Generic Name

Codeine

Mechanism

• Codeine is a weak μ‑opioid receptor agonist that requires metabolic activation to exert analgesic effects.
• *Δ‑9‑tetrahydrocannabinol (THC)‑like* activity at the central nervous system.
• Bioactivation:
• Hepatic CYP2D6 converts ~10 % of orally administered codeine to morphine, the active metabolite.
• The remaining ~90 % is excreted unchanged or as glucuronide conjugates.
• Resulting μ‑opioid receptor stimulation slows neuronal firing and inhibits pain‑signal transmission in the spinal cord, producing analgesia, sedation, and an antitussive effect.

Pharmacokinetics

• Absorption: Rapid (peak plasma in 30–60 min). Oral bioavailability ~70 %.
• Distribution: Moderate protein binding (~60 %). Lipid‑soluble, penetrates CNS, crosses blood‑brain barrier.
• Metabolism:
• CYP2D6‑mediated O‑demethylation → morphine.
• UGT2B7‑mediated glucuronidation → morphine‑3‑glucuronide, morphine‑6‑glucuronide.
• Elimination: Renal excretion unchanged or as metabolites; half‑life ~3–4 h (morphine metabolites: 2–4 h).
• Inversion: Poor metabolizer phenotype—reduced analgesia; ultra‑rapid metabolizer—heightened risk of morphine toxicity.

Indications

• Moderate to mild pain (post‑operative, musculoskeletal).
• Cough suppression in non‑severe, nonspecific cough.
• Adjuvant analgesia for opioid‑tolerant patients needing additional titration.
• Non‑acutely severe analgesia (reserved for when stronger opioids are contraindicated).

Contraindications

• Contraindications
• Known hypersensitivity to codeine, past
• Severe respiratory depression
• Uncontrolled asthma or severe COPD
• Neonatal abstinence syndrome risk (exposure in late pregnancy).
• Warnings
• CYP2D6 polymorphisms → inadequate analgesia vs. risk of respiratory depression.
• Addictive potential; monitor for misuse, diversion, withdrawal.
• Breastfeeding – codeine and metabolites cross milk; avoid in nursing mothers.
• Pediatric use limited; dose adjustment per age and weight.
• Concurrent CNS depressants (benzodiazepines, alcohol) → additive respiratory depression.

Dosing

• Administration: Oral solution, tablets, or buccal preparations. Avoid crushing formulations to preserve osmolarity.

Monitoring

• Respiratory rate & saturation in high‑risk patients.
• Pain score (e.g., VAS) to gauge efficacy.
• Constipation: stool patterns, pain relief side effects.
• Signs of drug abuse: early refill requests, suspicious behavior.
• Drug‑interaction screening: other CNS depressants, MAOI (if mixed therapy).
• Laboratory: liver function tests if prolonged use; serum creatinine if dosing adjustments needed.
• Breastfeeding mothers: ensure infant not exposed.

Clinical Pearls

• CYP2D6 Phenotype Check: In patients with inadequate analgesia, consider genotyping or phenotyping; ultra‑rapid metabolizers may need lower codeine or a non‑opioid alternative.
• Step‑down Therapy: Often used to taper from stronger opioids; tapering should be at least 2 days per 5 mg decrement to avoid withdrawal.
• Avoid Co‑Administration with SSRIs: Risk of serotonin syndrome is low but noted; major caution with MAOIs.
• Digestive Co‑therapy: Offer laxative dose 30 mg methylcellulose or senna to mitigate constipation; equally important in pediatric dosing.
• Allergy Test: For patients with iodinated contrast allergy, codeine’s structure is not iodine‑related, so no cross‑reactivity; but the metabolic pathway can mimic histamine release (rare).
• Codeine in Pregnancy: Classified B (positive data in animal studies). Nonetheless, prefer safer analgesics when feasible and monitor fetal development.

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• References

1. D. Huang, *Opioid Metabolism and Pharmacogenomics*, J. Pharm. Sci. 2021.

2. FDA Drug Safety Communications: Codeine‑related respiratory depression, 2024.

3. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 13th ed., 2023.