Codeine

Codeine is a naturally occurring opioid analgesic derived from the opium poppy (Papaver somniferum). It is classified as a mild to moderate strength opioid and is widely used as an analgesic, antitussive (cough suppressant), and antidiarrheal. Codeine is most commonly administered orally and is often combined with other agents such as paracetamol (acetaminophen), ibuprofen, or promethazine to enhance therapeutic effects or provide multi-symptom relief.

Despite its widespread medical use, codeine is a controlled substance due to its potential for abuse, dependence, and respiratory depression, particularly in certain populations with variable metabolism (notably ultrarapid CYP2D6 metabolizers).

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1. Classification

• Therapeutic Class: Opioid analgesic, antitussive

• Pharmacologic Class: Phenanthrene derivative

• ATC Code: R05DA04 (for cough), N02AA59 (analgesic combinations)

• Controlled Substance Schedule:

  • US: Schedule II (pure codeine), III or V (in combination, depending on dose)

  • UK: Class B drug (Schedule 2 or 5)

  • EU/MENA: Prescription-only; some OTC restrictions apply

• Natural source: Derived from morphine, or synthesized from thebaine

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2. Mechanism of Action

A. Analgesic Effect

• Prodrug that is metabolized into morphine via CYP2D6

• Morphine binds to μ-opioid receptors (MOR) in the central nervous system (CNS)

• Results in:

  • Inhibition of ascending pain pathways

  • Altered perception and emotional response to pain

  • Increased pain threshold

B. Antitussive Effect

• Acts on the medullary cough center in the brainstem

• Suppresses cough reflex regardless of the cause (central action)

C. Antidiarrheal Effect

• Slows gastrointestinal motility by interacting with μ-opioid receptors in the gut

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3. Therapeutic Indications

A. Analgesia

• Mild to moderate nociceptive pain, including:

  • Postoperative pain

  • Musculoskeletal pain

  • Dental pain

  • Headache (when used cautiously)

B. Cough Suppression

• Dry, non-productive cough

• Persistent cough unresponsive to non-opioid suppressants

C. Diarrhea (off-label)

• Short-term relief of non-infectious diarrhea (less common)

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4. Formulations

A. Single-Agent (Less Common)

• Codeine phosphate tablets: 15 mg, 30 mg, 60 mg

• Codeine syrup (antitussive): varies by country

B. Combination Products

• Codeine + Paracetamol (e.g., co-codamol)

• Codeine + Ibuprofen (e.g., Nurofen Plus)

• Codeine + Aspirin

• Codeine + Promethazine (cough/cold, e.g., Phenergan with Codeine)

• Codeine Linctus: syrup for dry coughs

C. Available Dosage Forms

• Oral tablets

• Effervescent tablets

• Capsules

• Syrups

• Elixirs

• Oral drops

• Soluble powders

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5. Dosing and Administration

A. Pain Management

• Adults: 15–60 mg orally every 4–6 hours; max 240 mg/day

• Children (12–17 years): 30–60 mg every 6 hours; max 240 mg/day

• Elderly: Use with caution; lower initial dose recommended

B. Cough

• Adults: 10–20 mg orally every 4–6 hours; max 120 mg/day

• Children: Contraindicated <12 years; caution 12–18 years

C. Special Considerations

• Administer with or after food to reduce GI upset

• Combination products should be dosed based on paracetamol or NSAID content

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6. Pharmacokinetics

• Absorption: Well absorbed orally; peak plasma concentration in 1–2 hours

• Distribution: Widely distributed; crosses the blood-brain barrier and placenta

• Protein binding: ~7–25%

• Metabolism:

  • Liver via CYP2D6 → morphine (active)

  • CYP3A4 → norcodeine (inactive)

  • Phase II conjugation → codeine-6-glucuronide (active)

• Elimination: Renal excretion

• Half-life: ~3 hours

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7. Contraindications

• Hypersensitivity to codeine or opioids

• Respiratory depression

• Acute or severe asthma

• Paralytic ileus

• Head trauma or raised intracranial pressure

• Children <12 years old (due to variable CYP2D6 metabolism)

• Post-tonsillectomy or adenoidectomy in children

• Breastfeeding (risk of neonatal opioid toxicity)

• Ultrarapid CYP2D6 metabolizers

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8. Precautions

• Renal or hepatic impairment

• Elderly patients: Increased sensitivity to CNS effects

• Seizure disorders: Lowers seizure threshold

• Substance abuse history

• Driving and machinery operation: Impairs alertness

• Asthma/COPD: Respiratory depression risk

• Constipation risk: Often requires prophylactic laxative

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9. Adverse Effects

A. Common

• Drowsiness

• Dizziness

• Nausea and vomiting

• Constipation

• Dry mouth

• Light-headedness

B. Serious

• Respiratory depression

• Urinary retention

• Hypotension

• Bradycardia

• Confusion or delirium

• Dependency/addiction

• Withdrawal symptoms upon discontinuation

C. Toxicity

• Signs: slow breathing, cyanosis, pinpoint pupils, stupor, coma

• Overdose antidote: Naloxone IV (opioid antagonist)

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10. Drug Interactions

A. CNS Depressants

• Alcohol

• Benzodiazepines

• Barbiturates

• Antipsychotics

• Sedating antihistamines

→ Additive respiratory depression

B. CYP2D6 Inhibitors

• Fluoxetine

• Paroxetine

• Quinidine

• Bupropion

→ Reduced conversion to morphine → ↓ analgesic effect

C. Enzyme Inducers

• Rifampin

• Carbamazepine

• Phenytoin

→ May alter metabolism, reduce efficacy

D. MAO Inhibitors

• Interaction can cause serotonin syndrome, respiratory depression

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11. Special Populations

A. Pediatrics

• Not recommended <12 years (FDA and EMA warning)

• Risk of fatal respiratory depression due to CYP2D6 variability

B. Geriatrics

• Increased risk of sedation, constipation, respiratory depression

• Use lowest effective dose

C. Pregnancy

• Category C (US): Use only if clearly needed

• Prolonged use in late pregnancy → neonatal withdrawal syndrome

D. Breastfeeding

• Contraindicated

• Neonatal toxicity has occurred in ultrarapid metabolizers

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12. Abuse, Tolerance, and Dependence

• Psychological and physical dependence may develop

• Codeine-containing cough syrups have been abused recreationally

• Tolerance develops to analgesic and sedative effects

• Withdrawal symptoms: insomnia, agitation, yawning, nausea, diarrhea, sweating

Measures to mitigate abuse:

• Prescription monitoring programs

• Limitations on OTC availability

• Patient education and gradual tapering to discontinue use

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13. Regulatory and Legal Considerations

• Many countries restrict OTC use or require prescription

• UK: Pack size limits for pharmacy (P) medicines

• US DEA Schedule:

  • Schedule II: pure codeine

  • Schedule III: codeine + paracetamol (<90 mg/unit)

  • Schedule V: codeine-containing syrups (<200 mg/100 mL)

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14. Examples of Common Codeine Products

Product	Contents	Indication
Co-codamol	Codeine + Paracetamol (8/500, 15/500, 30/500 mg)	Pain
Nurofen Plus	Codeine 12.8 mg + Ibuprofen 200 mg	Pain
Codeine Linctus	Codeine phosphate 15 mg/5 mL	Dry cough
Phenergan with Codeine	Promethazine + Codeine	Cough, cold
Robitussin AC (US)	Guaifenesin + Codeine	Cough
Tylenol #3 (US)	Codeine 30 mg + Paracetamol 300 mg	Pain

15. Monitoring Parameters

• Pain relief efficacy

• Signs of sedation or respiratory depression

• Bowel habits (constipation)

• Signs of misuse or abuse

• Liver function (especially with paracetamol combinations)

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16. Alternatives

• For pain:

  • Tramadol (caution with seizure risk)

  • NSAIDs (e.g., ibuprofen, naproxen)

  • Paracetamol alone

  • Morphine (for stronger opioid need)

• For cough:

• Dextromethorphan

• Pholcodine (withdrawn in some countries)

• Honey and herbal products (non-pharmacological)