Paracetamol with caffeine (Panadol Extra) available over the counter from pharmacies

The extent to which caffeine improves the analgesic effect of paracetamol is uncertain and may not be clinically meaningful. Published trials have assessed the effect of combining caffeine with paracetamol compared with paracetamol alone in conditions including tension-type⁴ and non-migrainous headaches⁵, postoperative pain^6,7, uterine cramping⁶ and primary dysmenorrhoea.⁸

Trials were generally of poor quality and had conflicting results: some showed a small benefit, most did not. For example, a trial of 320 young women found that a single dose of paracetamol with caffeine provided more pain relief for primary dysmenorrhoea 2 hours post dose than paracetamol (mean difference in pain relief scores* 0.27, 95% confidence interval 0.03 to 0.52, P = 0.03) but it is unclear whether this is clinically meaningful.⁸

In addition, there is no evidence on the effect of repeat dosing, as only single doses were studied (2–4 hours post dose) in the trials.^4–8

* Using a 5-point pain relief scale where 0 = none, 1 = a little, 2 = some, 3 = a lot and 4 = complete.

The amount of caffeine that can be ingested per day from paracetamol with caffeine is between 65 mg (1 tablet) and 520 mg (8 tablets).¹ Even a small dose of 50 mg caffeine can cause tachycardia, anxiety and ectopic beats.⁹ Toxicity is normally seen at doses > 500 mg, but this depends on tolerance.⁹

Take into account dietary and other medicinal sources of caffeine: people may not be aware from the brand name that a particular preparation contains caffeine. Consider whether paracetamol with caffeine is necessary: it cannot be assumed that it will be tolerated in the same way as paracetamol alone.

Medication-overuse (rebound) headache may occur with prolonged and frequent use of medicines used for headache, including those containing paracetamol and caffeine).^10,11

Medication-overuse headache is the most prominent sign of withdrawal⁹ and over time may lead to an imperceptible dependence on analgesic drugs.¹⁰ It can be diagnosed only after abstinence from the drug for a week or more.¹⁰

Pregnant women should not consume more than 200 mg caffeine per day, as this may increase the risk of spontaneous miscarriage.⁹ Consuming > 300 mg per day may also increase the risk of preterm delivery and foetal growth retardation.⁹

Caffeine is readily transferred to breast milk and young infants are poor metabolisers of caffeine.⁹ Infants who are breastfed by mothers consuming > 300 mg caffeine per day may become jittery and restless, and may experience sleep difficulties.⁹ No long-term adverse effects from consuming caffeine in breast milk have been documented.⁹

Caffeine is present in a variety of foods and beverages (Box 1) as well as in herbal, prescription and over-the-counter medicines.⁹

Advise people to take into account dietary and other medicinal sources of caffeine if paracetamol with caffeine is being taken so that they do not consume more than the recommended maximum of 520 mg caffeine per day.¹²

Inform people about adverse effects that may occur with higher doses of caffeine, including toxic symptoms such as anxiety, insomnia, gastrointestinal symptoms, increased heart rate and blood pressure, diuresis and dehydration.⁹ People experiencing anxiety or stress may benefit from reducing their caffeine intake to < 210 mg per day.¹³

Advise against the use for headache for more than 2–3 days per week to avoid medication-overuse headaches.^10,11 Encourage people to use a diary to monitor and record the frequency and severity of headaches and medicine use.

Warn people that paracetamol has many brands and is contained in other products such as cough and cold preparations. If the use of other paracetamol-containing preparations cannot be avoided, ensure that these are accounted for in the maximum dose of 4 g (8 tablets) paracetamol per day.

Box 1. Caffeine content of commonly consumed items compared with paracetamol with caffeine tablets13