In the second article in a new series on OTC medicines, Alan Nathan considers oral analgesics based on paracetamol

How does it act?

Paracetamol’s mechanism of action is not well understood. It has little anti- inflammatory activity but is an effective analgesic and antipyretic. It may selectively inhibit cyclo-oxygenase in the central nervous system rather than in peripheral tissues. It also appears to act peripherally at pain chemoreceptors.

What is it licensed for?

As for NSAIDs: treatment of mild and moderate pain from a wide variety of causes, including headache (specific OTC medicines for migraine are not covered in this article), dental and musculoskeletal pain and dysmenorrhoea. It also has antipyretic activity and is used in cold and flu medicines

Cautions

• Paracetamol is safe at normal therapeutic dosages, its only major drawback being hepatotoxicity in overdose. It is metabolised in the liver, where it is converted to a highly toxic intermediate that is normally detoxified by conjugation with glutathione. In overdose, this detoxification mechanism is overwhelmed and the free toxic metabolite causes hepatitis and necrosis, which can prove fatal. Paracetamol poisoning is particularly dangerous, as the toxic level may not be greatly above the therapeutic level. Also, symptoms of overdose may not appear for two days or more, allowing unwitting overdosage to continue.
• It is therefore extremely important to ensure that patients do not exceed the recommended dosage and do not use more than one paracetamol-containing product at a time.
• Maximum daily adult dose: 4,000mg. It is licensed for use in babies and children from three months (from two months if over 4kg and not born prematurely).

Additional Constituents

Codeine and dihydrocodeine

• These are weak opioid analgesics acting directly on opiate receptors in the brain. They are useful for treatment of mild to moderate pain.
• The main side-effect at non-prescription doses is constipation. There is also a risk of habituation, misuse and chronic daily headache syndrome with prolonged use. At doses above recommended OTC levels they can also cause respiratory depression, euphoria and sedation.

Caffeine

• A CNS stimulant, the rationale for its use is to alleviate the depression often associated with pain. It is also claimed to act synergistically with analgesics.
• Most preparations contain low doses, although they may be sufficient to add to gastrointestinal adverse effects. Caffeine is also habit-forming and may itself induce headache in large doses or on withdrawal.

Antihistamine

• Tension in muscles at the back of the neck is thought to be a contributory factor to tension headache. The sedating antihistamine doxylamine is included in one product for its claimed muscle- relaxant effect.

How effective are these products? 

• Evidence from clinical trials, systematic reviews and meta-analyses indicate that paracetamol and NSAIDs are effective and more or less equivalent in the OTC treatment of mild to moderate pain, including headache. NSAIDs appear to be more effective than paracetamol for dental pain and dysmenorrhoea.
• Paracetamol is a safe and effective analgesic and antipyretic for use in children, although ibuprofen appears to have a longer duration of action and to be a more effective antipyretic.
• Systematic reviews and meta-analyses have concluded that codeine in combination products adds little or nothing to analgesic efficacy.
• The evidence on caffeine is inconclusive: some trials have shown proprietary products containing caffeine to be more effective than single analgesics, while systematic reviews and meta-analyses have concluded that they add little or nothing to efficacy
• In a single controlled clinical trial, doxylamine in combination with paracetamol was found to be more effective than the analgesic alone.