Benefit and harm of Pregabalin in acute pain treatment – a systematic review with meta-analyses and trial sequential analyses
Fabritius ML1, Koyuncu S2, Strøm C3, Jæger P1, Petersen PL1, Geisler A2, Wetterslev J4, Dahl JB5, Mathiesen O2
1Department of Anaesthesiology, Centre of Head and Orthopaedics, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark, 2Department of Anaesthesiology, Zealand University Hospital, Køge, Denmark,3Emergency department, Holbæk Hospital, Holbæk, Denmark, 4Department of Clinical research, Copenhagen University Hospital, Copenhagen Trial Unit, Rigshospitalet, Copenhagen, Denmark, 5Department of Anaesthesiology and Intensive Care Medicine, Bispebjerg and Frederiksberg Hospitals, Copenhagen, Denmark
Pregabalin has demonstrated anti-hyperalgesic properties, and was introduced for treatment of acute pain in 2001. Since the first published clinical trial in 2001 the literature continues to suggest a beneficial effect of pregabalin in postoperative pain management.
Our aim with this systematic review was to evaluate both beneficial and harmful effects of pregabalin in postoperative pain management.
We included randomized, clinical trials investigating perioperative pregabalin treatment in adult patients. The review followed Cochrane methodology, in combination with trial sequential analyses (TSA) and the Grading of Recommendations Assessment, Development and Evaluation (GRADE). Conclusions were based primarily on low risk of bias trials.
The primary outcomes were 24-hour intravenous morphine consumption and the incidence of Serious Adverse Events (SAE)
A total of 97 randomized, clinical trials with 7201 patients were included in the review. Only 20 trials were classified as overall low risk of bias.
Twenty-four-hour morphine consumption is reported in figure 2.
In the subgroup analyses of pregabalin added on to a non-opioid, basic analgesic regimen, the 24-hour morphine consumption was reduced by 5.3 mg (2.1, 8.5; TSA adj. CI: 2.1, 8.5; GRADE: low). The subgroup analysis of pregabalin without any other non-opioid analgesics included only two trials and found a reduction of 13.7 mg (9.6, 17.8; TSA adj. CI: 9.6, 17.8; GRADE: low).
Incidence of SAEs was reported in 21 trials, with 55 SAEs reported in 12 of these trials, and 22 SAEs reported in 10 trials with overall low risk of bias. In trials with overall low risk of bias Peto’s OR was 2.9 (1.2, 6.8; TSA adj. CI: 0.1, 97.1; GRADE: moderate).
Strengths of the systematic review; pre-study registered protocol at PROSPERO, compliance to Cochrane guidelines, a comprehensive literature search, the risk of random error was evaluated using the TSA, and the risk of systematic error assessed using Cochrane bias tools, GRADE was used on all outcomes, and conclusions were based on trials with overall low risk of bias.
Limitations of the systematic review; conclusions of the systematic review mirror the limitations of the included trials: the risk of systematic error, few data on serious adverse events and short follow-up periods.
From trials with overall low risk of bias results were moderate to very low quality of evidence based on GRADE assessments. A clinical relevant beneficial effect of pregabalin may be present (GRADE low). The risk of harm seems imminent but the data are weakened (GRADE moderate) by a considerable under-reporting of SAEs.