Patients taking concomitant prescription opioids and gabapentin may be at an increased risk for opioid-related death, according to a new study published in PLOS Medicine.

Both gabapentin and opioids are commonly prescribed for the treatment of pain, making the likelihood of these two agents being prescribed together high, however, according to lead study author Tara Gomes, “no published studies have examined whether concomitant gabapentin therapy is associated with an increased risk of accidental opioid-related death in patients receiving opioids.”

To investigate whether co-prescription increases the risk of opioid-related death, the researchers conducted a population-based nested case-control study using a cohort of patients receiving prescriptions for opioids in Ontario, Canada. “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,” the authors write. “After matching, we included 1,256 cases and 4,619 controls.”

Concomitant use of gabapentin in the 120 days preceding the index data was considered the primary exposure. The researchers also looked at how gabapentin dose factored into risk. 

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The data showed that in the prior 120 days, 12.3% of cases and 6.8% of controls were prescribed gabapentin. Compared to opioid prescription alone, co-prescription significantly increased the odds of opioid-related death by 49% (adjusted odds ratio [aOR] 1.49, 95% CI 1.18–1.88, P<0.001), with moderate- and high-dose gabapentin increasing these odds to almost 60% (moderate dose [900–1799mg/day]: aOR 1.56, 95% CI 1.06–2.28, P=0.024; high dose [≥1800mg/day]: aOR 1.58, 95% CI 1.09–2.27, P=0.015).

With regard to nonsteroidal anti-inflammatory drugs (NSAIDs), a sensitivity analysis showed no significant association between concomitant opioid use and opioid-related death (aOR 1.14, 95% CI 0.98–1.32, P=0.083).

The authors note that additive respiratory depression, coupled with an increase in gabapentin absorption (due to opioid-induced slowing of gastrointestinal transit), are two factors that may explain why gabapentin contributes to the risk of death in opioid users.

Given this new data, the authors suggest clinicians be cautious when considering co-prescription of gabapentin and opioids. In patients where concomitant use is necessary, close monitoring is important, as is adjusting the opioid dose to minimize risk. “The clinical consequences of a potential drug-drug interaction are clear given the large number of people at risk of this fatal outcome,” conclude the authors. 

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