Non-fatal overdose risk associated with prescribing opioid agonists concurrently with other medication: Cohort study conducted using linked primary care, secondary care and mortality records

Addiction. 2023 Dec;118(12):2374-2383. doi: 10.1111/add.16306. Epub 2023 Aug 3.


Background and aims: An apparently protective effect of opioid agonist treatment (OAT) on all-cause and cause-specific mortality risk has been widely reported. Non-fatal overdose (NFO) often precedes subsequent drug-poisoning deaths. We hypothesized that benzodiazepines, gabapentinoids, antipsychotics, antidepressants, Z-drugs or opioids increase the NFO risk when co-prescribed with OAT.

Design: We conducted a cohort study using the Clinical Practice Research Datalink GOLD and Aurum databases. The cohort was linked to Hospital Episode Statistics admitted patient care data (HES-APC), neighbourhood- and practice-level Index of Multiple Deprivation quintiles and mortality records from the Office for National Statistics.

Setting: Primary care in England.

Participants: We studied patients with opioid use disorder, aged 18-64 years, who were prescribed OAT (15155 methadone and 5743 buprenorphine recipients) between Jan 1, 1998, and Dec 31, 2017.

Measurements: The main outcome examined was NFO risk during co-prescription of OAT with benzodiazepines, antipsychotics, gabapentinoids, antidepressants, Z-drugs or opioids. Overdose was defined according to International Classification of Diseases codes from the HES-APC data set. Negative binomial regression models were used to estimate weighted rate ratios (wRR) for NFO during co-prescription of OAT and benzodiazepines, antipsychotics, gabapentinoids, antidepressants, Z-drugs or opioids with periods of exclusive OAT usage.

Findings: Among 20 898 patients observed over 83 856 person-years, we found an elevated overdose risk that resulted in hospital admission during co-prescription of OAT with benzodiazepines [wRR: 1.45; 95% confidence interval (CI) = 1.26-1.67], gabapentinoids (wRR = 2.22; 95% CI = 1.77-2.79), Z-drugs (wRR = 1.60; 95% CI = 1.31-1.96), antipsychotics (wRR = 1.85; 95% CI = 1.53-2.25) and opioids (wRR = 1.28; 95% CI = 1.02-1.60). The risk ratio for antidepressant co-prescriptions was below unity (wRR = 0.90; 95% CI = 0.79-1.02) but this result was not statistically significant.

Conclusion: Elevated risk of non-fatal overdose among opioid agonist treatment recipients is associated with concurrent use of medication prescribed for other reasons.

Keywords: Antipsychotics; Z-drugs; benzodiazepines; gabapentinoids; opioid agonists; overdose.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid* / therapeutic use
  • Antidepressive Agents / therapeutic use
  • Benzodiazepines / therapeutic use
  • Cohort Studies
  • Drug Overdose* / drug therapy
  • Humans
  • Retrospective Studies
  • Secondary Care


  • Analgesics, Opioid
  • Benzodiazepines
  • Antidepressive Agents