Author: Michael Vlessides
The ongoing debate surrounding the efficacy of perioperative gabapentinoids in adult patients may be over, at least for the management of acute postoperative pain.
A team of Canadian researchers concluded that perioperative use of gabapentinoids yields no clinically significant analgesic effect, and comes with an increased risk for adverse events.
“Gabapentinoids are among the most frequently prescribed classes of drugs worldwide,” explained Michael Verret, MD, a resident at Laval University, in Quebec City. “Interestingly, approximately 95% of their use is for off-label indications, and the management of postoperative acute pain is an off-label use that has increased drastically in the last decade.
“However, scientific data to justify such use is divergent,” Dr. Verret said. “In fact, there’s increased concern about the net clinical benefit of gabapentinoids, as well as their potential for adverse effects. Clearly, there’s a need to evaluate the analgesic effects of gabapentinoids.”
The trial’s primary outcome was the intensity of postoperative acute pain. Secondary outcomes included postoperative subacute and chronic pain, opioid use, length of stay, and adverse events.
The investigators identified a total of 6,795 citations. Of these, 281 trials were included in the meta-analysis (67 at low or unclear risk for bias), comprising 24,682 patients. They also performed a series of a priori subgroup analyses, including type of funding; type of drug; dosage regimen; risk for bias; type of coanalgesia; type of surgery and anesthesia; type of population; timing of the intervention; type of pain; and type of comparator.
“About half of the trials evaluated gabapentin, and the other half evaluated pregabalin,” Dr. Verret said. “Most of the time, the gabapentinoids were administered before the surgery, and in about 10% of the trials, a regional analgesic was also used.”
With respect to the primary outcome, the meta-analysis found that gabapentinoids were associated with a statistically significant decrease in pain intensity at 12 hours, with a mean difference of 8.79 points on a 100-point scale (95% CI, –10.27 to –7.31). Yet as Dr. Verret was quick to point out, this difference was not meaningful in a clinical context.
Similar results were found throughout the other time points used in the analysis.
“The quality of evidence was low, mainly because of the heterogeneity and the risk of bias,” Dr. Verret said. “We also explored the source of the heterogeneity and observed that trials at low risk of bias tended to show a smaller effect.”
The observed effect of gabapentinoids was consistent regardless of the drug used, the type of surgery, the type of comparator, or the gabapentinoid dose.
Gabapentinoid use also was found to be associated with a statistically significant decrease in the use of opioids at 24 hours after surgery. Indeed, patients who received gabapentinoids received 7.90 mg less of the IV morphine equivalent than their counterparts who did not receive gabapentinoids (95% CI, –8.82 to –6.98).
No clinically significant effects were observed with respect to any of the trial’s secondary outcomes. Specifically, postoperative subacute pain showed a mean decrease of 5.82 points—on a 100-point scale—among patients who received gabapentinoids. The incidence of postoperative chronic pain yielded a relative risk of 0.89 (95% CI, 0.74-1.07) for those who received gabapentinoids. Patients who received gabapentinoids also had a longer hospital length of stay of 2.96 hours (95% CI, 0.28-5.63).
“We also observed a significant increase in dizziness and in visual disturbances among patients who received gabapentinoids,” he added. No significant differences were found between groups with respect to other potential adverse effects, such as ataxia or falls, delirium, or respiratory depression. Finally, gabapentinoid administration seemed to be protective against postoperative nausea and vomiting (relative risk, 0.77; 95% CI, 0.72-0.82).
The researchers also performed trial sequential analyses to help inform future research.
“The message here is that no further trials are needed with respect to postoperative acute pain,” Dr. Verret said.
These findings paint a clear picture of the value of gabapentinoids in this context. “Our results do not support the routine use of pregabalin or gabapentin for the management of postoperative pain in adults.”
Dosing Regimens Also Analyzed
The study drew considerable discussion from the crowd gathered at the ASA meeting. “Most of your studies just used a single preoperative dose of gabapentinoids,” noted one audience member. “If you do a subgroup analysis, what does that show?”
“In fact we did this subgroup analysis, looking at the timing of gabapentinoid administration, either before surgery, after surgery and at both times,” Dr. Verret replied. “About 15% of the time, multiple doses were used. And there was no difference in either postoperative acute or chronic pain according to the time of drug administration or the number of doses.”
“Are you saying that there is no need to explore this question any more and that we should not use gabapentinoids as part of a multimodal perioperative analgesia regimen?” asked session moderator Kamen V. Vlassakov, MD, an assistant professor of anesthesia at Harvard University, in Boston.
“Our sequential analyses were really about the outcome of postoperative acute pain intensity at the time points we examined,” Dr. Verret replied. “The results may be different for another outcome, but for this one, what we see is that if we continue to do trials on this subject, it is extremely unlikely that it would change the results.”