Presented at the 2012 AAPM Annual Meeting « Back

Effects of Concomitant Methadone and Diazepam on Urine Specimens of Patients with Chronic Pain

Samantha O. Luk, BS, sluk@ucsd.edu¹, Stephanie A. Tse, BS2, Rabia S. Atayee, PharmD BCPS², Joseph D. Ma, PharmD³, Brookie M. Best, PharmD MAS⁴, Amadeo J. Pesce, PhD DABCC⁵, (1) UCSD Skaggs School of Pharmacy and Pharmacetical Sciences, San Diego, California, (2) UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences, La Jolla, California, (3) Pharmacy, La Jolla, California, (4) UC San Diego, La Jolla, California, (5) Millennium Research Institute, San Diego, California

Background: Methadone and diazepam share metabolic pathways, specifically cytochrome P450 3A4 and 2C19, to produce the inactive methadone metabolite 2-ethylidene-1, 5- dimethyl-3, 3-diphenylpyrrolidine (EDDP) and active diazepam metabolites nordiazepam, temazepam, and oxazepam. As a result, there are concerns about drug interactions and adverse effects, including fatalities. Although these medications are often monitored through urine testing, there is limited knowledge on urine data. The study purpose was to examine urinary metabolite distributions in subjects concurrently taking methadone and diazepam. Methods: This was a retrospective analysis of deidentified data from testing done at Millennium Laboratories on urine specimens collected from 2010 to 2011. This study was granted IRB-exempt status by the UCSD Human Research Protection Program. Analyses and two sample t-tests were conducted on subjects on methadone and/or diazepam. Results: From 13,230 subjects on diazepam, 20,203 subjects on methadone, and 1,182 subjects were concurrently on methadone and diazepam. With concomitant administration, the nordiazepam fraction decreased by 28.8% (p < 0.0001), the temazepam fraction decreased 3.3% (p < 0.01), and the oxazepam fraction increased by 10.7% (p < 0.00001). In addition, there was an 11.2% increase in the metabolic ratio of EDDP to methadone (p < 0.00001). Conclusion: When methadone and diazepam are co-administered, metabolism shifts, resulting in a lower fraction of nordiazepam and temazepam; a higher fraction of oxazepam; and an increase in methadone metabolism. In addition, there appears to be a larger effect on urinary diazepam metabolites.

Funding: An unrestricted grant was given to the UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences to fund the summer internships by Millennium Laboratories, Inc.