RESUMEN
PURPOSE: The purpose is to characterize the CYP2D6 genotype and predict the phenotype of decedents of opioid overdose to determine if the ultrarapid (UM) phenotype is over-represented in opioid overdose deaths. CYP2D6 is the enzyme responsible for metabolism of various opioids implicated in overdose. The UM group may be at greater risk for overdose due to the rapid metabolism of hydrocodone, oxycodone, or tramadol to more active/potent metabolites than their peers with (poor) PM, (intermediate) IM, or (extensive) EM metabolic phenotypes. PATIENTS AND METHODS: Blood samples obtained during autopsy following an opioid overdose from 75 US military veteran decedents prescribed hydrocodone, oxycodone, or tramadol from one VA medical center were analyzed. DNA extraction, CYP2D6 genotyping, and copy number variation (CNV) testing were performed using the iPLEX® genotyping assay and MassARRAY. Phenotype prediction was based on Clinical Pharmacogenetics Implementation Consortium (CPIC) recommendations. Toxicology results were obtained from Medical Examiner reports of the deceased. Prescription medication information was extracted from archived medical records. RESULTS: The majority of the sample had a phenotype of EM metabolizer (75%), with 7% of the total sample having a UM metabolizer phenotype. In addition to hydrocodone, oxycodone, and tramadol (found in 41% of opioid positive samples), other opioids found in toxicology tests included diacetylmorphine, fentanyl, buprenorphine, and methadone. Two or more substances, including alcohol, benzodiazepines, and other potentially sedating medications, were found in nearly half of the opioid positive toxicology samples. CONCLUSION: In this study, 7% of veteran decedents of opioid overdose had CYP2D6 UM metabolic phenotype. The small sample size precludes a conclusion that the frequency of UM phenotype is greater than expected in North American Caucasian groups. The findings in this study do not support the hypothesis that the UM phenotype is over-represented in opioid overdose.
RESUMEN
BACKGROUND: Benzodiazepines are used to treat alcohol withdrawal (AW) but cause cognitive impairment, sedation, and ataxia, and interact with alcohol. Nonbenzodiazepine anticonvulsants are promising and possibly safer alternatives for the treatment of AW. OBJECTIVE: To compare follow-up measures of Epworth Sleepiness Scale (ESS), Penn Alcohol Craving Scale (PACS), ataxia rating, and Clinical Institute Withdrawal Assessment for Alcohol revised (CIWA-Ar) symptoms between alcohol-dependent individuals randomized to treatment with gabapentin or chlordiazepoxide. METHODS: A randomized, double-blind study was conducted in US veterans with alcohol withdrawal (DSM-IV criteria). Subjects requiring hospitalization or taking benzodiazepines or nonbenzodiazepine anticonvulsants were excluded. Twenty-six participants were randomized: 17 received gabapentin and 9 received chlordiazepoxide. Gabapentin doses were 1200 mg orally for 3 days, followed by 900 mg, 600 mg, and 300 mg for 1 day each. Chlordiazepoxide doses were 100 mg orally for 3 days, followed by 75 mg, 50 mg, and 25 mg for 1 day each. CIWA-Ar, ESS, PACS scales and evaluation for ataxia were administered daily. RESULTS: Follow-up mean ESS and PACS scores did not differ significantly between treatment groups in the early treatment period (days 1-4) but were lower (mean difference -3.70; 95% CI -7.21 to -0.19; p = 0.04) and (mean difference -6.05; 95% CI -12.82 to 0.72; p = 0.08), respectively, at the end of the treatment period (days 5-7) in gabapentin-treated subjects. CIWA-Ar scores were reduced similarly in both groups. Ataxia was not observed. No significant adverse events were noted. Limitations include our small sample size and 35% loss to follow-up at the end of the treatment period. CONCLUSIONS: In ambulatory veterans with symptoms of alcohol withdrawal, gabapentin treatment resulted in significantly greater reduction in sedation (ESS) and a trend to reduced alcohol craving (PACS) by the end of treatment compared to chlordiazepoxide treatment. Although limited by the small sample size, the suggestion of reduction in sleepiness and less craving warrants replication of the study with a larger sample.
