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.


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.

Author summary

Why was this study done?

  • Gabapentin is a drug often used together with opioids to treat chronic pain, and both of these drugs have been shown to suppress breathing, which can be fatal.
  • Concomitant opioid use can also increase the amount of gabapentin absorbed by the body, potentially leading to higher risks when these drugs are used together.
  • 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 dependent on gabapentin dose.
  • If there is an important interaction between these drugs, this would be of high clinical importance given the common combined use of these drugs.

What did the researchers do and find?

  • We conducted a matched case–control study among people treated with opioid painkillers in Ontario, the most populous province of Canada.
  • We determined concomitant gabapentin exposure among 1,256 individuals (cases) who died of an opioid-related cause and 4,619 matched controls.
  • We found that concomitant gabapentin and opioid exposure was associated with a 49% higher risk of dying from an opioid overdose.

What do these findings mean?

  • Clinicians should take great caution 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.


These findings are not unexpected.  Addicts also abuse gabapentin (anything to get high!)  Both have respiratory depressing effects.  However, on the plus side, together they’re quite synergestic in pain relieving ability–there’s an “opiate sparing” effect to gabapentin that is undeniable.  Buprenorphine is my first choice opioid for analgesia.  I often use it with gabapentin.