The Source of Methadone in Overdose Deaths in Western Virginia in 2004

Methadone exhibits a long and variable half-life of 15 to 55 hours together with the potential for multiple drug interactions (Wolff, 2002). Pharmacokinetic studies of methadone indicate that it has high oral bioavailability, a rapid and extensive distribution phase into the tissues of the brain, liver, kidneys, muscle, and lungs, and a very slow elimination phase as these extravascular sites slowly release methadone into the plasma (Intrussi and Verebely, 1972; Inturrisi et al., 1987). The elimination half-life of methadone has considerable interindividual variability due to genetic differences and environmental factors (Eap et al., 2002). In addition, sustained respiratory depression lasting 24 to 48 hours occurs despite the analgesic effect of methadone lasting only 4 to 6 hours (Wolff, 2002). Effects are intensified in methadone-naive patients, patients nonadherent to dosing regimens, those using multiple substances to attain euphoria, and patients prescribed CYP450-inducing medications. Liver dysfunction further prolongs elimination of methadone. These aforementioned characteristics increase methadone's potential for delayed toxicity and poisoning relative to other opioids (Wolff, 2002). Methadone has been used for the outpatient treatment of opioid addiction since 1966 (Joseph et al., 2000). Methadone maintenance treatment decreases illicit opioid use and decreases mortality among opioid-dependent patients (Gronbladh et al., 1990; Caplehorn et al., 1996; National Institutes of Health, 1999). Outside opioid treatment programs (OTPs), methadone prescribing surged in the last decade because of its reasonable cost and efficacious analgesic profile (Wheeler, 2000; Dickerson, 2001; Oregon Department of Human Services, 2003; Substance Abuse and Mental Health Services Administration [SAMHSA], 2004). Methadone prescriptions increased by 5-fold in New Hampshire from 2000 to 2003 (Andrew, Duval, abstract presented at the Joint Meeting of SOFT and TIAFT), 5-fold in Oregon from 1997 to 2001 (Oregon Department of Human Services, 2003), and 4-fold in North Carolina from 1997 to 2001 (Ballesteros et al., 2003; US Department of Justice [USDOJ], 2004). Similar pattern increases were noted for oxycodone and hydrocodone prescriptions, though to a lesser degree (USDOJ, 2004). From 1999 to 2005 methadone poisoning increased by 468% nationwide, while poisoning deaths due to heroin increased by 2.4% and other synthetic opioids increased by 138% (Fingerhut, 2008). Given the concomitant rise in methadone prescribing and methadone-related deaths, some have hypothesized that physician inexperience prescribing methadone for chronic pain is a potential contributor, and have taken steps to better educate physicians about appropriate prescribing practices (Oregon Department of Human Services, 2009; SAMHSA, 2009). In 2006, the Food and Drug Administration also lowered the starting dosage recommendation of methadone to 2.5 to 10 mg every 8 to 12 hours from 2.5 to 10 mg every 3 to 4 hours as needed for initiation of analgesic therapy in opioid-naive patients (Roxane Laboratories, 2000, 2006). The new recommended initial dose for treatment of opioid dependence is no more than 40 mg/d (Roxane Laboratories, 2006). Alternative reasons for the concomitant rise in methadone prescribing and mortality include increased opportunities for the nonmedical use and diversion of methadone (Cairns et al., 1996; Lehder et al., 2002; Sorg and Greenwald, 2002; Ballesteros et al., 2003; USDOJ, 2004; Paulozzi et al., 2009). Empiric data regarding the source of methadone in overdose deaths are limited. Estimates of the contribution of physician methadone prescriptions to opioid overdose deaths vary widely from 15% to 75% of medical examiner cases (Barrett et al., 1996; Ballesteros et al., 2003; Gagajewski and Apple, 2003; Shah et al., 2005; Paulozzi et al., 2009). Only 2 studies, under the same Centers for Disease Control and Prevention investigation, have used a prescription-monitoring program to link methadone prescriptions to overdose deaths (Hall et al., 2008; Paulozzi et al., 2009). Both studies found evidence of significant prescription opioid nonmedical use and a high prevalence of a history of substance abuse among overdose decedents in West Virginia, regardless of whether they were prescribed methadone from a physician or not (Hall et al., 2008; McLellan and Turner, 2008; Paulozzi et al., 2009). During the last decade there has been a 300% increase in medical examiner--investigated deaths in western Virginia identifying prescription opioids as a direct or contributing cause of overdose death (Wunsch et al., 2009). A recent study of opioid-related deaths in western Virginia from 1997 through 2003 reported that methadone was the most commonly identified opioid associated with accidental overdose (Wunsch et al., 2009). In that study, the source was not determined primarily because the Prescription Monitoring Program (PMP) was not established in Virginia until 2003. The objective of this study was (a) to describe methadone-related deaths secondary to poisoning in western Virginia from January 1, 2004, to December 31, 2004, and (b) to determine the source of the medication by linking medical examiner and OTP records with Virginia's PMP. We hypothesized that in most cases the source of methadone was from physician prescriptions for analgesia rather than for opioid addiction treatment or an illicit source.