Scotland's 2009-2015 methadone-prescription cohort: quintiles for daily-dose of prescribed methadone and risk of methadone-specific death.

BACKGROUND As methadone-clients age, their drug-related death (DRD) risks increase, more than doubling at 45+ years for methadone-specific DRDs. METHODS Using Community Health Index (CHI) numbers, mortality to 31 December 2015 was ascertained for 36,347 methadone-prescription-clients in Scotland during 2009-2015. Cohort-entry, quantity of prescribed methadone and daily-dose (actual or recovered by effective, simple rules) were defined by clients' first CHI-identified methadone-prescription after 30 June 2009 and used in proportional hazards analysis. As custodian of death-records, National Records of Scotland identified non-DRDs from DRDs. Methadone-specific DRD means methadone was implicated but neither heroin nor buprenorphine. RESULTS The cohort's 192,928 person-years included 1857 non-DRDs; 1323 DRDs (42%), 546 being methadone-specific DRDs. Actual/recovered daily-dose was available for 26,533 (73%) clients who experienced 420 methadone-specific DRDs. Top quintile for daily-dose at first CHI-identified methadone prescription was >90mg. Age 45+ years at cohort-entry (hazard ratio versus 25-34 years: 3.1, 95% CI: 2.4-4.2), top quintile for baseline daily-dose of prescribed methadone (versus 50-70 mg: 1.9, 1.1-3.1) and being female (1.3, 1.0-1.6) significantly increased clients' risk of methadone-specific DRD. CONCLUSIONS Extra care is needed when methadone daily-dose exceeds 90mg. Females' higher risk for methadone-specific DRD is new; and needs validation. Further analyses of prescribed daily-dose linked to mortality for large cohorts of methadone-clients are needed internationally; together with greater pharmacodynamic and pharmacokinetic understanding of methadone by age and gender. Balancing age-related risks is challenging for prescribers who manage chronic opiate dependency against additional uncertainty about the nature, strength and pharmacological characteristics of drugs from illegal markets. [249 words].