AbstractBackground and AimsAn 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.DesignWe 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.SettingPrimary care in England.ParticipantsWe 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.MeasurementsThe 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.FindingsAmong 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.ConclusionElevated risk of non‐fatal overdose among opioid agonist treatment recipients is associated with concurrent use of medication prescribed for other reasons.