Substance‐related disorders

Public health and politics: the demise of the ACT heroin trial Where is the commitment to evidence-based medicine? MJA 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 <http://www.mja.com.au/>". - - ©MJA1997 The communique issued by the Ministerial Council on Drug Strategy (MCDS) meeting on 31 July 1997 stated: "If a number of preconditions can be met, the ACT Government [will] undertake a small trial of the controlled availability of heroin involving 40 people". Yet on 19 August, Federal Cabinet stopped the trial on the doubtful grounds that the Commonwealth would be required to pass special legislation permitting importation of heroin -- a claim contested by both the Federal Attorney General and the Health Minister. The Prime Minister also claimed that a rigorous trial of medically prescribed heroin was tantamount to legalisation and would "send the wrong message".1 What messages of certainty did the Prime Minister and Cabinet send by extinguishing the heroin trial? Firstly, that the lucrative profits of illicit drug trafficking, the very engine of this problem, would not be threatened. Secondly, that this problem will continue to be dealt with predominantly by law enforcement, an approach now widely recognised to be prohibitively costly and hopelessly impractical.2 The decision also sends a powerful message to medical researchers throughout Australia. Six years of careful scientific work on a significant community problem, widespread consultation, publications in quality peer-reviewed journals, openness to scientific scrutiny,3 support by the Australian Medical Association, presidents of medical colleges, numerous leaders of the medical profession, police commissioners, directors of public prosecution and a royal commissioner are not enough. An important, but controversial, scientific research project will be brought down politically if opposed by 51% of respondents in a community opinion poll4 and if subjected to a relentless campaign of media vilification and misinformation (Media Watch, ABC Television, 9.30 pm, 1 September 1997). This makes a mockery of the present government's advocacy of evidence-based medicine. Federal Cabinet's decision follows a long-standing tradition of basing policy in the illicit drug area on politics rather than science. Federal Cabinet's decision follows a long-standing tradition of basing policy in the illicit drug area on politics rather than science. Pharmacological fundamentalism even prevents doctors from recommending the option of smoking cannabis for palliating the intractable symptoms of terminal illnesses.5 The frequency of major inquiries into illicit drug use in Australia (at least 25, including Royal Commissions, in the past 25 years)6 suggests both considerable community anxiety as well as doubt about the effectiveness of current policy. Between 1979 and 1995, heroin-related overdose deaths increased from 10.7 per million population to 67 per million.7 Other illicit drug outcomes have also deteriorated alarmingly, while illicit drug law enforcement cost an estimated $1.7 billion in 1992.8 A Parliamentary Committee concluded that "all the evidence shows, however, not only that our law enforcement agencies have not succeeded in preventing the supply of illicit drugs to Australian markets but that it is unrealistic to expect them to do so".9 While generous funding continues for illicit drug law enforcement in the absence of demonstrable benefit, funding for treatment remains limited despite generally impressive outcomes. Methadone maintenance treatment is supported by overwhelming evidence of safety, effectiveness in improving health outcomes, reducing deaths, reducing crime and improving social functioning.10 The total cost of all methadone programs in Australia was estimated recently to be $40 million per annum,11 met by Commonwealth, State and Territory governments and by patients. Pharmacological treatments, especially methadone, are far more effective at attracting and retaining heroin-dependent patients than non-pharmacological treatments. The median duration of stay in drug-free rehabilitation facilities is only three to four weeks12 compared with about two years for methadone.13 Methadone maintenance is not attractive to all seeking pharmacological treatment and is not effective for all prepared to try it. When it comes to pharmacological treatment for heroin dependence, one size certainly does not fit all. Hence the need to expand the range of pharmacotherapies. Heroin was only one of a number of pharmacological agents to be evaluated for the management of heroin dependence. The MCDS also supported the evaluation of a number of other agents, including the opioid antagonist naltrexone, the long-acting agonist l- a-acetylmethadol (LAAM), the agonist-antagonist buprenorphine, and sustained release oral morphine. These trials are to go ahead. An official decision to support a heroin trial became difficult to oppose on any logical grounds after the final results of the Swiss heroin trial were released recently.14 Health outcomes of this trial were extremely impressive. Among 1146 subjects treated for 18 months, there were no overdose deaths, only three new HIV infections, four new hepatitis B infections and five new hepatitis C infections. Reported income from illicit and semi-legal activities decreased from 69% to 10%, the number of offences dropped by 60%, court convictions declined significantly, employment increased from 14% to 32%, and there were net savings of approximately $A45 per patient per day. It is difficult to think of any new law enforcement, education or treatment approach in the illicit drug field in the past 30 years which can boast such promising results. Why have the health, social and economic outcomes from illicit drugs in Australia continued to deteriorate for so many years? Firstly, there has been a systematic failure to collect relevant evidence (such as would be obtained from a heroin trial). Secondly, policy (including funding) has been based on ideology rather than evidence. If we want to help drug users lead normal and useful lives and offer some hope to their families and their communities, the first step is an unswerving commitment to evidence-based policy and practice without political interference. Tragically, in this country illicit drug policy has become inviolable while politicans remain terrified of losing an election lest rationality be misinterpreted as "being soft on drugs". The 1997 MCDS support for a 40-participant pilot stage of the heroin trial undoubtedly marked a watershed for evidence-based policy -- not for legalisation. There is no reason to believe that a heroin trial would have led inevitably to drug legalisation. After all, Britain has permitted medically prescribed heroin for more than 70 years while retaining a similar illicit drug policy to the one in Australia. Legalisation, if it means indiscriminate provision of all classes and quantities of currently illicit drugs, defies common sense, will always remain a political impossibility and would contravene Australia's international treaty commitments. The arguments for a heroin trial are as compelling now as they were before the prime ministerial intervention. As Justice Wood pointed out, "Without such a trial . . . its efficacy or otherwise will never be known. Until attempted, it is very difficult to move forward or to consider alternative strategies".15 The heroin trial was needed, and is still needed, as a circuit-breaker to move Australia from policies based on arbitrary historical decisions to a firm foundation on evidence. As far as the heroin trial is concerned, "the fat lady has not yet sung". Alex D Wodak Director, Alcohol and Drug Service St Vincent's Hospital, Sydney, NSW Short J, Hawes R, Kerin J. Heroin trials not on says Howard. The Australian 1997 Aug 20: 1. Flynn SE. The transnational drug challenge and the new world order. Washington, DC: The Center for Strategic and International Studies, 1993. Bammer G, Douglas RM. The ACT heroin trial proposal: an overview. Med J Aust 1996; 164: 690-692. Cockburn M. Nation's voters divided over ACT drug trial. Sydney Morning Herald 1997 Aug 19: 6. Kassirer JP. Federal foolishness and marijuana. New Engl J Med 1997; 336: 366-367. Australian Parliamentary Group for Drug Law Reform. Australian Drug Law Reform Foundation. Drug lore: the questioning of our current drug law. Canberra: The Foundation, 1997. Hall W, Darke S. Trends in opiate overdose deaths in Australia, 1979-1995. National Drug and Alcohol Research Centre technical report No. 49. Sydney: The Centre, 1997. Collins DJ, Lapsley HM. Social costs of drug abuse in Australia. National Drug Strategy Research Monograph No. 30. Canberra: Commonwealth Department of Community Services and Health, 1991. Report by the Parliamentary Joint Committee on the National Crime Authority. "Drugs, crime and society". Canberra: AGPS, 1989. Review of methadone treatment in Australia. Final report. October 1995. Canberra: Commonwealth Department of Human Services and Health, 1995. Ward J, Mattick R, Hall W. Key issues in methadone maintenance treatment. Sydney: New South Wales University Press, 1992. Swift W, Darke S, Hall W, Popple G. Who's who? A report on the characteristics of clients seen at We Help Ourselves 1985-1991. National Drug and Alcohol Research Centre technical report No. 14. Sydney: The Centre, 1993. Drug and Alcohol Directorate. NSW methadone programme annual statistical report, 1995-1996. Sydney: NSW Health Department, 1997. Uchtenhagen A, Gutzwiller F, Dobler-Mikola A. Programme for a medical prescription of narcotics. Summary of the synthesis report. Berne: Swiss Federal Office of Public Health, 1997. Wood JRT. Royal commission into the New South Wales police service. Final report. Sydney: The Government of the State of New South Wales, 1997: 228. ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Alex D Wodak

How the NHMRC got its fingers burnt Konrad Jamrozik, Simon Chapman and Alistair Woodward MJA 1997; 167: 372-374 On 20 December 1996, Justice J Finn of the Federal Court of Australia handed down his judgment in the case of the Tobacco Institute of Australia (TIA) Ltd and others v the National Health and Medical Research Council (NHMRC) and others. Justice Finn concluded that, in developing its recommendations for control of environmental tobacco smoke, the NHMRC's Working Party on Passive Smoking erred significantly in regard to the consultative procedures that it employed. As the following discussion shows, the legal decision has profound implications for the NHMRC and the provision of expert advice to Australian governments on matters of health and health policy. The discussion has been prepared by three members of the NHMRC Working Party, but reflects their personal views and not necessarily those of the Working Party as a whole or those of the NHMRC. Introduction - The judgment - Implications of the judgment for the NHMRC - References - Authors' details Make a comment - - ©MJA1997 Introduction The action brought by the Tobacco Institute of Australia (TIA) Ltd and others against the National Health and Medical Research Council (NHMRC) and others was concerned with matters of process, not of science. In his Reasons for Judgment statement,1 Justice Finn said, "My concern is not with the science of the Draft Report nor with the public policy recommendations made" (p2). He ruled that the Working Party "failed to have regard to the submissions received" (p38) from the TIA, in that it was obliged to but failed "to give positive consideration to their contents as a fundamental element in its decision making" (p31). Early in its deliberations the Working Party had decided that, in responding to its term of reference requiring it "to review the relevant scientific evidence linking passive smoking to disease in adults and children",2 it would only consider evidence that had been published in the peer-reviewed scientific literature. It then applied transparent processes in making an extremely conservative calculation of the impact of passive smoking on the health of Australians. Next, it considered the present situation with regard to public policy and public opinion in relation to smoke-free policies. Finally, it produced a series of recommendations which proposed that, given the increasing amount of peer-reviewed scientific evidence of harm from environmental tobacco smoke and significant public concern and support for change, all workplaces and confined public places should become smoke-free. The judgment There were two major issues in the judgment. 1. What emphasis should be placed on different types of evidence? Section 12 of the National Health and Medical Research Council Act 1992 (Cwlth) provides that, whenever the NHMRC proposes to develop guidelines or recommendations, it must publish a notice to that effect, seek submissions from the public and interested bodies on the matter, publish the draft recommendations and seek further submissions on these before issuing a definitive report. In the first phase of consultation initiated by the Working Party on Passive Smoking, in April 1994, the TIA submitted a large volume of material, much of which fell into three broad categories: Reports on aspects of passive smoking. These were openly acknowledged as having been prepared at the request of the tobacco industry and as not being peer-reviewed. Articles from the scientific literature that were readily identifiable as having been written by people known to have been associated with tobacco companies at some time (as judged by criteria developed by Bero and Glantz3). A considerable proportion of these consisted of critiques of previous original, peer-reviewed research on passive smoking rather than independently produced new research. The tobacco industry has been quite successful in pursuing advice received from consultants in 1978 that it should have as much material published as possible that casts doubt on the scientific evidence that passive smoking is harmful to health.4,5 This dissident opinion then gains a life of its own by being repeatedly cited in peer-reviewed literature, often, but not always, by authors with known links to the tobacco industry. Published proceedings of apparently reputable scientific meetings. However, these were, in fact, meetings convened by the tobacco industry and allegedly attended by invitation only.6 The Working Party was faced with the question of how to define "relevant scientific evidence". Errors may result from excluding material from non-peer-reviewed literature. However, in this instance, inclusion of reports from outside the peer-reviewed domain could produce a bias of another kind, as the volume of material generated by the tobacco industry far outweighs that sponsored by other interest groups.7 The Working Party judged that the literature on a long-defined and closely investigated topic such as the effects of passive smoking on health was likely to be relatively unaffected by orthodox publication bias, which favours early, false positive reports.8,9 Accordingly, the Working Party chose to restrict its description of the scientific evidence to that available from peer-reviewed literature. This is the same position as that adopted by the International Agency for Research on Cancer in its regular reviews of the causes of human cancer.10 However, Justice Finn found that the NHMRC Act did not provide for the Working Party to apply a selective standard of whether the material it received was peer reviewed, and rejected the argument that application of such a standard was justified by its wide acceptance by the professional community in reviewing scientific evidence. 2. What constitutes proper consideration of submissions made to the NHMRC or one of its committees or working parties? Justice Finn found fault with a mechanism adopted by the Working Party on Passive Smoking of having research officers summarise the individual submissions received and, in the first instance, circulate these summaries to members of the committee (with full submissions available to all members on request). The summaries were an aid to identifying efficiently to which of the evolving chapters of the Working Party's report submissions might be most pertinent (notwithstanding that no weight was given to non-peer-reviewed material). Justice Finn did not overturn the Working Party's conclusion that passive smoking poses a significant risk to the health of Australians, but he stated that:1 ". . .'positive consideration' of a submission (i) would preclude the adoption of an a priori criterion which itself excluded a part or parts of that submission from actual consideration; and (ii) would involve 'an active intellectual process directed at that . . . submission'." (p31). Justice Finn did not say explicitly what evidence of "proper consideration" or "an active intellectual process" would have satisfied him, nor did he limit or define a submission. Not defining these terms opens the door for any organisation with sufficient resources to forward excessive amounts of material for "active intellectual processing". The lack of a definition of "proper consideration" is significant. A close reading of the judgment suggests that its strongest defence would have been for each member of the Working Party to have prepared a written critique on all of the four books, 122 scientific papers and other supporting documents sent to the NHMRC by the TIA, for those critiques to have been tabled and discussed at full meetings of the Working Party, for the minutes of those meetings to have recorded those discussions and their outcomes in detail, and for all members of the Working Party to have been prepared to have taken the witness stand to answer questions about the whole process and every document. This extremely onerous standard would stretch the present NHMRC and its system of committees to their very limits. While it is possible that in future a court might accept a less demanding standard, it is predictable that those appealing against the NHMRC would seek evidence of "consideration" in its widest sense. Implications of the judgment for the NHMRC Given that the 1992 NHMRC Act obliges the Council to embark upon a process of public consultation whenever it is proposing to issue regulatory recommendations (recommendations that require responses from relevant Australian governments) or guidelines on any matter falling within its charter, we now have a situation in which any party with a vested interest and sufficient resources can effectively slow down the NHMRC's provision of independent expert advice on important matters of public health policy, simply by submitting an overwhelming number of opinions and commissioned, non-peer-reviewed reports on the matter at issue. There would appear to be nothing stopping any manufacturer or other group involved in the production, sale or distribution of any possibly hazardous product from doing exactly the same thing. The NHMRC Secretariat has a limited budget (approximately $5.5 million, half of which is for staff salaries)11 and only a very small permanent workforce of 96 people that it supplements by temporary secondments from the Department of Health and Family Services. A very large proportion of its work is undertaken by academic and other experts who, while being mindful of the honour of being invited to serve the Australian public in this way, also feel duty-bound to accept the responsibility and to give their time and effort to providing the best possible advice to the community and its various governments. The recent case on passive smoking shows that, as the law stands, this rather unsophisticated arrangement is not adequate for dealing with potentially far-reaching questions of health and health policy where large vested interests are involved. One response would be for the Federal Government to expand the Secretariat and budget of the NHMRC to the point where dedicated, in-house experts would be permanently available to consider any matter that was referred to the Council for consideration. Alternatively, the NHMRC Act might be changed to define more closely the requirements and mechanisms for consultation to prevent the process of formulating policy becoming unworkably bogged down. The NHMRC should not retreat to a professionally dominated model that excludes participation by the wider community. The challenge is to create processes that are open, inclusive and democratic, in the sense that all interests are treated fairly. The NHMRC must juggle efficiency, equity and scarce resources -- not an easy task. One practical suggestion is that, in future, it should restrict the length of submissions to ensure that the Council, with limited resources, can give fair consideration to all. A third alternative is suggested by the history of tobacco control in the United Kingdom, where expert reports from the Royal College of Physicians have driven the debate on public policy.12-15 In the present circumstances, the Federal Government might do well to commission outside expert groups such as the universities or the medical colleges to produce reports. The government would get its advice, but the process of providing it would not be held up by legal challenges. References Federal Court of Australia. Tobacco Institute of Australia Ltd & Ors v National Health & Medical Research Council & Ors [1996] 1150 FCA 1 (20 December 1996). Full text decisions of the Federal Court of Australia from 1977 on the Internet at: < URL: http://www.austlii.edu.au/au/cases/cth/federal - ct/ > >. National Health and Medical Research Council Working Party. The health effects of passive smoking. Canberra: NHMRC, 1995: 3. Bero LA, Glantz SA. Tobacco industry response to a risk assessment of environmental smoke. Tobacco Control 1993; 2: 103-113. Roper Organization Inc. A study of public attitudes towards cigarette smoking and the tobacco industry. Vol 1. New York: Roper Organization Inc., 1978. Chapman S. Tobacco industry memo reveals passive smoking strategy. BMJ 1997; 314: 1569. Bero LA, Galbraith A, Rennie D. Sponsored symposia on environmental tobacco smoke. JAMA 1994; 271: 612-617. Bero LA, Glantz SA, Rennie D. Publication bias and public health policy on environmental tobacco smoke. JAMA 1994; 272: 133-136. Begg CB, Berlin JA. Publication bias: a problem in interpreting medical data. J Roy Stat Soc A 1988; 151: 419-463. Easterbrook PJ, Berlin JA, Gopalan R, Matthews DR. Publication bias in clinical resarch. Lancet 1991; 337: 867-871. O'Neill IK, Chen J, Bartsch H, editors. Relevance to human cancer of N -nitroso compounds, tobacco smoke and mycotoxins. Lyon: International Agency for Research on Cancer, 1991. (IARC Scientific Publications No. 105.) National Health and Medical Research Council. Review of the Implementation of the Strategic Plan 1994-1996. Document tabled in Federal Parliament, 26 August 1997. Royal College of Physicians. Smoking and health. London: Pitman, 1962. Royal College of Physicians. Smoking and health now. London: Pitman, 1971. Royal College of Physicians. Smoking or health. London: Pitman Medical, 1977. Royal College of Physicians. Health or smoking. London: Pitman Medical, 1983. Authors' details University of Western Australia, Perth, WA. Konrad Jamrozik, DPhil, FAFPHM, Associate Professor in Public Health. University of Sydney, Sydney, NSW. Simon Chapman, PhD, Associate Professor in Public Health and Community Medicine. Wellington School of Medicine, Wellington, NZ. Alistair Woodward, PhD, FAFPHM, Professor of Public Health. Reprints will not be available from the authors. Correspondence: Associate Professor K Jamrozik, Department of Public Health, University of Western Australia, Nedlands, WA 6907. E-mail: konrad AT talbot.epidem.uwa.edu.au Make a comment - - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia. We appreciate your comments.

Konrad Jamrozik · Simon Chapman · Alistair Woodward

Notable Case Ephedrine abuse causing acute myocardial infarction Jerome G L Cockings and Michael A Brown "On the street", the more expensive illegal psychostimulants, such as cocaine or amphetamine, may be mixed with or substituted for cheaper drugs such as ephedrine -- with added risk to the user. We report diffuse myocardial injury in a 25-year-old man who presented with pulmonary oedema after intravenously injecting himself with ephedrine, believing it to be amphetamine. MJA 1997; 167: 199-200 Introduction - Clinical record - Discussion - References - Authors' details - - Articles on similar material Introduction The abuse of psychostimulants, such as cocaine and amphetamines, is of concern in Australia -- they are among the most widely used of the illicit drugs after cannabis.1 Occupational use of stimulant drugs is also a problem -- there have been accidents involving heavy transport vehicles whose drivers had taken ephedrine.2 In addition, ephedrine may be taken by "recreational" drug abusers when it is mixed with or substituted for other illicit drugs such as amphetamines. Ephedrine has both cardiovascular and central nervous system effects, but, although the cardiovascular risks of major psychostimulants such as cocaine are well known,3 little has been reported for ephedrine. We report a patient who injected himself intravenously with ephedrine, sustaining diffuse myocardial injury which resolved with inotropic support and ventilation. Clinical record A 25-year-old man with a history of intravenous psychostimulant abuse presented to hospital with progressive dyspnoea two hours after injecting himself intravenously with a solution of a white powder he believed was amphetamine. He had no other medical history of note, was a non-smoker and had previously been well. There was no family history of sudden cardiac death. Serum lipid levels were not measured. On examination he was conscious but tachypnoeic and cyanosed. He was afebrile, tachycardic (pulse, 140 beats/min), normotensive (110/70 mmHg) and hypoxic (Pao2, 49 mmHg), with hypocapnia (Paco2, 33 mmHg), a mild alkalosis (pH, 7.45) and a pronounced leukocytosis (44 x 106 cells/L). He had a reduced cardiac output (2.2 L/min; normal range, 4.5-6.5 L/min), with a pulmonary artery occlusion pressure (an estimate of left atrial pressure) of 30 mmHg. There was bilateral "bat's wing" opacification on chest x-ray, consistent with a clinical diagnosis of pulmonary oedema. Within an hour of admission and treatment with diuretic and oxygen, further deterioration with cardiogenic shock necessitated intubation, ventilation and admission to an intensive care unit. Initially, the lungs were poorly compliant (49 mL/cmH2O; normal range, 70-100 mL/cmH2O) and the alveolar-arterial (A-a) O2 gradient was elevated (260 mmHg; normal range, < 50 mmHg when on 80% O2). He received continuous inotropic support with adrenaline, initially at 38 µg/min, which was steadily reduced over three days. By Day 3, his cardiac output was 5.5 L/min without inotropes. His respiratory function and gas exchange improved steadily and he was extubated on Day 5. Results of microbiological investigations (tracheal aspirate, blood culture and urine culture) were negative and antibiotics were not given. On admission, electrocardiograms revealed widespread ST-segment depression with T-wave inversion, consistent with subendocardial infarction and ischaemia. A posterior infarction could not be excluded. The peak serum creatine kinase (CK) level was 2360 U/L (normal range, 20-130 U/L) (CK-MB isozyme fraction, 6.1%; normally < 2%), with rises in serum levels of aspartate aminotransferase (to 222 U/L [normal range, < 45 U/L]) and lactate dehydrogenase (to 612 U/L [normal range, 110-230 U/L]). A technetium Tc 99m perfusion scan of the myocardium showed mild tracer uptake in the left myocardium and more intense uptake in the posterolateral wall, consistent with diffuse myocardial damage and an acute posterolateral infarction. Echocardiography soon after admission showed severe left ventricular dysfunction in all areas except the apex (which showed near-normal contractility), with a poor overall ejection fraction. There was mild mitral regurgitation with no vegetations. Right ventricular function was normal. On Day 6, mild to moderate impairment of left ventricular function was still present, maximum at the base, with mild ventricular dilatation. The patient continued to improve and was discharged from hospital nine days after admission. Laboratory analysis of the unused white powder identified only ephedrine. On review one month later the patient was symptom-free. The resting electrocardiogram showed non-specific ST-segment and T-wave changes. Exercise testing, carried out according to the Bruce protocol,4 was 13.5 min in duration and limited by fatigue. His peak heart rate was 192 beats/min, with no chest pain or ST-segment or T-wave changes. He attained an estimated oxygen consumption of 49 mL/kg per min (normal range, 50-70 mL/kg per min) and an aerobic capacity of 106% of the predicted value. At two months, echocardiography showed normal left ventricular function but persistent trivial mitral regurgitation with a minor prolapse of the anterior leaflet. The patient was counselled about the health risks (such as the risk of bacterial endocarditis) of continuing to inject illegally obtained drugs. Discussion Our patient presented with diffuse myocardial injury consistent with sympathomimetic abuse -- the agent was identified as ephedrine. He recovered adequately after intensive treatment. The stimulatory central nervous system effects of ephedrine -- increased arousal, restlessness and insomnia -- have been recognised for many years. Preparations of the herb ephedra were used in ancient Chinese medicines, and ephedrine, the active alkaloid, was identified in the late 19th century.5 Ephedrine is a direct agonist of both alpha and beta sympathetic receptors and an indirect adrenoreceptor agonist, causing release of noradrenaline from presynaptic sympathetic nerve terminals. Its cardiovascular effects include tachycardia, increased inotropy, arterial vasoconstriction and hypertension,6 and these are the effects for which it is used therapeutically. Amphetamine and pseudoephedrine have similar actions, although amphetamine has more pronounced central nervous system effects.7 Ephedrine is widely available, but despite the potential for abuse that this creates there are few reports of its cardiovascular risks. Bruno et al. described two cases of intracranial haemorrhage and one of a thalamic infarct following excessive ephedrine ingestion,6 highlighting the potential dangers of non-prescribed self-administration of this drug. Chronic cardiomyopathy was documented after long-term ingestion of ephedrine in a cough mixture.8 Myocardial injury occurred after ephedrine given therapeutically for hypotension during labour,9 and coronary artery spasm leading to myocardial injury has been described with pseudoephedrine ingestion.10 The mechanism of the myocardial injury caused by ephedrine overdose is probably similar to that caused by cocaine -- intense diffuse vasoconstriction of both the coronary and the systemic arterial systems, decreasing myocardial perfusion, increasing afterload, and increasing myocardial oxygen utilisation.3 Although severe hypertension would be expected with ephedrine overdose, and may have been present in our patient soon after the injection of ephedrine, on presentation he had severe acute left ventricular failure with a consequent fall in contractility and blood pressure. This necessitated inotropic support rather than the use of vasodilators. Various other factors may have contributed to the myocardial injury in our patient. There may have been contaminants in the syringe, and the injection of insoluble particulate matter may have caused vascular occlusion. This could have been compounded by catecholamine-enhanced platelet aggregation induced by ephedrine. Further, although no other agents were identified in the remaining unused powder, the original injection may have included another myotoxin. Pre-existing coronary artery disease was unlikely in an otherwise healthy young non-smoker. A coronary angiogram was not performed. Although the leukocytosis was pronounced, this was consistent with the severe physiological stress. Nevertheless, in the absence of any other antecedent events or prior myocardial disease, this case report strongly suggests that the acute myocardial infarction was precipitated by the self-injection of ephedrine. "On the street", small quantities of a cheaper drug such as ephedrine may be mixed with stimulants such as amphetamine. This case illustrates the risks associated with the total substitution of ephedrine and the subsequent injection of what is likely to have been a high dose of this drug. References Australian Social Issues Research 1991. Report on the national campaign against drug abuse. Sydney: Social Issues Household Survey 1985-1991. Canberra: AGPS, 1991. Staysafe Committee of NSW 1992. Staysafe 19: Alcohol and other drugs on NSW roads 1. The problem and countermeasures. Sydney: NSW Parliament, 1992. Goldfrank LR, Hoffman RS. The cardiovascular effects of cocaine. Ann Emerg Med 1991; 20: 165-175. Bruce RA. Exercise testing of patients with coronary artery disease. Principles and normal standards for evaluation. Ann Clin Res 1971; 3: 323-332. Kalix P. The pharmacology of psychoactive alkaloids from Ephedra and Catha. J Enthnopharmacol 1991; 32: 201-208. Bruno A, Nolte KB, Chapin J. Stroke associated with ephedrine use. Neurology 1993; 43: 1313-1316. Gawin FH, Ellinwood EH. Cocaine and other stimulants: actions, abuse and treatment. N Engl J Med 1988; 318: 1173-1182. To LB, Sangster JF, Rampling D, Cammens I. Ephedrine-induced cardiomyopathy. Med J Aust 1980; 2: 35-36. Menegakis NE, Amstey MS. Case report of myocardial infarction in labour. Am J Obstet Gynecol 1991; 165: 1383-1384. Weiner I, Tilkian AG, Palazzolo M. Coronary artery spasm and myocardial infarction in a patient with normal coronary arteries: temporal relationship to pseudo-ephedrine ingestion. Cathet Cardiovasc Diagn 1990; 20: 51-53. (Received 27 Feb, accepted 12 June 1997) Authors' details Royal Adelaide Hospital, Adelaide, SA. Jerome G L Cockings, FFICANZCA, FANZCA, Senior Registrar in Intensive Care; Michael Brown, MD, FRACP, Consultant Cardiologist. Reprints will not be available from the authors. Correspondence: Dr J G L Cockings, Consultant Intensivist, Princess Alexandra Hospital, Ipswich Road, Woolloongabba, Brisbane, QLD 4102. E-mail: J. Cockings@mailbox.uq.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/>

Michael A Brown

A cruel and unusual punishment Sentencing prisoners to hepatitis infection as well as to loss of liberty is a violation of human rights MJA 1997; 166: 116 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/>". - ©MJA1997 Prison authorities and governments must realise that the responsibility for the infection of a prisoner with a bloodborne virus, because means for prevention were not available within the prison, rests with them. We justify depriving people of their liberty for transgressing social norms on the grounds of protecting society or rehabilitating the person. However, in the case of illicit drug use, there is little evidence that either of these objectives is achieved by current approaches. Imprisonment exposes injecting drug users to greater risks of infection with bloodborne viruses (such as hepatitis B and C) than in the community. About half of all injecting drug users have histories of imprisonment; about half of all prisoners have histories of injecting drug use; and about half of all imprisoned injecting drug users inject drugs in prison.1 Infection with hepatitis C virus (HCV) is common among Australian injecting drug users and prisoners. Butler and colleagues' study of prisoners entering the New South Wales correctional system (in this issue of the Journal) showed that almost a third were seropositive for HCV, rising to two-thirds of those with a history of injecting drug use. HCV infection was significantly associated with a history of previous imprisonment, which accords with the results of other studies.2 Similarly, surveys of Australian injecting drug users find that histories of incarceration are among the strongest associations with HCV seropositivity. 3 A major survey of prison entrants in Victoria found high incidences of infection with both HCV and hepatitis B virus (HBV) among returning prison entrants -- 41 per 100 person-years among young male injecting drug users.4 While these data do not prove that infections are acquired in prison, the prison environment makes spread of blood-borne viruses more likely. The boredom, frustration and hopelessness felt by many prisoners potentially contribute to drug use. Many prisoners have no investment in the future, which will probably contain little except unemployment, further drug use and further imprisonment -- 64% of prison entrants in Victoria have been imprisoned previously. 5 They may believe they have nothing to lose (and some escape to gain) from drug use. In addition, prison policies may aggravate the problem of disease transmission. For example, sharing of injecting equipment is much more common in prison (where equipment is very scarce) than outside (where it is relatively freely available). 1 Efforts to detect drug use, such as urine screening, may drive prisoners from smoking marijuana (which has metabolites that can be detected in the urine for many days) to injecting heroin and amphetamines (which are rapidly cleared from the body). Prison practices may also prevent prisoners taking precautions against spread of bloodborne viruses. For example, despite official policy, urine screening is alleged by prisoners to be anything but random; in some prisons, prisoners claim that a request for bleach (for disinfecting injecting equipment) is followed the next day by a urine test. 6 Sanctions against drug use, such as loss of contact visits as punishment for a "dirty" urine, simply reinforce the original reasons for drug use. 6 Prisons take people from diverse settings who would not otherwise meet, create the opportunity to spread bloodborne viruses among them and then send them back to their original social networks as potential sources of infection. The situation varies for different bloodborne viruses. Despite the opportunities for transmission by injecting drug use, there has been very little transmission of HIV in Australian prisons. 7 However, this is not because conditions are not right for such transmission. It is because there is very little HIV among prison entrants as a result of harm reduction programs in the general community -- fewer than 5% of Australian injecting drug users were seropositive for HIV. 4 The recognition that reducing the spread of HIV is a more urgent priority than eradicating drug use (were the latter possible) has allowed our national AIDS and drug strategies to adopt such harm-reduction approaches (e.g., needle and syringe exchange and methadone maintenance programs). On the other hand, HCV is causing an epidemic among Australian injecting drug users that will be difficult to control. 2 Prisons are a key to this control; without rational approaches to the twin problems of injecting drug use and of HCV transmission in prisons, the epidemic will continue. The first step should be the recognition that incarceration offers nothing but ill to most injecting drug users. Alternative approaches to their problems will benefit both them and society. A serious reconsideration of the opportunities for spread of bloodborne viruses in prisons is the next step. Measures should include everything from lowering the cost to prisoners of razors and toothbrushes (so they will not share them), to provision of sterile injecting and tattooing equipment, peer education programs, transition programs to assist movement back to society (including referral to needle exchanges), proper drug substitution and drug treatment programs and hepatitis B vaccination. 8 It cannot be said often enough that the punishment is deprivation of liberty, and that is all. Prisoners should have available to them all the means for protecting themselves against infection with bloodborne viruses that are available outside prison, without qualification. Prison authorities and governments must realise that the responsibility for the infection of a prisoner with a bloodborne virus, because means for prevention were not available within the prison, rests with them. Nick Crofts Head, Epidemiology and Social Research, The Macfarlane Burnet Centre for Medical Research, Melbourne, VIC. 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. Evaluation of the National HIV/AIDS Strategy 1993-94 to 1995-96, Technical Appendix 4. Canberra: AGPS, 1996. Crofts N, Stewart T, Hearne P, et al. Spread of blood-borne viruses among Australian prison entrants. BMJ 1995; 310: 285-288. Crofts N, Jolley D, Kaldor J, et al. The epidemiology of hepatitis C virus infection among Australian injecting drug users. J Epidemiol Community Health. In press. Kaldor JM, Elford J, Wodak A, et al. HIV prevalence among IDUs in Australia: a methodological review. Drug Alcohol Rev 1993; 12: 175-184. Victorian Correctional Services Annual Prison Census, 1995. Melbourne: Department of Justice, 1996. 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. Dolan K, Hall W, Wodak A, Gaughwin M. Evidence of HIV transmission in an Australian prison [letter]. Med J Aust 1994; 160: 734. Dolan K, Wodak A, Penny R. AIDS behind bars. AIDS 1995; 9: 825-832. - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Nick Crofts

The agony of "ecstasy" How can we avoid more "ecstasy"-related deaths? MJA 1997; 166: 117 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/>". - ©MJA1997 "Ecstasy" (MDMA; 3,4-methylenedioxymethamphetamine) was developed by E Merck in 1914 as an appetite suppressant, but was never used clinically for that purpose. In the 1970s, it was used as an adjunct in psychotherapy, principally in the United States, but was banned in that country from 1985 because of its toxicity and potential for abuse.1 Over the past decade, the recreational use of MDMA has increased substantially, both in Australia and elsewhere.2 This use has been associated particularly with "dance parties" and "raves" and has recently captured public attention because of deaths from acute MDMA toxicity. it is currently impossible to predict which users will be most liable to experience toxic effects MDMA has a range of effects that can lead to acute toxic reactions, including hyperthermia, raised blood pressure, raised heart rate, cardiac arrhythmias and coagulopathy.3 Hypertension may lead in turn to stroke, and hyperthermia to rhabdomyolysis, dehydration and renal failure. These effects appear to be caused by the action of MDMA on serotonergic and dopaminergic systems, resulting in increased release of neurotransmitters.4 This may explain the overlap of signs and symptoms of MDMA toxicity with those of the serotonin syndrome.5 Chronic toxicity has also been reported in animal models, with lesions of serotonergic neurons in the central nervous system after a few doses of MDMA. In primates, recovery of such lesions is slow and possibly incomplete.6 It is not known whether such toxicity occurs in humans. Some of the metabolites of MDMA (e.g., methylenedioxyamphetamine and dihydroxymethamphetamine) may contribute to the toxicity of the drug.7,8 While certainly the best-known derivative of amphetamine, MDMA is only one of a range that have been used illicitly. Numerous other amphetamine analogues have appeared since the 1960s, either as recreational drugs in their own right, or as contaminants in illicit drug samples. Their popularity and availability have varied. Paramethoxyamphetamine (PMA) is one analogue of current importance in Australia. Ingestion of PMA, either alone or combined with MDMA, has resulted in several "ecstasy" deaths in this country over the last two years. It appears that in most of these cases, the drug users thought they were taking MDMA, but PMA was present as a contaminant. As there is no central collection of information on drug overdoses in Australia, it is difficult to determine accurately the number of ecstasy-related deaths. There have been about 12 such deaths in Australia over the last two years, with at least six of these involving PMA, either alone or combined with MDMA (Dr R James, Senior Forensic Pathologist, South Australian Forensic Science Centre, Adelaide, SA, personal communication). There is no published information on the number of individuals who required hospital admission or suffered non-fatal serious consequences from MDMA-PMA ingestion. It is important to recognise that the number of deaths related to MDMA is relatively small compared with the likely frequency of its use. Deaths from heroin overdoses are certainly a much more significant problem in Australian society; 152 heroin-overdose deaths were identified in NSW in 1992.9 Nevertheless, MDMA deaths are particularly puzzling as they are unpredictable. In some cases, other people appear to have taken similar quantities of ecstasy from the same source as the overdose victim, with only minor toxic effects. One theory is that variations in metabolism of the drug caused by genetic differences or concurrent use of other drugs may result in differential susceptibility to MDMA overdose.10 The causes of death after MDMA ingestion are not well documented. Certainly, hyperthermia and its consequences seem to be of major importance, and results of animal studies suggest that environmental temperature may be a critical determinant of susceptibility.11 This is the basis for recommendations about access to cool environments in nightclubs and other dance venues. However, the case reported by Parr and colleagues in this issue of the Journal suggests something different -- excessive consumption of fluids was the cause of death. Similar conclusions have been reached in cases of apparent MDMA toxicity in the United Kingdom. 12 The reason for such excessive fluid consumption is not understood, although MDMA is known to induce thirst. 13 In addition, high doses of amphetamine and amphetamine derivatives induce repetitive behaviours in animals and humans. 14 It is possible that the combination of thirst and repetitive behaviour patterns leads to excessive fluid intake. If urine output is also low, because of dehydration, impending renal failure and (possibly) other unidentified causes, then there is considerable potential for fluid overload and its consequences. What is the appropriate action to reduce further deaths from MDMA? Firstly, guidelines for its use should be considered. These should include recommendations on provision of suitable environments at venues where the drug is likely to be taken (e.g., adequate ventilation and access to "cooling-off" areas). Other guidelines need to address educating users about appropriate fluid intake, the dangers of combining ecstasy with other drugs (both illicit and prescribed), and the warning signs of toxicity. The latter are particularly important, as obvious signs of acute toxicity have been ignored in several cases, possibly through ignorance or concern about risk of arrest for possession of an illegal substance. The preparation of such guidelines is currently under way in Australia. A report on the toxic effects of MDMA 15 has been published by the Commonwealth Department of Health and Family Services, to form the basis for guidelines to be prepared by the individual States and Territories. We also need to know what drugs are available in the illicit market and the toxicity of each. The magnitude of the problem can be accurately assessed only if there is a national coordinating body to collate information from each of the State and Territory jurisdictions. In addition, while relatively little is known about MDMA, even less is known about PMA, and both drugs should be the subject of further research. Differences in individual susceptibility to MDMA-induced acute toxicity must also be addressed, as it is currently impossible to predict which users will be most liable to experience such effects. Jason M White Senior Lecturer, Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, SA Felix Bochner Professor of Clinical Pharmacology, University of Adelaide, and Head of Clinical Pharmacology, Royal Adelaide Hospital, SA Rodney J Irvine Research Fellow, Department of Clinical and Experimental Pharmacology, University of Adelaide, Adelaide, SA Steele TD, McCann UD, Ricaurte GA. 3,4-Methylenedioxymethamphetamine (MDMA, "Ecstasy"): pharmacology and toxicology in animals and humans. Addiction 1994; 89: 539-551. Solowij N, Hall W, Lee N. Recreational MDMA use in Sydney: a profile of ecstasy users and their experiences with the drug. Br J Addiction 1992; 87: 1161-1172. Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 3,4 methylenedioxymethamphetamine ("ecstasy"). Lancet 1992; 340: 284-287. McKenna DJ, Peroutka SJ. Neurochemistry and neurotoxicity of 3,4-methylenedioxymethamphetamine (MDMA; "Ecstasy"). J Neurochem 1990; 54: 14-22. Nierenberg DW, Semprebon M. The central nervous system serotonin syndrome. Clin Pharmacol Ther 1993; 53: 84-88. Ricaurte GA, Martello AL, Katz JL, Martello MB. Lasting effects of (+)-3,4-methylenedioxymethamphetamine (MDMA) on central serotonergic neurons in nonhuman primates: neurochemical observations. J Pharmacol Exp Ther 1992; 261: 616-622. Harvey JA, McMaster SE, Romano AG. Methylenedioxyamphetamine: neurotoxic effects on serotonergic projections to brainstem nuclei in the rat. Brain Res 1993; 619: 1-14. Hiramatsu M, Kumagai Y, Unger SE, Cho AK. Metabolism of methylenedioxymethamphetamine: formation of dihydroxymethamphetamine and a quinone identified as its glutathione adduct. J Pharmacol Exp Ther 1990; 254: 521-527. 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. Tucker GT, Lennard MS, Ellis SW et al. The demethylenation of methylenedioxymethamphetamine ("ecstasy") by debrisoquine hydroxylase (CYP2D6). Biochem Pharmacol 1994; 47: 1151-1156. Gordon CJ, Watkinson WP, O'Callaghan JP, Miller DB. Effects of 3,4-methylenedioxymethamphetamine on autonomic thermoregulatory responses of the rat. Pharmacol Biochem Behav 1991; 38: 339-344. Matthai SM, Davidson DC, Sills JA, Alexandrou D. Cerebral oedema after ingestion of MDMA ("ecstasy") and unrestricted intake of water. BMJ 1996; 312: 1359. Greer G, Tolbert R. Subjective reports of the effects of MDMA in a clinical setting. J Psychoactive Drugs 1986; 18: 319-327. Ellinwood EH, Lee TH. Dose- and time-dependent effects of stimulants. In: Asghar K, De Souza E, editors. Pharmacology and toxicology of amphetamine and related designer drugs. National Institute on Drug Abuse Research Monograph Series. Rockville, MD: US Department of Health and Human Services, 1989. White JM, Irvine RJ, Bochner F. Toxic effects of MDMA. Canberra: Commonwealth Department of Health and Family Services, 1996. - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Jason M White · Felix Bochner · Rodney J Irvine

Hepatitis B and C in New South Wales prisons: prevalence and risk factors Tony G Butler, Kate A Dolan, Mark J Ferson, Linda M McGuinness, Phillip R Brown and Peter W Robertson MJA 1997; 166: 127 For comment see Crofts 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/>". Abstract - Introduction - Methods - Laboratory methods - Statistical methods - Results - Participants - Serology and risk factors - Discussion - Acknowledgements - References - Authors' details - ©MJA1997 Abstract Objectives: To determine the prevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection among inmates entering the New South Wales correctional system and to examine risk factors for infection. Design: Cross-sectional survey. Setting: Reception Centre at Long Bay Correctional Centre, Sydney, New South Wales, June to December 1994. Participants: 408 adult male inmates received at the reception centre (28% of the 1450 new inmates eligible for compulsory HIV testing). Outcome measures: Presence of HBV core and surface antibody and surface antigen; HCV antibody; risk factors; inmates' knowledge about risk factors. Results: 37% of inmates tested positive for HCV antibody, 31% for HBV core antibody and 3.2% for HBV surface antigen (indicating recent infection or carrier status). Among those who reported a history of injecting illegal drugs, rates rose to 66% for HCV antibody and 43% for HBV core antibody. Prevalence of HBV and HCV antibodies was similar in Aboriginal and non-Aboriginal inmates, but HBV antigen carrier rate was significantly higher among Aboriginals (12% versus 2.2%). Knowledge about hepatitis risk factors was poor (only 20% named injecting drug use), although recidivists were significantly better informed than those new to the correctional system. Multivariate analysis identified injecting drug use, past exposure to hepatitis B virus and previous imprisonments as significant predictors for HCV infection, and age over 25 years and HCV antibodies for HBV infection. Conclusions: Results suggest that about a third of adult male prisoners entering the NSW correctional system may have been infected with HBV or HCV. Measures such as education about hepatitis risk factors and HBV vaccination are needed to reduce hepatitis transmission in this population. MJA 1997; 166: 127-130 Introduction The reported high prevalence of hepatitis B and C in prison populations is attributed to the disproportionate number of people in prisons who engage in risk behaviours, particularly injecting illegal drugs.1-8 It is estimated that up to 60% of inmates are committed for drug-related offences.9 Further, an Australian study estimated that during their incarceration 25%-44% of inmates occasionally injected illegal drugs, 14%-34% engaged in occasional anal intercourse and 5%-18% did both.10 Among inmates entering the Victorian prison system in 1991 and 1992, 39% were positive for hepatitis C antibody (including 64% of those reporting a history of injecting illegal drugs), 33% were positive for hepatitis B antibody and 2.5% for hepatitis B surface antigen.11 There are no recent studies of the prevalence of infection with hepatitis B and C viruses (HBV and HCV) in New South Wales prisons. Our study aimed to determine the prevalence of HBV and HCV infection among inmates entering the NSW correctional system and to examine the risk factors associated with these infections. Methods The study was performed at the Reception Centre at Long Bay Correctional Centre, Sydney, NSW, from June to December 1994. The Reception Centre receives about 51% of adult males entering the NSW correctional system, most of whom are then transferred to other prisons. At the time of our survey, all inmates entering NSW prisons were routinely screened for the human immunodeficiency virus (HIV) by public health nurses of the Corrections Health Service. Inmates were also invited to participate in the hepatitis survey. Recruitment depended on the nurses' availability to enrol inmates during HIV screening, and in busy periods it was not always possible to enrol all new inmates. No information was sought from those who did not agree to participate. Inmates who agreed to participate were briefed on the project and informed that a consent form had to be signed, a blood specimen was needed, and a risk factor questionnaire would be administered by the nurse. Nurses also asked inmates to describe ways in which hepatitis can be transmitted. All inmates who tested positive for HBV and HCV antibodies were counselled by public health nurses. HCV-positive inmates routinely receive follow-up liver function tests. Inmates who reported having had HBV vaccination were given booster vaccination if antibody tests indicated they were not immune. All other inmates who tested negative for HBV core antibody were offered hepatitis B vaccination. Ethics approval for the study was granted by the Eastern Sydney Area Health Service Ethics Committee and the NSW Department of Corrective Services. Laboratory methods HBV core antibody (indicating past exposure) was tested with an anti-HBc enzyme immunoassay kit (General Biologicals, Taiwan). Samples positive for HBV core antibody were tested for HBV surface antigen (indicating carrier status) with the HBsAg-enzyme immunoassay (Murex, Dartford); positive results were confirmed by HBs reverse passive haemagglutination assay (Serodia, Tokyo). Inmates who reported having been vaccinated against hepatitis B were tested for HBV surface antibody with the HBsAb-enzyme immunoassay (General Biologicals, Taiwan). A level of 30 IU/mL was considered the minimum necessary for immunity. HCV antibody was detected with the Innotest HCVAbIII assay (Innogenetics, Belgium). Reactive samples were retested in duplicate and, if again reactive, were tested with anti-HCV (Murex, Dartford). Samples that were reactive in each of the two types of assay were classified as positive, and those with discrepant results as equivocal. Statistical methods Relative risks were calculated with the statistical software Epi Info-6,12 and logistic regression was performed with the software SPSS-6. 13 The c 2 test was used to test for association between Aboriginality and serostatus. Results Participants About 1450 inmates were tested for HIV at the Long Bay Reception Centre between June and December 1994. Of these, 410 adult males (28%) consented to be screened for HBV and HCV antibodies. It is not known how many of the remainder were not invited to participate and how many refused. Two inmates were counted twice as they were released and reincarcerated during the study period. Results of their second tests were excluded from the analysis. The 408 subjects were aged 17-73 years (mean, 30.6 years; standard deviation, 10.1), and 296 (73%) had been imprisoned previously. Country of origin was: Australia, 80%; Europe, 8.6%; New Zealand and the Pacific Islands, 3.5%; Asia, 2.7%; the Middle East, 2.7%; and elsewhere or unknown, 2.5%. Forty-one inmates (10%) identified themselves as Aboriginal. Serology and risk factors Prevalence of HBV and HCV antibodies and HBV antigens is shown in Box 1 (below). About a third of inmates were positive for HBV core antibody (31%) or for HCV antibody (37%), with 21% positive for both. Among those who reported having received HBV vaccination, only 34% had HBV surface antibody levels (indicating immunity). No significant differences were found between Aboriginal and non-Aboriginal inmates in prevalence of HBV core and HCV antibodies. However, the HBV carrier rate was significantly higher among Aboriginals (12% versus 2.2%; c2 =11.8; P < 0.001). Among those reporting hepatitis B vaccination, more Aboriginals (50%) than non-Aboriginals (32%) had developed immunity, but the difference was not significant. The association between risk behaviours and HBV and HCV infection is shown in Box 2. The risk of each infection was significantly increased by a history of injecting drug use, previous imprisonment, sharing of injecting equipment, age over 25 years, injecting drug use during previous imprisonment, and tattooing (P< 0.05 or less). Risk also increased significantly with increasing numbers of previous imprisonments (P< 0.01 or less). Risk of HCV infection was also significantly increased by tattooing, sex with an injecting drug user and presence of HBV antibodies (P< 0.001). Among the 67 inmates who reported injecting drug use during a previous imprisonment, 77% were positive for HCV antibody and 56% for HBV antibody. In addition, among the 150 inmates positive for HCV antibody, only 14 (9%) did not report a history of injecting drug use. The following independent variables were entered into a logistic regression model, with HBV and HCV infection as separate outcome variables: injecting drug use, sex with an injecting drug user, tattoos, Aboriginality, age group (over 25 years versus 25 years and under), previous imprisonment, and HBV or HCV infection. For HCV infection, significant predictors were injecting drug use (odds ratio [OR], 19.9; P< 0.001), presence of HBV antibody (OR, 5.6; P< 0.001), and previous imprisonment (OR, 3.9; P< 0.001). For HBV infection, significant predictors were presence of HCV antibody (OR, 6.2; P< 0.001), and age over 25 years (OR, 3.4; P< 0.001). Among the 85 inmates positive for both HBV and HCV antibodies, 83 (98%) reported previous imprisonment, 78 (92%) reported injecting drug use, 40 (47%) reported sharing injecting equipment, 64 (75%) had tattoos, and 31 (36%) reported being tattooed in prison. Inmates' knowledge of risk factors for hepatitis B and C transmission is shown in Box 3 (below). Few inmates were knowledgeable about risk factors, with injecting drug use nominated by only 20% and tattooing by only 2%. However, those who had been imprisoned previously were significantly more likely to identify injecting drug use as a risk factor than those new to the correctional system, and significantly less likely to answer "no idea" about risk factors. Discussion Our results agree with those of a 1991-1992 study of Victorian prison inmates.11 We found that 37% of inmates were positive for HCV antibodies (39% in Victoria), 31% for HBV antibodies (33% in Victoria), and 3.2% for HBV surface antigen B (2.5% in Victoria). Our results also agree with those of two Victorian studies, which found rates of 62% and 68%, respectively, for HCV infection among injecting drug users.8,14 Extrapolating our results to the current NSW male prison population of over 6000 implies that almost 2000 inmates are likely to have been exposed to HBV, about 200 are HBV carriers, and over 2000 are HCV-antibody-positive. In contrast, there were 25 HIV-positive inmates in NSW correctional centres at the time of the study (0.4%; 23 male and 2 female) (unpublished data). NSW prison inmates are offered hepatitis B vaccination if their sentences exceed six months and they are considered "at risk". However, inmates with shorter sentences may also be at risk. We believe that all inmates have the right to be protected from possible infection and that all should start a course of hepatitis B vaccination on entry to the correctional system. It may be appropriate to use recently described accelerated vaccination schedules, which provide protective levels of anti-hepatitis B surface antibody relatively quickly.15 In addition, if hepatitis B vaccination courses are not completed in prison, inmates should be educated about the need to complete them after release. We found that among the 108 inmates (26%) who reported having had hepatitis B vaccination only a third were immune, possibly because of failure to complete the recommended vaccination schedule. Vaccination history could not be verified. We found that previous imprisonment was a significant risk factor for HCV infection, suggesting that measures to minimise the spread of hepatitis within prisons are essential. In addition, as many injecting drug users spend time in prison, it is an appropriate point for intervention to break the cycle of infection by educating them about risks for hepatitis transmission and providing vaccination. Prison education programs seem to have improved awareness about transmission of hepatitis, as inmates with a prison history were more likely to know the role of injecting drug use and less likely to have "no idea" about hepatitis transmission. However, knowledge was still poor, and only 2% of inmates identified tattooing as a risk factor for hepatitis transmission, which is of concern given the popularity of tattooing in this population. The link between tattooing and HCV infection has been identified elsewhere,16,17 and should receive more emphasis in hepatitis education programs. The recent decision by the NSW Department of Corrective Services to make condoms available in prisons may reduce hepatitis transmission. Other measures, such as removing obstacles for accessing bleach, and needle exchange, should also be considered in the fight to curb the spread of hepatitis. Our findings suggest that chronic hepatitis may become one of the prison system's major health concerns over the next two decades. Acknowledgements The study was funded in part by a grant from the NSW Health Department AIDS/Infectious Diseases Branch. We wish to thank the nursing staff at the NSW Corrections Health Service for assistance in data collection (Amanda Christensen, Sheryl Frewin, Marion Grey, Cherylyn Jesson, Linda Kemp, Jodie Lee, and Sandra Parsons). References Acedo A, Campos A, Bauza J, et al. HIV Infection, hepatitis, and syphilis in Spanish prison [letter]. Lancet 1989; 2: 226. Hull HF, Lyons LH, Mann JM, et al. Incidence of hepatitis B in the penitentiary of New Mexico. Am J Public Health 1985; 75: 1213-1214. Koplan JP, Walker JA, Bryan JA. Prevalence of hepatitis B surface antigen and antibody at a state prison in Kansas. J Infect Dis 1978; 137: 505-506. Melico-Silvestre A, Pombo V, Pereira A, et al. Seroepidemiological survey of transmissible infections in Portuguese prisoners [letter]. AIDS 1991; 5: 780-781. Decker M, Vaughn W, Brodie J, et al. Seroepidemiology of hepatitis B in Tennessee prisoners. J Infect Dis 1984; 150: 450-458. Chiaramonte M, Trivello R, Renzulli G, et al. Hepatitis B virus infection in prisons. J Hyg Camb 1982; 89: 53-58. Vlahov D, Nelson K, Quinn T, Kendig N. Prevalence and incidence of hepatitis C virus infection among male prison inmates in Maryland. Eur J Epidemiol 1993; 9: 566-569. Fairley CK, Leslie DE, Nicholson S, et al. Epidemiology and hepatitis C virus in Victoria. Med J Aust 1990; 153: 271-273. Corrections Health Service. Strategic Plan 1993-1998. Sydney: NSW Health Department, 1994. Douglas RM, Gaughwin MD, Ali RL, et al. Risk of transmission of the human immunodeficiency virus in the prison setting [letter]. Med J Aust 1989; 150: 722. Crofts N, Stewart T, Hearne P, et al. Spread of blood borne viruses among Australian prison entrants. BMJ 1995; 310: 285-288. Epi Info [computer program], version 6.0. Atlanta, Ga: Centers for Disease Control, 1994. SPSS-6: Statistical package for the social sciences [computer program], version 6. Chicago, Ill: SPSS Inc, 1994. Crofts N, Hopper J, Bowden S, et al. Hepatitis C virus infection among a cohort of Victorian injecting drug users. Med J Aust 1993; 159: 237-241. Bayas J, Bruguera M, Martin V, et al. Hepatitis B vaccination in prisons: the Catalonian experience. Vaccine 1993; 11: 1441-1444. Kaldor J, Archer, G, Buring M, et al. Risk factors for hepatitis C virus infection in blood donors: a case-control study. Med J Aust 1992; 157: 227-230. Holsen DS. Prevalence of antibodies to hepatitis C virus and association with intravenous drug abuse and tattooing in a national prison in Norway. Eur J Clin Microbiol Infect Dis 1993; 12: 673-676. (Received 10 Jan, accepted 21 Oct, 1996) Authors' details New South Wales Health Department, AIDS/Infectious Diseases Branch, Sydney, NSW. Tony G Butler, MSc, Public Health Officer. National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW. Kate A Dolan, BSc, Research Officer. South Eastern Sydney Area Health Service, Sydney, NSW. Mark J Ferson, FRACP, FAFPHM, Director of Public Health. NSW Corrections Health Service, Long Bay Correctional Centre, Sydney, NSW. Linda M McGuinness, Grad Dip HSc, RN, Assistant Director of Nursing; Phillip R Brown, MBA, FAFPHM, Chief Executive Officer. Microbiology Department, Prince of Wales Hospital, Sydney, NSW. Peter W Robertson, PhD, Serologist. No reprints will be available. Correspondence: Mr T G Butler, NSW Health Department, AIDS/Infectious Diseases Branch, Locked Bag 961, North Sydney, NSW 2059. - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Tony G Butler · Kate A Dolan · Mark J Ferson · Linda M McGuinness · Phillip R Brown · Peter W Robertson

Hyponatraemia and death after "ecstasy" ingestion Michael J A Parr, Heather M Low and Paull Botterill A 15-year-old girl collapsed with respiratory arrest after taking "ecstasy" at a "dance party". She presented to hospital with hyponatraemia and cerebral oedema and later died. We postulate that ingestion of large amounts of water contributed to the hyponatraemia. Advice to those using ecstasy at dance parties should be modified to suggest moderate fluid intake only and to emphasise the need to seek prompt medical attention for non-resolving symptoms. MJA 1997; 166: 136 For comment see White et al. 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/>". Introduction - Clinical record - Discussion - Acknowledgements - References - Authors' details - ©MJA1997 Introduction Recent deaths associated with ingestion of the illicit drug "ecstasy" have attracted widespread publicity and debate about the cause of death. Ecstasy (3,4-methylenedioxymethamphetamine; MDMA) is an ampheta mine derivative which has short-term hallucinogenic and stimulant effects, but in the long term may deplete brain serotonin by reducing numbers of serotonergic nerve terminals.1 Previous ecstasy-related deaths have involved hyperthermia, rhabdomyolysis, coagulopathy and cardiac toxicity.2 We report a death after ecstasy ingestion associated with hyponatraemia, a less well known complication. Clinical record A previously healthy 15-year-old girl was admitted to the Intensive Care Department in coma after a respiratory arrest. The evening before admission, she had been at a "dance party", where she had taken MDMA at about midnight. She was also believed to have drunk large quantities of water at the party, as then advised by health authorities (e.g., United Kingdom Health Education Authority, and National Poisons Unit), to counteract the hyperthermic effects of MDMA. About 0500, while still at the dance party, she began to vomit. After leaving the party she rested at a friend's house, where she had episodes of dry retching, impaired consciousness, confusion and some abnormal twitching movements. At 1000, about ten hours after ingestion of the MDMA, she was still drowsy and confused, and then collapsed with respiratory arrest while being walked downstairs. There was an estimated 12 minutes of hypoventilation and apnoea, with no cardiopulmonary resuscitation until an ambulance crew arrived. At 1023, on arrival of the ambulance crew, she was found to be in sinus tachycardia with palpable pulses, and she was intubated and ventilated by the crew. Spontaneous cardiac output was maintained throughout. She received naloxone, Hartmann's solution (1000 mL) and polygeline (Haemaccel, Hoechst) (500 mL) before arrival at hospital. At 1118, in the Emergency Department she was found to have: Glasgow Coma Scale score, 3; heart rate, 110 bpm; blood pressure, 80/50 mmHg; temperature, 32.8oC. She had bilateral papilloedema, fixed dilated pupils, no eye movements, no corneal, gag or cough reflexes and no reactions to pain. The hypotension did not respond to a further 1000 mL of 0.9% saline, and a noradrenaline infusion was started. This corrected the hypotension but did not improve the neurological status. At 1145, results of biochemical tests of blood taken before treatment in the Emergency Department showed reduced concentrations of serum electrolytes, suggesting haemodilution (see Box [below]). The haemodilution was corrected within six hours with infusion of 0.9% saline, moderate fluid restriction (total fluids, 60 mL/hour) and diuresis with frusemide and mannitol. At 1205, a chest x-ray revealed changes consistent with pulmonary oedema, and at 1245 computed tomography of the brain showed cerebral oedema with marked effacement of basal cisterns and inferior displacement of the brainstem. An electrocardiogram at 1400 was normal. Blood-gas analysis at 1500 showed respiratory alkalosis. Maximum serum creatine kinase level was raised, and there was no sign of coagulopathy (see Box [above]). On the second day of admission, the patient was making spontaneous efforts to breathe (on the ventilator) but otherwise her neurological status had not changed. She required noradrenaline to maintain blood pressure but had no cardiac arrhythmias. A nuclear magnetic resonance scan confirmed diffuse cerebral oedema, with decreased blood flow within the major cerebral vessels. Overnight, the patient deteriorated, developing diabetes insipidus and ceasing to breathe spontaneously. On the third day of admission, results of clinical examination were consistent with a diagnosis of brain death, and a cerebral angiogram confirmed this diagnosis. Postmortem findings showed diffuse brain swelling, with cerebellar tonsillar herniation and pituitary necrosis. Analysis of antemortem urine and blood revealed MDMA at levels of 430 ng/mL and 0.05 mg/L, respectively. No other drugs were detected. Discussion We report the death of a previously well young girl after ingestion of MDMA. The cause of death was thought to be hypoxic encephalopathy after respiratory arrest following acute water intoxication secondary to ingestion of MDMA. It would seem likely that hyponatraemia and cerebral oedema before the respiratory arrest were major factors in her death. The cerebral oedema is unlikely to have resulted from hypoxia after the respiratory arrest, as it would then usually be accompanied by bradycardia or asystole, neither of which was present. In addition, there was no evidence that the patient suffered cardiac arrhythmia, toxicity or infarction, which have caused other amphetamine-related deaths.3 The contribution of intravenous therapy to the hyponatraemia, fluid overload and cerebral and pulmonary oedema is unclear. Given the volumes (1500 mL) and osmotic concentrations (hypertonic or isotonic) of the solutions administered, any contribution is likely to have been small. The effects of MDMA are numerous and complex, and severe reactions are unpredictable.1 There have been many reports of MDMA-associated deaths caused by fulminant hyperthermia, coagulopathy and rhabdomyolysis,1 and clinical awareness of these problems seems high. However, many other complications of MDMA ingestion, such as hyponatraemia, may result in death or serious morbidity and have received less publicity. Instances of hyponatraemia after MDMA ingestion have been reported, with postulated causes that include ingestion of large quantities of water, the syndrome of inappropriate antidiuretic hormone secretion (SIADH) and contamination of the MDMA with other chemicals.4-9 Hyponatraemia raises a diagnostic dilemma, as its signs may be indistinguishable from those of MDMA intoxication. 10 There is evidence that morbidity associated with hyponatraemia is highest in children and women and is not related to either the magnitude or duration of the hyponatraemia.11 To our knowledge, this is the first Australian report of a fatality associated with ecstasy in which hyponatraemia and cerebral oedema appeared to be the main pathological processes. However, dissecting out the various factors involved in the death is extremely difficult. The roles of MDMA, the dance party environment, water ingestion, hyponatraemia, cerebral oedema, hypoxia, hypotension and SIADH are intertwined. The dance party environment encourages heavy exercise in a hot environment, with the advice to drink plenty of water. In the presence of high salt losses, this may produce hyponatraemia. Water ingestion may become uncontrolled as the individual attempts to treat symptoms or as the MDMA impairs rational judgement or possibly stimulates compulsive repetitive behaviour.12 Cerebral oedema as a result of hyponatraemia is well recognised and may result in tentorial herniation, respiratory arrest and cerebral hypoxia.11 SIADH has also been implicated in ecstasy-associated hyponatraemia.9 Although the mechanism is unclear, animal research suggests that serotonin increases secretion of antidiuretic hormone.13 Given the many people who take ecstasy without apparent ill-effect, it has acquired a safe reputation. Among the many adverse reactions, we must now include life-threatening hyponatraemia, which may have the same symptoms and signs as MDMA intoxication. To avoid adverse reactions, individuals using MDMA at dance parties are often advised to rest, avoid overheating, wear loose clothing and drink plenty of cool drinks.14 However, there is no evidence that this prevents adverse reactions. Furthermore, because of the possibility of hyponatraemia, this advice should be modified to suggest ingesting only moderate amounts of liquids. The importance of seeking medical attention promptly for non-resolving symptoms should also be emphasised. Acknowledgements The authors would like to thank the NSW Senior Deputy State Coroner, Mr John Abernethy, for releasing this information for publication, and Dr John A Henry of the National Poisons Unit, Guy's Hospital, London (UK), for assistance with this case. References Green AR, Goodwin GM. Ecstasy and neurodegeneration. BMJ 1996; 312: 149-150. Henry JA. Ecstasy and the dance of death. BMJ 1992; 305: 5-6. Dowling GP, McDonough E, Bost RO. Eve and ecstasy. A report of five deaths associated with the use of MDEA and MDMA. JAMA 1987; 257: 1615-1617. Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 3,4 methylenedioxymethamphetamine ("ecstasy"). Lancet 1992; 340: 284-287. Maxwell DL, Polkey MI, Henry JA. Hyponatraemia and catatonic stupor after taking "ecstasy". BMJ 1993; 307: 1399. Kessel B. Hyponatraemia after ingestion of "ecstasy" [letter]. BMJ 1994; 308: 414. Lehmann ED, Thom CH, Croft DN. Delayed severe rhabdomyolysis after taking "ecstasy". Postgrad Med J 1995; 71: 186-188. Milroy CM, Clark JC, Forrest AR. Pathology of deaths associated with "ecstasy" and "eve" misuse. J Clin Pathol 1996; 49: 149-153. Holden R, Jackson MA. Near fatal hyponatraemic coma due to vasopressin over-secretion after "ecstasy" (3,4-MDMA) [letter]. Lancet 1996; 347: 1052. Matthai SM, Davidson DC, Sills JA, Alexandrou D. Cerebral oedema after ingestion of MDMA ("ecstasy") and unrestricted intake of water [letter]. BMJ 1996; 312: 1359. Arieff AI. Management of hyponatraemia. BMJ 1993; 307: 305-308. Finch E, Sell L, Arnold D. Drug workers emphasise that water is not an antidote to drug [letter]. BMJ 1996; 313: 690. Brownfield MS, Greathouse J, Lorens SA, et al. Neuropharmacological characterization of serotoninergic stimulation of vasopressin secretion in conscious rats. Neuroendocrinology 1988; 47: 277-283. Shapiro H. Information for drug workers from ISDD. Ecstasy update. Druglink 1996; 11: 1. (Received 26 July, accepted 21 Nov, 1996) Authors' details Intensive Therapy Unit, Royal North Shore Hospital, Sydney, NSW. Michael J A Parr, MRCP, FRCA, Senior Registrar; currently, Consultant in Anaesthesia and Intensive Care, Frenchay Hospital, Bristol, UK; Heather M Low, FRACP, Senior Staff Specialist. NSW Institute of Forensic Medicine, Sydney, NSW. Paull Botterill, FRCPA, Pathologist. No reprints will be available. Correspondence: Dr H M Low, Intensive Therapy Unit, Royal North Shore Hospital, St Leonards, NSW 2065. - To top of article - ©MJA 1997 <URL: http://www.mja.com.au/> © 1997 Medical Journal of Australia.

Heather M Low · Paull Botterill