AIMS: To describe the health-related harms associated with the misuse of benzodiazepines/z-drugs, prescription opioids, gabapentinoids, and psychostimulants in Ireland by examining trends in their involvement in treatment demand, non-fatal intentional drug overdoses (IDOs), and drug related deaths (DRDs).

METHODS: A repeated cross-sectional study using data from the National Drug Treatment Reporting System (NDTRS), the National Self-Harm Registry Ireland (NSHRI) and the National Drug Related Deaths Index (NDRDI) between 2010 and 2020. Trends over time (2010-2020) in treatment demand, IDOs and DRDs involving benzodiazepines/z-drugs, prescription opioids excluding opioid agonist therapy drugs, gabapentinoids, or psychostimulants (alone or concurrently), adjusting for age and gender (Negative Binomial Regression).

FINDINGS: A total of 102,661 treatment entry cases; 51,126 people presenting with at least one IDO; and 3626 DRDs included. Benzodiazepines/z-drugs were involved in 341 per 1000 treatment entry cases; 408 per 1000 IDOs; and 546 per 1000 DRDs, followed by prescription opioids (36 per 1000 treatment entry cases; 133 per 1000 IDOs; and 207 per 1000 DRDs) and gabapentinoids (5 per 1000 treatment entry cases; 54 per 1000 IDOs; and 118 per 1000 DRDs). Benzodiazepines/z-drugs, and prescription opioid involvement was stable over time with little or no changes observed in treatment demand, IDOs and DRDs. However, NPS-Benzodiazepines (etizolam) involvement in DRDs increased by 47 % annually (Adjusted Rate Ratio (ARR) 1.47, 95 % Confidence Interval (CI) 1.30-1.65, p < 0.0001). Gabapentinoids (primarily pregabalin) associated with a large annual increase in treatment demand (+44 % annually, ARR 1.44, 95 % CI 1.36-1.52, p < 0.0001), DRDs (+35 % annually, ARR 1.35, 95 % CI 1.25-1.46, p < 0.0001), and IDOs (+9 % annually, ARR 1.09, 95 % CI 1.07-1.10, p < 0.0001). Polysubstance use harms increased with respect to treatment demand, IDOs and DRDs over study period.

CONCLUSIONS: While benzodiazepines account for the greatest overall harm with respect to treatment demand, IDOs and DRDs, gabapentinoids (primarily pregabalin) had the largest annual increase in harm over the study period.