Antitussive Drugs

Antitussive drugs suppress the cough reflex. They are used for dry, distressing cough once the cause has been assessed, and they are harmful when cough clears sputum or protects the airway. Evidence for benefit in acute cough is weak.

Classification. Opioids (codeine, morphine, methadone, pholcodine), centrally acting non-opioids (dextromethorphan), peripheral agents (benzonatate, levodropropizine), neuromodulators (gabapentin, pregabalin, low dose amitriptyline) and P2X3 antagonists (gefapixant).

Mechanism. Opioids act on mu receptors in the medullary cough centre. Dextromethorphan acts centrally as an NMDA antagonist. Peripheral agents numb stretch receptors in the airway. Neuromodulators reduce central sensitisation in cough hypersensitivity. Gefapixant blocks ATP at P2X3 receptors on vagal C fibres.

Pharmacokinetics. Codeine is a prodrug converted to morphine by CYP2D6, so ultra-rapid metabolisers can develop toxicity and poor metabolisers gain no effect. Dextromethorphan is also cleared by CYP2D6 and inhibitors raise levels.

Codeine. 15 to 30 mg orally three to four times daily, maximum 120 mg in 24 hours. Contraindicated under 12 years, in adolescents with respiratory compromise and in breastfeeding.

Dextromethorphan. 10 to 20 mg every 4 hours or 30 mg every 6 to 8 hours, maximum 120 mg in 24 hours. Not advised under 6 years.

Morphine. Low dose sustained release 5 mg twice daily, rising to 10 mg twice daily, is specialist use for refractory chronic cough.

Gabapentin. 300 mg once daily, increased over weeks to a maximum of 1800 mg daily in divided doses as tolerated, for refractory chronic cough. Reduce dose in renal impairment.

Low dose amitriptyline. 10 mg at night, increased as tolerated, for refractory chronic cough.

Gefapixant. 45 mg twice daily in refractory chronic cough, in regions where it is licensed. Causes taste disturbance.

Pholcodine. Withdrawn in several regions because it can sensitise to neuromuscular blocking agents, and is avoided.

First step. Treat the cause. Stop an ACE inhibitor, which causes dry cough within weeks to months, and switch to an angiotensin receptor blocker such as losartan 50 mg daily. Cough resolves in 1 to 4 weeks. Treat asthma, upper airway cough syndrome and reflux where relevant.

Acute cough. Most are self-limiting. A suppressant is used briefly at night only when dry cough disturbs sleep. Honey 2.5 to 5 mL at bedtime is an option in children over 1 year.

Chronic refractory cough. Neuromodulators and low dose morphine are specialist options after the cause is treated.

Palliative care. Codeine, morphine or methadone linctus for cough in lung cancer and advanced disease.

Avoid. Productive cough, asthma exacerbation, COPD with sputum retention and airway obstruction.

Adverse effects. Opioids cause drowsiness, constipation, nausea, respiratory depression and dependence. Dextromethorphan causes dizziness and, in overdose, hallucinations and serotonin toxicity. Gabapentin causes sedation and dizziness. Amitriptyline causes dry mouth, constipation and urinary retention.

Interactions. Dextromethorphan with SSRIs, MAO inhibitors or other serotonergic drugs risks serotonin syndrome. Codeine with CYP2D6 inhibitors loses effect. Opioids add to sedatives, alcohol and gabapentinoids.

Misuse. Codeine and dextromethorphan are misused, so limit supply and duration.

Monitoring. Response over 1 to 2 weeks, sedation, bowel function and mood.

Special groups. Pregnancy: avoid codeine in late pregnancy because of neonatal respiratory depression and withdrawal. Breastfeeding: avoid codeine. Children: avoid suppressants under 6 years. Older adults: sedation, constipation and falls. Renal impairment: reduce codeine, morphine and gabapentin. Hepatic impairment: reduce dose of opioids.

Referral and escalation. Cough lasting over 2 weeks needs a chest radiograph and sputum testing for tuberculosis before suppression, especially in HIV or in settings with high tuberculosis burden. Haemoptysis, weight loss, night sweats, hoarseness, breathlessness or an abnormal radiograph need urgent assessment.