Date Published: October 3, 2017
Publisher: Public Library of Science
Author(s): Tara Gomes, David N. Juurlink, Tony Antoniou, Muhammad M. Mamdani, J. Michael Paterson, Wim van den Brink, Alexander C. Tsai
Abstract: BackgroundPrescription opioid use is highly associated with risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription. Although gabapentin is widely perceived as safe, drug-induced respiratory depression has been described when gabapentin is used alone or in combination with other medications. Because gabapentin and opioids are both commonly prescribed for pain, the likelihood of co-prescription is high. However, no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids. The objective of this study was to investigate whether co-prescription of opioids and gabapentin is associated with an increased risk of accidental opioid-related mortality.Methods and findingsWe conducted a population-based nested case–control study among opioid users who were residents of Ontario, Canada, between August 1, 1997, and December 31, 2013, using administrative databases. Cases, defined as opioid users who died of an opioid-related cause, were matched with up to 4 controls who also used opioids on age, sex, year of index date, history of chronic kidney disease, and a disease risk index. After matching, we included 1,256 cases and 4,619 controls. The primary exposure was concomitant gabapentin use in the 120 days preceding the index date. A secondary analysis characterized gabapentin dose as low (<900 mg daily), moderate (900 to 1,799 mg daily), or high (≥1,800 mg daily). A sensitivity analysis examined the effect of concomitant nonsteroidal anti-inflammatory drug (NSAID) use in the preceding 120 days. Overall, 12.3% of cases (155 of 1,256) and 6.8% of controls (313 of 4,619) were prescribed gabapentin in the prior 120 days. After multivariable adjustment, co-prescription of opioids and gabapentin was associated with a significantly increased odds of opioid-related death (odds ratio [OR] 1.99, 95% CI 1.61 to 2.47, p < 0.001; adjusted OR [aOR] 1.49, 95% CI 1.18 to 1.88, p < 0.001) compared to opioid prescription alone. In the dose–response analysis, moderate-dose (OR 2.05, 95% CI 1.46 to 2.87, p < 0.001; aOR 1.56, 95% CI 1.06 to 2.28, p = 0.024) and high-dose (OR 2.20, 95% CI 1.58 to 3.08, p < 0.001; aOR 1.58, 95% CI 1.09 to 2.27, p = 0.015) gabapentin use was associated with a nearly 60% increase in the odds of opioid-related death relative to no concomitant gabapentin use. As expected, we found no significant association between co-prescription of opioids and NSAIDs and opioid-related death (OR 1.11, 95% CI 0.98 to 1.27, p = 0.113; aOR 1.14, 95% CI 0.98 to 1.32, p = 0.083). In an exploratory analysis of patients at risk of combined opioid and gabapentin use, we found that 46.0% (45,173 of 98,288) of gabapentin users in calendar year 2013 received at least 1 concomitant prescription for an opioid. This study was limited to individuals eligible for public drug coverage in Ontario, we were only able to identify prescriptions reimbursed by the government and dispensed from retail pharmacies, and information on indication for gabapentin use was not available. Furthermore, as with all observational studies, confounding due to unmeasured variables is a potential source of bias.ConclusionsIn this study we found that among patients receiving prescription opioids, concomitant treatment with gabapentin was associated with a substantial increase in the risk of opioid-related death. Clinicians should consider carefully whether to continue prescribing this combination of products and, when the combination is deemed necessary, should closely monitor their patients and adjust opioid dose accordingly. Future research should investigate whether a similar interaction exists between pregabalin and opioids.
Partial Text: Prescription opioid overdoses are an ongoing public health concern across North America, contributing to more than 15,000 deaths in the United States in 2015 . Most opioid-related deaths result from respiratory depression, and co-administration of central nervous system (CNS) depressants is an important and avoidable risk factor for death. Recent evidence showed that co-prescription of benzodiazepines with opioids increases the risk of overdose death nearly 4-fold , leading to the introduction of black box warnings on the packaging for both products in August 2016 . Furthermore, prescription opioid use has been shown to be highly associated with future risk of opioid-related death, with 1 of every 550 chronic opioid users dying within approximately 2.5 years of their first opioid prescription .
We identified 2,914,971 ODB-eligible individuals who received a prescription opioid over the study period; of these, 1,391 potential cases met our inclusion criteria (Fig 1), and 1,256 (90.3%) of these were matched to at least 1 control, leading to a total of 4,619 controls included in our study. All cases had prescription opioids found on postmortem toxicology, and 24 (1.9%) also had heroin present in their system at the time of death. Of those with heroin involved in their death, fewer than 6 had been exposed to a prescription for gabapentin in the prior 120 days.
In this large study spanning more than 16 years, we found that approximately 8% of patients receiving opioids were co-prescribed gabapentin and that co-prescription was associated with a 50% increase in the risk of dying of opioid-related causes. A very high dose of co-prescribed gabapentin was associated with a near doubling of this risk. In contrast, and as expected, no such risk was observed among opioid recipients concomitantly prescribed NSAIDs. Our findings thus support the existence of a life-threatening drug–drug interaction between gabapentin and opioids in routine clinical practice.