Paracetamol (Acetaminophen): Uses, Mechanisms, Safety, and Risks

Paracetamol is one of the most widely used over-the-counter medications for pain and fever worldwide. While it is generally considered safe at recommended doses, its mechanism of action remains incompletely understood, and concerns about toxicity, especially with overdose or long-term use, have grown in recent years.

Mechanisms of Action

Paracetamol’s analgesic and antipyretic effects are thought to involve inhibition of central cyclooxygenase (COX) enzymes, particularly COX-2, but evidence is conflicting regarding which isoenzymes are targeted and how (Ayoub, 2021; Przybyła et al., 2020; Bührer et al., 2021). Other proposed mechanisms include modulation of serotonergic pathways, activation of endocannabinoid and TRPV1 systems, and effects on ion channels, though not all are fully confirmed (Ayoub, 2021; Przybyła et al., 2020; Bührer et al., 2021).

Effectiveness and Clinical Applications

Paracetamol is recommended as a first-line or adjunct treatment for acute and chronic pain, especially in populations where NSAIDs or opioids are contraindicated, such as the elderly or those with comorbidities (Freo et al., 2021; Conaghan et al., 2019). However, its efficacy for chronic pain conditions like osteoarthritis is modest, with only minimal improvements over placebo (Freo et al., 2021; Conaghan et al., 2019; Leopoldino et al., 2019). In neonatology, paracetamol is as effective as ibuprofen or indomethacin for closing patent ductus arteriosus in preterm infants, with a potentially better safety profile for gastrointestinal and renal side effects (Ohlsson & Shah, 2022; Härkin et al., 2016).

Safety, Toxicity, and Long-Term Risks

At therapeutic doses, paracetamol is well-tolerated, but overdose can cause severe, sometimes fatal, liver injury due to the formation of a toxic metabolite (NAPQI) and glutathione depletion (Chidiac et al., 2023; Prescott, 2023; Wang et al., 2017; Prescott, 1983; Forrest et al., 1982; Brune et al., 2015). Chronic use is associated with increased risks of gastrointestinal bleeding, hypertension, cardiovascular, renal, and hepatic adverse events, especially at higher doses (McCrae et al., 2018; Roberts et al., 2015; Conaghan et al., 2019). Safety in pregnancy is under scrutiny, with some evidence suggesting possible neurodevelopmental and reproductive risks to the fetus, though findings are not definitive (McCrae et al., 2018; Bauer et al., 2021; Bührer et al., 2021).

Key Papers for Subtopics

• Mechanisms of action: (Ayoub, 2021; Przybyła et al., 2020; Bührer et al., 2021)- Overdose and hepatotoxicity: (Chidiac et al., 2023; Prescott, 2023; Wang et al., 2017; Prescott, 1983; Forrest et al., 1982; Brune et al., 2015)- Guideline recommendations and efficacy: (Freo et al., 2021; Conaghan et al., 2019; Leopoldino et al., 2019)- Pregnancy and developmental risks: (McCrae et al., 2018; Bauer et al., 2021; Bührer et al., 2021)- Pediatric/neonatal use (PDA): (Ohlsson & Shah, 2022; Härkin et al., 2016)Figure 1: Consensus on paracetamol's safety and effectiveness.

Conclusion

Paracetamol remains a mainstay for pain and fever relief due to its accessibility and general safety at recommended doses. However, its modest efficacy for chronic pain, potential for severe toxicity in overdose, and emerging concerns about long-term and prenatal use highlight the need for careful, individualized use and ongoing research.

These papers were sourced and synthesized using Consensus, an AI-powered search engine for research. Try it at https://consensus.app

References

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