title: Lenalidomide for complex regional pain syndrome type 1: lack of efficacy in a phase II randomized study.
abstract: Complex regional pain syndrome (CRPS) is a potentially debilitating chronic pain syndrome with a poorly understood but likely neuroimmune/multifactorial pathophysiology associated with axonal injury. Based on the potential contribution of proinflammatory cytokines to CRPS pathogenesis and prior research with thalidomide, we investigated lenalidomide, a thalidomide derivative, for CRPS treatment. We conducted a phase II, randomized, double-blind, placebo-controlled study to evaluate the efficacy of oral lenalidomide 10 mg once daily in consenting patients with unilateral or bilateral CRPS type 1. The study comprised 12 weeks of treatment followed by a long-term extension. The primary efficacy outcome was reduced pain in the index limb, defined as ≥30% improvement from baseline using an 11-point numeric rating scale. One hundred eighty-four subjects enrolled. The primary endpoint was not met because equal proportions of treated (16.1%) and control (16.1%) subjects achieved the outcome; however, lenalidomide was well tolerated, with no evidence of neuropathy or major adverse effects. This study is the largest controlled, blinded clinical trial in subjects with chronic CRPS using the Budapest research criteria. It demonstrates the feasibility of conducting high-quality clinical trials in CRPS type 1 and provides considerations for designing future trials.
  
  
  CONCLUSIONS
  This article reports an adequately powered, controlled clinical trial in subjects with CRPS. Treatment and placebo were equally effective, but the study demonstrated that lenalidomide treatment is feasible in this population. The study provides examples to consider in designing future CRPS trials.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, Charlottesville, Virginia; Adynxx Inc, San Francisco, California. Electronic address: donaldcmanning@gmail.com.
authors.forename: Donald C
authors.initials: DC
authors.lastname: Manning
authors.affiliation: Department of Neurology, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Alexander
authors.affiliation: Department of Neuroscience and Neurology, Albert Einstein College of Medicine, Bronx, New York.
authors.forename: Joseph C
authors.initials: JC
authors.lastname: Arezzo
authors.affiliation: Celgene Corporation, Summit, New Jersey.
authors.forename: Alyse
authors.initials: A
authors.lastname: Cooper
authors.affiliation: Center for Pain Studies, Rehabilitation Institute of Chicago, Chicago, Illinois.
authors.forename: R Norman
authors.initials: RN
authors.lastname: Harden
authors.affiliation: Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts; Department of Pathology (Neuropathology), Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
authors.forename: Anne Louise
authors.initials: AL
authors.lastname: Oaklander
authors.affiliation: Division of Pain Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Srinivasa N
authors.initials: SN
authors.lastname: Raja
authors.affiliation: Center for Clinical Research, Salem, North Carolina.
authors.forename: Richard
authors.initials: R
authors.lastname: Rauck
authors.affiliation: Department of Neurology, Drexel University, Philadelphia, Pennsylvania.
authors.forename: Robert
authors.initials: R
authors.lastname: Schwartzman
mesh_terms: D000368:Aged; D018712:Analgesics, Non-Narcotic / Q000009:adverse effects / Q000627:therapeutic use*; D002908:Chronic Disease; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D012019:Reflex Sympathetic Dystrophy / Q000188:drug therapy* / Q000503:physiopathology; D013792:Thalidomide / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018712:Analgesics, Non-Narcotic; D013792:Thalidomide; D000077269:Lenalidomide
keywords: Complex regional pain syndrome; clinical trial; cytokines; immunomodulation; lenalidomide; thalidomide