Can a patient allergic to codeine (opioid analgesic) be cross-allergic to morphine (opioid analgesic)?

Cross-Allergy Between Codeine and Morphine

Yes, patients allergic to codeine are likely to be cross-allergic to morphine due to their similar chemical structures, and fentanyl or hydromorphone should be used as alternative opioids in these patients.

Structural and Chemical Basis for Cross-Allergy

Codeine and morphine share a similar phenanthrene alkaloid structure with a critical 6-hydroxy group that is responsible for allergic reactions:

• Both drugs belong to the same chemical class (phenanthrene alkaloids) 1
• The hydroxyl group at the 6 position of the basic phenanthrene structure is the key allergenic determinant 1
• Codeine is metabolized to morphine in the body, with morphine being the active metabolite 2, 3

Evidence for Cross-Reactivity

The cross-reactivity between codeine and morphine is well-documented in clinical guidelines:

• Opioids are an uncommon cause of anaphylaxis, but when allergic reactions occur, they typically affect drugs with similar chemical structures 4
• True allergic reactions to opioids are rare, but naturally occurring compounds like morphine and codeine can cause allergic reactions 5
• The diagnosis of opioid anaphylaxis often rests on a careful history and the exclusion of other possibilities 4

Alternative Opioid Options

For patients with confirmed allergies to codeine or morphine:

• Fentanyl is the recommended first-line alternative for patients with morphine and codeine allergies 6
• Hydromorphone is the recommended second-line alternative 6
• These synthetic opioids have different chemical structures that don't contain the allergenic 6-hydroxy group found in morphine and codeine 7

Clinical Management Algorithm

1. Confirm true allergy vs. intolerance:

   • Distinguish between true allergic reactions (urticaria, rash, bronchoconstriction, laryngeal edema) and common opioid side effects (nausea, vomiting, constipation) 5
   • Non-specific histamine release from morphine and codeine can mimic allergic reactions but is not a true allergy 4

2. If true allergy to codeine is confirmed:

   • Avoid all phenanthrene-based opioids (morphine, codeine, hydrocodone)
   • Use synthetic opioids with different chemical structures:
     • Fentanyl (25-50 mcg IV every 30-60 minutes as needed) 6
     • Hydromorphone (0.2-0.6 mg IV every 2-3 hours as needed) 6

3. Monitor closely for adverse reactions even with alternative opioids:

   • Respiratory depression
   • Sedation
   • Hypotension
   • Nausea and vomiting 6

Important Caveats and Considerations

• Genetic polymorphisms affecting CYP2D6 can alter codeine metabolism to morphine in 7-10% of Caucasians and up to 30% of Asians 6, but this is unrelated to allergic potential
• Challenge testing for suspected opioid allergies should only be performed in specialist centers 4
• When switching between opioids due to allergies, dose reductions of 25-50% are necessary to avoid inadvertent overdose 4

Documentation and Communication

Clearly document the specific nature of the allergic reaction to codeine in the patient's medical record to ensure all healthcare providers are aware of the potential cross-reactivity with morphine.