Cough Drugs — Complete Pharmacological Reference

Overview: The Cough Reflex

"The reflex is complex, involving the central and peripheral nervous systems as well as the smooth muscle of the bronchial tree." — Goodman & Gilman's The Pharmacological Basis of Therapeutics

Classification of Cough Drugs

1. OPIOID ANTITUSSIVES

Mechanism

"Cough suppression can be achieved without altering the protective glottal function." — Goodman & Gilman's

Codeine (Methylether of Morphine)

• Class: Opioid (μ-receptor agonist)
• Mechanism: Central — direct depression of the medullary cough center
• Antitussive dose: 15 mg orally (lower than analgesic doses)
• Efficacy: Effective against pathologic cough and cough in normal volunteers; limited efficacy in COPD patients and acute cough of common cold
• Route: Oral
• ADRs: Sedation, respiratory depression (at higher doses), constipation, physical dependence, nausea
• Special notes:
  • Long-standing gold standard antitussive
  • Avoid in children (variable CYP2D6 metabolism → unpredictable toxicity)
  • Contraindicated with MAO inhibitors
  • Exacerbates wheezing via histamine release (rare)

Morphine / Diamorphine

• Class: Strong opioid
• Use: Reserved for palliative control of cough and pain in terminal cancer patients
• Slow-release morphine can partially control severe chronic idiopathic cough
• ADRs: Physical dependence, sedation, respiratory depression, GI constipation
• Note: Diamorphine is not prescribed in the United States

2. NON-OPIOID (OPIOID-RELATED STRUCTURE) ANTITUSSIVES

Dextromethorphan (DXM)

• Full name: D-3-methoxy-N-methylmorphinan; dextrorotatory stereoisomer of a methylated levorphanol derivative
• Class: Non-narcotic antitussive — does NOT bind μ-opioid receptors
• Mechanism: Acts centrally to elevate the cough threshold; also inhibits neuronal serotonin uptake; at high doses acts at NMDA receptors
• Dose: 10–20 mg every 4 hours OR 30 mg every 6–8 hours; max 120 mg/day; extended-release forms approved for twice-daily dosing
• Efficacy: Nearly equal potency to codeine; effective in adults for upper respiratory tract infections; not effective in children
• Onset/Duration: Antitussive effects persist 5–6 hours
• Forms: Liquids, syrups, capsules, soluble strips, lozenges, freezer pops; widely available OTC; also found in combination products with antihistamines, expectorants, decongestants
• ADRs:
  • At therapeutic doses: few side effects; fewer GI effects and less constipation than codeine
  • Does not inhibit ciliary activity
  • High doses: dizziness, nausea, vomiting, headaches, hallucinations, euphoria, dissociative effects, perceptual distortions, impaired motor coordination (NMDA receptor activity — "robo-tripping")
• Drug interactions:
  • MAO inhibitors — CONTRAINDICATED: risk of CNS depression and death (serotonin syndrome)
• FDA ban: Banned in children < 6 years of age due to deaths from OTC cold/cough formulations
• No analgesic or addictive properties

Pholcodine [3-O-(2-morpholinoethyl)morphine]

• Class: Opioid-related structure; does not act at opioid receptors
• Mechanism: Non-opioid; central cough suppression
• Efficacy: At least as effective as codeine
• Pharmacokinetics: Long half-life → can be given once or twice daily
• Availability: Used in many countries outside the USA; not available in the US

Levopropoxyphene

• Stereoisomer of dextropropoxyphene (weak opioid)
• Devoid of opioid effects; sedation is a reported side effect
• Dose: 50–100 mg every 4 hours
• Not available in the USA

Noscapine

• Opioid derivative; used as antitussive in several countries
• Not available in the USA

3. PERIPHERAL ANTITUSSIVES

Levodropropizine

• Mechanism: Nonopioid; peripheral inhibition of sensory cough receptors in the airways
• Efficacy: Favorable benefit/risk profile compared with dextromethorphan
• Used especially in contexts where central side effects are undesirable

Benzonatate

• Local anesthetic-type drug; suppresses cough by anesthetizing stretch receptors in the respiratory tract
• Used in clinical practice as a non-opioid antitussive

4. NEUROMODULATORS (For Chronic/Refractory Cough)

Gabapentin

• Mechanism: Acts on voltage-gated calcium channels; modulates NMDA receptors (presynaptic) → reduces transmitter release and postsynaptic excitability; may affect GABA neurotransmission in spinal cord and brain
• Evidence: RCT showed gabapentin significantly reduced cough frequency and visual analogue scores + improved Leicester Cough quality-of-life scores in refractory cough
• Combined therapy: Pregabalin + speech pathology therapy was more effective than speech pathology alone

Pregabalin

• Related to gabapentin; similar mechanism
• Used in combination with speech/respiratory physiotherapy

Amitriptyline

• Tricyclic antidepressant; central antinociceptive action
• In a randomized trial vs codeine/guaifenesin for post-viral cough: amitriptyline led to complete response in most subjects; none in codeine/guaifenesin group achieved complete response
• Modulates presynaptic NMDA receptors

"The effectiveness of neuromodulators suggests that chronic cough can be a neuropathic condition in some patients." — Murray & Nadel's Textbook of Respiratory Medicine

5. EXPECTORANTS

Guaifenesin

• Most widely used expectorant
• Mechanism: Increases the volume of respiratory secretions and reduces viscosity → facilitates expectoration
• Found in many OTC preparations, often combined with dextromethorphan
• Evidence for efficacy is limited
• Note: Often combined with antitussives (codeine/guaifenesin) in compound preparations

6. MUCOLYTICS

"Despite a lack of good evidence, mucolytic agents are often used to facilitate expectoration by reducing sputum viscosity in patients with chronic bronchitis." — Murray & Nadel's

7. AROMATIC AGENTS & DEMULCENTS

• Menthol: Acts through cold-sensitive TRP receptor (TRPM8); inhibits capsaicin-induced cough in normal volunteers; decongestant effect in the nose
• Eucalyptus: Decongestant effects in the nose; short-term relief of cough
• Demulcents: Thick sugary preparations that form a protective layer at mucosal surfaces; component of many proprietary cough preparations

Special Drug Interaction Warning

Treatments for Chronic Cough by Underlying Cause

Pediatric Cautions

• Dextromethorphan: FDA-banned in children < 6 years due to deaths
• Codeine: Use in any purpose in young children is being reconsidered due to CYP2D6 polymorphism variability leading to unpredictable opioid conversion
• For most children with acute cough from viral URTI: conservative management (watchful waiting) is preferred

• Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14e
• Katzung's Basic and Clinical Pharmacology, 16e
• Murray & Nadel's Textbook of Respiratory Medicine
• Textbook of Family Medicine, 9e

• Dark navy header with frozen panes for easy scrolling
• Section dividers (blue) separating drug classes: Opioid, Non-opioid, Peripheral, Neuromodulators, Expectorants, Mucolytics, Aromatics
• Safety warnings (red highlight) for contraindications, FDA bans, and pediatric restrictions
• Alternating row colours for readability