provided in the report [8].

Sympathectomy – Sympathectomy for CRPS has not been compared with placebo or sham surgery in randomized controlled trials [77]. Low-quality observational evidence suggests the possibility of benefit from chemical or surgical sympathectomy. However, sympathectomy is associated with high rates of adverse effects including increased pain, new neuropathic pain, and bothersome sweating [78].

In the author's experience, aggressive PT, pain management, and encouragement of the patient to work beyond the pain typically obviates the need for procedural treatments. Sympathectomy should be used only in patients who have shown a previous response to nerve blockade (eg, who have sympathetically dependent pain) and who are fully informed about the potential complications of the procedure.

Other modalities have been described selectively in patients with uncommon complications of CRPS. Intrathecal baclofen may relieve dystonia in patients with CRPS [79], though data are limited [29]. Focal dystonia may also respond to botulinum toxin injections [1,4]. Hyperbaric oxygen therapy may be useful when skin breakdown and ulcer occurs in CRPS patients. However, it may take many sessions to achieve benefit, and only one randomized trial supports the use of this approach [80].

PROGNOSIS

Long-term disability — The prognosis of CRPS is uncertain, with highly variable rates of poor and favorable outcomes in different studies. Nevertheless, a substantial proportion of patients have some degree of prolonged disability. The range of findings is illustrated by the following:

In a population-based report of 102 Dutch patients with CRPS followed for an average of 5.8 years since disease onset, the following outcomes were observed [81]:

Ongoing CRPS fulfilling diagnostic criteria was present in 64 percent.

Patients considered themselves as recovered, stable, or worse due to progressive disease in 30, 54, and 16 percent of cases, respectively.

Patients resumed their previous work completely, resumed work with adjustments, or were unable to work in 41, 28, and 31 percent of cases, respectively.

A retrospective population-based study of 74 cases of CRPS found that resolution of symptoms, sometimes spontaneously, occurred in 74 percent of patients [82]. Symptom duration ranged from 1 to 60 months (median 7 months).

Litigation and work-related compensation issues are involved in a substantial proportion of cases of CRPS cared for in tertiary pain management clinics, present in 17 and 54 percent, respectively, in one study in the United States [83].

Risk of recurrence — Recurrence of CRPS is not uncommon; estimates of recurrence range from approximately 10 to 30 percent, with the higher rates occurring in younger patients, including children [84,85]. Recurrences can occur spontaneously or with cold exposure, but they also appear to be triggered by trauma or new surgery of the affected limb or of an unaffected remote site and by emotional trauma [85-88]. (See "Complex regional pain syndrome in children".)

In a study of 1183 consecutive patients with CRPS, recurrences were seen in 10 percent of patients [85]. The recurrence of CRPS occurred twice as often in a different limb than in the initial episode (76 patients) compared with recurrence in the originally affected limb that had become largely asymptomatic (34 patients). In 10 patients, CRPS started in symmetric limbs. Recurrences were usually spontaneous (53 percent) and were often associated with few signs and symptoms. Most of the remainder was associated with trauma or surgery (32 and 12 percent, respectively). The estimated incidence of a recurrence was 1.8 percent per patient per year.

PREVENTION

Role of vitamin C after distal radius fracture — There has been interest in preventive strategies for CRPS in high-risk groups, such as older patients with distal radius fractures. Vitamin C in particular has been suggested as a low-risk intervention that might accelerate fracture healing and limit excessive soft tissue injury via antioxidant mechanisms. However, data in patients have been inconsistent.

Support for vitamin C is based on results of two randomized trials from the same group [89,90]. In the larger of the two trials, 416 older females with distal wrist fractures were randomly assigned to one of three daily doses of vitamin C (200, 500, or 1500 mg) or placebo for 50 days [90]. Over a one-year follow-up period, CRPS was less prevalent in those who received vitamin C (any dose versus placebo, 2.4 versus 10.1 percent). A subsequent trial of vitamin C (500 mg daily) versus placebo in 336 adults with acute distal radius fractures found no difference between groups in the rate of CRPS (8 percent in both groups), disability scores, and other functional outcomes at six weeks and one year post-fracture [91]. A 2021 systematic review of approximately 2000 patients found that prophylactic vitamin C at 500 to 1000 mg daily dose for up to 50 days after orthopedic injury or trauma was associated with reduced rates of CRPS [92]. A meta-analysis of the three trials (n = 890) found a nonsignificant trend toward benefit of vitamin C (risk ratio 0.45, 95% CI 0.18-1.13) [93]. Overall quality of the evidence was assessed as low based on the low number of events and inconsistency among trials.

While vitamin C is a low-risk intervention, we do not find the evidence to be compelling enough to warrant routine use in all patients with distal fractures or other high-risk injuries. We counsel all adults with fractures to maintain adequate whole-food intake of protein, vitamin C, calcium, and vitamin D for six to eight weeks following fracture to promote healing. Vitamin C is reasonable to supplement for six to eight weeks after distal radius fractures in patients with poor baseline nutritional status or those who cannot comply with whole-food intake. A typical dose is 500 mg daily. (See "General principles of definitive fracture management", section on 'Overview and basic measures including nutrition'.)

A 2009 clinical guideline from the American Academy of Orthopaedic Surgeons includes a moderate-strength recommendation for vitamin C in patients with distal radius fractures for the prevention of disproportionate pain but has not been revised since publication of the third randomized trial [94]. At least one CRPS guideline also includes a recommendation for vitamin C for preventive purposes [29].

Early mobilization after limb injury may also reduce the risk of CRPS, though there are no high-quality data to confirm benefit. Patients with fractures require accurate assessment of fracture healing to strike an appropriate balance between proper fracture healing, which requires a sufficient period of immobilization, and avoidance of prolonged immobilization, which increases the risk of complications. (See "General principles of acute fracture management" and "General principles of definitive fracture management", section on 'Fracture healing'.)

Care of patients with a history of CRPS — There is limited evidence to guide strategies for the prevention of recurrences or relapses of CRPS. Elective surgery should be performed when features of previous episodes of CRPS have improved and when the patient is stable; surgery should be avoided during exacerbations. Additional perioperative and surgical strategies include maintenance of optimal perfusion of the affected limb, avoidance of tourniquet hemostasis, and perioperative intravenous infusion of mannitol. In one series of 47 patients with CRPS undergoing surgery involving a previously affected extremity, use of these measures was associated with a recurrence rate of CRPS of 13 percent. The recurrence was mild and temporary in five of the six patients in whom it occurred [95].

Other measures that have been proposed to prevent or minimize risk of recurrence include intensive rehabilitation, sympathetic block before surgery, regional anesthesia/analgesia techniques, pretreatment with perioperative calcitonin prophylaxis, and neuromodulation postsurgery [86,87,96-98]. However, the data supporting use of these approaches are limited. Most reports are of small case series, and some are limited to children. Thus, these approaches have not been tested in randomized trials, and it is uncertain whether the results in children can be generalized to CRPS in adults. CRPS in children is reviewed separately. (See "Complex regional pain syndrome in children".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain" and "Society guideline links: Complex regional pain syndrome".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Complex regional pain syndrome (The Basics)")

SUMMARY AND RECOMMENDATIONS

Multidisciplinary therapeutic approach – A multidisciplinary approach is suggested for the management of complex regional pain syndrome (CRPS). Interventions appropriate for all patients with CRPS include patient education, physical therapy (PT), and occupational therapy (OT). (See 'General principles' above.)

Physical and occupational therapy – We suggest referral to an appropriate therapist immediately after the diagnosis is established. PT, which can be performed twice daily at home for patients in all stages of disease, should ideally begin before limitation of movement occurs to maintain range of motion and prevent contractures. (See 'Physical and occupational therapy' above.)

Psychosocial and behavioral therapy – Patients with CRPS who have preexisting or suspected psychologic or psychiatric issues and those who have insufficient improvement with physical and pharmacologic therapies may benefit from psychosocial and behavioral management. (See 'Psychosocial and behavioral therapy' above.)

Pharmacotherapy

Titration and goals – Pharmacologic and invasive procedures for pain control are individualized and generally used in an escalating fashion, beginning with those that are relatively safe and for which there is some evidence of effectiveness and progressing to other interventions if a desired response is not achieved after a few weeks of therapeutic trial. The goals of pain management are to allow active participation in a rehabilitation regimen and to restore movement and strength of the affected limb. (See 'Approach to pharmacotherapy' above.)

Medication options – For patients with early CRPS who require treatment for pain, we suggest starting with one (or more) of the following agents (Grade 2C):

-Ibuprofen 400 to 800 mg three times a day or naproxen 250 to 500 mg twice daily (see 'Nonopioid oral analgesics' above)

-An adjunctive medication for neuropathic pain, such as gabapentin, amitriptyline, or nortriptyline (see 'Adjuvant medications for neuropathic pain' above)

-A short-term bisphosphonate course for patients with early CRPS who have pain and abnormal uptake on bone scan (see 'Bisphosphonates' above)

-Topical lidocaine cream (2 to 5%) or topical capsaicin cream (0.075%) (see 'Topical creams' above)

Management of patients with refractory pain – Referral to a pain management specialist with experience in management of CRPS is appropriate for patients with progressive symptoms and signs of CRPS who have an unsatisfactory response to initial measures. Interventional options for such patients include trigger/tender point injections, regional sympathetic nerve block, and spinal cord or peripheral nerve stimulation. (See 'Interventional options for refractory pain' above.)

Prognosis – The prognosis of CRPS is uncertain, but a substantial proportion of patients have some degree of prolonged disability. (See 'Prognosis' above.)

Prevention – We counsel all adults with fractures to maintain adequate whole-food intake of protein, vitamin C, calcium, and vitamin D for six to eight weeks following fracture to promote healing. For patients with distal radius fractures who have poor baseline nutritional status or who cannot comply with whole-food intake, we suggest vitamin C supplementation (Grade 2C). A typical dose of vitamin C is 500 mg orally daily for six to eight weeks after fracture. (See 'Prevention' above.)

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References

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