403: Do genes moderate the effect of opioid therapy? A systematic review

Topic: Clinical Science
Subtopic: Pain category (ICD-11), Acute postsurgical pain, Pharmacological treatments

Background and Aims: Opioids are widely used for pain management globally. Their average treatment effect is small to modest for different types of pain such as acute musculoskeletal pain, [1] chronic non-cancer pain, [2] and some types of cancer pain, such as breakthrough pain.[3] However, there is documented evidence of heterogeneity of treatment effects following opioid therapy, [4] and certain gene variants are known to influence opioid metabolism, efficacy, and safety.[5] However, this evidence includes studies of any design, from in vitro studies, to observational studies, and clinical trials. There has not been a systematic evaluation of whether gene variants formally moderate the effect of opioid therapy for pain in randomised controlled trials.

The primary aim of this review is to investigate whether gene variants relevant to the efficacy and toxicity of opioids moderate the effect of opioids on pain and adverse drug reactions (ADRs).

Methods: This review was prospectively registered on PROSPERO (CRD420261285132). We searched PubMed, EMBASE, and Cochrane CENTRAL
from their inception to 19 February, 2026.

We included randomised controlled trials (trials) enrolling people with any pain condition (e.g. acute pain, chronic pain, cancer pain). We excluded trials involving experimental pain. Eligible interventions were any opioid analgesic administered via any route. Trials had to have investigated the moderating effect of genes identified in the ClinPGx platform relevant (i.e., classified as being 'significant') to opioid efficacy, or toxicity, or both. All comparators were eligible (e.g. other opioids, no treatment, placebo, etc.).

Co-primary outcomes were pain intensity and ADRs.

Risk of bias was assessed with the ROBUST-RCT tool. The credibility of effect modification was assessed with the ICEMAN tool.

For each trial, we computed the treatment-by-gene interaction test and will compute the p-value for the interaction by a Z-test.[6] Analyses were done in Stata v19.

Results: We included 6 trials (n = 668 participants). Trials investaged the moderating role of the following genes: ABCB1, CCL11, COMT, CYP2D6, CYP3A4, CYP3A5, IL-16, and OPRM1. Trials were not homogeneous enough to allow meta-analysis to be performed.

All studies were at high risk of bias and the credibility of effect modification of all trials were low. Low credibility was driven by lack of evidence of a priori specification of analyses.

With the exception of a limited number of analyses (3/18 for pain, 0/45 for ADRs), we found no evidence of opioid x genotype interaction for most analyses and genes. There were two exceptions.

Amongst individuals undergoing orthopaedic surgery, those with the ABCB1 gene moderated the effect of morphine (vs no morphine; 1 trial, p = 0.006). In another trial involving patients with cancer pain, the CCL11 gene moderated the effect of oxycodone (vs morphine) (1 trial, p = 0.017).

Conclusions: Based on the available evidence from six trials, there is little support for clinically meaningful opioid–genotype interactions across the genes examined.

The majority of analyses found no significant interaction effects for either pain outcomes or adverse drug reactions, and the two exceptions identified were each based on single trials and should be interpreted cautiously. The overall findings are further limited by high risk of bias across all studies and low credibility of effect modification.

Until higher-quality, prospectively designed pharmacogenomic trials are conducted, routine genotyping to guide opioid prescribing should not be recommended on the basis of current evidence.

References: [1] Drugs. 2024 Mar;84(3):305-317.

[2] JAMA. 2018 Dec 18;320(23):2448-2460.

[3] CA Cancer J Clin. 2024 May-Jun;74(3):286-313.

[4] Clin Pharmacol Ther. 2019 Jul;106(1):204-210.

[5] Curr Treat Options Oncol. 2022 Oct;23(10):1353-1369.

[6] BMJ 2003;326:219.

Presenting Author: Giovanni E Ferreira
Submitting Author: Giovanni Ferreira

Senior Author: Giovanni E. Ferreira

IASP 2026 Global Year theme of Neuropathic Pain: No

• Selina Sov: NA - University of Sydney
• Aili Langford: PhD - University of Sydney
• Christine Lin: PhD - University of Sydney
• Andrew McLachlan: PhD - University of Sydney
• Christopher Maher: DMedSc - University of Sydney
• Christina Abdelshaheed: PhD - University of Sydney
• Giovanni E Ferreira: PhD - University of Sydney