Do opiates increase the risk of cancer?

There is no escaping an uncomfortable truth: severe, debilitating pain is often only alleviated by opioids. This analgesic potency, however, comes at a price that includes addiction, dependence, respiratory depression, constipation and nausea. 

New analgesics could help reduce the NHS’s opioid dependence. According to Practical Pain Management, pharmaceutical companies had 16 new analgesics and eight products containing tetrahydrocannabinol or cannabinoid in phase III studies for pain during 2022.²

Patients need analgesic innovations. Pain is, for instance, almost always inevitable with cancer. A meta-analysis of 10 studies of breast cancer and two of lung malignancies found that, on average, 40 per cent of patients experienced pain during and up to three months after treatment. The prevalence varied from 4 to 77 per cent across the 12 studies.³ About half of cancer survivors live with long-term pain, which can arise from the cancer or when chemotherapy or radiation damage nerve fibres.⁴

Recently, researchers writing in the Royal Society’s journal Open Biology warned that using opiates (natural opioids) long-term may increase cancer risk.⁵ In addition to binding to mu receptors in the CNS to alleviate pain, morphine affects peripheral tissues. The paper summarises case control, cohort, epidemiological and experimental evidence suggesting that opioid consumption or addiction influence the risk of developing, among other malignancies, lung, oesophageal, pancreatic, gastric, laryngeal and bladder cancer.⁵ 

The evidence is currently inconclusive and contradictory so Pharmacy Magazine spoke to the corresponding author of the Open Biology paper, Dr Tabarak Malik, associate professor of biochemistry, Jimma University, Ethiopia, to better understand the controversy. 

Opioids and cancer

“Morphine can affect tumour cell proliferation, migration and angiogenesis [new blood vessel formation], all of which are critical in cancer progression,” Professor Malik says. 

“The mechanisms behind these extra-analgesic effects are not fully understood, but various signalling pathways may be involved. Morphine can also suppress T-lymphocytes, which can further complicate cancer treatment.” (T-lymphocytes, a subtype of white blood cell, attack many cancers.)

Opium poppies synthesise more than 100 alkaloids.⁵ “Raw opium contains five main alkaloids: morphine, noscapine, codeine, thebaine and papaverine. Some of these alkaloids bind to classical opioid receptors; the others mediate non-opioid effects,” Professor Malik says. 

“Opium’s effect on cancer could be more or less than the sum of its parts. Some combinations of alkaloids may be synergistic; some may have a weaker effect on cancer risk than the individual alkaloids alone. The specific mechanisms through which different opium alkaloids may interact to influence cancer risk are not well understood.”

Opiates’ place as drugs of abuse adds further layers of complexity to studies assessing their link with cancer. “Opiate users may have other risk factors, such as poor diet, exposure to environmental toxins and other health issues, that contribute to cancer risk, making it difficult to isolate the effect of opiate use,” Professor Malik says. “Even if researchers try to control for confounders using statistical methods, there may still be unmeasured or unknown factors.” 

The way an addict uses the drug also makes a difference. “Smoking opium can produce various compounds, such as polycyclic aromatic hydrocarbons, that are known carcinogens,” Professor Malik says. “Opiates consumed orally are metabolised by the liver and excreted through the kidneys, so smoking opium or inhaling opium vapours is likely to pose a higher cancer risk than oral administration. However, even oral use may still increase the risk of certain cancers.” 

In theory at least, using opioids to relieve cancer pain could hasten progression or facilitate metastatic spread, particularly in the early non-palliative setting. “Opioids can suppress the immune system, which may reduce the body's ability to detect and fight cancer cells,” says
Professor Malik. 

“Opioids also stimulate the release of certain growth factors, such as vascular endothelial growth factor, that can promote the growth and spread of cancer cells. However, while some studies suggest that opioid use may be associated with a higher risk of cancer recurrence or worse outcomes, others have not found any significant association.” 

Much of the research considered in the paper evaluates natural alkaloids, so what about synthetic opioids? “There are some differences between natural and synthetic opioids that may impact their carcinogenic potential. Natural opioids, such as morphine and codeine, contain various alkaloids that can contribute to their carcinogenic effects,” Professor Malik comments. 

“In contrast, synthetic opioids, such as fentanyl and methadone, are chemically synthesised and may be less likely to be associated with cancer risk than natural opiates, but further studies are needed.” 

For example, tramadol, a partial opioid agonist, has a different chemical structure and mechanism of action to natural opioids. “While tramadol is considered to have a lower potential for abuse and dependence compared to full agonists, such as morphine, there is limited evidence of its carcinogenic potential,” Professor Malik says. 

“Some research suggests that tramadol induces apoptosis [‘cell suicide’] of colorectal cancer stem cells and so reduces the risk [of this malignancy]. More research is needed to fully understand the implications of opioid use, including partial agonists and synthetic opioids, on cancer risk.”