Does taking gabapentin with opioids raise overdose death risk?
People on prescription opioids who were also given gabapentin had about 50% higher odds of dying from an opioid overdose, with the greatest risk at moderate-to-high gabapentin doses.
Source
Gabapentin, opioids, and the risk of opioid-related death: A population-based nested case-control study
Study at a glance
- Design
- Case-control — Nested case-control study within all Ontario public-drug-plan opioid recipients (1997-2013): coroner-confirmed accidental opioid deaths matched to up to four living opioid users on a disease risk index, age, sex, year and kidney disease; exposure was a gabapentin prescription in the prior 120 days.
- N
- N=5875 · 1,256 matched cases (opioid-related deaths) and 4,619 matched controls drawn from 2,914,971 opioid recipients; all were receiving opioids for non-cancer pain.
- Population
- Adults aged 15-105 eligible for Ontario public drug coverage (mostly under 65 and low-income) with an active opioid prescription and no cancer or palliative care.
- Outcome
- Odds of accidental opioid-related death with concomitant gabapentin versus opioids alone, overall and by gabapentin dose.
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What they did
Using linked health records for everyone in Ontario who received publicly funded opioids between 1997 and 2013, the researchers identified people whose deaths the coroner confirmed were accidental and opioid-related. Each death was matched with up to four living opioid users of similar predicted risk, age, sex, year and kidney-disease history. They compared how often cases and controls had filled a gabapentin prescription in the previous 120 days, adjusting for opioid dose, other sedating drugs, alcohol use disorder and other health factors, and repeated the analysis for NSAIDs as a comparison drug that should not add risk.
What they found
Gabapentin had been prescribed recently to 12.3% of those who died versus 6.8% of controls. Co-prescription was linked to 49% higher odds of opioid-related death (adjusted odds ratio 1.49); moderate and high gabapentin doses were linked to odds ratios of 1.56 and 1.58, low doses to a non-significant 1.32, and very high doses (2,500 mg a day or more) to 1.83. NSAID co-prescription showed no significant link, and in 2013 nearly half of Ontario gabapentin users also received an opioid.
The limits
What it doesn't show
As an observational study it cannot prove gabapentin causes the deaths; people prescribed both drugs may differ in ways not captured, such as pain severity (confounding by indication). The sample was mostly low-income people under 65 on public drug coverage, so it may not generalise to all opioid users. Only dispensed, government-reimbursed prescriptions were seen, so adherence, cash or illicit drug use and the reason gabapentin was prescribed are unknown. The dose categories had overlapping confidence intervals, so the dose-response pattern is suggestive rather than firm.
Key terms
- Nested case-control study
- A case-control study drawn from inside a defined cohort, where people who had the outcome are compared with sampled people from the same cohort who had not.
- Adjusted odds ratio
- The odds of exposure among cases divided by the odds among controls, after statistically accounting for other factors; above 1 means exposure is more common in cases.
- Drug-drug interaction
- When one drug changes the effect or level of another; here gabapentin and opioids both depress breathing and opioids may raise gabapentin absorption.
- Confounding by indication
- Bias that arises because the reason a drug is prescribed (such as severe pain) may itself be linked to the outcome.
- Negative control exposure
- An exposure not expected to affect the outcome, used to check for bias; here NSAIDs.
- Morphine milligram equivalents
- A way to convert doses of different opioids to a common scale based on morphine, so total opioid dose can be compared and adjusted for.
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Common questions
Why check NSAIDs as well?
NSAIDs are also painkillers but are not expected to add to opioid breathing suppression. If NSAID users had shown the same excess risk, it would suggest the gabapentin result simply reflects sicker or more pain-affected patients. The NSAID association was small and not significant, which supports a specific gabapentin effect.
How could gabapentin make opioids more dangerous?
Both drugs depress the central nervous system and breathing. Opioids also slow the gut, which may let more gabapentin be absorbed, raising its blood level, so the effects add together.
Does this mean gabapentin should never be combined with opioids?
Not necessarily. The authors suggest careful dose titration, lower doses in lung or kidney disease, avoiding other sedatives, and warning patients about overdose signs when the combination is needed.
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