Methadone-Associated Mortality:
Report of a National Assessment

Part 4. Findings

Concern over methadone-associated mortality is not new. Extensive surveillance data have documented such deaths ever since methadone's introduction as an analgesic and its subsequent use in the treatment of opioid addiction. This has occurred within the context of increased abuse of all opioid drugs (Crane, meeting presentation, 2003; ONDCP, 2002; SAMHSA, 2001).

The current analysis has prompted a number of important findings, described in the following pages.

Recent Increases in Methadone Use Are Related to Its Use as an Analgesic

The greatest incremental growth in methadone distribution in recent years is associated with use of the drug as an analgesic and its distribution through pharmacies rather than through OTPs (Governale, meeting presentation, 2003; DEA, 2003) (Figure 2). However, the growth in distribution of methadone through pharmacies has been overshadowed by the increase in distribution of oxycodone and hydrocodone.

Figure 2. Percent Change in Distribution of Methadone and Three Comparison Drugs, from Baseline Year 1998 through 2002

Source: Data from IMS Health, National Prescription Audit Plus,
courtesy of Laura A. Governale, PharmD.

By comparison, distribution of methadone through OTPs remained relatively flat during the period measured (Howard, meeting presentation, 2003) (Figure 3).

Figure 3. Distribution of Methadone through OTPs and Pharmacies, Compared

Source: Data derived from DEA ARCOS-2;
methadone pharmacy 2000 data are an interpolated estimate.

Although use of all formulations of methadone has shown steady, incremental growth over the past several years (Figure 4), the distribution of tablets (most often used in pain management) and diskettes has surpassed that of liquid formulations (most often used by OTPs). For example, the rate of increase from 1999 to 2002 was far greater for tablets (331 percent) than for either diskettes (147 percent) or liquids (175 percent). In 2002, about 55 percent of all methadone distributed nationwide was in the form of tablets or diskettes (Howard, meeting presentation, 2003).

Figure 4. Methadone Distribution, by Formulation, 1998 - 2002 (grams per 100,000 population)

Source: Adapted from DEA ARCOS-2 data provided by June E. Howard.

In 2002, OTPs accounted for the largest amount of methadone products purchased (68 percent), followed by pharmacies (29 percent). However, whereas OTPs purchased 98 percent of all the methadone sold in liquid form and 79 percent of all the methadone sold in diskette form in the U.S., pharmacies accounted for 88 percent of all purchases of the tablet form (OTPs purchased only 1.75 percent of the tablets). Within OTPs nationwide during 2002, 65 percent of methadone was distributed as liquids, 26 percent as diskettes, and less than one percent as tablets (Howard, meeting presentation, 2003).

Increases in Methadone-Associated Mortality Also Are Related to Its Use as an Analgesic

The greatest incremental growth in methadone distribution in recent years is associated with use of the drug as an analgesic and its distribution through pharmacies. In fact, distribution of solid methadone formulations (tablets and diskettes), primarily through pharmacies, has surpassed distribution of the liquid formulations that are the mainstay of dispensing in OTPs. From 1998 through 2002, the volume of methadone distributed through pharmacies increased five-fold, whereas the volume distributed through OTPs increased only 1.5-fold. In 2002 alone, pharmacies accounted for 88 percent of all purchases of methadone tablets (DEA, 2003). Data from the DEA's ARCOS system indicate that the growth in methadone distribution overall has lagged far behind the increases seen for other opioid analgesics, such as oxycodone and hydrocodone products (DEA, 2003).

The DEA data are supported by independent information from IMS Health, which tracks drug prescriptions and sales through selected channels of distribution (Governale, meeting presentation, 2003). From 1998 to 2002, the number of retail prescriptions filled each year for oxycodone, hydrocodone, morphine, and methadone all increased. While fewer prescriptions were written for methadone than for the other three opioids, the number of prescriptions for methadone increased three-fold between 1998 and 2003 (from 0.5 to 1.8 million prescriptions) - a rate of increase larger than that for the other three drugs. The number of units of methadone in solid form distributed through retail channels averaged a 38 percent annual increase, whereas comparatively minor growth was seen for solid formulations distributed through OTP channels.

Taken together, the data confirm a correlation between increased methadone distribution through pharmacy channels and the rise in methadone-associated mortality. This supports the hypothesis that the growing use of oral methadone, prescribed and dispensed for the outpatient management of chronic pain, explains the dramatic increases in methadone consumption and the growing availability of the drug for diversion to abuse.

OTPs and the Revised Federal Regulations Are Not Significant Contributors to Methadone-Associated Mortality

A major concern of the National Assessment participants was whether OTPs and the revised SAMHSA regulations governing the manner in which OTPs administer and dispense methadone have contributed to recent increases in methadone-associated mortality. The SAMHSA regulations effective in 2001 (42 CFR Part 8) allow patients - especially those who are relatively advanced in the course of treatment - to take home doses of methadone on an increased number of days.

Examination of the data available to the National Assessment participants indicates that OTPs and the 2001 regulatory changes did not have a significant effect on rates of methadone-associated mortality. As already noted, the upward trend in fatalities involving methadone appeared prior to 2001 and, thus, preceded SAMHSA's regulatory changes (Kallan, 1998). The trend in methadone-associated deaths parallels death rates associated with other opioid agents (SAMHSA, 2003). In the cases in which the sources of methadone associated with deaths could be traced, OTPs did not appear to be involved. Within OTPs, patient deaths during the start-up (induction) phase - the period of highest risk for in-treatment mortality - are rare due to Federal regulations that impose specific requirements on the induction ("loading") dose, as well as improvements in patient care that resulted from the SAMHSA requirement that OTPs must be accredited.

Further, the growth in the number of OTPs administering methadone and in the number of persons receiving methadone treatment has been modest and does not parallel the rate of increase in methadone-associated deaths. Although the data remain incomplete, National Assessment participants concurred that methadone tablets and/or diskettes that have become available through channels other than OTPs are most likely the central factor in recent increases in methadone-associated mortality.