Smokers with other dependencies - The too-hard basket:

Tuesday 12 October 2004

Presenters:

Renée Bittoun

Dear Colleagues,

Renee Bittoun gave an update of current thoughts on smoking cessation before moving onto some case studies of people with other dependencies.

Ms Bittoun described genetic variations in nicotine receptors and metabolism that may predispose to dependency. She mentioned research suggesting that nicotine has antidepressant properties. This may help to explain the risk of relapse into depression among previously depressed people who try to quit smoking, and leads to the intriguing idea that nicotine patches could be used to treat depression. She told us about nicotine interactions with alcohol, caffeine and insulin.

The short plasma half life of nicotine (about 40 minutes) corresponds conveniently well to the standard cigarette packet size of about 20 a day, a fact that Ms Bittoun suggests tobacco companies have long been well aware of. Most smokers strive to keep their nicotine plasma concentrations at their particular desired levels, and will do so regardless of the nicotine content of their cigarettes. Smokers of low nicotine cigarettes may end up having higher levels of carbon-monoxide as they inhale more deeply.

Plasma nicotine concentrations form a bell-curve in the smoking population, with new smokers such as children having lower concentrations and highly dependent groups, such as people with schizophrenia, at the top end of the curve.

Average plasma concentrations may be a measure of dependence, and are lower in countries with waxing smoking epidemics (such as China) than in countries such as the US with waning epidemics. As low-dependence smokers quit more readily, there is higher dependence among people continue to smoke, which will have implications for the effectiveness of treatments in future. There are reports of falling effectiveness of such treatments as over the counter nicotine replacement.

Quit rates for spontaneous quitters are about 5% at one year, and pharmacotherapies roughly double quit rates over placebo. 50% of relapses happen in the first week, dropping to 10% in the second, so early follow-up and support is important, and 3 months abstinence is long term abstinence.

Ms Bittoun doesn't put much by the 'quit date', suggesting "why not today?". This was supported by an observation from the floor that people with mental illnesses, especially schizophrenia, may find quit dates very intimidating.

She reviewed the evidence base for treatments: bupropion and nicotine replacement treatment (NRT) of all types have a good evidence base, with evidence of better results from combinations of NRT, and NRT combined with bupropion. Interestingly she observed that about a quarter of people get a great result from bupropion but it is impossible to know in advance who will respond, and if they haven't responded within 2 weeks, it is time to stop.

Ms Bittoun wished to stress to the audience that combination NRT means two patches and/or gums and more if occasionally necessary ... 'whatever it takes to not smoke'. We need to understand that this is the very common direction we are going with NRT.

Thumbs were down for the evidence for: hypnotherapy, acupuncture, psychotherapy, weaning by cutting number of cigarettes smoked a day or their nicotine content, and shibboleths like the 4 Ds ('delay', 'distract', 'deep breaths', 'drink glass water').

The first case study that followed featured simultaneous adverse 'speed-like' reactions to bupropion in a husband and wife both on methadone maintenance, after starting bupropion on their quit day and after a strong warning from the pharmacist about risk of seizure (the wife had a history of benzodiazepine related seizures many years before, and was now on maintenance diazepam). It was suggested that the bupropion should have been started a week before the quit date to prevent confounding anxiety from nicotine withdrawal. NRT might be the better first line choice in people who have had agitated reactions to antidepressants in the past.

A second case was a 38 year old man with hazardous level after-work drinking, whose history suggested strong priming by smoking. As he chose the option of controlled drinking, the focus was on smoking cessation using NRT to help achieve the alcohol goal.

To finish off, Renee Bittoun told the audience about "chop-chop". In Sydney there is a growing market for locally-grown black market tobacco, or "chop-chop", which many people wrongly believe is more organic and less harmful. In fact there has been evidence of dangerous contamination with moulds, and analysis has shown such choice ingredients as lawn clippings and cabbage! A possible down-side to our cigarette pricing policies.

Summary by Richard Hallinan and Andrew Byrne.

Book reviews may reveal as much about reviewers as their books.

“Addiction”, August 2004. Posted 10 Sept 04

Dear Colleagues,

I enjoy reading book reviews, partly because I rarely get around to reading the works themselves. Editor Griffith Edwards, author of numerous books himself, often undertakes such reviews in Addiction. He sometimes declares, but apparently does not act on his conflict of interest as an author of books on alcoholism, a field in which he is a peerless authority. In the reviews, he often reveals as much about himself as his subject. When authors’ views depart from his own, he often praises aspects of the work and then turns to indecorous and pointed criticism. For example, this month ina review of what promises to be a fascinating new book on drugs in China by some (we are told) eminently qualified authors (Dikotter, Laamann and Xun): “Unfortunately, at the same time it is a text marred by serious weaknesses.The intention is early declared of debunking ‘narcophobic discourse’ and that phrase is wearily repeated page after page. The authors go on to state that their aim ‘is to provide a critical analysis of narcophobic discourse and an in-depth examination of the social costs of government attempts to police the bloodstream of the nation’ - what is to be made of that strange image is unclear.” writes Edwards of this historical work. Then: “… it is evident that these writers have no intention of weighing the evidence dispassionately or seeing two sides of any question.”


What Edwards surprisingly omits from his review is that indeed 20th century China is probably one of the few shining examples of prohibition actually having the desired effect (law enforcement leading to near elimination drug use). But this was only achieved at the cost of civil liberties to an unprecedented degree in human history (and hence the belabouring of the ‘anti-narcotic’ sentiments by these authors, I imagine). Rather than discussing the merits of such rather major issues, or historical lessons for others, Edwards heaps scorn on these authors for what he perceives as theirpainting ‘opium as good’ and ‘narcophobia’ as bad (Edwards seems to espouse the exact opposite).

Opium, like most traditional drugs, can be both ‘good’ and ‘bad’ in different circumstances. Edwards knows that. Despite lacking a scientific basis, the blanket prohibition philosophy Edwards appears to support has proven to be counter-productive in most countries. Current prohibitions in our own society are associated with continued and often increasing and widespread availability of drugs to our citizens, most worrying, to the very young, poor and vulnerable. Edwards knows that. In addition, such policies deny medical uses of appropriate drugs in some instances (eg. cannabis,amphetamine, heroin). Edwards knows that. Yet he still sings the same old tune that appears to place confidence in the current prohibitions. The world is moving on, albeit slowly, and, while nobody I know has seriously suggested placing drugs on the supermarket shelves, there are better means to effective drug control than those existing in most countries currently.



According to London press reports, cannabis is now virtually decriminalised in the UK, an issue Edwards has yet to address to my knowledge. Portugal has apparently decriminalised all psychoactive drugs. The Dutch and Swiss now prescribe heroin to a small proportion of their addicts, as does the UK. Germany now has federal laws legalizing injecting rooms. South Australia decriminalized cannabis almost 30 years ago. Canberra, Darwin, Belgium, Holland … the list goes on. The lack of serious commentary in Addiction on these major issues does not reflect well on the journal’s management.


Edwards and co-authors have also written in reviews that the American prohibition period needs closer attention for its positive side, citing respected academic historian Ian Tyrrell. Can they be serious? Did the trains run on time? An underlying implication is that if we just tried a little harder that prohibition (of psychoactive drugs and/or alcohol) mightjust ‘work’. When I sent a mild letter pointing to these inconsistencies, Addiction used their “Iguana” chat column* to attempt to patronise and humiliate me, even suggesting that I take some tablets and lie down! Therewas no offer of genuine debate on the issues ‘between people of goodwill’ (to quote Edwards). Just a reminder that the editor’s decision is final. On another occasion: “I hope, however, you will think me in no waydiscourteous if I say that I do not see it as useful to re-open correspondence with you about …”. [Meaning, on this occasion, that a lead article ‘Additional methadone increases craving for heroin …’ remainsunchallenged despite the serious implications.]

In the review on drugs in China, as a further example which some may interpret as intolerance or a lack of equipoise, Edwards is extremely critical of some possible minor errors which would detract little from the authors’ overall message about drugs in China. Morphine is implied to be ‘semi-synthetic’; penicillin introduction in the 1940’s “took care of its [opium’s] medical uses”; tobacco is described as a stimulant. None of these seem like hanging offences to me and the meanings are reasonably clear, even if not all necessarily pin-point accurate from these non-medical authors.


In the July edition, Edwards also featured himself in one of a pair of book reviews on alcohol history in, respectively, Canada and the United States. Edwards spends over a third of his review commenting upon the appropriateness or otherwise of a media announcer deigning to write a historical work. He castigates the poor amateur on ‘getting caught up with the history of prohibition’ upon which Edwards then launches into his own opinions again: ‘Prohibition is an experience from which America has had difficulty moving on, but a book that reinforces such perseveration is not a recommended guide.’ After lambasting the authors over three more alleged errors, he goes out below the belt saying that ‘The validity of such claims should be checked out before being put into a newscast.’ This review is sadly unhelpful in informing us on the book’s general merits.

Robin Room is a frequent author in Addiction’s pages, whether reviews, research or commentary. He writes two alcohol book reviews, one being of a classic text (a suggestion I made to Griffith Edwards some years ago – with a submission on De Quincey’s confessions book* - a suggestion Addiction has finally chosen to act upon, albeit un-attributed). It is hard to write two lengthy reviews about alcohol policy without stating categorically the negative consequences of prohibition (which I was fascinated to learn was also tried, without lasting success, in some jurisdictions in Canada, Norway, Turkey, Soviet Russia and Finland up to 1930 - and also Box Hill insuburban Melbourne I understand). But Room manages to avoid writing about the unpleasantness of the prohibition period(s), despite the substantial loss of life, crime, corruption and under-age drinking attributed toenforced temperance policies. Intriguingly, these terms are not used, nor their consequences addressed. Room knows the best approaches to alcohol harms, including restricted hours of sales, age limits, responsible bartending, scaled taxation, honest labelling, limited advertising, driver breath testing and education, all within community expectations and tolerance. Yet for some reason, he stops short of being definitive on the inappropriateness of blanket prohibition of alcohol, leaving this perilous door yet wide open.
Life goes on. Our 100 year old flagship journal miraculously continues too, and will likely outlive Edwards, Room, Byrne and other current players. So will harm minimisation policies, variations upon which doctors have beenespousing since the time of Hippocrates.

comments by Andrew Byrne ..

*Copies available on request.

Important and novel findings from Suboxone� study in Sydney

Drug Alcohol Rev (2004) 23;3:311-318

A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Bell J, Byron G, Gibson A, Morris A.

Dear Colleagues,

These researchers are to be congratulated on one of the first studies of its kind. They report on responses in 17 consenting 'stable' buprenorphine patients who were offered transfer to the combination product containing naloxone which, after the first week, was dispensed once weekly and taken by the patient unsupervised rather than daily dispensing as previously.

Most research I have read on buprenorphine employs the drug for new patients presenting for treatment, measuring illicit drug use and treatment retention. However, very useful clinical evidence is also derived from comparing existing practice with the experimental condition. The combination buprenorphine and naloxone product ('Suboxone®') was approved for unsupervised use in the US over 2 years ago despite most of the existing research being on supervised dosing. We are told that the combination drug is equally effective and has theoretically less prospect for diversion as it contains an antagonist which if injected will cause withdrawals in those dependent on heroin or methadone.

The most surprising finding in this pilot study was that when transferred to the combination drug, nearly all patients required substantially higher doses of buprenorphine. Of the 15 successful cases, 4 needed double or more of the original dose of buprenorphine. One needed triple while the rest required more modest increases averaging about 50% at the transfer time.

"The switch from buprenorphine (Subutex®) to the combination product (Suboxone®) was associated with mild withdrawal symptoms for 24 hours in the first subject. Thereafter, 13 subjects had about a 50% increase in dose when switching (from an average dose of 8.5 mg Subutex® to day 1 Suboxone® average of 12.2 mg); in no cases were there complaints of either intoxication or withdrawal."

The possible 10% quoted absorption of naloxone may be responsible for antagonising the opioid effects, at least temporarily. Three patients reported withdrawals when starting the combination product. One of them chose to withdraw from the study altogether rather than taking increased doses offered. Thus it would appear that the combination drug may not be bio-equivalent and therefore not 'equally effective' as pure buprenorphine, especially for high-dose patients since 32mg is the current maximum recommended dose. Another explanation might be that the subjects in this trial were originally taking inadequate doses of the pure drug. Yet, since they were 'stable' such doses must have been associated with positive outcomes at the time.

Those intent upon eventual abstinence may have been disappointed that after six months in these 'stable' patients the mean buprenorphine dose were still significantly higher than at the start of the trial (up from 9 to 11mg daily [22%]). Apart from the withdrawals, there were some major events with one patient suffering a stroke and another becoming pregnant despite the strict protocol (Suboxone® is contraindicated in pregnancy). It must also be a concern that despite only enrolling stable, employed patients, by the end of the study four of the fifteen were unemployed. In spite of being chosen for their stability, there was still use of illicit drugs in about 6 patients according to urine toxicology reported. At least one patient was using such drugs frequently.

Since doses were dispensed unsupervised, in order to check for compliance, patients agreed to random call-back arrangements. Despite this, four patients (27%) failed to do so, claiming they had work commitments. Yet it appears that they were still permitted to continue with unsupervised medication. This reported finding could mean that some of the four patients had already consumed or even on-sold their medication.

It is puzzling that these patients had not been receiving any take-home doses despite being long-term and 'stable'. Nor do the authors address second daily administration of buprenorphine in these cases as recommended by the manufacturer. They write at length on the benefits of take-away doses and of the difficulties with daily attendance. Indeed, Australian Commonwealth guidelines on opioid maintenance point out that retention rates are reduced when take-away doses are not available. Even the original strict NSW buprenorphine prescribing guidelines allowed stable patients 2 take-away doses weekly with certain conditions. Most Australian jurisdictions now permit up to 5 take-away buprenorphine doses per week with few reports of problems. The use of strict 7-day dosing should be exceptional and dispensed doses used judiciously as an added incentive to normalise the dependent life style.

It is clear that opioid maintenance can be very successful with twice (or even once) weekly supervision. The researchers' final statement is that 'using access to unsupervised dosing to promote abstinence from heroin probably limits the potential benefits of unsupervised administration to a very small proportion of patients.'

comments by Andrew Byrne ..

No link between expansion of methadone treatment and methadone related deaths: Addiction journal study finds.

Addiction 2004 99: 846-854 (July)

Overdose deaths attributed to methadone and heroin in New York City, 1990-1998. Bryant WK, Galea S, Tracy M, Markham Piper T, Tardiff KJ, Vlahov D.

Dear Colleagues,

This comprehensive review of coroner's records yields important information on the relative harms of street heroin versus prescribed and street methadone in a large city during a period of continued increases in both 'markets'. This group from the New York Academy of Medicine quotes the origin of this study as suggestions that methadone was 'killing more people than heroin' (in the 1990s in England, where supervised dosing was exceptional). Some even advised that opioid maintenance treatment be reviewed or even withdrawn for this reason (Newcombe, 1996).

From 1990-98 the number of patients in NYC on methadone maintenance treatment (MMT) increased from 26,000 to 34,000 yet the number of deaths in which methadone was a contributor varied between 85 and 145 each year with no trend. Out of a total of 7451 overdose deaths reported during the 9 year study period, only 121 (1.6%) deaths were due to methadone alone. Another 900 (12%) were reported as due to methadone, in combination with cocaine (40%), heroin (30%), alcohol (41%). There was an overlap of 400 deaths in which both heroin and methadone contributed.

Heroin deaths increased from 300 to almost 700 per year in the first 4 years of the study period after which they levelled off and then dropped to around 500 annually in the last 3 years. These were more likely to be 'single drug' overdoses of which there were around 900, comprising 20% of all deaths attributed to heroin.

During most years of the study there were 3 to 6 times as many deaths from heroin as from methadone with an upward trend for heroin and no trend for methadone (p=0.16) from 1990 to 1998. Males accounted for 80% of the deaths with an even split of white, black and Hispanic at 33% each.

Considering the 5 boroughs of New York City, (Manhattan, Queens, Brooklyn, Bronx and Staten Island) this would appear to be up to 100 overdose deaths per million population annually overall. This compares with Australian figures of between 20 and 40 for the same period, up to 20 in the UK and as low as 2 in some European countries such as Holland and Switzerland. These figures seem to reflect the degree of 'zero tolerance' policy implementation, with lower mortality rates being seen with the introduction of harm reduction measures such as buprenorphine, methadone, injecting rooms, needle services and heroin prescription trials.

The authors report an 'intriguing' and unexplained finding that Staten Island had a much lower rate of overdose death (2.4% of the total). They recommend further study of how some areas, despite no shortage of drug users, report much lower fatality rates. They speculate on the possible effects of income levels and poverty by region.

The message from this study is that one can expand methadone treatment in an urban setting AND permit take-away doses (nearly all NYC MMT patients receive 'Sunday bottles') WITHOUT a corresponding increase in overdose deaths from methadone. Indeed, there is probably a corresponding reduction in the number of heroin overdoses, although this is harder to measure with the long time frames involved here.

Bryant WK, Galea S, Tracy M, Markham Piper T, Tardiff KJ, Vlahov D. Overdose deaths attributed to methadone and heroin in New York City, 1990-1998. Addiction (2004) 99: 846-854

comments by Andrew Byrne ..

Cannabis interventions in dual diagnosis and opioid dependent patients

10th August, 2004

Presenters:

Dr Jan Copeland and Ms Etty Matalon, NDARC, UNSW.

Chair: Dr Ray Seidler
This seminar raised issues that we face every day in our practices regarding behavioural change associated with drug use. Although the worst consequences of cannabis pale in comparison with alcohol and other drugs, it is still a widely used drug which many perceive to be a major problem in their lives.

Dr Copeland began by giving an overview of the use of cannabis in the Australian community. The best figures come from household studies showing that about a third of Australians have ever used cannabis and about one in six young people aged 14-19 are daily smokers of the drug. Hospital admission details show that while rare in the over 50s, cannabis use problems were commonly reported on admission in the younger age groups. We were told that up to 31.7% of 'current users' met criteria for DSM IV cannabis use disorder and 21% for dependence on the drug. Even ignoring the DSM criteria, the extent of the problem is shown by the numbers seeking treatment in Australia which, Dr Copeland told us, have tripled in a decade.

Of a large sample of Australian heroin injectors, 40% had current cannabis dependence diagnosis, being almost as common as anxiety disorder (51%) and alcohol problems (49%). US findings were similar but one wonders if the patients were prescribed adequate doses of methadone where the mean daily dose should be over 70mg and possibly higher.

We were reminded that cannabis smoke was more potent than tobacco smoke in some respects, although much less in quantity is consumed by the average cannabis smoker. There is thus a potential for causing or exacerbating cancer, asthma, bronchitis, etcetera. UNSW surveys show that nearly all the cannabis used in Australia is smoked, even though oral absorption was possible, it was often delayed and unpredictable. New methods of delivery were being developed using sprays or 'super-heated' rather than burned material from the cannabis sativa plant. High potency forms of the drug such as hashish resin or oil contain high concentrations of the active ingredients, the main one being tetra-hydro cannabinol (THC). Paradoxically, they may therefore be less harmful in some respects, having fewer impurities. Various street myths about cannabis were discussed, especially regarding drug delivery, absorption, deep breaths, bongs (dry and wet varieties), etcetera.

Even in those who are not yet intent on quitting, Dr Copeland said that there was much useful advice to give people to reduce the harms from cannabis use. They should be advised not to use bongs, especially of the 'dry' variety. They should be taught that it is illogical to inhale deeply and keep the breath for as long as possible, as is often practised. They should probably avoid leaves, stems and seeds . and just use the high concentration 'heads' of the cannabis plant. This results in a higher concentration of THC and thus a lower amount of exposure to CO, tars, soot, etc for the given amount of intoxicant. Mixing cannabis with tobacco was probably unwise although the practice is almost universal, at least in Sydney. [I wonder if it is true that Melbourne practice is more commonly to smoke straight cannabis without added tobacco.]

Next Etty Malyon showed us a number of impressive, professional publications, some aimed at patients, others at health care workers to use in formal treatment programs. One was a self-help explanatory program aimed at assisting those who are ready to quit. Another contained a step by step program of implementing goals towards lasting change in those prepared for a more formal series of face to face interventions. The programs dealt with drug use cues, drug diary entries, choosing dates for change, writing up pros and cons of drug use, discussing all of the above, etc. Depression was raised on numerous occasions as needing to be seriously addressed in those trying to quit cannabis, meaning both drug and non-drug approaches need to be considered. These interventions would be ideal in general practice and some could be initiated in pharmacies, methadone clinics or needle outreach services.

These hand-outs are available at modest cost to practitioners. Contact Dr Jan Copeland at UNSW for details.

Like all drugs, cannabis may have good and bad effects. Hence, although it was not part of the evening's 'main feature', I include a recent newspaper report from Dr Copeland's own research centre (NDARC). They found that nearly two-thirds of people using cannabis for medical reasons had decreased or stopped taking other medications. Participants also reported that cannabis was useful in preventing side effects caused by conventional medicines. The most common medical conditions the cannabis users suffered were arthritis, chronic pain, depression, nausea, muscle spasms and weight loss. Up to 70 per cent of those using 'medical cannabis' would be willing to be involved in a trial of an alternative form of cannabis, such as a spray, according to their survey. Last year NSW Premier Bob Carr announced a trial of possible therapeutic benefits of cannabis. The NDARC survey was a recommendation of the working party on the medical use of cannabis.

In another item from London, Wolff, Winstock (yes, our own 'Adam', from Bankstown) and co-workers in an SSA conference abstract published in Addiction Biology, March issue, gave the results of self-report questionnaires given to 337 multiple sclerosis patients in three English hospitals (2 London, one county). With a 75% response rate, almost half had used cannabis at some point and about one in five used the drug monthly. Only four (4%) of the 110 who had ever used cannabis developed increased weakness while one (1%) reported hallucinations. Almost three quarters stated that they would try the drug if it were legal. It would appear to have benefits for certain patients and a low side-effect profile. Yet dependence develops in a proportion and the dangers of smoked products are ever-present, each limiting the usefulness of therapeutic cannabis at present.

It is intriguing that tincture of cannabis was very widely prescribed in Australia prior to the current prohibitions of the 1950s. I could find no reports of ill-effects or dependence.

comments by Andrew Byrne ..

Reference

Cannabis use in patients with multiple sclerosis. Wolff K, Chong MS, Wise K, Tanton C, Winstock A, Ennis M, Silber K. SSA Symposium Abstracts (in Addiction Biology March 2004 p103-104)

Mortality risk among new onset injection drug users

Addiction (2004) 99:946-954

Vlahov D, Wang C, Galai N, Bareta J, Mehta SH, Strathdee SA, Nelson KE.

Dear Colleagues,

This important and elegant piece of research demonstrates several crucial features of drug use in a group of 256 'early' injecting drug users over a 12 year period. Subjects were recruited from a variety of sources, mostly word-of-mouth in Baltimore, USA, all with a history of less than 2 years since first injecting drugs. The study's end point was death yet several other important findings on the natural history of drug use are also revealed.

At recruitment 70% were male, 94% were African-American and mean age was 30. HIV rate was 22%. There were 90% currently injecting, 25% more than once daily. Just 25% had ever had drug addiction treatment, only 2% on methadone maintenance treatment (MMT). The authors state that 'needle sharing and shooting gallery use were not uncommon'.

With 69 known deaths among the 256 during the 12 year study period, the overall mortality rate was 3.3 per 100 patient years. Thus on average, over 3% of the sample died each year of the twelve. Yet the rate was not at all even, showing a peak at 6 to 8 years which was around 8 times the 'expected' US mortality. At 2, 4, 10 and 12 years from recruitment, the mortality figures were about 4 times that expected for the same sex/age controls. These figures in turn were about 2 to 4 times the actual Baltimore City mortality data which appear to be worse than elsewhere in the country.

These findings are surprising as there is neither an early nor a late peak of mortality as some had suspected, but a higher risk of death around 6 to 8 years from initial injecting with levelling out again after that. Even if the HIV cases are excluded, the peaks and other trends persist, but with less accentuation.

Follow-up rates at 5 and 10 years were ~75% and ~60%. The researchers found at the 5 (and 10) year follow up (respectively) that 54% (48%) were still injecting, 5.6% (5.7%) heroin alone; 15.7% (11.3%) cocaine alone; 79% (70%) alternating cocaine and heroin. Important to note is that fully half of the subjects had ceased injecting. About 9% were in treatment, 3% (6%) on MMT, 6% (3%) abstinence based. Self reported health rating of 'good' or better was reported by 82% at 5 years and 94% at 10 years. Needless to say, these figures exclude the large numbers who had dropped out or died.

It is a tragic reality of the American health care system that it took ten years for methadone treatment to become available for 6.3% of the sample (initially 2% and 3.1% at 5 years). Knowing that more than 75% of the 256 were heroin users, the uptake of methadone and abstinence based treatments seems very low and probably reflects the lack of treatment available in Baltimore as well as the low socio-economic status of many of the subjects in this study. The death rates of MMT patients is generally less than 1% per annum. If only the other good citizens of Baltimore had acted on the impressive economic good sense of funding methadone and other treatments for addictions, many of the deaths reported here would have been avoided (and household insurance premiums would probably have been lower).

comments by Andrew Byrne ..

Slow release oral morphine versus methadone

Addiction (2004) 99: 940-945

A crossover comparison of patient outcomes and acceptability as maintenance pharmacotherapies for opioid dependence. Mitchell TB, While JM, Somogyi AA, Bochner F.

Dear Colleagues,

This study took 18 consenting methadone maintenance (MMT) patients and transferred their treatment to once daily, supervised slow-release oral morphine. They then reported up to 8 weeks progress and return to methadone. Fifteen managed the transfer without difficulty, three returning to MMT prematurely. Reports of symptoms, side effects and preferences over up to six weeks in the 15 were positive, about three quarters preferring the morphine tablets, only one in five preferring the original methadone. While this is not scientific proof of a superior treatment, it is certainly an indication that morphine can be an acceptable alternative for most MMT patients, with certain reported benefits in a proportion of them.

The initial conversion ratio used was 3.5:1 but every single patient required increased doses for withdrawal symptoms, up to an average of 4.6:1. thus, for example, a patient on 100mg of methadone might need up to 460mg of morphine. At least two of the 11 cases (18%) returned to MMT on higher doses (45 to 50 and 120 to 130). One of these, interestingly, was already on the maximum dose according to the range quoted (25-120mg daily), but evidently needed still more on medical review when returning to methadone.

The mean methadone dose in this Adelaide trial at 78mg daily is higher than previous reports. However, it is likely that the optimal mean dose is yet to be reached, although increases are happening slowly elsewhere (D'Aunno et al). Until the mean dose of methadone is nearer 100mg (like Dole's very first report) it is probable in my view that a proportion of patients will suffer, simply by being prescribed inadequate doses. The lowest doses overall may be in England and Victoria (Aust) where one finds poor quality maintenance treatment along with either too much supervision (Victoria) or too little, as in the UK. New South Wales also has many treatment deficiencies, most glaring being a lack of treatment services in high risk areas such as the Hunter Valley, South-western and inner Sydney. There are also unreasonable restrictions and a lack of flexibility in some aspects of management, especially with buprenorphine.

I understand that in NSW, morphine has been approved for over 100 patients who have been previously registered as dependency cases. The approvals are mostly for slow release oral morphine for 'pain management', often after motor accidents, infections or skin grafts following overdoses. Supervision of doses is not always compulsory. It is not usually possible to completely separate an individual requirement for opiates for (1) dependency or (2) analgesia purposes . and it may not matter, except for some legal aspects.

This study from Adelaide adds further evidence that a wider variety of opioids can be safe and effective in dependency situations and the old view of 'methadone for dependency and morphine for pain' is dated and arbitrary. Thus we now need to find out if we can improve on 'trial and error' to determine optimal management for our patients using methadone, buprenorphine or alternative oral or even parenteral opioids in pharmacotherapy for dependence.

Congratulations to Addiction for showcasing this seminal study as the lead article for the month. Note this study followed a rigorous report by the same authors on morphine's pharmacokinetics (see below). The first such report I can find is from Dr Sherman in Melbourne, followed by Whitton et al in Sydney (both 1996).

Refs: Mitchell TB, White JM, Somogyi AA, Bochner F. Comparative pharmacodynamics and pharmacokinetics of methadone and slow-release oral morphine for maintenance treatment of opioid dependence. Drug Alc Depend (2003) 72;1:85-94]

Whitton G, Sunjic S, Webster I, Wickes W. Use of morphine mixture to stabilize opiate dependence. 1996 Drug Alc Review 15: 427

Sherman JP. Managing heroin addiction with a long-acting morphine product (Kapanol). Med J Aust 1996:165;239

Comments by Andrew Byrne ..

Adolescent drug use study; curious conclusions; curious editorial practices at 'Addiction'. Author replies.

Addiction (2004) 99:897-906

The adolescent behavioural repertoire as a context for drug exposure: behavioural autarcesis at play. Chen C-Y, Dormitzer CM, Butierrez U, Vittetoe K, Gonzales GB, Anthony JC. Addiction (2004) 99:897-906
[NOTE: comments from senior author below]

Dear Colleagues,

This extensive 6-country, 12,000-subject survey of adolescent behaviours derived from the authors' hypothesis of the existence of some innate individual behavioural protection, termed 'autarcesis' by them. It is self-evident that some children are more inclined than others to use drugs or alcohol and, for that matter, to become involved in other risk taking behaviours. It is of crucial interest to parents to know if this is amenable to change. From previous research, we know that about half of the influence leading to drug dependence is environmental and the other half genetic. However, to my knowledge, there is no documented means either to predict which specific individuals are at a greater risk of initiating drug use, nor any definite means to alter the risk. That notwithstanding, there could be nothing more attractive to parents than to know of such factors, if they exist, to improve their children's chances of avoiding drugs.

The study was a massive exercise involving a cross sectional survey including details of drug 'exposure' ('were you offered?') and drug use as well as numerous other activities such as praying, church attendance, sports and dating, etc. The average age of 12,000 subjects was 16 (r 12-19). Being school based questionnaires, the study excluded those underprivileged children not attending school.

Unsurprisingly, those who spent time praying and going to church were less like to be exposed to and to use drugs. This interesting finding is not of much scientific merit with no indication of causation. Drug exposure/use may protect young people from attending church - or vice versa. For a more scientifically rigorous evaluation initial drug exposure and its capital consequence see the study by Vlahov and associates in New York in the same journal [Mortality risk among new onset injection drug users. Vlahov D, Wang C, Galai N, Bareta J, Mehta SH, Strathdee SA, Nelson KE. Addiction (2004) 99:946-954 - summary on request.].

The evidence provided by the authors does not prove their interesting theory on my reading, yet they seem confident that it does. I would proffer that a motor car may display 'autarcesis', just as these authors propose in these children. It has protection against rain, heat, wind and collision. Yet such protection is not a single, definable quality, but rather a combination of all the elements required to make a solid conveyance: steel, tyres, duco, glass, electrical and braking systems for example. Nevertheless, safety of the young from external mischief is such a major issue that this debate must be useful. There can be few issues as pressing as drug uptake and use among the young in our societies.

Addiction editor Griffith Edwards has evidently permitted this study to be viewed by at least two chosen experts prior to publication since two "letters to the editor" give individual comments on the study in the very same edition of Addiction. I am concerned that Edwards did not wait for the normal process of scientific discourse, neither did he caption these letters as invited commentary which they appear to be. Further, in this case Edwards chooses to print two highly critical comments ahead of the usual time for genuine correspondence from the scientific community (or 'people of goodwill' as Edwards puts it). To be productive, such commentary should be even-handed, giving differing points of view. Even the titles given to these letters are critical ... and some might even say derogatory ["Is 'autarcesis' the emperor's new clothes? A comment on Chen et al. (2004)"; "Protection from etymologic infection"]. A detailed reply from the authors appeared a month later as a normal letter-in-reply. When I raise these issues, I am reminded of editorial finality, bordering on truculence (copy on request). 'Letters' authors I have contacted state that they were asked to comment on a pre-publication items, which they duly did. Edwards might be lucent enough to let us know exactly how many such requests were made and what criteria were used for publication.

Having over 12,000 adolescent subjects in 6 countries with NIDA backing, this study is rather 'weighty' in several respects. Yet there seems to be a 'disconnect' between its data and its conclusions regarding a nebulous yet attractive concept of autarcesis or 'drug-proofing'. These wide-ranging data still deserve closer scrutiny in my view, and the authors should be commended on such a novel study of adolescent drug experiences.

comments by Andrew Byrne ..

The senior author Professor Jim Anthony was asked by me to comment on the above. He wrote the following and suggested it be appended herewith:

"Autarcesis is not an object or a property. It is the name of a process or force that has manifestations we can observe. One distant analogy is gravity. Gravity, like autarcesis, is not an object nor is it a property. It is a process or force.

"An autarceologic process is one that helps shield the organism from exposure to a toxic agent or that helps the organism resist the toxic exposure once effective contact has occurred, but autarcesis is a non-specific process. That is, any shielding or resistance strengthening is generic and is not specific to any particular toxic agent as an induced antibody response might be specific to an antigen.

"There are other forces or processes that help shield or protect against a toxic agent, but they have the character of 'specific' shielding or 'specific' resistance strengthening (see 'antibody').

"Our thesis is that aspects of thhe adolescent behavioral repertoire serve an autarceologic function, helping in a non-specific way to shield the youth from drug-taking or to induce in a non-specific way a strengthening of resistance against offers or opportunities to try drugs.

"This feature of the adolescent behavioral repertoire is not 'innate' by any means, and we think of it as a very malleable repertoire (particularly once drug use 'comes on board').

"In many ways, the autarcesis concept is superior to 'risk factor' and 'protective factor' concepts because it conveys a mechanism, albeit of a non-specific character."

Jim Anthony, Epidemiology, Michigan State University

Methadone and buprenorphine related deaths rare in Paris study

Addiction 2004 99: 978-988

A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I.

Dear Colleagues,

This adds to the modest amount of published research on the major French 'experiment' with buprenorphine, starting in 1996. To add another variable, two years after the release of unrestricted buprenorphine prescription, methadone treatment also became available, albeit in a more structured manner.

This is a detailed report of 60 consecutive overdose deaths in Paris over a 5 year period from 1997 in which buprenorphine (34), methadone (35) or both (9) were found in the post-mortem toxicology. An exhaustive investigation of each case classified the relative contribution (if any) of the two drugs towards the death. Unfortunately as a retrospective study, the authors were not able to determine the subjects' treatment status.

Despite buprenorphine being prescribed at a rate about 8 times that of methadone in France, the numbers of deaths most likely attributable to each drug were about the same (12 versus 14). In these deaths, as in other reports, an average of about 4 other drugs (excluding nicotine) was found, and in one case there were 13 additional drugs! Alcohol, benzodiazepines and other opioids were the most common, sometimes in very high concentrations. Heroin (morphine) was also found in toxic levels in 5 buprenorphine cases and 6 methadone subjects. Other cases either had clear alternative causes of death (eg. homicide, suicide, burns, carbon monoxide, etc) or else the cause of death could not be determined (12 cases).

In 1995 there were ~500 opioid overdose deaths in France. This annual rate had reportedly dropped to 100 by 1999. During this period, Australian overdose deaths increased relentlessly. Due to its restricted status, methadone in France is generally reserved for the more difficult cases. The authors state: "From the beginning, methadone appears to have had the image in France of 'a drug of last resort' for the most desperate cases". Hence the higher per-patient death rates are probably a combination of the drug's higher toxicity as well as it being used in higher risk circumstances clinically in France.

When compared, the figure of 60 deaths in a five year period is reassuringly low. This is in stark contrast to 900 methadone overdose deaths reported in New York City over a 9 year period (Bryant and colleagues in last month's Addiction). The difference is so great that it would appear France is doing something right while America is doing something wrong. Treatment access is doubtless a factor, and one can only speculate about the contribution of so-called US zero tolerance or 'harm maximization' policies as being related to the marked differences in outcomes in what is essentially the same social phenomenon in two very large, sometimes very tough cities on opposite sides of the Atlantic. New York's Rockefeller laws, with long mandatory jail terms for relatively minor drug offences, seem not to have had the desired effect, yet it seems they are politically very hard to reverse. It is good to know that the US has finally introduced buprenorphine treatment but sad to learn that, like methadone, most of the people who need it either cannot afford it or it is simply find that it is not available in their neighbourhood.

Comments by Andrew Byrne ..

Pirnay S, Borron SW, Giudicelli CP, Tourneau J, Baud FJ, Ricordel I. A critical review of the causes of death among post-mortem toxicological investigations: analysis of 34 buprenorphine-associated and 35 methadone-associated deaths. Addiction (2004) 99: 978-988

Injecting room discussed at public meeting in Redfern

1pm - 5pm Sat 24th July 2004

Public Meeting held in the Redfern Community Centre, Hugo Street, 'the block', Redfern.

Chaired by Lord Mayor Clover Moore

Dear Colleagues,

Despite a rainy, cold Saturday afternoon, there was a huge turn-out to a meeting called by Lord Mayor Clover Moore to gauge public feeling about her public statements last month about a comprehensive series of initiatives including an injecting room to address drug issues in Redfern. Clover Moore chaired proceedings firmly but fairly in what was sometimes a charged atmosphere. I estimate that there were over 250 people present. Some were the same faces as who attended the last meeting on the subject convened by Trevor Davies to call for an injecting room in Redfern. Also present this time were City Councillors, Senator Arthur Chesterfield Evans, 'Uncle Dick', Dr Alex Wodak, Professor Paul Haber, Superintendent Dennis Smith and many other community elders.

Ms Moore gave a brief introduction and outlined the problems including community unrest, crime, unemployment, childhood problems, mental disease, drugs and deaths. All speakers agreed that each problems needs to be tackled in turn by the appropriate agencies with coordinated, Koori-friendly strategies. Some of these are in place, some being developed and others in the formulation stage.

There were representatives of youth services, housing officers, drug treatment agencies, police and aboriginal groups. These were put in touch with enquiring citizens by Ms Moore, councillors and staff attending who were 'networking' busily all afternoon. The meeting was only starting to break up 5.30pm.

At least 40 local residents took up the Mayor's invitation to address the meeting on their main concerns. One 'affected' aboriginal woman interjected almost constantly throughout the meeting. She was like a Greek chorus, responding to nearly every point as it was raised, often as a Devil's advocate or in a quasi-humorous manner. Ironically, perhaps, this woman represented many of the contradictions of the community. In contrast to her often meandering comments, on a couple of occasions she became perfectly lucid with perceptive comments. She was permitted to address the meeting microphones at least twice, staunchly defending the Mayor and the police in turn after some very critical comments by others, both white and aboriginal. I noted from many of the aboriginal speakers that 'politically incorrect' terms are still commonly used in normal speech, without the pejorative manner sometimes assumed in other circles.

Most of the comments were extremely positive and optimistic while all conceding that there were problems of a greater of lesser dimension requiring additional services. Everyone agreed that addiction treatments were lacking and many spoke in favour of an injecting room, but not in isolation. At least four people stated that they were drug users and had various 'takes' on what needed to be done. Others were residents who enjoyed living in the area but described numerous ways in which their lives had been affected. Some distinguished themselves as having bought houses in the area to show their commitment to the community. They also described public drug use, discarded needles, overdoses and in one case a drug death in their own driveway only a block from Eveleigh Street which is reputedly an epicentre of a drug use and sales to rival Kings Cross or Cabramatta.

After Superintendent Smith gave his outline of the new policing proposals, Dr Alex Wodak pointed to some of the statistics indicating the undeniable extent of the problems and the overloaded local treatment services. I pointed out that the two local detox services for alcoholics and drug addicts (Basement 82 at Prince Alfred Hospital and Langton Hospital) had both been closed down in disgraceful moves by health authorities. Drs Haber and Wodak were at pains to say that they had fought serious competition for funds in the public hospital systems over the years, and that new funds had already been allocated for new detox services.

Both doctors pointed to the increase in HIV cases overseas when needle services had been compromised. Thus proposals to close such services in or near 'the Block' in Redfern could risk such an epidemic here and spreading elsewhere in New South Wales with a very mobile population. They cited studies in Canada, the US and by the WHO showing the utility and cost-effectiveness of needle availability. With it, drug users also come into contact with health professionals, education and treatment referrals. But such services cannot prevent overdose deaths nor can they be assured to collect all their issued needles. Hence an injecting room is a natural response to high degrees of public drug use and overdoses. It would also be a means to getting some addicts into treatment. We were told that methadone and buprenorphine can cut crime rates dramatically as shown by statistics on the NSW Government web sites.

While there were many suggestions and varied emphases on the issues, only two speakers were completely opposed to Clover Moore's overall initiatives. One revealed serious personal criticisms of the Mayor citing salary and employment conditions. The other stated that the community needed to depend more upon its own 'culture' and had no need of outside help. This denied that at least half the community was non-Koori and clearly 'culture' had not been enough thus far to prevent drug mayhem and deaths of young users. Neither speaker had constructive alternative suggestions but represented a minority and negative view amongst the large numbers who spoke in support of the Mayor's approaches.

Dr Wodak mentioned, almost in passing, the experimental but promising use of prescribed heroin in some European countries for the small (1-3%) proportion of drug users who cannot cope with existing treatments (detox, rehab, methadone, buprenorphine, naltrexone, etc). He said that these measures should be considered at some stage, but ought not to take precedence over proven life-saving facilities such as medically supervised injecting rooms. Others had pointed out the need for primary health care for both drug users and the rest of the community. One resident (non-drug using, white) pointed out that an injecting room would mean that children would not see people shooting up all the time and this may break the cycle of drug use being 'normal'.

All in all it was an uplifting and positive afternoon. Reassuring to know that so many people are anxious to have an input into community matters. And that there was at least 90% of details which were agreed upon. Resolutions were mooted to call for more funding, enabling legislation, etcetera for better employment programs, health facilities and housing for the Redfern community.

comments by Andrew Byrne ..