Effectiveness, cost effectiveness and safety of gabapentin versus placebo as an adjunct to multimodal pain regimens in surgical patients: A placebo controlled randomised controlled trial with blinding (The GAP study)

Design: Pragmatic placebo-controlled RCT with blinding of participants, care teams and researchers and an internal pilot phase (Phase 1). Phase 1 will determine the feasibility of recruitment from three surgical populations (cardiac, thoracic, abdominal). Progression to Phase 2 will depend on showing satisfactory recruitment in Phase 1. The full RCT will evaluate the effectiveness and cost effectiveness of gabapentin (as an adjunct to standard analgesia) vs placebo. Participants will be randomised in a 1:1 ratio to the usual multimodal analgesia regimen plus gabapentin or placebo. Setting: Two NHS hospitals (Bristol and Southampton) providing all three types of surgery. Target population: Adults undergoing non-emergency cardiac, thoracic and abdominal surgery. Inclusion criteria: Adults undergoing non-emergency surgery: cardiac surgery (surgery on the heart and great vessels carried out via midline sternotomy); thoracic surgery (surgery on the lungs and surrounding tissues); abdominal surgery (open or laparoscopic surgery within the abdominal cavity). Exclusion criteria: Participants may not enter study if ANY of the following apply: 1) Expected to have a minimum length of hospital stay of less than 2 days; 2) Taking anti-epileptic medication(s); 3) Allergy to gabapentin; 4) Planned epidural analgesia; 5) Planned use of any gabapentanoids in the peri-operative analgesic protocol other than the study medication (this includes but is not restricted to: pregabalin, enacarbil gabapentin, 4-methylpregabalin and phenibut); 6) Known renal impairment (for such patients, estimated glomerular filtration rate (eGFR) <30ml/min/1.732); 7) Weight <50kg; 8) Inability to provide written informed consent to participate in the trial; 9) Unwilling to participate in follow-up; 10) Prisoners; 11) Already taking gabapentin; 12) Rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose galactose malabsorption; 13) Currently taking an investigational medicinal product as part of another clinical trial. Health technologies being assessed: Usual multimodal analgesia regimen for each surgical group plus 600 mg gabapentin (or placebo) one hour prior to surgery and 600 mg a day gabapentin (or placebo), (300 mg in the morning and 300 mg in the evening) given post-operatively for 2 days. Measurement of costs and outcomes: The primary outcome for the full trial will be length of post -operative hospital stay. Secondary outcomes include: 1) Opioid consumption in the period from surgery until hospital discharge; 2) Acute post-operative pain assessed using the visual analogue scale (VAS) completed at 1hr, 4 hr, 12 hr post-surgery and then twice daily to discharge; 3) Adverse health events from randomisation to 4 months including side effects of medication (e.g. nausea; vomiting; pruritus; sedation; confusion) and on-going pain; 4) HRQoL measured using the EQ-5D 5 level questionnaire and Short-form (SF) 12 completed at baseline and at follow-up at approximately 4 weeks and 4 months; 5) Resource use to 4 months (measured during the hospital stay, at 4 weeks and 4 months); 6) Chronic pain measured at baseline and at 4 months using the brief pain inventory (BPI). Sample size: We will aim to recruit 1500 patients in total, with a minimum of 376 per surgical stratum. This will provide at least 90% power at 5% significance (two sided) to detect a difference in the proportion of patients discharged at current median time (5 days for cardiac and abdominal surgery, 3 days for thoracic surgery) of 12.5% in each stratum and 80% power to detect a difference of 10% in any surgical strata recruiting in excess of 430 participants. We expect to recruit about 500 participants in Phase 1 and 1000 more by the end of Phase 2. Criteria for progression from Phase 1 to 2 will be at least 60% of patients referred for surgery eligible to participate in GAP and at least 50% consent to randomisation after 6 months of recruitment. Project timetable: 48 months: 8m set-up; 30m recruitment (Phase 1: 12m; Phase 2: 18m); 4m follow up on all participants; 6m analysis and report. Expertise in team: The team is multidisciplinary and includes patients, surgeons and anaesthetists from each specialty, a clinician with pain management expertise (director of the Bristol Integrated Pain Management Health Integration Team, HIT), trialists and a health economist.