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Drug Interactions

If Codeine Isn't Working There May Be A Drug Interaction

Medicines with codeine are among the most often prescribed medicines in the United States.1 However, some patients taking codeine may not have pain relief with the usual doses. About 7% of Caucasians are missing the enzyme CYP2D6. These individuals are known as "poor metabolizers". CYP2D6 metabolizes codeine to its active metabolite morphine - the compound that is responsible for pain relief. This means that CYP2D6 poor metabolizers will not have a therapeutic benefit of pain relief from codeine at the usual therapeutic doses.2,3,4 However, at these doses, the patients who are missing CYP2D6 may still have the unpleasant adverse effects of codeine.4 Adverse effects may include sedation, headache, dizziness, blurred vision, nausea, itching, flushing, and dry mouth.

Some medications are potent inhibitors of CYP2D6. Inhibitors of CYP2D6 include amiodarone and quinidine (medicines for cardiac arrhythmias), fluoxetine, paroxetine, and sertraline (SSRIs that may be used to treat depression), haloperidol (antipsychotic), and indinavir (an HIV protease inhibitor). Patients taking such medications may have the same problems with codeine as the "poor metabolizers". They would not obtain pain relief, but they may have the unpleasant side effects.

In general, when patients don't respond as expected to any medication, the possibility of a drug interaction and drug-induced adverse effects should be considered. Every time a new drug is prescribed, the patient and healthcare providers should review the patient's medications and screen for drug interactions. For more information about potential interactions with codeine, please refer to

  1. Latner AW. The Top 200 Drugs of 1999. The More Things Change, the More They Stay the Same. Pharmacy Times. April 2000.
  2. Caraco Y, Sheller J, Wood AJ. Pharmacogenetic determination of the effects of codeine and prediction of drug interactions. J Pharmacol Exp Ther 1996; 278:1165-74.
  3. Poulsen L, Brosen K, Arendt-Nielsen L, Gram LF, Elbaek K, Sindrup SH. Codeine and morphine in extensive and poor metabolizers of sparteine: pharmacokinetics, analgesic effect and side effects. Eur J Clin Pharmacol 1996; 51:289-95.
  4. Eckhardt K, Li S, Ammon S, Schanzle G, Mikus G, Eichelbaum M. Same incidence of adverse drug events after codeine administration irrespective of the genetically determined differences in morphine formation. Pain 1998; 76:27-33.


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The University of Arizona Center for Education and Research on Therapeutics
Arizona Health Sciences Center
Tucson, Arizona  85724-5018

Funded in part by AHCPR grant 1 U18 HS10385-01

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