Long‐term adverse effects of paracetamol – a review

Paracetamol is currently marketed as an analgesic and antipyretic, to be used for no more than 3 days without consulting a doctor 8. However, due in part to its inclusion in the WHO analgesic ladder, as well as decades of clinical experience, it is also prescribed in chronic conditions such as osteoarthritis and lower back pain. Recently, meta‐analyses of the randomized controlled trials (RCTs) covering these conditions have shown the effect sizes to be modest, although still statistically significant, compared with placebo (averaging a 4–5% reduction in pain) 9, 10, 11, 12. Despite this, paracetamol continues to be recommended as first‐line treatment in UK guidelines 13, and attempts to remove it as a recommendation from the UK’s National Institute for Health and Care Excellence (NICE) guidance on osteoarthritis raised considerable concerns among medicines regulators and various specialist societies 14, particularly as this would leave opioids as the major alternative. Given the current opioid addiction epidemic ongoing in several US states 15, and a desire not to repeat this in the UK 16, 17, the introduction of opioids earlier in the pain management pathway is unlikely to be viewed favourably.

Paracetamol has less of an analgesic effect in chronic use than previously thought; there needs to be greater emphasis on accurately determining the harms of long‐term use at therapeutic doses. This helps clinicians to balance harms against likely benefits for individual patients and allows regulators to make recommendations on its availability in OTC preparations. The acute effects of paracetamol ingestion in overdose are well known 18. Harms with long‐term therapeutic use are less clear. Concerns have been raised over the effects on the cardiovascular, respiratory, renal, gastrointestinal and central nervous systems, as well as potential effects in the offspring of pregnant women ingesting Paracetamol.

The present review summarizes our understanding of the evidence on the adverse effects of paracetamol in long‐term therapeutic use, informs clinicians of the risks and provides a clearer picture of the underpinning evidence base. This will, in turn, allow clinicians to discuss with their patients the relative benefits and harms of long‐term paracetamol use.

The mechanism of action of paracetamol is not completely understood but is likely to involve (COX‐2) inhibition. Traditional nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit cyclooxygenase (COX) enzymes, preventing the metabolism of to COX enzymes also have a separate peroxidase function, and metabolize PGG2 to, which, in turn, is converted to several different PGs by local tissues according to their individual needs 2, 19, 20. Unlike the closely related NSAIDs, paracetamol interferes with the peroxidase activity of COX isoenzymes, predominantly COX‐2, particularly when the cellular environment is low in arachidonic acid and peroxides 2, 19, 20. This explains paracetamol’s apparent ‘central’ effect in earlier studies (as COX‐2 is constitutively expressed in neural tissue) 19, 21, and why it appears to be ineffective in inflamed tissues (where peroxide and arachidonic acid are abundant), seen in conditions such as rheumatoid arthritis. A proposed COX‐3 isoenzyme (an exon splice variant of COX‐1 seen in insects and rodents) has not been found in humans, and further studies suggest that paracetamol has no clinically significant effects on the COX‐1 exon splice variants found so far in humans

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