The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness

Objectives The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication coingestion decreases the effectiveness of hydrocodone. Methods This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patient's pain and nausea were quantified using a 100-mm visual analog scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (ORs) were calculated to compare clinically significant VAS changes between CYP2D6 users and nonusers. Results A total of 250 (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6 drug users were one-third as likely to respond to hydrocodone (OR = 0.33, 95% confidence interval [CI] = 0.1 to 0.8) and more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1). Conclusions CYP2D6 drug–drug interactions appear to change effectiveness of commonly prescribed drugs in the ED. Drug–drug interaction should be considered prior to prescribing CYP2D6 drugs. Resumen Objetivos El citocromo hepatico 2D6 (CYP2D6) es una enzima saturable responsable del metabolismo de aproximadamente un 25% de los medicamentos conocidos. Las interacciones con el CYP pueden alterar la eficacia de medicamentos prescritos. La hidrocodona es muy dependiente del metabolismo del CYP2D6 para la analgesia, el ondansetron es inactivado por el CYP2D6 y la analgesia de la oxicodona es en gran medida independiente del CYP2D6. El objetivo fue determinar si la toma conjunta de farmacos CYP2D6 disminuia la efectividad de la hidrocodona. Metodologia Estudio observacional prospectivo llevado a cabo en un servicio de urgencias (SU) universitario de Estados Unidos. Se incluyo a los sujetos que referian dolor o nauseas y se excluyeron aquellos que no hablaban ingles, menores de 18 anos de edad, que tenian insuficiencia hepatica o renal o estaban diagnosticados de dolor cronico o los que presentaban vomitos periodicos. Se obtuvo una historia detallada de la toma de farmacos en las 48 horas previas a la visita al SU. Se cuantifico el dolor y las nauseas del paciente mediante una escala visual analogica (EVA) de 100 milimetros en el momento inicial previamente a la administracion del farmaco y tras las dosis de hidrocodona, oxicodona y ondansetron. Se utilizo un modelo mixto con efecto de sujeto aleatorio para determinar la interaccion entre la toma de farmacos con interaccion con el CYP2D6 y la efectividad del farmaco. Se calcularon las razones de ventajas (odds ratios, OR) para comparar los cambios de la EVA clinicamente significativos entre los consumidores y no consumidores de farmacos con interaccion con el CYP2D6. Resultados Doscientos cincuenta (49,8%) de los 502 incluidos habian tomado al menos un sustrato, inhibidor o inductor farmacologico del CYP2D6, suplementos o drogas ilicitas en las 48 horas anteriores a la visita al SU. Los consumidores de farmacos con interaccion con el CYP2D6 fueron un tercio mas propensos a responder a la hidrocodona (OR = 0,33, IC 95% = 0,1 a 0,8), y tuvieron mas del triple de probabilidades que los no consumidores para responder al ondansetron (OR = 3,4, IC 95% = 1.3 a 9,1). No hubo diferencias significativas en la efectividad de la oxicodona entre los consumidores y no consumidores de farmacos que interactuan con el CYP2D6 (OR = 0,53, IC 95% = 0,3 a 1,1). Conclusiones Las interacciones farmacologicas con el CYP2D6 parecen cambiar la efectividad de medicamentos comunmente prescritos en el SU. Se deberian considerar las interacciones farmacologicas previamente a la prescripcion de farmacos que interactuan con el CYP2D6.