GABAPENTIN SAFETY ALERT WITH OPIOID COMBINATION?

The combined use of opioids and gabapentin (multiple brands) may raise the risk for opioid-related death, according to results of a population-based nested case-control study from Ontario, Canada.

"We found that people prescribed higher doses of gabapentin had an increased risk of dying of an opioid-related cause, even after adjusting for the dose of opioid they were being prescribed," Tara Gomes, MHSc, of the Institute for Clinical Evaluative Sciences, Toronto, Canada, told Medscape Medical News.

"In particular, people taking more than 2500 mg of gabapentin daily had a nearly twofold increased risk compared to people prescribed opioids alone," said Dr Gomes, principal investigator of the Ontario Drug Policy Research Network.

The study was published online October 3 in PLOS Medicine.

Risky Combo?

Gabapentin is often used in conjunction with opioids to treat chronic pain. Both of these drugs suppress breathing, which can be fatal, the authors note. In addition, the use of gabapentin concomitantly with opioids can increase the amount of opioid absorbed by the body, potentially leading to higher risk.

"Despite these potential risks, so far no studies have examined whether the concomitant use of gabapentin and opioids really increases the likelihood of accidental opioid-related death and whether this risk is gabapentin dose dependent," they write.

To investigate, the researchers used an administrative healthcare database to identify 1256 residents of Ontario whose cause of death was related to opioid use. The investigators matched each of these persons with up to four control persons who also used opioids (4619 control participants).

Overall, 12.3% of case patients (155 of 1256) and 6.8% of control patients (313 of 4619) were prescribed gabapentin in the 120 days preceding the index date.

After multivariable adjustment, the risk for an opioid-related death was 49% higher in patients recently exposed to gabapentin and opioids compared to those exposed to opioids alone (adjusted odds ratio [aOR], 1.49; 95% confidence interval [CI], 1.18 - 1.88; P = .0009).

In the dose-response analysis, exposure to moderate (900 to 1799 mg/d) or high (>1800 mg/d) doses of gabapentin was associated with a nearly 60% increase of opioid-related death compared to exposure to opioids alone (moderate dose: aOR, 1.56; 95% CI, 1.06 - 2.28; P = .0235; high dose: aOR, 1.58; 95% CI, 1.09 - 2.27; P = .0149).

As expected, the researchers note, there was no significant association between coprescription of opioids and nonsteroidal anti-inflammatory drugs and opioid-related death.

The large sample size and the use of population-based coroner's records to ascertain opioid-related deaths are strengths of the study, the researchers say. The fact that the study included only individuals eligible for public drug coverage in Ontario, which includes the elderly (aged 65 and older) and younger people receiving social assistance, and that information on indication for gabapentin use was not available are limitations.

As with all observational studies, confounding due to unmeasured variables is a potential source of bias, the researchers note.

Dr Gomes said she is "not aware of guidelines that have made specific recommendations around the combined use of these products. In fact, it is likely that clinicians have chosen to use these two drugs together to treat chronic pain in an attempt to avoid using high doses of opioids in their patients."

The findings in this study suggest that "caution" is needed when combining gabapentin and opioids. "Patients treated with opioids and gabapentin should be closely monitored, and may need to have their doses adjusted to avoid potential drug overdose," the researchers write.

Interpret With Caution

However, Robert Duarte, MD, director of Northwell Health's Pain Center of the Neuroscience Institute, Great Neck, New York, who was not involved in the study, urged caution in interpreting the findings.

"This is just one study, and there could be other variables at play here," he told Medscape Medical News, adding, "I have never had a patient on gabapentin with any respiratory depression."

However, "gabapentin prescriptions are on the rise," Dr Duarte noted. "Because doctors are hesitant to prescribe opioids, gabapentin is somewhat of a go-to drug. With more and more gabapentin prescriptions being written, now we may be seeing a potential risk, which we were not really well informed about in the past. This study gives us an awareness that we should be alert to, but I don't think clinicians should be alarmed and say, 'Now I'm not going to write gabapentin.'

"The study doesn't show cause and effect, and it's not something that should put fear in clinicians, but it is something to be aware of," he concluded.

The study received no commercial funding. The authors and Dr Duarte have disclosed no relevant financial relationships.