Regular use of pharmaceutical opioids and subsequent risk of cancer: a prospective cohort study and Mendelian randomization analysis

Mahdi Sheikh; Allison Domingues; Karine Alcala; Ryan Langdon; Daniela Mariosa; Xiaoshuang Feng; Peter Sarich; Marianne F Weber; Vivian Viallon; Agnes Fournier; Farin Kamangar; Reza Malekzadeh; Chris Gillette; Mara Z Vitolins; Meredith C B Adams; Shama Virani; Elmira Ebrahimi; Tom Dudding; Tessel E Galesloot; Lambertus A Kiemeney; Nathaniel Rothman; Stella Koutros; Jifang Zhou; Sallie-Anne Pearson; Marie-Odile Parat; Paul Brennan; Mattias Johansson; George Davey Smith; Hilary A Robbins

doi:10.1016/j.eclinm.2025.103439

Regular use of pharmaceutical opioids and subsequent risk of cancer: a prospective cohort study and Mendelian randomization analysis

EClinicalMedicine. 2025 Nov 11:89:103439. doi: 10.1016/j.eclinm.2025.103439. eCollection 2025 Nov.

Authors

Mahdi Sheikh¹, Allison Domingues¹, Karine Alcala¹, Ryan Langdon¹, Daniela Mariosa¹, Xiaoshuang Feng¹, Peter Sarich², Marianne F Weber², Vivian Viallon^{1

3}, Agnes Fournier⁴, Farin Kamangar⁵, Reza Malekzadeh⁶, Chris Gillette^{7

8}, Mara Z Vitolins⁸, Meredith C B Adams⁹, Shama Virani¹, Elmira Ebrahimi¹, Tom Dudding¹⁰, Tessel E Galesloot¹¹, Lambertus A Kiemeney¹¹, Nathaniel Rothman¹², Stella Koutros¹², Jifang Zhou¹³, Sallie-Anne Pearson¹⁴, Marie-Odile Parat¹⁵, Paul Brennan¹, Mattias Johansson¹, George Davey Smith¹⁶, Hilary A Robbins¹

Affiliations

¹ Genomic Epidemiology Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
² School of Public Health, University of Sydney, Sydney, Australia.
³ Nutrition and Metabolism Branch, International Agency for Research on Cancer (IARC-WHO), Lyon, France.
⁴ Université Paris-Saclay, UVSQ, Inserm, Gustave Roussy, CESP, Villejuif, France.
⁵ Department of Biology, School of Computer, Mathematical, and Natural Sciences, Morgan State University, Baltimore, MD, United States.
⁶ Digestive Oncology Research Center, Digestive Diseases Research Institute, Tehran University of Medical Sciences, Tehran, Iran.
⁷ Department of PA Studies, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
⁸ Department of Epidemiology and Prevention, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
⁹ Department of Anesthesiology, Artificial Intelligence, Translational Neuroscience, and Public Health Science, Wake Forest University School of Medicine, Winston-Salem, NC, United States.
¹⁰ Bristol Dental School, University of Bristol, Bristol, United Kingdom.
¹¹ Science Department IQ Health, Radboud University Medical Center, Nijmegen, the Netherlands.
¹² Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.
¹³ School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, China.
¹⁴ Medicines Intelligence Research Program, School of Population Health, University of New South Wales Sydney, Australia.
¹⁵ School of Pharmacy and Pharmaceutical Sciences, University of Queensland, Brisbane, Australia.
¹⁶ MRC Integrative Epidemiology Unit, University of Bristol, Bristol, BS8 2BN, United Kingdom.

Abstract

Background: Opium consumption was classified as "carcinogenic to humans" by the International Agency for Research on Cancer (IARC). We investigated whether use of pharmaceutical opioids, derived from or synthesized to mimic opium, is associated with cancer risk using separate observational and genetic analyses.

Methods: Observational analysis included 472,955 participants in the UK Biobank prospective cohort (2006-2022). Genetic analysis included 2-sample Mendelian Randomization (MR) analyses using data from 14 independent genome-wide-association-studies (N = 9931-357,292). Adjusted hazard ratios (a-HR) or odds ratios (ORs) associated with regular opioid use were assessed for six established opium-related cancers (lung, pancreatic, bladder, esophageal, oropharyngeal, and laryngeal) and seven non-opium-related cancers (prostate, breast, colon, endometrial, kidney, ovarian, and brain).

Findings: In UK Biobank, regular opioid use was associated with increased risk of opium-related cancers among ever-smoking [a-HR = 1.33 (95% CI = 1.22-1.43)] and never-smoking participants [a-HR = 1.32 (1.10-1.59)], but not non-opium-related cancers [a-HR = 0.96 (0.91-1.02)]. Risk increased with opioid strength [a-HR = 1.30 (1.20-1.40) for weak opioids; a-HR = 1.86 (1.43-2.40) for strong opioids, p-trend < 0.0001] and duration of action [a-HR = 1.32 (1.22-1.42) for short-acting; a-HR = 1.65 (1.24-2.18) for long-acting opioids, p-trend < 0.0001]. Both observational and genetic analyses showed increased risks for most opium-related cancers, including lung [a-HR = 1.39 (1.27-1.53); MR-Odds Ratio (OR) = 1.17 (1.07-1.29)], pancreas [a-HR = 1.24 (1.01-1.52); MR-OR = 1.34 (1.11-1.62)], bladder [a-HR = 1.26 (1.02-1.56); MR-OR = 1.15 (1.03-1.29)], esophagus [a-HR = 1.18 (0.94-1.49); MR-OR = 1.24 (1.01-1.52)], and larynx [a-HR = 1.37 (0.85-2.20); MR-OR = 1.29 (1.04-1.61)]. Except for an inverse association with prostate cancer [a-HR = 0.83 (0.76-0.91); MR-OR = 0.99 (0.92-1.05)], associations were null for non-opium-related cancers.

Interpretation: Regular use of pharmaceutical opioids was associated with elevated risk for cancers caused by opium, but not other cancers.

Funding: US National Institutes of Health, French National Cancer Institute.

Keywords: Addiction; Anelgesics; Carcinogenic; Malignancy; Narcotics.