Rates of paracetamol overdose continue to rise in Australia

Paracetamol is one of the most commonly used over-the-counter analgesics in Australia. Although health professionals may assume that patients know how to use paracetamol, overdose rates continue to rise. Public misunderstanding about the safety of paracetamol is contributing to misuse and accidental overdose. Easy access to large quantities of paracetamol may also be contributing to intentional overdose.

Confusion about appropriate indications, formulations and dosing requirements may lead to mistakes when giving medicines to infants and children aged under 12 years. GPs and pharmacists play key roles in educating patients and carers of infants and children about the safe use of paracetamol. However, as paracetamol overdose is also a concern in adults, public health interventions might be needed to reduce the rate of overdose in Australia.

(Image shows crystals of paracetamol, also known as acetaminophen, as seen through a microscope. Photo: hekakoskinen, Getty images) 

• Paracetamol is often recommended as first-line therapy for management of mild acute pain or chronic pain that is not relieved by non-pharmacological approaches.
• Health professionals have a valuable role to play in improving consumer awareness of the potential risks of paracetamol misuse and overdose.
• Because it is such a widely available medicine, it is important that consumers can identify paracetamol as an active ingredient in multiple products.
• Patients and carers need information to help them distinguish between different formulations and the different dosing regimens for adults and children.

Paracetamol is a recommended first-line treatment for mild acute or chronic pain that is not relieved by non-pharmacological approaches, such as reassurance, rest, ice or heat packs.¹

The recommended maximum daily oral dose of paracetamol in adults and children over 12 years is 500–1000 mg every 4–6 hours, with a maximum of 4 g (4000 mg) in a 24-hour period.^1-3

For modified-release (MR) paracetamol, the recommendation is 1330 mg every 6–8 hours, with a maximum of 3990 mg in a 24-hour period.^1,2

In children aged 1 month to 12 years, the recommended daily oral dose of paracetamol is 15 mg/kg (up to a maximum of 1 g) every 4–6 hours as required, with no more than four doses (or 4 g) in a 24-hour period.²

Despite these clear guidelines, a study published in the Medical Journal of Australia (MJA) in 2019 showed that paracetamol-related hospital admissions in Australia increased by 3.8% per year between 2007–08 and 2016–17.⁴

Intentional self-poisoning and accidental paediatric overdoses make up a large proportion of paracetamol-related incidents.⁵

Knowledge gaps among carers of young children may contribute to unintentional paracetamol misuse and overdose.^6-8

In 2012–13, there were 10,620 hospital admissions resulting from poisoning by pharmaceuticals in children and young people, with 37% of these cases due to non-opioid analgesics (including paracetamol, which accounted for 84% of non-opioid analgesic cases).⁹

Of the 10,620 cases of poisoning by pharmaceuticals, 0.6% occurred in infants aged under 12 months, and 9.1% occurred in children aged 1–4 years.⁹

Multiple studies have highlighted deficiencies in patient knowledge about paracetamol use, including:^8,10-12

• lack of recognition that paracetamol is an active ingredient in generic and brand name medicines^8,10,11
• uncertainty surrounding the maximum daily dose^10-12
• lack of knowledge about the risks of taking two over-the-counter medicines both containing paracetamol^8,12
• perceived safety of paracetamol because it is available over the counter
• lack of awareness that misuse of paracetamol can cause liver damage^8,10
• confusion between immediate release and MR paracetamol dosing.¹³

In addition, people may use excessive doses because the desired effect has not been achieved, or substitute adult formulations for paediatric formulations because the paediatric formulation is unavailable or because they think that adult formulations will be more effective.¹⁴

Patients and carers need information on paracetamol’s intended indication of use, preparation strength, dose in milligrams (or millilitres), route of administration, maximum daily dose, and maximum duration of use, as children can be at risk of toxicity with chronic dosing.¹⁴

In a retrospective analysis of data from three major Australian databases (Australian Institute of Health and Welfare National Hospital Morbidity Database [NHMD], the New South Wales Poisons Information Centre [NSWPIC] and the National Coronial Information System [NCIS]) published in the MJA in 2019, the annual number of paracetamol-related hospital admissions and incidence of paracetamol-related liver injury in Australia increased more rapidly than the national population over the 10 years between 2007–08 and 2016–17.⁴

Paracetamol is known to be the medicine most frequently responsible for calls to Poisons Information Centres in Australia.¹⁵

This aligns with data from the Australian Institute of Health and Welfare (AIHW) National Drug Strategy Household Survey 2016, which showed that ‘pain killers/analgesics and opioids’ were the most commonly misused class of pharmaceutical in 2016 (3.6%).¹⁶

Increased rate of paracetamol-related admissions and liver injury

The NHMD included data for 95,668 hospital admissions resulting from paracetamol poisoning between 2007–08 and 2016–17.⁴

The data showed a 44.3% increase in paracetamol poisoning diagnoses over the study period, equivalent to an increase of 3.8% per year.⁴

Over 75% of these cases were associated with self-harm.⁴

These numbers relate to overdoses with single-ingredient preparations, containing either immediate release or MR paracetamol.⁴

The age groups captured by the study ranged from 0–4 years of age, through to 85 years and over. The median age of patients from NSWPIC data was 18 years.⁴

The most marked increases of paracetamol overdose-related admissions from 2007–08 to 2016–17 occurred in children and adolescents, with absolute increases of 133% in children aged 10–14 years and 61% in adolescents aged 15–19 years.⁴

Large relative increases were also seen in older age groups, with a 160% increase in people aged 65–69 and 70–74 years, and a 253% increase in patients aged 85 years and older.⁴

A 108% increase in the rate of paracetamol poisoning with toxic liver disease was observed over the study period, from 116 cases in 2007–08 to 241 cases 2016–17 (a 7.7% increase per year).⁴

Liver injury was likely due to paracetamol poisoning, but other causes could not be excluded.⁴

Increased rates of intentional and MR paracetamol overdose

The number of intentional paracetamol overdoses increased from 1263 in 2004 to 2235 in 2017, which is an overall increase of 77% (3.3% per year).⁴

The annual number of MR paracetamol overdoses increased by 38.3% per year between 2004 (2 cases) and 2017 (259 cases).⁴

Increased size of overdoses

The size of paracetamol overdose also increased over the study period.⁴

The median number of paracetamol tablets (for both immediate and MR formulations) taken in overdose increased from 15 tablets in 2004 to 20 tablets in 2017.⁴

Overdoses were larger with MR paracetamol than immediate release formulations (19 versus 16 tablets).⁴

The total amount of paracetamol consumed was also higher with MR paracetamol (12.6 g versus 8 g).⁴

The clinical significance of increased overdose size may be related to the increased rates of liver injury. There are data to suggest the dose of paracetamol ingested per kilogram of body weight may predict the likelihood of liver damage.¹³

Deaths related to paracetamol have remained constant

Unlike the annual rate of paracetamol-related hospital admissions, the number of deaths related to paracetamol has remained fairly constant.⁴

Changes to treatment guidelines in managing paracetamol overdose (such as when to discontinue acetylcysteine infusion in cases of overdose with MR paracetamol) may account for this.⁵

Paracetamol is the most common reason for acute liver failure in the United States and the UK.¹⁷ Similar findings have been observed in parts of Australia. A retrospective cohort study based on data from patients admitted to the Victorian Liver Transplant Unit between 2001 and 2017 found that paracetamol toxicity was the most common cause of acute liver failure, making up 50% of total cases.¹⁸

While hepatotoxicity may occur with standard doses of paracetamol, it is rare.¹⁹

Toxicity is influenced by age, comorbidities, alcohol use, nutritional status (such as malnourishment), concurrent medicine use (including herbal medicines) and genetics.²⁰

Is MR paracetamol more dangerous?

Toxicity is also influenced by the formulation of paracetamol. MR formulations can produce unpredictable pharmacokinetics, making these types of overdoses difficult to treat.²¹

Overdose with MR paracetamol displays complex pharmacokinetics due to prolonged absorption time and delayed serum peak concentrations. This may be attributed to delayed disintegration of tablets and potential formation of pharmacobezoars (clumps of tablets) in the gastrointestinal tract.²¹

Additionally, confusion between immediate release and MR paracetamol dosing (maximum of 8 versus 6 tablets/day, respectively) can lead to large overdoses with MR paracetamol.¹³

What about children?

In children, similar risk factors for hepatotoxicity with paracetamol apply, including nutrition and dehydration. The risk may also be higher when paracetamol is used at therapeutic doses in children with febrile illness.^1,22

Restricting non-pharmacy retail sales

A study conducted in Sweden in 2017 found an increase in paracetamol poisoning from 2009, which was the same year that paracetamol was made available from non-pharmacy retailers.²³

European countries which do not allow non-pharmacy retailers to sell paracetamol have fewer calls to poisons centres about paracetamol.²⁴

Making packs and doses smaller

Reductions in pack sizes may reduce overdose sizes, as there is evidence to suggest that overdose with paracetamol is often impulsive.²⁵

In response to increasing rates of misuse and overdose (both accidental and intentional) with over-the-counter paracetamol, changes were made in the USA and UK in 2011, to either reduce tablet strength or update paediatric dosing instructions for clarity.^26-28

The US Food and Drug Administration (FDA) considered that reducing the amount of paracetamol to 325 mg per tablet would reduce the risk of overdose and, therefore, reduce the risk of exceeding the threshold for liver injury. Labelling changes were also introduced, including a boxed warning on prescription paracetamol products with information about the risk of liver damage.²⁹

In the UK, pack sizes of paracetamol are smaller than in Australia. Following a reduction in pack sizes in the UK in 1998, there has been a decrease in paracetamol-related hospital admissions, liver injuries and deaths.²⁵

In 2013, the TGA made schedule changes so that unscheduled paracetamol must be in a primary pack containing not more than 20 tablets or capsules.³⁰

The pack size was reduced from 25 to 20 500 mg tablets (that is, a reduction to 10 g of paracetamol in total per pack).³⁰

This number of tablets is still potentially hepatotoxic (10 g of paracetamol is considered toxic),⁵ and larger packs of paracetamol containing 100 tablets are still available for purchase.³¹

The authors of the 2019 MJA study stated that the 2013 changes implemented by the TGA had little impact on overdose size.⁴

They suggested that more restrictive changes, such as further reductions to pack sizes, may reduce paracetamol overdose in Australia.⁴

Talking to a pharmacist about MR paracetamol

In 2019, the TGA announced that MR paracetamol products will be changed from Schedule 2 to Schedule 3 on 1 June 2020. This means that people buying MR paracetamol in Australia will have to speak to a pharmacist before they can purchase the medicine.

This follows the European Medicines Agency (EMA) decision to suspend marketing of all MR paracetamol products in the EU.³² The EMA considered that the advantages did not outweigh the complexity of managing overdose with MR paracetamol.^32,33

People over 12 years of age need to be aware of these points.

• Paracetamol is the active ingredient in several pain and fever relief medicines and combination medicines (eg, for cold and flu).
• Overdose can occur when taking more than one paracetamol-containing medicine.
• The maximum daily dose of 4 g in any 24-hour period should not be exceeded for adults and children aged > 12 years.

Carers giving paracetamol for pain relief to babies and children less than 12 years of age should follow this advice.

• Always choose the correct paracetamol formulations and strength for the child's age.
• Always read the medicine label and packaging before use.
• Know the child's weight – the recommended dose of paracetamol for children (15 mg/kg) is based on ideal body weight for the child’s height.
• Never exceed the maximum recommended dose for children, of 15 mg/kg every 4–6 hours (to a maximum of 1 g), and no more than 4 doses in a 24-hour period.
• Measure liquid medicines accurately, using the syringe or device provided.
• Record all medicines given to the child, and when they were given.
• Store medicines out of reach of children.