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Observational Study
, 14 (10), e1002396

Gabapentin, Opioids, and the Risk of Opioid-Related Death: A Population-Based Nested Case-Control Study

Observational Study

Gabapentin, Opioids, and the Risk of Opioid-Related Death: A Population-Based Nested Case-Control Study

Tara Gomes et al. PLoS Med.


Background: Prescription 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 findings: We 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.

Conclusions: In 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.

Conflict of interest statement

TA is supported by a New Investigator Award from the Canadian Institutes for Health Research (CIHR). DNJ has provided expert opinion on medicolegal matters, some of which have involved opioids (in no instances has DNJ engaged in paid work for or against opioid manufacturers.) Income received from speaking or expert testimony is tithed by The Sunnybrook Department of Medicine as part of their academic practice plan. MMM has served on advisory boards and reports honoraria from Bristol-Myers Squibb, Eli Lilly and Company, Glaxo Smith Kline, Hoffman La Roche, Novartis, Novo Nordisk, Pfizer, and Astra Zeneca, all outside the submitted work. WvdB received honoraria from Lundbeck, Indivior, Mundipharma, Novartis, Bioproject, Eli Lilly and Pfizer. All other authors report no conflicts of interest.


Fig 1
Fig 1. Inclusion/exclusion criteria applied to cases and controls.
Details of cohort development, including identification of cases and potential controls, as well as inclusion and exclusion criteria applied prior to matching. ODB, Ontario Drug Benefit.
Fig 2
Fig 2. Association between co-prescription with gabapentin and opioids and opioid overdose.
Association between co-prescription of gabapentin and opioids and opioid overdose, adjusted for age, opioid dose, medication use in the prior 120 days (pregabalin, SSRIs, other antidepressants, benzodiazepines, other psychotropic drugs/CNS depressants, long-acting opioid, methadone/buprenorphine), number of drugs dispensed in the past 6 months, alcohol use disorder, chronic lung disease, diabetes, Charlson Comorbidity Index, number of opioid prescribers in the past 6 months, and number of pharmacies dispensing opioids in the past 6 months. Neutral exposure model (NSAIDs) is also adjusted for gabapentin use in prior 120 days. NSAID, nonsteroidal anti-inflammatory drug.

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Grant support

This study was funded by a grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC; Grant #06673; TG, DNJ, MMM). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.