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Do opiates increase the risk of cancer?

Opioid prescribing is declining– yet 5.4 million people in England received these drugs during 2020/21.1 There’s clearly still a long way to go as concerns grow about possible cancer risk associated with long-term use.

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.

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.”

“The reduction in opioid prescriptions saved almost 350 lives and prevented about 2,100 incidents of patient harm”

Influence of pharmacogenetics on pain relief

During the 1960s, researchers recognised that differences in metabolic rate meant that plasma concentrations of nortriptyline could vary 30- to 40-fold in people treated with the same dose.6 We now know why: some people metabolise medicines broken down by CYP2D6 more rapidly than others. 

Give an ultrafast metaboliser a drug broken down by CYP2D6 and they may not reach therapeutic blood levels. Give a slow metaboliser the same drug at the same dose, and high blood levels may cause adverse events. 

When CYP2D6 yields an active metabolite, ultrafast metabolisers may develop side-effects and slow metabolisers may not benefit. 

“Pharmacogenetic prescribing guidelines exist for several drugs, but there are more genetic variants to discover,” says Neil Ward, vice president and general manager of PacBio EMEA, which develops and manufactures “highly accurate sequencing solutions”.

PacBio performed an “initial calculation” suggesting that the cost of ineffective SSRI and opioid prescriptions because of pharmacogenetic differences could reach £41m. “This estimate includes only ineffective prescriptions because people either lack CYP2D6 or are ultrafast metabolisers, which is 8 and 2 per cent of the UK population respectively,” Ward says. The estimate did not include the costs of pharmacogenetic testing, alternative medicine and treating adverse events.

“Our estimate includes one gene and two families of medicines,” Ward concludes. “It is a drop in the ocean for the wider economic benefits offered by pharmacogenetics, not to mention improved patient care. It is exciting that we are starting to see this reflected in the NHS’s Genomic Medicine Strategy but the UK needs to consolidate its place as a leader in pharmacogenetics.”

Reducing harm

The opiate-cancer controversy shows just how much we still need to learn about opioids despite them being used for millennia. It is clear that reducing potential harm is important – which is why pharmacists need to remain vigilant for interactions. 

Activating opioid receptors stimulates dopamine release, which gives the feeling of pleasure, and suppresses noradrenaline release. As tolerance develops, people take higher doses. To maintain homeostasis, the number of noradrenaline receptors rises. This makes interactions between opioids and other drugs that affect noradrenergic function, such as selective serotonin reuptake inhibitors (SSRIs) and norepinephrine reuptake inhibitors (SNRIs), more likely.

“Opioids can activate the sympathetic nervous system and potentially cause side-effects such as constipation, sleep disturbances, and increased heart rate and blood pressure,” Professor Malik warns. “SNRIs also affect the noradrenergic system and can potentially increase these side-effects or interact with opioids to increase the
risk of adverse events. 

“Taking opioids and serotonergic medications can increase the risk of developing serotonin syndrome. This risk depends on the specific combination of medications. Some opioids, such as pethidine, dextromethorphan and tramadol, are particularly high-risk when used with serotonergic antidepressants.”

From a population level, reducing prescribing also cuts the risk of harm from opioids. According to NHS England, in less than three years, the reduction in opioid prescriptions saved almost 350 lives and prevented about 2,100 incidents of patient harm – but the NHS can’t rest on its laurels.  

NHS England has therefore released a ‘framework for action’ to optimise care for adults who are prescribed medicines associated with dependence or withdrawal symptoms, such as benzodiazepines, z-drugs, gabapentinoids, antidepressants and opioids for chronic non-cancer pain. It calls for action on five fronts:1

  • Personalised care and shared decision-making, including the intended outcome, potential benefits, risks and harm, and whether to continue, stop or taper treatment
  • Offer interventions and services that are alternatives to medicines
  • Helping people who want to reduce or stop treatment
  • Whole systems approaches
  • Population health management, such as monitoring access to services, reviewing medicines if evidence suggests they may no longer be effective and supporting patients at risk of dependence and withdrawal.

Positive step

“Pharmacists are well-placed to help reduce inappropriate prescribing of high-strength painkillers such as opioids and other addictive medicines,” says James Davies, director for England at the RPS. “Pharmacy teams can often also spot repeat purchases of OTC medicines by patients so can intervene and give advice on the management of chronic pain.

“This new framework is a positive step towards improving patient care by supporting medicine reviews and shared decision-making to help people reduce their use of medicines that are no longer providing much clinical benefit.”

Few widely used medicines face the same scrutiny as opioids. While the evidence about long-term opioid use and cancer risk is limited and contradictory, there is enough to give pause for thought. Healthcare professionals need to explain the balance of risks and benefits to each patient, says Professor Malik. 

“Opiates remain an important class of medications for managing pain in conditions including myocardial infarction, acute crush injuries and cancer,” he says, “but their use requires careful consideration of their benefits and potential risks.”

Key facts

  • Opiates remain an important class of medications for managing pain but their use requires careful consideration
  • Researchers are warning that using opiates long-term may increase cancer risk
  • NHS England has released a ‘framework for action’ to help ICBs and primary care optimise care for adults prescribed medicines associated with dependence or withdrawal symptoms.


  1. Optimising personalised care for adults prescribed medicines associated with dependence or withdrawal symptoms: Framework for action for integrated care boards (ICBs) and primary care
  2. Practical Pain Management
  3. Journal of Pain and Symptom Management 2022;63:e317-e335
  4. Biomedicine & Pharmacotherapy 2022; 156:113871
  5. Open Biology 2023; 13:220355
  6. British Journal of Clinical Pharmacology 2002; 53:111-22
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