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Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study.
PLoS Med. 2017 Oct; 14(10):e1002396.PM

Abstract

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.

Authors+Show Affiliations

Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada.Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Sunnybrook Research Institute, Toronto, Ontario, Canada. Department of Medicine, University of Toronto, Toronto, Ontario, Canada.Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.Li Ka Shing Knowledge Institute, St. Michael's Hospital, Toronto, Ontario, Canada. Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Ontario, Canada. Department of Medicine, University of Toronto, Toronto, Ontario, Canada. Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada.Institute for Clinical Evaluative Sciences, Toronto, Ontario, Canada. Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada.Department of Psychiatry, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Pub Type(s)

Journal Article
Observational Study

Language

eng

PubMed ID

28972983

Citation

Gomes, Tara, et al. "Gabapentin, Opioids, and the Risk of Opioid-related Death: a Population-based Nested Case-control Study." PLoS Medicine, vol. 14, no. 10, 2017, pp. e1002396.
Gomes T, Juurlink DN, Antoniou T, et al. Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Med. 2017;14(10):e1002396.
Gomes, T., Juurlink, D. N., Antoniou, T., Mamdani, M. M., Paterson, J. M., & van den Brink, W. (2017). Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. PLoS Medicine, 14(10), e1002396. https://doi.org/10.1371/journal.pmed.1002396
Gomes T, et al. Gabapentin, Opioids, and the Risk of Opioid-related Death: a Population-based Nested Case-control Study. PLoS Med. 2017;14(10):e1002396. PubMed PMID: 28972983.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study. AU - Gomes,Tara, AU - Juurlink,David N, AU - Antoniou,Tony, AU - Mamdani,Muhammad M, AU - Paterson,J Michael, AU - van den Brink,Wim, Y1 - 2017/10/03/ PY - 2017/04/05/received PY - 2017/08/25/accepted PY - 2017/10/4/entrez PY - 2017/10/4/pubmed PY - 2017/10/11/medline SP - e1002396 EP - e1002396 JF - PLoS medicine JO - PLoS Med VL - 14 IS - 10 N2 - 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. SN - 1549-1676 UR - https://www.unboundmedicine.com/medline/citation/28972983/Gabapentin_opioids_and_the_risk_of_opioid_related_death:_A_population_based_nested_case_control_study_ L2 - https://dx.plos.org/10.1371/journal.pmed.1002396 DB - PRIME DP - Unbound Medicine ER -