Home | Issues | Guidelines | More... | Topics | Search

Research

Mortality associated with New South Wales methadone programs in 1994: lives lost and saved

John R M Caplehorn and Olaf H Drummer

MJA 1999; 170: 104-109
For editorial comment, see Ali & Quigley
 

Mortality associated with NSW maintenance programs was independently investigated. The first report from this project presented the case histories of the 13 patients who died in the first two weeks of treatment.⁷ It identified 10 probable cases of fatal iatrogenic methadone toxicity (ie, where prescribed doses of methadone either caused or contributed to fatal accidental drug toxicity).⁷ This, the second report, presents an estimate of the relative risk of fatal accidental drug toxicity in the first two weeks and later maintenance. It also presents estimates of the effect of admission to methadone maintenance on the risk of fatal accidental drug toxicity and of the number of lives saved by NSW maintenance programs in 1994.

In late 1995 the database at the NSW Health Department's Division of Analytical Laboratories was searched to identify 1994 coronial cases in which methadone was detected in postmortem specimens. These analytical laboratories receive specimens for toxicological analysis in all cases of sudden death referred to the NSW State Coroner. Autopsy, toxicology and police reports and the statements of family and friends, prescribers and other witnesses were collected from coronial files.

The methadone treatment histories of the deceased were extracted from data held by the NSW Health Department's Pharmaceutical Services Section. The Department also provided data on the number of people admitted to and treated with methadone maintenance in NSW in 1994.

Cases were grouped according to the source of the methadone: methadone syrup given as maintenance treatment; methadone syrup diverted from the maintenance program; and methadone tablets (Physeptone; Glaxo Wellcome, Boronia, Vic.) prescribed for pain relief. As the Sydney black market consists almost entirely of methadone syrup diverted from maintenance programs,⁸ illicit drug users who obtained methadone from an unknown source were classified as having taken diverted syrup.

We used two parallel classifications of cause of death -- that on the official pathologist's report, and our own. In our classification, we initially established cause of death independently of one another, with one of us (O H D) blind to the official cause of death. Cases were first categorised as "accidental drug toxicity" and "other". The "other" category included suicides, deaths from natural causes and trauma, and deaths in which drug toxicity was considered to have contributed to a death from natural causes. The "accidental drug toxicity" cases were further categorised into "methadone" and "other drug or drugs" on the basis of whether or not methadone was considered to have either caused or made a significant contribution to the death.

There were no simple criteria for establishing the contribution of methadone to deaths involving other drugs. However, as deaths to which methadone contributed closely resembled cases of fatal methadone toxicity,^2,3,7 a relatively confident decision could be made after a thorough examination of the documentary and toxicological evidence and the autopsy report.^2,7,9-12

Police statements and photographs of the deceased at the scene of death provided some assistance. A brownish, frothy oedema fluid was often observed coming from the deceased's mouth or nose (see Box 1).⁷ Witnesses' statements provided a guide to likely tolerance and chronologies of ingestion and of the development of symptoms and signs of toxicity.^2,7 These statements were particularly useful in cases involving methadone as death usually occurred some hours after the drug was taken,¹⁴ and some time after the development of coma (see Box 1).^2,3,7,10,11

Postmortem blood methadone concentration was helpful but not definitive, as fatal concentration varies widely with tolerance^11,12 and the blood concentration of methadone increases after death.¹⁵ Moreover, the postmortem increase in blood methadone concentration varies unpredictably from one part of a cadaver to another.¹⁶

The autopsy findings were remarkably consistent in cases of fatal drug toxicity involving methadone, with the immediate cause of death being pulmonary oedema secondary to hypoventilation.^2,7,10,11 As methadone toxicity usually causes a gradually worsening hypoventilation, the hypoxia and resulting pulmonary hypertension are generally prolonged and severe, and significant quantities of water and electrolytes, large proteins and red blood cells leak from the pulmonary capillaries into the air spaces. Consequently, brownish oedema fluid was often observed in the large airways and the lungs were unusually heavy (see Box 1). Microscopic examination of lung specimens often showed areas of patchy bronchopneumonia and other evidence of prolonged hypoventilation and suppression of the cough reflex.^2,7,10

The 95% confidence intervals of mortality rates were calculated by dividing the estimates by significance factors taken from a published table.¹⁸ The standard errors of the relative risks were estimated using the binomial approximation of the Poisson distribution.¹⁹

In 18 of the 29 cases involving diverted methadone syrup, either a bottle used to dispense methadone syrup (5 cases), a statement from a witness (10 cases), or both (3 cases), indicated that the maintenance program was the source of the methadone. In the remaining 11 cases, it was assumed methadone syrup was obtained from the black market.⁸ In 16 of the 18 cases involving methadone tablets, either a statement from the prescribing doctor (8 cases), a tablet bottle (4 cases), or both (4 cases), indicated the source of the methadone. The remaining two people had professional access to methadone tablets and committed suicide.

We excluded the three Queensland maintenance patients, the neonate and all cases involving methadone tablets, leaving 67 cases in the study.  

Witnesses' statements or autopsy reports indicated that methadone syrup was injected in 16 of the 26 cases we classified as accidental drug toxicity to which diverted methadone contributed. One of the 10 cases involving oral ingestion of diverted methadone was that of an infant who either took or was given some of his mother's syrup.  

We also agreed with official pathologists' conclusions that six NSW methadone patients died from accidental drug toxicity after being in maintenance treatment for at least two weeks (Box 2). An approximation of the total time methadone patients spent in treatment in NSW in 1994 was derived from the average of the number in treatment at the beginning and end of the year (7975 and 9038, respectively).²² The 170.5 person-years spent in the first two weeks' maintenance were subtracted from the average of the totals, 8506.5, to estimate the total time spent in later maintenance -- 8336 person-years. When this was used as the denominator, the rate of fatal accidental drug toxicity in later maintenance was 0.72 deaths per thousand per year (Box 3).

When combined with the previous estimate, the risk of fatal accidental drug toxicity in the first two weeks of treatment in NSW in 1994 was estimated to have been 97.8 times the risk later in maintenance (95% CI RR, 36.7-260.5 times). Based on the results of a previous study,¹ the rate of fatal accidental drug toxicity for addicts on the street was estimated to be 10.4 per thousand per year. Using this estimate, the risk of fatal accidental drug toxicity in the first two weeks of methadone maintenance in NSW in 1994 was 6.7 times the risk before admission (95% CI RR, 3.3-13.9 times).  

To adjust for possible bias, we assumed that up to three of the 11 cases classified as involving diverted methadone syrup may have actually involved methadone tablets. When added to the two cases involving diverted methadone syrup in which there were differences in the official and study classifications of cause of death (Box 2), the number of lives saved may increase by up to five. Consequently, the upper limit of the confidence interval increased to give an adjusted 95% CI of 29 to 128 lives saved.

If all 10 cases of fatal iatrogenic methadone toxicity⁷ and 26 deaths to which diverted syrup contributed had been avoided, NSW maintenance programs would have saved 104 lives in 1994 (adjusted 95% CI, 65-164 lives saved), making them up to 53% more effective at saving lives (adjusted 95% CI, 37%-124%).

As there was complete agreement between our classification and that of official pathologists, our estimate of the relative risk of fatal accidental toxicity in the first two weeks and later maintenance is unlikely to have been significantly affected by misclassification of causes of death. Further, in estimating that NSW methadone programs saved 68 lives in 1994, we allowed for the difference between our opinion and that of the official report on the role of diverted methadone in two cases when calculating the upper limit of the adjusted 95% confidence interval (29-128) for the number of lives saved by NSW maintenance programs.

Another consideration in estimating the number of lives saved is that mortality among patients discharged from maintenance is only an approximation of preadmission risk. If the real risk on the streets was higher than our estimate, NSW methadone programs would have saved more lives and admission to maintenance would not have caused such a dramatic increase in the risk of fatal accidental drug toxicity. Conversely, if the real risk was lower, the reverse applies.

Our estimates of the number of lives saved and the increase in the risk of fatal accidental drug toxicity associated with admission to maintenance are approximations only. However, as our estimated 71% reduction in mortality is very similar to that observed in the US during the early 1970s, in Sweden during the 1980s, in Germany in the 1990s and Australia during the 1970s and 1980s,¹ they are probably reasonably accurate.

Previous Australian studies have also identified mortality associated with methadone programs. Eighteen people died from methadone toxicity in Western Australia in the years 1975 to 1980. However, there were virtually no such deaths after WA maintenance patients were required to take their methadone under supervision.²³ In South Australia, nine maintenance patients died from drug toxicity in the years 1984 to 1994, while 12 other people died from the toxic effects of diverted methadone syrup.²² The number of deaths per 1000 SA maintenance patients was approximately 75% of that observed in our study. Our finding that diverted methadone syrup contributed to 26 deaths in NSW in 1994 is supported by the results of a previous investigation which suggested that diverted methadone syrup was involved in up to 100 deaths between July 1990 and December 1995.⁶

The WA experience²³ suggests the number of deaths from diverted methadone syrup is related to the number of takeaway doses dispensed to maintenance patients for consumption on subsequent days. In 1994, two-thirds of private sector patients received four takeaway doses a week, with some programs giving five or six a week to newly admitted patients.²⁴ Although the NSW Health Department argued against such practices, there was no policy enforcement.²⁴ To minimise the diversion of methadone syrup from maintenance programs, the NSW Health Department should monitor and ensure compliance with its current policy which strictly limits the number of takeaway doses available to recent admissions while giving stable, long-term patients access to generous takeaway privileges.

A serious problem with iatrogenic methadone toxicity was identified in Victoria, where 10 deaths occurred among newly admitted methadone patients in the last six months of 1989.² As Victorian methadone programs treated fewer than 1200 maintenance patients in this period, the rate of iatrogenic methadone toxicity was many times that observed in our study. It is noteworthy that, during 1989, the number of Victorian maintenance patients and programs increased rapidly and a number of inexperienced and poorly trained prescribers entered the field.^2,3 Persons with minimal or no tolerance were prescribed initial, daily methadone doses of 50-70 mg, with fatal results.²

Two recent British studies, from Sheffield and Manchester, have similarly identified significant numbers of deaths from iatrogenic methadone toxicity early in maintenance treatment.^4,5 These problems also arose after the relaxation of admission criteria and during a period of rapid increase in the numbers of maintenance patients and the involvement of new, inexperienced prescribers.^4,5

While the official criteria for admission to methadone maintenance in NSW have not changed since 1988,²⁵ they were not being implemented in 1994.²⁶ Statements made by its Chairman in 1996 indicate that the NSW Medical Committee had not been applying the official admission criteria for some time.²⁶ This is significant because, under the NSW Poisons Act, the Medical Committee advises the NSW Health Department on applications from doctors to prescribe methadone maintenance to addicts.

There were also problems with prescriber training. Since 1993, the NSW Methadone Prescribers' Accreditation Program has used the Methadone prescribers' manual as its course material.²⁷ Contrary to NSW Health Department policy,²⁵ the "Manual" states heroin users need not have a history of physiological dependence on opioids to be eligible for maintenance treatment.^26,27 We urge the NSW Health Department to revise its Methadone prescribers' manual,²⁷ review prescriber training and to ensure compliance with its current admission criteria for maintenance treatment.^25,26

In 1994, Victorian and Queensland methadone prescribers were required to examine new patients during the first days of maintenance for signs of toxicity.^28,29 Unfortunately, the NSW Health Department did not, and still does not, have a similar policy. Indeed, many private practitioners in NSW are only available to see maintenance patients one day a week (see Box 1), and the day-to-day supervision of patients attending public clinics is left to nurses working in busy dispensaries.

The first two weeks of methadone maintenance will always be the "danger period" owing to the difficulty in determining a safe and effective starting dose. There is wide variation in opioid-na•ve individuals' response to and ability to metabolise and excrete methadone,³⁰ and applicants' self-reports of recent drug use are an unreliable measure of tolerance.⁷ Given this uncertainty and variability, it is not possible to define safe, effective starting doses of methadone.

We recommend prescribers be made aware of the risks, signs and symptoms of methadone toxicity and be required to examine newly admitted patients every day for the first one to two weeks of maintenance. People seeking methadone maintenance should be required to give written consent after being warned about the dangers of misleading their doctor and of the use of other drugs, particularly benzodiazepines.^7,31 We believe that the forthcoming NSW methadone maintenance treatment clinical practice guidelines will address these issues.

We strongly recommend the establishment of independent, expert committees to investigate methadone-related deaths in States and Territories with maintenance programs. These committees should be modelled on those used to monitor anaesthesia-related deaths.

1. Caplehorn JRM, Dalton MSYN, Haldar F, et al. Methadone maintenance and addicts' risk of fatal heroin overdose. Substance Use Misuse 1996; 31: 177-196.
2. Drummer OH, Opeskin K, Syrjanen SM, Cordner M. Methadone toxicity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathology 1992; 13: 346-350.
3. McPherson CJ. Coronial inquiry into methadone related deaths. Melbourne: State Coroner Victoria, 1996.
4. Clark JC, Milroy CM, Forrest ARW. Deaths from methadone use. J Clin Forensic Med 1995; 2: 143-144.
5. Cairns A, Roberts ISD, Benbow EW. Characteristics of fatal methadone overdose in Manchester, 1985-94. BMJ 1996; 313: 264-265.
6. Sunjic S, Zador D. Methadone-related deaths in New South Wales, Australia, 1990-1995. Euro-Methwork Newsletter 1998; issue 13: 11.
7. Caplehorn JRM. Deaths in the first two weeks of maintenance treatment in NSW in 1994: identifying cases of iatrogenic methadone toxicity. Drug Alcohol Rev 1998; 17: 9-17.
8. Darke S, Ross J, Hall W. The injection of methadone syrup in Sydney, Australia. Sydney: National Drug and Alcohol Research Centre, 1995. (Technical Report No. 23).
9. Helpern M, Rho Y-M. Deaths from narcotism in New York City: incidence, circumstances and postmortem findings. NY State J Med 1966; 66: 2391-2408.
10. Siegel H, Helpern M, Ehrenreich T. The diagnosis of death from intravenous narcotism. J Forensic Sci 1966; 11: 1-16.
11. Segal RJ, Catherman RL. Methadone -- a cause of death. J Forensic Sci 1974; 19: 64-74.
12. Worm K, Steentoft A, Kringsholm B. Methadone and drug addicts. Int J Leg Med 1993; 106: 119-123.
13. Transcript of Proceedings, Case 011 0487/95. New South Wales Coroner's Court Westmead.
14. Ruigrok M, Caplehorn J. A case of near-fatal methadone toxicity following repeated injections of methadone [letter]. Drug Alcohol Rev 1997; 16: 433.
15. Pounder DJ, Jones GR. Post-mortem drug redistribution -- a toxicological nightmare. Forensic Sci Int 1990; 45: 253-263.
16. Levine B, Wu SC, Dixon A, Smialek JE. Site dependence of postmortem blood methadone concentrations. Am J Forensic Med Path 1995; 16: 97-100.
17. Drug and Alcohol Directorate. NSW methadone program 1993/94: annual statistical report. Sydney: NSW Health Department, 1995.
18. Bailar JC, Ederer F. Significance factors for the ratio of a Poisson variable to its expectation. Biometrics 1964; 20: 639-643.
19. Armitage P, Berry G. Statistical methods in medical research. 3rd ed. Oxford: Blackwell Scientific, 1994: 131.
20. Caplehorn JRM, McNeil DR, Kleinbaum DG. Clinic policy and retention in methadone maintenance. Int J Addict 1993; 28: 73-89.
21. Caplehorn JRM, Irwig L, Saunders JB. Physicians' attitudes and retention of patients in their methadone maintenance programs. Substance Use Misuse 1996; 31: 663-677.
22. Williamson PA, Foreman KJ, White JM, Anderson G. Methadone-related overdose deaths in South Australia, 1984-1994. Med J Aust 1997; 166: 302-305.
23. Swensen G. Opioid drug deaths in Western Australia: 1974-1984. Aust Drug Alcohol Rev 1988; 7: 181-185.
24. Transcript of Proceedings, Case 010 1924/94. New South Wales Coroner's Court Glebe, Thursday 15th June 1995: 31-37.
25. Directorate of the Drug Offensive. Policies and Procedures for the Methadone Treatment of Opioid Dependence in NSW. Sydney: New South Wales Department of Health, undated: 15, pars 4.3.1 and 4.3.2.
26. Caplehorn JRM. Official and de facto admission criteria for methadone maintenance in New South Wales, Australia [letter]. Drug Alcohol Rev 1998; 17: 121-122.
27. Bell J, O'Connor D. Methadone prescribers' manual. Sydney: NSW Health Department, 1993: 11, 23.
28. Public Health Branch. Victorian methadone program guidelines for providers. Melbourne: Department of Health and Community Services, 1995: 7, par 3.5.2. (No. 93/0388).
29. Bolton M, Reynolds A, Biggs L. Queensland methadone program: policy and procedures and treatment manual. Brisbane: Queensland Health, 1995: 35, par 4.14.
30. Wolff K, Sanderson M, Hay AWM, Ralstrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1991; 37: 205-209.
31. Caplehorn JRM. More on iatrogenic methadone toxicity [letter]. Drug Alcohol Rev 1998; 17: 467-468.

Victorian Institute of Forensic Medicine, Melbourne, VIC.
Olaf H Drummer, PhD, Head of Scientific Services, and Associate Professor, Department of Forensic Medicine, Monash University.

Reprints: Dr J R M Caplehorn, Department of Public Health and Community Medicine, Building A27, University of Sydney, Sydney, NSW 2006.
Email: johnc@dph1.health.usyd.edu.au

©MJA 1998
Make a comment

Home | Issues | Guidelines | More... | Topics | Search

Readers may print a single copy for personal use. No further reproduction or distribution of the articles should proceed without the permission of the publisher. For permission, contact the Australasian Medical Publishing Company.
Journalists are welcome to write news stories based on what they read here, but should acknowledge their source as "an article published on the Internet by The Medical Journal of Australia <http://www.mja.com.au>".
<URL: http://www.mja.com.au/> © 1998 Medical Journal of Australia.
We appreciate your comments.

Back to text