Methadone-Associated Mortality:
Report of a National Assessment


Appendix 4. Past Investigations of Methadone-Associated Mortality

Epidemiologic / Descriptive Studies of Methadone-Associated Mortality
Reference Location/Date Subjects/Design Comments
Dole et al., 1971 New York,
1960s		 Series of 2 cases in a methadone program. Accidental overdose not otherwise specified.
Gardner, 1970 London,
1965-1969 		Descriptive study of 12 methadone deaths. Concludes that at least 7 deaths occurred due to lack of opioid tolerance, while 8 resulted from too high a starting dose (greater than 70 mg).
Baden, 1970 New York,
1967-1970		 Report on 24 deaths in a methadone program and 8 not in OTP. Half of the methadone deaths were related to abuse of alcohol and other drugs. Of 8 methadone-associated deaths outside OTP, 5 involved oral overdoses (2 in opioid-naïve subjects), 3 involved IV abuse of methadone.
Gearing and Schweitzer, 1974 New York,
1964-1971		 Long-term descriptive study on outcomes of subjects in OAT. Causes of death in 153 subjects are not detailed, but at least 30 percent were polydrug-related.
Roizin et al., 1972 New York,
1972		 Series of 14 deaths, 57 percent of whom were receiving methadone. Methadone doses ranged from 40-180 mg/d. Polydrug abuse was implicated in most cases, including morphine (4) and quinine (2).
Greene et al., 1974 District of Columbia,
1970-1973		 Descriptive study of methadone death rate. Methadone deaths increased sharply following diversion to illicit markets - 46.2 percent of decedents were not opioid-tolerant - and were curtailed sharply by restricting dispensing to licensed clinics rather than private physicians.
Appel et al., 2000 New York,
1966-1976		 176 deaths among 1,544 patients in and out of OAT program. Overall, 93 deaths occurred during methadone treatment and 83 after leaving treatment. Only 2 deaths during treatment were opioid-related.
Concool et al., 1979 East Harlem, NY,
1969-1976		 Review of deaths in patients enrolled in OAT, with risk assessment. The mortality rate was 20 per 1000 patients, with deaths largely due to alcoholism and violence. None of the deaths were directly attributed to methadone.
Caplan et al., 1983 Maryland,
1975-1980		 77 deaths in which methadone was present. Methadone was the sole agent in 18 deaths. There was an overlap in serum methadone levels across sole-agent deaths, polydrug deaths, and non-drug-related deaths with methadone present.
Kringsholm et al., 1988 Denmark,
1968-1986		 Descriptive study of drug deaths. 20 percent of drug deaths during abstinence were due to methadone. No details of circumstances were provided.
Petry et al.,
1998		 New York,
1975-1986		 Review of 325 deaths among OAT patients receiving methadone. During a 12-year period, deaths attributed to medical causes (especially AIDS) dramatically increased, while drug overdose deaths held fairly constant at low levels.
Harding-Pink, 1991 Geneva, Switzerland,
1981-1986		 Description of 25 deaths associated with methadone. 14 deaths were caused by methadone, of which 3 occurred in the first two weeks of treatment and 6 less than two weeks after leaving treatment; 9 were caused by a combination of opioids and methadone. 15 deaths were associated with concurrent benzodiazepine use.
Davoli et al., 1993 Italy,
1980-1988		 Matched case control analysis of IV drug abusers in OAT. The risk of overdose death was higher for subjects who had left methadone treatment, particularly within the first year (odds ratio: 7.98).
Drummer et al., 1990, 1992 Victoria,
Australia, 1990		 10 deaths in methadone-treated patients. Deaths occurred in the early stages of OAT, at doses ranging from 45-70 mg (mean: 53 mg). Six subjects had additional CNS-active drugs present; all had chronic hepatitis; 5 had bronchopneumonia.
Kringsholm, et al. 1994 Denmark,
1987-1991		 Descriptive study of drug deaths. Against a background of increasing fatalities, with most also involving IV heroin, methadone poisoning cases increased significantly in 1991. About half the victims were on methadone maintenance at the time of death.
Neeleman and Farrell, 1997 England and
Wales,
1974-1992		 Retrospective longitudinal survey. Poisoning deaths involving methadone (alone or in combination) rose 80 percent over a 3-year period. However, there was no evidence that this was disproportionate to the increase in heroin deaths.
Barrett et al., 1996 Harris County, Texas,
1987-1992		 Investigation of 91 deaths involving methadone. A team of CDC investigators found that 85 percent of deaths involved polydrug abuse and only 20 percent of decedents were in OAT at the time of death. Only 11 cases were attributed directly to methadone toxicity.
La Harpe and Fryc, 1995 Geneva, Switzerland,
1987-1993		 Description of 24 deaths associated with methadone. No deaths occurred in first two weeks of methadone treatment, 3 occurred less than 2 weeks after leaving OAT, 11 involved concurrent use of benzodiazepines, 8 involved concurrent use of alcohol, and 11 iinvolve concurrent use of heroin.
Goldstein and Herrera,1995 Albuquerque,
1971-1993		 Long-term follow-up of 1,019 patients registered in methadone OAT. 34 percent of patients died in the 22 years since starting methadone therapy. More than a third of the deaths were related to drug abuse. Subjects were 4-6 times more likely to die than non-addicts.
Clark et al., 1995 Sheffield, England,
1991-1994		 18 subjects; case study. 7 subjects died in the early stages of methadone treatment (and had received doses in the range of 30-100 mg). 3 died after long-term use and 8 died from non-prescribed drug use. Multiple drug use was common but was not judged to have played a major role in most deaths.
Cairns et al., 1996 Manchester, England,
1985-1994		 90 subjects; case study. The number of methadone deaths increased in during the study period. Methadone was the sole cause of death in 52 cases, while 36 died from other drug use. Methadone cases represented 15 percent of total fatal drug overdoses during the study period.
Williamson et al., 1997 South Australia,
1984-1994		 47 fatalities, with risk assessment. Widespread use of methadone tablets for chronic pain led to a disproportionate increase in deaths . The death rate increased sharply in 1993-94 concurrent with the opening of private methadone clinics.
Caplehorn, 1998 Sydney , Australia, 1994 13 subjects; case study. Of 13 patient deaths, 10 died in the first two weeks of treatment, during methadone induction; doses ranged from 25-110 mg (median: 40 mg).
Caplehorn and Drummer, 1999 Sydney, Australia, 1994 Review of 86 methadone-associated deaths; risk assessment. Of 89 deaths, 29 involved diversion of methadone syrup and 18 the use of methadone tablets. 38 patients died during OAT. The risk of death in the first 2 weeks was 6.7 times that of addicts outside OAT, but was reduced 98-fold later during methadone maintenance treatment.
Zador and Sunjic, 2000 New South Wales, Australia,
1990-1995		 238 methadone-associated deaths examined. 44 percent of deaths were drug-related, with most (92 percent) involving polydrug abuse; 42 percent occurred during the first week of methadone treatment.
Drummer, 1997 Victoria, Australia,
1994-1997		 89 deaths in which methadone was detected. Toxic methadone concentrations overlapped those in non-drug-related deaths in which methadone was present. Those starting OAT or who used the drug occasionally were at the greatest risk of death.
Valmana et al., 2000 London, England, 1997 Review of 40 methadone-associated deaths. Of 40 methadone-related deaths, 72 percent did not involve prescribed methadone. These decedents were younger (median age: 22 years) than those who died of prescribed methadone (median age: 37 years), suggesting more chaotic abuse patterns in younger persons.
Perret et al., 2000 Geneva, Switzerland,
1994-1998		 36 methadone cases, out of 106 total drug abuse fatalities. 35 of 36 decedents used illicit drugs in combination with methadone. Of 21 deaths attributed to methadone, only a third of those decedents were in OAT. Methadone-attributed deaths remained constant at 3-5 per year throughout the study period, while overall drug abuse deaths declined markedly.
Eastwood, 1998 London, England, 1998 Description of 13 childhood deaths. Of 13 children poisoned with methadone syrup prescribed to a parent, five died. Methadone serum concentrations in children who died overlapped that in children who survived.
Karch and Stephens, 2000 San Francisco,
1997-1998		 38 cases involving methadone (out of 3,317 examined). Methadone was cited as a cause of death in 21 cases, although blood methadone concentrations were identical in this group and in the group in whom methadone was an incidental finding.
Buster et al., 2002 Amsterdam, The Netherlands,
1986-1998		 5,200 methadone-maintained patients observed. 68 overdose deaths were recorded in a group of 5,200 methadone patients, with a modest increase during first 2 weeks of treatment. The overall death rate was 2.3 per 1000 patient-years.
Heinemann et al., 2000 Hamburg, Germany,
1990-1999		 Surveillance of drug-related poisonings. An increase in methadone-related fatalities coincided with declines in heroin deaths. 65 percent of methadone decedents were not enrolled in an OTP.
Bartu et al., 2002 Western Australia,
1993-1999		 84 methadone-related deaths evaluated. 74 percent of deaths were caused by a combination of drug effects, with benzodiazepines present in 75 percent of those cases. 57 percent were not in an OTP at the time of death. Methadone-associated mortality peaked in 1998 at 7.7 per 1000 patients treated, one year after expansion into the private sector.
Green et al., 2000 South Australia,
1996-1999		 35 cases of methadone causing or contributing to death. Of 10 patients receiving methadone maintenance treatment, 4 died within the first week. Eight non-OAT cases involved diverted methadone, while 7 involved other drugs as well. Mean age of the decedents was 25 years.
Oliver et al., 2002 Sheffield, England,
1997-1999		 82 drug-abuse related deaths. Deaths attributed wholly or partially to methadone declined from 37 percent to 18 percent during the study period, against a background of increased methadone prescribing.
Squires,
2000		 Scotland,
1994-2000		 Surveillance report on methadone-related deaths. Methadone deaths peaked in 1996 and then declined, while methadone prescriptions increased by 18 percent. 45 percent of deaths involved persons not prescribed methadone, all but 2 involved drug abuse-related causes, and there were no deaths within one month of starting methadone maintenance. Of decedents who were prescribed methadone, 60 percent were on observed dosing at the time of death.



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