Paracetamol

Paracetamol is a para-aminophenol analgesic and antipyretic with negligible anti-inflammatory and antiplatelet activity. It is the usual first-line oral analgesic for mild to moderate pain, the baseline agent in multimodal perioperative analgesia, and a leading cause of drug-induced acute liver failure when taken in excess.

Class. Non-opioid analgesic and antipyretic. It is not an NSAID.

Mechanism. Incompletely defined. Proposed actions are central inhibition of prostaglandin synthesis, enhancement of descending serotonergic inhibition, and a brain metabolite (AM404) acting on cannabinoid and vanilloid receptors.

Pharmacokinetics. Oral bioavailability is 63 to 89%, with peak concentrations at 30 to 60 minutes (delayed by food, opioids and anticholinergics, hastened by metoclopramide). Intravenous onset is 5 to 10 minutes, with peak analgesia at about 1 hour and duration of 4 to 6 hours. Half-life is 1.5 to 3 hours, longer in neonates and liver disease.

Metabolism. Hepatic glucuronidation (about 50 to 60%) and sulphation (about 30%, more important in children). Some 5 to 10% is oxidised by CYP2E1 to N-acetyl-p-benzoquinone imine, which is detoxified by glutathione. Depleted glutathione allows hepatocyte injury.

Indications are mild to moderate pain, fever, and opioid-sparing analgesia after surgery or trauma. It has first-line use in osteoarthritis pain, headache, dysmenorrhoea and musculoskeletal pain, and is the preferred antipyretic and analgesic in pregnancy.

Adults and adolescents over 50 kg

• Oral: 500 mg to 1 g every 4 to 6 hours. Minimum interval 4 hours. Maximum 4 g in 24 hours.
• Intravenous: 1 g every 6 hours, infused over 15 minutes. Minimum interval 4 hours. Maximum 4 g in 24 hours.
• Rectal: 1 g every 4 to 6 hours. Maximum 4 g in 24 hours. Absorption is slower and less predictable than oral.

Weight under 50 kg (any age)

• Oral: 15 mg/kg every 4 to 6 hours. Intravenous: 15 mg/kg every 6 hours over 15 minutes.
• Maximum 60 mg/kg in 24 hours, not above 4 g in 24 hours. Some paediatric labels allow up to 75 mg/kg daily for short courses.

Children from 3 months. 15 mg/kg orally every 4 to 6 hours, maximum 4 doses and 60 mg/kg in 24 hours, single dose not above 1 g.

Neonates and infants under 3 months. Dosing is weight and gestation dependent. Term neonates usually receive 10 mg/kg intravenously every 6 to 8 hours, maximum 30 mg/kg in 24 hours. Preterm infants need specialist neonatal dosing by postmenstrual age.

Loading, titration and duration. No loading dose or titration is used routinely. Use the lowest effective dose for the shortest time. Review the need after 3 days for fever and after 10 days for pain in self-medicated use.

Reduced ceiling. Limit to a maximum of 2 g in 24 hours in chronic alcohol excess, chronic malnutrition, chronic liver disease, severe dehydration or sepsis with low glutathione reserve.

Contraindications. Hypersensitivity. Severe hepatocellular insufficiency or acute liver failure (intravenous label). Use with great caution in active liver disease.

Boxed-warning-level risk. Dose-related hepatotoxicity, including from unintended duplication across combination products. Acute single ingestion of 150 mg/kg or 12 g (whichever is lower) in an adult is potentially hepatotoxic. The threshold is 75 to 100 mg/kg in people with enzyme induction, malnutrition or chronic alcohol excess. Repeated supratherapeutic dosing over 24 hours or more also causes injury.

Common prescribing errors.

• Giving the adult intravenous dose (1 g) to a patient under 50 kg.
• Confusing mg with mL (10 mg/mL solution).
• Combining oral, rectal and intravenous doses without totalling them.
• Prescribing a combination product (cold remedy, codeine or tramadol combination) alongside plain paracetamol.
• Misreading oral suspension strength (120 mg/5 mL and 250 mg/5 mL are both in use, so confirm the concentration before calculating volume).

Adverse effects. Uncommon at therapeutic dose. Intravenous infusion can cause hypotension. Rare reactions include rash, Stevens-Johnson syndrome, toxic epidermal necrolysis, acute generalised exanthematous pustulosis, thrombocytopenia and neutropenia. High anion gap metabolic acidosis from 5-oxoproline accumulation occurs with chronic use in malnourished or septic patients, renal impairment, and especially with concurrent flucloxacillin.

Interactions. Regular use of 2 g daily or more for several days raises the INR in people taking warfarin. Enzyme inducers (rifampicin, carbamazepine, phenytoin, phenobarbital, chronic alcohol) increase production of the toxic metabolite. Flucloxacillin increases risk of high anion gap acidosis. Metoclopramide speeds absorption. Colestyramine reduces absorption if given within 1 hour. Zidovudine may increase neutropenia risk with prolonged use.

Special groups

• Pregnancy: preferred analgesic and antipyretic. Use the lowest effective dose for the shortest time; prolonged high-dose exposure has been linked to adverse offspring outcomes in observational data, which are contested.
• Breastfeeding: compatible at usual doses.
• Older adults: no adjustment unless frail, underweight or malnourished; use the reduced ceiling.
• Kidney impairment: creatinine clearance 10 to 50 mL/min, give every 6 hours or longer; under 10 mL/min, every 8 hours. Avoid prolonged regular use.
• Liver impairment: use the 2 g ceiling in chronic disease; avoid in severe or acute failure.
• Regional: widely available without prescription, so ask about home use and duplicate products before dosing. Repeated supratherapeutic dosing for febrile illness in young children is a recognised cause of hepatic injury.

Formulations. Tablets 500 mg (1 g in some markets), soluble tablets, oral suspension (120 mg/5 mL and 250 mg/5 mL), suppositories (60 mg to 1 g), and intravenous solution 10 mg/mL in 50 mL and 100 mL containers.

Administration. Oral doses may be taken with or without food. Give the intravenous infusion over 15 minutes. Intravenous vials may be diluted in 0.9% sodium chloride or 5% glucose to no less than 1 part in 10 and used within 1 hour. Calculate the intravenous volume by weight in patients under 50 kg.

Baseline. Weight, alcohol history, nutritional state, current medicines (including combination products) and liver function if chronic liver disease or prolonged high-dose use is planned.

Monitoring. Pain score and temperature. Liver enzymes if treatment exceeds a few days at high dose or in risk groups. INR in patients on warfarin taking regular doses. Anion gap and lactate if unexplained acidosis develops in a chronic user.

Therapeutic drug monitoring. Not used routinely. Serum paracetamol is measured about 4 hours after a single acute ingestion and plotted against a treatment line.

Stopping thresholds. Stop for jaundice, rising transaminases, new rash or suspected overdose.

Referral and escalation. Any suspected ingestion over the hepatotoxic thresholds, or unexplained transaminase rise, needs same-day poison advice and intravenous acetylcysteine decisions. A usual regimen is 150 mg/kg over 1 hour, then 50 mg/kg over 4 hours, then 100 mg/kg over 16 hours, ideally started within 8 hours of ingestion; shortened regimens are used in some centres.