BackgroundOpioid use disorder (OUD), which is most commonly exhibited as addiction, is a persistent chronic disease that places a burden on families and society. Various peripheral traits have been linked to OUD in the past, but research on this topic is insufficient.MethodsSeven male patients with OUD and 7 male healthy controls with matched demographic and clinical data were enrolled in this study. Peripheral blood RNA was used to construct an rRNA-removed library and a small RNA library. The peripheral transcriptomic differences between the two groups were investigated using RNA-seq. Differentially expressed messenger RNAs (mRNAs), long non-coding RNAs (lncRNAs), circular RNAs (circRNAs) and microRNAs (miRNAs) were identified by bioinformatics methods, and functional enrichment analysis with differentially expressed RNAs was performed to investigate the potential biological mechanisms of OUD.ResultsA total of 229 mRNAs (115 upregulated, 114 downregulated), 416 lncRNAs (191 upregulated, 225 downregulated), 17 circRNAs (16 upregulated, 1 downregulated) and 74 miRNAs (42 upregulated, 32 downregulated) were differentially expressed between the OUD group and the healthy control group. Functional enrichment analysis with differentially expressed mRNAs showed that immunity, GnRH secretion, and PI3K-Akt signaling pathways were associated with OUD. Immunity-, JAK-STAT-, and insulin-related pathways were enriched in functional enrichment analysis of target genes predicted by differentially expressed miRNAs.ConclusionWe identified hundreds of differentially expressed genes that were enriched in immunity, GnRH secretion and PI3K-Akt signaling pathways. Some genes with significant changes might be used as potential biomarkers for progression and treatment of OUD.