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The study of sex-specific genetic associations with opioid response may improve the understanding of inter-individual variability in pain treatments. We investigated sex-specific associations between genetic variation and opioid response. We identified participants in the RIGHT Study prescribed codeine, tramadol, hydrocodone, and oxycodone between 01/01/2005 and 12/31/2017. Prescriptions were collapsed into codeine/tramadol and hydrocodone/oxycodone. Outcomes included poor pain control and adverse reactions within six weeks after prescription date. We performed gene-level and single-variant association analyses stratified by sex. We included 7169 non-Hispanic white participants and a total of 1940 common and low-frequency variants (MAF &gt; 0.01). Common variants in  MACROD2  (rs76026520),  CYP1B1  (rs1056837, rs1056836), and  CYP2D6  (rs35742686) were associated with outcomes. At the gene level,  FAAH ,  SCN1A , and  TYMS  had associations for men and women, and  NAT2 ,  CYP3A4 ,  CYP1A2 , and  SLC22A2  had associations for men only. Our findings highlight the importance of considering sex in association studies on opioid response.

Identification of sex-specific genetic associations in response to opioid analgesics in a White, non-Hispanic cohort from Southeast Minnesota