Methadone-Associated Mortality:
Report of a National Assessment

Part 2. Background

Methadone has a number of unique pharmacologic properties, such as its slow onset and long duration of action, its relatively low need for dose escalation because of tolerance, its antagonism of the glutamate receptor N-methyl-D-aspartate (NMDA), its inhibition of serotonin/norepinephrine reuptake, and its very modest cost - all of which make it an appropriate choice for opioid therapy of pain and addiction (Savage, meeting presentation, 2003 [see http://www.samhsa.gov]; Lobert, 2003; Bruera, 2002; Payte, et al., 1994; Joseph and Woods, 1994; Kreek, 1992; Ettinger, et al., 1979).

Methadone's Pharmacology and Mechanisms of Action

A synthetic opioid, methadone is among the most thoroughly studied drugs in modern medicine. Approved by the FDA in 1947 as an analgesic, by 1950 methadone was being used to treat the painful symptoms of withdrawal from heroin and other opioids. In 1964, researchers discovered that continuous, daily maintenance doses of oral methadone allowed opioid-addicted patients to function more normally in recovery (Payte, 1991; Zweben and Payte, 1990; Dole, 1988; Gearing and Schweitzer, 1974).

Oral methadone, whether used for addiction treatment or pain relief, is available as a solid tablet, a rapidly dissolving wafer (diskette), and a premixed liquid, all of which are essentially bioequivalent (Mallinckrodt, 1995, 2000; Roxane, 1995, 1998, 2000). Each of the formulations is 80 to 95 percent bioavailable (compared with only 30 percent for oral morphine) and readily absorbed (Eap, et al., 2000; Inturrisi, 1972b).

Methadone is stored extensively in the liver and secondarily in other body tissues. Its elimination half-life averages 24 to 36 hours at steady state, but may range from 4 to 91 hours. Because of this long half-life, achieving steady-state serum methadone levels (SMLs) - in which drug elimination is in balance with the amount of drug remaining in the body - requires, on average, from 4 to 5 days, although it can take much longer in some individuals. When methadone is initiated, before a steady state is achieved, a rule of thumb is that half of each day's dose remains in the body to be added to the next day's new dose, producing rising SMLs (which can reach dangerous levels if doses are excessive). After each dose, the SML typically reaches a peak in 3 to 4 hours (with a range of 1 to 5 hours), although individual physiologic responses differ for a variety of reasons (Eap, et al., 2002, 1988).

Largely as a function of liver enzyme activity, methadone is broken down to form a number of inactive metabolites (Foster, et al., 1999; Kreek, et al., 1979). Drugs that induce activity of these enzymes can accelerate methadone metabolism, abbreviate the duration of its effects, lower the SML, and precipitate abstinence (withdrawal) syndrome. Conversely, drugs that inhibit these enzymes can slow methadone metabolism, raise the SML, and extend the duration of drug effects (Eap, et al., 1999). When interactions with other substances occur, changes in SMLs can result in under- or over-medication. Genetic and environmental factors also act on the enzymes, leading to considerable individual variation in methadone potency (Nakamura, et al., 1982; Robinson and Williams, 1971). Equally important to this kinetic variability, however, is the wide inter-individual and intra-individual variation in opioid tolerance, which is highly dependent on dosing history and even can reflect external stimuli and environment (Eap, et al., 2002, 1988).

Methadone's Safety Profile

Through many years of clinical trials and experience, methadone has been shown to have a favorable safety profile when used as indicated (Stine, et al., 1998; Payte and Zweben, 1988; Zweben and Payte, 1990). Few serious adverse reactions and no cumulative organ damage have been associated with daily administration of appropriate doses over more than 20 years in some patients. Mortality from all causes is many-fold lower in methadone-treated patients than in untreated opioid addicts. Studies consistently have shown that the risk of communicable diseases (such as HIV and hepatitis C) is significantly reduced by participation in methadone maintenance therapy, even in patients who do not achieve total abstinence from illicit drug use (Appel, et al., 2000; Backmund, et al., 2001; Bell and Zador, 2000). Moreover, research shows that patients in whom methadone therapy is discontinued have mortality rates three to four times higher than patients in whom methadone therapy is continued (Goldstein and Herrera, 1995; Concool, et al., 1979; Gearing and Schweitzer, 1974).

Still, methadone is a potent drug; fatal overdoses have been reported over the years (Baden, 1970; Gardner, 1970; Clark, et al., 1995; Drummer, et al., 1992). As with most other opioids, the primary toxic effect of excessive methadone is respiratory depression and hypoxia, sometimes accompanied by pulmonary edema and/or aspiration pneumonia (White and Irvine, 1999; Harding-Pink, 1993). Among patients in addiction treatment, the largest proportion of methadone-associated deaths have occurred during the drug's induction phase, usually when (1) treatment personnel overestimate a patient's degree of tolerance to opioids, or (2) a patient uses opioids or other central nervous system (CNS) depressant drugs in addition to the prescribed methadone (Karch and Stephens, 2000; Caplehorn, 1998; Harding-Pink, 1991; Davoli, et al., 1993). In fact, when deaths occur during later stages of treatment, other drugs usually are detected at postmortem examination (Appel, et al., 2000). In particular, researchers have called attention to the "poison cocktail" resulting from the intake of multiple psychotropic drugs (Borron, et al., 2001; Haberman, et al., 1995) such as alcohol, benzodiazepines, and other opioids. When used alone, many of these substances are relatively moderate respiratory depressants; however, when combined with methadone, their additive or synergistic effects can be lethal (Kramer, 2003; Payte and Zweben, 1998).

It is important to note that postmortem blood concentrations of methadone do not appear to reliably distinguish between individuals who have died from methadone toxicity and those in whom the presence of methadone is purely coincidental (Drummer, 1997; Caplan, et al., 1983). This poses challenges for efforts to achieve more accurate forensic determinations of cause of death in such cases, and underscores the need for appropriate case definitions, as well as for improved systems to gather and classify premortem and other data for surveillance and prevention purposes (Hanzlick, 1997; Baden, 1978).

National Data on Methadone Use and Associated Mortality

Data from MedWatch - the FDA's Safety Information and Adverse Event Reporting Program - indicate that, from 1970 through 2002, 1,114 cases of methadone-associated deaths in adults were reported. Critically, a greater number of methadone-associated deaths were reported in 2001 alone than during the entire period from1990 through 1999; this number doubled again in 2002 (Ouelette-Hellstrom, et al., meeting presentation, 2003).

Reports from U.S. poison control centers also show that the overall number of opioid-related deaths has been on the rise, with many cases involving oxycodone and hydrocodone (Budnitz, meeting presentation, 2003; Litovitz, et al., 2002; Fingerhut and Cox, 1998; Cone, et al., 2003; Florida Department of Law Enforcement, 2002; Eastwood, 1998). Similarly, data from the Drug Enforcement Administration (DEA) National Forensic Laboratory System (NFLS) indicate that seizures by law enforcement agencies of illicitly obtained opioid analgesics such as hydrocodone and oxycodone have outpaced seizures of methadone; nevertheless, methadone seizures have been increasing as well (Howard, meeting presentation, 2003). Methadone tablet seizures increased 133 percent between 2001 and 2002; in contrast, seizures of liquid methadone increased only 11 percent during the same period (Howard, meeting presentation, 2003).

Recently, the availability of low-cost, high-purity heroin in some parts of the U.S. has fostered increased rates of abuse, since such heroin can be smoked or ingested intranasally by new users, eliminating the need for injection and thus fostering experimentation (SAMHSA, 2001; McCaffrey, 1999). In such cases, miscalculations of drug purity have led to fatal overdoses. As a result, death rates among IV heroin users are 13 times greater than those for the population as a whole (Zickler, 2001; SAMHSA, 2002).

The abuse of opioids other than heroin also is of concern. According to SAMHSA's 2001 National Household Survey on Drug Abuse, the number of new non-medical users of prescription drugs has increased steadily since the mid-1980s. The greatest part of this increase involves non-medical use of opioid analgesics, which increased from 400,000 persons in the mid-1980s to about 2 million in 2000 (Crane, meeting presentation, 2003; SAMHSA, 2001). Data from SAMHSA's Drug Abuse Warning Network (DAWN) indicate that, in 2002, heroin/morphine, cocaine, and alcohol in combination with other drugs - such as opioid analgesics or marijuana - were the substances most often mentioned in national data on drug-related deaths reported through DAWN (SAMHSA, 2003).

From 1994 to 2001, DAWN recorded an increasing number of opioid analgesic mentions in drug-related emergency department visits, with the largest increases reported for oxycodone (352 percent), methadone (230 percent), and hydrocodone (131 percent). In 2001, "opioid dependence" (presumed to involve addiction rather than solely physical dependence) was the most frequently mentioned motive for abuse of opioid analgesics, followed by "suicide attempts," "psychotropic effects" and "unknown" or "other" motives (SAMHSA, 2003).

State-Level Data on Methadone Use and Associated Mortality

In 2002 and 2003, concerns were heightened by news reports of methadone-associated deaths in Maine, Florida, and North Carolina - all States in which per capita distribution of methadone tablets through pharmacies exceeds the national average (Associated Press, 2002; Ballesteros, et al., 2003; Sanford, 2002; Sorg, 2002, Sorg and Greenwald, 2002). These data suggest a correlation between increased pharmacy distribution of methadone tablets for pain management and increased problems with methadone, including methadone-associated deaths.

In Maine, surveillance data depict an increase in methadone-associated fatalities that roughly parallels the increase in all drug deaths between 1997 and 2002 (Sorg, meeting presentation, 2003; Sorg, 2002). Opioid analgesics - most often heroin/morphine, oxycodone, and methadone - were present in 71 percent of the deaths reported in the State and were identified as causative in 53 percent (Sorg and Greenwald, 2002). The number of deaths in which methadone was detected doubled between 1999 and 2000, leveled off in 2001, then increased again in 2002 (Sorg, 2002). A high rate of mental illness and physical disorders (such as heart, lung, and liver disease), along with concomitant use of psychiatric medications and benzodiazepines, also were found in decedents (Sorg and Greenwald, 2002).

In Florida, cases of methadone-associated mortality showed a large increase from 2001 to 2002. Although in the first six months of 2002 most deaths (83 percent) were attributed to use of multiple drugs, the number in which methadone was deemed to be causative roughly equaled those in which it was merely "present" (FDLE, 2002).

In North Carolina, the number of deaths associated with methadone increased five-fold from 1997 through May 2001, for a total of 198 cases over that five-year period (Sanford, meeting presentation, 2003). When the source of the methadone could be determined (in about half the cases), physician prescription orders were identified in 75 percent, with the rest obtained from non-medical sources (e.g., prescribed to a relative/friend, obtained at a party, or "street purchase"). Only four percent of the decedents were participating in addiction treatment at or near the time of death, and OTPs were considered an unlikely source of the methadone involved in the fatal cases (Ballesteros, et al., 2003; Sanford, 2002). During the time period examined, the amount of methadone dispensed through retail outlets (primarily pharmacies) in North Carolina increased four-fold; the amount distributed through OTPs increased only two and a half times (Sanford, meeting presentation, 2003; Sanford, 2002).

In Washington State, methadone-associated deaths during the period 1993 through 2002 roughly paralleled those associated with oxycodone and hydrocodone (Figure 1). Concomitant use of multiple drugs was reported in 92 percent of deaths involving methadone (Gordon, meeting presentation, 2003).

Figure 1. Deaths Associated With Opioid Analgesics in Washington State

Source: Washington State data courtesy of Ann Marie Gordon, MS.

In Texas, which experienced an increase in methadone-associated fatalities during the early 1990s (Barrett, et al., 1996), cases of overdose involving persons being treated in OTPs actually declined between 1999 and 2002 (Maxwell, meeting presentation, 2003). Over the same period, the number of death certificates that included mention of methadone increased three-fold. Thus, while overdose mortality was declining among OTP patients, such fatalities were rising in the overall population (Maxwell, meeting presentation, 2003).

In States that have collected, analyzed, and reported relevant data, methadone-associated mortality appears to be increasing, although the absolute number of cases remains a relatively modest portion of the total number of drug-related deaths (SAMHSA, 2002). Methadone seldom is reported as the sole cause of death. In those relatively rare cases, the drug often was ingested accidentally. The majority of methadone-associated deaths involved at least one other drug, often another opioid or central nervous system depressant such as alcohol or a benzodiazepine (Borron, et al., 2001; Haberman, et al., 1995).