Complex regional pain syndrome: Which treatments show promise?

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Applied Evidence

Complex regional pain syndrome: Which treatments show promise?

J Fam Pract. 2005 July;54(7):599-603

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References

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2. Commentary on RSD focus article Bandolier 2002. Available at:www.jr2.ox.ac.uk/bandolier/booth/painpag/wisdom/RSD.html.

3. Petchkrua W, Weiss DJ, Patel RR. Reassessment of the incidence of complex regional pain syndrome type 1 following stroke. Neurorehabil Neural Repair 2000;14:59-63.

4. Braus DF, Krauss JK, Strobel J. The shoulder-hand syndrome after stroke: a prospective clinical trial. Ann Neurol 1994;36:728-733.

5. Zollinger PE, Tuienebreijer WE, Kreis RW, Breederveld RS. Effect of vitamin C on frequency of reflex sympathetic dystrophy in wrist fractures: a randomised trial. Lancet 1999;354:2025-2028.

6. Kingery WS. A critical review of controlled clinical trials for peripheral neuropathic pain and complex regional pain syndromes. Pain 1997;73:123-139.

7. Perez RS, Kwakkel G, Zuurmond WW, de Lange JJ. Treatment of reflex sympathetic dystrophy (CRPS type 1). a research synthesis of 21 randomized clinical trials. J Pain Symptom Manage 2001;21:511-526.

8. Jadad AR, Carroll D, Glynn CJ, McQuay HJ. Intravenous regional sympathetic blockade for pain relief in reflex sympathetic dystrophy: a systematic review and a randomized, double-blind crossover study. J Pain Symptom Manage 1995;10:13-20.

9. Turner JA, Loeser JD, Deyo RA, Sanders SB. Spinal cord stimulation for patients with failed back surgery syndrome or complex regional pain syndrome: a systematic review of effectiveness and complications. Pain 2004;108:137-147.

10. Grabow TS, Tella PK, Raja SN. Spinal cord stimulation for complex regional pain syndrome: an evidencebased medicine review of the literature. Clin J Pain 2003;19:371-383.

11. Geurts AC, Visschers BA, van Limbeek J, et al. Systematic review of aetiology and treatment of post-stroke hand oedma and shoulder-hand syndrome. Scan J Rehabil Med 2000;32:4-10.

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13. Price DD, Long S, Wilsey B, Rafii A. Analysis of peak magnitude and duration of analgesia produced by local anesthetics injected into sympathetic ganglia of complex regional pain syndrome patients. Clin J Pain 1998;14:216-226.

14. Adami S, Fossaluzza V, Gatti D, et al. Bisphosphonate therapy of reflex sympathetic dystrophy syndrome. Ann Rheum Dis 1997;56:201-204.

15. Varenna M, Zucchi F, Ghiringhelli D, et al. Intravenous clodronate in the treatment of reflex sympathetic dystrophy syndrome. A randomized double blind, placebo controlled study. J Rheumatol 2000;27:1477-1483.

16. Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M. The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: two years’ follow-up of the randomized controlled trial. Ann Neurol 2004;55:13-18.

17. Oerlemans HM, Goris JA, de Boo T, Oostendorp RA. Do physical therapy and occupational therapy reduce the impairment percentage in reflex sympathetic dystrophy? Am J Phys Med Rehabil 1999;78:533-539.

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Psychological therapy starts with teaching patients that 1) pain sensations in CRPS type 1 do not indicate tissue damage, and 2) reactivation of the affected limb is important. With persistent symptoms, clinical psychological assessment is recommended, eventually followed by cognitive behavioral therapy.

Pain management starts with oral or topical medications typically used for other neuropathic pain conditions (eg, amitriptyline (Elavil), gabapentin (Neurontin), opioids, and nonsteroidal antidepressants). The guideline also recommends steroids, calcitonin, and alpha-1 adrenoceptor antagonists (terazosin [Hytrin] or phenoxybenzamine [Dibenzylene]). With persistent symptoms, intravenous regional sympathetic blocks (IRSBs) and somatic nerve blocks are recommended. According to the guideline, treatment for resistant cases may progress to epidural catheters for sympathetic blockade, spinal cord stimulation, intrathecal baclofen (Lioresal), or sympathectomy.¹

Reviews of medication trials show minimal effectiveness

Meta-analyses and systematic reviews of the literature reveal that many of the treatments recommended in the guidelines are minimally if at all effective, or have been inadequately researched.^6-12 This is particularly so concerning invasive therapies such as sympathetic ganglion block,¹³ sympathectomy,¹² and spinal cord stimulation^9,10 that introduce the possibility of adverse effects. Yet, evidence is equally sparse for common pain therapies in CRPS type 1, such as nonsteroidal anti-inflammatory drugs, antidepressants, opiates, or antiseizure medications.

Systematic review and meta-analysis of medication trials for CRPS only partially agree.^6-8,11 A 1999 systematic review concluded that oral corticosteroids demonstrated a consistent and long-term analgesic effect in CRPS.⁶ This review identified only limited data to suggest an analgesic effect from topical dimethylsulfoxide (DMSO), epidural clonidine and IRSB with ketanserin (not available in the US), and bretylium. The review concluded there was contradictory evidence of an analgesic effect from calcitonin or intravenous phentolamine and most likely no effect, and evidence against the effectiveness of guanethidine and reserpine IRSBs, and droperidol and atropine IRSBs.⁶

A 1995 systematic review of IRSBs concluded as well that overall there was no effect on pain, but a single RCT of each bretylium and ketanserin showed an analgesic effect.⁸ In a systematic review focused on upper extremity post-stroke CRPS (also known as shoulder-hand syndrome), 1 RCT was identified, and indicated that corticosteroids had an analgesic effect.¹¹ High-quality evidence for the use of intramuscular calcitonin was lacking.¹¹

Calcitonin may be one exception. A systematic review of medical treatment for CRPS type 1 identified 21 randomized trials, enough to undertake a statistical analysis of the analgesic effect of 4 types of treatment: sympathetic suppressors, guanethidine, intravenous regional blocks, and calcitonin.⁷ Of the 4, only calcitonin appeared to have a significant beneficial effect on pain.⁷

IV bisphosphonates show promise. More recently, intravenous bisphosphonates have demonstrated clinical and analgesic benefits in 2 small but high-quality RCTs.^14,15 Strikingly, short-term therapy of 3 to 10 days of IV alendronate (Fosamax) or clodronate (Bonefos) without adverse effects resulted in significant overall improvements for the duration of the 2 trials, 4 weeks¹⁴ and 180 days.¹⁵

Nonpharmacologic treatments

Nonmedical treatments that have been studied include spinal cord stimulation, physical therapy, occupational therapy, and acupuncture. Spinal cord stimulation demonstrated a modest long-term (2-year) reduction in pain and improvement in health related quality of life in 1 RCT,¹⁶ but with no improvement in patient functioning and a 34% rate of adverse occurrences.⁹ Similarly, physical therapy and occupational therapy have been studied only in 1 large RCT (n=135).

Treatment with physical therapy did decrease pain compared with occupational therapy and control therapy,¹⁷ but revealed no improvement in active range of motion with physical or occupational therapy compared with control therapy.¹⁷ Furthermore, physical therapy led only to uncertain diminishment of impairment when data were analyzed in 2 different ways, 1 of which showed a benefit of physical and occupational therapy over control treatment,¹⁸ 1 of which did not.¹⁹

Acupuncture demonstrated no improvement over sham treatment.²⁰

Applying the evidence: Medical treatment

Choose any of the therapies least likely to do harm and supported by evidence of efficacy: topical 50% DMSO cream (SOR: B), intravenous bisphosphonates (SOR: A), or limited courses of oral corticosteroids (SOR: B). Despite some contradictory findings in the literature,^6,17,18 other studies demonstrate that physical therapy^18,19 and calcitonin⁷ reduce pain, and neither is likely to cause harm (SOR: B).

FAST TRACK

Despite some contradictory findings, studies demonstrate that physical therapy and calcitonin reduce pain and are unlikely to cause harm

Epidural clonidine injection,⁶ IRSB with bretylium,^6-8 and spinal cord stimulation^9,16 have demonstrated some efficacy, but due to the invasiveness of the treatments and the modest benefits, patients should be counseled carefully before initiating these therapies (SOR: B) (TABLE 1).

Therapies to avoid. Therapies to avoid due to lack of evidence, lack of efficacy, or likelihood of adverse outcomes include IV regional blocks with everything but bretylium,^6-8 sympathetic ganglion blocks with local anesthetics (very short duration of analgesia),¹³ systemic intravenous sympathetic inhibition,⁶ acupuncture,²⁰ and sympathectomy (SOR: B).¹²