Patients who are prescribed pregabalin concomitantly with opioids may be at increased risk for opioid-related death, according to a population study published in the Annals of Internal Medicine.1
The study included Ontario residents eligible for public drug coverage who received prescription opioids between August 1, 1997, and December 31, 2016. Case patients (n=1417) died of an opioid-related cause, excluding deaths from suicide or homicide. The index date was the date of the opioid-related death. Each case patient was matched with up to 4 control participants (n=5097) for age, sex, index year, history of chronic kidney disease, and Charlson comorbidity score.
Concomitant exposure to pregabalin and opioid medications in the 120 days preceding the index date was found to be associated with an increased risk for opioid-related death compared with opioid exposure alone after multivariable adjustment (adjusted odds ratio [aOR], 1.68; 95% CI, 1.19-2.36).
Sensitivity analyses in which control participants were also matched for recent use of a central nervous system depressant (eg, benzodiazepine, antidepressant), indicated similar results, with use of pregabalin overlapping the index date (aOR, 1.81; 95% CI, 1.26-2.60) and (aOR, 2.00; 95% CI, 1.39-2.88) after matching on prior use of central nervous system depressants.
This elevated risk for death with concomitant use of pregabalin and opioids was found to be dose dependent, with a higher dose of pregabalin carrying a higher risk for opioid-related death compared with no pregabalin exposure (aOR, 2.51; 95% CI, 1.24-5.06), and a low to moderate dose of pregabalin carried a lower, but still significant, risk for opioid-related death (aOR, 1.52; 95% CI, 1.04-2.22).
“Although current product monographs for gabapentin contain warnings about serious adverse events when this agent is combined with opioids, those for pregabalin do not. The importance of our finding warrants a revision of the pregabalin product monographs,” noted the study authors.
In an editorial accompanying this article, Douglas C. Throckmorton, MD, Deputy Director for Regulatory Programs, and Janet Woodcock, MD, Director of the Center for Drug Evaluation and Research, both at the US Food and Drug Administration, point to potential confounding factors not accounted for in the study, namely, the clinical decision making leading to the concurrent prescription of these 2 drug classes and the nature of drug-drug interactions at play.
“Determining the right interventions also requires a fuller understanding of the patterns of use, how they may lead to abuse, and the clinical consequences of this abuse,” they added. “For example, understanding how patients come to be prescribed both an opioid and a gabapentinoid would be of great value.”
1. Gomes T, Greaves S, van der Brink W, Antoniou T, Mamdani MM. Pregabalin and the risk for opioid-related death: a nested case-control study. [published online August 21, 2018]. Ann Intern Med. doi:10.7326/M18-1136.
2. Throckmorton DC, Woodcock J. Combined gapapentinoid and opioid use: the consequences of shifting prescribing trends. [published online August 21, 2018]. Ann Intern Med. doi:10.7326/M18-2175.