Impact of CYP2D6 genotype on opioid use disorder deprescription: an observational prospective study in chronic pain with sex-differences

Javier Muriel; Jordi Barrachina; Guillermo Del Barco; Cristian Carvajal; Mónica Escorial; César Margarit; Pura Ballester; Ana María Peiró

doi:10.3389/fphar.2023.1200430

Impact of CYP2D6 genotype on opioid use disorder deprescription: an observational prospective study in chronic pain with sex-differences

Front Pharmacol. 2023 May 31:14:1200430. doi: 10.3389/fphar.2023.1200430. eCollection 2023.

Authors

Javier Muriel¹, Jordi Barrachina^{1

2}, Guillermo Del Barco², Cristian Carvajal², Mónica Escorial^{1

2}, César Margarit^{1

3}, Pura Ballester¹, Ana María Peiró^{1

3

4}

Affiliations

¹ Pharmacogenetic Unit, Clinical Pharmacology Unit, Alicante Institute for Health and Biomedical Research (ISABIAL), Alicante, Spain.
² Occupational Observatory, University Miguel Hernández, Elche, Spain.
³ Pain Unit, Department of Health of Alicante-General Hospital, Alicante, Spain.
⁴ Bioengineering Institute, Toxicology and Environmental Health, University Miguel Hernández, Elche, Spain.

Abstract

Introduction: Opioid deprescription is the process of supervised tapering and safe withdrawal when a potentially inappropriate use is detected. This represents a challenge in chronic non-cancer pain (CNCP) patients who may respond differently to the procedure. Our aim was to analyze the potential impact of CYP2D6 phenotypes and sex on the clinical and safety outcomes during an opioid use disorder (OUD) tapering process. Methods: A prospective observational study was conducted on CNCP ambulatory OUD patients (cases, n = 138) who underwent a 6-month opioid dose reduction and discontinuation. Pain intensity, relief and quality of life (Visual analogue scale, VAS 0-100 mm), global activity (GAF, 0-100 scores), morphine equivalent daily dose (MEDD), analgesic drugs adverse events (AEs) and opioid withdrawal syndrome (OWS, 0-96 scores) were recorded at basal and final visits. Sex differences and CYP2D6 phenotypes (poor (PM), extensive (EM) and ultrarapid (UM) metabolizers based on CYP2D6*1, *2, *3, *4, *5, *6, *10, *17, *41, 2D6*5, 2D6 × N, 2D6*4 × 2 gene variants) were analyzed. Results: Although CYP2D6-UM consumed three-times less basal MEDD [40 (20-123) mg/day, p = 0.04], they showed the highest number of AEs [7 (6-11), p = 0.02] and opioid withdrawal symptoms (46 ± 10 scores, p = 0.01) after deprescription. This was inversely correlated with their quality of life (r = -0.604, p < 0.001). Sex-differences were evidenced with a tendency to a lower analgesic tolerability in females and lower quality of life in men. Discussion: These data support the potential benefits of CYP2D6-guided opioid deprescription, in patients with CNCP when OUD is detected. Further studies are required to understand a sex/gender interaction.

Keywords: CYP2D6; chronic pain; deprescription; opioid use disorder; pharmacogenetics; sex-differences.

Grants and funding

The work was partially funded by a grant from the Spanish Pain Foundation (Ref: BF4-16-02) for short training stay on advanced genotyping techniques at CICAB (Clinical Research Centre, Extremadura University Hospital and Medical School, Badajoz, Spain). This study has been funded by Instituto de Salud Carlos III (ISCIII) through the project “ICI2020/0046” and co-funded by the European Union.