Chapter 12: Pharmacology of Codeine

1. Introduction/Overview

Codeine, an alkaloid derived from the opium poppy Papaver somniferum, represents one of the most historically significant and widely utilized opioid medications. As a prototypical weak opioid agonist, it occupies a unique position in therapeutic arsenals for pain and cough management. Its clinical relevance stems from a perceived favorable balance between efficacy and safety relative to more potent opioids, though this perception requires careful scrutiny in light of contemporary understanding of its pharmacogenomics and abuse potential. The drug’s importance in medical education extends beyond its direct applications, serving as a fundamental model for understanding opioid receptor pharmacology, prodrug metabolism, and the complexities of analgesic stewardship.

Learning Objectives

• Describe the chemical classification of codeine and its relationship to the broader opioid agonist family.
• Explain the prodrug mechanism of action of codeine, detailing its conversion to morphine and subsequent mu-opioid receptor agonism.
• Analyze the pharmacokinetic profile of codeine, with particular emphasis on the critical role of cytochrome P450 2D6 (CYP2D6) in its biotransformation.
• Evaluate the approved therapeutic indications for codeine, distinguishing between its analgesic and antitussive applications.
• Identify major adverse effects, drug interactions, and special population considerations that inform safe clinical prescribing practices.

2. Classification

Codeine can be classified according to multiple schemas encompassing its chemical structure, pharmacological action, and regulatory status.

Chemical and Pharmacological Classification

Chemically, codeine is classified as a phenanthrene derivative opioid. It is a natural opium alkaloid, specifically 3-methylmorphine. Its core structure consists of a pentacyclic phenanthrene ring system, which is characteristic of morphine and related compounds. The methylation at the 3-position distinguishes it from morphine and significantly alters its pharmacological properties.

Pharmacologically, codeine is primarily classified as a weak opioid receptor agonist. It is a prodrug, with its analgesic effects largely dependent on biotransformation to active metabolites. Within the broader opioid classification system, it is considered a step 2 analgesic on the World Health Organization (WHO) analgesic ladder, positioned between non-opioid analgesics (step 1) and strong opioids like morphine (step 3).

From a regulatory perspective, codeine is classified as a controlled substance in most jurisdictions. In the United States, it is typically listed as a Schedule II, III, or V controlled substance under the Controlled Substances Act, depending on its formulation and concentration. Preparations containing limited quantities of codeine combined with other non-controlled medications, such as certain cough syrups, may be assigned to Schedule V.

3. Mechanism of Action

The mechanism of action of codeine is complex and fundamentally reliant on metabolic activation, a feature that underpins both its therapeutic effects and its variable clinical response.

Receptor Interactions and Pharmacodynamics

Codeine itself possesses weak affinity for opioid receptors. Its primary mechanism of analgesic action is mediated through its O-demethylation to morphine, a conversion catalyzed by the hepatic cytochrome P450 enzyme CYP2D6. Morphine is a potent agonist primarily at the mu-opioid receptor (MOR). The binding of morphine to the MOR activates inhibitory G-proteins (G_i/G_o), leading to a cascade of intracellular events.

The activation of MOR results in the inhibition of adenylate cyclase, reducing intracellular cyclic adenosine monophosphate (cAMP) levels. It also promotes the opening of potassium channels, leading to hyperpolarization of the neuronal membrane, and inhibits voltage-gated calcium channels on presynaptic terminals. The net effect is a reduction in neuronal excitability and a decreased release of pronociceptive neurotransmitters, such as substance P and glutamate, from primary afferent neurons in the dorsal horn of the spinal cord. Supraspinally, opioid receptor activation in areas like the periaqueductal gray and rostral ventromedial medulla activates descending inhibitory pathways that further modulate pain transmission.

The antitussive effect of codeine appears to be less dependent on conversion to morphine and may involve a distinct mechanism. Codeine is believed to suppress the cough reflex by a direct action on the cough center in the medulla oblongata. This effect may involve sigma receptors or other non-mu opioid pathways, though the precise molecular targets remain less clearly defined than those for analgesia.

Prodrug Activation and Pharmacogenomic Implications

The CYP2D6-mediated conversion is the critical determinant of codeine’s efficacy. Genetic polymorphism in the CYP2D6 gene leads to significant population variability in enzyme activity, categorized into four primary phenotypes:

• Poor Metabolizers (PMs): Individuals lacking functional CYP2D6 activity. These patients experience minimal conversion of codeine to morphine, resulting in subtherapeutic or absent analgesia. This phenotype is found in approximately 5-10% of the Caucasian population and varies across ethnic groups.
• Extensive Metabolizers (EMs): Individuals with normal CYP2D6 function, representing the most common phenotype.
• Intermediate Metabolizers (IMs): Individuals with reduced enzyme activity.
• Ultrarapid Metabolizers (UMs): Individuals with multiple functional gene copies leading to exceptionally high CYP2D6 activity. In these patients, rapid and extensive conversion to morphine can lead to unexpectedly high serum morphine levels, posing a risk of opioid toxicity even at standard doses. This phenotype is more common in populations from Northeast Africa, the Middle East, and Oceania.

This pharmacogenetic variation necessitates consideration of therapeutic failure in PMs and life-threatening respiratory depression in UMs, particularly in pediatric patients or following tonsillectomy/adenoidectomy.

4. Pharmacokinetics

The pharmacokinetic profile of codeine is characterized by extensive metabolism, moderate bioavailability, and significant interindividual variability.

Absorption

Codeine is readily absorbed from the gastrointestinal tract following oral administration. Its bioavailability is approximately 50%, which is higher than that of morphine, due to lower first-pass metabolism. Peak plasma concentrations (C_max) are typically achieved within 60 to 120 minutes (t_max) post-ingestion. Absorption is not significantly affected by food, though concomitant intake may slightly delay t_max. Codeine phosphate is also available in injectable formulations, providing complete bioavailability when administered parenterally, though this route is seldom used in contemporary practice.

Distribution

Codeine is widely distributed throughout body tissues. It crosses the blood-brain barrier, though less efficiently than morphine. The volume of distribution (V_d) is approximately 3 to 6 L/kg, indicating extensive tissue binding. Plasma protein binding is relatively low, ranging from 7% to 25%, primarily to albumin. Codeine readily crosses the placental barrier and is excreted into breast milk, which has significant implications for use during pregnancy and lactation.

Metabolism

Hepatic metabolism is the principal route of codeine elimination and is the source of its pharmacological activity. Metabolism proceeds via three main pathways:

1. O-Demethylation (CYP2D6): This is the major pathway for analgesic activation, producing morphine (approximately 5-15% of the dose). Morphine is subsequently glucuronidated to morphine-3-glucuronide (M3G, inactive) and morphine-6-glucuronide (M6G, active).
2. N-Demethylation (CYP3A4): This pathway forms norcodeine, which possesses minimal analgesic activity.
3. Glucuronidation (UGT2B7): Direct conjugation of codeine to codeine-6-glucuronide, which may possess weak analgesic properties.

The relative activity of CYP2D6 versus CYP3A4 and UGT enzymes dictates the balance between activation to morphine and alternative metabolic routes. Drugs that inhibit or induce these cytochrome P450 enzymes can profoundly alter codeine’s effects.

Excretion

Renal excretion is the primary route of elimination for codeine and its metabolites. Approximately 70-90% of a dose is excreted in urine within 24 hours, with only 5-15% as unchanged codeine. The remainder is excreted as conjugates of codeine, morphine, and norcodeine. A small fraction undergoes biliary excretion and is eliminated in feces. The elimination half-life (t_1/2) of codeine is approximately 2.5 to 4 hours in adults with normal hepatic and renal function. The half-life of its active metabolite, morphine, is longer (2 to 4 hours), but the duration of analgesic effect is typically 4 to 6 hours, aligning with dosing intervals for immediate-release formulations.

5. Therapeutic Uses/Clinical Applications

The therapeutic applications of codeine are primarily confined to two domains: analgesia and cough suppression. Its use has become more restricted in recent years due to safety concerns, particularly in specific patient populations.

Approved Indications

Analgesia: Codeine is indicated for the management of mild to moderate pain where treatment with a non-opioid analgesic alone is insufficient. It is almost always administered in combination with non-opioid analgesics such as acetaminophen or acetylsalicylic acid (e.g., co-codamol, co-codaprin). These combinations provide additive or synergistic analgesia, potentially allowing for lower doses of each component. Its role is typically as a step 2 agent on the WHO analgesic ladder.

Antitussive: Codeine is used as a cough suppressant for non-productive, distressing cough. It acts centrally to raise the threshold for cough reflex activation. Its use for this indication has declined significantly, especially in pediatric patients, due to risks of respiratory depression and the availability of alternative non-opioid agents.

Off-Label Uses

Historically, codeine was used for antidiarrheal effects due to opioid-induced reduction in gastrointestinal motility. However, this application is now obsolete with the availability of safer, non-absorbed agents like loperamide. Its use in managing dyspnea or in palliative care settings is extremely limited and not evidence-based, with stronger opioids like morphine being preferred for symptomatic relief of breathlessness.

6. Adverse Effects

The adverse effect profile of codeine is consistent with that of other opioid agonists, though the incidence and severity may differ due to its lower potency. Adverse effects are primarily mediated through activation of mu-opioid receptors in the central nervous system and gastrointestinal tract.

Common Side Effects

Frequently observed side effects, which are often dose-dependent and may diminish with continued use, include:

• Central Nervous System: Drowsiness, sedation, dizziness, lightheadedness, and cognitive clouding.
• Gastrointestinal: Nausea and vomiting (stimulation of the chemoreceptor trigger zone), constipation (reduced gut motility and increased sphincter tone), and dry mouth.
• Other: Sweating, flushing, and pruritus (itching), particularly of the face and trunk, which is histamine-mediated.

Serious/Rare Adverse Reactions

More severe adverse effects necessitate immediate medical attention and often require discontinuation of therapy.

• Respiratory Depression: This is the most serious acute toxicity associated with opioids. Codeine can cause dose-dependent depression of the brainstem respiratory centers, reducing responsiveness to carbon dioxide. The risk is markedly elevated in CYP2D6 ultrarapid metabolizers, in patients with underlying respiratory conditions (e.g., COPD, sleep apnea), and when combined with other central nervous system depressants.
• Hypotension and Bradycardia: Opioids can induce vasodilation and reduce sympathetic tone, potentially leading to orthostatic hypotension and syncope.
• Dependence and Addiction: Chronic use of codeine can lead to physical dependence, characterized by tolerance and withdrawal symptoms upon cessation. Psychological addiction and misuse are significant public health concerns.
• Serotonin Syndrome: Although a weak agent in this regard, codeine has very limited serotonergic activity. The risk is primarily theoretical but could be potentiated by concomitant use with other serotonergic drugs.
• Adrenal Insufficiency and Androgen Deficiency: Chronic opioid use, including codeine, may suppress the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes.

Black Box Warnings and Safety Communications

Regulatory agencies have issued stringent warnings regarding codeine use:

• Post-Tonsillectomy/Adenoidectomy Analgesia in Children: A black box warning contraindicates the use of codeine for pain management in children following these procedures due to reports of fatal respiratory depression, primarily in CYP2D6 ultrarapid metabolizers.
• Use in Pediatric Cough and Cold: Codeine is contraindicated for cough and cold in all children under 18 years of age due to the risk of serious breathing problems.
• Maternal Use During Breastfeeding: Strong warnings advise against maternal use while breastfeeding, as codeine and morphine can be concentrated in breast milk and cause fatal respiratory depression in nursing infants, particularly if the mother is a CYP2D6 ultrarapid metabolizer.

7. Drug Interactions

Codeine participates in numerous pharmacokinetic and pharmacodynamic drug interactions that can alter its efficacy or increase toxicity.

Major Pharmacokinetic Interactions

• CYP2D6 Inhibitors: Drugs such as fluoxetine, paroxetine, bupropion, quinidine, and cinacalcet can inhibit the conversion of codeine to morphine, potentially rendering it ineffective for analgesia. This interaction effectively converts an extensive metabolizer into a phenotypic poor metabolizer.
• CYP2D6 Inducers: Agents like rifampin may theoretically increase conversion, but this interaction is less clinically documented.
• CYP3A4 Inhibitors: Drugs like ketoconazole, itraconazole, clarithromycin, and ritonavir may inhibit the N-demethylation pathway, potentially shunting more metabolism toward the CYP2D6 pathway and increasing morphine formation. Conversely, CYP3A4 inducers (e.g., carbamazepine, phenytoin, St. John’s wort) may enhance norcodeine formation and reduce morphine production.

Major Pharmacodynamic Interactions

• Other Central Nervous System Depressants: Concomitant use with alcohol, benzodiazepines, barbiturates, sedative-hypnotics, other opioids, or certain antidepressants (e.g., tricyclics) produces additive sedation, respiratory depression, and cognitive impairment. This combination significantly increases the risk of overdose and death.
• Muscle Relaxants: May enhance neuromuscular blockade and respiratory depression.
• Anticholinergic Drugs: May compound the constipating and urinary retentive effects of codeine.
• Monoamine Oxidase Inhibitors (MAOIs): Concurrent use is contraindicated due to the potential for severe and unpredictable reactions, including excitation, hyperpyrexia, and cardiovascular instability.
• Mixed Agonist-Antagonist Opioids: Drugs like pentazocine or buprenorphine may precipitate withdrawal in opioid-dependent patients and reduce the analgesic efficacy of codeine.

Contraindications

Absolute contraindications to codeine use include:

• Significant respiratory depression or acute asthma exacerbation.
• Known or suspected paralytic ileus.
• Hypersensitivity to codeine or other opioid agonists.
• Concurrent use of monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping such treatment.
• For analgesia following tonsillectomy/adenoidectomy in children.
• For cough and cold in children under 18 years of age.
• In mothers who are breastfeeding.

8. Special Considerations

Prescribing codeine requires careful evaluation of patient-specific factors that can dramatically alter the risk-benefit ratio.

Pregnancy and Lactation

Pregnancy (Category C): Codeine crosses the placenta. Chronic use during pregnancy can lead to neonatal opioid withdrawal syndrome (NOWS) upon delivery, characterized by irritability, hypertonia, tremors, feeding difficulties, and respiratory distress. Use during labor may cause respiratory depression in the newborn. It should be used during pregnancy only if the potential benefit justifies the potential fetal risk, typically reserved for short-term management of severe pain unresponsive to non-opioid alternatives.

Lactation: Codeine and its active metabolite morphine are excreted in human milk. Maternal use while breastfeeding is strongly discouraged and contraindicated by many regulatory agencies. In mothers who are CYP2D6 ultrarapid metabolizers, standard doses can lead to high levels of morphine in milk, which has been associated with life-threatening respiratory depression in nursing infants. If use is absolutely necessary, the infant must be monitored closely for signs of sedation and respiratory depression.

Pediatric and Geriatric Considerations

Pediatric Patients: As noted, the use of codeine in children is now highly restricted. Children are more susceptible to the respiratory depressant effects of opioids. The variability in CYP2D6 activity makes dosing unpredictable and dangerous. It is contraindicated for cough/cold under age 18 and for post-tonsillectomy pain. For other types of moderate pain in older children and adolescents, it should be used with extreme caution, at the lowest effective dose, and with close monitoring, only when alternatives are not appropriate.

Geriatric Patients: Older adults often have reduced hepatic and renal function, altered body composition, and increased sensitivity to central nervous system depressants. These factors can lead to increased peak concentrations, prolonged elimination half-life, and exaggerated pharmacodynamic responses (sedation, respiratory depression, constipation). Dosing should initiate at the low end of the therapeutic range, with careful titration and frequent reassessment. Age-related conditions like benign prostatic hyperplasia can be exacerbated by codeine’s anticholinergic effects, increasing the risk of urinary retention.

Renal and Hepatic Impairment

Renal Impairment: The clearance of codeine and its active metabolites, particularly morphine-6-glucuronide (M6G) which is renally excreted, is reduced in renal failure. This can lead to accumulation and increased risk of toxicity, including profound sedation and respiratory depression. Codeine should be used with great caution in patients with moderate to severe renal impairment (creatinine clearance < 30 mL/min), often requiring dose reduction, extended dosing intervals, or avoidance altogether.

Hepatic Impairment: Since codeine undergoes extensive hepatic metabolism, liver disease can impair its clearance and alter the metabolic pathway ratios. In cirrhosis, presystemic metabolism may be reduced, increasing bioavailability. The capacity for glucuronidation may be preserved longer than oxidative metabolism, potentially altering the metabolite profile. Codeine should be administered cautiously in patients with hepatic impairment, starting with low doses and careful monitoring for signs of opioid excess.

9. Summary/Key Points

Codeine pharmacology is defined by its status as a prodrug and the consequent critical influence of pharmacogenetics on its clinical effects.

Summary

• Codeine is a weak opioid agonist and a natural phenanthrene alkaloid used for mild-to-moderate pain and non-productive cough.
• Its analgesic efficacy is predominantly dependent on CYP2D6-mediated O-demethylation to morphine, a potent mu-opioid receptor agonist. Its antitussive action is more direct and less reliant on this conversion.
• Pharmacokinetics involve good oral absorption, extensive hepatic metabolism via CYP2D6, CYP3A4, and UGT pathways, and renal excretion of metabolites. The half-life is approximately 3-4 hours.
• Therapeutic use is now heavily circumscribed, especially in children, due to risks of fatal respiratory depression linked to CYP2D6 ultrarapid metabolizer status.
• The adverse effect profile mirrors that of opioids, with constipation, nausea, sedation, and the serious risk of respiratory depression being most prominent.
• Numerous drug interactions exist, primarily with CYP2D6 inhibitors/inducers and other central nervous system depressants.
• Special population considerations mandate extreme caution or outright avoidance in pediatric patients, breastfeeding mothers, the elderly, and those with renal or hepatic impairment.

Clinical Pearls

• Therapeutic failure of codeine for pain may indicate a CYP2D6 poor metabolizer phenotype; alternative analgesia should be sought rather than dose escalation.
• Unexplained sedation or respiratory depression at standard doses, especially in a child or breastfeeding infant, should prompt consideration of a CYP2D6 ultrarapid metabolizer status in the patient or the mother.
• Codeine is not a first-line agent for any condition in modern therapy. Its use should be reserved for situations where benefits clearly outweigh risks and safer alternatives are unavailable or ineffective.
• When prescribed, the duration should be limited to the shortest period necessary, and patients should be counseled on risks, including dependence and dangerous interactions with alcohol and other sedatives.
• Combination products containing acetaminophen impose an additional ceiling dose due to the risk of hepatotoxicity from the non-opioid component.

References

1. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.
2. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
3. Golan DE, Armstrong EJ, Armstrong AW. Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. 4th ed. Philadelphia: Wolters Kluwer; 2017.
4. Trevor AJ, Katzung BG, Kruidering-Hall M. Katzung & Trevor's Pharmacology: Examination & Board Review. 13th ed. New York: McGraw-Hill Education; 2022.
5. Katzung BG, Vanderah TW. Basic & Clinical Pharmacology. 15th ed. New York: McGraw-Hill Education; 2021.
6. Brunton LL, Hilal-Dandan R, Knollmann BC. Goodman & Gilman's The Pharmacological Basis of Therapeutics. 14th ed. New York: McGraw-Hill Education; 2023.
7. Whalen K, Finkel R, Panavelil TA. Lippincott Illustrated Reviews: Pharmacology. 7th ed. Philadelphia: Wolters Kluwer; 2019.
8. Rang HP, Ritter JM, Flower RJ, Henderson G. Rang & Dale's Pharmacology. 9th ed. Edinburgh: Elsevier; 2020.