Gabapentin as an adjunct to multimodal pain regimens in surgical patients: the GAP placebo-controlled RCT and economic evaluation

Background Gabapentin is an anticonvulsant medication with a United Kingdom licence to treat partial seizures and neuropathic pain. It is used off-licence for acute pain and is frequently added to multimodal analgesic regimens after surgery to try and reduce opioid use while controlling pain effectively. Objective To test the hypothesis that gabapentin reduces opioid use after major surgery and speeds up recovery, thereby reducing postoperative hospital length of stay compared to standard multimodal analgesia. Design, setting and participants The GAP study was a multicentre, blinded, randomised controlled trial in patients aged ≥ 18 years, undergoing cardiac, thoracic or abdominal surgery with an expected postoperative stay of ≥ 2 days in seven National Health Service hospitals. The trial was designed to provide 90% power to detect a difference of 12.5% in the proportion of participants discharged by the median length of stay in each specialty (500 participants/specialty), which was reduced to 80% (340 participants/specialty) due to COVID-19-related recruitment challenges. Interventions Participants were randomised 1 : 1 (stratified by surgical specialty) to receive either gabapentin (600 mg before surgery, 300 mg twice daily for 2 days after surgery) or placebo as an adjunct to multimodal pain regimens. Main outcome measures Primary outcome was length of stay. Secondary outcomes included acute and chronic (Brief Pain Inventory) pain, total opioid use, adverse health events, health-related quality of life (-EQ-5D-5L, Short Form questionnaire-12 items physical component score and mental component score), resource use; cost-effectiveness (outcome measure quality-adjusted life-years using EQ-5D, five-level version). Results One thousand one hundred and ninety-six (cardiac 500, thoracic 346, abdominal 350) participants consented and were randomised. Baseline characteristics were well balanced across the two groups: median age: 68 years; male sex 796/1195 (66.4%). Of the participants, 223/1195 (18.7%) did not receive all prescribed medication or received medication out of window. There was no difference in length of stay; median placebo ( n = 589): 6.15, gabapentin ( n = 595): 5.94 days hazard ratio for discharge 1.07, 95% confidence interval (0.95 to 1.20), p = 0.26. Opioid use in-hospital differed between surgical specialties ( p = 0.001); in the abdominal specialty, it was significantly lower in the gabapentin group in 4 of the first 5 postoperative days range −26% (−46% to 0%) to −36% (−52% to −14%), with no differences in the cardiac specialty nor in the thoracic specialty beyond day 2. During follow-up , opioid use was similar in the two groups across all specialties. Acute pain beyond 24 hours was similar ( p ≥ 0.15). The incidence of one or more serious adverse events was placebo: 189/595 (31.7%); gabapentin: 195/599 (32.6%). Health-related quality of life was similar EQ-5D: mean difference −0.014 (−0.036 to 0.009), Short Form questionnaire-12 items physical component score: −0.87 (−1.71 to −0.04), Short Form questionnaire-12 items mental component score: at 4 weeks 0.74 (−1.71 to 0.42) and 4 months −0.55 (−1.61 to 0.51). Differences in costs and quality-adjusted life-years favoured placebo, and gabapentin was not considered cost-effective. Limitations GAP study tests the application of gabapentin to major body cavity surgery, but not major non-body cavity surgery, or non-major surgery. The fixed dose and limited duration of gabapentin may reduce applicability to certain populations. Reducing the power to 80% reduced the ability of the trial to detect a beneficial effect of gabapentin. Conclusions Among patients undergoing major cardiac, thoracic and abdominal surgery, adding gabapentin to multimodal analgesic regimes did not result in a change in length of stay, opiate use in two specialties, acute pain, or health-related quality of life, nor was it cost-effective. Future work Trials to assess the place of gabapentin in major non-body cavity surgery (e.g. joint replacement), or non-major (e.g. day-care) surgery should be considered. Trial registration This trial is registered as Current Controlled Trials ISRCTN63614165. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme (NIHR award ref: 15/101/16) and is published in full in Health Technology Assessment ; Vol. 30, No. 9. See the NIHR Funding and Awards website for further award information.