Regular opium use and subsequent incidence of cancer
Authors: David C Whiteman
Journal: The Lancet Global Health (2020)

Opium is derived from the resin of the opium poppy (Papaver somniferum) and has been harvested and used for medicinal and recreational purposes since ancient times. Extracts have been found at prehistoric sites across western, southern, and central Europe from the early Neolithic period (pre-400 BC),1Tétényi P Opium poppy (Papaver somniferum): botany and horticulture.Hortic Rev (Am Soc Hortic Sci). 1997; 19: 373-408Google Scholar and methods for extraction and use featured frequently in Assyrian, Greek, and Roman texts.2Kritikos PG Papadaki S The history of the poppy and of opium and their expansion in antiquity in the eastern Mediterranean area. United Nations Office on Drugs and Crime, Vienna1967Google Scholar Spread of opium to the Middle East is believed to have followed the conquests of Alexander the Great,1Tétényi P Opium poppy (Papaver somniferum): botany and horticulture.Hortic Rev (Am Soc Hortic Sci). 1997; 19: 373-408Google Scholar with further spread to India and China presumed to have followed Arabian traders.3Brownstein MJ A brief history of opiates, opioid peptides, and opioid receptors.Proc Natl Acad Sci USA. 1993; 90: 5391-5393Crossref PubMed Scopus (322) Google Scholar Today, opium use is widespread; estimates suggest nearly 30 million users of non-prescription opiates worldwide. Although opium's medicinal properties have brought undoubted benefits, the harms associated with unsupervised use are well documented. In most parts of the world, recreational opium is either ingested or inhaled as smoke. Concerns have been raised that regular opium users might have higher rates of cancer than non-users. When heated, opium generates pyrolysis products such as polycyclic aromatic hydrocarbons and volatile organic compounds, which are known carcinogens. Recent biomarker studies have detected high levels of these carcinogens among people who used opium but not tobacco,4Etemadi A Poustchi H Calafat AM et al.Opiate and tobacco use and exposure to carcinogens and toxicants in the Golestan cohort study.Cancer Epidemiol Biomarkers Prev. 2020; (published online Jan 8.)DOI:10.1158/1055-9965.EPI-19-1212Crossref PubMed Scopus (13) Google Scholar including among users who ingested opium but did not smoke it. Refined opium residues might be frequently incorporated into ingested opium products, although how widespread this practice is remains unknown. A systematic review5Kamangar F Shakeri R Malekzadeh R Islami F Opium use: an emerging risk factor for cancer?.Lancet Oncol. 2014; 15: e69-e77Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar reported increased risks of bladder cancer and cancers of the upper gastrointestinal and respiratory tracts associated with opium use. The studies in the review largely had case-control or cross-sectional design, with consequent concerns about bias and confounding casting some doubt on the veracity of the associations.5Kamangar F Shakeri R Malekzadeh R Islami F Opium use: an emerging risk factor for cancer?.Lancet Oncol. 2014; 15: e69-e77Summary Full Text Full Text PDF PubMed Scopus (58) Google Scholar In The Lancet Global Health, Mahdi Sheikh and colleagues6Sheikh M Shakeri R Poustchi H et al.Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.Lancet Glob Health. 2020; 8: e649-e660Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar report a new analysis of 10-year follow-up data from a cohort study in Golestan province (northeast Iran), which provides fresh insights into the association between opium use and cancer. The Golestan cohort is perhaps uniquely placed to address this association, given the high prevalence of opium use (approaching 20% in that population) but relatively low levels of alcohol and tobacco exposure by global standards.7Pourshams A Khademi H Malekshah AF et al.Cohort profile: the Golestan cohort study—a prospective study of oesophageal cancer in northern Iran.Int J Epidemiol. 2010; 39: 52-59Crossref PubMed Scopus (193) Google Scholar Although use of opium in the study was measured by self-report, the authors have previously shown very high repeatability of the survey instrument, as well as validation of self-reported use against urinary metabolites.8Abnet CC Saadatian-Elahi M Pourshams A et al.Reliability and validity of opiate use self-report in a population at high risk for esophageal cancer in Golestan, Iran.Cancer Epidemiol Biomarkers Prev. 2004; 13: 1068-1070PubMed Google Scholar Follow-up of the cohort was thorough, and strong efforts were made to establish cancer diagnoses in this dispersed, largely rural population through histology, verbal autopsy, and medical records, as well as through the cancer registry.6Sheikh M Shakeri R Poustchi H et al.Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.Lancet Glob Health. 2020; 8: e649-e660Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar It seems unlikely that many clinical cases of cancer were missed; even so, such misclassification would, on average, tend to bias risk estimates towards the null. The authors observed systematically higher risks of cancers overall among opium users compared with never users, with significantly increased risks of cancers of the lung, larynx, bladder, pancreas, and oesophagus.6Sheikh M Shakeri R Poustchi H et al.Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.Lancet Glob Health. 2020; 8: e649-e660Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar At most of those body sites, there was some evidence (albeit inconsistent across body sites) of a dose-dependent effect of opium use, whereby heavy users tended to have higher risks than light users (heavy users had at least an 8 times greater lifetime consumption of opium than did light users in all analyses). Perhaps unexpectedly, the magnitude of risks of cancer at most body sites did not differ between those who smoked opium compared with those who ingested opium.6Sheikh M Shakeri R Poustchi H et al.Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.Lancet Glob Health. 2020; 8: e649-e660Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar Key exceptions were cancers of the liver and brain, for which elevated risks were observed only among those who ingested opium but did not smoke it. How should these findings be interpreted? These data, although strongly suggestive, do not establish causality. A key concern is possible residual confounding by other causal factors, particularly tobacco smoke. The authors addressed this issue by separately classifying participants into mutually exclusive, cross-classified categories of opium and tobacco use (ie, never used either opium or tobacco, use of opium alone, use of tobacco alone, and use of both opium and tobacco).6Sheikh M Shakeri R Poustchi H et al.Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.Lancet Glob Health. 2020; 8: e649-e660Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar Such analyses run into problems with statistical power because of small numbers of exposed cases in each of the categories but, even so, significantly elevated risks of oesophageal, bladder, and laryngeal cancer were observed among those who used opium but not tobacco, essentially ruling out a confounding effect of tobacco to explain these associations. Those who used both opium and tobacco had greatly elevated risks of laryngeal and lung cancers, much higher than those who used opium alone or tobacco alone, suggesting potential synergy between these two factors. Larger studies with longer follow-up are needed to resolve questions of specificity and synergy; such data are unlikely to be forthcoming in the foreseeable future. Based on the findings from this well-conducted prospective cohort study,6Sheikh M Shakeri R Poustchi H et al.Opium use and subsequent incidence of cancer: results from the Golestan Cohort Study.Lancet Glob Health. 2020; 8: e649-e660Summary Full Text Full Text PDF PubMed Scopus (40) Google Scholar and building on previous observational and biomarker studies, the evidence now favours the conclusion that opium users have an increased risk of cancer at several body sites. Therefore, although causality has not been definitively established, these data provide further grounds for concern that recreational use of opium through smoking or ingestion confers carcinogenic hazards, in addition to many other health effects. I was a member of BEACON, the Barrett's and Esophageal Adenoncarcinoma Consortium, as were several of the authors on Sheikh and colleagues' Article, and as such I have co-published as a consortium member with Behnoush Abedi-Ardekani, Fahrad Islami, Sanford M Dawsey, Christian C Abnet, Paul D Pharoah, Paul Brennan, Reza Malekzadeh, Neal D Freedman, and Farin Kamangar. I am supported by a research fellowship (APP1155413) from the National Health and Medical Research Council of Australia. Opium use and subsequent incidence of cancer: results from the Golestan Cohort StudyOpium users have a significantly higher risk of developing cancers in different organs of the respiratory, digestive, and urinary systems and the CNS. The results of this analysis show that regular use of opiates might increase the risk of a range of cancer types. Full-Text PDF Open Access