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

Prodrug Conversion

Analgesic effect depends largely on morphine formation.

Poor metabolizers → minimal analgesia Ultra-rapid metabolizers → increased morphine levels → toxicity risk

Indications

Commonly combined with:

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

Classic opioid toxidrome:

Treatment:

Comparison Within Class

Compared to Morphine:

Compared to Tramadol:

Compared to Oxycodone: