Pharmacologic Treatments in Upper Extremity Complex Regional Pain Syndrome: A Review and Analysis of Quality of Evidence

Background: The purpose of this study was to assess the quality of evidence informing on common pharmacologic modalities used in upper extremity complex regional pain syndrome (CRPS). Methods: A literature search was performed for primary prospective trials that reported on the pharmacologic treatment of CRPS type I and II specific to the upper extremity. Thirty-one trials were included and evaluated by 2 independent reviewers according to the Oxford Levels of Evidence (LOE), modified Coleman Methodology Score, and the revised Consolidated Standards of Reporting Trials (CONSORT) score. Cohen’s kappa coefficient was calculated to measure interrater reliability. Results: Twenty-two Oxford LOE I and 9 level II trials met the inclusion criteria. Overall, there was high interrater reliability in the Oxford LOE (100% agreement), modified Coleman Methodology Score (87% agreement), and CONSORT score (94% agreement). The pharmacologic interventions with the highest quality of evidence supporting use in treatment of upper extremity CRPS were bisphosphonates and ketamine. Interventions that lack high-quality evidence are tricyclic antidepressants (TCAs) and topical dimethyl sulfoxide (DMSO). Pharmacologic agents that remain inconclusive are calcitonin, gabapentin, mycophenolate, probiotics, steroids, nonsteroidal anti-inflammatory drugs, vitamin C, and N-acetylcysteine. Agents with limited benefit are mannitol, isosorbide dinitrate, guanethidine, and morphine. Conclusions: Based on the evidence evaluated in this study, bisphosphonates should be considered as a first-line medication in the treatment of CRPS. In patients presenting with chronic or refractory CRPS, strong consideration should be given for the use of ketamine. Adjunct treatment in the acute setting should include TCAs and/or topical DMSO.