Paracetamol (acetaminophen) overdose and hepatotoxicity: mechanism, treatment, prevention measures, and estimates of burden of disease

ABSTRACT

Introduction

Paracetamol is one of the most used medicines worldwide and is the most common important poisoning in high-income countries. In overdose, paracetamol causes dose-dependent hepatotoxicity. Acetylcysteine is an effective antidote, however despite its use hepatotoxicity and many deaths still occur.

Areas covered

This review summarizes paracetamol overdose and toxicity (including mechanisms, risk factors, risk assessment, and treatment). In addition, we summarize the epidemiology of paracetamol overdose worldwide. A literature search on PubMed for poisoning epidemiology and mortality from 1 January 2017 to 26 October 2022 was performed to estimate rates of paracetamol overdose, liver injury, and deaths worldwide.

Expert opinion

Paracetamol is widely available and yet is substantially more toxic than other analgesics available without prescription. Where data were available, we estimate that paracetamol is involved in 6% of poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. These estimates are limited by lack of available data from many countries, particularly in Asia, South America, and Africa. Harm reduction from paracetamol is possible through better identification of high-risk overdoses, and better treatment regimens. Large overdoses and those involving modified-release paracetamol are high-risk and can be targeted through legislative change.

KEYWORDS:

• Acetaminophen
• acetylcysteine
• hepatotoxicity
• overdose
• poisoning
• poisons information center
• paracetamol

Article highlights

• Paracetamol (acetaminophen) is one of the most used medicines worldwide. It is safe if taken at therapeutic doses, however is commonly taken in overdose, where it can cause hepatotoxicity.

• Risk factors for toxicity include: very large overdoses, overdose with modified release paracetamol, delays to treatment, treatment with enzyme inducers, malnutrition, and chronic alcohol use.

• Acetylcysteine is an effective antidote. It replenishes glutathione stores, allowing detoxification of paracetamol’s toxic reactive metabolite. Recently, many changes to acetylcysteine treatment regimens have emerged to better treat high-risk overdoses and minimize adverse reactions. Other emerging potential treatments include fomepizole and calmangafodipir.

• Epidemiological data on paracetamol poisoning are limited or non-existent in many parts of the world. Based on available data, we estimate that paracetamol is involved in 6% of global poisonings, 56% of severe acute liver injury and acute liver failure, and 7% of drug-induced liver injury. We estimate that 0.4% of paracetamol poisoning cases are fatal.

• Access to paracetamol differs widely internationally, some countries allow unlimited non-pharmacy sales while some only allow sales in pharmacies. Available pack sizes also vary substantially.

• Some countries have introduced effective interventions aimed at reducing self-harm poisonings with paracetamol. This includes pack size restrictions in the UK and Denmark, and Denmark placing an age limit on sales.

Declaration of interest

A Chidiac is the recipient of a PhD stipend from Reckitt Benckiser as part of an untied educational grant awarded to R. Cairns. R. Cairns has also recieved conference speaker fees/honoraria from Reckitt Benckiser and The Pharmacy Guild of Australia. These funders had no role in the preparation of this review. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

One reviewer receives research funding on the safety of acetaminophen from the US sponsor (J&J), there are no personal financial relationships. The remaining reviewers have no other relevant financial relationships or otherwise to disclose.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/17425255.2023.2223959

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This paper was not funded.