Introduction
Dextromethorphan is a widely available antitussive medication commonly found in over-the-counter cough and cold preparations. As the d-isomer of levorphanol, it belongs to the morphinan class of medications but lacks significant opioid analgesic properties or addictive potential at recommended doses. First approved by the FDA in the 1950s, dextromethorphan has become one of the most commonly used cough suppressants worldwide.
Mechanism of Action
Dextromethorphan exerts its antitussive effects primarily through non-competitive antagonism of N-methyl-D-aspartate (NMDA) receptors in the cough center located in the medulla oblongata. Additionally, it acts as a sigma-1 receptor agonist and demonstrates weak serotonin reuptake inhibition. Unlike opioid antitussives such as codeine, dextromethorphan has minimal affinity for mu-opioid receptors at therapeutic doses, which accounts for its significantly lower abuse potential and reduced respiratory depression effects.
Indications
Dextromethorphan is FDA-approved for the temporary relief of cough due to minor throat and bronchial irritation as may occur with the common cold or inhaled irritants. It is indicated for symptomatic treatment of non-productive cough and should not be used for chronic cough associated with smoking, asthma, emphysema, or when excessive secretions are present.
Dosage and Administration
Adults and children 12 years and older: 10-20 mg every 4 hours, or 30 mg every 6-8 hours (maximum 120 mg/24 hours) Children 6-12 years: 5-10 mg every 4 hours, or 15 mg every 6-8 hours (maximum 60 mg/24 hours) Children 4-6 years: 2.5-5 mg every 4 hours, or 7.5 mg every 6-8 hours (maximum 30 mg/24 hours) Not recommended for children under 4 yearsAvailable formulations include syrups, lozenges, gel caps, and extended-release formulations. Should be administered with a full glass of water. Dosing adjustments are necessary in hepatic impairment and in patients taking CYP2D6 or CYP3A4 inhibitors.
Pharmacokinetics
Absorption: Rapidly absorbed from the gastrointestinal tract with oral bioavailability of approximately 11% due to extensive first-pass metabolism. Peak plasma concentrations reached within 2-3 hours. Distribution: Widely distributed throughout body tissues. Crosses the blood-brain barrier. Protein binding is minimal (60-80%). Metabolism: Extensive hepatic metabolism primarily via CYP2D6 to dextrorphan (active metabolite with higher NMDA receptor affinity) and via CYP3A4 to 3-methoxymorphinan (inactive metabolite). Genetic polymorphisms in CYP2D6 can significantly affect metabolism. Elimination: Renal excretion with elimination half-life of 2-4 hours in extensive metabolizers and up to 24 hours or more in poor metabolizers.Contraindications
- Hypersensitivity to dextromethorphan or any product components
- Patients taking monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOI therapy
- History of asthma or respiratory depression
- Children under 4 years of age
- Patients with phenylketonuria (for phenylalanine-containing formulations)
Warnings and Precautions
- Serotonin syndrome risk: Use with caution when co-administered with serotonergic drugs
- CYP2D6 poor metabolizers: Increased risk of adverse effects due to reduced metabolism
- Hepatic impairment: Requires dose reduction due to reduced metabolism
- Respiratory conditions: Use caution in patients with chronic respiratory diseases
- Psychiatric effects: May cause dizziness, confusion, or visual disturbances
- Pregnancy: Category C - use only if potential benefit justifies potential risk
- Breastfeeding: Excreted in human milk; use caution
Drug Interactions
- MAOIs: Risk of serotonin syndrome (contraindicated)
- SSRIs/SNRIs: Increased risk of serotonin syndrome
- CYP2D6 inhibitors (quinidine, fluoxetine, paroxetine): Increased dextromethorphan levels
- CYP3A4 inhibitors (ketoconazole, erythromycin): Increased dextromethorphan levels
- Other CNS depressants: Additive sedative effects
- Serotonergic drugs: Increased serotonin syndrome risk
Adverse Effects
Common (≥1%):- Dizziness
- Drowsiness
- Nausea
- Gastrointestinal upset
- Nervousness
- Confusion
- Restlessness
- Visual disturbances
- Serotonin syndrome
- Severe allergic reactions
- Respiratory depression (with overdose)
- Bradycardia
- Hypertension
Monitoring Parameters
- Cough frequency and severity
- CNS effects (drowsiness, dizziness)
- Signs of serotonin syndrome (agitation, hyperreflexia, clonus)
- Respiratory status in patients with underlying pulmonary disease
- Hepatic function in patients with liver impairment
- Signs of abuse or misuse
Patient Education
- Use only as directed for temporary cough relief
- Do not exceed recommended dosage
- Avoid alcohol and other CNS depressants during therapy
- Be aware of potential drowsiness; avoid driving or operating machinery
- Check other medications for additional dextromethorphan content to avoid overdose
- Seek medical attention if cough persists beyond 7 days or is accompanied by fever, rash, or persistent headache
- Store safely away from children due to risk of accidental overdose
- Report any unusual side effects or symptoms of serotonin syndrome
References
1. FDA Drug Approval Package. Dextromethorphan Hydrobromide. 1958. 2. Werneke U, Jamshidi F, Taylor DM, et al. Conundrums in neurology: diagnosing serotonin syndrome - a meta-analysis of cases. BMC Neurol. 2016;16:97. 3. Taylor CP, Traynelis SF, Siffert J, et al. Pharmacology of dextromethorphan: Relevance to dextromethorphan/quinidine (Nuedexta®) clinical use. Pharmacol Ther. 2016;164:170-182. 4. Schwartz AR, Pizon AF, Brooks DE. Dextromethorphan-induced serotonin syndrome. Clin Toxicol (Phila). 2008;46(8):771-773. 5. CYP2D6 allele nomenclature. The Human Cytochrome P450 (CYP) Allele Nomenclature Database. 2023. 6. American College of Chest Physicians. Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines. Chest. 2006;129(1 Suppl):1S-23S. 7. Micromedex Solutions. Dextromethorphan. Truven Health Analytics. 2023. 8. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Dextromethorphan. 2023.