Award Title: 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)
Funder: Department of Health and Social Care

Abstract: Gabapentin is a medicine used to treat epilepsy and pain caused by damaged nerves. Recently, doctors have begun using gabapentin to treat pain after an operation, with the intention of reducing the amount of other drugs needed while maintaining good pain relief. Doctors want to try to reduce the amount of other drugs because they cause side effects, often delaying discharge from hospital and leading to slower recovery. There is uncertainty about whether adding gabapentin to the usual drug regimen will result in good pain relief, fewer side effects overall (including side effects from all of the drugs used to treat pain) and faster recovery after surgery._x000D_
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We want to conduct a study known as a randomised controlled trial (RCT), in which patients undergoing different types of surgery (heart, chest/lungs and belly/gut) are allocated by chance to receive gabapentin or an identical looking dummy pill in addition to the usual drug regimen for each type of surgery. We will give patients gabapentin or a dummy pill one hour before surgery and for two days after surgery. Every other aspect of care will stay the same. We will then compare information about participants who received gabapentin with information about participants who received the dummy pills to determine whether gabapentin reduces the amount of time patients stay in hospital after the operation, the amount of other pain medication they take, and to assess how gabapentin influences pain in hospital and four months after surgery. We will also perform a health economic analysis to determine whether using gabapentin provides better health outcomes for patients undergoing surgery and is cost-effective for the NHS relative to current pain management protocols._x000D_
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We have chosen to conduct the study in patients undergoing different types of major surgery (heart, chest/lungs and belly/gut), rather than just one. We are using this approach because we want to ensure that the results can be applied to patients undergoing different operations and who receive different types of care. We will conduct the study in two phases. In phase 1, we will determine whether we can recruit patients from the three different types of surgery and whether patients are able to take gabapentin or dummy pills as instructed. We expect Phase 1 to take a year. If successful, we will move on to Phase 2 and continue recruiting. We hope to recruit a total of 1500 patients (up 500 from each type of surgery). Patients will be recruited from two hospitals, Bristol and Southampton. The overall duration of the study will be 4 years. The team includes a patient, surgeons, doctors with expertise in treating pain in the different types of surgery, researchers with expertise in conducting clinical trials and a health economist.

Lay Abstract: 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._x000D_
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Setting: Two NHS hospitals (Bristol and Southampton) providing all three types of surgery._x000D_
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Target population: Adults undergoing non-emergency cardiac, thoracic and abdominal surgery._x000D_
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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)._x000D_
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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._x000D_
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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._x000D_
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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)._x000D_
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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._x000D_
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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._x000D_
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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.

Research Activity Codes: 6.1 PHARMACEUTICALS
Health Categories: GENERIC HEALTH RELEVANCE