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. 2023 May 13;12(10):3449.
doi: 10.3390/jcm12103449.

Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation/Genotypes Changes in Patients with Chronic Pain

Laura Agulló  1   2 , Javier Muriel  1 , César Margarit  3 , Mónica Escorial  1   2 , Diana Garcia  4 , María José Herrero  5 , David Hervás  6 , Juan Sandoval  4 , Ana M Peiró  1   2
Affiliations

Sex Differences in Opioid Response Linked to OPRM1 and COMT genes DNA Methylation/Genotypes Changes in Patients with Chronic Pain

Laura Agulló et al. J Clin Med. .

Abstract

Analgesic-response variability in chronic noncancer pain (CNCP) has been reported due to several biological and environmental factors. This study was undertaken to explore sex differences linked to OPRM1 and COMT DNA methylation changes and genetic variants in analgesic response. A retrospective study with 250 real-world CNCP outpatients was performed in which data from demographic, clinical, and pharmacological variables were collected. DNA methylation levels (CpG island) were evaluated by pyrosequencing, and their interaction with the OPRM1 (A118G) and COMT (G472A) gene polymorphisms was studied. A priori-planned statistical analyses were conducted to compare responses between females and males. Sex-differential OPRM1 DNA methylation was observed to be linked to lower opioid use disorder (OUD) cases for females (p = 0.006). Patients with lower OPRM1 DNA methylation and the presence of the mutant G-allele reduced opioid dose requirements (p = 0.001), equal for both sexes. Moreover, COMT DNA methylation levels were negatively related to pain relief (p = 0.020), quality of life (p = 0.046), and some adverse events (probability > 90%) such as constipation, insomnia, or nervousness. Females were, significantly, 5 years older with high anxiety levels and a different side-effects distribution than males. The analyses demonstrated significant differences between females and males related to OPRM1 signalling efficiency and OUD, with a genetic-epigenetic interaction in opioid requirements. These findings support the importance of sex as a biological variable to be factored into chronic pain-management studies.

Keywords: DNA methylation; chronic pain; epigenetics; pharmacogenetics; sex differences.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure A1
Figure A1
Flow chart of the included patients and their studies of provenance. CNCP, chronic noncancer pain.
Figure A2
Figure A2
Degree of association between the methylation value of the different sites of OPRM1 (gene OPRM1 position, gop 1 to 5) and COMT (gene COMT position, gcp 1 to 7) genes. The intense garnet colours correspond to very high degrees of association.
Figure 1
Figure 1
The OPRM1 (μ-opioid receptor 1) and COMT (catechol-O-methyltransferase) gene promoter region. The locations of the CpG sites are represented by knobs and translation start sites (ATG) are shown in bold.
Figure 2
Figure 2
Distribution of methylation values (%) at each CpG site of the COMT (sites 1–7) and OPRM1 (sites 1–5) genes.
Figure 3
Figure 3
Effect of OPRM1 DNA methylation (%) on opioid use disorder per sex according to male (M) or female (F).
See this image and copyright information in PMC

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