The Effect of CYP2D6 Drug-Drug Interactions on Hydrocodone Effectiveness

Abstract

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. 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. 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). 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. El citocromo hepático 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 ondansetrón 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 fármacos CYP2D6 disminuía la efectividad de la hidrocodona. Estudio observacional prospectivo llevado a cabo en un servicio de urgencias (SU) universitario de Estados Unidos. Se incluyó a los sujetos que referían dolor o náuseas y se excluyeron aquéllos que no hablaban inglés, menores de 18 años de edad, que tenían insuficiencia hepática o renal o estaban diagnosticados de dolor crónico o los que presentaban vómitos periódicos. Se obtuvo una historia detallada de la toma de fármacos en las 48 horas previas a la visita al SU. Se cuantificó el dolor y las náuseas del paciente mediante una escala visual analógica (EVA) de 100 milímetros en el momento inicial previamente a la administración del fármaco y tras las dosis de hidrocodona, oxicodona y ondansetrón. Se utilizó un modelo mixto con efecto de sujeto aleatorio para determinar la interacción entre la toma de fármacos con interacción con el CYP2D6 y la efectividad del fármaco. Se calcularon las razones de ventajas (odds ratios, OR) para comparar los cambios de la EVA clínicamente significativos entre los consumidores y no consumidores de fármacos con interacción con el CYP2D6. Doscientos cincuenta (49,8%) de los 502 incluidos habían tomado al menos un sustrato, inhibidor o inductor farmacológico del CYP2D6, suplementos o drogas ilícitas en las 48 horas anteriores a la visita al SU. Los consumidores de fármacos con interacción con el CYP2D6 fueron un tercio más propensos a responder a la hidrocodona (OR = 0,33, IC 95% = 0,1 a 0,8), y tuvieron más del triple de probabilidades que los no consumidores para responder al ondansetrón (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 fármacos que interactúan con el CYP2D6 (OR = 0,53, IC 95% = 0,3 a 1,1). Las interacciones farmacológicas con el CYP2D6 parecen cambiar la efectividad de medicamentos comúnmente prescritos en el SU. Se deberían considerar las interacciones farmacológicas previamente a la prescripción de fármacos que interactúan con el CYP2D6. The efficacy of many commonly used medications may be altered by variation in metabolism. For example, the analgesic effect of hydrocodone, the most prescribed medication in the United States,1 is largely dependent on metabolic activation for analgesic efficacy.2-4 Hydrocodone is metabolized by the hepatic cytochrome 2D6 (CYP2D6) to hydromorphone. As hydromorphone is approximately five times as potent as hydrocodone, the efficacy of hydrocodone is much higher in patients who have high activity in this metabolic pathway. Conversely, ondansetron is inactivated by CYP2D6, so decreased metabolism by this pathway should increase ondansetron's antiemetic effects. CYP2D6 metabolizes approximately 25% of known pharmaceuticals.5 Pharmacokinetic differences have been demonstrated between CYP2D6 genotype subgroups for a range of medications,6, 7 including hydrocodone.2 While genetic variation accounts for some differences in drug effect, genotype identification does not consistently predict the efficacy or safety of pharmaceuticals.8, 9 This is likely due to the complexity of the human–drug interface; factors upstream and downstream from the encoded enzyme contribute to the ultimately observed clinical effect. For example, CYP2D6 inhibition by drug–drug interaction alters the pharmacokinetics of medication metabolism.10-12 However, the effect of drug–drug interactions on the effectiveness of medications administered in the emergency department (ED) has not previously been investigated. The objective of this study was to examine the effect of CYP2D6 drug–drug interactions on CYP2D6-dependent medication effectiveness. Our unifying hypothesis is that the effectiveness of the study drug (hydrocodone, oxycodone, or ondansetron) will be dependent on CYP2D6-dependent drug use within 48 hours of ED presentation. Furthermore, the effectiveness of hydrocodone will be decreased in patients taking other CY2D6-dependent drugs, the effectiveness of ondansetron will be increased in patients taking CY2D6-dependent drugs, and the effectiveness of oxycodone (which is not primarily metabolized by CYP2D612, 13) will not differ between 2D6 users and nonusers. We also explored the association of effectiveness with genotype in a limited number of subjects. This was a prospective observational study. Our local institutional review board approved this study and all subjects provided informed consent. The study was conducted in an academic U.S. ED with approximately 72,000 patient visits per year. A convenience sample of ED patients was enrolled between June 4, 2012, and January 25, 2013. Enrollment was performed between the hours of 9 a.m. and 5 p.m., as this has been demonstrated to be the most representative demographic sampling times with the least amount of sampling bias in our ED.14 Subjects were included if they had self-reported pain or nausea identified during their initial nursing assessments. All pain and nausea complaints were eligible for inclusion; for example, ankle sprain, undifferentiated abdominal pain, gastroenteritis, and chemotherapy-related nausea complaints were included. Patients were excluded if they were unable to speak English, were younger than 18 years old, had liver or renal failure, or were previously diagnosed with chronic pain (including those who took opioid medications daily) or cyclic vomiting. In patients with dementia or critical illness who were able to comprehend the study and visual analog scale (VAS) methods (see below), the drug ingestion history was reconciled with the health care proxy. Patients were approached after triage, after initial stabilization, or after initial nursing assessment following ambulance arrival. Detailed medication histories for the preceding 48 hours prior to ED visit were obtained. All prescription, nonprescription, vitamin, herbal supplement, and illicit drugs were captured along with their doses and time since the patient's last dose. Treatment decisions and medication orders were made by the patient's ED provider in the main ED or by symptom-based triage protocols. Patients receiving 5 mg of oxycodone (with or without 325 mg of acetaminophen), 5 mg of hydrocodone/500 mg of acetaminophen, or 4 mg of ondansetron were followed to evaluate medication effectiveness throughout their ED courses. These medications are the three most commonly administered medications in our ED. CYP2D6 activates hydrocodone to hydromorphone,2 inactivates ondansetron,15 and plays a minimal role in the analgesic efficacy of oxycodone12, 16, 17 (Figure 1). A 100-mm VAS was used as the assessment tool for both pain and nausea symptoms. This scale has been validated as a reliable tool for a semiquantitative assessment of acute pain and nausea in a wide variety of ED patients.18-24 Patients' pain and nausea were quantified by VAS at baseline prior to medication administration. Repeat VAS scores were obtained between 30 and 90 minutes following hydrocodone, oxycodone, and/or ondansetron administration in the ED. VAS scores were obtained after doses of 5 mg of oxycodone, 5 mg of hydrocodone, or 4 mg of ondansetron. Only single doses of study drugs were followed. Patients who received more than one study medication throughout their ED stays had serial VAS scores recorded for each medication. A second VAS measurement was not taken if another medication for the same indication was given in the intervening time (example: if morphine was given for pain, or if oxycodone was given after hydrocodone before a repeat VAS could be obtained, these scores were excluded from analysis). Therefore, the analysis included only serial VAS values for each study drug when no additional drugs for the same indication were given between VAS measurements. However, ondansetron could be given to patients for nausea after they received hydrocodone or oxycodone and serial VAS for both nausea and pain could be followed. If hydrocodone was given followed by oxycodone later in the ED stay, VAS scores could only be included for the first drug if two scores had been obtained prior to oxycodone administration. If the study drug was repeated during the ED stay, only the first administration was followed for VAS analysis; repeat doses were not analyzed. Intravenous, oral, and sublingual 4 mg of ondansetron administrations were captured since all routes have near equivalent bioavailability.25, 26 All patient-reported medications were categorized as CYP2D6 substrate, inhibitor, inducer, or not CYP2D6-dependent using the University of Indiana CYP450 Interaction Table.27 Substrates and inhibitors were considered CYP2D6 enzyme-dependent drugs for the effectiveness analysis. We initially planned on using a scoring system to account for variable effect of substrates, inhibitors, and inducers, although the infrequency of inducers made this distinction irrelevant. The presence of CYP2D6 interaction was considered dichotomous: it was present if the subject had taken an inhibitor or a substrate of the enzyme. Fifty-three patients were randomized for CYP2D6 genotyping by a random number generator after study drug was ordered by the ED provider. Genotyping was provided by LabCorp using the CYP2D6/2C19 Amplichip.28 Genotyping with the Amplichip accounts for 26 distinct CYP2D6 polymorphisms and allele duplication categorizing the individual's genotype into one of four predicted metabolizer groups: poor metabolizer, intermediate metabolizer, extensive metabolizer, or ultrarapid metabolizer. The intermediate and extensive groups were combined for clinical effectiveness analysis. All cases were reviewed for adverse drug events; all symptoms charted by ED providers were abstracted by an ED pharmacist (DH). Naranjo scores29 were calculated for all possible adverse drug events that occurred after the study drugs were administered. Any symptoms with Naranjo scores of 5 or greater were considered probable adverse drug events. Ten percent of the cases were reviewed by a second investigator (AAM), and the kappa statistic was calculated. The primary outcome was clinically significant VAS change between CYP2D6 users and nonusers. The secondary outcomes were the overall prevalence of CYP2D6 drug interactions and ΔVAS after study drug administration between CYP2D6 users and nonusers in the study population. Descriptive statistics were used to characterize demographic data, the prevalence of CYP2D6 drugs taken, and CYP2D6 drug–drug interactions in the study population. Wilcoxon rank sum was used to compare differences in clinically significant VAS change between CYP2D6 users and nonusers. A clinically significant VAS change was considered to be 13 mm for odds ratio analysis.19 Our a-priori power calculation showed that 33 patients in each group would detect a 13 mm VAS score difference between the groups at a power of 0.8 and a significance of 0.05 using a Wilcoxon rank sum test. We used a mixed model with random subject effect to determine if the interaction between CYP2D6-dependent drug ingestion within 48 hours of ED presentation and study drug group was significant. Data analysis was performed using JMP 10. A total of 502 of 655 (76.6%) approached patients consented to enrollment. The overall demographics of the sample were representative of the ED population during the sampling period (Table 1). A total of 146 (29.1%) had nausea and/or vomiting, and 468 (93.2%) had pain. A total of 286 (56.9%) of the patients were enrolled through triage; the remainder were enrolled in the ED after initial stabilization or after ambulance arrival (Figure 2). The median number of all medications, herbals, vitamins, or supplements taken by patients in the 48 hours prior to ED presentation was three (range = 0 to 33, interquartile range [IQR] = 1 to 6). 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 (Figure 3). Of these, 239 (47.6%) had taken substrates, 30 (6.0%) had taken inhibitors, and one (0.2%) had taken an inducer. Sixty-three subjects reported use of illicit drugs, only three reported cocaine use (a CYP2D6 substrate). There was no difference in illicit drug use between groups. Oxycodone was administered to a total of 142 patients, hydrocodone to 91 patients, and ondansetron to 117 patients. Twenty-nine received both oxycodone and ondansetron, while 12 received both hydrocodone and ondansetron. Four patients received both hydrocodone and oxycodone. Two patients received all three medications while in the ED. A total of 125 of the oxycodone patients, 83 of the hydrocodone patients, and 93 of the ondansetron patients had serial VAS scores obtained. The remainder of the patients were either administered an additional medication for the same indication or were discharged prior to the second VAS being obtained. There was no difference in timing of the first and second VAS scores between the study drugs (oxycodone, mean = 55.5 minutes, 95% confidence interval [CI] = 52.9 to 58.1 minutes; hydrocodone, mean = 57.1 minutes, 95% CI = 53.7 to 60.4 minutes; and ondansetron, mean = 57.4 minutes, 95% CI = 54.3 to 60.4 minutes). Overall, oxycodone and hydrocodone had similar effectiveness (mean ΔVAS = 24.1, 95% CI = 19.9 to 28.2 vs. ΔVAS = 21.5, 95% CI = 16.8 to 26.1, respectively; p = 0.417). There were clinically significant VAS changes in 74 (59.2%) of the oxycodone group, 49 (59.0%) of the hydrocodone group, and 68 (73.1%) of the ondansetron group. There was no difference in effectiveness between those randomized in triage versus those enrolled in the main ED for either oxycodone or hydrocodone (p = 0.431 and p = 0.368, respectively). The proportion of subjects having clinically significant responses to ondansetron and hydrocodone differed between subjects taking CYPD26 medications and those not taking CYP2D6 medications. Patients taking CYP2D6 medications were more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1) and only one-third as likely to respond to hydrocodone (OR = 0.33, 95% CI = 0.1 to 0.8). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1). The interaction between CYP2D6 drug ingestion within 48 hours of ED presentation was significant (p = 0.0009), indicating that the effect of the CYP2D6-dependent drug ingestion on VAS scores differed by study drug. There was a significant reduction in hydrocodone effectiveness, by VAS change, when patients had coingestion of one or more CYP2D6-dependent medications in the 48 hours prior to ED presentation. Conversely, the effectiveness of ondansetron was increased when patients had coingested one or more CYP2D6-dependent medications. There was no change in oxycodone effectiveness when controlled for CYP2D6 medication coingestion (Table 2). There were no adverse drug events scored as “probable” by the Naranjo scale following oxycodone, hydrocodone, or ondansetron administration. Interrater reliability was 1.0 when 10% of the cases were reviewed. Fifty three subjects were genotyped for CYP2D6 metabolizer status. Of the 53, a total of 41 (77.3%) were extensive metabolizers, eight (15.1%) were intermediate metabolizers, three (5.7%) were poor metabolizers, and one (1.9%) was an ultrarapid metabolizer, on of these subjects received oxycodone, hydrocodone, or ondansetron while in the ED. Overall, genotype was not of study medication effectiveness, although the of poor and ultrarapid limited this analysis. controlled for CYP2D6 was a significant association with increased ondansetron effectiveness by VAS change in the intermediate and extensive metabolizer group (p = The VAS change in the one ultrarapid patient receiving hydrocodone was only 12 This patient had taken considered a CYP2D6 inhibitor, 4 hours prior to ED presentation. In our ED the effectiveness of two commonly prescribed drugs metabolized by CYP2D6 was with the reported use of other drugs metabolized by this enzyme. The effectiveness of hydrocodone, a drug made more potent by CYP2D6 was decreased and the effectiveness of ondansetron, a drug that is inactivated by CYP2D6 was increased in the of other CYP2D6 and The most for these is that substrate for CYP2D6 in decreased metabolism of the study that this drug–drug interaction alters medication effectiveness. CYP2D6 drug–drug interactions are of our study population to the ED taking one or more or inhibitors of this enzyme. CYP2D6 plays role in the metabolic of oxycodone in While oxycodone analgesia is not considered a of oxycodone is metabolized by CYP2D6 to a more potent not a difference in oxycodone effectiveness between CYP2D6 users and given the by of metabolic in the of enzyme and and due to drug interaction in ultrarapid this an of study. Drug–drug interaction is more likely to when efficacy or safety are dependent on a single metabolic pathway with limited metabolic as CYP2D6. metabolism is dependent on a can much an Substrates may not in similar enzyme inhibition when as are will it to the metabolic of all medications they Therefore, this is for a that the provider the clinical of drug interaction on medications they to Overall, the effectiveness of oxycodone and hydrocodone was similar with approximately having clinically significant in pain. This is with prior that have identified equivalent Our study to this by that the proportion of patients clinically significant due to hydrocodone is altered by the presence of drug–drug While have that medications prescribed in the ED with the our study that these interactions in clinically significant changes in medication effectiveness. of these is that oxycodone should be hydrocodone due to more clinical of drug–drug be that a higher ΔVAS was observed in CYP nonusers given hydrocodone, that hydrocodone may be in these patients. of a patient's medication and prospective identification of these interactions may in ED medication and patient to medications. As were only able to genotype approximately 10% of our the of on the effectiveness of medications administered in the ED. However, this the of ED patients in a study. is that the one ultrarapid metabolizer, who would be to have increased analgesia from hydrocodone, not have a clinically significant and that this occurred in the of a CYP2D6 We to following this in These are limited by the of self-reported medication ingestion histories and self-reported effectiveness for opioid pain medications. While the VAS has been validated in similar patients in the all patients pain in and a clinically significant in pain may between patients. and both validated 13 mm of change to be clinically significant when with pain As patients more medications, they are more likely to have more These patients may be more likely to be taking opioid medications the effectiveness of additional due to hours from the time of ED presentation may have been of a for some drugs with This may in increased CYP2D6 enzyme effectiveness of hydrocodone. This time period was to five of a number of CYP2D6 drugs. this overall bias decreased effectiveness, only observed a in hydrocodone effectiveness. of patients may the of the CYP2D6 genotype are known to have a higher prevalence of ultrarapid or poor metabolizer However, more than of our ED population speak and the CYP2D6 genotype the prevalence observed in other Therefore, that this the genotype in our study group is representative of our overall ED is possible that prior adverse drug to hydrocodone are with an ultrarapid metabolizer could bias the a more significant effect of CYP2D6 medication However, that only approximately of the population are ultrarapid metabolizers, and no one has demonstrated that CYP2D6 genotype is with adverse drug to hydrocodone. Genotyping of only 10% of the has limited the of the study medication effectiveness by genotype of CYP2D6-dependent drugs were less likely to clinically significant in pain after receiving hydrocodone. Conversely, ondansetron was more likely to in clinically significant of nausea in CYP2D6 There was no change in oxycodone effectiveness in CYP2D6 users and nonusers. CYP2D6 drug–drug interactions change effectiveness of commonly prescribed drugs in the ED. Drug–drug interaction should be considered prior to prescribing CYP2D6-dependent drugs.