Opioid use disorder (OUD) is a major global-scale social issue affecting public health. The high potential for addiction and dependence makes opioid use a significant concern, contributing to substance-related disorders. Both genetic and environmental factors contribute to the predisposition to OUD, with the opioidergic, dopaminergic, and GABAergic systems playing primary roles in itsonset.

This narrative review documents the association between genes and their variants related to these three systems, along with current evidence on epigenetic interventions in OUD. Relevant studies investigating candidate-gene associations and molecular mechanisms were synthesized to highlight genetic variants and epigenetic processes linked to OUD.

Genetic associations play a prominent role in OUD, with several single-nucleotide variants identified in affected populations. Key genes implicated include OPRM1, OPRD1, OPRK1, PDYN, OPRL1, and POMC from the opioidergic system; DRD1, DRD2, DRD3, DRD4, ANKK1, and COMT from the dopaminergic system; and GABRA2, GABRB3, GABRG2, GAD1, and GAD2 from the GABAergic system. Evidence also indicates that chronic opioid use is associated with epigenetic changes through posttranslational histone modifications and DNA methylation. However, limitations in existing studies include small sample sizes, limited replication, and potential stratification biases.

Although many candidate-gene associations have been proposed for OUD, robust evidence remains limited. Large, ancestrally diverse genome-wide association studies (GWAS) and systematic replication studies are urgently needed. A deeper understanding of the genetic, epigenetic, and neurobiological bases of addiction will be essential for the development of precisely targeted medications to improve prevention and treatment outcomes for OUD.