CODEINE

1. Drug Name

• Generic Name: Codeine

• Brand Names: Tylenol with Codeine, Fiorinal with Codeine, Codrix, various generics.

2. Drug Classification

• Class: Opioid analgesic, antitussive

• Subclass: Naturally occurring opioid alkaloid

3. Mechanism of Action

• Analgesic Mechanism: Codeine is a prodrug that is metabolized into morphine, its active form. It acts primarily as a weak agonist at the μ-opioid receptors in the CNS, where it produces analgesic and antitussive effects.

• Antitussive Effect: Codeine suppresses the cough reflex in the brainstem’s cough center, reducing the frequency and intensity of cough.

• Metabolic Activation: Codeine’s analgesic potency depends on its conversion to morphine by the liver enzyme CYP2D6. Individuals with genetic variations in CYP2D6 may experience reduced or enhanced effects due to altered metabolism.

4. Pharmacokinetics

• Absorption: Well absorbed orally, with an approximate bioavailability of 50-60%.

• Distribution: Volume of distribution (Vd) is approximately 3-6 L/kg, indicating moderate distribution; approximately 7-25% bound to plasma proteins.

• Metabolism: Primarily metabolized in the liver through O-demethylation by CYP2D6 to morphine, with additional pathways involving glucuronidation.

• Excretion: Elimination half-life (t½) of codeine is approximately 3 hours. It is primarily excreted via the kidneys, with 5-10% as unchanged drug and the rest as metabolites.

• Special Considerations: Genetic polymorphisms affecting CYP2D6 (e.g., ultra-rapid metabolizers) may lead to a stronger opioid response and an increased risk of toxicity.

5. Indications

• Primary Indications:

  • Management of mild to moderate pain.

  • Symptomatic relief of cough.

• Off-label Uses:

  • Sometimes used in the management of chronic pain in combination with other analgesics.

• Populations Benefiting Most: Often prescribed for patients requiring intermittent pain control or as an adjunct to other pain management methods.

6. Dosage and Administration

• Adult Dosing:

  • Pain: 15-60 mg orally every 4-6 hours as needed; maximum 360 mg/day.

  • Cough: 10-20 mg every 4-6 hours as needed; maximum 120 mg/day.

• Pediatric Dosing: Not recommended for children under 12 years; use caution in patients 12-18 years, especially with respiratory risk factors.

• Route: Oral (tablet, solution).

• Renal/Hepatic Impairment Adjustments:

  • In renal impairment (CrCl <30 mL/min): Dosage adjustment and extended dosing intervals recommended.

  • In hepatic impairment: Use with caution and at lower initial doses.

7. Contraindications

• Hypersensitivity to codeine or other opioids.

• Significant respiratory depression, especially in unmonitored settings.

• Acute or severe bronchial asthma.

• Postoperative pain management in children following tonsillectomy and/or adenoidectomy (due to respiratory risks).

• Use in patients with CYP2D6 ultra-rapid metabolizer status due to the risk of rapid morphine conversion and toxicity.

8. Warnings and Precautions

• Black Box Warnings: Risk of addiction, abuse, and misuse; serious, life-threatening respiratory depression; ultra-rapid metabolism in children leading to fatal respiratory depression.

• Pregnancy and Lactation: Use with caution; risk of neonatal opioid withdrawal syndrome with prolonged use during pregnancy. Codeine and its metabolites can be transferred in breast milk, posing risks to the infant.

• CYP2D6 Metabolism Variability: Increased risk of toxicity in ultra-rapid metabolizers; may have insufficient effects in poor metabolizers.

• Respiratory Depression: Monitor especially in patients with respiratory conditions or on concomitant CNS depressants.

• Monitoring Parameters: Respiratory rate, mental status, and symptoms of misuse.

9. Adverse Effects

• Common Adverse Effects (>10%): Nausea, vomiting, constipation, drowsiness, dizziness.

• Less Common but Clinically Significant: Dry mouth, sweating, euphoria, pruritus.

• Serious Adverse Reactions: Respiratory depression, hypotension, anaphylactic reactions, dependence, and withdrawal symptoms.

10. Drug Interactions

• Major Drug Interactions:

  • CNS Depressants (e.g., benzodiazepines, alcohol): Enhanced risk of sedation, respiratory depression, and death.

  • CYP2D6 Inhibitors (e.g., fluoxetine, paroxetine): May reduce codeine’s efficacy by inhibiting conversion to morphine.

• Food-Drug Interactions: Food may delay but not significantly alter absorption.

• Lab Interference: No notable lab interactions, though opioid metabolites may show up in drug screening tests.

11. Clinical Pharmacology

• Pharmacodynamic Profile: Codeine’s pharmacological effects are primarily derived from morphine production and μ-opioid receptor activation. Its cough suppression is thought to be independent of the opioid receptor and may involve direct suppression of the medullary cough center.

• Additional Pharmacological Effects: Has mild antitussive properties at lower doses without strong analgesic effects.

12. Special Populations

• Pregnancy: Category C; potential risks for the fetus if used in prolonged high doses.

• Lactation: Contraindicated due to risk of significant transfer through breast milk, especially in mothers with high CYP2D6 activity.

• Geriatric Use: Dose cautiously, due to increased sensitivity to side effects such as respiratory depression.

• Renal/Hepatic Impairment: Adjust doses as necessary due to altered metabolism and excretion.

13. Therapeutic Uses

• First-Line Use: Effective for mild-to-moderate pain control in cases where NSAIDs are contraindicated.

• Combination Therapy: Often combined with non-opioid analgesics (e.g., acetaminophen) for enhanced efficacy in pain management.

• Clinical Trials and Efficacy: Shown to be moderately effective for short-term pain and cough suppression but is limited by potential for dependence and respiratory depression.

14. Monitoring and Follow-Up

• Recommended Lab Tests: Liver and kidney function in long-term therapy.

• Patient Symptom Checklists: Monitor for respiratory issues, changes in alertness, and potential signs of misuse or withdrawal.

• Therapeutic and Toxic Levels: Regular monitoring of patient response and adverse effects, particularly in those with altered CYP2D6 metabolism.

15. Overdose Management

• Symptoms of Overdose: Respiratory depression, bradycardia, lethargy, cold/clammy skin, hypotension, coma.

• Treatment Protocols:

  • Administer naloxone for respiratory depression.

  • Gastric lavage and activated charcoal if the ingestion is recent.

• Supportive Measures: Oxygenation and ventilation if necessary, cardiac monitoring, and treatment of seizures if they occur.

16. Patient Counseling Information

• Key Counseling Points:

  • Take codeine only as prescribed to reduce the risk of dependence.

  • Avoid other CNS depressants, including alcohol, while taking this medication.

  • Report any symptoms of difficulty breathing, confusion, or severe drowsiness.

  • Discuss any history of breathing issues or medications you are currently taking with your doctor.

• Signs Requiring Immediate Attention: Respiratory difficulties, extreme drowsiness, confusion, rash, or any signs of an allergic reaction.