OPIOID analgesics (eg, morphine, oxycodone and fentanyl), and antipyretic analgesics such as paracetamol and ibuprofen are among the most commonly used medicines for pain or fever globally. We don’t often consider the effects of these medicines on the immune system, although they have been reported since the mid-1970s (here, here, and here).

However, the impact of these medicines on the immune system may have implications for the management of infectious diseases, vaccinations, surgical and critical care, and in people who are immunocompromised. We recently reviewed the literature and published our findings in the British Journal of Clinical Pharmacology.

We identified three key areas of interest:

  • Certain pharmaceutical opioids, namely morphine, may increase risk of infection.
  • Antipyretic analgesics may affect antibody response to vaccines when administered prophylactically rather than therapeutically.
  • There may be potential to repurpose antipyretic analgesics for the treatment of some infectious diseases.

Opioids and the immunity

We identified evidence from laboratory and animal studies that morphine suppresses key cells of innate immunity (eg, natural killer cells, macrophages, neutrophils, mast cells and dendritic cells). There is some preliminary support from human studies which have demonstrated greater risk of infection (such as invasive pneumococcal disease) in people receiving certain opioids, including morphine, oxycodone and fentanyl.

For example, in the critical care setting, a retrospective cohort study from South Korea found that people administered opioid analgesics for more than one month may have approximately double the risk of dying compared with matched patients in critical care who are opioid-naïve, although it did not look at immune status. A US retrospective cohort study in 5994 individuals with sepsis found those treated with opioids had higher mortality at 28 days. Again, it did not look at immune status. In a case-control study, also from the US, a long-acting opioid formulation and higher opioid dose were associated with greater risk of pneumococcal infection. Furthermore, the findings from retrospective cohort studies and randomised observational trials showed morphine was associated with greater suppression of innate immune cells, and in some cases with increased risk of infection, in the context of cancer surgery compared with other opioid analgesics (here, here, and here).

Antipyretic analgesics and vaccinations  

We also found evidence from laboratory and animal studies that non-steroidal anti-inflammatory drugs (NSAIDs) inhibit humoral (antibody-mediated) immunity, but enhance cell-mediated immunity. This has potentially important implications for vaccinations.

Human studies have shown that antipyretic analgesics may suppress the body’s desirable immune response to vaccines when administered prophylactically, as shown by a reduction in attained antibody levels (here, here, here, and here). Although the clinical implications of this remains unclear, the theoretical risks include reduced vaccine efficacy.

Importantly, we did not identify specific studies looking at the effects of antipyretic analgesics for COVID-19 vaccinations (primary or booster). Much of the experience comes from other clinical settings; for example, childhood or adult vaccinations for diphtheria, tetanus, pertussis, or pneumococcal vaccines.

Can NSAIDs be repurposed for COVID-19?

Despite initial debate around the use of NSAIDs in COVID-19, clinical trials and large cohort studies have shown that these medicines are not associated with greater risk of mortality or increased severity of COVID-19 infection (here, and here).

Our review has identified that indomethacin has an antiviral effect on COVID-19 in vitro and is currently being piloted in combination with ketotifen (an antihistamine that is also a mast cell stabiliser) in humans with COVID-19. The combination is thought to enhance the antiviral effects against COVID-19, although the specific antiviral and immunomodulatory effects of indomethacin (alone or combined with other agents such as ketotifen) have not yet been explored in humans.

Definitive trials evaluating the benefits and harms of this drug in COVID-19 infection are needed, particularly in the critically ill and those who may not be responding to current best treatments. It is essential to determine the stage of COVID-19 infection that may benefit from NSAID treatment and the ideal dose and duration of treatment using sound clinical pharmacology principles.

Our review highlights that much research is needed to understand the roles of some commonly used medications on the immune system, particularly as the implications of this emerging field are relevant across most, if not all, medical disciplines. Given the potential widespread impacts on health and health practice, it is important for governments, funders, policymakers and researchers to prioritise research in this area in order to optimise possible outcomes for our patients with infectious diseases.

Dr Christina Abdel Shaheed is an Early Career Development Fellow in the School of Public Health at the University of Sydney. She is also affiliated with the Institute for Musculoskeletal Health, and Sydney Local Health District.

Dr Justin Beardsley is Senior Lecturer at the Sydney Institute for Infectious Diseases and Westmead Clinical School.

Professor Richard Day is Professor of Clinical Pharmacology and Toxicology at UNSW Sydney, St Vincent’s Hospital, and St Vincent’s Clinical School.

Professor Andrew McLachlan is Head of School and Dean of Pharmacy in the Sydney Pharmacy School at the University of Sydney.




The statements or opinions expressed in this article reflect the views of the authors and do not represent the official policy of the AMA, the MJA or InSight+ unless so stated.

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