In Response

Abstract

Our systematic review1 was created as outlined in our search strategy by an experienced information specialist. The PRISMA guidelines published in 2009 do not endorse searching clinical trial registries.2,3 Recently, the Methodological Expectations of Cochrane Intervention Reviews4 has been updated with the following statement: Searches for studies should be as extensive as possible in order to reduce the risk of publication bias and to identify as much relevant evidence as possible. Although ClinicalTrials.gov is included as one of the registers within the WHO ICTRP portal, it is recommended that both ClinicalTrials.gov and the ICTRP portal are searched separately due to additional features in ClinicalTrials.gov. However, prompted by Dr. Chelly’s comments5 we have conducted an updated analysis using the ClinicalTrials.gov data to determine whether: (1) there is evidence of a publication bias and (2) the positive effects of pregabalin we reported are maintained. With the new data sets included from the 3 unpublished Pfizer pregabalin studies using participants that received 300 mg of pregabalin 3 months after surgery on the incidence of chronic postsurgical pain after total knee arthroplasty (22/59 pregabalin vs 27/61 placebo),6 total abdominal hysterectomy (22/127 pregabalin vs 14/141 placebo),7 and inguinal hernia repair (5/101 pregabalin vs 3/101 placebo),8 the pooled odds ratio for the incidence of chronic postsurgical pain with the 5 pregabalin studies becomes an odds ratio 0.73 (0.28–1.89, P = 0.51). These new data question the positive pregabalin findings published to date with respect to the prevention of chronic postsurgical pain. We are supportive of the position that IRB-approved clinical trials should be registered and reported to ensure that publication bias is minimized when assessing clinical trials and meta-analyses. However, and in view of the fact that it is unlikely that the unpublished Pfizer data will ever become part of the peer-reviewed literature, it remains to be determined how data not undergoing the scrutiny of rigorous peer review should be weighed against published studies. Our review article was written to examine the use of this class of medication in the perioperative setting for the prevention of chronic postsurgical pain based on the published literature available at that time. Studies evaluating the effectiveness of these agents in the acute and chronic postoperative pain settings continue to be published with mixed results.9,10 It remains to be seen what the final verdict will be with respect to the benefits versus risks of these medications in the perioperative setting. Some institutions have adopted them routinely in a multimodal perioperative care pathway, whereas others have stepped away given the side-effect profiles of these medications. To that end, Dr. Chelly reiterates our cautionary note regarding the use of larger doses of the α-2-Δ ligands given the increase in sedation and somnolence in the acute postoperative period seen most often in the elderly population and patients with compromised renal function. Once again, given the limited number of studies identified in our review, the clinical heterogeneity of the trials identified, and the now documented evidence of a pregabalin publication bias,2 future well-designed, appropriately powered studies are needed to clarify whether the α-2-δ calcium channel blockers have a role in the prevention of chronic postsurgical pain. Hance Clarke, MD, MSc, FRCPC Duminda N. Wijeysundera, MD, PhD, FRCPC Department of Anesthesia and Pain Management Toronto General Hospital, University Health Network, Merit Award Recipients Department of Anesthesia University of Toronto Toronto, Ontario [email protected] Robert P. Bonin, PhD Centre de Recherche Université Laval Robert-Giffard Université Laval, Québec Beverley Orser, MD, PhD, FRCPC Department of Anesthesia Sunnybrook Health Sciences Centre, Toronto Marina Englesakis, BA, MLIS Information Specialist for Surgical Division, Neurosciene, and Medical Education University Health Network, Toronto Joel Katz, PhD Department of Psychology York University, Toronto, Ontario, Canada