Gabapentin linked to increased risk of opioid-related death

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Second-line treatment for CPSP includes the anticonvulsant gabapentin.

Gabapentin linked to increased risk of opioid-related death

Reuters Health News

Concomitant use of gabapentin and opioids is associated with a significantly increased risk of opioid-related death, according to a Canadian case-control study.
"When we started this study, we were aware of the potential for an interaction between opioids and gabapentin but weren’t sure whether the combined use of these drugs led to clinically relevant risks,” Dr. Tara Gomes from St. Michael's Hospital and University of Toronto, in Canada, told Reuters Health by email. “Therefore, our finding that even moderate doses of gabapentin were associated with a 60% increased risk of opioid-related death was important, and the fact that this increases to a twofold higher risk among people getting very high doses is concerning.”
Gabapentin is commonly used as an adjunctive treatment for chronic pain, but it can also induce respiratory depression, so its label warns about possible respiratory depression when combined with opioids.
Dr. Gomes’s team used information from several Ontario and Canadian databases to examine whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids.
Overall, 12.3% of cases (opioid-related deaths) and 6.8% of controls were prescribed gabapentin in the prior 120 days, according to the October 3 PLoS Medicine online report.
The odds of an opioid-related death were 49% higher among people recently exposed to gabapentin and opioids, compared with those exposed to opioids alone, even after adjustment for a variety of potential confounders.
Moderate daily doses of gabapentin (900 to 1799 mg) were associated with 56% increased odds of opioid-related death, high doses (800 mg or more) with 58% increased odds, and very high doses (2500 mg or more) with 83% increased odds.
In an exploratory analysis, 46% of gabapentin users in 2013 received at least one concomitant prescription for an opioid.
“The high degree to which patients are being prescribed both of these drugs was surprising to us,” Dr. Gomes said. “The fact that half of people prescribed gabapentin are also being treated with an opioid highlights the importance of this finding.”
“The most effective way for us to reduce the risks associated with combined opioid and gabapentin use is to raise awareness among prescribers, pharmacists, and patients of this interaction,” she said. “Currently, there is very little understanding of the potential risks of using these drugs together, and so we need to make sure that those involved in clinical care are made aware of this potentially dangerous combination.”
“Pregabalin is a drug similar to gabapentin, which we anticipate is also frequently used with opioids to manage chronic pain,” Dr. Gomes added.
“We were not able to study this potential drug-drug interaction in this analysis because pregabalin was only funded by the government near the end of our study period.” She hopes that future investigations will explore this issue.
Dr. Toby Weingarten from Mayo Clinic, Rochester, Minnesota, who recently described postoperative respiratory depression in patients treated with multimodal analgesic therapy and gabapentin, told Reuters Health by email,
"The results from Gomes et al. are very troubling because they suggest that chronic use of gabapentinoids when paired with opioid therapy are associated with higher rates of opioid-related deaths. This finding is in agreement with what we are seeing with the perioperative use of these medications.”
“These findings suggest that use of these medications should not be taken lightly, and that their use (especially when being initiated) needs to be closely monitored,” he said. “When prescribing gabapentinoids, patients should be started on subtherapeutic doses, and doses slowly increased to therapeutic range. Too often patients are placed on therapeutic levels of these drugs (eg, gabapentin 600 tid) without slow escalation, resulting in oversedation.”
“Further, when these medications are used concomitantly with opioids, utmost caution should be exercised,” Dr. Weingarten said. “I feel strongly that during the initiation of these medications, patients need to check in closely with their healthcare provider to ensure that oversedation is not occurring. Also, a trial of these medications should be linked to de-escalation of the dose of opioids.”
Dr. Alyssa M. Peckham from Midwestern University College of Pharmacy, Glendale, Arizona, who recently conducted a similar retrospective analysis, told Reuters Health by email, "This manuscript echoes our alarming findings of increased risk of respiratory depression when gabapentin is overused, specifically in concert with opioid overuse. The work by Gomes et al. provides an additional important contribution: because these investigators could measure mortality, they have provided a direct link between gabapentin/opioid misuse and risk of death.”
“The main message that physicians and all healthcare providers should receive is that gabapentin is a drug with abuse potential, has been misused at high dosages by patients treated in the US and Canada, and has the potential to increase risk of respiratory depression and mortality specifically when misused in concert with opioids,” she said. “In the United States, gabapentin has become a Schedule-V controlled substance in Kentucky and is a Prescription Drug Monitoring Program (PDMP) mandatory reportable drug in at least six other states. Clinicians should be familiar with his/her local legislative policy, and remain up-to-date in anticipation of potential regulation changes specific to gabapentin.”
Dr. Peckham added, “other global approaches may include: (1) expansion of abuse deterrent medication formulations, (2) socioeconomic strategies, and (3) expansion of opportunities for accessible and affordable substance abuse treatment.”
—Will Boggs, MD