Codeine Interactions With CYP2D6 Inhibitors

Codeine Interactions With CYP2D6 Inhibitors

Tramadol and SSRI

69. T.R. is a 42-year-old man who suffered a right tibial fracture requiring pinning and external fixation. He is now able to ambulate with crutches. Before discharge from the hospital, four acetaminophen 500 mg with hydrocodone 5-mg tablets throughout the day provided good pain control. At the time of discharge, T.R.'s pain regimen was changed to acetaminophen 325 mg with codeine 60 mg, two tablets orally every 3 to 4 hours, owing to his pharmacy benefit limitations. T.R. calls your office because the acetaminophen with codeine is not controlling his pain even when he takes two tablets every 3 hours. T.R. also is taking oral paroxetine 20 mg every morning for his chronic depression. His physician is considering switching his medication to tramadol or acetaminophen with oxycodone. What changes in T.R.'s therapy can be recommended to provide better pain control?

Codeine is metabolized to morphine in the liver by CYP2D6 isoenzymes. Concurrent administration of codeine with agents that inhibit the CYP2D6 system, such as paroxetine, fluoxetine, amiodarone, and ritonavir, may reduce the conversion of codeine to morphine and influence drug response.²²⁹ In addition, this isoenzyme shows genetic polymorphism and individuals may demonstrate ultrarapid, extensive, or poor metabolism. Recognition of these potential drug interactions is important because concurrent administration of CYP2D6 inhibitors may make some patients appear to be poor metabolizers and less responsive to codeine, which, in fact, may not be true.

Oxycodone, hydrocodone, and tramadol are also substrates for the CYP2D6 isoenzyme. Although a potential interaction exists between oxycodone and paroxetine, little evidence at this time indicates that oxycodone requires conversion to an active metabolite via the 2D6 pathway to be an effective analgesic. However, tramadol is partially metabolized by CYP2D6 and has an active metabolite. Concurrent administration with a CYP2D6 inhibitor could potentially reduce analgesic activity.²²⁹

Coadministration of tramadol and paroxetine could potentially cause more serious problems in this patient. Tramadol has SSRI-like activity because it decreases the synaptic reuptake of norepinephrine and serotonin. Coadministration with SSRI agents, such as paroxetine, fluoxetine, fluvoxamine, and citalopram, can put the patient at risk for serotonin syndrome.²³⁰ Signs and symptoms associated with serotonin syndrome include diaphoresis, chest pain, tachycardia, hypertension, confusion, psychosis, agitation, and tremor. Neurotoxicity can be severe and may progress to seizures or coma. Therefore, tramadol is not a good choice for this patient.

Similarly, tramadol can interact with the antimigraine agents known as “triptans,” because their mode of action includes enhancing serotonin activity centrally. Therefore, combinations of tramadol, SSRI, or triptans are relatively contraindicated and require close and judicious monitoring.

It would be reasonable to consider either acetaminophen with oxycodone or hydrocodone for pain control in this patient, especially because he has experienced good pain control with the hydrocodone preparation in the past.

Posted in: General Care,Pain and Its Management