title: Systematic review of enriched enrolment, randomised withdrawal trial designs in chronic pain: a new framework for design and reporting.
abstract: Enriched enrolment, randomised withdrawal (EERW) pain trials select, before randomisation, patients who respond by demonstrating a predetermined degree of pain relief and acceptance of adverse events. There is uncertainty over the value of this design. We report a systematic review of EERW trials in chronic noncancer pain together with a critical appraisal of methods and potential biases in the methods used and recommendations for the design and reporting of future EERW trials. Electronic and other searches found 25 EERW trials published between 1995 and June 2014, involving 5669 patients in a randomised withdrawal phase comparing drug with placebo; 13 (median, 107 patients) had a randomised withdrawal phase of 6 weeks or less, and 12 (median, 334) lasted 12 to 26 weeks. Risks of bias included short duration, inadequate outcome definition, incomplete outcome data reporting, small size, and inadequate dose tapering on randomisation to placebo. Active treatment was usually better than placebo (22/25 trials). This review reduces the uncertainty around the value of EERW trials in pain. If properly designed, conducted, and reported, they are feasible and useful for making decisions about pain therapies. Shorter, small studies can be explanatory; longer, larger studies can inform practice. Current evidence is inadequate for valid comparisons in outcome between EERW and classical trials, although no gross differences were found. This systematic review provides a framework for assessing potential biases and the value of the EERW trials, and for the design of future studies by making recommendations for the conduct and reporting of EERW trials.
authors.affiliation: Pain Research and Nuffield Division of Anaesthetics, University of Oxford, Oxford, United Kingdom Centre for Pain Research, University of Bath, Bath, United Kingdom Division of Neurological Pain Research and Therapy, Department of Neurology, University Hospital, Kiel, Germany Centre for Pain Management and Palliative Care & Regional Centre for Excellence in Palliative Care, Haukeland University Hospital, Bergen, Norway Institute for Work & Health, Toronto, ON, Canada Queen's University, Kingston General Hospital, Departments of Anesthesiology & Perioperative Medicine and Biomedical & Molecular Sciences, Kingston, ON, Canada Division of Clinical and Translational Research, Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA Analgesic Solutions, Natick, MA, USA Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA Leeds Institute of Health Sciences, University of Leeds, Leeds, United Kingdom Department R449, AbbVie, North Chicago, IL, USA qd Consulting, LLC, Durham, NC, USA RCN Research Institute, Warwick Medical School, University of Warwick, Coventry, United Kingdom 8002 Davis Dr, Clayton, MO, USA Division of Preventive Medicine, University of Alberta, Edmonton, AB, Canada.
authors.forename: R Andrew
authors.initials: RA
authors.lastname: Moore
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Wiffen
authors.forename: Christopher
authors.initials: C
authors.lastname: Eccleston
authors.forename: Sheena
authors.initials: S
authors.lastname: Derry
authors.forename: Ralf
authors.initials: R
authors.lastname: Baron
authors.forename: Rae F
authors.initials: RF
authors.lastname: Bell
authors.forename: Andrea D
authors.initials: AD
authors.lastname: Furlan
authors.forename: Ian
authors.initials: I
authors.lastname: Gilron
authors.forename: Simon
authors.initials: S
authors.lastname: Haroutounian
authors.forename: Nathaniel P
authors.initials: NP
authors.lastname: Katz
authors.forename: Arthur G
authors.initials: AG
authors.lastname: Lipman
authors.forename: Stephen
authors.initials: S
authors.lastname: Morley
authors.forename: Paul M
authors.initials: PM
authors.lastname: Peloso
authors.forename: Steve N
authors.initials: SN
authors.lastname: Quessy
authors.forename: Kate
authors.initials: K
authors.lastname: Seers
authors.forename: Scott A
authors.initials: SA
authors.lastname: Strassels
authors.forename: Sebastian
authors.initials: S
authors.lastname: Straube
mesh_terms: D000700:Analgesics / Q000009:adverse effects* / Q000627:therapeutic use*; D059350:Chronic Pain / Q000188:drug therapy*; D006801:Humans; D016032:Randomized Controlled Trials as Topic / Q000379:methods*; D012107:Research Design; D012307:Risk Factors; D013375:Substance Withdrawal Syndrome / Q000209:etiology*; D013997:Time Factors; D035501:Uncertainty
chemical_list: D000700:Analgesics