title: Placebo responses in long-standing complex regional pain syndrome: a systematic review and meta-analysis.
abstract: The typical placebo response (ie, the nonspecific effects in the placebo group including benign natural course, regression to the mean, expectation/conditioning effects, and others) in randomized trials in complex regional pain syndrome (CRPS) is unknown. We recently observed a surprising near-absence of placebo response in a randomized controlled trial we conducted on patients with long-standing (≥6 months) CRPS. To investigate the idea that there may be an absence of placebo response in long-standing CRPS further, we conducted a systematic review and meta-analysis of placebo responses in randomized controlled trials conducted in patients with CRPS of ≥6 months. We systematically identified suitable randomized controlled trials published between 1966 and September 2013. We calculated the mean difference and standard error of the mean difference for placebo responses and synthesized individual effect sizes at 4 specified time periods of interest (15-30 minutes, 1 week, 3-4 weeks, and 6 weeks or more) via meta-analysis using the method of inverse-variance. Heterogeneity was assessed according to the I(2) statistic. For primary analysis, we pooled trial-specific effect sizes over the 4 time points. We analyzed data from 340 participants from 18 trials out of a possible 361 participants from 20 trials (94% of participants analyzed). Significant heterogeneity was present between trials; therefore, we interpreted trends from visual inspection of individual trials and pooled estimates. Placebo response was significant at the earliest time period (15-30 minutes). There was no significant evidence of placebo response at any of the other time periods. These results inform the design of future trials, and they caution against the "therapeutic" use of placebo in long-standing CRPS.
  
  
  CONCLUSIONS
  In this meta-analysis of placebo responses in randomized controlled trials in long-standing CRPS, published during 1966 to 2013, we found no evidence for placebo analgesia, except at very early time points. Results inform the design of future placebo analgesia research in long-standing CRPS.
authors.affiliation: Pain Research Institute, Department of Translational Medicine, University of Liverpool, Liverpool, United Kingdom. Electronic address: gashiraimbizvo@hotmail.com.
authors.forename: Gashirai K
authors.initials: GK
authors.lastname: Mbizvo
authors.affiliation: Department of Biostatistics, University of Liverpool, Liverpool, United Kingdom.
authors.forename: Sarah J
authors.initials: SJ
authors.lastname: Nolan
authors.affiliation: Pain Research Institute, Department of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Department of Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Turo J
authors.initials: TJ
authors.lastname: Nurmikko
authors.affiliation: Pain Research Institute, Department of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Department of Pain Medicine, Walton Centre NHS Foundation Trust, Liverpool, United Kingdom.
authors.forename: Andreas
authors.initials: A
authors.lastname: Goebel
mesh_terms: D020918:Complex Regional Pain Syndromes / Q000523:psychology* / Q000628:therapy*; D006801:Humans; D015990:Placebo Effect
keywords: Complex regional pain syndrome; meta-analysis; placebo response; randomized controlled trials; reflex sympathetic dystrophy