Codeine
| Codeine |  |
|---|---|
| Brand Names | — (often combination products) |
| Drug Class | Opioid (Weak μ-agonist, Prodrug) |
| Primary Indication | Mild–Moderate Pain, Antitussive |
| Relative Potency | ~0.1× Morphine |
| Mechanism | Prodrug → CYP2D6 → Morphine |
| Hypoglycemia Risk | N/A |
| Respiratory Depression | Yes (dose-dependent) |
| Controlled Substance | Schedule II or III (varies by formulation) |
| FDA Approval | 1950 |
Overview
Codeine is a weak μ-opioid receptor agonist used for mild to moderate pain and cough suppression.
Its analgesic effect depends on hepatic conversion to morphine via CYP2D6. Genetic variability in CYP2D6 significantly influences both efficacy and toxicity.
Because of its unpredictable metabolism, codeine use has declined in many settings.
Mechanism of Action
Primary Mechanism
- Weak μ-opioid receptor agonist
Prodrug Conversion
- CYP2D6 converts codeine → morphine (active metabolite)
Analgesic effect depends largely on morphine formation.
Poor metabolizers → minimal analgesia Ultra-rapid metabolizers → increased morphine levels → toxicity risk
Indications
- Mild to moderate pain
- Cough suppression (antitussive)
Commonly combined with:
- Acetaminophen
- Aspirin
Not appropriate for severe pain.
Contraindications
Absolute:
- Significant respiratory depression
- Acute severe bronchial asthma
- Known CYP2D6 ultra-rapid metabolizer status
Pediatric Warning:
- Contraindicated in children after tonsillectomy/adenoidectomy
- Avoid in children <12 years
Relative / Caution:
- Hepatic impairment
- Renal impairment
- Concurrent CNS depressants
Dosing
Typical adult dose:
- 15–60 mg every 4–6 hours
Maximum:
- Usually limited by combination product (e.g., acetaminophen content)
Renal impairment:
- Dose adjustment required
Pharmacokinetics
Absorption:
- Oral
Metabolism:
- CYP2D6 → morphine (active)
- CYP3A4 → norcodeine
Half-life:
- ~3 hours
Elimination:
- Renal
Genetic variability strongly affects clinical response.
Adverse Effects
Common:
- Sedation
- Constipation
- Nausea
- Dizziness
Serious:
- Respiratory depression
- Hypotension
- Physical dependence
Ultra-rapid metabolizers are at higher risk of toxicity.
Drug Interactions
CYP2D6 inhibitors (↓ analgesia):
- Fluoxetine
- Paroxetine
- Bupropion
CNS depressants:
- Benzodiazepines
- Alcohol
- Other opioids
Monitoring
Clinical:
- Pain control
- Sedation level
- Respiratory rate
Special attention:
- Lack of efficacy (possible poor metabolizer)
- Signs of toxicity (possible ultra-rapid metabolizer)
Clinical Pearls
- Codeine is a prodrug requiring CYP2D6 activation.
- Poor metabolizers → little to no analgesia.
- Ultra-rapid metabolizers → increased morphine production and toxicity.
- Lower potency than morphine (~0.1×).
- Frequently combined with acetaminophen — monitor total APAP dose.
- Avoid in children due to unpredictable metabolism.
Toxicity
Comparison Within Class
Compared to Morphine:
- Much weaker
- Requires metabolic activation
Compared to Tramadol:
- Simpler mechanism
- Less serotonergic activity
Compared to Oxycodone:
- Less potent
- Less reliable analgesia