====== Codeine ======

<WRAP right 340px>
<WRAP infobox>
^ Codeine | {{ :neuro:opioids:codeine_structure.svg?200 |}} |
| Brand Names | — (often combination products) |
| Drug Class | [[neuro:opioids:start|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 |
</WRAP>
</WRAP>

===== 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.

<WRAP clear></WRAP>

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===== Mechanism of Action =====

**Primary Mechanism**
  * Weak μ-opioid receptor agonist  

**Prodrug Conversion**
  * CYP2D6 converts codeine → morphine (active metabolite)  

Analgesic effect depends largely on morphine formation.

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

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===== Indications =====

  * Mild to moderate pain  
  * Cough suppression (antitussive)  

Commonly combined with:
  * Acetaminophen  
  * Aspirin  

Not appropriate for severe pain.

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<WRAP contra>
===== 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  

</WRAP>

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<WRAP details>
===== 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  

</WRAP>

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<WRAP details>
===== Pharmacokinetics =====

Absorption:
  * Oral  

Metabolism:
  * CYP2D6 → morphine (active)  
  * CYP3A4 → norcodeine  

Half-life:
  * ~3 hours  

Elimination:
  * Renal  

Genetic variability strongly affects clinical response.

</WRAP>

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<WRAP details>
===== Adverse Effects =====

Common:
  * Sedation  
  * Constipation  
  * Nausea  
  * Dizziness  

Serious:
  * Respiratory depression  
  * Hypotension  
  * Physical dependence  

Ultra-rapid metabolizers are at higher risk of toxicity.

</WRAP>

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<WRAP details>
===== Drug Interactions =====

CYP2D6 inhibitors (↓ analgesia):
  * Fluoxetine  
  * Paroxetine  
  * Bupropion  

CNS depressants:
  * Benzodiazepines  
  * Alcohol  
  * Other opioids  

</WRAP>

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<WRAP monitoring>
===== Monitoring =====

Clinical:
  * Pain control  
  * Sedation level  
  * Respiratory rate  

Special attention:
  * Lack of efficacy (possible poor metabolizer)  
  * Signs of toxicity (possible ultra-rapid metabolizer)  

</WRAP>

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<WRAP pearls>
===== 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.  

</WRAP>

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===== Toxicity =====

Classic opioid toxidrome:
  * CNS depression  
  * Respiratory depression  
  * Miosis  

Treatment:
  * [[neuro:opioids:naloxone|Naloxone]]

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===== Comparison Within Class =====

Compared to [[neuro:opioids:morphine|Morphine]]:
  * Much weaker  
  * Requires metabolic activation  

Compared to [[neuro:opioids:tramadol|Tramadol]]:
  * Simpler mechanism  
  * Less serotonergic activity  

Compared to [[neuro:opioids:oxycodone|Oxycodone]]:
  * Less potent  
  * Less reliable analgesia  

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===== Related =====

  * [[neuro:opioids:start|Opioids]]
  * [[neuro:opioids:morphine|Morphine]]
  * [[neuro:opioids:tramadol|Tramadol]]
  * [[neuro:opioids:naloxone|Naloxone]]