Substance‐related disorders

To the Editor: From 1 February to 30 June 2001, 277 602 prescriptions for the smoking cessation drug bupropion hydrochloride (Zyban, GlaxoSmithKline) were processed. The Health Insurance Commission approved 343 737 prescriptions for bupropion between 1 February and 30 June.1 Comparing this figure with the 277 602 processed scripts, some 66 135 (19.2%) scripts went unfilled. One reason for this may have been extensive publicity given to reports of deaths and numerous adverse reactions following bupropion use. The website of the Australian Drug Reactions Advisory Committee (ADRAC) reports that, as at 22 June, there had been 18 reports of deaths in patients aged from 30 years to 69 years who were using or who had recently stopped using bupropion.2 ADRAC summarised intelligence on these deaths thus: ... there were a variety of reported causes of death and not a single consistent mode of death. In addition to being smokers, several patients had other existing risk factors for unexpected death such as alcohol abuse, diabetes or cardiomyopathy. Eleven of the 18 patients had an alternative explanation for death that was at least as plausible as a possible effect of bupropion. In four reports, the available information was very limited and it was not possible to assess the cause of death. Further information is being sought on three cases to aid assessment of the cause of death.2 Smokers are at 3.1 times greater risk of dying (from any cause) than non-smokers and twice as likely to die from coronary disease and stroke.3 People with depression are three times as likely to be daily smokers4 and have double the suicide rate of non-smokers.5 In Australia, sudden coronary fatalities occur at a rate of about 450 per million people aged under 65,6 perhaps at a rate of 355 per million in non-smokers and about double that in smokers. In three months (the period of recommended bupropion use), one would expect 180 deaths per million smoker-users. Thus, among 277 602 Australian smokers, 50 might die during any given three-month period without any added risk from bupropion. This estimate helps to place the 18 fatalities reported to ADRAC in context. The 277 602 scripts represent about 9.5% of Australia's 2.9 million regular smokers. These people, their families and doctors deserve to have their anxieties about the risks of using bupropion addressed. We would urge the government to commission urgently a case–control study of morbidity and mortality among smokers and their relationships to use or non-use of bupropion.

Simon C Chapman · Konrad Jamrozik

To the Editor: The National Health and Medical Research Council has launched new Australian alcohol guidelines1 to help reduce alcohol-caused deaths in Australia, estimated to have been 3290 in 1997.2 Male drinkers are advised to drink no more than an average of 40 g alcohol per day and females no more than an average of 20 g of alcohol per day to prevent chronic health problems (eg, alcoholic liver cirrhosis). Furthermore, it is recommended that, provided there are no other situational or individual risk factors (such as driving or being pregnant), men drink no more than 60 g on any day and women no more than 40 g to prevent acute conditions associated with bouts of intoxication (eg, alcohol-related injuries). Volumes of alcohol intake reported at each NHMRC risk level by 10 030 respondents to the 1998 National Drug Strategy Household (NDSH) survey were calculated.3 The data were weighted for age and sex. Volumes of alcohol reported to have been consumed at different risk levels were summed for all subjects and expressed as percentages of the total reported consumption of the sample. It was found that 39% of total consumption was categorised as being drunk by people who exceeded low-risk limits for chronic harm (36% for men, 45% for women). It was found that 51% of total consumption occurred on days when the drinker exceeded low-risk limits for acute harm (53% for men and 47% for women). Drinking that was risky for either acute or chronic harm was found to comprise 67% of total consumption (see Table). For young men aged 18–24 years this figure was 93% of all alcohol consumed. These estimates are conservative, as the level of drinking reported in the 1998 NDSH survey is consistent with an adult per capita consumption of only 46.5% of that estimated by the Australian Bureau of Statistics for that year on the basis of import, export and production data.3 The high proportion of all alcohol consumed that places drinkers at risk of serious harm helps explain why per capita alcohol consumption correlates so closely with levels of suicide, road death, homicide, liver cirrhosis and other causes of death.4 It follows that policies which reduce the total consumption of alcohol in Australia will reduce the associated health and economic costs by reducing levels of risky drinking. Further, policies which successfully reduce high-risk drinking will also reduce total population consumption of alcohol. Percentage of alcohol consumed at risk levels for acute and/or chronic harm, as specified in the new Australian alcohol guidelines,1 by age and sex (n = 10 030, weighted data) Age (years) Females (%) Males (%) Total (%) 14–17 71.3 77.4 75.1 18–24 82.3 92.9 89.9 25–39 68.1 66.4 66.9 40–64 67.7 62.0 63.6 65 + 46.5 39.5 41.4 All ages 68.4 66.5 67.0

Tim R Stockwell · Penny Heale · Tanya N Chikritzhs · Paul Dietze · Paul Catalano

Despite a scientific history spanning barely five decades, the field of alcohol and drugs is now a legitimate medical subspecialty. The conceptual base is developing, evidence-based approaches are being used, and more effective interventions are now available.1 With the first adoption of a scientific perspective came the development of more rigorous diagnosis and several robust screening questionnaires, which have proved valuable in research but are not yet widely used in clinical practice. Progress has been made in improving detection rates and in providing interventions for at-risk patients. Now, the Royal Australasian College of Physicians is establishing a Chapter of Addiction Medicine, reflecting the growing scientific base of the alcohol and drug field and paving the way for future expansion. Interventions. In the past decade or two, new and more effective drug treatments have been developed, and the pharmaceutical industry now sees alcohol and drug dependence as a new area for research and development. For alcohol dependence, acamprosate has been shown to promote abstinence or assist in reducing alcohol consumption in a substantial proportion of alcohol-dependent patients.2 Naltrexone, an opioid antagonist, may achieve similar results, but the evidence is less impressive than for acamprosate, and naltrexone's action of blocking opioid analgesics precludes pain management with morphine or other opioids. Brief cognitive-behavioural interventions have been used to help "problem drinkers" reduce their drinking to safer levels before their drinking has health, social or financial complications. For smokers, improved forms of nicotine replacement, nicotine replacement without prescription, and the combination of nicotine replacement with bupropion,3 have made smoking cessation more effective. As reduced smoking prevalence owes more to improved smoking cessation rates than to reduced smoking initiation, these are important developments. Smoking prevalence remains unacceptably high in some vulnerable populations, including Indigenous Australians, prison inmates, and people with alcohol and drug or mental health problems. For heroin dependence, buprenorphine, a partial opioid agonist released in Australia in 2001, is the second effective pharmacological treatment, methadone being the first.4 Naltrexone was introduced in 1997 amid extravagant claims for its effectiveness, but these have not been confirmed, strengthening the arguments for a more evidence-based approach. Perhaps the most important recent advance for people with illicit drug dependence has been the belated recognition that health and social interventions are less costly, more effective and less inclined to result in collateral damage than criminal justice interventions. Increasingly, drug treatment is being combined with criminal justice interventions, although methadone treatment, which was introduced officially in Australia in 1970, was not used in prisons in Australia until 1986. Buprenorpine is also very effective for ambulatory heroin detoxification, although obstacles must first be overcome before it can be made readily available from general practices. Management of selected amphetamine-dependent patients with prescribed dexamphetamine has shown encouraging results overseas, and there has been a successful Australian feasibility trial.5 Prevention. Following the decline in per-capita alcohol consumption over the past 20 years, alcohol-related mortality fell substantially during the 1990s. Alcohol-related brain damage declined after the introduction of thiamine-fortified flour in 1991. Tobacco-related deaths have fallen considerably among men and levelled off in women, reflecting the steady decline in smoking prevalence and per-capita tobacco consumption in recent decades. Antismoking campaigns have played a small part in this decline, with other factors including increased prices, reduced advertising, and restrictions on smoking in public places. Outcomes for prevention of illicit drug use have been extremely disappointing. Drug overdose deaths increased from six in 1964 to 958 in 1999, before dropping sharply in 2001 as a result of a "heroin drought". The control of HIV infection among and from injecting drug users in Australia is a major public health achievement, with successful early and comprehensive programs encompassing explicit and peer-based education, needle syringe programs, methadone treatment and community development. Rapid implementation of these programs was facilitated by the adoption of harm minimisation as Australia's official national drug policy in 1985. Remaining challenges. The alcohol and drug field still struggles to be emancipated from moral and politically inspired constraints. Although there are now better outcomes from the intake of legal drugs, they are still responsible for 97% of drug-related mortality. Moreover, alcohol and tobacco account for half of the 20 years' lower life expectancy of Indigenous Australians. Primary and secondary prevention for alcohol and tobacco needs to be more widely available from general practices. General practice is also an appropriate setting for shared-care management of heroin-dependent patients with methadone or buprenorphine. Improved outcomes for illicit drugs await a political decision to accept that health and social interventions are more effective than law enforcement.

Alex D Wodak

For editorial comment, see Saunders & Richards Abstract - Methods - Results - Discussion - Conclusions - Acknowledgements - References - Authors' details Abstract Objective: To estimate the prevalence of dependent or daily heroin users in Australia, and to compare the prevalence in Australia with that in other developed countries. Design: We applied three different methods of estimation (back-projection, capture-recapture, and multiplier) to data on national opioid overdose deaths in Australia, first-time entrants to methadone maintenance treatment, and heroin-related arrests in New South Wales. We compared our estimates with estimates derived by similar methods in countries of the European Union. Data sources: Data on national opioid overdose deaths were obtained from the Australian Bureau of Statistics. Data on methadone entrants in NSW were extracted from a database maintained by the NSW Department of Health. Data on arrests for heroin-related offences were supplied by the NSW Police Service. Results: The best estimates of the number of dependent heroin users in Australia in 1997-1998 from the three methods of estimation were between 67 000 and 92 000 and the median estimate was 74 000. The population prevalence was 6.9 per 1000 adults aged 15-54 years. The prevalence of heroin dependence in Australia is the same as that in Britain (7 per 1000) and within the range of recently derived estimates in the European Union (3-8 per 1000 adults aged 15-54 years). Conclusions: Although the exact figures need to be interpreted with caution, our estimates suggest that Australia has a substantial public health problem with dependent heroin use that is of a magnitude similar to that in comparable European societies. In Australia, dependent heroin users are typically daily, or near-daily, injectors of heroin, and of other opioid and sedative drugs when heroin is not available. They continue to use heroin despite the risks of being arrested for drug or property crimes, imprisoned for heroin-related offences, contracting infectious diseases, and overdosing.1Credible estimates of the number of dependent heroin users are needed to plan appropriate public policy responses to the consequences of dependent heroin use.2 These consequences, which have negative effects on the community and public health,3 include bloodborne virus transmission,4 premature death from overdose,5 and crime.6 The need for credible estimates is especially pertinent now, because an increased rate of fatal overdoses over the past five years4 has prompted claims in the popular media that there has been a substantial increase in heroin use in Australia in recent years. Household surveys of drug use are not well suited to estimating the prevalence of dependent heroin use, for several reasons. First, heroin use is likely to be under-reported in household surveys because it is an illegal and stigmatised behaviour.7 Second, dependent heroin users' lifestyles also make them less likely to live in conventional households and less likely to participate in household surveys, because of either their unavailability at the time the interviewer calls or their reluctance to be interviewed.8 Third, household surveys may underestimate the number of dependent heroin users in the population, because heroin users are heavily concentrated in a small number of geographic areas where heroin is most readily available.8 When these areas are represented in national samples in proportion to the contribution to the total population, the estimated population rates of heroin use are usually underestimated in national surveys.9 There is no widely accepted "gold standard" method for estimating the size of the "hidden population" of dependent heroin users. The most widely used approach has been to look for a convergence of estimates derived by applying a number of different indirect methods of estimation to data on the consequences of dependent heroin use, such as overdose death and persons seeking treatment.10 We used this strategy to estimate the number of dependent heroin users in Australia. Our aims were: to estimate the number of dependent heroin users in Australia; and to compare the estimated population prevalence in Australia with that in comparable European societies. Methods Data sources Estimates were derived from secondary analyses of the following datasets: national data on the number of fatal opioid overdoses per year between 1964 and 1997 compiled by the Australian Bureau of Statistics; the NSW Health Department's methadone client database between 1987 and 1998, provided by the Pharmaceutical Services Branch (PSB); and data on arrests for heroin offences in the period 1997-1999 from the NSW Police Service. Each of these datasets is likely to be incomplete to different degrees and in different ways. The number of opioid overdose deaths may be underestimated if the cause of death is not recognised as opioid-related. Data on methadone entrants are more likely to be complete because methadone can not be prescribed in NSW until a registration form is completed and identity checks are undertaken to prevent a person registering more than once. Data on arrests for heroin-related offences do not include heroin-dependent people who are arrested for non-drug-related offences, such as property offences. The aim of the study was to look for convergence of estimates derived from "multiple measures of independent imperfection".11 Methods of estimation Three indirect methods were used to estimate the number of dependent heroin users in NSW and Australia. Multiplier methods used the number of national opioid overdose fatalities and NSW methadone maintenance therapy (MMT) clients. For mortality, we used both the conventional multiplier of 100 (which assumes an annual overdose mortality rate of 1%),12 and a multiplier of 125, derived from a meta-analysis of cohort studies of treated heroin users (which suggests an annual mortality rate of 0.8%).9 The multiplier of 3 for MMT was derived from a study of demand for this type of treatment in Australia.13 Capture-recapture estimates were based on the numbers of individuals entering MMT (1995-1998) and arrested for heroin offences (1997-1998), using methods described elsewhere.9 The capture-recapture estimates were across periods of one year, rather than capture-recapture across different data sources in the same time period.14 Back-projection methods were applied to data on national fatal opioid overdose and first-time entrants to MMT in NSW to estimate the incidence and prevalence of heroin dependence. The form of back-projection used was that suggested by Becker and colleagues15,16 (see ref. 17 for details). The current study examined the degree of convergence between the back-projection estimates derived from the two different data sources. A national estimate was derived directly from national opioid overdose deaths. NSW estimates were derived from NSW MMT and arrest data. The NSW estimates were doubled to produce national estimates. This was done because NSW has consistently accounted for just under half of all opioid overdose deaths in Australia since 1979,5 and for just over half of the number of people enrolled in MMT in Australia.6 Results National estimates The estimates produced by the various methods are shown in Box 1. The best estimate for each method for Australia varied between 67 000 and 92 000, with a median of 74 000 and a mean of 77 000. The range of individual estimates was much wider, between 39 000 and 120 000. The degree of consistency between the best estimates derived from different methods from different data sources was reassuring, especially the agreement between the trends in the two back-projection methods over the period 1970-1997 (Box 2). This consistency provides some reassurance that the true estimate of the number of dependent heroin users in Australia is within our range of estimates. In the absence of any consensus on differential weighting of the estimates, we have taken the median national estimate of 74 000 as the best estimate. This represents a population prevalence of dependent heroin use in Australia of 6.9 per 1000 adults aged 15-54 years, with a range of 5.8-8.6 per 1000. Crude estimates of the number of heroin-dependent people in each of the Australian States and Territories can be derived by allocating the estimated number of heroin users in Australia as a whole (74 000) to each jurisdiction in proportion to the contribution that each jurisdiction made to national opioid overdose deaths in the period 1994-1998. On this basis, NSW is estimated to have 35 400 dependent heroin users, just under half of the national estimate (48%). The estimated number of 19 600 heroin-dependent persons in Victoria accounted for 27% of the national estimate. NSW and Victoria therefore account for 75% of all the estimated number of heroin-dependent persons in Australia. The smaller States accounted for the remaining 25%. The estimated numbers of dependent heroin users in the smaller States, particularly Queensland and Tasmania, appear to be underestimates in that they imply that an implausibly high proportion of dependent heroin users are currently receiving treatment. Because better local estimates need to be derived by applying our methods to data in each of the smaller States, we have not reported these estimates here. Discussion Several methods of estimating the size of the population of people who are heroin dependent in Australia have produced estimates that vary between 67 000 and 92 000 people. The median estimate is 74 000, which equals a population prevalence of 6.9 per 1000 population aged 15-54 years. Each estimation method makes assumptions that are of uncertain validity. Although these uncertainties mean that the estimates presented here should be interpreted with caution, there are a number of reasons why our estimates provide a better basis for public policy than more speculative estimates in the popular media. Firstly, there is reassuring convergence between estimates produced by different methods. The two back-projection estimation methods, applied to two very different datasets (new entrants to methadone treatment and opioid overdose deaths), produced estimates that were in close agreement. The ranges of estimates derived by plausibly varying the assumptions also substantially overlapped.17 The estimates produced by the mortality and treatment multiplier methods and the capture-recapture estimates were similar to those produced by the back-projection methods. Secondly, the estimated national prevalence rate is in the middle of the range of estimates of problem drug use derived recently by similar methods in Europe (3-8 per 1000 adults aged 15-54 years).18 The Australian prevalence is the same as the estimated prevalence of heroin dependence in the United Kingdom (7 per 1000 adults aged 15-54 years).18 Several factors explain the discrepancy between our estimates and media estimates of 200 000 Australian heroin users. Our estimate is of dependent heroin users, who are highly visible in a small number of geographic areas in Sydney and Melbourne. This means that they often attract media attention out of all proportion to their numbers. Within these areas, intoxicated dependent heroin users are often highly visible, dealing and using drugs, and leaving discarded injecting equipment in public places. Dependent heroin users who are involved in criminal activities engage in high rates of breaking and entering houses.19 The national estimate for 1997 (74 000) represents a doubling of the 34 000 estimated in 1984-198720 and a 25% increase on the estimate of 59 000 in the period 1988-1993.13 During this time, there was a corresponding increase in the rate of heroin dependence from 3.7 per 1000 in 1984-1987 to 5.9 per 1000 in 1988-1993 and to 6.9 per 1000 in 1997. The back-projection estimates produce trends in numbers that are consistent with these earlier estimates (Box 2). There are three plausible reasons why the number of dependent heroin users has increased in Australia over the past decade. First, there has been a substantial increase in the availability of very pure and very cheap heroin in Australia in the past two decades. The very limited historical data indicate that the purity of street heroin in Sydney has increased from 10% in 197921 to a mean of 60% in 1993-1995.22 The nominal price has remained stable at $30 for a street "cap", but the effective price per ounce of pure heroin has declined from about $16 000 in 1979 dollars to $5000 in 1999 dollars; the difference is even greater when account is taken of inflation.9 Second, the high purity and low price have meant that it has been easier for new users to initiate heroin use by non-injecting routes, such as smoking or inhaling the fumes of heroin heated on aluminium foil. This may have permitted more naive users to begin heroin use before making a transition to injecting.19 Third, the rise in heroin use in birth cohorts born in the latter half of the 20th century is paralleled by similar trends in a range of psychosocial disorders among young adults,23 including depression, suicide, antisocial behaviour and eating disorders. These trends and the reasons for them have been extensively reviewed by Rutter and Smith,23 who conclude that the increases are real. Conclusions Our estimated prevalence of heroin dependence in Australia (74 000 people; a population rate of 6.9 per 1000 adults aged 15-54 years) is similar to that in countries of the European Union. The media attention given to opioid overdose deaths in Australia in recent years has created a false impression that the prevalence of heroin dependence is unusually high in Australia. Other data suggest that, in Australia, dependent heroin use causes a substantial public health5 and public order problem,9 but the current estimates suggest that the number of dependent heroin users is of the same order of magnitude as in Britain and other European societies from which Australia's population has largely derived. Acknowledgements Both the National Centre in HIV Epidemiology and Clinical Research and the National Drug and Alcohol Research Centre are funded by the Commonwealth Department of Health and Aged Care. References Hall W, Lynskey M, Degenhardt L. Heroin use in Australia: its impact on public health and public order. NDARC Monograph No. 42. Sydney: UNSW, 1999. Stimson GV, Judd A. Estimating the scale and nature of drug problems: the relationship between science, policy and drug strategy. In: European Monitoring Centre for Drugs and Drug Addiction. Estimating the prevalence of problem drug use in Europe. EMCDDA Scientific Monograph No. 1. Luxembourg: Office for Official Publications of the European Communities, 1997; 19-26. Mathers C, Vos T, Stevenson C. The burden of disease and injury in Australia. Canberra: AIHW, 1999. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS, hepatitis C and sexually transmissible infections in Australia. Annual Surveillance Report. Sydney: NCHECR, 1999. Hall W, Degenhardt L, Lynskey M. Opioid overdose mortality in Australia, 1964-1997: birth cohort trends. Med J Aust 1999; 171: 34-37. Hall W. Methadone maintenance treatment as a crime control measure. Crime Justice Bull 1996; 29: 1-12. Griffiths P, Farrell M, Howe S. Local prevalence estimation: can an inner city prevalence survey produce useful information? In: European Monitoring Centre for Drugs and Drug Addiction. Estimating the prevalence of problem drug use in Europe. EMCDDA Scientific Monograph No. 1. Luxembourg: Office for Official Publications of the European Communities, 1997; 67-72. Darke S, Ross J, Zador D, Sunjic S. Heroin-related deaths in New South Wales, Australia, 1992-1996. Drug Alcohol Depend 2000; 60: 141-150. Hall W, Ross J, Lynskey M, et al. How many dependent opioid users are there in Australia? NDARC Monograph No. 44. Sydney: UNSW, 2000. Hartnoll R. Cross-validating at local level. In: European Monitoring Centre for Drugs and Drug Addiction. Estimating the prevalence of problem drug use in Europe. EMCDDA Scientific Monograph No. 1. Luxembourg: Office for Official Publications of the European Communities, 1997; 247-161. Cook TD, Campbell DT. Quasi-experimentation: design and analysis issues for field settings. Chicago: Rand McNally, 1979. Frischer M. Estimating the prevalence of drug abuse using the mortality multiplier method: an overview. In: European Monitoring Centre for Drugs and Drug Addiction. Estimating the prevalence of problem drug use in Europe. EMCDDA Scientific Monograph No. 1. Luxembourg: Office for Official Publications of the European Communities, 1997; 113-126. Hall W. The demand for methadone maintenance treatment in Australia. NDARC Technical Report No. 28. Sydney: UNSW, 1995. Hook EB, Regal RR. Capture-recapture methods in epidemiology: methods and limitations. Epidem Rev 1995; 17: 243-264. Becker NG, Watson LF, Carlin JB. A method of non-parametric back-projection and its application to AIDS incidence data. Stat Med 1991; 10: 1527-1542. Becker NG, Watson LF, Marschner IC, et al. Assessing the extent of the Australian HIV epidemic from AIDS surveillance data. Aust J Pub Health 1993; 17: 226-231. Law M, Ross J, Lynskey M, Hall W. Back projection estimates of the number of dependent heroin users in Australia. Addiction 2000; in press. European Monitoring Centre for Drugs and Drug Addiction. Extended annual report on the state of the drugs problem in the European Union 1999. Luxembourg: Office for Official Publications of the European Communities, 1999. Maher L, Dixon D, Lynskey M, Hall W. Running the risks. Heroin, health and harm in South Western Sydney. Sydney: UNSW, 1998. National Drug Abuse Data System NDADS. How many heroin users are there in Australia? Statistical Update No. 5. March 1988. Williams ES. Australian Royal Commission of Inquiry into Drugs. Canberra: AGPS, 1980. Weatherburn D, Lind B. Drug law enforcement policy and its impact on the heroin market. Sydney: NSW Bureau of Crime Statistics and Research, 1995. Rutter M, Smith DJ, editors. Psychosocial disorders in young people: time trends and their causes. Chichester: John Wiley and Sons, 1995. (Received 5 Jun, accepted 25 Aug, 2000) Authors' details University of New South Wales, Sydney, NSW. Wayne D Hall, PhD, Professor and Executive Director, National Drug and Alcohol Research Centre; Joanne E Ross, PhD, Lecturer, National Drug and Alcohol Research Centre; Michael T Lynskey, PhD, Lecturer, National Drug and Alcohol Research Centre; Matthew G Law, PhD, Senior Lecturer, National Centre in HIV Epidemiology and Clinical Research; Louisa J Degenhardt, BA(Hons), Senior Research Assistant, National Drug and Alcohol Research Centre. Reprints: Professor W D Hall, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052. w.hallATunsw.edu.au 1: Estimates of the number of dependent heroin users in New South Wales and Australia (rounded to nearest 1000) Method of estimation Estimate for Australia Range of estimates Back-projection National overdose deaths NSW methadone maintenance therapy entrants 67000 71000 39000-120000* 47000-109000* Capture-recapture Methadone maintenance therapy episodes Arrests for heroin offences 82000 86000 68000-109000† 78000-102000† Multiplier estimates Overdose fatalities (x 100) (x 125) MMT entrants (x 3) 74000 92000 68000 - - - Median estimate 74000 - *Ranges from sensitivity analyses. †95% confidence intervals around estimates. Back to text Back to text

Wayne D Hall · Joanne E Ross · Michael T Lynskey · Matthew G Law · Louisa J Degenhardt

Editorial Alcohol: the good, the bad and the ugly It may be protective against cardiovascular disease, but alcohol is not all good MJA 2000; 173: 231-232 Many recent studies from various countries have consistently highlighted the good effects of alcohol.1 This protective association with alcohol is fairly specific to cardiovascular disease and does not seem to operate for other causes of death. The studies support the notion that the National Health and Medical Research Council (NHMRC) recommendation of two standard drinks a day for women and four standard drinks a day for men2 is sensible advice. That, however, is not the end of the alcohol story. Virtually all of us, as medical students, were exposed to the "bad" of alcohol. Our texts provided lists of diseases caused by the direct effects of high-risk alcohol consumption, as well as the effects of acute intoxication, dependence and withdrawal. Our experience in the wards reinforced these descriptions. In 1997, 3290 Australians (70% men) died of injury and disease caused by high-risk drinking.3 Most of them died of stroke, alcoholic cirrhosis, road injury, suicide, or alcohol dependence. On average, 19 years of life were lost for each person who died of an alcohol-caused condition. At the same time, high-risk drinking was responsible for 72 300 hospitalisations and 403 795 hospital bed-days in Australia; these were predominantly due to falls, alcohol dependence, assaults, or road injuries.3 As medical students, we also witnessed the havoc wrought by alcohol-associated injuries. Between 1990 and 1997, 31% of all driver and pedestrian deaths on Australian roads were alcohol related.4 More than 70% of people with serious alcohol-related road injuries were male (compared with 56% of people with serious non-alcohol-related road injuries). More than half these men were between the ages of 15 and 24 years. The "ugly" was often not seen by medical students. The psychosocial and economic effects of alcohol were rarely spoken about or observed. The annual cost of alcohol misuse in Australia has been estimated at $3.8 billion -- a substantial amount of this is a result of decreased occupational productivity, often a result of hangover-related absenteeism and poor job performance.5 It is estimated that 75% of men and women who have consumed alcohol report that they have experienced hangovers at least once, and 15% experience hangovers at least monthly.5 The leading causes of burden of disease in 15-24-year-old Australian males include alcohol dependence and harmful use, and three other disorders that are related to alcohol: road traffic accidents, suicide, and self-inflicted injury.6 World-wide, alcohol is the fourth leading cause of disability, involving 15.8 million people. In First World regions it is the leading cause, and in Third World regions it is the fourth largest cause, of male disability.7 The recently published National Survey of Mental Health and Wellbeing8 indicates that most Australians (83% of men and 63% of women) report that they have consumed at least 12 drinks of alcohol in the preceding year, and one in 15 (6.5%) have had an alcohol-use disorder in the past 12 months. More men (9.4%) than women (3.7%) had an alcohol-use disorder in the past 12 months, and this is greatest among 18-34-year-olds (almost 16% of men). There is considerable comorbidity between alcohol use and other mental disorders.8 Forty-eight per cent of Australian women with an alcohol-use disorder also suffer from anxiety, affective or other drug-use disorders, compared with 15% of women without alcohol-use disorder; 34% of men with an alcohol-use disorder have another mental disorder. The relation between alcohol and mental disorders is complex: each may cause the other, or both may be related to some underlying cause. Alcohol can also have a devastating effect on families -- more than two-thirds of domestic incidents are alcohol related. Are we making headway against these problems? The initial good news, that since 1978 alcohol consumption in Australia has been progressively falling, is tempered by the slowing of this fall since 1993, and a slight increase in some States. The 1998 National Drug Strategy Household Survey found evidence of increased binge drinking and a softening of attitudes to drinking and driving. In dealing with the problems of alcohol, we need to be aware of two phenomena: Many alcohol-related problems in the community occur in a very large number of people consuming, on a long term basis, above-average but socially acceptable quantities of alcohol, rather than in the much smaller number of persons consuming very large quantities of alcohol.9 Much of the damaging effect of alcohol, particularly in young people, results from episodic (binge) drinking rather than dependent daily consumption of alcohol. These findings have important public health implications. The first point can be partially but effectively addressed by brief intervention strategies delivered by trained GPs as part of their usual strategies.10 However, the second point requires a greater public health commitment to responsible social drinking. Linking alcohol taxes to the alcohol content of beverages is one useful strategy.11 Our strategies need to recognise that people can drink acutely in damaging fashion even if their average weekly consumption is less than the NHMRC limits. Greg Whelan Professor, Department of Drug and Alcohol Studies St Vincent's Hospital, and Physician, Turning Point Alcohol and Drug Centre Inc, Melbourne, VIC Alan T Gijsbers Physician, Department of Drug and Alcohol Studies St Vincent's Hospital, and Turning Point Alcohol and Drug Centre Inc, Melbourne, VIC Doll R. The benefit of alcohol in moderation. Drug Alcohol Rev 1998; 17: 353-363. Pols RG, Hawks DV. Is there a safe level of daily consumption of alcohol for men and women? 2nd ed. Canberra: AGPS, 1992. Chikritzhs T, Jonas H, Heale P, et al. Alcohol caused deaths and hospitalisations in Australia, 1990-1997. National Alcohol Indicators Bulletin No. 1, December 1999. Chikritzhs T, Stockwell T, Heale P, et al. Trends in alcohol-related road injury in Australia, 1990-1997. National Alcohol Indicators Bulletin No. 2, May 2000. Wiese JG, Shiplak MG, Browner WS. The alcohol hangover. Ann Intern Med 2000; 132: 897-902. Mathers C, Vos T, Stevenson C. Burden of disease and injuries in Australia. Canberra: Institute of Health and Welfare, 1999. Murray CJL, Lopez AD. The Global Burden of Disease: a comprehensive assessment of mortality and disability from diseases, injuries and risk factors in 1990 and projected to 2020. Cambridge, Mass: Harvard University Press on behalf of the World Health Organization and the World Bank, 1996. Teesson M, Hall W, Lynskey M, et al. Alcohol and drug use disorders in Australia: implications of the National Survey of Mental Health and Wellbeing. Aust N Z J Psychiatry 2000; 34: 206-213. Kreitman N. Alcohol consumption and the preventive paradox. Br J Addiction 1986; 81: 353-363. Bien TH, Miller WR, Tonigan JS. Brief interventions for alcohol problems: a review. Addiction 1993; 88: 315-336. Richardson J. Alcohol taxes: the case for reform. Med J Aust 1990: 152: 619-620. Make a comment

Greg Whelan · Alan T Gijsbers

For Debate Should we conduct a trial of distributing naloxone to heroin users for peer administration to prevent fatal overdose? Simon R Lenton and Kim M Hargreaves MJA 2000; 173: 260-263 Abstract - Should there be a trial - Suggested trial design - Conclusion - References - Authors' details - - More articles on Drugs and alcohol Abstract Heroin overdose is a major cause of death among heroin users, and often occurs in the company of other users. However, sudden death after injection is rare, giving ample opportunity for intervention. Naloxone hydrochloride, an injectable opioid antagonist which reverses the respiratory depression, sedation and hypotension associated with opioids, has long been used to treat opioid overdose. Experts have suggested that, as part of a comprehensive overdose prevention strategy, naloxone should be provided to heroin users for peer administration after an overdose. A trial could be conducted to determine whether this intervention improves the management of overdose or results in a net increase in harm (by undermining existing prevention strategies, precipitating naloxone-related complications, or resulting in riskier heroin use). The rate of fatal heroin overdose in Australia has risen from 10.7 per million in 1979 to 67.0 per million in 1995; similar increases have been reported in other developed countries.1 Heroin users have an excess mortality about 13 times that of their age-matched peers,2 with annual mortality rates of between 1% and 3%.3 Although non-fatal overdoses are common among heroin users, overdose remains a major cause of death among this group,4 even in countries with high rates of HIV among injecting drug users.5 The central nervous system (CNS) depressants benzodiazepines and/or alcohol are often also present in the blood of people who died of heroin-related overdose.3,6In many fatal heroin overdoses there is ample opportunity for intervention: approximately 60% of deaths occur in the company of others,3,4,6-8 mostly other users, and sudden death after injecting is rare (about 15% of deaths).6,9 Death occurs more than three hours after injection in 22%-52% of cases.3 Furthermore, most overdoses occur in a home or other dwelling.9 Witnesses to fatal overdoses only call an ambulance in about 10% of cases,6 and there is no intervention before death in 79% of cases.3 Reasons for not calling an ambulance include fear of police involvement,8,10 ambulance costs,7 and previous negative experiences with hospital staff.10 Since the early 1990s, experts have suggested that naloxone hydrochloride, an opioid antagonist (Box), which has long been used to treat opioid overdose, should be provided to heroin users for administration by their peers in an overdose situation.8,24,38-40 This is one of a range of interventions aimed at reducing the incidence of fatal overdose, including: overdose prevention (eg, educating heroin users about risk factors for overdose and ways of reducing the risks, and increasing numbers in methadone maintenance treatment); and overdose management (eg, providing basic first aid training to heroin users, with emphasis on the need to call an ambulance).41 Naloxone has been available over-the-counter from pharmacies in Italy since 1995 and therefore available for peer administration. There are unpublished reports of authorised distribution for peer administration in Jersey (UK) and Berlin (Germany), and underground distribution through needle exchanges in San Francisco and Chicago, USA. However, to our knowledge, its use by heroin users and their peers has not yet been evaluated. In July 1998, the Health Department of Western Australia (HDWA) commissioned the National Drug Research Institute to explore the feasibility of conducting a trial of naloxone provision for peer administration. We discuss the issues to be considered in deciding whether or not a trial should proceed. The views expressed here are ours and not necessarily those of the HDWA. Should there be a trial of naloxone for peer administration? Distribution of naloxone for peer administration is clearly an intervention with potential to reduce the number of fatal heroin overdoses. However, from a public health perspective, questions remain regarding the impact of naloxone on the uptake and effectiveness of other overdose prevention strategies. Additionally, there is a risk of subsequent morbidity or mortality if no medical follow-up occurs after naloxone administration. These concerns can best be addressed by a multisite longitudinal study of naloxone provision within a carefully monitored group. Below, we summarise the issues to be considered in recommending such a trial. Method of administration The preferred route for peer administration would be intramuscular (see Box). Shelf life and stability Naloxone has a shelf life of 18 months to 2 years, depending on the product form and preparation. Because of this short shelf life, a trial would attempt to determine whether drug users replace expired stock. Furthermore, there are concerns about naloxone's stability and susceptibility to environmental factors. If it is made available for peer administration, it is likely to be left in the glove box of cars or carried in pockets or bags for extended periods of time. Although it is preferable that naloxone be stored in accordance with the manufacturers' recommendations, one manufacturer reports it has been stored at 40ºC for six months, and frozen for up to a month, without compromising its chemical stability (Brenda Fox, Medical Affairs Pharmacist, Fauldings Ltd, 1998, personal communication). Half-life and recurrent overdose Another major concern about the wider availability of naloxone relates to its short duration of effect: its elimination half-life is estimated to be 30-90 minutes, with individual differences due to variations in metabolism.12 Although evidence to date suggests that recurrent overdose is rare,18,23,42 there is the potential for resedation to occur, particularly when longer-acting opioids such as methadone have been used, or additional drugs have been consumed after naloxone administration. Thus, it will often be necessary to administer subsequent doses of naloxone. Research in Victoria suggests that, when ambulance staff administer an intramuscular dose of up to 1.6 mg total dose, few, if any, problems arise, with 90% of patients regaining consciousness (Dr Paul Dietze, Senior Research Fellow, Turning Point Drug and Alcohol Centre Inc, 1999, personal communication). As part of a trial, it may be appropriate to supply two 0.8 mg/2 mL prefilled syringes of naloxone for intramuscular administration (to allow a subsequent dose if necessary), accompanied by appropriate instructions on administration, polydrug intoxication, and the need for medical review. Airway management and first aid In many overdose situations all that is necessary to improve an individual's condition is to provide ventilatory support.27 Even after naloxone is administered, ventilatory support is required until it takes effect. The ability to administer first aid, in particular expired air resuscitation, should therefore be viewed as an integral part of any education provided for peer-administered naloxone. Information about possible complications and how to identify them should also be included. Polydrug use The use of other CNS depressants, particularly alcohol and benzodiazepines, is common in overdoses involving heroin,3,6,8,43,44 but should not preclude a trial of naloxone. Removal of the opioid effect with naloxone could prevent a fatality,40 minimise associated morbidity, and provide time in which to use other interventions. If CNS stimulants are used in conjunction with opioids, naloxone has the potential to unmask their associated toxicity and produce aggression, hypertension, acute pulmonary oedema, cardiac arrhythmia, or seizures.45,46 This may be more of a concern where cocaine use, particularly "speedballs" (heroin mixed with cocaine), is increasingly common among heroin users.47 Overdose prevention strategies should continue to warn users about polydrug use. Solitary heroin users Using heroin alone is a significant risk factor for overdose, as is using heroin in the company of others and then being left to "sleep it off". One of the arguments against the distribution of naloxone for peer administration is that it will have no impact on the death rate among solitary injecting drug users. The dangers of using drugs alone or failing to monitor sleeping drug users should be emphasised in a trial of naloxone. Naloxone administration by intoxicated peers Concern has been expressed that peers available to administer naloxone may be intoxicated, but this is also likely with other overdose management strategies. Some current strategies are quite complex and require vigilance, such as expired air resuscitation, monitoring, checking the pulse, and so on. Naloxone administration, particularly with a prefilled syringe, seems no more complicated, and its use should not be precluded because the person administering it may be affected by drugs. Undermining other overdose strategies Availability of naloxone for peer administration may undermine existing overdose prevention and management strategies, notably calling an ambulance. Research supports this, with many heroin users believing that peer administration of naloxone would negate the need to call an ambulance.8,40,48 Thus, some non-fatal overdose victims may not be transported to hospital.48 This is similar to what occurs in many Australian States after naloxone administration -- overdose patients refuse to be transported to hospital or, alternatively, leave hospital against medical advice. In these situations, wherever possible, the individual is placed in the care of a "responsible person", and in several States ambulance staff provide a pamphlet which outlines potential risks and gives basic first aid information. A similar intervention should be included in any trial of naloxone provision, with users encouraged to seek medical review after peer-administration of naloxone. Impact on heroin use among current users It has been suggested that some heroin users, if they believe that their peers can revive them with naloxone, might take more risks with their use of heroin.38 It is unlikely that this behaviour would become widespread, not least because of the unpleasant effect of naloxone in precipitating withdrawal in opioid-dependent people.8,24,39 According to heroin users, factors other than the likelihood of overdose or strategies available to prevent it influence drug use.48 Removing barriers to first use Naloxone provision could make heroin use appear safer and therefore encourage its uptake by novices. However, similar concerns were raised about the wider availability of needles and syringes, and there is no evidence that these measures have encouraged injecting among those previously not using needles.49 Rapid detoxification There is anecdotal evidence to suggest that some people take opioid antagonists to lower their tolerance and reduce the amount of heroin needed to achieve their desired level of intoxication. This has the potential to increase the individual's risk of overdose. Naltrexone, an oral opioid antagonist, is now more readily available for the treatment of opioid dependence and therefore people are more likely to use this treatment to lower their opioid tolerance than naloxone. However, the extent to which naloxone is used to reduce dependence should be assessed as part of a trial. Suggested trial design As peer administration of naloxone would take place within drug-using networks, a network sampling strategy is appropriate. This would recruit heroin users (and their peers) who have experienced and/or witnessed multiple overdose events. The trial could compare "first aid plus naloxone access and training" with "first aid only" across three Australian States over a 12-month period. An initial intake of 450 heroin users should produce a final sample of 250 individuals at 12 months, and about 180 overdose events for investigation.48 Power calculations for logistic regression analyses on a final sample of 250 would produce a power of 97% for events with a probability of 0.2, and 88% for events with a probability of 0.1, with an odds ratio of 2.0 with variables correlated at 0.4. Contamination between the intervention and control groups is a potential problem. In States with large populations of users in regional centres, geographical distance could be used to counteract this. It may also be possible to have a larger control group and place control respondents who gain access to naloxone into a third group. This would maintain the integrity of the control group, while allowing some analysis of the diffusion of the "naloxone training and access" intervention into other groups. Economic cost We estimate the cost of running a trial at three sites to be about $300 000, of which the cost of naloxone would be about $25 000 (1250 doses) at full retail price. Trial results could contribute to an economic modelling of the potential cost effectiveness of naloxone distribution. Dietze et al50 have estimated the cost of ambulance attendance for heroin overdoses in Victoria at over $1 million per annum, which they regard as cost effective in terms of preventing serious injury and death. If naloxone is recommended for more widespread distribution in the future, research suggests that many heroin users (75%) would be willing to pay for their own naloxone,51 which would further reduce the cost of the intervention. Legal issues A number of legal issues are raised by the possibility of conducting a trial of peer-administered naloxone. Central to this is the mechanism of providing naloxone to trial participants. If provided on prescription under Schedule 4, both the patient and the prescriber would be legally compromised when, as is likely, a third person administers the drug. Trial participants could be issued with a permit to access the drug, but this would compromise confidentiality. The drug could be rescheduled from Schedule 4 to Schedule 3 (dispensed by pharmacists only and stored out of public access) for the purposes of the trial, although the requirement for supervised dispensing could not be guaranteed given that the drug is likely to be passed to a third person. The drug could be removed from scheduling for persons involved in a possible future trial under an agreement between the research consortium and the relevant statutory body. While, to our knowledge, this has not been done before, it would enable the identity of trial participants to remain confidential. This would simplify the issue of naloxone provision and/or administration by a third person, and may also limit the exposure of participating agencies to civil action. Conclusion Faced with increasing heroin overdose deaths, the provision of naloxone to heroin users for peer administration is one of a range of interventions worth trialling. However, questions remain as to whether it can appropriately be used by peers as part of a comprehensive first aid intervention, and whether it improves outcomes, or results in net increases in harm. Net harm could increase as a result of undermining existing strategies, naloxone-related complications, or riskier heroin use. Many of these questions could be answered by a multisite longitudinal study of naloxone provision within a carefully monitored group. References Darke S, Ross J. Fatal heroin overdoses resulting from non-injecting routes of administration, NSW, Australia, 1992-1996. Addiction 2000; 95: 569-573. English DR, Holman CDJ, Milne E, et al. The quantification of drug caused morbidity and mortality in Australia. 1995 edition. Canberra: Commonwealth Department of Human Services and Health, 1995. Darke S, Zador D. Fatal heroin "overdose": a review. Addiction 1996; 91: 1765-1772. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney Australia. 1. Prevalence and correlates of non-fatal overdose. Addiction 1996; 91: 405-411. Davoli M, Perucci CA, Rapiti E, et al. A persistent rise in mortality among injection drug users in Rome, 1980 through 1992. Am J Public Health 1997; 87: 851-853. Zador D, Sunjic S, Darke S. Heroin-related deaths in New South Wales, 1992: toxicological findings and circumstances. Med J Aust 1996; 164: 204-207. Loxley W, Davidson P. Forgetting to breathe: opioid overdose and young injecting drug users in Perth. Perth: Curtin University of Technology, National Centre for Research into the Prevention of Drug Abuse, 1998. McGregor C, Darke S, Ali R, Christie P. Experience of non-fatal overdose among heroin users in Adelaide, Australia: circumstances and risk perceptions. Addiction 1998; 93: 701-711. Darke S, Ross J. Heroin-related deaths in South Western Sydney: 1992-1996. Sydney: The University of New South Wales, National Drug and Alcohol Research Centre; 1998. Gore C. Report of the Pilot Heroin Overdose Peer Education project -- March 1997. NSW: Centre for Education and Information on Drugs and Alcohol, 1997. MIMS (Australia). 1998 MIMS Annual. Sydney, NSW: Intercontinental Medical Statistics (Australasia), 1998: 1176-1177. Chamberlain JM, Klein BL. A comprehensive review of naloxone for the emergency physician. Am J Emerg Med 1994; 12: 650-660. David Bull Laboratories (Australia). Naloxone hydrochloride injection. USP product information. Melbourne Vic: David Bull Laboratories; 1992. Boots Pharmaceuticals (Australia). Narcan injection and Narcan Neonatal injection. Product information. Sydney, NSW: The Boots Company (Australia) Pty Ltd, 1993. Moore RA, Rumack BH, Conner CS, Peterson RG. Naloxone: underdosage after narcotic poisoning. Am J Dis Child 1980; 134: 156-158. Jasinski DR, Martin WR, Haertzen CA. The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol Exp Ther 1967; 157: 420-426. Barsan WG, Olinger CP, Adams HP, et al. Use of high dose naloxone in acute stroke: Possible side-effects. Crit Care Med 1989; 17: 762-767. Jacobs I, Oxer H. The use of naloxone in the pre-hospital management of narcotic overdose. Perth: Western Australian Pre-Hospital Care Research Unit; 1998. Bernard S, Barger W. An audit of two different doses of intramuscular naloxone in prehospital narcotic overdose. Melbourne: Melbourne Ambulance Service, 1995. Sporer KA, Firestone J, Isaacs SM. Out-of-hospital treatment of opioid overdoses in an urban setting. Acad Emerg Med 1996; 3: 660-667. Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema. Ann Emerg Med 1987; 16: 1294-1296. Osterwalder JJ. Naloxone -- for intoxications with intravenous heroin and heroin mixtures: harmless or hazardous? A prospective clinical study. Clin Toxicol 1996; 34: 409-416. Seidler D, Sthülinger GH, Fischer G, et al. After antagonization of acute opiate overdose: a survey at hospitals in Vienna. Addiction 1996; 91: 1479-1487. Strang J, Darke S, Hall W, et al. Heroin overdose: the case for take-home naloxone. BMJ 1996; 312: 1435. Kanof PD, Handelsman L, Aronson MJ, et al. Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. J Pharmacol Exp Ther 1992; 260: 355-363. Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th edition. New York: McGraw Hill, 1996: 549-551. Moss J. Ambulances say "no" to Narcan. Connexions 1997; 17: 29. Gaddis GM, Watson WA. Naloxone-associated patient violence: an overlooked toxicity? Ann Pharmacother 1992; 26: 196-198. Judson BA, Himmelberger DU, Goldstein A. The naloxone test for opiate dependence. Clin Pharmacol Ther 1980; 27: 492-501. Neal JM. Complications of naloxone. Ann Emerg Med 1988; 17: 765-766. Ward S, Corall IM. Hypertension after naloxone. Anaesthesia 1983; 38: 1000-1001. Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784. Azar I, Turndorf H. Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg 1979; 58: 524-525. Flacke JW, Flacke WE, Williams GD. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977; 47: 376-378. Brimacombe J, Archdeacon J, Newell S, Martin J. Two cases of naloxone-induced pulmonary oedema -- the possible use of phentolamine in management. Anaesth Intensive Care 1991; 19: 578-580. Harrington LW. Acute pulmonary edema following use of naloxone: a case study. Crit Care Nurse 1988; 8: 69-73. Yealy DM, Paris PM, Kaplan RM, et al. The safety of prehospital naloxone administration by paramedics. Ann Emerg Med 1990; 19: 902-905. Darke S, Hall W. The distribution of naloxone to heroin users. Addiction 1997; 92: 1195-1199. Strang J, Farrell M. Harm minimisation for drug misusers: when second best may be best first. BMJ 1992; 304: 1127-1128. Strang J, Powis B, Best D, et al. Preventing opiate overdose fatalities with take-home naloxone: pre-launch study of possible impact and acceptability. Addiction 1999; 94: 199-204. Hall W. Reducing the toll of opioid overdose deaths in Australia. Drug Alcohol Rev 1999; 18: 213-220. Vilke GM, Buchanan J, Dunford JV, Chan TC. Are heroin overdose deaths related to patient release after prehospital treatment with naloxone? Prehosp Emerg Care 1999; 3: 183-186. Bammer G, Sengoz A. Non-fatal heroin overdoses. Med J Aust 1994; 161: 572-573. Coleridge J, Cameron PA, Drummer OH, McNeil JJ. Survey of drug-related deaths in Victoria. Med J Aust 1992; 157: 459-462. Hsu W, Rao RB, Nelson LS. Naloxone hazards overstated. Clin Toxicol 1997; 35: 215-217. Buchwald A. Naloxone use: side effects may occur. Ann Emerg Med 1988; 17: 765. Hando J, Darke S. NSW Drug Trends 1997. Findings from the Illicit Drug Reporting System (IDRS). Sydney: The University of New South Wales, National Drug and Alcohol Research Centre, 1998. Hargreaves K, Lenton S. The Naloxone Feasibility Study. Perth, Western Australia: National Drug Research Institute, Curtin University of Technology, 2000. In press. Des Jarlais DC, Friedman SR. AIDS and the use of injected drugs. Sci Am 1994; February: 56-62. Dietze PM, Cvetkovksi S, Rumbold G, Miller P. Ambulance attendance at heroin overdose in Melbourne: the establishment of a database of Ambulance Service records. Drug Alcohol Rev 2000; 19: 27-33. Darke S, Ross J, Cohen J, Hall W. Context and correlates of non-fatal overdose among heroin users in Sydney. Sydney: The University of New South Wales, National Drug and Alcohol Research Centre, 1994. Authors' details National Drug Research Institute, Curtin University, Perth, WA. Simon R Lenton, MPsych(Clin), Research Fellow. Kim M Hargreaves, BA, Research Associate. Reprints: Mr S R Lenton, National Drug Research Institute, GPO Box U1987, Perth, WA 6845. simonATndri.curtin.edu.au Make a comment Naloxone hydrochloride NALOXONE HYDROCHLORIDE is an opioid antagonist that competitively binds to µ-opiate receptors to reverse the respiratory depression, sedation and hypotension associated with opioids. It does not reduce the respiratory depression caused by non-opioid central nervous system (CNS) depressants, such as alcohol and benzodiazepines, and lacks pharmacological activity in the absence of opioids.11 Naloxone is classified under Schedule 4 of the Poisons Schedule (prescription only) and is available either as ampoules or prefilled syringes (Min-I-Jet [CSL Ltd]). It is effective when given by intravenous, intramuscular or subcutaneous injection,12 being rapidly distributed to the brain and other body tissues. Effects are observed within 1-2 minutes of intravenous administration and 2-5 minutes of intramuscular or subcutaneous administration.13,14 Naloxone has been administered millions of times in emergency departments for opioid overdose;12 in very large doses (eg, 20 times the recommended dose in a 30-month-old15 and up to 24mg/70kg in adults16); and over a number of weeks to evaluate efficacy and toxicity in patients with acute stroke,17 without major complications. Naloxone in the prehospital setting When used to treat opioid overdose, naloxone has been reported to improve consciousness and alertness in 64%-80% of patients within 10 minutes of administration,18,19 and in other patients it improved respiration. As long as blood pressure can still be recorded, its administration can be beneficial.20 Naloxone-related complications have been reported after treatment of opioid overdose.20-22 However, many of the apparent drug reactions observed could also have resulted from the overdose itself.22,23 Treatment of heroin overdose in the United Kingdom and Australia suggests that such reactions are rare, with no significant problems reported after hundreds of administrations.24 Naloxone does have the potential to precipitate opioid withdrawal symptoms when administered to opioid-dependent people,25,26 and may result in generalised convulsions.11,22 Those in acute withdrawal can become aggressive and endanger themselves and others.27,28 Withdrawal symptoms are typically less severe after intramuscular than intravenous administration.29 With the correct equipment (eg, prefilled syringes), intramuscular administration is also easier to perform and has a longer duration of action. The disadvantage of intramuscular administration is the delayed onset of action. Naloxone in the postoperative setting Naloxone is used after surgery to reverse the CNS depression caused by opioids administered during the procedure. Naloxone complications have been documented in this setting,30 with an increased risk when pre-existing hypertension and cardiovascular disease are present.31 Many of the complications reported - hypertension, atrial and ventricular tachycardia, fibrillation, left ventricular failure, pulmonary oedema, and sudden death12,32-34 - occurred in patients with underlying cardiac or pulmonary disease. Pulmonary oedema attributed to naloxone administration has also been reported among individuals with no underlying medical conditions.21,34-36 Many patients who experience adverse effects do so after an operation when multiple medications have been administered, so the causal role of naloxone is uncertain.12,37 Back to text

Simon R Lenton · Kim M Hargreaves

Personal Perspective The New South Wales Drug Summit: a view from a local foreign observer Jeffrey H Samet MJA 2000; 173: 264-265 1. "The Drug Summit was just a political exhibition" - 2. "All agree on one thing" - 3. "I hope that this forum does not end up as some sort of factionalised debate" - Acknowledgements - References - Authors' details - - More articles on Drugs and alcohol In December 1998, on sabbatical leave from Boston University School of Medicine, I spent time at the University of Sydney's Faculty of Medicine, because I thought that the Australian experience had something special to teach those of us in the United States working on the "drug problem". The timing was remarkable -- illicit drug policy became a captivating major news topic, culminating in the Drug Summit in Sydney in May 1999.1 Drug abuse, despite its importance from personal, public health, public safety and economic perspectives, has not received comparable concerted public attention within the United States in a generation or more. The dynamics of the Australian discussion were fascinating, but certain opinions expressed seemed in need of reconsideration. 1. "The Drug Summit was just a political exhibition -- nothing useful will come of it." This point of view, prevalent before and during much of the Drug Summit, was extremely cynical and not constructive. Not acknowledging the existence of a problem is a very well known practice in the world of drugs and alcohol. In fact, the first goal in the treatment of patients who misuse drugs is getting them to acknowledge that a problem exists.2No one expects to fix the problem the first few times it is addressed. The same perspective should frame the discussion about activities that recently took place in the New South Wales Parliament. Firstly, it was significant that the drug issue was widely acknowledged as a major societal problem. Secondly, it was remarkable that politicians joined together with the most experienced professionals and affected individuals to search for understanding and common ground on how to address the issue. This phenomenon should be recognised for what it was: major progress. The summit enabled politicians to gain, at minimum, a basic understanding of the issues of addiction and substance misuse. Politicians will in future be better able to assess drug policy proposals. The extensive media coverage educated Australia's citizens, both adults and young people, about the realities of falling victim to mind-altering substances. It reminded members of society that drug abuse is a scourge and the reality of drug addiction is painful and sad. History teaches us that this lesson is all too quickly forgotten, and such refresher lessons play a valuable role.3 The Drug Summit's very existence was a very important and useful event. Cynicism was inappropriate. 2. "All agree on one thing, nothing in the past has been successful." One early conclusion, announced after the first day of the Summit, was a condemnation of past efforts. Australian newspaper headlines echoed the theme of past failures. This summary critique was not an appropriate keynote to an Australian drug summit. Absence of either a cure or a recipe for prevention does not equate with a past record of failure. Clearly, the drug problem is huge and ever in need of innovative approaches to combat it; nonetheless, Australia has much about which to be proud in its approach to illicit drug use. One in four injecting drug users in the United States are infected with HIV.4 As a consequence, the individual suffering, high costs of medical care, and transmission to non-injecting partners and newborns are immense burdens on society. This scenario has been largely avoided in Australia, where fewer than 3 in 100 injecting drug users are infected with HIV.5,6 This is success, incredible success, and hopefully not ephemeral success. The existence of a treatment system in which thousands of individuals each year in Australia get help in their struggle to deal with their addiction is progress. Of course, striving to expand and improve the quality of those services and the institution of trials to find innovative new approaches are required, but there has been unequivocal progress in this field. Research successes are also notable. The best data in the world on heroin overdose have been collected and analysed by the Australian National Drug and Alcohol Research Centre.7,8 As a result, approaches to intervention have been developed and this "silent epidemic" is no longer silent in Australia. HIV prevention, extensive treatment (even if insufficient), and innovative practical research are recognised Australian successes in this field. 3. "I hope that this forum does not end up as some sort of factionalised debate ... -- a war on drugs versus legalisation; zero tolerance versus harm reduction." The discourse at the Drug Summit covered important issues, but the terms used in the illicit drug policy discussion often got confused. Consequently, some messages were at risk of misinterpretation. "Harm reduction" is not synonymous with "legalisation". The goals are different. The message is different. Equating these terms does injustice to both issues. There are data to support the effectiveness of some harm reduction efforts and there is a desire to collect data for other proposed harm reduction efforts.9,10 This situation is quite different from a theoretical discussion of the harms and benefits of legalisation of certain aspects of illicit drug use. The latter is a public policy question with enormous potential consequences unlikely to be subjected to the rigours of scientific testing to assess efficacy. On the other hand, it is very useful to subject novel approaches to harm reduction to the careful scrutiny of clinical trials before broader dissemination. The inappropriate equating of these terms is detrimental and should be strongly resisted. It is important to realise that drug problems are an area where agreement on desirable outcomes is possible. The path to those outcomes has been hampered by a disturbing and remarkable amount of factional debate. In this most useful public health discussion, absence of cynicism, recognition of past success, and clarity of terms will serve to remove impediments from a struggle that will continue long after the wonderfully focused efforts of the NSW Drug Summit have become a fading memory. We in the United States can learn from Australia's willingness to publicly confront these issues. Acknowledgements I am indebted to Drs James Rankin, Paul Haber, Alex Wodak and Wayne Hall, who were so kind to me during my sabbatical term in Australia and who provided feedback about this manuscript. Without their openness and generosity of spirit I would not have had the opportunity to see what I saw or write what I wrote. References Swan N. Drug doings down under. JAMA 1999; 281: 1782-1783. Samet JH, Rollnick S, Barnes H. Beyond CAGE: a brief clinical approach after detection of substance abuse. Arch Intern Med 1996; 156: 2287-2293. Musto D. The American disease: origins of narcotic control. New York: Oxford University Press, 1987. Centers for Disease Control and Prevention. HIV/AIDS surveillance report. 1997; 9(2): 1-44. Kaldor JM, Elford J, Wodak AD, et al. HIV prevalence among IDUs in Australia: a methodological review. Drug Alcohol Rev 1993; 12: 175-184. MacDonald M, Wodak AD, Ali R, et al. HIV prevalence and risk behaviour in needle exchange attenders: a national study. Med J Aust 1997; 166: 237-240. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney, Australia I. Prevalence and correlates of non-fatal overdose. Addiction 1996; 91: 405-411. Darke S, Ross J, Hall W. Overdose among heroin users in Sydney, Australia I. Responses to overdose. Addiction 1996; 91: 413-417. Hurley SF, Jolley DJ, Kaldor JM. Effectiveness of needle-exchange programmes for prevention of HIV infection. Lancet 1997; 349: 1797-1800. Drucker E, Lurie P, Wodak A, Alcabes P. Measuring harm reduction: the effects of needle and syringe exchange programs and methadone maintenance on the ecology of HIV. AIDS 1998; 12(Suppl A): S217-S230. Authors' details Section of General Internal Medicine and the Clinical Addiction Research and Education (CARE) Unit, Departments of Medicine and Social and Behavioral Sciences, Boston University Schools of Medicine and Public Health, Boston, MA. Jeffrey H Samet, MD, MPH, Associate Professor of Medicine and Public Health. Reprints: Associate Professor J H Samet, Section of General Internal Medicine, Research Unit, 91 East Concord Street, Suite 200, Boston Medical Center, Boston, Massachusetts, 02118 USA. jsametATbu.edu Make a comment

Jeffrey H Samet

Viewpoint An analgesic role for cannabinoids Christopher W Vaughan and Macdonald J Christie Cannabinoids have significant analgesic properties in animal models, particularly for chronic pain states, but there are few human studies. An endogenous cannabinoid system, with specific receptors and transmitters, has recently been discovered. This discovery has led pharmacologists to explore the potential of synthetic cannabinoids to selectively target chronic pain disorders without producing the side effects associated with cannabis. Well-controlled clinical trials on cannabinoids, and cannabinoid delivery systems, are now required. MJA 2000; 173: 270-272 The endogenous cannabinoid system and pain - Evidence for analgesic efficacy - Adverse effects - The place for analgesia - Conclusion - References - Authors' details - - More articles on Drugs and alcohol Natural and synthetic cannabinoids produce a range of pharmacological effects with a number of potential therapeutic applications, including the treatment of pain.1-3 However, the political climate prevailing for much of the latter half of the 20th century has censored investigation of its potential therapeutic properties. Recently, expert groups convened by the British Medical Association, the House of Lords, and the United States National Institutes of Health have concluded that cannabinoids may have therapeutic efficacy under some conditions.1,4,5 These groups have recommended further study into the therapeutic benefits of cannabis and cannabinoids, particularly in relation to the relief of chronic pain. Several developments provide compelling arguments to re-examine the medical use of cannabis and cannabinoids. Recent studies on the molecular nature of cannabinoid receptors and their endogenous ligands have provided a rational basis to understand and extend empirical observations of therapeutic efficacy. The development of synthetic cannabinoids, some of which are currently the subject of controlled human trials, has raised hopes of enhanced benefits and reduced side effects. Widespread illicit use, partial relaxation of legal sanctions, and dispassionate assessments of the severity of adverse effects have eased some of the public concern over the dangers of cannabis. The endogenous cannabinoid system and pain The actions of Δ-9-tetrahydrocannabinol (THC), the principal active component in cannabis, can be understood in terms of the natural functions of the endogenous cannabinoid system, which has only recently been identified. Functional, cellular and molecular studies suggest that cannabinoids might have important applications in specific pain conditions (more detailed reviews are available elsewhere2,3). There are at least two distinct human cannabinoid receptors: CB1 and CB2 receptors (more types may yet be found).6 CB1 receptors are located in brain regions involved in mood, motor control, memory formation, regulation of food intake, autonomic control and processing of noxious or painful information, and in peripheral autonomic and reproductive systems. CB2 receptors are found within immune and reproductive tissues. The distinct localisation of CB1 and CB2 receptors is consistent with many of the therapeutic and adverse effects of cannabinoids, and raises the possibility that synthetic agents (unlike THC, which acts on both CB1 and CB2 receptors) can be developed to selectively target different physiological systems. THC mimics a group of natural substances produced within the body, including anandamide.7 These endogenous cannabinoids are partly similar to other neuromodulators in that they are synthesised within the brain, are released from neurones after stimulation, activate specific receptors, and undergo rapid uptake and degradation. However, there is still a great deal to be learned about this novel class of neuromodulators. There is now an intensive research effort to design drugs that will modify the metabolism of endogenous cannabinoids to influence these physiological functions in novel ways.8 Animal studies have clearly demonstrated that THC, synthetic cannabinoids, and endogenous cannabinoids produce analgesia and potentiate opioid analgesia.2,3 In many respects, the analgesic actions of cannabinoids and opioids are similar, although the two classes of drugs act on different receptors and act via partially distinct cellular mechanisms in pain control systems.2 Recent studies predict that cannabinoids might be effective in specific chronic pain states. The efficacy of cannabinoids is increased in nociceptive and inflammatory pain.9 In addition, cannabinoids (unlike opioids) maintain their analgesic activity in neuropathic or nerve injury induced pain and reduce the associated allodynia and hyperalgesia.10,11 Evidence for the analgesic efficacy of cannabinoids in humans Although opioids are the most important drugs used to treat moderate to severe pain, some clinically important pain states, particularly neuropathic pain, are relatively insensitive to opioid treatment.12 Anecdotal evidence suggests that cannabinoids produce relief from pain in humans, but there are few well controlled clinical trials.1,4,5,13 Some studies have reported that THC and related analogues have acute analgesic activity, and relieve postoperative pain and chronic pain associated with cancer, multiple sclerosis and familial Mediterranean fever;14-17 others have reported that these compounds have no analgesic effect, or even produce hyperalgesia.18,19 It is difficult to reconcile the results of these studies given the different doses or purity of cannabinoid extracts, routes of administration (smoked, oral, intramuscular, intravenous), subject numbers and selection (naive or habitual users, patients with chronic pain), and the methods of analgesia testing.5 Adverse effects of cannabinoids There is a risk of serious adverse effects of cannabis, but these have often been overstated.20 The adverse effects, although sufficiently serious to restrict legitimate medical use, should be considered in the context of potential benefits and the severity of disorders for which its use is contemplated. Many drugs (including opioids) currently used for similar indications, particularly intractable pain, are associated with much more serious risks, such as respiratory depression. More extensive comparisons of the therapeutic benefits and adverse effects of cannabinoids are available elsewhere.1,2,5,13,21-23Cannabis is sufficiently intoxicating to impair ability to carry out critical tasks safely for several hours after consumption.23 Although intoxication is sought by recreational users, it is often cited as a reason to discontinue therapeutic use. Cannabis can produce temporary distress and panic, transient psychosis, exacerbation of pre-existing mental illness, particularly schizophrenia,23 and has been linked to an increased risk of suicide.24 Medical use of cannabis would be contraindicated in individuals with a history of these responses or predispositions. Regular recreational use of cannabis can lead to dependence, as defined by standard criteria for substance-misuse disorders.23 While the incidence of serious cannabis dependence is difficult to estimate, regular heavy use, producing a state of near-continuous intoxication, occurs in 5%-10% of regular recreational users. The potential for dependency disorders among medical cannabis users is uncertain, but, by analogy with other addictive drugs such as opioids, prevalence of addiction would be expected to be relatively low with appropriate therapeutic use. In this regard, the US Drug Enforcement Administration has recently transferred oral THC (dronabinol) from a Schedule II to a Schedule III non-narcotic drug.25 Cannabis produces acute tachycardia, and long term exposure produces postural hypotension and bradycardia.2,5,13,23 The severity of this risk has not been established, but is of sufficient concern to exclude individuals with a history of cardiovascular disorders from clinical trials. Smoked cannabis carries similar risks of respiratory disorders as smoked tobacco, which restricts the circumstances for which this route of administration can be considered. The place of smoked cannabis for analgesia Some disorders seem to respond better to smoked cannabis, whereas others are relieved just as well by oral THC, which is legally available for clinical use (as dronabinol) in many parts of the world.5,13 The reasons for these differences are still unknown. Subjective reports indicate that smoked cannabis produces a more rapid and reliable effect than oral THC, permitting the patient to titrate desired actions while minimising side effects.2,22 Cannabis smoke contains carcinogens and airway irritants which increase the risk of cancers of the mouth, throat and lung, but the severity of this risk has not been established. However, smoked cannabis might prove more beneficial to some patients if the risks of smoking are outweighed by benefits such as relief from intractable pain. Limited availability of smoked marijuana was recommended by both the House of Lords committee4 and the Institute of Medicine21 as an interim solution. In the long term, delivery systems such as inhalation devices are needed to provide patients with non-smoked, rapid-onset cannabinoid delivery systems for rapid, precise control over both beneficial and adverse effects.5,13,21 Such developments and licensing are expected to take at least five years. Conclusion There is some experimental evidence to suggest that cannabinoids may have therapeutic efficacy in various pain states, but there is an urgent need for well controlled clinical trials to establish the utility of both natural and synthetic cannabinoids, and cannabinoid delivery systems. Pharmacologists have only just begun to explore the therapeutic potential of synthetic cannabinoids that might avoid the undesirable side-effects of psychomotor impairment, cognitive disruption and intoxication. Smoked cannabis does not have long term prospects as a therapeutic agent, but there is some evidence and sufficient pharmacokinetic grounds to expect this mode of administration to have benefits in terms of patient control over desired and adverse effects. Major international expert groups have therefore recommended on compassionate grounds that smoked cannabis be made available to patients with severe debilitating diseases while superior cannabis delivery systems are being developed. References British Medical Association. Therapeutic uses of cannabis. Amsterdam: Harwood Academic Publishers, 1997. Grotenhermen F, Russo E. Cannabis and cannabinoids -- pharmacology, toxicology and therapeutic potential. New York: Haworth Press. In press. Howlett AC. Pharmacology of cannabinoid receptors. Annu Rev Pharmacol Toxicol 1995; 35: 607-634. House of Lords Select Committee on Science and Technology. Cannabis: the scientific and medical evidence. HL Paper 151. London: The Stationery Office, 1998. Available at <http://www.parliament.the-stationery-office.co.uk/pa/ ld199798/ldselect/ldsctech/151/15101.htm>. National Institutes of Health. Report on the medical uses of marijuana. 1997. <www.nih.gov/news/medmarijuana/MedicalMarijuana.htm>. Accessed 24 July 2000. Devane WA, Dysarz FA 3d, Johnson MR, et al. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol 1988; 34: 605-613. Devane WA, Hanus L, Breuer A, et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946-1949. Beltramo M, Stella N, Calignano A, et al. Functional role of high-affinity anandamide transport, as revealed by selective inhibition. Science 1997; 277: 1094-1097. Jaggar SI, Hasnie FS, Sellaturay S, et al. The anti-hyperalgesic actions of the cannabinoid anandamide and the putative CB2 receptor agonist palmitoylethanolamide in visceral and somatic inflammatory pain. Pain 1998; 76: 189-199. Bian D, Nichols ML, Ossipov MH, et al. Characterization of the antiallodynic efficacy of morphine in a model of neuropathic pain in rats. Neuroreport 1995; 6: 1981-1984. Mao J, Price DD, Lu J, et al. Two distinctive antinociceptive systems in rats with pathological pain. Neurosci Lett 2000; 280: 13-16. National Health and Medical Research Council. Acute pain management scientific evidence. Canberra: NHMRC, 1999. Ashton CH. Biomedical benefits of cannabinoids? Addiction Biol 1999; 4: 111-126. Noyes R Jr, Brunk SF, Avery DAH, et al. The analgesic properties of delta- 9-tetrahydrocannabinol and codeine. Clin Pharmacol Ther 1975; 18: 84-89. Staquet M, Gantt C, Machin D. Effect of a nitrogen analog of tetrahydrocannabinol on cancer pain. Clin Pharmacol Ther 1978; 23: 397-401. Jain AK, Ryan JR, McMahon FG, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol 1981; 21: 320S-326S. Holdcroft A, Smith M, Jacklin A, et al. Pain relief with oral cannabinoids in familial Mediterranean fever. Anaesthesia 1997; 52: 483-486. Hill SY, Schwin R, Goodwin DW, Powell BJ. Marihuana and pain. J Pharmacol Exp Ther 1974; 188: 415-418. Raft D, Gregg J, Ghia J, et al. Effects of intravenous tetrahydrocannabinol on experimental and surgical pain. Psychological correlates of the analgesic response. Clin Pharmacol Ther 1977; 21: 26-33. Chesher GB, Christie MJ, Morgan JP. Science signals a new understanding of marihuana. Drug Alcohol Rev 1994; 13: 307-317. Joy JE, Watson SJ, Benson JA, editors. Marijuana and medicine: assessing the science base. Washington, DC: National Academy Press, 1999. Gowing LR, Ali RL, Christie P, et al. Therapeutic use of cannabis: clarifying the debate. Drug Alcohol Rev 1998; 17: 445-452. Hall W, Solowij N, Lemon J. The health and psychological consequences of cannabis use. National Drug Strategy Monograph Series No. 25. Canberra: AGPS, 1994. Beautrais AL, Joyce PR, Mulder RT. Cannabis abuse and serious suicide attempts. Addiction 1999; 94: 1155-1164. Department of Justice, Drug Enforcement Administration. Schedules of Controlled Substances: rescheduling of the Food and Drug Administration approved product containing synthetic dronabinol [(-) Δ9-(trans)-tetrahydrocannabinol] in sesame oil and encapsulated in soft gelatin capsules from Schedule II to Schedule III. (Doc. 99-16833) Federal Register 1999; 64(127): 35928-35930. Available at <http://frwebgate.access.gpo.gov/cgi-bin/getdoc.cgi?dbname=1999_ register&docid=99-16833-filed>. Authors' details Department of Pharmacology, University of Sydney, Sydney, NSW. Christopher W Vaughan, PhD, MBiomedE, R D Wright Research Fellow; Macdonald J Christie, PhD, BSc(Hons), Head of Department and Medical Foundation Fellow. Reprints: Dr C W Vaughan, Department of Pharmacology, The University of Sydney, Sydney, NSW 2006. chrisvATpharmacol.usyd.edu.au Make a comment

Christopher W Vaughan · Macdonald J Christie

Editorial Alcohol and cardiovascular disease: still a research priority? MJA 2000; 173: 116-117 More precision in measuring drinking levels and patterns will give a firmer basis for advice about drinking The evidence amassed to date on the link between moderate alcohol intake and reduced risk of dying of cardiovascular disease might be thought already sufficient to bracket sceptics of alcohol's protective effect with doubters of manned lunar missions and members of the Flat Earth Society. Published studies demonstrating this link can now be counted in the hundreds, and no fewer than six plausible underlying biological mechanisms have been identified.1 In this issue of the Journal yet another study reports this link: Simons and colleagues show moderate alcohol intake to be associated with increased survival in elderly people.2 Their study is an elegant example of the genre and drawn from a highly respected prospective study of risk factors for death and illness in the population of Dubbo, New South Wales. The two fields of epidemiology and alcohol studies have much to learn from each other Alternative explanations for the protective effect of moderate alcohol intake, relying on ever more tenuous confounding effects, have been discredited one by one. The apparently protective effect of moderate alcohol consumption has so far survived the use of controls for sociodemographic status,3 for the "sick quitter hypothesis"4 (ie, the suggestion that many abstainers have stopped drinking because of serious illness), for the amount of cholesterol in the diet,5 and even for the degree of social isolation.6 As evidenced in the study by Simons et al,2 the protective effect is fairly specific to cardiovascular disease and does not operate for other major causes of death in older people such as cancer. While a handful of recent studies have failed to find a protective effect for moderate drinking,7,8 these are still heavily outnumbered by those with positive findings.1 In fact, the range of different countries and cultures in which the phenomenon has been documented is also testimony to its robustness, even if different levels of consumption appear to provide the benefit in different drinking cultures.1 So, does medical science need further research on this topic? My contention is that, while the basic protective properties of moderate alcohol consumption appear to have been identified, the precision of the measurement of drinking levels and patterns in these studies needs to be sharpened if we are to have a firmer basis for advising people how to drink to avoid ill-health. The recent major systematic review commissioned by the National Health and Medical Research Council to underpin revisions to Australia's national guidelines on low risk drinking found that nearly all epidemiological studies in this area only attempt to measure one of the important dimensions of alcohol consumption: total volume of drinking, usually expressed as average intake per day.1 Despite recent evidence that pattern of drinking plays a role independent of volume,9 large-scale epidemiological studies rarely include simple items in their questionnaires tapping this dimension, such as frequency of drinking five or more drinks in one day, or maximum amount consumed on one day. Simons et al make a rare contribution to our knowledge by providing an analysis of mortality risk, based not only on average volume of alcohol across all days, but also on usual amount consumed on a drinking day. Clearly, these can be very different measures (eg, seven drinks in a day once a week versus one drink every day of the week).2 While the power of the analyses in Simons et al is limited by sample size, usual consumption of five or more drinks for men and of three or four drinks in a day for women was not associated with a significantly reduced risk of death.2 It should be noted, however, that questions regarding "usual" consumption tend to suffer from a bias towards low-consumption occasions and against less frequent occasions of high intake.10 Forthcoming World Health Organization guidelines on measurement of alcohol consumption advise that a superior method is the "graduated quantity frequency", in which respondents are asked how often they drink at each of different levels of consumption, starting with the highest (eg, "How often do you drink 20 drinks on one day?").10 The same guidelines identify another problem bedevilling attempts to convert the results of alcohol studies into precise advice for drinkers: assumptions about the alcohol content of drinks reported vary between studies and are usually not empirically based. A number of studies from different countries have attempted to document usual-serve sizes employed by random samples of drinkers and found these to vary significantly from those usually assumed by researchers.11,12 One study found that the bias created towards under-reporting of consumption was massive in one particular population subgroup: Afro-American women.13 One striking consequence of a failure to measure pattern of alcohol consumption adequately can be the false identification of special benefits from one type of alcoholic beverage over another. Wine is often reported as being most associated with benefits, but being a wine drinker as opposed to a beer and spirits drinker is a marker for many other things, including a tendency towards a more consistent pattern of daily drinking rather than occasional "bingeing".14 A well known Danish study,3 often cited as evidence for a greater benefit of wine over other drinks, measured alcohol consumption by only asking about how much people usually drank if they drank every day. Because this is a less frequent pattern for heavy drinkers of beer and spirits, many of the latter will have been falsely categorised as light or moderate drinkers, thus significantly biasing against finding protective effects for these beverages. The two fields of epidemiology and alcohol studies have much to learn from each other. If epidemiological studies of risk factors for heart disease do not improve their measurement of patterns and levels of alcohol use, it will remain very hard to give precise advice to drinkers who wish to minimise harms and maximise benefits of alcohol consumption. In reality, despite hundreds of studies into the protective effects of alcohol in relation to heart disease, research into this area has only just begun. Timothy R Stockwell Director National Centre for Research into the Prevention of Drug Abuse Curtin University of Technology, Perth, WA Single E, Ashley MJ, Bondy S, et al. Evidence regarding the level of alcohol consumption considered to be low-risk for men and women. Final report. Canberra: National Health and Medical Research Council, 2000. URL: <http://www.nhmrc.health.gov.au/advice/alc-comp.htm> (accessed 29 June 2000). Simons LA, McCallumJ, Friedlander Y, et al. Moderate alcohol intake is associated with survival in the elderly: the Dubbo Study. Med J Aust 2000; 173: 121-124. Gronbaek M, Deis A, Sorensen TIA, et al. Mortality associated with moderate intakes of wine, beer or spirits. BMJ 1995; 310: 1165-1169. Rehm J, Sempos CT. Alcohol consumption and all-cause mortality: questions about causality, confounding and methodology. Addiction 1995; 90: 493-498. Rehm J, Sempos CT. Alcohol consumption and all-cause mortality. Addiction 1995; 90: 471-480. Murray RP, Rehm J, Shaten J, Connett JE. Does social integration confound the relation between alcohol consumption and mortality in the Multiple Risk Factor Intervention Trial (MRFIT)? J Stud Alcohol 1999; 60: 740-745. Leino EV, Romelsjo A, Shoemaker C, et al. Alcohol consumption and mortality. II. Studies of male populations. Addiction 1998; 93: 205-218. Hart CL, Smith GD, Hole DJ, Hawthorne VM. Alcohol consumption and mortality from all causes, coronary heart disease, and stroke: results from a prospective cohort study of Scottish men with 21 years follow up. BMJ 1999; 318: 1725-1729. Rehm J, Ashley KJ, Room R, et al. On the emerging paradigm of drinking patterns and their social and health consequences. Addiction 1996; 91: 1615-1621. World Health Organization (Substance Abuse Department). International guidelines for monitoring alcohol consumption and harm. Geneva: WHO. In press. Stockwell T. Information provided in Australia about the size of "standard drinks". Med J Aust 1992; 156, 295. Lemmens P. The alcohol content of self-report "standard drinks". Addiction 1994; 89: 593-602. Kaskutas L, Graves K. An alternative to standard drinks as a measure of alcohol consumption. Paper presented at International Conference on the Measurement of Drinking Patterns, Alcohol Problems and the Connection; 2000 April 2-7; University of Stockholm, Sweden. In press. Doll R. One for the heart. BMJ 1997; 315: 1664-1668. Make a comment

Timothy R Stockwell

Introduction Concern about cannabis use is not new: ordinances were passed in 8th-century Egypt prohibiting use of hemp drugs, transgressors being subject to tooth extraction!1 In the 19th century, controversy over widespread cannabis use led to the Indian Hemp Drugs Commission, a large-scale investigation into the health effects (both physical and mental) of cannabis use. The Commission's wide-ranging report found that the relationship between cannabis and "mental injury" was complex, and criticised many witnesses for their obvious bias.2 Social, moral and political agendas continue to influence both cannabis research and the "cannabis debate".3 Are there grounds for concern? Cannabis is now widely used by young people in Australia, mostly intermittently. However, 7% of 17-year-old girls and 11% of boys the same age use it at least weekly.4 Furthermore, the concentration of the primary psychoactive component of cannabis, δ-9-tetrahydrocannabinol, may have increased in recent years due to hydroponic cultivation and cross-breeding,5 although the evidence for this is patchy.3 The implications for the mental health of users are unclear; the more pressing issue may be the as yet unquantified impact of a declining age of initiation into cannabis use.6There are several potential psychological harms of cannabis use (Box). The link between cannabis and psychosis remains the most intriguing. Specifically, cannabis has been noted to cause psychotic-like symptoms during intoxication, to lead to a "cannabis psychosis", to increase the relative risk of schizophrenia, and to affect the clinical course of established schizophrenia.11 Population studies, such as the Epidemiologic Catchment Area study in the United States, confirm an association between cannabis use and psychotic symptoms. In this study, daily marijuana use over a year was associated with a 2.4-times greater risk of psychotic experiences, while any use was associated with a 1.3-times greater risk for self-reported psychotic experiences when compared with non-users. The relative risk for daily users remained significant after adjustment for other substance abuse and baseline psychiatric diagnoses.12 Is there a specific "cannabis psychosis?" The case for a specific acute "cannabis psychosis" is based largely on case reports and case series that link a history of cannabis use with a psychotic presentation. Two types of presentation are described: a "toxic psychosis", in which psychotic symptoms are associated with confusion. This generally occurs after ingestion of large amounts of cannabis in someone with no significant psychiatric history, and recovery is usually rapid with abstinence;13 and a functional psychosis occurring without confusion (exacerbation of schizophrenia, and schizophreniform psychoses). The case for a true functional psychosis caused by cannabis is more vexed than the case for a "toxic psychosis", with various authors describing a heterogeneous clinical picture, often with manic features.14 The better-designed studies suggest that it is, in fact, hard to delineate a specific functional cannabis psychosis. McGuire and colleagues examined all patients presenting with psychotic symptoms at two London hospitals, comparing those with positive and negative results on urinary cannabinoid screening.15 Using structured interviews, they found a similar spread of diagnoses and illness onset among case and control patients, with similar numbers of first admissions and symptom profiles. Cannabis and schizophrenia Does cannabis cause schizophrenia? Perhaps the more worrying question is whether cannabis causes chronic psychosis, particularly schizophrenia. The work of Andreasson and others examined this question in a cohort of male Swedish conscripts, followed up through a national psychiatric case register.16 They found that having used cannabis between one and 10 times at conscription increased the relative risk of schizophrenia to 1.3, the risk rising to 6.0 for those who had used cannabis on 50 or more occasions. However, this relative risk was reduced after adjustment for factors which independently contributed to the risk of schizophrenia. While this study provides some of the strongest evidence for a link between cannabis and psychosis, methodological concerns have been raised. These include the temporal gap between self-reported cannabis use at conscription and later schizophrenia, the potential confounding role of other substance use (particularly as amphetamines were a major drug of abuse during the study period), the adequacy of psychological assessment at conscription, and the reliability of self-reported drug use at conscription.3 Nevertheless, the association between cannabis use and schizophrenia is strengthened by studies which demonstrate that cannabis is widely used among people with schizophrenia. A recent study in Newcastle examined substance use in all outpatients with schizophrenia, finding 29.9% of subjects had some use of cannabis in their lifetime, with 7.7% and 28.3% of subjects having lifetime diagnoses of cannabis abuse and dependence, respectively.17Notably, alcohol was more commonly used than cannabis, while amphetamines were the third most commonly used substance. A number of hypotheses have been proposed to explain the prevalence of cannabis use in schizophrenia. Apart from the causation/precipitation role, it has been suggested that cannabis is used as self-medication for psychotic or dysphoric symptoms, or to ameliorate the side effects of antipsychotic drugs. Alternatively, the relationship may reflect the common peaks of onset of schizophrenia and cannabis use (particularly as prevalence samples are seldom compared with age- or sex-matched general population controls), or the role of underlying factors such as demographic differences. How might cannabis use affect established schizophrenia? Clinical intuition suggests that cannabis has an adverse effect on the clinical course, a view supported by some well-designed studies. Linszen and colleagues studied 93 subjects with schizophrenia prospectively over a year, finding a higher rate of relapse in the cannabis-users than in the non-users, with a differential risk of relapse according to level of cannabis use.18 This effect persisted after adjustment for age, sex, age at first hospital admission, and alcohol use. However, this study was limited by the failure to consider the role of polysubstance use, reliance on self-report alone, and the gross measure of compliance used. Data from the Epidemiologic Catchment Area study also support a relationship between an alcohol- or cannabis-use disorder and a higher risk for hospitalisation in those with schizophrenia over a year.19 However, in this study, substance use covaried with depressive rather than psychotic symptoms, suggesting a complex relationship between substance use and symptoms in schizophrenia. Confounding issues: The relationship between cannabis and psychosis is thus far from straightforward. Cannabis is rarely the only substance used. Other factors, such as personality, may confound the relationship. One study found higher rates of schizotypy in volunteer cannabis users, raising the possibility that the relationship between cannabis and psychosis is mediated by a premorbid "psychosis prone" personality.20 Mueser and colleagues have identified antisocial personality as a common factor underlying both schizophrenia and substance-use disorders.21 Methodological concerns, such as the failure to assess and control for use of other substances and reliance on the case-study method, make it difficult to draw firm conclusions in this area. A possible neurophysiological link Recent findings in neuroscience have lent credence to a link between cannabis and psychosis. An endogenous cannabinoid system has been identified, with one type of cannabinoid receptor (CB1) found in the hippocampus, associated cortical areas, cerebellum and basal ganglia.22 In rat brain, cannabinoid receptors have been shown to collocate with dopamine D1 receptors,23 and cannabis administration increases the activity of tyrosine hydroxylase (an enzyme linked to dopamine metabolism).24 These findings hint at the mechanism through which cannabis could lead to psychosis, by modulation of dopaminergic transmission. The discovery of cannabinoid receptors has also led to the discovery of endogenous cannabinoids, among them anandamide (from the Sanskrit word for "bliss"). Such discoveries have encouraged some researchers to speak of a "cannabinoid hypothesis" of schizophrenia, likening the cognitive deficits of schizophrenia to those induced temporarily by δ-9-tetrahydrocannabinol. Indeed, a recent study found higher levels of two endogenous cannabinoids in cerebrospinal fluid in 10 patients with schizophrenia compared with 11 non-psychotic control patients.25 The authors suggested this may represent the response of the cannabinoid system to dopamine imbalance, or may reflect an underlying pathogenic "hypercannabinergic" state. This intriguing result can be viewed as preliminary only, because of the small number of subjects and the paucity of information about possible confounding factors, particularly substance use. The role of cannabinoids is being investigated in other neurological conditions, including Huntington's chorea and Tourette's syndrome. Such theories, while appealing, remain purely speculative. A hundred years have passed since the Indian Hemp Drugs Commission. The research that has followed confirms an association between cannabis and psychosis, but the nature of the connection remains elusive. We clearly see a need for further carefully controlled, prospective clinical studies, as well as insights from neuroscience, to clarify whether the relationship is causal or, in fact, due to factors common to both cannabis and psychosis. However, in the meantime, we believe it is important to inform young people with psychosis of the possible impact of ongoing cannabis use on their symptoms, particularly on the risk of relapse. References Dhunjibhoy JE. A brief resume of the types of insanity commonly met with in India, with a full description of Indian "hemp insanity" peculiar to the country. J Ment Sci 1930; 76: 254-264. Mikuriya TH. Physical, mental and moral effects: The Indian Hemp Drugs Commission Report. Int J Addict 1968; 3: 253-270. Hall W, Solowij N, Lemon J. The health and psychological consequences of cannabis use. National Drug Strategy Monograph Series No. 25. Canberra: AGPS, 1994. Donnelly N, Hall W. Patterns of cannabis use in Australia. National Drug Strategy Monograph Series No. 27. Canberra: AGPS, 1994. Adams IB, Martin BR. Cannabis: pharmacology and toxicology in animals and humans. Addiction 1996; 91: 1585-1614. Greenfield SF, O'Leary G. Sex differences in marijuana use in the United States. Harv Rev Psychiatry 1999; 6: 297-303. Fergusson DM, Horwood LJ. Early onset cannabis use and psychosocial adjustment in young adults. Addiction 1997; 92: 279-296. Yamaguchi K, Kandel DB. Patterns of drug use from adolescence to adulthood. II. Sequences of progression. Am J Public Health 1984; 74: 668-672. Solowij N. Cannabis and cognitive functioning. Cambridge: Cambridge University Press, 1998. Thornicroft G. Cannabis and psychosis. Is there epidemiological evidence for an association? Br J Psychiatry 1990; 157: 25-33. Hall W. Cannabis use and psychosis. Drug Alcohol Rev 1998; 17: 433-444. Tien AY, Anthony JC. Epidemiological analysis of alcohol and drug use as risk factors for psychotic experiences. J Nerv Ment Dis 1990; 178: 473-480. Bernhardson G, Gunne L-M. Forty-six cases of psychosis in cannabis abusers. Int J Addict 1972; 7: 9-16. Thacore VR, Shukla SRP. Cannabis psychosis and paranoid schizophrenia. Arch Gen Psychiatry 1976; 33: 383-386. McGuire P, Jones R, Harvey I, et al. Cannabis and acute psychosis. Schizophr Res 1994; 13: 161-168. Andreasson S, Allebeck P, Engstrom A, Rydberg U. Cannabis and schizophrenia. Lancet 1987; 2: 1483-1486. Fowler IL, Carr VJ, Carter NT, Lewin TJ. Patterns of current and lifetime substance use in schizophrenia. Schizophr Bull 1998; 24: 443-455. Linszen DH, Dingemans PM, Lenior ME. Cannabis abuse and the course of recent onset schizophrenic disorders. Arch Gen Psychiatry 1994; 51: 273-279. Cuffel BJ, Chase P. Remission and relapse of substance use disorders in schizophrenia. Results from a one-year prospective study. J Nerv Ment Dis 1994; 182: 342-348. Williams JH, Wellman NA, Rawlins JNP. Cannabis use correlates with schizotypy in healthy people. Addiction 1996; 91: 869-877. Mueser KT, Rosenberg SD, Drake RE, et al. Conduct disorder, antisocial personality disorder and substance use disorders in schizophrenia and major affective disorders. J Stud Alcohol 1999; 60: 278-284. Herkenham M, Lynn AB, Little MD, et al. Cannabinoid receptor localization in brain. Proc Natl Acad Sci U S A 1990; 87: 1932-1936. Herkenham M. Cannabinoid receptor localization in brain: relationship to motor and reward systems. Ann N Y Acad Sci 1992; 654: 19-32. Hernandez ML, Garcia-Gil L, Berrendro F, et al. Æ-9-tetrahydrocannabinol increases activity of tyrosine hydroxylase in cultured fetal mesencephalic neurons. J Mol Neurosci 1997; 8: 83-91. Leweke FM, Giuffrida A, Wurster U, et al. Elevated endogenous cannabinoids in schizophrenia. Neuroreport 1999; 10: 1665-1669. Authors' details Manly Hospital, Sydney, NSW. Diana R McKay, FRANZCP, Psychiatrist. University of Sydney Academic Psychiatry, Royal North Shore Hospital, Sydney, NSW. Christopher C Tennant, MD, FRANZCP, Professor of Psychiatry. Potential psychological harms of cannabis use Cannabis has been associated with: early school leaving (the strength of the association lessening after adjusting for cannabis users' poor school performance before cannabis use);7possible progression to other illicit drug use;8an "amotivation" syndrome (now felt to represent chronic intoxication in heavy long-term users); dependence;3subtle impairments in information processing;9 and psychosis.10

Diana R McKay · Christopher C Tennant

The evidence so far is not promising Since July 1997, the Australian media have uncritically reported therapeutic claims that naltrexone, an orally well-absorbed, long-acting opioid antagonist, can be used to "cure" heroin dependence. Naltrexone displaces heroin from opioid receptors in the brain, blocking the effects of any opioid agonists while the patient continues to take it. It has no opioid agonist effects and hence is "non-addictive". The current media enthusiasm ignores the reported modest success of naltrexone maintenance in the treatment of heroin dependence over almost 20 years.1,2 Research has shown that induction onto naltrexone is difficult, compliance poor, treatment retention disappointing and abstinence an uncommon outcome.1,3,4 More than 20 years ago the consensus was that naltrexone maintenance has a limited role in treatment of opioid-dependent street users, although it may be useful for drug-dependent professionals and parolees.5 Renewed enthusiasm for naltrexone was based on the claim that it can be used to accelerate withdrawal from heroin and other opioids, allowing immediate induction onto naltrexone maintenance. Because naltrexone may precipitate distressing withdrawal symptoms, naltrexone-accelerated withdrawal is performed under general anaesthesia or light sedation (using benzodiazepines and other symptomatic medications). Induction is followed by naltrexone maintenance for six to 12 months. Media enthusiasm for combined naltrexone-accelerated withdrawal and maintenance has not been shared by many addiction specialists in Australia,6 the United Kingdom7 or the United States.8-10 They have been concerned that this type of induction adds to the expense and possibly reduces the safety of a relatively ineffective maintenance treatment. However, professional scepticism was overwhelmed by the media's recitation of yet to be published claims that the combined procedure achieved abstinence rates of 70%-80% at three months. The article by Bell and colleagues11 in this issue of the Journal is the first peer-reviewed Australian report of naltrexone-accelerated withdrawal under light sedation, followed by naltrexone maintenance. It is a pilot study of 30 patients who were followed up for three months. Although there was no comparison group, the results reinforce the concerns expressed by addiction specialists about the efficacy and safety of naltrexone-accelerated withdrawal and maintenance. Three months after treatment, seven patients (23%) were still abstinent from opioids, only two of whom were still taking naltrexone. One patient had died of a heroin overdose, while most returned to heroin use or methadone maintenance (7 and 11, respectively). Of the six (20%) who were still taking naltrexone, four engaged in the risky practice of using heroin after briefly interrupting the naltrexone maintenance. Patient selection may be one explanation for the marked discrepancy between these results and those reported in the media. Most of the patients in Bell and colleagues' study had long histories of heroin dependence, and half were in methadone maintenance treatment. Although none of these characteristics is said to exclude patients from naltrexone treatment, patients treated in private clinics appear to have much shorter dependence careers and stronger family and social support. The death observed in this case series, and other deaths overseas,3 raise concerns about the safety of naltrexone maintenance. These concerns have been dismissed by promoters of naltrexone-accelerated withdrawal, who assert -- without evidence -- that naltrexone is life-saving. The overdose fatality rate in treated heroin addicts has been estimated at a little less than 1% annually.12 There is no evidence that mortality rates in naltrexone-accelerated withdrawal and maintenance are better than this; they may well be worse, as has been reported in one controlled study.3 Strong conclusions should not be drawn about the efficacy of the procedure on the basis of Bell et al's data, even though favourable reports from less rigorously conducted studies have been accepted uncritically. The role of naltrexone (and other agents to assist in opiate withdrawal) in opioid dependence should be clearer on completion in 2001 of controlled trials of the combined procedure, with and without anaesthesia, as part of the National Evaluation of Pharmacotherapies for Opioid Dependence. In the meantime, thanks to an uncritical media, aggressive marketing and political intervention, Australia is in the midst of a large, uncontrolled experiment using naltrexone-accelerated withdrawal and maintenance to treat unselected opioid-dependent people in the absence of systematic national monitoring of efficacy, safety, or adverse events. It is of particular concern that we have no way of monitoring overdose deaths that may occur when patients discontinue naltrexone maintenance and relapse to heroin use, when research indicates that most unselected patients do return to heroin use.1 There are lessons to be learned from the introduction of naltrexone-accelerated withdrawal and maintenance in Australia. Firstly, decision-making about research and service provision for illicit drug dependence requires the same rigour and evidence demanded elsewhere in medicine. In the absence of this evidence, false expectations of cure will continue to be raised and dashed, scarce research and treatment funding will be wasted, and little progress will be made in improving treatment outcomes. Management of drug dependence has more in common with a marathon than a 100 m sprint. Secondly, all new interventions in medicine should be assumed ineffective and possibly unsafe until proven otherwise. No good evidence has yet been presented to challenge the assumption that naltrexone, however packaged, is at best modestly effective, and at worst unsafe, in management of unselected cases of opioid dependence. Wayne D Hall Professor of Drug and Alcohol Studies, National Drug and Alcohol Research Centre, University of New South Wales Sydney, NSW Alex Wodak Director, Alcohol and Drug Service, St Vincent's Hospital, Sydney, NSW Reprints: Professor W D Hall, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052. Mattick RP, Bell J, Daws LC, et al. Review of evidence on the effectiveness of antagonists in managing opioid dependence. National Drug and Alcohol Research Centre Monograph No 34. Sydney: National Drug and Alcohol Research Centre, 1997. Judson BA, Goldstein A. Naltrexone treatment of heroin addiction: One-year follow-up. Drug Alcohol Depend 1984; 13: 357-365. Miotto K, McCann MJ, Rawson RA, et al. Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Drug Alcohol Depend 1997; 45: 131-145. San L, Pomarol G, Peri JM, et al. Follow-up after a six-month maintenance period on naltrexone versus placebo in heroin addicts. Br J Addiction 1991; 86: 983-990. Thomas M, Kauders F, Harris M, et al. Clinical experiences with naltrexone in 370 detoxified addicts. In: Julius D, Renault P, editors. Narcotic antagonists: naltrexone. Vol 9. Rockville, MD: National Institute on Drug Abuse, 1976: 88-92. xHall W, Mattick RP, Saunders J, Wodak A. Rapid opiate detoxification treatment. Drug Alcohol Rev 1997; 16: 325-327. Gossop M, Strang J. Rapid anaesthetic-antagonist detoxification of heroin addicts: what origins, evidence base and clinical justification? Br J Intensive Care 1997; 7: 66-69. O'Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA 1998; 279: 229-234. Kleber HD. Ultrarapid opiate detoxification. Addiction 1998; 93: 1629-1633. Helman BH, Czechowicz D. NIDA scientific report of ultra rapid detoxification with anesthesia (UROD). Opinion of the consultants and criteria relating to evaluating the safety and efficacy of UROD. Washington: National Institute on Drug Abuse, 1996. Bell J, Young M, Masterman S, et al. A pilot study of naltrexone-accelerated detoxification in opioid dependence. Med J Aust 1999; 170: 26-30. English D, Holman CJD, Milne E, et al. The quantification of drug caused morbidity and mortality in Australia 1995 edition. Canberra: Commonwealth Department of Human Services and Health, 1995.

Wayne D Hall · Alex Wodak

Abstract Objective: 1. To determine whether naltrexone-accelerated detoxification with minimal sedation is an acceptable and effective form of induction onto naltrexone. 2. To monitor outcomes of detoxified patients. Design: Observational study. Setting: Medical ward of a general hospital (for detoxification) and a community clinic (for follow-up) in Sydney, NSW, 1998. Patients: 15 heroin users and 15 people seeking withdrawal from methadone. Intervention: Detoxification used naltrexone (12.5 or 50 mg), with flunitrazepam (2-3 mg), clonidine (150-750 µg) and octreotide (300 µg) for symptomatic support. Patients remained awake and were discharged when they felt well enough. Follow-up was daily for four days and then weekly for up to three months for supportive care. Main outcome measures: Acute side effects; patient ratings of severity and acceptability of withdrawal; nights of hospitalisation; rates of induction onto naltrexone; retention in treatment over three months; and relapse to opioid use. Results: Acute withdrawal with delirium lasted about four hours. Octreotide was crucial for controlling vomiting; with octreotide no patient required intravenous fluids. There were no major complications. Eighteen patients (60%) reported that it was a "quite" acceptable procedure, 18 (60%) required only one night's hospitalisation, and 24 (80%) were successfully inducted onto naltrexone (defined as taking naltrexone on Day 8). Three months later, six (20%) were still taking naltrexone (with four of these occasionally using heroin) and seven (23%) were abstinent from opioids, including five not taking naltrexone. Eleven had gone onto methadone maintenance, seven had relapsed to heroin use, and one had died of a heroin overdose. Conclusions: Rates of induction onto naltrexone were comparable with those reported for accelerated detoxification under sedation, suggesting that it can be performed successfully with minimal sedation. As in other studies of naltrexone maintenance, retention was low, and relapse to heroin use was common. Introduction Since 1997, accelerated (or "rapid") detoxification has been vigorously promoted as part of a "cure" for heroin addiction. Detoxification involves providing symptomatic assistance during the acute withdrawal syndrome that occurs about 8-12 hours after last heroin use and lasts four to five days. In accelerated detoxification the process of withdrawal is speeded up with an opioid antagonist such as naltrexone,1 which precipitates a more severe but relatively brief abstinence syndrome. Private clinics in Australia have performed several hundred episodes of naltrexone-accelerated detoxification in the past 18 months. However, there has been little systematic investigation of accelerated detoxification, and existing studies are limited by variation in methods, poor research design, and lack of data on long-term outcomes.2,3 Safety is a crucial issue. Greater levels of sedation are assumed to make the procedure more tolerable, but increase the risk of aspiration.4 General anaesthesia with intubation presumably reduces this risk,2 but makes the procedure expensive. Our study was undertaken to determine whether naltrexone-accelerated detoxification can be performed with minimal sedation in awake patients. The rationale was to identify a safe, acceptable and affordable procedure for use in formal trials of accelerated detoxification as a treatment for addiction. A secondary aim was to monitor outcomes of detoxified patients treated for three months with naltrexone. Methods The study was performed in 1998 and approved by the Ethics Committee, South Eastern Sydney Area Health Service. Recruitment Enrolment criteria were either current dependence on heroin or methadone treatment for at least 12 months, and wish to transfer to naltrexone maintenance. Methadone patients were not required to be stable (abstinent from heroin) but simply to have a strong desire to discontinue methadone treatment. Exclusion criteria were serious intercurrent medical or psychiatric problems, pregnancy, and concurrent benzodiazepine or alcohol dependence. Because of publicity when the trial was announced by the New South Wales Government, no active recruitment measures were necessary. Participants were enrolled in blocks of four or six: the first four people to contact were booked for assessment, and no further bookings taken until these four had undergone detoxification. The process was repeated until 15 heroin and 15 methadone users had been enrolled. Assessment All patients were interviewed by a nurse and a doctor. Interviews lasted about an hour and covered drug use and treatment history, explanation of the proposed treatment, and exploration of patient goals and motivation. Standardised questionnaires (Severity of Dependence Scale [SDS], Severity of Opiate Withdrawal Scale, Quality of Life Inventory and System Checklist-90, a global checklist of psychological functioning) were administered. Each patient was allocated a case manager who attended detoxification and conducted follow-up. Case managers comprised a psychologist, a registered nurse and a pharmacist with counselling qualifications. Detoxification Detoxification was performed in a medical ward of a general hospital. Patients presented at 8 am, underwent a brief medical assessment (including urine pregnancy test for women), and had the procedure outlined again. Those with a history of constipation were given an enema. The approach to detoxification was primarily supportive, with repeated explanation of expected symptoms, and potential risks and benefits. Patients received oral premedication with flunitrazepam (2 mg) and clonidine (150 µg). Half an hour later, they were given oral naltrexone at a dose of 12.5 mg (first five patients) or 50 mg (subsequent patients). Oral ondansetron (4 mg) was given orally to the first four patients to control vomiting, and then intravenously when vomiting became established. However, it was observed to be ineffective and was replaced by subcutaneous octreotide (100 µg) in subsequent patients. During acute withdrawal, further clonidine (150 µg, four-hourly) and flunitrazepan (1 mg) were given if patients reported feeling agitated. Oral buscopan (200 mg, four-hourly) was given for complaints of abdominal cramps, and oral quinine sulfate (300 mg, eight-hourly) for leg cramps. Additional doses of octreotide (100 µg) were given in the evening of detoxification and the next morning. Naltrexone was given at a dose of 50 mg/day from Day 2 onwards. Patients were discharged when well enough, with instructions to continue taking this dose of naltrexone. Follow-up After discharge, patients were seen daily for four days and then weekly at a community clinic. They were encouraged to telephone between visits, and a weekly support group was available. Counselling involved feedback on their progress, wellbeing and side effects, and clarification of their objectives. They were also repeatedly warned of the risk of overdose as a result of diminished opioid tolerance while taking naltrexone. The case manager conducted research interviews on Days 35 and 91. Outcome measures During detoxification, severity of withdrawal was monitored four-hourly using the Objective and Subjective Withdrawal Scales,5 which assess signs and symptoms of withdrawal, excluding delirium. Patients were also asked to rate the severity and acceptability of withdrawal on Likert scales. Adverse reactions were monitored throughout withdrawal and over the following three months. Key outcomes were acceptability of detoxification to patients, duration of hospitalisation, success of induction onto naltrexone maintenance, retention on naltrexone, and psychoactive drug use over the ensuing three months (the latter measured with the Opiate Treatment Index6 and confirmed by urine tests). Patients were deemed to have "dropped out" of the trial if they ceased taking naltrexone for a continuous 28-day period. The last day they were known to have taken naltrexone was considered the day of attrition. Results All 30 applicants booked for assessment underwent accelerated detoxification. Their characteristics are shown in Box 1. Most had extensive histories of drug use, high levels of dependence as reflected in SDS scores, and significant social dislocation (low levels of employment and few stable relationships). Nine of the methadone patients reported heroin use in the month before detoxification. Detoxification The pattern of detoxification was predictable. The increase in initial naltrexone dose from 12.5 mg to 50 mg after the first five patients caused withdrawal to be shorter but no obvious change in severity. After premedication with flunitrazepam and clonidine, most patients became drowsy or fell into a light sleep. About 40-60 minutes after administration of naltrexone (50 mg), patients woke abruptly and began to complain of agitation and discomfort. All reported that symptoms were quite different from those of spontaneous heroin withdrawal. Symptoms escalated over the next 30 minutes, and most patients were moderately distressed. Thereafter, almost all entered a delirium for about three to four hours; they were often confused but not aggressive, none required restraint, and nursing care was straightforward. Six patients were found to have self-medicated with benzodiazepines while in hospital and were less easily managed, as higher doses of benzodiazepines appeared to increase delirium and disinhibition. After about four hours, delirium and agitation subsided. Patients felt miserable, often depressed, withdrawn and exhausted. Most had only a vague recollection of the acute phase of withdrawal. Over the ensuing 24 hours, they became increasingly alert but reported feeling "flat", "washed out" and dysphoric, and most ate little. Average dose of clonidine on Day 1 was 415 µg (range, 150-750 µg). Fourteen patients received further clonidine on Day 2. Severity of withdrawal Scores on the Objective and Subjective Withdrawal Scales did not differ significantly between the methadone and heroin groups when compared by F tests. Objective withdrawal scores peaked two hours after naltrexone administration, with a median of 5 (range, 2-9; out of a possible maximum of 13). Scores decreased within 12 hours and, at 24 hours post-naltrexone, median score was 0 (range, 0-6). Subjective withdrawal severity could not be rated during the acute phase. At 24 hours post-naltrexone, scores ranged widely, from 0-42 with a median of 23 (out of a possible maximum of 64, where 42 = quite severe). However, the primary feature of withdrawal -- delirium -- was not assessed by this scale. The first four patients who received ondansetron but not octeotride during withdrawal (three from heroin and one from methadone) all experienced repeated vomiting for more than 24 hours and required intravenous fluid replacement. All subsequent patients received octreotide. Their gastrointestinal symptoms are shown in Box 2. Vomiting was common and could occur throughout the first 48 hours, but most of those who vomited did so only once, and none required intravenous fluids. Patients withdrawing from methadone had more gastrointestinal symptoms than those withdrawing from heroin. Duration of hospitalisation varied. Among patients withdrawing from heroin, 11 needed only one night's hospitalisation, while the other four needed two nights. Patients withdrawing from methadone tended to need longer hospitalisation: seven stayed one night, five stayed two, and the other three stayed three, four and five nights, respectively. Patients who did not receive otreotide also tended to need longer hospitalisation. Patient ratings of detoxification Patient ratings of acceptability and subjective severity of the procedure are shown in Box 3. Most rated it as moderately to extremely severe, but moderately to completely acceptable. Eighteen reported that the procedure was "quite acceptable". Many volunteered that they preferred this experience to the prolonged symptoms of conventional detoxification. However, ratings were not available for five patients who had dropped out by Day 7, when they were first asked to rate their experience. Outcomes Retention (defined as continuing to take naltrexone regularly) is shown in Figure 1. One patient in the methadone group found detoxification too traumatic and was recommenced on methadone maintenance while still an in-patient. At Day 8, retention in each group was 12/15 (80%). Thereafter, attrition was progressive, with 17 people (57%) continuing to take naltrexone at Day 35, seven (23%) at Day 63, and five (17%) at Day 91. The methadone group tended to discontinue naltrexone earlier. Eight patients who discontinued naltrexone (and are therefore not included in these retention figures) underwent repeat accelerated detoxification, including two who underwent a third detoxification. Only one of these was still taking naltrexone at Day 91. Detailed outcomes after three months (Day 91) are shown in Figure 2. Although most patients discontinued naltrexone, this did not necessarily indicate relapse to opioid use. Five patients who had discontinued claimed to be abstinent from opioids (defined as a continuous 28-day period free of opioid use). This was confirmed by serial urine tests in four patients. The other moved interstate within a week of detoxification and did not have urine tests, but reported being drug-free during follow-up telephone interviews. Continuing to take naltrexone was not always associated with abstinence from opioids. Of the six patients still taking naltrexone at three months, four reported sporadically omitting one or two doses, using heroin, and then resuming naltrexone. However, their level of heroin use was clearly less than before detoxification. Another patient from the heroin group who continued taking naltrexone remained abstinent from heroin but took up cannabis smoking. Cannabis use increased from nil before detoxification to 10 "cones" per day at three months. There was no increase in self-reported use of non-opioid drugs among other patients. The patient who died had discontinued naltrexone use after five weeks. Three weeks after last attending the clinic and receiving a week's supply of naltrexone, this patient died of a heroin overdose. Two other patients who relapsed to heroin use reported overdosing and being revived with naloxone after misjudging their level of tolerance. Discussion We found that heavy sedation was not necessary for effective accelerated detoxification. Of 30 patients who underwent naltrexone-accelerated detoxification with only light sedation, 18 (60%) reported that it was "quite" acceptable, and 24 (80%) were successfully inducted onto naltrexone. However, attrition was high; three months later only six patients (20%) were still taking naltrexone (four of whom occasionally used heroin), and only seven (23%) were abstinent from opioids. Recent literature on opioid withdrawal has focused on controlling withdrawal symptoms with medications, at the expense of psychological treatment.7 However, use of multiple medications, including sedatives and anaesthetics, increases the risk.8 For example, a recent Spanish study of accelerated detoxification performed under sedation in an intensive care unit reported a complication rate of 4.3%, with six of 300 patients requiring intubation, and one developing aspiration pneumonia.4 In contrast, no acute life-threatening complications occurred in our study, but it was too small to establish safety definitively. The main risk we identified was self-medication with benzodiazepines, which led to greater agitation and disinhibition. Although the procedure was performed with no problems in a hospital ward, it could not be performed safely without close professional supervision. Our technique of detoxification was "ultra-rapid" -- acute detoxification was complete within hours. The acute phase was not as difficult for patients as the 48 hours post-detoxification, when they experienced gastrointestinal distress and feelings of exhaustion. Withdrawal from methadone appeared more severe, with more gastrointestinal side effects, higher ratings of severity, and longer inpatient stays. There are few published, systematic studies of withdrawal under sedation for comparison with our study. After detoxification under anaesthesia, symptoms can occasionally be severe,9 and a recent study reported that significant withdrawal symptoms persisted at least a week later.10 Our rate of induction onto naltrexone (80%) was comparable with rates reported by most others for accelerated detoxification. The only randomised trial to date to compare accelerated and conventional detoxification found rates of induction (defined as taking naltrexone at Day 8) of 65% after clonidine alone, 60% after buprenorphine, and 54% after combined naltrexone-clonidine.11 These differences were not statistically significant. In our study, hospitalisation for at least one night was probably crucial to our higher rate of induction onto naltrexone. Most studies of naltrexone maintenance have shown high dropout rates and high relapse rates to heroin use,12 similar to our findings. For example, a recent review calculated that, for people who took a first dose of naltrexone after conventional induction, average reported attrition was 39% in the first two weeks.13 Although claims have been made that mean retention on naltrexone is one to six months, depending on patient selection and quality of adjunctive services,14 this value is skewed by the small proportion of patients who take naltrexone long term, for whom the treatment is highly successful. In our study, which involved unselected patients with poor prognostic indicators, retention (defined as continuing to take naltrexone) was 58% at one month, 23% at two months, and 17% at three months (or 20% including the patient who resumed naltrexone use after repeat detoxification). Most of those who relapsed entered methadone treatment. A report on 781 heroin users in Western Australia estimated that 87% of those who underwent detoxification continued with naltrexone, with subsequent retention rates of 60% at one month, 44% at two months and 33% at three months.15 However, as these figures were based on monthly prescriptions dispensed, they may slightly overestimate retention. Another Australian study of naltrexone reported that only two of 43 patients (5%) took naltrexone for six months.16 Some studies have reported much higher rates of heroin abstinence after naltrexone treatment than ours. For example, a recent study of patients undergoing accelerated detoxification under anaesthesia reported 60% of patients were free of heroin use six months later.9 However, this was based on a telephone survey of patients who could be contacted, and would require confirmation in more rigorous trials. A Spanish study reported that 93% of 300 patients were abstinent from opioids a month after accelerated detoxification under sedation (confirmed by urine testing).4 This is in stark contrast with most previous results.12,13 Naltrexone maintenance carries risk, with a report of suicides and fatal overdoses.17 In our study, despite repeated warnings about diminished opioid tolerance when taking naltrexone, one patient died of a heroin overdose and two others reported overdosing after misjudging their tolerance. Others may have had similar experiences but not reported them. This problem needs special monitoring, as post-naltrexone deaths may be hard to identify; naltrexone is almost never found at postmortem toxicological analysis as overdose occurs when the drug is stopped. Therefore, any major study of naltrexone risk needs to monitor death records. From our data, accelerated detoxification with light sedation resulted in induction and retention rates similar to those found in most published studies of naltrexone. Randomised trials are required to compare techniques of detoxification, and our study has identified a low-cost, low-risk approach for use in such trials. However, results will not be available for years. In the meantime, as uptake of accelerated detoxification has far outstripped research, results of this pilot study may help consumers and health professionals judge the claims made for naltrexone treatment. Acknowledgements This study was funded by NSW Health. References Riordan CE, Kleber HD. Rapid opiate detoxification with clonidine and naltrexone. Lancet 1980; 5: 1079-1080. O'Connor PG, Kosten TR. Rapid and ultrarapid opioid detoxification techniques. JAMA 1998; 279: 229-234. Kleber HD. Ultra-rapid opiate detoxification. Addiction 1998; 92: 1929-1933. Seoane A, Carrasco G, Cabre L, et al. Efficacy and safety of two new methods of rapid intravenous detoxification in heroin addicts previously treated without success. Br J Psych 1997; 171: 340-345. Handelsman L, Cochrane KJ, Aronson MJ, et al. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse 1987; 13: 293-308. Darke S, Hall W, Heather N, et al. Development and validation of a multidimensional instrument for assessing outcome of treatment among opioid users: the opiate treatment index. Br J Addict 1992; 87: 593-602. Mattick RP, Hall W. Are detoxification programmes effective? Lancet 1996; 347: 97-100. Mayor S. Specialists criticise treatment for heroin addiction. BMJ 1997; 314: 1365. Rabinowitz J, Cohen H, Tarrasch R, Kotler M. Compliance to naltrexone after ultra-rapid opiate detoxification. Drug Alcohol Depend 1997; 47: 77-86. Scherbaum N, Klein S, Kaube H, et al. Alternative strategies of opiate detoxification: evaluation of the so-called ultra-rapid detoxification. Pharmacopsychiatry 1998; 31: 205-209. O'Connor PG, Carroll KM, Shi JM, et al. Three methods of opioid detoxification in a primary care setting: a randomized trial. Ann Intern Med 1997; 127: 526-530. Jaffe J. Pharmacological treatment of opioid dependence: Current techniques and new findings. Psychiatric Annals 1995; 25: 369-375. Tucker T, Ritter A. Naltrexone: a literature review. Melbourne: Turning Point Alcohol and Drug Centre, 1998. Kleber HD. Naltrexone. J Substance Abuse Treatment 1985; 2: 117-122. Australian Medical Procedures Research Foundation. Perth Naltrexone Trial report. Perth: AMPRF, 1999. Foy A, Sadler C, Taylor A. An open trial of naltrexone for opiate dependence. Drug Alcohol Rev 1998; 17: 167-174. Miotto K, McCann MJ, Rawson RA, et al. Overdose, suicide attempts and death among a cohort of naltrexone-treated opioid addicts. Drug Alcohol Depend 1997; 45: 131-134. Authors' details The Langton Centre, Sydney, NSW. James R Bell, BA, FRACP, Director; Malcolm R Young, RN, Registered Nurse; Sibyl C Masterman, MA(Psych), Psychologist; Amanda Morris, B Pharm, Pharmacist. National Drug and Alcohol Research Centre, Sydney, NSW. Richard P Mattick, PhD, Director of Research. National Centre for Epidemiology and Population Health, Australian National University, ACT. Gabriele Bammer, PhD, Senior Fellow.

James R Bell · Malcolm R Young · Sibyl C Masterman · Amanda Morris · Richard P Mattick

For Debate "Acculturating" heroin use Viewpoint: the proposed ACT heroin trial has not comprehensively considered the variability in the needs of heroin users Matt D Gaughwin MJA 1996; 164: 692-693 Introduction - References - Authors' Details - - More articles on Drugs and alcohol Acculturation: "The adoption and assimilation of an alien culture",1 used here to mean the mutual consideration of the viewpoints of two cultures (heroin users and non-users) for the benefit of each. Introduction Despite much thinking and talking about heroin, Australia, like most countries, has not come close to solving the problems associated with heroin use. The proposal by researchers at the National Centre for Epidemiology and Population Health (NCEPH) and the Australian Institute of Criminology (AIC) to conduct trials of the prescription of heroin is a welcome attempt to improve the lives of Australians who use heroin, their families and communities. The purpose of this article is to argue that the NCEPH/AIC proposal has prematurely focused on one way of providing heroin which is too narrow and too restrictive; that some of the criteria for "success" of the pilot studies seem to be arbitrary; and that some of the criteria for termination of the project are unreasonable. I also suggest some alternative approaches to providing heroin on a trial basis. The proposal is for two pilot studies, each of six months' duration, followed by a trial of two years. Each stage of the proposal is contingent on the "success" of the previous stage. The core of the proposal is to provide heroin for injection to users who attend a special clinic up to three times a day to receive heroin and/or methadone under close supervision. Any radical approaches to opiate dependence (such as providing heroin) will be constrained by political and practical considerations. At the outset the investigators associated their proposal with the prevalent paradigm, which seeks to contain heroin users by locking them up or treating them. Thus, the report on feasibility of the trial1 states that the project "must not be linked with permissive attitudes to illicit drug use and must be coupled with continuing law enforcement and prevention activity against illicit drug use". It seems reasonable to ask whether such views allow adequate exploration of alternative approaches to providing heroin. If these statements indicate undue sensitivity to the perceptions of those with negative views about heroin use, then it follows that any strategy for providing heroin would tend to be very restrictive. In stage 2 of the feasibility research into the views of dependent heroin users, most people questioned were clients of the ACT methadone program (209) and relatively few had never received treatment (14) or were treatment "drop-outs" (8).2There is little indication that a wide range of heroin users have been comprehensively questioned about possible methods of providing heroin or of evaluating the pilots or trial. By concentrating on clients of the ACT methadone program in which "in both 1993 and 1994, half the people who entered the program had dropped out within a few months",2 a premature and limited view of heroin and methadone provision may have been obtained. Criteria for success of the pilot studies have been established but are not necessarily justified. The first pilot study will be successful if a stable dose of heroin or heroin plus methadone is "found" for "more than half of the participants".2 These criteria seem arbitrary and restrictive -- should participants who do not receive stable doses of heroin but nevertheless have better lives (improved health, less involvement in crime) be regarded as unsuccessful? What is the rationale for concluding that the first pilot project is a success if 51% ("more than half") of participants achieve a stable dose of heroin? Why not 25% or 75%? The progression of the second pilot study to the full-scale trial is contingent on the acceptability to heroin users of being randomised to receive either their choice of heroin, methadone or both or, in the control group, to receive methadone alone. Again, this criterion seems too restrictive in that it gives preference to the design of a trial over improvements in the lives of heroin users. In my view, the latter should be given greatest weight as a criterion at all stages of the project, even if it means redesigning the full-scale trial. The relative lack of consideration for the potential variability in the needs of individual heroin users is taken to a logical but unreasonable conclusion in the criteria for termination of a trial. One criterion will be if prescribed heroin "has value for only a subgroup of dependent heroin users". This is unreasonable because, for example, if subgroups that were most likely to engage in crime or experience overdose benefited most, then continuing to prescribe heroin for them would surely be appropriate. Another model for provision of heroin in a pilot program might be decentralised prescription by selected specialist or general practitioners in a few regions, based primarily on individual assessment of needs and on potential risks to individuals and communities. One seeming advantage of the NCEPH/AIC proposal is the strategy of proceeding by incremental steps, each dependent on the satisfactory outcome of the previous one. However, with only a limited initial model of heroin provision and restricted concepts of progress or "success", any potential convergence to some "ideal" model or, indeed, divergence to more than one, is restricted. If there were several initial models, there would be more opportunity to select those that are effective. The impetus for the project arose, in part, from concerns that current approaches to the problems associated with heroin use "might not be effective".2 It follows that one focus could be on those for whom current approaches are not effective. If we see heroin users as individuals with individual needs, we might be led to alternative ways of making heroin available and of evaluating its usefulness. If we focus first on the things that heroin users and their communities want to change (e.g., crime, disease risk, cost, overdose) and only later on methods of delivery, it seems to me we will have a better chance of making a substantive contribution that will help ameliorate the problems of heroin use. Arguably, heroin and heroin users are seen as alien by most Australians. By showing people that heroin users are their fellow Australians, sometimes with a particular set of difficulties, we might begin their "acculturation" and not confine them in prisons and clinics or drive them to extremes of behaviour and thereby disable them. In conclusion, I urge the NCEPH/AIC to consider revising its approach to heroin prescription, and politicians, bureaucrats and others to support more comprehensive consideration of how to solve the problems associated with heroin use. The Commonwealth, States and Territories need to keep this issue on the public health agenda and to provide mechanisms and resources to enable the discussions and research to continue. References Burchfield R W, editor. A Supplement to the Oxford English Dictionary. Oxford, Oxford University Press, 1972. Bammer G. Report and recommendations of stage 2 feasibility research into the controlled availability of opioids. Canberra: National Centre for Epidemiology and Population Health, Australian National University and the Australian Institute of Criminology, 1995. Author's DetailsDrugs and Alcohol Resource Unit, Royal Adelaide Hospital, Adelaide SA. Matt D Gaughwin,PhD, FAFPHM, Acting Director. Correspondence: Dr M D Gaughwin, Drugs and Alcohol Resource Unit, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000.

Matt D Gaughwin

Viewpoint Heroin addiction: the science and ethics of the new treatment pluralism As approaches to treating heroin addiction grow in number, their ethics and their meaningful contribution to the science in this field need more careful consideration Matt D Gaughwin and Philip Ryan MJA 1999; 170: 129-130 Introduction - Questions of ethics - Questions of science - Ways forward - References - Authors' details - - More articles on Drugs and alcohol Introduction There is a new pluralism of approaches to treating heroin addiction. Many trials are concerned with relatively small populations of heroin users, among whom researchers hope to demonstrate, by various methods, that one drug or treatment is effective and safe, and perhaps better than, another. At the other extreme are clinics which offer treatments -- such as ultrarapid opiate detoxification (UROD), in which heroin addicts are given opiate antagonists while anaesthetised so that they do not consciously experience withdrawal symptoms -- at a price, and not necessarily with a special interest in evaluation and research. Such approaches have their place, but they can never address the question of how much of what treatments we need to help stem the tide of heroin problems in the community. That question has scientific and ethical implications about the design of trials and treatments and the application of the results of trials to communities. Questions of ethics There are two categories of ethical issues associated with the new treatment pluralism. Firstly, ethics as they relate to individuals and, secondly, ethics as they relate to populations. The proponents of trials, and perhaps the ethics committees that consider these trials, are more concerned with ethics in relation to the individual trial participants. The ethical obligations of treating clinicians, whether they are working in franchised clinics or research institutions, are clear. They must adequately inform patients about the treatments, which must be as safe as they can be. Whether a procedure such as anaesthesia should be used at all for a clinical condition that is not life threatening was raised by Hall and Mattick,1 and countered by Seivewright and Greenwood,2 who said that the same argument is not used for childbirth or dental treatment. There is an important ethical discussion yet to be had about the extent to which we should introduce new elective procedures which require anaesthesia. Importantly, the risk -- perhaps increased risk -- of death from heroin overdose (as a consequence of reduced opiate tolerance) that can accompany poor compliance with naltrexone means that there is a great responsibility to inform patients being treated with naltrexone about that specific risk. There is also an urgent ethical responsibility to decide whether that risk is too great for some or all participants, and thus to act to reduce or eliminate the risk even if that means stopping or modifying trials and treatments. Also, there is yet to be a comprehensive ethical discussion about the allocation of resources for these new treatments. We do not deny that there is a place for new treatments. Rather, in the face of inadequate resources for existing proven treatments (such as methadone), the effect of introducing new treatments or trials on the ability of heroin addicts seeking help to actually obtain that help needs to be considered. Addiction to opiates is a multifaceted problem which may require multifaceted solutions. If we accept a humanitarian view of treatment, including treatment within trials, we must accept our ethical obligation to offer a treatment that we know works if a trial participant or a patient in a UROD clinic "drops out" of a new treatment. Some heroin users, desperate for help, hardly have a choice, and will enrol in a trial of an unknown treatment because standard treatments (such as methadone maintenance) are relatively unavailable. The other, often neglected, dimension is that of public health ethics. Trials which are publicly funded have special ethical obligations to ensure, as far as possible, that the questions being asked, and the design and evaluation of trials, are in the public's best interest -- that is, what a public given the chance to deliberate adequately about the issue would choose. Because there are no standards for deliberation about public health issues such as heroin addiction,3 propsals for trials may be approved or denied at the discretion of those who hold the relevant power. Thus, the ACT heroin trial was halted by the Prime Minister and Cabinet, while State governments, such as the South Australian government, announced trials of rapid opiate detoxification4 without comprehensive consultation and deliberation with the public, heroin addicts or the clinicians who treat them. The idiosyncrasy of such approaches must militate against sustainable solutions to the problem of heroin addiction, and raises the ethical question of how rational and reasonable approaches to this problem can be given a "fair go". If there has not been meaningful public deliberation about proposals, we believe their proponents can not claim that they are ethical trials in a public sense. Questions of science This emergence of a pluralism of approaches to heroin problems brings with it scientific difficulties. As more and more treatments are trialled, we increase the difficulty and the cost of designing studies that can determine which collection or combinations of treatments are better than others. This does not negate the value of small trials, but it does raise the question of the relationship between trials and evaluation of treatments as a whole. The diversity of treatments and trials is wide, ranging from uncontrolled small case series through modest-sized randomised trials to modest treatment programs. It is the view of one researcher that ". . . we are likely to get poorly designed, incompatible trials . . . which produce inconclusive results, ie a null effect in a study lacking adequate power".5 Indeed, a pilot study of naltrexone treatment in New South Wales6 concluded that about 450 participants would be needed for a randomised trial of adequate power -- considerably more than the 100-200 participants proposed for the randomised trials in SA and NSW. Many trials are of short duration, whereas the problem of addiction often occurs over many years. Thus, deciding when to measure outcomes becomes an important issue. Trials risk being irrelevant to the real world of addiction if they ask questions or evaluate outcomes relevant to the short term only. As in cancer epidemiology, we should develop standards for evaluating endpoints in heroin addiction trials so that we might, as with cancer, agree that after a certain period someone is "cured" of their addiction. Or, if we consider addiction to be a chronic relapsing condition, we might perhaps model trials for heroin addiction on those for treating diseases such as epilepsy or diabetes. Moreover, we must never forget that there can be a vast gulf between efficacy demonstrated in clinical trials and meaningful control of a public health problem. Ways forward The new pluralism in treatments for heroin addiction is fragmented and uncoordinated, with no particular strategic direction. This is not surprising given the lack of an agreed strategic framework on which to design treatments and trials in the area of drug addiction. However, a strategic framework will be successful only if all those with an interest in the problem -- experts and non-experts alike -- are justly and fairly engaged in ways which consider and account for the diversity of views about heroin. It is encouraging that the National Drug and Alcohol Research Centre has recently been contracted to coordinate the trials of new pharmacological treatments (Associate Professor Richard Mattick, Director of Research, National Drug and Alcohol Research Centre, University of New South Wales, personal communication). Perhaps this Centre might take on the wider role of considering the ethical and scientific questions we have raised here. In summary, the new pluralism in treatments for heroin addiction poses some dilemmas. We should welcome the opportunities they may offer, but approach them cautiously and comprehensively so that we avoid the traps of ill-considered science and ill-considered ethics. References Mattick R, Hall R. Are detoxification programs effective? Lancet 1996; 347: 97-100. Seivewright N, Greenwood J. What is important in drug misuse treatment? Lancet 1996; 347: 373-376. Gaughwin M. Why Australia needs minimum standards of deliberation for public health. Med J Aust 1998; 168: 228-229. Minister for Human Services, South Australia. Rapid heroin withdrawal treatment trial [media release]. Adelaide: Department of Human Services, March 2 1998. Caplehorn J. Reply to Hall et al: on ROD, UROD and ODs. Drug Alcohol Rev 1998; 17: 222-223. Foy A, Sadler C, Taylor A. An open trial of naltrexone for opiate dependence. Drug Alcohol Rev 1998; 17: 167-174. Authors' details Department of Public Health, University of Adelaide, Adelaide, SA. Matt D Gaughwin, PhD, FAFPHM, Senior Clinical Lecturer; Philip Ryan, MB BS, FAFPHM, Lecturer. Reprints will not be available from the authors. Correspondence: Dr M D Gaughwin, Drug and Alcohol Resource Unit, Level 5, Services and Teaching Wing, Royal Adelaide Hospital, North Terrace, Adelaide, SA 5000. Email: mgaughwin@medicine.adelaide.edu.au

Matt D Gaughwin · Philip Ryan

For Debate The ACT heroin trial proposal: an overview The authors of the proposal describe the trial and its development Gabriele Bammer and Robert M Douglas MJA 1996; 164: 690-692 Introduction - Aims and outcome measures - Pilot studies - Full-scale clinical trial - Development of the proposal - The future - References - Authors' details - - More articles on Drugs and alcohol Introduction The proposal for a "heroin trial" in the Australian Capital Territory (ACT) builds on growing evidence that treatment is the most cost-effective approach to problems resulting from illicit drug use.1-4 A four-year feasibility study was undertaken after overwhelming encouragement from a national seminar of drug treatment and policy experts. It resulted in a proposal which addresses a key issue, is clinically workable, able to be rigorously evaluated and has minimal risks. The trial comprises two pilot studies and a full-scale clinical trial; evaluation is central and debate is welcomed. Aims and outcome measures The core of the proposed "heroin trial" is a clinical trial to compare a new treatment option against the current gold standard. In essence, it is a regular trial of a new treatment. The question to be asked is: If maintenance treatment for opioid dependence is expanded, so that both injectable diacetylmorphine (heroin) and oral methadone are available, is this more effective than current maintenance treatment with oral methadone alone? Measures of effectiveness are: Ability to attract dependent heroin users into treatment; Ability to prevent premature drop-out from treatment; Ability to improve health and well-being, including reducing drug use and criminal behaviour and improving social functioning; and Cost-effectiveness. Pilot studies The first step would be to conduct two six-month pilot studies in the ACT. First pilot study: This would involve 40 participants who meet the following eligibility criteria: Either currently or formerly on the ACT methadone program; and Able to prove ACT residence since 1993. Half would be drawn from volunteers currently receiving methadone treatment, who would prefer the expanded treatment option, and half from volunteers who have dropped out of methadone treatment. Equal numbers of men and women would be included from each of these groups. Participants would have a choice of treatments: injectable diacetylmorphine alone; injectable diacetylmorphine and oral methadone; and oral methadone alone. All could change treatments at will, within the limits of medical safety. To warrant moving to the second pilot study, the first would have to show that: A stable maintenance dose of injectable diacetylmorphine or injectable diacetylmorphine plus oral methadone could be found for more than half the participants; Participants could safely and easily move between the three treatment options; and There was improvement in at least half of the outcome measures for health and well-being. The first pilot study would also allow investigation of the pharmacokinetics and psychopharmacology of diacetylmorphine, especially effects on driving skills. Stability is a key issue for the first pilot study. Stabilised consumption within a defined therapeutic range was identified as a criterion for effective maintenance treatment by a meeting of experts on drug substitution organised by the World Health Organization in May 1995. Participants in the proposed trial would be able to attend the clinic to inject heroin up to three times a day. Current Swiss experience is that this works very well;5 those who cannot be stabilised on heroin under these conditions are prescribed a low dose of methadone as well. Second pilot study: This would be a small randomised controlled trial with 250 participants and the same eligibility criteria as the first pilot study. In contrast to the first pilot study, half the participants would be allocated to the choice of treatment options and half to oral methadone alone. The second pilot study would: Further investigate the questions addressed in the first pilot study; Begin to examine attraction into, and retention in, treatment; and Assess if randomisation is practicable for this group. A full-scale randomised controlled trial is the standard and most rigorous way to test a new treatment option. However, before launching such a full-scale trial, it is necessary to test whether it is practicable for dependent drug users. If not, there will be hard decisions about the value of less convincing forms of assessment. Alternatively, if drop-outs from the randomised pilot study are relatively few, then the sample size would be sufficient for statistically meaningful comparisons on outcome measures. Full-scale clinical trial This would involve: 1000 participants in three cities; and Volunteers drawn evenly from three groups: dependent heroin users who have never been in treatment; those who have dropped out of treatment; and those currently in methadone treatment. The trial would run for two years. In the first year it would be a randomised controlled trial, but in the second all participants would be given choice of treatment. At the end of the trial there could be evidence-based assessment of the role of diacetylmorphine in maintenance treatment, the subgroups in whom this treatment is most likely to be useful, and other indications and contraindications. This would allow a more balanced perspective on medical prescription of this drug. Development of the proposal The proposal resulted from a four-year feasibility study that concluded that the benefits of testing this new treatment option outweighed the risks. While all currently available options (such as methadone maintenance, detoxification, residential rehabilitation and counselling) are beneficial for some dependent users, none appear satisfactory for a further significant proportion. Additional options are needed. Diacetylmorphine is not the only potential new treatment; others include buprenorphine, levomethadyl acetate (LAAM), naltrexone and injectable methadone. However, the feasibility study focused on diacetylmorphine because it is the most controversial, among the least carefully studied and the preferred option for many dependent heroin users. Some of the controversy arises from uncertainties about whether prescribing diacetylmorphine can have positive outcomes, whether it can be cost-effective and whether stability is achievable on this short-acting opioid. These questions can be resolved only through empirical research and are the focus of the trial. Moral arguments about the value of maintenance treatment, about providing treatment for self-inflicted problems and about making a currently illicit substance available under carefully controlled conditions are not resolvable but are open to ethical debate (some issues are covered by Ostini et al.6). Finally, controversy arises because a trial has risks. These include that dependent heroin users may move to the ACT; a trial may lead to more permissive attitudes to illicit drug use; the trial drugs may cause road accidents or be diverted onto the black market; participants may congregate at the trial site; women in the trial may give birth to diacetylmorphine-affected babies; and a trial might further institutionalise or marginalise dependent heroin users. Much of the feasibility research involved working with critics of a trial, firstly to identify these risks and then to develop ways to minimise them. In summary, these include using well-defined eligibility criteria, not providing take-away doses of heroin, strictly supervising injection at the clinic, carefully monitoring participants before they leave and setting the trial within the current context of law enforcement and preventive activities. Potential risks would also be carefully monitored. The feasibility research was conducted in collaboration with the Australian Institute of Criminology. Well over 100 people have been involved -- as collaborators, assistants and advisers -- and many hundreds have provided feedback through workshops, seminars and discussions. Opinions have also been elicited from around 5000 members of the general community through ACT and national surveys. A wide range of options was initially explored. The development of a proposal that was clinically workable, able to be rigorously evaluated and minimised risks was an iterative process -- any one change to the protocol could have multiple ramifications. The process involved integrating both the findings of many disciplines (anthropology, clinical science and health care, criminology, demography, economics, epidemiology, law, pharmacology, philosophy, political science, policy analysis, psychology, sociology and statistics) and the insights of the key interest groups (people who are or have been dependent on heroin, police, people involved in providing treatment and other services to illicit drug users, the general community and policy makers). Heroin has long been prescribed for dependent users in the United Kingdom and, while there is evidence that this can be a useful option, it is contested. The same is true of historical evidence from the United States. No evaluation to date has been as rigorous as would now be required before introducing a new treatment. Other countries, most notably Switzerland and the Netherlands, are either undertaking, or about to undertake, "heroin trials".5,7 Much will be learnt from them, but many questions will remain unanswered and these are the focus of the ACT proposal. The future The future of the trial is now in the hands of the policy makers. The immediate stimulus for the feasibility research came from the deliberations of an ACT Legislative Assembly Select Committee on HIV, Illegal Drugs and Prostitution in early 1991.8 The final report and recommendations from the feasibility study9 were presented to the ACT Chief Minister, Ms Kate Carnell, in June 1995; she has maintained that a trial will not proceed without support from other States and financing from outside the ACT. In the meantime, we welcome public and private critiques and debate on the proposal. If a trial does eventuate it must be as well conceived as possible. Opportunities for clinical trials are rare and justified only when there is a real research question, with doubt about the outcome. In addition, trials are expensive. We estimate the cost of the two pilot studies alone at $2.3 million. A trial cannot be paid for from funding currently allocated to drug treatment or research; there are too many other urgent priorities. New money will have to be allocated --ultimately, this is the real test of political will. Of necessity this overview must be brief. A more detailed proposal can be found in the 1995 report on feasibility of the heroin trial.9 The results of the feasibility research are presented in four reports, thirteen working papers and, to date, 16 peer-reviewed papers, which are available from the authors (for a selection see references 10-14). A detailed response to the critique by Dr Matt Gaughwin is also available from the authors. References Gerstein DR, Johnson RA, Harwood HJ, et al. Evaluating recovery services: The California drug and alcohol treatment assessment (CALDATA). General report submitted to the State of California, Department of Alcohol and Drug Programs by National Opinion Research Center at the University of Chicago and Lewin-VHI Inc, Fairfax Virginia. Sacramento: California Department of Alcohol and Drug Programs, 1994. National Institute in Drug Abuse. Drug abuse treatment. An economical approach to addressing the drug problem in America. Rockville MD: US Department of Health and Human Services, Public Health Service, Alcohol, Drug Abuse, and Mental Health Administration, 1991. Odyssey House. Drugs in our community. Unpublished report. Melbourne: Odyssey House. Rydell CP, Everingham SS. Controlling cocaine. Supply versus demand programs. Santa Monica: RAND Drug Policy Research Centre, 1994. Uchtenhagen A, Dobler-Mikola A, Gutzwiller F. Medically controlled prescription of narcotics: fundamentals, research plan, first experiences. In: Rihs-Middel M, Lewis DC, Clerc J, et al., editors. The medical prescription of narcotics: scientific foundations and practical experiences. Freiburg: Huber verlag. In press. Ostini R, Bammer G, Dance P, Goodin R. The ethics of experimental heroin maintenance. J Med Ethics 1993; 19: 175-182. Health Council of the Netherlands: Committee on Pharmacological Interventions in Heroin Addicts. The prescription of heroin to heroin addicts. The Hague: Health Council of the Netherlands, 1995. (Publication no. 1995/12E.) Legislative Assembly for the Australian Capital Territory. Select Committee on HIV, Illegal drugs and Prostitution. Second interim report. A feasibility study on the controlled availability of opioids. Canberra: Legislative Assembly for the Australian Capital Territory, 1991. Bammer, G. Report and recommendations of stage 2 feasibility research into the controlled availability of opioids. Canberra: National Centre for Epidemiology and Population Health, Australian National University and the Australian Institute of Criminology, 1995. Hartland N, McDonald D, Dance P, Bammer G. Australian reports into drug use and the possibility of heroin maintenance. Drug Alcohol Rev 1992; 11: 175-182. Bammer G. Should the controlled provision of heroin be a treatment option? Australian feasibility considerations. Addict 1993; 88: 467-475. Bammer G, Weekes S. Becoming an ex-user: insights into the process and implications for treatment and policy. Drug Alcohol Rev 1994; 13: 285-292. Bammer G, Stevens A, Dance P, et al. Controlled heroin availability in Australia? How and to what end? Int J Addict 1995; 30: 991-1007. Stevens A, Ostini R, Dance P, et al. Police opinions of a proposal for controlled availability of heroin in Australia. Policing Soc 1995; 5: 303-312. Authors' details National Centre for Epidemiology and Population Health, Australian National University, Canberra, ACT. Gabriele Bammer, PhD, Fellow. Robert M Douglas, MD, FAFPHM, Director. No reprints will be available. Correspondence: Dr G Bammer, National Centre for Epidemiology and Population Health, The Australian National University, Canberra, ACT 0200. Email: Gabriele. BammerATanu.edu.au

Gabriele Bammer · Robert M Douglas

For Debate The heroin trial we had to have Viewpoint: the climate of prohibition has prevented dispassionate scientific assessment of the trial Nick Crofts MJA 1996; 164: 694-695 Introduction - References - Authors' details - - More articles on Drugs and alcohol Introduction That we treat heroin as a special drug is one of the great anomalies of this dark age of drug prohibition and the so called "War on Drugs". This is the one-sided policy that attempts to reduce consumption of illicit drugs by reducing supply through interdiction and incarceration. The war is being waged by policy makers, law enforcement and the military throughout the world. The effects of this social policy pervade the daily lives of all citizens, whether they know it (through the drug-related death of a friend or relative or through being burgled) or not (through taxes which pay for the imprisonment of drug users or through increased insurance premiums because of drug-related crime). It is scarcely credible in this era of sceptical rationality that a social policy with such far-reaching effects is based on little more than an almost religious faith in the doctrine of prohibition -- a policy based on racism, commercial exploitation, colonialism and the worldwide export of United States domestic policy.1 The proposed trial of medical prescription of heroin to heroin-dependent people in the Australian Capital Territory (ACT) would provide important data for more informed decision-making about heroin policy. Prohibition has the effect of demonising heroin and dehumanising heroin users. Objections to limited, scientific attempts to obtain information for rational debate about the best, least harmful method of integrating heroin and other opium use into our society eventually derive from the absolute need to defend the essentially untenable position of prohibition. Such objections have been vigorously raised about the proposed ACT trial. Were the proponents of prohibition sure of their position, they would have nothing to lose from such trials, which could adduce only further evidence of the need to direct every effort towards abstinence. On the other hand, objections to the proposed methods of the trial need careful consideration. Objections that the trial will not answer multiple questions about heroin use and treatment overlook the specificity of its aims. Indeed, the modest aims and careful development of realistic outcome indicators are outstanding features of the proposed trial. Equally, the objection that such a trial will equate to, or advance, the legalisation of heroin is fundamentally flawed. The medical prescription of heroin to those who are heroin-dependent maintains the current problematic view of heroin use -- the problem is simply medicalised. This, I would argue, is actually a retrograde step for legalisation, as medicalisation will make medical (rather than legal or moral) arguments paramount and very difficult to counter. We should have sufficient experience with methadone maintenance treatment to recognise this, but the voice of the methadone consumer has generally been silenced. For instance, maintenance therapy is often justified and used as a form of social control, particularly for reducing crime by heroin users, while masquerading as a medical treatment. There should, of course, be multiple options for those dependent on opiates and having trouble with this dependence. One option is oral methadone and others could include injectable heroin and buprenorphine. Each needs careful, controlled scientific examination; this is extraordinarily difficult in the context of prohibition, which creates so many confounders (e.g., necessary involvement of the heroin user in a criminal milieu, enormously inflated cost of drugs on the black market and resulting peer pressure to participate in crime). Information from properly planned and conducted scientific research is desperately needed to underpin policy and treatment approaches; the ACT trial will clearly provide a very important piece of this information. It would enable us (as a society) to assess the best methods of delivering injectable heroin in cooperation, rather than in competition, with other substitution approaches. It is an unfortunate reality that the ACT researchers must operate within a prohibitionist framework. Although prohibition has been shown to be harmful,2 legalisation has not as yet been convincingly shown to be less harmful. This needs an incremental approach, an adducement of evidence until the balance of judgement is swayed from supporting prohibition to regulation. The ACT researchers must be in a bind about the cost of the trial. On the one hand, the trial and its results will be so intensely scrutinised that it must be, and be seen to be, totally credible scientifically. This is expensive and leads to the charge that one small trial, on one small aspect of our relationship with heroin, will expend an inordinate proportion of our drug research budget. The researchers have made it clear that funding for the trial must be "new" money, raising the question of the trial's viability in the current political climate. However, the potential returns are so great as to outweigh this objection -- few other areas of research are likely to return so much, especially by attracting a wider range of the heroin-dependent into treatment that is cheap in comparison with imprisonment. The issue of morality often underlies the arguments. Moral arguments have their place, but are meaningful only when based on accurate information. The morality that rejects a place for opiates in this society because they are dangerous, when the danger demonstrably comes more from their illegality than from the drugs themselves, is flawed. I have often pondered why it is heroin that we have demonised and suspect that such violent reactions must be extremely attractive to those waging the War on Drugs. The obverse of approaches considered to "condone" heroin use are those which make it as dangerous as possible. It is a strange morality which argues for so many deaths to prevent the use of a substance that is relatively harmless under controlled conditions -- a morality that has given us enormous epidemics of HIV infection among children of heroin users in the United States and elsewhere. This is a morality which I suspect most people would not support without the intense social conditioning of the War on Drugs. The proposed trial would not provide all the information about heroin that is needed as a basis for public policy. It cannot, and should not, tackle holistic questions about the "best" (least harmful, most beneficial) relationship between heroin and society. Answering these questions needs data on more than the medical aspects of the relationship. However, this trial will provide some key data; what more should be required from a single study? References McCoy A. A historical review of opium and heroin production. Washington DC: Office of Special Technology, US Department of Defence, 1994. Wodak A, Owens R. Drug prohibition: a call for change. Sydney: UNSW Press, 1996. Authors' details Epidemiology and Social Research, Macfarlane Burnet Centre for Medical Research, Melbourne, VIC. Nick Crofts, MB BS, MPH, FAFPHM, Head. No reprints will be available from the author. Correspondence: Dr N Crofts, Epidemiology and Social Research, Macfarlane Burnet Centre for Medical Research, PO Box 254, Fairfield, VIC 3078.

Nick Crofts

Viewpoint The force of numbers: why hepatitis C is spreading among Australian injecting drug users while HIV is not The hepatitis C virus requires expanded strategies to control its spread Nick Crofts, Campbell K Aitken, John M Kaldor Reader response added, 6 July 1999, with reply from the authors. MJA 1999; 170: 220-221 Introduction - References - Authors' details - - More articles on Drugs and alcohol Introduction The hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) are both bloodborne viruses, are both spread through needle-sharing and other practices of injecting drug users (IDUs), and both represent serious health risks for Australian IDUs. Despite these similarities, in Australia the epidemiology of these viruses differs greatly. The prevalence of HCV among IDUs is about 65%, whereas that of HIV is less than 3%; this difference is mirrored by their respective incidences, about 15% per year for HCV and less than 1% per year for HIV.1,2 While new HIV diagnoses in heterosexual IDUs are rare, estimates of new HCV infections in the same group range from 6000 to 10 000 per year.1Should we conclude from these differences that our current approaches to prevention of bloodborne viruses among IDUs (which are based on the harm-reduction philosophy and include needle and syringe distribution, methadone maintenance therapy, peer education and advocacy) are ineffective? This is unlikely for two reasons. Firstly, HIV has a very low incidence in Australian IDUs, but continues to spread rapidly among IDUs in many parts of the United States and in other populations lacking equally comprehensive prevention strategies. Secondly, there have been dramatic declines in transmission of other viruses (hepatitis B and D) among Australian IDUs since the mid 1980s.1 The effectiveness of just one element of our harm reduction programs -- needle and syringe exchange -- has been well demonstrated,3 and is supported by an American study which found that IDUs in needle exchange programs were seven times less likely to be exposed to HCV than those who were not.4 Can the difference be explained by HCV spreading in a different manner to HIV? Sexual transmission of HCV is rare5 and is unimportant epidemiologically, while the reverse applies for HIV. Both viruses are transmitted between IDUs by blood contact. The determinants of the epidemics are background virus prevalence, virus infectiousness and the existence of behaviour that permits spread. Sharing needles and syringes is generally acknowledged as the most important means of spread between IDUs, and has consistently been found to be the major association with HCV transmission among IDUs worldwide. Since the early 1980s, in response to the threat of HIV infection, there have been substantial declines in needle-sharing among Australian IDUs. About 13% of IDUs in Melbourne reported having shared a needle and syringe in the preceding month in 1994, compared with 38% in 1989.6 Nevertheless, it remains a problem, and higher proportions of IDUs who share needles and syringes are found among substantial minority groups, such as Vietnamese migrants and prisoners.6,7 There is emerging evidence of the importance of blood contact between IDUs in ways other than sharing needles and syringes. Videotapes of groups of IDUs reveal many opportunities for exposure to viruses through blood contaminating equipment other than needles and syringes. This includes swabs, spoons, water vials and tourniquets, as well as fingers, other body parts and surfaces in the immediate environment.1 For example, a user applying a tourniquet to a partner's arm might deposit a tiny smear of blood on skin which is subsequently punctured by a needle, or wipe blood from an injection site and let the swab fall onto a communal tabletop. The risk associated with such behaviour is greater for HCV than for HIV, because the higher infectiousness of HCV8 means smaller amounts of blood can efficiently transmit the infection. Two studies have attempted to quantify IDUs' risk of HCV transmission in the absence of needle-sharing: one found an incidence of about 4% per year among those who reported never sharing needles and syringes, compared with about 17% per year among those who did;9 the second, 11.9% compared with 30.2%.10 Both studies potentially suffered from misclassification bias, with some of those reporting never sharing actually having shared. Such bias would exacerbate the difference between the two incidences, further supporting the conclusion that the majority of HCV infections among Australian IDUs are associated with needle-sharing. Risky behaviour permits the blood contact necessary for both HCV and HIV transmission, and the higher infectiousness of HCV undoubtedly explains some of the difference in incidence. Background viral prevalence is the other critical factor. HCV prevalence is now so high that even very occasional sharing of needles and syringes carries an extreme risk of HCV infection, to which must be added the unknown but non-negligible risk due to "environmental" contamination. With a low-prevalence virus such as HIV, high-risk behaviour must be far more frequent and prevalent in a population before the risks of transmission become large enough to sustain continued spread. Given the much higher infectiousness of HCV per contact episode and its much higher prevalence in Australian IDUs relative to HIV, the difference in incidence comes down to the force of numbers. The Table combines background prevalences of HCV and HIV, estimates of infectiousness, and carrier rates to illustrate the difference in infection risk encountered by IDUs in Australia. On the basis of these crude estimates, an IDU sharing a needle used by another IDU of unknown infection status is at somewhere between 150 and 800 times higher risk of infection with HCV than HIV. Despite this somewhat sobering picture, it should be noted that there are tentative indications that HCV incidence in Australian IDUs has been declining in recent years. Modelling has suggested that incidence may have fallen from around 18% per year before 1987 to around 12% per year thereafter;1 a Victorian cohort study found a decline from 16.6 cases per 100 person-years in 1990-91 to 8.1 per 100 person-years in 1994-95, matched by declines in behavioural risk;9 and HCV prevalence among IDUs tested for the first time at a methadone maintenance program in Melbourne decreased from 75% in 1992 to 50% in 1995.12 The conclusion from all these considerations is that control of the HCV epidemic requires more intense concentration on reducing needle-sharing and other risky behaviour, and will require a greater effort to decrease incidence than HIV has. This has been seen with HIV infection among IDUs in other countries -- epidemics which have reached high prevalences have proven much harder to control than epidemics which have not taken off before interventions began. Further decreases in needle-sharing will require increased support for accepted programs (increased funding and reach of needle exchange programs, pharmacy sales, peer education) as well as consideration of new strategies. These should urgently include needle exchange programs in prisons (where needle-sharing is the norm)13 and youth training centres, safe injecting spaces, special programs for Aboriginal IDUs and people of non-English-speaking background, and deregulation of supply of needles and syringes so they can be purchased from outlets such as service stations and convenience stores. Other strategies, such as promoting transition to the smoking rather than injecting of illicit drugs, are worth further research and consideration. Finally, the importance of hygiene with regard to injecting environments and conditions must be strongly and routinely stressed. Without serious commitment to new and expanded strategies -- especially needle exchange -- the HCV epidemic will continue, with its high and growing toll of illness and cost. References Crofts N, Jolley D, Kaldor J, et al. The epidemiology of HCV infection among injecting drug users in Australia. J Epidemiol Community Health 1997; 51: 692-697. National Centre in HIV Epidemiology and Clinical Research. HIV/AIDS and related diseases in Australia: annual surveillance report, 1998. Sydney: National Centre in HIV Epidemiology and Clinical Research, University of New South Wales, 1998. Hurley SF, Jolley DJ, Kaldor JM. Effectiveness of needle-exchange programs for prevention of HIV infection. Lancet 1997; 349: 1797-1800. Hagan H, Des Jarlais DC, Friedman SR, et al. Reduced risk of hepatitis B and hepatitis C among injection drug users in the Tacoma Syringe Exchange Program. Am J Public Health 1995; 85: 1531-1536. Wyld R, Robertson JR, Brettle RP, et al. Absence of hepatitis C virus transmission but frequent transmission of HIV-1 from sexual contact with doubly-infected individuals. J Infect 1997; 35:163-166. Crofts N, Webb-Pullman J, Dolan K. An analysis of trends over time in social and behavioural factors related to the transmission of HIV among injecting drug users and prison inmates. Canberra: AGPS, 1996. Louie RL, Krouskos D, Gonzalez M, Crofts N. Vietnamese-speaking injecting drug users in Melbourne: the need for harm reduction programs. Aust N Z J Public Health 1998; 22: 481-484. Patz JA, Jodrey D. Occupational health in surgery: risks extend beyond the operating room. Aust N Z J Surg 1995; 65: 627-629. Crofts N, Aitken CK. Incidence of bloodborne virus infection and risk behaviours in a cohort of injecting drug users in Victoria, 1990-1995. Med J Aust 1997; 167: 17-20. van Beek I, Dwyer R, Dore GJ, et al. Infection with HIV and hepatitis C among injecting drug users in a prevention setting: retrospective cohort study. BMJ 1998; 317: 433-437. MacDonald M, Wodak AD, Ali R, et al. HIV prevalence and risk behaviour in needle exchange attenders: a national study. The Collaboration of Australian Needle Exchanges. Med J Aust 1997; 166: 237-240. Crofts N, Nigro L, Oman K, et al. Methadone maintenance and hepatitis C virus infection among injecting drug users. Addiction 1997; 92: 999-1005. Crofts N, Thompson S, Wale E, Hernberger F. Risk behaviours for blood-borne viruses in a Victorian prison. Aust N Z J Criminol 1996; 29: 20-28. Authors' details Centre for Harm Reduction, Macfarlane Burnet Centre for Medical Research, Fairfield, VIC. Nick Crofts, MB BS, Director; Campbell K Aitken, PhD, Senior Research Officer. National Centre in HIV Epidemiology and Clinical Research, Darlinghurst, NSW. John M Kaldor, PhD, Deputy Director. Reprints will not be available from the authors. Correspondence: Dr N Crofts, Centre for Harm Reduction, Macfarlane Burnet Centre for Medical Research, PO Box 254, Fairfield, VIC 3078. Email: croftsATburnet.edu.au 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/> Estimated percentage probabilities of infection with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) associated with a single injection with a needle previously used by an Australian injecting drug user (IDU) of unknown infection status HIV HCV IDU population prevalence estimates9,11 (A)2.1% 62.4% Carrier rates1 (B)100% 80% Needlestick infection probability estimates8 (C) High Low 0.4% 0.3% 10.0% 2.7% Probability of infection (A x B x C)High Low 0.0084% 0.0063% 4.9% 1.3% Ratio of probabilities (HCV/HIV)High Low 778 155 Back to text Reader response to this article, 6 July 1999: The "IDU population prevalence" and "needlestick infection probability" of HCV versus HIV (62% versus 2.5% and some 0.3% versus 5.0%) make it clear why HCV is progressing in such a spectacular fashion in the IDU population. The differences of "carrier rates" (80% versus 100%) are almost inconsequential. If IDUs were to have their communual injecting sessions with partners who were also HCV-negative, there would be no easy way for them to get infected. This implies that IDUs should be encouraged to find out their own HCV-status and get tested regularly. Injecting partners should be encouraged to find out the HCV-status of each other. The parallels with HIV are clear. What this excellent article did not mention was that injecting partners are already self-selecting for HIV - they choose partners who are likely to be also HIV-negative. This would go a long way towards explaining why "new HIV diagnoses in heterosexual IDUs are rare". Alfred Nassim 50 Sloane Street London SW1X 9SN England Authors' reply, 6 July 1999: There is anecdotal evidence that injecting drug users (IDUs) may be discriminating in relation to their own and others HIV status in some situations; for instance, if sharing of injecting equipment is unavoidable (as in prison), and one person is known to be infected with HIV, that person will go last with the needle and syringe. We are not aware of any published research evidence supporting the existence or prevalence of these behaviours. As to public health authorities promoting this behaviour as a strategy for IDUs uninfected with the hepatitis C virus (HCV) to protect themselves against infection, we remain unconvinced. Firstly, networks of IDUs are determined by other and potentially more powerful forces than knowledge of each other's HCV status. Secondly, prevalence of HCV in most IDU networks is so high as to make such a strategy impracticable. Lastly, this strategy raises the possibility of fostering yet more discrimination against HCV-infected IDUs, perhaps even within their own social networks. A corollary of this approach is that HCV-infected IDUs should only inject with each other, which raises the possibility of reinfection with different genotypes - unless the strategy is reduced to the absurd level of injecting only with others of the same genotype. As with HIV, effective public health strategies will rest on an acceptance of everyone being responsible for their own safety, and action to ensure that this is in fact possible for everyone. Dr Nick Crofts Dr Campbell Aitken Professor John Kaldor Back to top of article. Back to top of reader's response.

Nick Crofts · Campbell K Aitken · John M Kaldor

Editorial Accidental drug toxicity associated with methadone maintenance treatment As patient tolerance varies widely, methadone prescribers and users need to be better informed about the risks of overdose MJA 1999; 170: 100-101 Methadone, a long-acting oral opioid agonist, was first used to treat opioid dependence in the United States in 1964, and was introduced into Australia in 1969. While countries such as the United Kingdom have also shown interest in the use of methadone for heroin withdrawal, Australia has more commonly used it as a maintenance therapy. Currently, there are around 23 000 clients in methadone treatment throughout Australia, and this number is growing at around 15% per annum. Methadone treatment is the main clinical response to heroin addiction in Australia. Randomised controlled trials and controlled observational studies have shown methadone to be effective in reducing heroin use.1 Methadone treatment has also been found to be effective in reducing criminality, the risk of contracting HIV infection and the risk of deaths from overdose, and is associated with improvements in health and social functioning.1 The report by Caplehorn and Drummer in this issue of the Journal reminds us that, as with all medical treatments, there are risks associated with methadone treatment.2 Looking at deaths associated with New South Wales methadone maintenance programs in 1994, the authors identified two problem areas -- the period of induction into methadone treatment and the diversion of methadone to non-treatment populations. Despite the mortality associated with methadone maintenance treatment, Caplehorn and Drummer estimate that the New South Wales program saved 68 lives in 1994. The risk of overdose during induction into methadone therapy can be reduced by better training of prescribers in assessing the degree of opioid dependence and tolerance. These skills are now included in learning objectives developed at the request of the National Methadone Committee,3 and methods for assessing prescribers' competence in this area are currently being developed by an expert group (Robert Hughes, Director, National Drug Strategy, Drug Strategy and Population Health, Social Marketing Branch, Public Health Division, Department of Health and Aged Care, Canberra, ACT, personal communication). Routine regular monitoring for signs of intoxication and withdrawal is also an important consideration, and shared care protocols to improve the relationship and communication between prescribers and dispensers of methadone during patients' induction phase are under development in several jurisdictions -- such protocols need national consistency. In Australia, contention persists among clinicians and policymakers about the most appropriate dosing regimen for initiating methadone therapy. The dosing range and recommended increments in the first weeks of methadone treatment set out in the current National policy on methadone treatment4 have been criticised for being too rigid and not able to take account of variation in "real-world" practice. At the National Methadone Conference (Melbourne, 21-23 November, 1996), prescribers argued that inadequate starting doses will drive patients who experience withdrawal symptoms to "top up" the prescribed dose of methadone with heroin, benzodiazepines or illicit methadone. Thus, there is a need to find a balance between effective dosing while minimising the risk of overdose, and allowing flexibility in clinical judgement. To maintain the good reputation of methadone programs in Australia, it is crucial to establish credible guidelines on safe and effective induction into methadone treatment. To that end, a meeting to be held in early 1999 aims to establish evidence-based guidelines. This scientific review should provide a useful framework for informing the development of policy for induction, stabilisation and assessment of patients in methadone treatment. Illicit methadone use has been found to be widespread both overseas and in Australia.5 The most common reason reported for this use has been self-treatment of opiate withdrawal.6 Rarely, users report using methadone for its euphoric effects, and this is much more likely if the methadone is injected.7 There have been a variety of approaches to limiting the potential for diversion of methadone supplies. For example, in South Australia, the volume of takeaway doses is expanded to up to 100 mL to reduce the likelihood of injection. Other States have limited the timing and numbers of takeaway doses. A systematic review of these approaches is required to determine the most effective way of responding to this problem. In view of the mortality associated with methadone maintenance treatment highlighted in this issue of the Journal,2 there is a risk that there will be calls for further restrictions on methadone availability. While this may reduce the number of methadone-related deaths, it may inadvertently lead to an increase in the number of heroin-related deaths. Thus, it seems that the important lesson in methadone-related mortality is that we must ensure that both prescribers and potential users of methadone are aware of the risks of overdose, particularly for those who are not opioid tolerant. Robert L Ali Chair, National Expert Advisory Committee on Illicit Drugs Adelaide, SA Allan J Quigley Director, Clinical Research and Policy Development WA Alcohol & Drug Authority, Perth, WA Ward J, Mattick RP, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Amsterdam: Harwood Academic Publishers, 1998. Caplehorn JRM, Drummer OH. Mortality associated with NSW methadone programs in 1994: lives lost and saved. Med J Aust 1999; 170: 104-108. Allsop S, Bell J, Brough R, et al. Learning objectives for methadone prescribers. Canberra: AGPS, 1997. National Drug Strategy. National policy on methadone treatment. Canberra: AGPS 1997. Darke S, Ross J, Hall W. Prevalence and correlates of the injection of methadone syrup in Sydney, Australia. Drug Alcohol Depend 1996; 43: 191-198. McLellan AT. Methadone diversion in the USA (1998). In: Hall W, editor. Proceedings of an international opioid overdose symposium. Sydney: National Drug & Alcohol Research Centre, 1998. (Monograph No. 35.) Darke S, Hall W. Levels and correlates of polydrug use among heroin users and regular amphetamine users. Drug Alcohol Depend 1995; 39: 231-235.

Robert L Ali · Allan J Quigley

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 Abstract - Introduction - Methods - Results - Discussion - Acknowledgements - References - Authors' details - - More articles on Drugs and alcohol Abstract Objectives: To estimate the effects of methadone programs in New South Wales on mortality. Design and cases: Retrospective, cross-sectional study of all 1994 New South Wales coronial cases in which methadone was detected in postmortem specimens taken from the deceased. Cases were people we identified as patients in NSW methadone maintenance programs or those whose deaths involved methadone syrup diverted from maintenance programs. Outcome measures: Relative risks of fatal, accidental drug toxicity in the first two weeks of treatment and later; the number of lives lost as a result of maintenance treatment; preadmission risks and the number of lives saved by maintenance programs, calculated from data from a previous study. Results: There was very close agreement between this study's classifications and official pathology reports of accidental drug toxicity. The relative risk (RR) of fatal accidental drug toxicity for patients in the first two weeks of methadone maintenance was 6.7 times that of heroin addicts not in treatment (95% CI RR, 3.3-13.9) and 97.8 times that of patients who had been in maintenance more than two weeks (95% CI RR, 36.7-260.5). Despite 10 people dying from iatrogenic methadone toxicity and diverted methadone syrup being involved in 26 fatalities, in 1994 NSW maintenance programs are estimated to have saved 68 lives (adjusted 95% CI, 29-128). Conclusions: In 1994, untoward events associated with NSW methadone programs cost 36 lives in NSW. To reduce this mortality, doctors should carefully assess and closely monitor patients being admitted to methadone maintenance and limit the use of takeaway doses of methadone. Introduction Methadone maintenance greatly reduces heroin addicts' risk of death.1 A 15-year follow-up of patients in New South Wales showed methadone maintenance saved lives by reducing addicts' risk of fatal heroin overdose.1 When combined in a meta-analysis with the results of overseas cohort studies, the relative risk of death in methadone maintenance was a quarter that of addicts not in treatment (95% CI, 0.19-0.33).1 However, methadone maintenance is also a cause of death. Patients are at risk of fatal iatrogenic toxicity and other drug users may die from taking methadone syrup diverted from maintenance programs.2-6Mortality 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. Methods This study was approved by the Human Research Ethics Committee of the Western Sydney Area Health Service and the NSW State Coroner. 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 tolerance11,12 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 Statistical analysis We used published estimates of NSW methadone patients' risks of death after leaving treatment as approximations of 1994 NSW methadone patients' risks before admission to treatment.1Rates were adjusted for age, as the risk of death was significantly higher for those aged 20-29 years compared with those aged 30-39 years.1 Weighted average risks were calculated in the knowledge that, in 1994, 68% of NSW maintenance patients were at least 30 years of age.17 We assumed half of those admitted to maintenance were aged 20-29 years and half 30-40 years. 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 Results Methadone was detected in postmortem material from 89 NSW coronial cases in 1994. These cases comprised 41 methadone maintenance patients (38 registered with the NSW Health Department and three with the Queensland Health Department), one neonate being breastfed by a NSW methadone maintenance patient, 29 cases considered to have involved methadone syrup diverted from the NSW methadone program, and 18 cases considered to have involved methadone tablets. 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. Methadone maintenance patients Box 2 shows that, of the 38 NSW maintenance patients, 13 died in the first two weeks after admission, and 25 died later in treatment. We and the official pathologists concluded that 12 of the 13 fatalities in the first two weeks of maintenance and six of the 25 deaths later in treatment were caused by accidental toxicity. Three of six deaths from accidental drug toxicity among established maintenance patients were caused by heroin, one by dextromoramide, one by the combined effects of heroin and dextroproxyphene, and one involved injected methadone syrup. Diverted methadone syrup Box 2 shows that, for the 29 cases involving diverted methadone, we concluded methadone contributed to 26 of 27 deaths from accidental drug toxicity compared with 24 of 26 on the official pathologists' reports. One death which we classified as accidental drug toxicity was officially attributed to bronchopneumonia with methadone intoxication as a contributing factor. In another case, we concluded injected, diverted methadone contributed to a death which was officially attributed to acute heroin poisoning. 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. Relative risks of accidental drug toxicity We concurred with official pathologists' conclusions that 12 patients died of accidental drug toxicity during the first two weeks of maintenance treatment in NSW in 1994 (see Box 2). To calculate the rate of fatal accidental drug toxicity, we estimated the total time patients spent in the first two weeks of maintenance treatment. In 1994, 4449 people were admitted to methadone maintenance in NSW. Assuming all new admissions stayed at least two weeks in treatment,20,21 patients spent approximately 170.5 person-years in the first two weeks of maintenance. Using this estimate as the denominator, the rate of fatal accidental drug toxicity in the first two weeks of maintenance was 70.4 deaths per thousand per year (Box 3). 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). Lives saved by NSW maintenance programs The age-adjusted approximation of the expected mortality from all causes among heroin addicts was 15.5 deaths per thousand per year (95% CI, 11.0-21.9 deaths).1 Using this estimate, 132 deaths would have been expected to occur in 8506.5 person-years (95% CI, 93-187 deaths). As 64 people either died while receiving maintenance (38) or from the toxic effects of diverted methadone (26), NSW methadone programs are estimated to have saved 68 lives in 1994 (95% CI, 29-123 lives saved). To save one life approximately 125 patients needed to be given methadone maintenance for a year (95% CI, 69-293 patients). 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%). Discussion We found that, in NSW in 1994, the risk of fatal accidental drug toxicity in the first two weeks of methadone maintenance was nearly seven times the risk before admission to treatment. A previous report suggested that this excess mortality was primarily the result of iatrogenic methadone toxicity.7 However, the risk of fatal accidental drug toxicity later in maintenance was approximately one-hundredth the risk in the first two weeks of treatment and less than one-tenth the risk before admission. 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. Acknowledgements For their advice and generous assistance, we thank the NSW State Coroner at Glebe, the Westmead Court, the Division of Analytical Laboratories, and the Pharmaceutical Services Branch of the NSW Health Department, and the Drugs of Dependence Unit, Queensland Health Department. We also thank Professor Geoffrey Berry of the Department of Public Health and Community Medicine, University of Sydney, who assisted with the statistics and presentation of results. References Caplehorn JRM, Dalton MSYN, Haldar F, et al. Methadone maintenance and addicts' risk of fatal heroin overdose. Substance Use Misuse 1996; 31: 177-196. 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. McPherson CJ. Coronial inquiry into methadone related deaths. Melbourne: State Coroner Victoria, 1996. Clark JC, Milroy CM, Forrest ARW. Deaths from methadone use. J Clin Forensic Med 1995; 2: 143-144. Cairns A, Roberts ISD, Benbow EW. Characteristics of fatal methadone overdose in Manchester, 1985-94. BMJ 1996; 313: 264-265. Sunjic S, Zador D. Methadone-related deaths in New South Wales, Australia, 1990-1995. Euro-Methwork Newsletter 1998; issue 13: 11. 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. 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). 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. Siegel H, Helpern M, Ehrenreich T. The diagnosis of death from intravenous narcotism. J Forensic Sci 1966; 11: 1-16. Segal RJ, Catherman RL. Methadone -- a cause of death. J Forensic Sci 1974; 19: 64-74. Worm K, Steentoft A, Kringsholm B. Methadone and drug addicts. Int J Leg Med 1993; 106: 119-123. Transcript of Proceedings, Case 011 0487/95. New South Wales Coroner's Court Westmead. Ruigrok M, Caplehorn J. A case of near-fatal methadone toxicity following repeated injections of methadone [letter]. Drug Alcohol Rev 1997; 16: 433. Pounder DJ, Jones GR. Post-mortem drug redistribution -- a toxicological nightmare. Forensic Sci Int 1990; 45: 253-263. Levine B, Wu SC, Dixon A, Smialek JE. Site dependence of postmortem blood methadone concentrations. Am J Forensic Med Path 1995; 16: 97-100. Drug and Alcohol Directorate. NSW methadone program 1993/94: annual statistical report. Sydney: NSW Health Department, 1995. Bailar JC, Ederer F. Significance factors for the ratio of a Poisson variable to its expectation. Biometrics 1964; 20: 639-643. Armitage P, Berry G. Statistical methods in medical research. 3rd ed. Oxford: Blackwell Scientific, 1994: 131. Caplehorn JRM, McNeil DR, Kleinbaum DG. Clinic policy and retention in methadone maintenance. Int J Addict 1993; 28: 73-89. Caplehorn JRM, Irwig L, Saunders JB. Physicians' attitudes and retention of patients in their methadone maintenance programs. Substance Use Misuse 1996; 31: 663-677. Williamson PA, Foreman KJ, White JM, Anderson G. Methadone-related overdose deaths in South Australia, 1984-1994. Med J Aust 1997; 166: 302-305. Swensen G. Opioid drug deaths in Western Australia: 1974-1984. Aust Drug Alcohol Rev 1988; 7: 181-185. Transcript of Proceedings, Case 010 1924/94. New South Wales Coroner's Court Glebe, Thursday 15th June 1995: 31-37. 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. Caplehorn JRM. Official and de facto admission criteria for methadone maintenance in New South Wales, Australia [letter]. Drug Alcohol Rev 1998; 17: 121-122. Bell J, O'Connor D. Methadone prescribers' manual. Sydney: NSW Health Department, 1993: 11, 23. 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). Bolton M, Reynolds A, Biggs L. Queensland methadone program: policy and procedures and treatment manual. Brisbane: Queensland Health, 1995: 35, par 4.14. Wolff K, Sanderson M, Hay AWM, Ralstrick D. Methadone concentrations in plasma and their relationship to drug dosage. Clin Chem 1991; 37: 205-209. Caplehorn JRM. More on iatrogenic methadone toxicity [letter]. Drug Alcohol Rev 1998; 17: 467-468. (Received 22 Sep 1997, accepted 18 Oct 1998) Authors' details Department of Public Health and Community Medicine, University of Sydney, NSW. John R M Caplehorn, MB BS, MPH, PhD Student. 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 1: A case of fatal iatrogenic methadone toxicity This 1995 NSW case highlights the danger of daily doses of 30-40mg methadone in non-tolerant individuals and presents a classic history of fatal iatrogenic toxicity. The deceased had clear, early signs of methadone toxicity: somnolence; unsteady gait; vomiting; and a general feeling of being unwell. The terminal events were also typical: prolonged coma following sleep; very slow, deep, irregular, noisy breathing; brown pulmonary oedema fluid coming from the mouth or nose. Six weeks before his death, the 19-year-old man was admitted to hospital with hypothermia, pneumonia, right brachial plexus neurapraxia, rhabdomyolysis and acute renal failure after a heroin overdose. He reported using amphetamines for six months and heroin for two weeks. Liver function test and echocardiogram findings were normal, and at discharge three days later his serum creatinine level had fallen from 0.18mmol/L to 0.10mmol/L (upper normal limit, 0.12mmol/L). He was referred to a short-stay, residential program and told the admitting officer he had had problems with alcohol for five years, cannabis for seven years and amphetamines for one year, but had only used heroin six times. While he was considered suitable for admission to a drug-free rehabilitation program, this was delayed pending full recovery of his arm. However, he was advised not to wait to enter this program as he was facing trial for a criminal offence. Soon after, the deceased apparently told a general practitioner and a methadone prescriber he had been using heroin daily for a year. He was prescribed 30mg methadone, with the dose to be increased by 5mg every day for six days and then reviewed. The deceased vomited several times after receiving his second dose (35mg). The next morning, he was difficult to rouse, had trouble walking and urinating and kept falling asleep. His father was unable to contact the methadone prescriber, who was on holiday, and the nurses at the private methadone clinic did not seem to have recognised the seriousness of the situation. By late afternoon he felt much better and travelled by public transport to receive his last dose of methadone (35mg) at 1830. That evening he seemed well, was in a very good mood and ate a large dinner. However, he was still having difficulty urinating. He went to bed at 2245. Around 0645 the next morning his father was unable to wake him, he was breathing deeply, noisily and irregularly and had brown fluid coming from his mouth. After about fifteen minutes he stopped breathing and died. At autopsy, the body weighed 72kg. No "track" or recent injection marks could be identified. The lungs weighed 960g (right) and 860g (left) and were described as "very oedematous and congested". The heart and liver were macroscopically and microscopically normal. The postmortem blood methadone concentration was 0.32mg/L. No other drugs were detected in blood, bile or urine samples. The investigating pathologist determined the cause of death was methadone toxicity. The Deputy NSW State Coroner determined the fatal toxicity was caused by the administration of three daily doses of methadone (30mg, 35mg and 35mg).13 At the inquest, the deceased's methadone prescriber said he did not physically examine methadone patients and had not rejected an applicant for maintenance in the past two years. He routinely saw methadone patients only one day a week at a private methadone clinic.13 Back to text 2: Causes of death determined in this study and in official pathologists' reports for 38 patients in New South Wales methadone maintenance programs and 29 people whose deaths involved methadone diverted from maintenance programs Accidental drug toxicityMethadone*Other drug(s)Other causes of deathMethadone maintenance patientsDeath in first two weeksThis study11 1 1 Official report10 2 1 Death after two weeksThis study1 5 19 Official report1 5 19 Diverted methadoneThis study26 1 2 Official report24 2 3 TotalsThis study38 7 22 Official report 35 9 23 *Methadone either caused or contributed to the death. Back to text 3: Rates of fatal accidental drug toxicity and relative risks of fatal accidental drug toxicity and sudden death from all causes for patients in New South Wales methadone maintenance programs in 1994Rate Relative (Deaths/1000/yr) risk 95%CI Deaths from accidental drug toxicityIn first two weeks' maintenance70.4 36.3-122.8 after two weeks' maintenance0.72 0.26-1.57 First two weeks' maintenance v.out of treatment* 6.7 3.3-13.9 First two weeks' maintenance v.after two weeks' maintenance 97.8 36.7-260.5 Out of treatment* v.after two weeks' maintenance 12.2 4.8-30.6 Deaths from all causesOut of treatment* v.all maintenance 3.5 2.2-5.6 Out of treatment* v.after two weeks' maintenance 5.2 3.1-8.7 *Calculated from approximations derived from previously published data. Back to text

Olaf H Drummer · John R M Caplehorn

Prescribing heroin: nothing to fear but fear itself? Illicit drug policy based on punitive measures has failed, and it is time to seek a healthcare approach MJA 1998; 168: 590-591 The worsening global problem of illicit drugs will have been under discussion at the United Nations General Assembly Special Session on Drugs (UNGASS) in New York this month (8-10 June), just a few days before this issue of the Journal is published. The international crisis to which the United Nations is responding reflects decades of preferring to view the world as we would like it to be rather than as it is. Despite decades of alarming deterioration in outcomes associated with illicit drugs, the International Day Against Drug Abuse and Illicit Trafficking (26 June) is likely to be marked by yet more grandiloquent pronouncements of unachievable goals. In another editorial in this issue, Manderson describes the evolution of the complex drug control web in which we are now caught.1 Whenever new evidence has emerged of increasing illicit drug production and poorer outcomes, the reflex response of the international community has been to attempt to even more vigorously reduce supply. Genuine efforts to develop evidence-based alternative approaches, such as the proposed Australian Capital Territory heroin trial in 1997, have all too often been resisted by politicians. Senior Australian law enforcement officers have recently begun to question the traditional reliance on efforts to control illicit drug supply, with some calling for greater emphasis on treatment.2 After a recent meeting, Australian police commissioners "formally agreed to consider a range of strategies focusing on rehabilitation and avoiding the criminal justice system".2 Victorian Police Chief Commissioner, Mr Neil Comrie, said commissioners had decided to "almost wipe the slate clean" on current strategies.2 Australian criminal intelligence experts have stated that "law enforcement efforts are having only a limited effect on the amount of heroin offered at street level", and concluded that "it is obvious that current policies are not working".3 Some health interventions against illicit drugs, such as methadone treatment and needle exchange programs, have proved remarkably effective. Pharmacological treatments, of which methadone is by far the most important, attract and retain a substantial proportion of drug users and are strongly supported by evidence of safety and effectiveness.4 As both drug users and the broader community benefit substantially by recruitment and retention of users in treatment, the allocation of additional funding for monitoring and evaluation of trials of new pharmacological treatments in the recent "tough on drugs" statements by the Prime Minister should be warmly welcomed. These treatments include the partial opioid agonist buprenorphine, two opioid agonists (sustained-release oral morphine [SROM] and l-a-acetyl-methadol [LAAM]) and the opioid antagonist naltrexone. Each of these agents has particular advantages compared with methadone: buprenorphine and LAAM are safer and offer less costly alternate-day dispensing; SROM does not accumulate; and naltrexone avoids euphoria or dependence. However, there is no current evidence that these agents are more attractive or effective than methadone. By contrast, some trials have found that treatment retention, which often correlates well with other outcomes, was better for prescribed heroin than for methadone.5-7 There is a long history of pharmacological therapy for illicit drug users. More than 40 government clinics prescribed injectable morphine in the United States between 1919 and 1923.8 Heroin prescribing to treat heroin dependence commenced in the United Kingdom in 1926 and continues today,8 although this practice has been uncommon and rarely evaluated. A surprisingly extensive practice of prescribing amphetamine to amphetamine-dependent patients exists in the United Kingdom (Philip Fleming, Consultant Psychiatrist, Portsmouth Drug and Alcohol Service, Southsea, Hampshire, UK, 1998, personal communication), but is poorly documented and insufficiently evaluated. In this issue of the Journal, Metrebian and colleagues present the results of a UK study of relatively intractable patients allowed to choose treatment with either injectable heroin or injectable methadone.9 This study provides further support for the feasibility of prescribing heroin. The fact that more than one-third of patients chose injectable methadone should reassure those who assume that heroin prescription will prove irresistible to heroin injectors. Diversion of prescribed heroin to others was apparently not a problem, even though some prescriptions were dispensed weekly. Retention in treatment was unimpressive, but these patients had previously proved refractory to multiple treatment modalities. Illicit drug use, injecting risk behaviour, criminal activity, social functioning, health status and psychological adjustment all improved. Although the authors did not compare prescription of injectable drugs with other treatments, this study provides further support for conducting rigorously designed heroin trials. Whether prescribed heroin is suitable only for a heroin-dependent subgroup who do not respond to oral methadone or could be extended successfully to selected treatment-naive heroin users is a question that may also need to be answered one day. Right now, the study by Metrebian et al is also of interest in Australia because the harmful practice of methadone syrup injection is becoming increasingly common, and it is conceivable that parenteral methadone prescription might prove less harmful. The rationale for evaluation of medical prescription of heroin is based mainly on the need for dramatically improved treatment outcomes. The results of the recently completed heroin trial in Switzerland showed impressive health, social and economic gains,7 although the lack of a control arm inevitably limits any conclusions. Patients all had extensive histories of previous unsuccessful attempts at treatment (including methadone treatment). Retention on heroin prescription was considerably better than contemporary national retention rates for oral methadone treatment (although better staffing of the experimental program makes such comparisons problematic). After the Swiss heroin trial, 71% of voters in a national referendum supported continuation of this treatment, with majorities in all 26 cantons. It is hard to think of any new intervention in the illicit drug area in the last quarter-century that has shown such promise. On 6 June this year, the New York Academy of Medicine hosted the first international scientific meeting on heroin trials, reflecting growing international interest. A heroin trial will commence soon in the Netherlands, with trials under consideration in the UK, Germany, Spain, Austria and Canada.10 Interestingly, police chiefs in 10 of the 12 largest cities in Germany have been pressing for such a trial.10 The increasing interest in heroin trials is partly the result of authorities' growing acknowledgement of the failure of current policy. Were responses to illicit drugs to be decided entirely on the basis of evidence rather than fear and rhetoric, Australia would now be awaiting the results of the pilot stage of the ACT heroin trial. Demand for heroin is currently met by adulterated supplies of unknown concentration obtained from criminals. It seems probable that drug users and the general community would be better off if at least part of this demand were met by sterile heroin of known concentration prescribed by medical practitioners. Most doctors faced with a complex, chronic, relapsing-remitting disorder would prefer to choose from a range of effective treatments rather than rely on a single agent. The trials of new pharmacological agents are likely to extend and improve our therapeutic repertoire for treating heroin dependence. And there is still a compelling case for proceeding with a scientifically rigorous Australian heroin trial when political factors allow. Alex Wodak Director, Alcohol and Drug Service St Vincent's Hospital, Sydney, NSW Manderson D. Drug abuse and illicit trafficking. Med J Aust 1998; 168: 588-589. Harris T. Police switch strategies in war on drugs. The Australian 25-26 Apr 1998: 9. Australian Bureau of Criminal Intelligence. Australian illicit drug report 1996-97. Canberra: The Bureau,1997. Ward J, Mattick R, Hall W. Methadone maintenance treatment and other opioid replacement therapies. Amsterdam: Harwood Academic Publishers, 1998. Hartnoll R, Mitcheson M, Battersby A, et al. Evaluation of heroin maintenance in controlled trial. Arch Gen Psychiatry 1980; 37: 877-884. McCusker C, Davies M. Prescribing drug of choice to illicit heroin users: the experience of a UK community drug team. J Substance Abuse Treatment 1996; 13: 521-531. Uchtenhagen A. Summary of the synthesis report. In: Uchtenhagen A, Gutzwiller F, Dobler-Mikola A, editors. Programme for a medical prescription of narcotics: final report of the research representatives. Zurich: Institute for Social and Preventive Medicine, University of Zurich, 1997. Rihs-Middel M, editor. The medical prescription of narcotics. Scientific foundations and practical experiences. Seattle: Hogrefe and Huber. 1997. Metrebian N, Shanahan W, Wells B, Stimson GV. Feasibility of prescribing injectable heroin and methadone to opiate-dependent drug users: associated health gains and harm reductions. Med J Aust 1998; 168: 596-600. Nadelmann E. Commonsense drug policy. Foreign Affairs 1998; Jan/Feb: 111-126. 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/>

Alex Wodak

Abstract Objective: To assess the feasibility of offering the choice of prescribing injectable heroin (diamorphine) or injectable methadone to opiate-dependent injecting drug users and to assess whether there are health and social gains associated with prescribing injectable opiates. Design: A protocol-driven prospective observational study. Type of injectable opiate received was based on self-selection. Setting: A large west London drug clinic. Patients: Fifty-eight patients admitted to the clinic between 1 June 1995 and 31 December 1996, who were long term opiate-dependent injecting drug users, who had previously tried and failed oral methadone and who were apparently unable or unwilling to give up injecting. Main outcome measures: Retention in treatment, illicit drug use, HIV risk behaviour, criminal activity, social functioning, health and psychological status as measured by self-report, urinalysis and doctors' ratings. Results: Thirty-seven patients (64%) chose heroin and 21 (36%) chose injectable methadone. Fifty (86%) were retained in treatment after three months, 40 (69%) after six months and 33 (57 %) after 12 months. Among those in treatment at three months, there were significant reductions in illicit drug use, illicit drug-injecting risk behaviour, and criminal activity, and significant improvements in social functioning, health status and psychological adjustment. Generally, these gains were sustained between three, six and 12 months. Doctors' ratings of health and urinalysis results further supported these findings. Conclusions: Injectable heroin is not always the drug of choice. This intervention retained most patients in treatment with substantial benefits to both patients and the community. Prescribing injectable opiates to long term injecting drug users is a feasible treatment option. Introduction Opiate dependency is a major public health and social problem. Oral methadone treatment is the most common form of treatment for opiate dependency, and its effectiveness has been well demonstrated.1 However, Britain is one of the few countries where doctors can legally prescribe pharmaceutical heroin (diamorphine) and injectable methadone, and injectable opiates have been prescribed for opiate dependency since the 1920s in the case of heroin, and since the 1970s in the case of methadone.2Despite the legality of this practice, numbers of patients receiving such treatment remain small. Methadone accounts for 96% of all opiate prescriptions for treating drug dependency in the United Kingdom;3 injectable heroin accounts for only 2% of the total number of prescriptions for opiates;4 and methadone ampoules make up 9% of all methadone prescriptions.3 While injectable methadone is prescribed by doctors attached to specialist drug services, general practitioners and private doctors, a special licence from the Home Office is required to prescribe injectable heroin, and most doctors with such licences work in specialist drug services.5 Injectable opiate prescribing has not been guided by clinical protocols, but has been characterised by a high level of flexibility in decisions about eligible patients and dosage. The prescribing of injectable opiates has been the source of international controversy and debate. A large research trial has been undertaken in Switzerland6 and, in Australia, a heroin trial was designed to determine the impact of offering the choice of an injectable opiate prescription.7 However, the Australian Federal Government has decided that this trial will not proceed. It has been argued that injectable opiate prescribing may attract resistant opiate-dependent users into, and retain them in, treatment, with potential health and social benefits, including a reduction in crime,8 but there is a lack of scientific evidence on which to base these claims. The Swiss trial found that heroin prescribing retained drug users in treatment, with reductions in crime and improvements in health status.6 However, results of the most influential research carried out in the UK -- a randomised controlled trial comparing maintenance with oral methadone with heroin -- were inconclusive.9 In that study, the heroin group were better retained in treatment, but they continued to inject regularly and use illicit opiates in small amounts, which could lead to increasing clinic caseloads. On the other hand, the oral methadone group were more likely to either drop out of treatment or become abstinent. There were higher arrest rates and higher levels of drug involvement and criminal activity among those who did not become abstinent. Other studies have also found conflicting results.10-12 In this study we aimed to assess the feasibility of offering opiate-dependent injecting drug users the choice of treatment with injectable heroin (diamorphine) or injectable methadone, and to examine possible health and social gains associated with prescribing injectable opiates. Methods This pilot study was carried out at a west London drug treatment clinic. The clinic's protocol aimed to reduce illicit drug use and HIV risk behaviours; to improve physical, psychological and social functioning; and to move patients on to oral methadone treatment en route to abstinence. Eligible patients met the following criteria: aged over 21 years; dependent on opiates; unable or unwilling to give up injecting (defined by injecting for a minimum of three years with consistent injecting over the previous nine months and evidence of injecting over the past three months); previously failing oral methadone treatment (defined by regular continued use of illicit opiates while receiving oral methadone, continuing to inject regularly and receiving doses of oral methadone in excess of 80 mg/day); and problems relating to drug use in areas of health, social functioning or crime. Patients chose treatment with either injectable diamorphine (heroin) or injectable methadone. After a one-month induction period, they were required to stay with their drug of choice. A ceiling dose of 200 mg/day of either drug was set, and the treatment dose was achieved through tolerance testing over one week and stabilisation over the first month; after this time doses could only be reduced. Drugs were dispensed at the clinic daily (Monday to Friday with weekend doses taken home) for the first few weeks and then less frequently (a few times a week or weekly). After their initial tolerance test, patients were not permitted to inject on-site. To reduce the risk of injectable opiates being diverted to others, patients had to return used ampoules (batch numbers were checked) before receiving further ampoules. Criteria for disciplinary discharge from the study were evidence of "double-scripting" (receiving an additional prescription for opiates for drug dependency outside the clinic), dealing in the injectable opiates prescribed in this study, violence in the clinic, continual and persistent evidence of illicit drug use, consistently failing to return used ampoules, and injecting outside the clinic in the hospital grounds. The Australian Opiate Treatment Index (OTI)13 -- a multidimensional scale measuring illicit drug use, HIV risk behaviour, criminal activity, social functioning, physical and psychological health -- was administered to patients at entry and at three-monthly intervals. This instrument, which has been validated in both Australia13 and the UK,14 has a high correlation with doctors' and nurses' reports and with urine results at opiate treatment settings.14 Clinic doctors used standardised instruments to rate patients' health and psychological well-being at entry and at three-monthly intervals. These instruments included a physical rating scale for recording doctors' opinions of patients' physical health, including cardiovascular, respiratory, gastrointestinal, central nervous system and injecting-related health (Tallack F, Metrebian N, The Centre for Research on Drugs and Health Behaviour, London, 1996), and the Brief Psychiatric Rating Scale15 for recording doctors' judgements of patients' psychopathology. In addition, illicit drug use was measured through random urine tests throughout the treatment. Statistical analysis Tests of significance included t tests for related samples, and McNemar's chi-squared tests for dichotomous and ordinal data. Results from parametric and non-parametric tests were compared where normal approximations to the underlying distributions were suspect. We considered a P value of 0.05 to be significant. Results Fifty-eight subjects were recruited to the study. Forty-two (72%) were male, 50 were white (86%), and their median age was 38 years (range, 24-49 years). Their median duration of injecting heroin was 19.5 years (range, 4-30 years), and they had been in opiate treatment a median of four times previously (range, 2-17 times). Thirty-seven (64%) chose to receive diamorphine, 21 (36%) chose methadone. A higher mean dose of diamorphine was prescribed over three months (diamorphine, 181.43 mg/day [SD, 22.2; range, 120-200] v. methadone, 148.18 mg/day [SD, 45.1; range, 100-200) and over 12 months (185.24 mg/day [SD, 15.7; range, 150-200 v. 161.25 mg/day [SD, 46.4; range, 90-200]). Fifteen of the patients prescribed heroin (71%) reported experiencing night-time withdrawal symptoms as a result of heroin's shorter duration of action and were thus given an additional prescription for oral methadone. The mean dose of additional oral methadone was 24 mg/day (SD, 5.2; range, 20-30). A number of patients were found loitering in the vicinity of the clinic after their prescriptions were dispensed, and one was found injecting the prescription while still on hospital premises. No other major postdispensing problems were reported in the surrounding community. Fifty patients (86%) were still in treatment after three months, 40 (69%) after six months and 33 (57%) after 12 months. Reasons for discontinuing treatment are given in Box 1. Patients still in treatment at three months had significantly reduced their consumption of illicit drugs (with the exception of amphetamines, which did reduce, but not significantly), and made positive changes in all health and social domains. Self-reported criminal behaviour was initially low and further significantly reduced. There were significant improvements in social functioning (employment, housing, relationships and involvement in drug-using networks), health status and psychological adjustment. HIV risk behaviour (injecting and sexual risk behaviour -- the OTI considers any injecting as risk behaviour), and illicit drug-injecting risk behaviour (frequency of injecting and sharing of illicit drugs) reduced significantly. Although not significant, levels of sexual risk behaviour reduced slightly. There were no significant differences in measures of health and social behaviour between three and six months (data not shown), except for illicit drug injecting, which increased, although at six months it was still significantly less than at entry (1.13 [SD, 2.06] v. 5.66 [SD, 4.11]; P < 0.0001). Between six and 12 months, there were significant reductions in HIV risk behaviour, illicit drug-injecting risk behaviour and sexual risk behaviour, but no other significant changes. Results of urinalysis suggest that there were (non-significant) reductions in tranquilliser, amphetamine, and cocaine use between entry and three months, and between three and six months, which were sustained between three and 12 months. Few patients receiving injectable methadone were using illicit opiates. Measures of health and psychological status as reported by clinic doctors suggest health and psychological well-being had significantly improved at three months and these improvements were generally sustained. These findings were similar to measures of self-report. All measures reported at six and 12 months had significantly improved or reduced compared with measures obtained for the same sample at entry, with the exception of HIV risk, sexual risk and doctors' rating of psychological well-being, which had not significantly reduced or improved at six months but did reach significance again at 12 months. There were no differences found in drug use, health or social status reported at entry between those leaving treatment before 12 months and those remaining. Discussion These pilot study findings showed that opiate-dependent injecting drug users with long injecting careers (most started between 1970 and 1982) and for whom opiate treatment had failed multiple times previously were attracted into and retained by therapy with injectable opiates. Compared with drug users in a national UK study of oral methadone maintenance programs,16 our patients were older (38 v. 29 years) and had been injecting for longer (19.5 v. 9 years). While some clinicians17 and drug users' forums perceive a high demand for heroin treatment, our findings suggest that heroin is not always the drug chosen by users, with over one-third choosing injectable methadone. There has been much discussion about the correct dose of heroin.18 Over 12 months doses remained within the limit of 200 mg/day. In the Swiss study patients were stabilised on much higher doses of 500-600 mg/day.19 While interpretation of our findings is limited by the absence of a control group receiving oral methadone therapy and by reliance on self-report data, this is one of few studies to systematically examine the use of injectable opiates in treating opiate dependence, and the results will be used to inform a multicentre randomised controlled trial. In our study, at six months, 31% of patients had left treatment, and 40% of the 25 who left over the full 12 months were discharged because they violated the study protocol. Only two (16%) requested a move to oral methadone therapy and one became abstinent. There was one fatality (from hepatic failure) but no overdoses. By comparison, in the Swiss study of 366 patients receiving injectable heroin,20 18% had left treatment at six months and, of these, 48% switched to another treatment modality (mostly methadone maintenance) and 25% were excluded for threat of violence or other inappropriate behaviour. Four died and there were no overdoses. The retention rate in our study was higher than that reported by a national study of oral methadone maintenance programs at one month15 (86% v. 78%), and similar at six months (69% v. 67%).21 This suggests that the long-term opiate-dependent drug users in our study were well retained in treatment. Other studies have found similar high retention levels.9-11 There are concerns that prescribing injectable opiates might encourage drug users to continue injecting and discourage them from accepting oral methadone treatment or becoming abstinent.9 It is impossible to know whether our patients would have been more likely to move towards abstinence had they received oral methadone. However, these patients were long-term opiate-dependent drug users who had had a median of four previous opiate treatments and had tried and failed at least two oral methadone treatments without achieving abstinence. Our patients made significant health and social gains and experienced significantly reduced drug-related harm in the first three months. These gains were generally sustained between three and six, and six and 12 months. At entry, there were no significant differences in health and social status between patients later discharged from treatment and those who remained in the study. There has been some concern that patients' health might deteriorate while receiving prescribed injectable drugs.10 Previous research has shown little improvement in health and social wellbeing.9-11 The study by Battersby et al10 of drug users at high risk from serious physical illness, including HIV, found one individual developed a life-threatening illness (cervical spine osteomyelitis resulting from intravenous drug use) but survived, several injected into their femoral vein (a highly dangerous practice which carries a high risk of causing deep venous thromboses) and the health of 20% deteriorated. However, the authors concluded that "it was not possible to determine the nature of risk taking that would have occurred ... in the absence of the present treatment intervention". By contrast, we found that, although some patients were also injecting into their femoral vein, two moved to oral methadone because of poor health related to injecting and one died, for those remaining in treatment significant improvements were made in health, psychological adjustment and social functioning. These improvements were seen between entry and three months, and sustained between three, six and 12 months. There was also a reduction in illicit drug-injecting risk behaviour. Doctors' ratings of patients' health and psychological well-being verified these improvements. The problems of vein care associated with injectable opiates need to be weighed up against benefits in client attraction and retention, and in the provision of clean pharmaceutical drugs and injecting equipment, and advice on safer injecting practices and healthcare. Our findings do not support the suggestion that prescribing injectable opiates eliminates illicit drug use and criminal activity,22-24 as both declined significantly, but neither was eliminated. Similar results have been obtained by other studies.9-11 Results of urinalysis corroborated self-reported non-opiate drug use. However, it was not possible to corroborate self-reported opiate use as we could not differentiate between illicit and prescribed heroin. Diversion of prescribed opiates to others is of particular concern when there is no observed on-site injecting. While the clinic attempted to reduce the risk of such diversion, ways of corroborating self-reported compliance with prescription and illicit opiate use are needed. Prescribing injectable opiates is one of many options in a range of treatments for opiate-dependent drug users. In showing that it attracts and retains long term resistant opiate-dependent drug users in treatment and that it is associated with significant and sustained reductions in drug use and improvements in health and social status, our findings endorse the view that it is a feasible option. Further research is needed to examine the potential benefits of this treatment at both an individual and community level. Randomised controlled trials comparing alternative treatments and their relative cost effectiveness are required to fully assess this treatment option. Acknowledgements The Centre for Research on Drugs and Health Behaviour is core funded by the North Thames Office of the NHS Executives Research and Development Directorate. Riverside Mental Health Trust Substance Misuse Service, Ealing, Hammersmith and Hounslow and Kensington, Chelsea and Westminster Health Authorities funded this study. Thanks to all the clients who took part in the research, and to the clinic staff: Colin Small, Mark Lee, Victor Mtutu, Sue Byers, Movena Lucus, Gail Jones, Nicky Meux and Sam Nyeck. References Farrell M, Ward J, Mattick R, et al. Methadone maintenance treatment in opiate dependence: a review. BMJ 1994; 309: 997-1001. Strang J, Gossop M, editors. Heroin addiction and drug policy: the British system. Oxford: Oxford Medical Publications, 1994. Strang J, Sheridan J, Barber N. Prescribing injectable and oral methadone to opiate addicts: results from the 1995 national postal survey of community pharmacies in England and Wales. BMJ 1996; 313: 270-272. Strang J, Sheridan J. Heroin prescribing in the "British System" of the mid 1990s: data from the 1995 national survey of community pharmacies in England and Wales. Drug Alcohol Rev 1997; 16: 7-16. Sell L, Farrell M, Robson P. Prescription of diamorphine, dipipanane and cocaine in England and Wales. Drug Alcohol Rev 1997; 16: 221-226. Uchtenhagen A. Summary of the synthesis report. In: Uchtenhagen A, Gutzwiller F, Dobler-Mikola A, editors. Programme for a medical prescription of narcotics: final report of the research representatives. Zurich: Institute for Social and Preventive Medicine, University of Zurich, 1997. Bammer G. Should the controlled provision of heroin be a treatment option? Australian feasibility considerations. Addiction 1993; 83: 467-475. Metrebian N, Shanahan W, Stimson GV. Heroin prescribing in the UK: an overview. Eur Addict Res 1996; 2: 194-200. Hartnoll RL, Mitcheson MC, Battersby A, et al. Evaluation of heroin maintenance in controlled trial. Arch Gen Psych 1980; 37: 877-883. Battersby M, Farrell M, Gossop M, et al. "Horse trading": prescribing injectable opiates to opiate addicts. A descriptive study. Drug Alcohol Rev 1992; 11: 35-42. McCusker C, Davis M. Prescribing drug of choice to illicit heroin users: the experience of a UK Community Drug Team. J Subst Abuse Treat 1996; 13; 6: 521-531. Stimson GV, Oppenheimer E. Heroin addiction treatment and control in Britain. London: Tavistock Publications, 1982; 229-252. Darke S, Hall W, Wodak A, et al. Development and validation of a multi-dimensional instrument for assessing outcome of treatment among opioid users: the Opiate Treatment Index. Br J Addict 1992; 87: 733-742. Adelekan M, Green A, DasGupta N, et al. Reliability and validity of the Opiate Treatment Index among a sample of opioid users in the United Kingdom. Drug Alcohol Rev 1996; 15: 261-270. Overall JE, Gorham DR. The brief psychiatric rating scale. Psych Rep 1962; 10: 799-812. The Task Force to Review Services for Drug Misusers. Report of an independent review of drug treatment services in England. London: Department of Health, 1996; 61-64. Marks J. Who killed the British System? Druglink 1995; 10: 21. Strang J, Farrell M. Treatment of heroin users [letter]. BMJ 1994; 308: 718. Farrell M, Hall W. The Swiss heroin trials: testing alternative approaches [letter]. BMJ 1998; 316: 639. Uchtenhagen A, Dobler-Mikola A, Gutzwiller F. Medical prescription of narcotics. Eur Addict Res 1996; 2: 201-207. Gossop M, Marsden J, Stewart D, et al. The National Treatment Outcome Research Study in the United Kingdom: six month follow-up outcomes. Psych Addict Behav 1997; 11: 324-337. Beckett D. Prescription of controlled drugs to addicts. BMJ 1983; 287: 127. Connell PH. Drug dependence in Great Britain: a challenge to the practice of medicine. In: Steinberg, editor. Scientific basis of drug dependence. London: Churchill Livingstone, 1969. Marks J. Opium the religion of the people. Lancet 1985; i: 1439-1440. (Received 9 Sep 1997, accepted 24 Apr 1998) Authors' details The Centre for Research on Drugs and Health Behaviour, Department of Social Science and Medicine, Imperial College School of Medicine, London, United Kingdom. Nicky Metrebian, BA(Hons), Research Fellow; Gerry V Stimson, PhD, Professor, and Director. Chelsea and Westminster Drug Treatment Unit, Riverside Mental Health Trust Substance Misuse Service, London, United Kingdom. William Shanahan, MRCPsych, Lead Clinician, and Clinic Director. Riverside Mental Health Trust, London, United Kingdom. Brian Wells, MRCPsych, Trust Medical Director. Reprints: Ms N Metrebian, The Centre for Research on Drugs and Health Behaviour, Department of Social Science and Medicine, Imperial College School of Medicine, 200 Seagrave Road, London SW6 1RQ, United Kingdom. E-mail: n.metrebian@cxwms.ac.uk 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 ".

Nicky Metrebian · William Shanahan · Brian Wells · Gerry V Stimson

Wernicke's encephalopathy and thiamine fortification of food: time for a new direction? We should be fortifying beer to target the people who develop this disorder MJA 1998; 168: 534-535 Wernicke's encephalopathy (WE) usually occurs in people who have been drinking alcohol heavily and not eating, but can also occur after persistent vomiting or during hunger strikes. It is characterised by an acute global confusional-apathetic state with ophthalmoplegia or nystagmus. The ophthalmoplegia and confusion respond to thiamine treatment. Korsakoff's amnesic psychosis is associated with WE. Typically, it is recognised when the confusion clears in response to treatment with thiamine. While Korsakoff's psychosis (KP) sometimes responds slowly to thiamine, it is often persistent. Wernicke's encephalopathy is not easy to differentiate from other impairments of mental function in alcohol abusers. There is no rapid confirmatory special investigation. A patient with WE can die before being brought to hospital, and, in hospital, if the condition is not quickly recognised it is likely to lead to permanent memory damage in the form of Korsakoff's psychosis.1 Australia appears to have had both a higher incidence of WE than other comparable countries, and more people requiring long term care because of KP.2 In the 1980s, our national incidences of acute WE and of KP were estimated at about 6.5 cases/100 000 adults per year,3 and 22 cases/100 000 adults per year, respectively. As WE is not easily differentiated (as mentioned above) and as KP does not usually respond to thiamine treatment, this is evidently a disease complex more suitable for prevention than treatment. Public health measures have been under active discussion by Commonwealth health authorities since the problem was set out in a 1979 conference.4 In 1987, the National Health and Medical Research Council (NHMRC) recommended addition of thiamine to beer and flagon wine.5 However, nutrification of alcoholic beverages was unprecedented and was opposed by both brewers and anti-alcohol groups. After more discussion the NHMRC adopted the compromise suggested by its Nutrition Committee, that thiamine be added to bread flour as a first measure.6 Thiamine fortification of white bread is common in other industrial countries, introduced to restore losses of this vitamin from wheat by the refining process. Addition of thiamine to bread flour (at 6.4 mg/kg) was made mandatory in Australia on 1 January 1991. The Federal Government did not set up a system to monitor the effect of bread fortification, but information is accumulating that there has been some effect. A retrospective survey of records from the 17 major public health hospitals in greater Sydney for cases of Wernicke-Korsakoff syndrome (WKS) over the 10 years to 1993 showed that numbers of acute cases of WE or KP were lower in 1992 and 1993 than for any of the years preceding fortification.7 In this issue of the Journal, Harper and colleagues report on neuropathological postmortem examination of over 2000 brains at the NSW Institute of Forensic Medicine in 1996 and 1997.8 WKS can be identified by its effects on the mammillary bodies and walls of the third ventricle, and needs to be distinguished from changes caused by Alzheimer's disease, infarction, hypoxia and head injury. With the use of standardised techniques and special stains, 25 cases of WKS were identified, giving a prevalence of 1.1%. This is less than half the rate of 2.8% that Harper found in 4677 people (1783 postmortem brain examinations and 2894 hospital patients) in Western Australia between 1973 and 1978.1 Only two of the 25 NSW cases reported in this issue had been diagnosed at autopsy as acute WKS; six were diagnosed as acute-on-chronic and 17 as chronic. No note of ophthalmoplegia or nystagmus was found in hospital records for the 18 cases for which these were available.8 The neuropathology survey is thus showing a different end of the Wernicke-Korsakoff spectrum than the hospital record survey,7 which specifically sought new, acute cases. Both report from the Sydney area. A third look at WKS trends across Australia is afforded by comparing national mortality data obtainable from the Australian Bureau of Statistics for 1984 and 1989 (before fortification) with data for 1993 and 1996 (after fortification). Deaths from "other thiamine deficiency", "Korsakov's alcoholic psychosis" and "alcoholic cardiomyopathy" (some of which were presumably the result of thiamine deficiency) declined 22% from a combined two-year total of 329 to 255. By contrast, combined deaths from "other alcoholic dementia", "alcohol dependence syndrome" and "non dependent use of alcohol" increased somewhat from 452 to 493. A continuation of the survey of inpatient records in Sydney's 17 public general hospitals7 now includes data to 1996.9 Disregarding 1991, as it was the transition year, the average incidence of acute cases of WE or KP in the five years since fortification (1992-1996) was 40% lower than in the five years before fortification (1986-1990). This difference was statistically significant (P < 0.002),9 but the downward trend is not continuing -- the average of 41 acute cases per year for 1995 and 1996 was no lower than the 40 cases per year in 1992 and 1993.9 Increased thiamine intake from bread seems the most likely explanation for the apparent reductions of Wernicke-Korsakoff syndrome in Australia in the 1990s. Clinical diagnosis is subject to error, and postmortem diagnosis is based on morphological, and not chemical, characteristics. However, the decline, determined by different methods in three different studies,7-9 appears to be consistent over several years. Although the occurrence of Wernicke-Korsakoff syndrome in Australia appears to have been reduced by thiamine fortification of bread, it has not been eliminated. As nearly all cases occur in heavy alcohol drinkers, beer is probably a more appropriate vehicle for thiamine nutrification than bread. Prominent psychiatrist Eric Dax first suggested this 30 years ago.2 Beer is the preferred beverage of patients presenting with Wernicke's encephalopathy;7,10 the taste of thiamine hydrochloride can merge with the flavour of beer11 (but not with that of table wine); and it has been estimated that addition of thiamine to beer would be much more cost-effective than adding it to bread.12 It is clearly time for Commonwealth and State health authorities, the brewers and the NHMRC to seriously reconsider trialling the addition of thiamine to Australian beers -- to make them nutritionally the best in the world. Leslie R Drew Senior Lecturer, Department of Psychiatry A Stewart Truswell Professor of Human Nutrition University of Sydney, Sydney, NSW Victor M, Adams RD, Collins GH. The Wernicke-Korsakoff syndrome and related neurologic disorders due to alcoholism and malnutrition. 2nd ed. Philadelphia: FA Davis, 1989. Yellowlees PM. Thiamin deficiency and prevention of Wernicke-Korsakoff syndrome. A major public health problem. Med J Aust 1986; 145: 216-219. Gold J, Perdices M, Lardnet K, et al. The Wernicke-Korsakoff Project. Final report to the NH&MRC. Sydney: School of Public Health and Tropical Medicine, 1986. Prevention of alcohol-related brain damage. The report of a national workshop, Canberra 5-6 April 1979. Canberra: Commonwealth Department of Health, 1979. National Health and Medical Research Council. Report of 104th Session, November 1987. Canberra: NHMRC. 1988. National Health and Medical Research Council. Report of 108th Session, November 1989. Canberra: NHMRC, 1990. Ma JJ, Truswell AS. Wernicke-Korsakoff syndrome in Sydney hospitals: before and after thiamine enrichment of flour. Med J Aust 1995; 163: 531-534. Harper C, Sheedy D, Lara A, et al. Prevalence of Wernicke's encephalopathy in Australia: has thiamine fortification of flour made a difference? Med J Aust 1998; 168: 542-545. Rolland S, Truswell AS. Wernicke-Korsakoff syndrome in Sydney hospitals after six years' thiamin enrichment of bread. Public Health Nutrition 1998. In press. Price J. The Wernicke-Korsakoff syndrome in Queensland, Australia: antecedents and prevention. Alcohol Alcoholism 1985; 20: 233-242. Price J, Theodoros MT. The supplementation of alcoholic beverages with thiamine -- a necessary preventive measure in Queensland? Aust N Z J Psychiatry 1979; 13: 315-320. Connelly L, Price J. Preventing the Wernicke-Korsakoff syndrome in Australia: cost-effectiveness of thiamin-supplementation alternatives. Aust N Z J Public Health 1996; 20: 181-187. - 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/>

Leslie R Drew

Abstract Objective: To determine the prevalence of the Wernicke-Korsakoff syndrome (WKS) in Australia and compare this with previous studies. Design and setting: Prospective autopsy study at the New South Wales Institute of Forensic Medicine, 1996-1997. Methods: Brains of deceased people (aged over 15 years) derived from 2212 sequential autopsies performed between 1 January 1996 and 31 December 1997 were studied macroscopically and microscopically to identify cases of WKS. Main outcome measures: Standard histological criteria for WKS and any available clinical data. Results: Twenty-five cases of WKS were identified (prevalence, 1.1%), mostly among the 5.9% of the 2212 people who had a history suggestive of alcohol abuse. Only four cases (16%) had been diagnosed during life. Conclusions: There has been a significant reduction in the prevalence of WKS in Australia since the introduction of thiamine enrichment of bread flour. While the prevalence is still higher than in most other Western countries, further research is needed before adding thiamine to alcoholic beverages can be recommended. Introduction Wernicke-Korsakoff syndrome (WKS) is a potentially fatal neurological disorder caused by thiamine (vitamin B1) deficiency. It is easily treated by thiamine supplementation, with most people showing dramatic clinical improvement. Biochemical studies in the 1980s showed that 10%-20% of Australians had a low thiamine intake, with those who used alcohol excessively being particularly "at risk",1 and previous autopsy studies had shown that Australia had the highest recorded prevalence of WKS in the world, with most cases occurring among those who abused alcohol.2-5 To address these problems, the Australian Health Ministers' Council recommended the mandatory enrichment of bread flour with thiamine. Consequently, since 1991 bread flour in Australia has contained not less than 6.4 mg of thiamine per kilogram.6 Human thiamine requirements have been estimated to be 1.0-1.5 mg daily.7 The major food sources of thiamine are cereal products. Although thiamine is naturally present in the grains used to produce flour, much is removed during some types of processing, and thiamine enrichment of flour has been practised in a number of countries for many years.8,9 It is a mandatory requirement in the United Kingdom, Canada, and Denmark, while in the United States enrichment is not mandatory, but most flour is enriched. Since the introduction of thiamine enrichment of rice and flour, thiamine deficiency is said to have virtually disappeared in countries such as Japan and the US.10,11 Our aim was to establish whether this safe and simple public health measure has reduced the prevalence of WKS in Australia, and hence to determine whether we need to consider alternative public health measures such as adding thiamine to all flours used in food preparation or even to alcoholic beverages.12 Methods We prospectively studied all sequential autopsies of people aged over 15 years (as WKS is rare in a younger population in Western countries) from the NSW Institute of Forensic Medicine in Sydney during 1996 and 1997. In line with standard autopsy procedures, brains were fixed in 10% formol saline for at least two weeks. After careful external examination and removal of the brainstem and cerebellum, the brain was cut in the coronal plane, the first cut being made at the level of the anterior (ventral) tip of the mammillary bodies. The hemispheres were then cut at 10 mm intervals. The brainstem and cerebellum were separated by dividing the right and left cerebellar peduncles. The cerebellum was sectioned in the sagittal plane through the vermis and through the lateral hemispheres. The brainstem was sectioned in the horizontal plane at 3 mm intervals. The brain slices were examined, paying particular attention to the mammillary bodies and the regions around the third ventricle and the floor of the fourth ventricle. It has been shown that the mammillary bodies are abnormal on microscopic examination in 99%-100% of cases of WKS.3,13 The mammillary bodies were measured in three dimensions and brain slices were photographed if any macroscopic abnormality was noted. Blocks of tissue were taken for paraffin embedding and the preparation of histological sections. The principal block for this study incorporated both of the mammillary bodies and the walls of the third ventricle. Blocks from other regions of the brain were taken according to routine neuropathological protocols of the Institute of Forensic Medicine and the Neuropathology Department.4 These varied depending on the clinical history, cause of death, and general autopsy findings. Sections were cut at 10 mm and stained with haematoxylin and eosin. Brains were stored until each case was completed, so that, if necessary, additional blocks of tissue could be taken for further examination. This was particularly important if an abnormality was identified in the section of the mammillary bodies. A number of other diseases can affect the mammillary bodies, but these can usually be easily differentiated from WKS.5,14 All cases were examined microscopically by a neuropathologist (C H) without knowledge of the relevant clinical history or the macroscopic findings. In all cases in which WKS was suspected, the mammillary body section was also stained with reticulin, Weil myelin, glial fibrillary acidic protein, Perl's iron stain, Bodian silver impregnation, and Nissl stain for neurones. The purposes of these stains are summarised in Box 1. Clinical histories and general pathological data were correlated with the neuropathological findings. Statistical comparisons were made with data from a previous, similar study3 using chisquared statistics with Yates' correction factor and relative risk with 95% confidence intervals. Results We diagnosed 25 forensic cases of WKS from 2212 brains, giving an overall prevalence of 1.1%. Box 2 compares the prevalence data with those of a similar Australian study (including both forensic and hospital cases of WKS) undertaken by one of the authors (C H) from 1973 to 1981,3 and shows that there has been a statistically significant reduction in the prevalence of WKS. The mean age at death of the people with WKS was 55 years; 23 (95%) were men. Hospital medical records, located for 18 of the 25 deceased people with WKS, showed that alcohol appeared to have been a predisposing factor for WKS in 16 (89%). Of the remaining two, one was a man with paraplegia who was totally dependent and required gastrostomy feeding, and the other man had both lung and bowel cancer. Information available at autopsy indicated that 5.9% of the 2212 brains studied were from people with a history which suggested an alcohol problem, giving a prevalence of WKS in an Australian forensic population with a history suggestive of alcohol problems of 19%. A clinical diagnosis of WKS (Korsakoff's psychosis) during life had been made in only four (16%) of the 25 deceased whose WKS was identified at autopsy. However, two others had a diagnosis of alcohol-related brain damage. The hospital records located for 18 deceased people with WKS showed that four had severe amnesia (Korsakoff's psychosis), two others had memory problems and three had ataxia or unsteady gait. None were reported to have ophthalmoplegia or nystagmus, which are commonly described clinical signs in WKS.15 Three had a history of epilepsy. Eight (44%) had been given thiamine (vitamin B1) supplements during one or more of their hospital admissions. The diagnosis of WKS in this study was based on typical pathological abnormalities, which will not be described in detail as this information is available in current neuropathological texts.6 In brief, lesions are seen in a characteristic distribution -- in the mammillary bodies and around the walls of the third and fourth ventricles. Macroscopic findings vary depending on the stage of the disease (see Box 3). There were two acute cases, six acute-on-chronic cases (evidence of both acute and chronic damage to mammillary bodies), and 17 chronic cases. These data are compared with those of a previous study3 in Box 4. Discussion Our findings show a significant reduction in the prevalence of WKS in Australia compared with the findings of a similar study of forensic cases between 1973 and 1981 (see Box 2).3 The two forensic populations were similar, even though these two studies were conducted in different Australian States (New South Wales and Western Australia) and at different times. Laws relating to deaths which must be reported to the Coroner and undergo forensic autopsy are almost identical in these two States. Moreover, one of the authors (J H) was the Director of the Forensic Department in Perth, WA, at the time of the first study and is currently the Director of the NSW Institute of Forensic Medicine, where the current study was carried out; he commented that the profiles of cases in the two autopsy studies were very similar. The high prevalence of WKS at autopsy in Australia2-5 has been reflected in clinical studies, with, for example, 170 cases of WKS being identified among 1100 total inpatients at Queensland's largest hospital for the mentally ill.12 However, a retrospective study of records from 17 major Sydney hospitals from 1978 to 1993 showed that the number of acute cases of WKS was lower in 1992 and 1993 than in any of the other years.16 This suggests that dietary enrichment of bread flour with thiamine may have had an impact on the occurrence of acute cases of WKS. Our finding of fewer cases of acute WKS compared with the earlier WA study also supports this (see Box 4, above). As patients with acute WKS who are treated appropriately with parenteral thiamine respond within days, and signs and symptoms usually resolve completely, not all cases will progress to chronic disease. The development of chronic disease is not fully understood, but many chronic cases of WKS are likely to be the result of recurrent episodes of either clinical or subclinical thiamine deficiency.17 WKS is said in the medical textbooks to have a characteristic clinical picture of mental changes (confusion, obtundation), ataxia, and eye signs (nystagmus, ophthalmoplegia). However, as shown in this study and previously, analysis of clinical signs and symptoms of patients diagnosed with WKS post mortem reveals that a minority of cases have the full clinical picture and about a third exhibit only mental changes.15 Thus, the diagnosis can be easily overlooked. Many authors agree that WKS can develop as a result of repeated "subclinical" episodes of thiamine deficiency,18 so that studies of the prevalence of this disorder based on clinical findings are unsatisfactory and may underestimate the true incidence.15 Given that most of the cases of WKS we identified were chronic, some explanation must be sought for the significant reduction in the prevalence of this disease within six years of the introduction of thiamine enrichment of bread flour. There are four possible explanations: 1. A true reduction in the number of new (acute) cases of WKS as a result of the increase in dietary thiamine, and reduced numbers of "at risk" cases. 2. An improvement in the clinical status of patients who already have WKS and a reduced occurrence of further clinical or "subclinical" episodes of thiamine deficiency.17 This could result in an increase in the longevity of patients with existing WKS -- for example, through a reduction in the sudden unexpected deaths seen among chronic alcoholics. 3. A general improvement in the health status of the Australian population, independent of the introduction of thiamine supplementation. 4. Publication of the high prevalence of WKS in Australia may have led to an increased awareness, particularly among health professionals, of the necessity for thiamine treatment in "at risk" patients. Almost half of the 25 people whose WKS was identified at autopsy had been treated with thiamine in hospital. This increased awareness and therapeutic intervention may have played a role in the reduced prevalence. It is likely that each of these explanations played a part in reducing the prevalence of WKS. However, the relative importance of each will only be clarified with time and further study as the enrichment of bread flour with thiamine, has only been in place for six years. It should be noted that the results of this study may in fact underestimate the beneficial effect of the enrichment of bread flour with thiamine as many of the cases of chronic WKS will have developed before the enrichment program commenced. Further prevalence studies should be carried out in, say, another five years, and this information, together with biochemical studies of the thiamine status of the Australian population, will enable rational decisions to be made with regard to other public health programs, such as fortification of alcoholic beverages with thiamine. Our findings neither support nor confirm the prediction of Price and Theodorous that many people who abused alcohol would not be protected by a flour enrichment program because alcoholic beverages are, "for a hazardously long period of their lives, their only form of caloric intake".12 However, they had suggested, on the basis of this prediction, that thiamine supplementation of alcoholic beverages might be a more effective preventive measure, and in reviewing this proposal Connelly and Price noted that fortification of beverages, rather than bread flour, would be more cost-effective by a factor of 20-40-fold.19 Although there has been a significant decrease in the prevalence of WKS in Australia since the introduction of thiamine enrichment of bread flour in 1991, the rate is still higher than in most other Western countries5 and there is a need to maintain vigilance in the management of patients, particularly those with known or suspected alcohol problems. Acknowledgements This research was supported by the Australian Brewers' Foundation and by the National Health and Medical Research Council (Grant number 943302). We are grateful to all the staff at the NSW Institute of Forensic Medicine for their assistance and cooperation. References Wood B, Breen KJ. Clinical thiamine deficiency in Australia: the size of the problem and approaches to prevention. Med J Aust 1980; 1: 461-464. Harper C. Wernicke's encephalopathy: a more common disease than realised. J Neurol Neurosurg Psychiatry 1979; 42: 226-231. Harper CG. The incidence of Wernicke's encephalopathy in Australia -- a neuropathological study of 131 cases. J Neurol Neurosurg Psychiatry 1983; 46: 593-598. Harper CG, Gold J, Rodriguez M, Perdices M. The prevalence of the Wernicke-Korsakoff syndrome in Sydney, Australia: a prospective necropsy study. J Neurol Neurosurg Psychiatry 1989; 52: 282-285. Harper C, Fornes P, Duyckaerts C, et al. An international perspective on the prevalence of the Wernicke- Korsakoff syndrome. Metab Brain Dis 1995; 10: 17-24. Harper C, Butterworth R, editors. Nutritional and metabolic disorders. 6th ed. London: Arnold, 1997: 601-664. Freeman RM, editor. Rational use of vitamins in practice. Toronto: JB Lippincott, 1979: 115-122. Axford DWE, Williams DA. Flour enrichment around the world. Br Flour Milling Baking Res Assoc 1981; 4: 156-163. Bauerfeind JC. Nutrification of food. In: Shiks ME, Young VR, editors. Modern nutrition in health and disease. 7th ed. Philadelphia: Lea and Febiger, 1988. Figueroa WG, Sargent F, Imperiale L, et al. Lack of avitaminosis amongst alcoholics. J Clin Nutrition 1953; 1: 179-199. Sebrel WH. Enrichment: good gift of yesterday. Cereal Science Today 1966; 11: 228-230. Price J, Theodorus MT. The supplementation of alcoholic beverages with thiamin: a necessary preventative measure in Queensland. Aust N Z J Psychiatry 1979; 13: 315-320. Victor M, Adams RD, Collins GH. The Wernicke- Korsakoff Syndrome. Philadelphia: Davis, 1989. Schubert T, Friede RL. Transneuronal mammillary atrophy. J Neurol 1979; 221: 67-72. Harper CG, Giles M, Finlay-Jones R. Clinical signs in the Wernicke-Korsakoff complex -- a retrospective analysis of 131 cases diagnosed at autopsy. J Neurol Neurosurg Psychiatry 1986; 49: 341-345. Ma JJ, Truswell S. Wernicke-Korsakoff syndrome in Sydney hospitals: before and after thiamine enrichment of flour. Med J Aust 1995; 163: 531-534. Lishman WA. Cerebral disorders in alcoholism. Syndromes of impairment. Brain 1981; 104: 1-20. Lishman WA. Alcohol and the brain. Br J Psychiatry 1990; 156: 635-644. Connelly L, Price J. Preventing the Wernicke-Korsakoff syndrome in Australia: cost-effectiveness of thiamin-supplementation alternatives. Aust N Z J Public Health 1996; 20: 181-187. (Received 7 Aug1997, accepted 16 Feb 1998) Authors' details Department of Pathology, University of Sydney, and Royal Prince Alfred Hospital, Sydney, NSW. Clive G Harper, MD, FRCPA, Professor; Donna L Sheedy, BA, Research Assistant; Ana I Lara, Technical Assistant. Network for Brain Research into Mental Disorders, Prince of Wales Hospital, Sydney, NSW. Therese M Garrick, RN, BNurs, Research Assistant. New South Wales Institute of Forensic Medicine, Sydney, NSW. John M Hilton, MB ChB, FRCPA, Director; Jack Raisanen, MD, Forensic Neuropathologist. Reprints: Professor C G Harper, Department of Pathology, University of Sydney, NSW 2006. E-mail: clivehATpathology.su.oz.au 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 ".

Clive G Harper · Donna L Sheedy · Ana I Lara · Therese M Garrick · John M Hilton · Jack Raisanen

Public health and politics: the demise of the ACT heroin trial To the Editor: Wodak cites the support of the Australian Medical Association for the proposed ACT heroin trial in his editorial.1 The Federal Executive of the AMA supported the trial but the Queensland Branch (AMAQ) opposed it. The basic premise of Wodak's editorial is that stopping the trial showed lack of support for evidence-based medicine. AMAQ opposed the trial on the grounds that there was little scientific evidence, and what evidence there was came only from Switzerland and much of it was dubious at best. A view was expressed at AMAQ Council that the proposed stages of the trial were an unpleasant experiment on Australian society. The reason for Wodak's response lies in the second paragraph of his editorial, where he refers to the lucrative profits from trafficking of illicit drugs. Wodak and the trial's supporters appear to believe that liberal use of free heroin would threaten the profits of drug traffickers, but for that to be so heroin would have to be widely available in the community. Thus, the purpose of the trial was not to determine efficacy, as the authors of the trial, like Wodak, knew the outcome -- the introduction of free heroin throughout Australia. Christopher J Alroe Member, Australian Medical Association Queensland Branch Council; and Senior Consultant, Rockhampton District Mental Health Service, PO Box 4055, Rockhampton, QLD 4700 Wodak AD. Public health and politics: the demise of the ACT heroin trial [editorial]. Med J Aust 1997; 167: 348-349. 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 ".

Christopher J Alroe

Collateral damage from alcohol abuse: the enormous costs to Australia Curtailing the rippling effect of irresponsible drinking MJA 1998; 168: 6-7 Alcohol abuse is a problem that could affect any member of society, including the majority who are abstinent or use alcohol in moderation. Although much has been written about alcohol abuse and its effects on the drinker, there has been less emphasis on the deleterious effects on innocent bystanders, such as the physical, emotional and/or financial loss or damage. The spectrum of this "collateral damage" includes alcohol-related violence, road accidents, family problems, adverse pregnancy outcomes, consequences of alcohol abuse by doctors, and the resultant financial burdens incurred by society. Past studies have found that alcohol abuse plays a significant role in violent crime.1 It is estimated that about 13% of Australians aged 14 years and over (well over one million people) have been physically abused at least once by someone affected by alcohol, while 16% have had their property damaged at least once.2 Alcohol has also been implicated in about one-third of sexual assault cases.3 In 1992, 294 people died from alcohol-related assaults in Australia.1 Drunk drivers put not only their own lives in peril, but also pose a significant risk to other road users. In NSW in 1995, of the 620 people killed in road accidents, 141 (including 37 passengers and pedestrians) died in alcohol-related accidents. In addition, 298 non-drivers were seriously injured.4 Even more dramatic examples of alcohol-related transport accidents have been recorded internationally, such as the tragic Exxon Valdez oil spill in Alaska in 1989. At least 1% of the population (about 180 000 people) have a close family member with a serious alcohol problem. Isolation, neglect, aggression and disruption within the family, particularly spouse abuse, are frequent.5 Sexual and financial problems, stress, verbal and physical abuse, separations and divorce are also common between couples where at least one partner abuses alcohol.6 A Victorian report in 1988 found that alcohol was definitely or possibly involved in 53% of several thousand reported incidents of family violence.7 Children are particularly affected by having an alcoholic parent and they are more likely to become depressed,5 have lower IQ,8 and be alcohol dependent themselves in the future.9 In 1992, there were 226 hospital episodes resulting from alcohol-related child abuse in Australia.1 However, the extent of family problems is probably underestimated because there is underreporting of alcohol-related domestic violence. Maternal alcohol abuse is associated with adverse perinatal outcomes. These include the fetal alcohol syndrome, pseudo-Cushing's syndrome, alcohol withdrawal in the newborn, and increased risk of perinatal mortality.10 The incidence of fetal alcohol syndrome has been estimated to be between one and two per thousand live births, or 250 to 500 new cases per year in Australia.11 Alcohol abuse among doctors may lead to impaired clinical judgement and skills. While it is widely believed that alcohol abuse may be common among medical professionals, it is very difficult to identify doctors with alcohol-related problems. In the 12 months to March 1996, the NSW Medical Board heard 31 matters related to "impaired registrants", of which five were related to alcohol abuse.12 Similar problems may also occur in other health care workers. The costs of this to society include the costs of litigation, as well as the costs of patients' excess morbidity and mortality. The financial burden of alcohol abuse to the Australian community is substantial. In 1992, the costs of alcohol abuse were estimated to be $4.5 billion, or $250 for every man, woman and child in Australia.13 About three-quarters of these costs were tangible, including lower productivity because of lost work days, health care costs, road accident costs and legal and court costs. About 93% of the total tangible costs were borne by business and government. The intangible costs of about $1 billion include the value of loss of life, and pain and suffering of road accident victims.13 The extent of the problems and costs of alcohol abuse is enormous, but they can be reduced or prevented. About 84% of the costs ($3.8 billion) have been deemed avoidable and potentially amenable to public policy initiatives and behaviour changes.13 While health interventions may play a role, by detection and treatment of alcohol misuse, tougher measures need to be taken in other areas to prevent hazardous drinkers from doing harm to themselves and also to others. Such measures might include: alcohol taxation to reflect alcohol content of beverages rather than the cost of manufacture; major aim of liquor law reforms to be reduction of alcohol-related harm; strict enforcement of liquor laws by both police and state licensing authorities; mandatory training in liquor laws of bar staff, managers and licensees; and a truly independent alcohol advertising regulation authority. The NSW Parliament has enacted legislation which requires hotels, clubs and restaurants not to serve alcohol to patrons with certain defined behaviour suggesting intoxication (Liquor and Registered Clubs (Harm Minimisation) Act (NSW) 1997). The fines for drunken patrons who refuse to leave entertainment premises, if requested to do so, have been increased from $2000 to $5000. These measures are a necessary, but only preliminary, step to place the onus of responsibility on alcohol abusers for their actions, to encourage retailers to adopt a strict code of conduct and to protect the public from the consequences of irresponsible drinking. Yen F Tai Medical Student, University of Sydney, NSW John B Saunders Head, Department of Alcohol and Drug Studies University of Queensland, Brisbane, QLD David S Celermajer Associate Professor of Medicine, University of Sydney, NSW English DR, Holman CDJ, Milne E, et al. The quantification of drug caused morbidity and mortality in Australia. Canberra: Commonwealth Department of Human Services and Health, 1995. National Campaign Against Drug Abuse. National Household Drug Survey report. Canberra: AGPS, 1993: 2. Victorian Community Against Violence. A profile of rapes reported to police in Victoria 1987-1990. Melbourne, 1991. Roads and Traffic Authority, New South Wales. Road traffic accidents in NSW -- 1995. Sydney: Roads and Traffic Authority, 1996: 84-86. Orford J. Family coping. In: Proceedings of the International Congress on Alcohol, Other Drugs and the Family; 1988 November 27-30; Sydney: Alcohol and Drug Foundation, 1989: 30-35. Straussner SLA. The impact of alcohol and other drug abuse on the American family. Drug Alcohol Rev 1994; 13: 393-399. Law Reform Commission of Victoria. Homicide. Report No. 40. Melbourne: The Commission. 1991: 149. Ervin C, Little R, Streissguth A, Beck D. Alcoholic fathering and its relation to child's intellectual development: A pilot investigation. Alcohol Clin Exp Res 1984; 8: 362-365. McCaul ME, Turkkan JS, Svikis DS, et al. Alcohol and drug use by college males as a function of family alcoholism history. Alcohol Clin Exp Res 1990; 14: 467-471. Rankin JG, Ashley MJ. Alcohol-related health problems. In: Last J, Wallace R, editors. Public health and preventive medicine. 13th ed. Connecticut: Appleton-Lange, 1992: 741-767. Abel EL, Sokol RJ. Incidence of fetal alcohol syndrome and economic impact of FAS related anomalies. Drug Alcohol Depend 1987; 19: 51-70. New South Wales Medical Board. Annual report for the period ending 31 March 1996. Sydney: The New South Wales Medical Board, 1996. Collins DJ, Lapsley HM. The social costs of drug abuse in Australia in 1988 and 1992. National drug strategy monograph series No. 30. Canberra: Commonwealth Department of Human Services and Health, 1996. ©MJA 1997 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/> © 1997 Medical Journal of Australia.

Yen F Tai · John B Saunders · David S Celermajer