Opium, opioids, and an increased risk of death

BMJ 2012; 344 doi: http://dx.doi.org/10.1136/bmj.e2617 (Published 17 April 2012) Cite this as: BMJ 2012;344:e2617
  1. Irfan A Dhalla, assistant professor
  1. 1Department of Medicine, St Michael’s Hospital, Toronto, ON, Canada M5B 1W8
  1. dhallai{at}smh.ca

Beyond overdose the risks are incompletely understood

Opium has been used medicinally and recreationally for millennia. A century ago, it was claimed that 15% of American doctors and a quarter of Chinese men were addicted to opium.1 2 Since then, owing to a combination of criminalisation, stigmatisation, medicalisation, and the availability of other psychoactive drugs, the use of opium has almost completely ceased in many countries and purified semi-synthetic and synthetic opioids are much more widely used. Opium use is largely limited to regions in central Asia where the opium poppy is cultivated.

In the linked cohort study conducted in the Iranian province of Golestan (doi:10.1136/bmj.e2502), Khademi and colleagues find that opium use is associated with almost double the risk of death from any cause.3 The key drivers of this increased risk were cardiovascular disease and cancer rather that respiratory and central nervous system depression, which are the mechanisms of death in opioid overdose. Opium use in this cohort was also associated with an increased risk of death from asthma and chronic obstructive pulmonary disease, cirrhosis, tuberculosis, and other infections.

These findings give rise to two obvious questions. Firstly, does opium use truly increase the risk of death from such a wide variety of diseases? Secondly, what is the relevance of these results to doctors who practise in countries where opium is no longer in use?

Cause of death in the current study was determined by a verbal autopsy questionnaire carried out by the general practitioner. This method is superior to the use of routine death certificate data, although undoubtedly inferior to postmortem examination, and it is entirely appropriate as a research tool. The authors provide evidence of its reliability and validity for distinguishing between broad categories of death. Nevertheless, without postmortem examination it is impossible to know the true cause of death in some instances, especially when death was not witnessed. But although misclassification bias may have occurred, it is unlikely to entirely explain the increased risk of death from cancer, where verbal autopsy has good face validity, and it cannot be invoked to explain the overall increase in mortality.

Several studies with relatively weak epidemiological designs have suggested that opium use may be associated with coronary artery disease. The evidence that opium use causes cancer, especially oesophageal cancer, is more robust. Khademi and colleagues used several techniques to adjust for confounding. In addition to adjusting for potential confounders in their main analysis, they conducted several subgroup and sensitivity analyses, all of which suggest that the association between the use of opium and death cannot be explained by pre-existing poverty, smoking, or other sources of confounding. It is noteworthy that the increased risk of death was seen in people who smoked opium as well as in those who took it orally.

We tend to think of direct effects when we read epidemiological reports, but the increased risk of death in the current study might have been mediated by the myriad consequences of addiction, rather than by opium use itself. Missionary doctors in China were acutely aware that “slaves of the habit . . . become old, infirm and incapacitated before their time,”4 just as doctors today are acutely aware that patients addicted to cocaine or heroin often have health problems that are only indirectly related to the psychoactive substances they consume or the routes by which they are administered.

For all these reasons, Khademi and colleagues’ conclusion that opium use increases the risk of death across a variety of diseases is probably true.

In high income countries doctors rarely, if ever, encounter someone who uses opium. However, millions of patients with chronic non-cancer pain are prescribed opioids, such as morphine, codeine, oxycodone, and hydromorphone. Are these patients, like opium users, also at increased risk of death? And if so, is this solely because of an increased risk of overdose, or are patients who are prescribed opioids also at increased risk of dying from cancer, cardiovascular disease, and infection?

The findings of a propensity score matched cohort study conducted in the United States indicated that, in older adults with osteoarthritis, all cause mortality is almost twice as high in patients prescribed opioids as it is in those prescribed non-steroidal anti-inflammatory drugs.5 There is little doubt that patients prescribed high doses of opioids (in excess of 100 mg of morphine or equivalent a day) are at increased risk of a fatal accidental overdose.6 7 However, as with opium, the use of prescription opioids may also increase the risk of death from other causes. An exploratory study conducted in Ontario found that deaths in young and middle aged adults prescribed opioids were more common than in a reference population, and that deaths from overdose were not the main driver of this difference.8

In an era when doctors are increasingly becoming aware of the harms caused by prescription opioids, the findings of Khademi and colleagues’ study should remind us not only that opium is harmful, but also that opioids have substantial risks that are incompletely understood. For the management of chronic non-cancer pain, a better prescription may be caution.


Cite this as: BMJ 2012;344:e2617


  • Research, doi:10.1136/bmj.e2502
  • Competing interests: The author has completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declares no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years, and no other relationships or activities that could appear to have influenced the submitted work.

  • Provenance and peer review: Commissioned; not externally peer reviewed.