Codeine - Drug Monograph

Introduction

Codeine is an opioid analgesic and antitussive medication derived from the opium poppy, Papaver somniferum. As a naturally occurring phenanthrene alkaloid, it has been used clinically for over a century for its pain-relieving and cough-suppressing properties. Codeine is classified as a Schedule II controlled substance in the United States due to its potential for abuse and dependence, though it is available in some combination products as Schedule III or V depending on formulation.

Mechanism of Action

Codeine exerts its therapeutic effects primarily through conversion to morphine via the cytochrome P450 2D6 (CYP2D6) enzyme system. Codeine itself has weak affinity for mu-opioid receptors, but its active metabolite morphine is a potent agonist at central nervous system mu-opioid receptors. This activation:

• Alters pain perception in the brain and spinal cord
• Depresses the cough reflex center in the medulla oblongata
• Produces sedation and euphoria by affecting the limbic system
• Causes respiratory depression by reducing brainstem responsiveness to carbon dioxide

The analgesic effect is dose-dependent and varies significantly based on individual CYP2D6 metabolism status.

Indications

• Mild to moderate pain: As monotherapy or in combination with non-opioid analgesics
• Cough suppression: For nonproductive cough when non-opioid antitussives are inadequate
• Diarrhea: Off-label use for symptomatic relief (though other agents are preferred)

Dosage and Administration

• Not recommended for children under 12 years due to respiratory depression risk
• Contraindicated for post-tonsillectomy/adenoidectomy pain management in children
• Avoid use in adolescents 12-18 years with obesity or respiratory conditions

• Renal impairment: Reduce dose or avoid in severe impairment
• Hepatic impairment: Use with caution and consider dose reduction
• Elderly: Start with lower doses due to increased sensitivity
• CYP2D6 poor metabolizers: Reduced efficacy for analgesia
• CYP2D6 ultra-rapid metabolizers: Increased risk of toxicity

Available formulations: tablets, capsules, and liquid solutions, often in combination with acetaminophen or aspirin.

Pharmacokinetics

• O-demethylation by CYP2D6 to morphine (active)
• N-demethylation by CYP3A4 to norcodeine
• Glucuronidation to codeine-6-glucuronide

Contraindications

• Significant respiratory depression
• Acute or severe bronchial asthma
• Known or suspected gastrointestinal obstruction
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days
• Hypersensitivity to codeine or other opioid analgesics
• Post-operative pain management in children following tonsillectomy/adenoidectomy

Warnings and Precautions

• Risk of respiratory depression and death, especially in children
• Risk of medication errors due to confusion between mg and mL dosing
• Risk of accidental ingestion by children

• Addiction, abuse, and misuse potential
• Life-threatening respiratory depression
• Neonatal opioid withdrawal syndrome with prolonged use during pregnancy
• Interactions with drugs affecting cytochrome P450 isoforms
• Risks from concomitant use with benzodiazepines or other CNS depressants
• Adrenal insufficiency with long-term use
• Severe hypotension in volume-depleted patients
• Increased intracranial pressure in head injury patients
• Seizures in patients with seizure disorders

Drug Interactions

• CNS depressants (benzodiazepines, alcohol, sedatives): Additive CNS depression
• CYP3A4 inhibitors (ketoconazole, clarithromycin): Increased codeine levels
• CYP2D6 inhibitors (paroxetine, fluoxetine): Decreased morphine formation
• MAOIs: Serotonin syndrome risk
• Mixed agonist/antagonist opioids (pentazocine, butorphanol): May reduce analgesia

• Anticholinergic drugs: Increased risk of urinary retention and constipation
• Diuretics: Reduced efficacy due to release of antidiuretic hormone

Adverse Effects

• Drowsiness, sedation
• Constipation
• Nausea, vomiting
• Lightheadedness, dizziness

• Pruritus
• Sweating
• Dry mouth
• Miosis

• Respiratory depression
• Hypotension
• Bradycardia
• Seizures
• Serotonin syndrome
• Adrenal insufficiency
• Anaphylaxis
• Arrhythmias

Monitoring Parameters

• Respiratory rate and depth (especially during initiation)
• Blood pressure and heart rate
• Pain intensity and relief
• Bowel function (prevent constipation)
• Mental status changes
• Signs of misuse or addiction
• For chronic use: renal and hepatic function
• In elderly: increased monitoring for falls and cognitive effects

Patient Education

• Take only as prescribed; do not increase dose without consultation
• Avoid alcohol and other CNS depressants
• May cause drowsiness - avoid driving or operating machinery
• Report any difficulty breathing or unusual drowsiness
• Manage constipation with increased fluids, fiber, and possibly stool softeners
• Do not abruptly stop medication after prolonged use
• Store securely away from children and others
• Dispose of unused medication properly
• Inform all providers of codeine use
• Be aware of potential for dependence with long-term use

References

1. FDA Prescribing Information: Codeine Sulfate Tablets (2022) 2. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133-S153. 3. Crews KR, Gaedigk A, Dunnenberger HM, et al. Clinical Pharmacogenetics Implementation Consortium guidelines for cytochrome P450 2D6 genotype and codeine therapy: 2014 update. Clin Pharmacol Ther. 2014;95(4):376-382. 4. Smith HS. Opioid metabolism. Mayo Clin Proc. 2009;84(7):613-624. 5. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 6th ed. American Pain Society; 2008. 6. WHO Expert Committee on Drug Dependence. Thirty-sixth report. World Health Organization; 2015. 7. UpToDate: Codeine Drug Information (2023) 8. Lexicomp Online: Codeine Monograph (2023)