• DRUG-RELATED SIDE EFFECTS AND ADVERSE REACTIONS
• Metabolic Side Effects of Drugs and Substances
• GASTROENTEROLOGY
• Safety
• TRANSPLANTATION

In many countries around the world, paracetamol toxicity is the number one cause of acute liver failure in instances of intentional and unintentional overdose. Furthermore, many of these cases result in liver transplantation, which prompts questions about why paracetamol is still available as an over-the-counter (OTC) product. The last study that was conducted to measure liver transplant associated with paracetamol toxicity concluded in 2015 and is referred to as the SALT study (Study of Acute Liver Transplantation).1 This editorial aims to discuss why further research has not been conducted on this topic and reflects on why paracetamol is still available as an OTC product.

The SALT study was a multinational, multicentre, case population study conducted in seven countries to describe cases of acute liver failure related to paracetamol overdose and liver transplantation. Before this study, acute liver failure transplants were poorly described in the literature. The study included 52 transplant centres in European countries who contributed 9479 cases registered for liver transplantation, of which 600 were for acute liver failure transplantation (ALFT) and 114 were for overdose. In 97% of these overdose cases, the toxic drug was paracetamol. Furthermore, in the 301 ALFT cases without clinical aetiology, 81 had been found to be exposed to paracetamol but without overdose within 30 days.1 The study also found that most overdoses (63.0%) were intentional suicide attempts. At the same time, 18 530 tons of paracetamol were sold in the seven countries included in the SALT study so that, on average, one case of paracetamol overdose resulting in ALFT occurred for each 167 tons of paracetamol sold.1

Although other multicentre studies and case reports have been conducted since the SALT study in 2015, these studies reviewed liver transplantation due to acute liver toxicity of any nature, not necessarily paracetamol overdose. These outcomes cannot provide direct evidence for the argument that changes need to be made in paracetamol’s availability as an OTC product. Paracetamol is still the almost exclusive cause of liver transplantation related to acute drug overdose, with an average of one case per six million inhabitants per year in over seven countries.1

A study in European countries revealed notable differences in OTC paracetamol pack size restrictions: Austria (30 g), UK (16 g), Ireland (12 g), Italy (15 g), Germany (10 g) and France (8 g). In contrast, many Eastern European countries do not enforce such limits, resulting in a higher incidence of poisonings. Despite this, the proportion of paracetamol related enquiries to poisons information centres remained consistent across countries, regardless of pack size restrictions. However, enquiry rates were lower in countries where paracetamol was available only in pharmacies.2

The SALT study underscores the importance of restricting access to paracetamol, particularly in non-pharmacy outlets.1 For example, after Sweden liberalised sales, a significant rise in poisonings prompted the government to reinstate pharmacy only sales.2 In 1998, the UK introduced legislation limiting the pack size of paracetamol and aspirin sold outside pharmacies, reducing it from 25 to 16 tablets or capsules. A review of 17 studies confirmed that this measure significantly reduced poisoning cases, particularly those related to self-harm. Further strategies, such as better labelling, patient education, and early interventions, were suggested to enhance the impact.3 Subsequent research reinforced these findings. A comparative study between the UK and Ireland demonstrated that reducing pack sizes in the UK led to fewer hospital admissions and deaths from overdoses, recommending similar policies in other countries with high poisoning rates.4

Also, a 2005 systematic review highlighted the importance of combining pack size restrictions with mental health support and improved access to poison control services for sustained success. Reducing paracetamol pack sizes could be an effective method for preventing poisoning and self-harm. Integrating public education and psychological support could further improve outcomes.5

Nevertheless, despite dosage limits, abusing paracetamol remains relatively easy. Reducing the strength or the number of tablets available OTC is unlikely to deter misuse effectively. For those determined to overdose, limiting pack sizes offers little deterrence. In our view, restricting sales to pharmacies and requiring a prescription is the only approach that can significantly mitigate the risk of abuse.

So why has there not been a study conducted to determine liver transplant associated with paracetamol overdose in the US when the medication is so readily available? Furthermore, why do we market this product as ‘safe’ when there is a clear risk for damage to a vital organ? It is no surprise that the cost of liver transplantation continues to rise with advancements in technology and immunotherapies. This section aims to breakdown the cost of a liver transplant in the US to analyse the risk and benefit of continuing to supply paracetamol OTC.

A recent review analysed the annual data on the cost of a liver transplantation from 2016 to 2019.6 The study broke down the costs according to age, sex, race, comorbidities, liver aetiologies, liver complications, socioeconomic status, insurance type and hospital region of the patient. They also organised the data based on the year the liver transplant was received. According to the SALT study,1 the most common factors associated with liver transplant due to paracetamol toxicity were women and a mean age of 33.6 years. Looking at the economic analysis, the average cost of a liver transplant for women in the US in 2016 was US$149 628.86, and for patients aged 18–24 years the average cost was $165 224.07. In 2019, the cost for women increased to $159,970.79, but the cost for patients aged 18–24 years decreased to $149 789.97. Overall, we continue to see a rise in costs associated with liver transplant that can be detrimental to the economic status of a household in the US.6 On the other hand, the affordability and accessibility of paracetamol OTC remains the same, and the average cost of a bottle of 100 tablets of 325 mg paracetamol is $4.50 or about $0.05 per tablet.

After discussing what we already know about previous studies on liver toxicity due to paracetamol overdose and the associated costs of a liver transplant due to this toxicity, the question still remains, why is paracetamol available as an OTC product? Paracetamol is an antipyretic analgesic that works to inhibit cyclooxygenase in the central nervous system, selectively. It is also known that >60 million Americans consume paracetamol on a weekly basis, making it one of the most accessible products on the market.7

In high concentrations, paracetamol is metabolised by hepatocytes in the liver by components of the cytochrome P450 system to a reactive intermediate, N-acetyl-p-benzoquinone imine. High concentrations of N-acetyl-p-benzoquinone imine deplete cellular glutathione stores and form paracetamol protein adducts, which causes oxidative stress to the mitochondrial cells and eventually programmed necrosis of liver cells.8

In 2011, the US Food and Drug Administration released a safety announcement which asked drug manufacturers to limit the strength of paracetamol in prescription drug products to 325 mg, which would most commonly be combination products of opioids and paracetamol.9 Furthermore, they added a boxed warning to packages containing paracetamol products, highlighting the potential for severe liver injury with consumption. Although this warning and dose limitation is a step in the right direction to protect and educate consumers on the effects of exceeding the recommended daily limit of paracetamol, further research is needed to determine impact.

On the other hand, other OTC products, such as proton pump inhibitors, do not pose nearly as high of a risk for vital organ damage, but there are regulations in place to limit the amount consumed. For example, omeprazole (Prilosec) is available in the US in low doses for short term use to lower acid production in the gastrointestinal tract. The regulations in place for this product help to protect patients from the side effects of using higher doses for extended periods of time without the clinical guidance of a healthcare provider. For more serious conditions that require bile acid suppression, such as gastro-oesophageal reflux disease, healthcare providers can provide higher doses of proton pump inhibitors for longer durations to treat this condition in a regulated setting.10 This knowledge leads back to the main discussion of this editorial: why is paracetamol readily available as an OTC product without regulation for dose and duration?

Current clinical trials of paracetamol toxicity show a clear need for further research in the US to quantify how many patients are being treated with liver transplantation for either intentional or unintentional paracetamol overdose. Since the SALT study done in 2015, there has been minimal research into this correlation and the impact on the large population of paracetamol users in the US.

After reviewing the current research available, an updated clinical trial looking at liver transplantation associated with paracetamol toxicity is needed in the US to access any potential changes that need to be made to the accessibility of this OTC product, as well as evaluate the effects of the 2011 implementation of Food and Drug Administration regulations to limit prescription dosages of paracetamol.

Although paracetamol is a product that has been used for many years to help reduce pain and fever, research clearly outlines its potential harm to the liver. Patient education is one of the first steps to minimise adverse events. As healthcare providers, it is crucial for us to provide guidance on how to safely utilise this medication in the prescription setting and OTC.

In conclusion, further research is needed to modernise the data available for the association between liver toxicity and transplantation due to paracetamol toxicity. With more research, clarity will arise to determine if more changes need to be made to limit OTC product dosages for the safety of the patient population that uses paracetamol regularly.