APSAD annual scientific meeting. Brisbane Nov 17-19 2003. Day 3

Australian Professional Society on Alcohol and other Drugs (APSAD)

On the third and final conference day Professor Ian Webster spoke eloquently about how we may need to change our thinking on drug and alcohol matters to look at a wider picture. He gave many examples from history, pointing out that by the time antibiotics for TB and other infections were invented, the incidence of bacterial diseases was already very much in decline. Thus he emphasised the multifactorial nature of causations for change and that nothing could work unless it had community support. The Australian experience with random breath testing, first starting in Tasmania, caused immediate and significant reductions in road deaths. Several terms were new to me this week, one being �communitarian�.

The second speaker was renowned Kiwi researcher David Fergusson whose studies include a rigorous longitudinal follow-up of over 1000 individuals born in Christchurch in 1974. Their exposure to, problematic use or and/or dependency on cannabis is just one of many facets which have been closely examined every year or so for over 25 years.

Professor Fergusson said that being involved in cannabis epidemiology, he was obliged to deal with drug law reformers but did not see himself as an advocate. He stated that most researchers have some pre-conceived ideas, such as �cannabis is safe� or �cannabis is extremely dangerous� (neither of which is probably true). Thus they often end up proving their own ideas without necessarily contributing much to science. He used the example of Vegemite which could become the subject of a health study. One might find common harmful associations while others might show no significant difference between those who eat Vegemite and normal controls who (naturally) shun the product. This example is telling as for nutritional reasons Vegemite had its salt content changed at one time to reduce its potential public health impact.

The rest of this third day was given over to numerous papers in concurrent sessions covering a variety of dependency subjects, including Aboriginal Health, prevention strategies, brief interventions, psychostimulant treatments (much speculation here, apparently ), Drug Courts and Diversion from the judicial system. Afternoon parallel sessions mostly continued from the morning but also included parenting, pregnancy and more alcohol subjects.

The final session included some very important items including release of the new General Practice smoking cessation guidelines by Robyn Richmond, self help report from We Help Ourselves (WHO) by Garth Popple and other discussion about dissemination of evidence into practice. I think that Professor Saunders was the only medical doctor in this final line-up of eight. Despite supplying most of the public health dependency interventions in Australia, GPs and pharmacists were not well represented this year. Perhaps the next APSAD conference in Perth, WA in November 2004 will redress this issue.

Comments by Andrew Byrne ..

APSAD annual scientific meeting. Brisbane Nov 17-19 2003. Day 2

Australian Professional Society on Alcohol and other Drugs (APSAD)

Dear Colleagues,

This action-packed second conference day had a couple of light points which punctuated an otherwise serious scientific program on dependency management, policy, etc.

Three keynote plenary speakers were led by George Koob talking on how basic sciences can inform treatment decisions. He had written an amusingly-titled paper �Cocaine Reward and Dopamine Receptors: Love at First Site� which was parallel to much of his talk. But there seems to be a complete �disconnect� between such coherent scientific efforts to understand addiction and the almost complete absence of logic in American drug treatment policy over the years. The next speaker, Professor Rudolf Moos, also from California, seemed to be equally hampered in his talk on �how treatment should inform and influence research�. As regards opiates, only a small proportion of the total US dependent population receive appropriate treatment, thus skewing findings, outcomes and policies when compared with other western countries where most people have access to treatment. It was still a privilege indeed to hear the seven invited, diverse and eminent American speakers during the conference (Ling, Vocci, Davis, Maxwell, Grabowski were the others).

The last plenary speaker was Margaret Hamilton giving her ideas on getting research into practice. She gave a �mea culpa� (or her customized plural �we-are culpa�) concerning deficiencies of her own institution. She conceded that sometimes important findings were still not promulgated before researchers �went on to write the next paper�. This is not unique to her institution, of course, nor to our field. However, it is a reminder that we all need to look at our current practices and see if they are consistent with established guidelines as well as new innovations as defined by the evidence. This applies to drug prescribing as well as other components or �black box� factors which are always harder to define than drug, dose and manner of administration.

One of the light points was an afternoon debate on the premise �Are we drowning in the gene pool?� Wittily introduced by Ross Young, two opposing teams of 3 took turns to make light of the subject, starting with Alison Ritter. She had done some homework on drosophila fruit flies put through a silo-like �enebriometer�, courtesy of some ancient vivisecting biologist. George Koob gave a brief but pointed speech including sex, drug and rock/roll, thus taking the genetic low moral ground, but gaining at the same time total audience sympathies. Professor Moos also gave an amusing and increasingly contradictory description of the subject for the affirmative. After the use of an early Picasso absinthe drinker the day before, Dr Barbara Mason ended the presentations (following John Whitfield from RPAH and Nick Martin) with a Degas reproduction, including male emigr� looking the worse for the popular fin-de-siecle drink.

Modern technology now allows a unique level of audience participation using remote multi-choice equipment. On the Monday, a panel discussion on clinical alcohol presentations used the device to gain audience responses to numerous questions (there were 10 seconds of agonising �musak� after which beautiful color-coded histograms appeared for each of the several options). Gerry Springer uses a similar technique on some of his seedier shows, I believe. Even some unlikely options were chosen by participants, eg: response to intoxicated patient: �telephone 000 and hit him with a ruler�!. It was somewhere between a jury room and a flesh market as case histories were gradually revealed and the various possible treatment interventions canvassed by first the audience and then the panels in turn. The alcohol cases on Monday were followed on the Tuesday with an opiate using pregnant woman and a violent stimulant abuse case. The panels included Ingrid van Beek, Alan Gijsbers, Richard Mattick, Roger Brough and many more. For some reason these interesting sessions were not well attended yet other sessions on opioid therapies, pain management, club drugs, rapid detox, neurobiology, genetics etc were nearly all full to overflowing during the conference. It was a shame that there were not more middle sized rooms in the hotel complex, but it is always difficult to predict such matters ahead of time.

A second session on neurobiology included Professor Mac Christie speaking on neuroadaptation followed by papers on club and party drugs and the users� personality traits, genetic polymorphism etc from a Hong Kong study by Alfreda Stadlin. Frank Vocci took the prize for complexications with his final paper on GABA-B receptors and their possible effects in cocaine withdrawals (something others say does not exist). His statements about the occasional incomprehensibility of his papers was appreciated by the audience. The issue of using dexamphetamine or other stimulants for cocaine users was raised by several speakers during the conference.

There was an illuminating session on the 1999 NSW Drug Summit and its longer term consequences given by Dr Tony Gill, John Leary and Larry Pierce, chaired by James Bell. We were reminded that short term political expedience can sometimes give rise to longer term benefits. Substantially more funding was put into public methadone services; case management was made mandatory and clinic accreditation and a take-away dose review commenced. After a comment about the public clinics� withdrawal of all take-home doses due to alleged problems with diversion, John Grabowski made some pertinent comments from the audience. He said that research in the US showed that most diverted methadone was in fact used by other addicts who were not currently registered, thus making �another layer of unofficial treatment�. Professor Grabowski also quoted research showing that take-away dosing improves retention rates and overall outcomes of methadone treatment in his own country, the USA. Despite being generally considered more conservative than Australia, US authorities now allow a week or even more consecutive �home� dosing in certain long term, stable cases. A user representative at the meeting stated that she found the attention paid to consumer views at the NSW Drug Summit were generally not followed up with actions, including the �Treatment Agreement� and other matters. She said it was �lip service only� for some of the �too difficult� issues. It was also said that despite leading many changes in drug treatments, that the NSW Health Department had done very little in evaluating these policy changes for their benefits and costs.

The chair reminded us that the most novel outcome of the Summit was the Kings Cross injecting room which has indeed been extensively evaluated - with almost universally positive outcomes officially reported. It was recently granted a 4 year extension and now attracts up to 350 injectors daily.

There were also parallel sessions on prevention, dual diagnosis, workforce development, NGO�s, tobacco, diversion/policing, etc. All were well received and choice was very difficult on some occasions.

The �Rankin Oration� was given in the presence of Jim Rankin by Margaret Hamilton who donned yet another hat to give an impression of what the future might bring. No clairvoyant, she nevertheless made many far-sighted predictions about �virtual conferences�, tropical island existence, brain �chips� and intimate interactive telecommunications. She confessed to not understanding all the neurobiology but said she was starting to make some inroads after all the lectures on the limbic system, transmitter chemicals and the like.

Incredibly, not content with launching two publications the previous day, she also announced yet another book, this time from Turning Point in collaboration with Trevor King who was also present and took a bow. I look forward to seeing how the Victorians approach this field and how it needs to be improved.

There was a private meeting of the newly formed Chapter of Addiction Medicine (RACP) of which there are almost 150 members across all states and territories. The APSAD annual general meeting was held on the Monday evening with a psychiatry college sub-group meeting also held at the conference.

The conference dinner was held in the Sheraton ballroom which was almost unrecognisable from an hour earlier as the stage was set for pseudo-Phantom of the Opera and para-Pavarotti and Bialla Boheme, each bringing joy and sonorous shrills to the air. We even had the world cup theme sung as a trio! [Nessun dorma for those who know Turandot, the opera]

Dr James Bell gave a witty address showing how the need for a Chapter of Addiction Medicine was itself a kind of dependency, complete with craving, salience and divers other attributes. He raised a few laughs with his comparison of the Foundation Fellowship Committee with Phillip Ruddock (any babies overboard here?), and a reference to certain doctors keeping their patients on high doses of drugs in order to minimise the time they spend with them, maintain their dependency and �to ensure the viability of their practices�. Serious allegations, even in the bacchanalian context.

The wine flowed, the dance floor filled and several dour professors became agile dancers and ardent romantics. Some others ended up under the table, in one case literally. A credit to the organising committee in Brisbane.

Comments by Andrew Byrne ..

APSAD annual scientific meeting. Brisbane Nov 17-19 2003. Day 1

Monday 17th Nov 2003

Australian Professional Society on Alcohol and other Drugs (APSAD)

Dear Colleagues,

The first day of the APSAD conference incorporated a very full program from 9am until 10pm. Welcome formalities were performed by Professor John Saunders, Aboriginal Elder Auntie Roz Graham and Minister Trish Worth with a letter of support to all delegates from the Prime Minister. Mats Berglund from Sweden then spoke about �what government can expect from treatment�, followed by a historical perspective from Neal Blewett regarding the Australian response to drugs and viral diseases over the past 20 years. He gave a hilarious description of his own need to back-track after seemingly supporting decriminalisation of cannabis as a federal minister in the 1980s.

A new magazine called �Of Substance� was then launched by Brian Watters and Margaret Hamilton. This quarterly is hoped to fill a �niche� in the dependency market. Its first two copies will be free, then it will cost $50 per year.

A bewildering array of concurrent sessions were then held in six separate rooms. First were post detoxification vocational services in cities. Next were �free papers� on opiate dependence treatment, starting with a description by Deborah Zador of a rather negative opinion survey of 104 English patients on injectable methadone and heroin. Those on methadone expressed a preference for heroin and many found prescribed doses inadequate. Malcolm Dobbin described the explosion in prescribing of benzodiazepines, long acting morphine and other drugs and their negative impacts. Nico Clark told us about some buprenorphine patients who required morphine and other drugs for serious surgical pain. One such was given up to 300mg morphine daily but sent home, still sick and immobile, with a prescription for daily methadone 40mg from a chemist they could not get to. Such a patient should have had adequate analgesic doses dispensed, regardless of existing �regulations� which should be waived when they stand in the way of good treatment. If the patient were not considered safe with such medicines then the GP and/or district nurse should have been called in to assist with supervision. Nick Lintzeris then reminded us of how little research literature there is on the interaction between benzodiazepines and opiates. He quoted the few animal studies which supported the notion of additive effects, consistent with the French experience of buprenorphine overdose deaths of which 80% were associated with benzodiazepines, alcohol being involved in most of the rest. A series of 50 rapid detox cases were then presented by a Sydney group, half the cases receiving a naltrexone implant with the remainder oral prescription. Nine of the 24 oral cases had relapsed in a six month period compared with only one of the implant group.

Carolyn Edmonds and Jason White performed a wonderful service by carefully examining the effect of a single dose of naltrexone on binge drinking footballers, double blind, cross-over in about 10 subjects. They found no overall effect on quantity of alcohol consumed but some effects of the perception of the drink itself. This session included numerous other short papers on alcohol. Jane Maxwell started the session on party drugs, explaining that research in this area was particularly messy, as well exemplified by the �Science� paper on MDMA which had to be withdrawn by its authors after erroneous conclusions due to the wrong reagent being used in lab experiments. She reminded us of the very local nature of some drug habits and differences which can occur even between adjacent areas. This was taken up by John Grabowski, also from Texas, in his afternoon plenary speech on the use of dexamphetamine in cocaine users. There was also a session on �pathways to treatment� and the �consumer perspective�.

The afternoon started with 6 parallel sessions followed by a wonderful description of the �science of opiate treatment� by Wim van den Brink from Holland. His own heroin trial for treatment resistant addicts was described in detail (smoked/injected; up to a gram per day; good outcomes in treatment; bad outcomes returned with end of trial) as well as his support for higher doses in methadone treatment. This was echoed by John Grabowski who described several approaches to psychostimulant use in the USA. Next we had the launch of yet another publication �Dealing with Risk�, also by Margaret Hamilton and Brian Watters. I wonder if it is a record for the same pair to launch two publications at opposite ends of the same (very long) day? Copies were handed out to all delegates the following morning (perhaps as a reward for making it to the second day!).

The evening brought welcome drinks and nibbles, followed by three international speakers on pharmacotherapies for alcoholism. It was nice to see our interstate and overseas colleagues again but a shame that so much about alcohol research was repeated while the wine flowed freely and perhaps we should have been relaxing.

comments by Andrew Byrne ..

New England Journal trial supports office based buprenorphine treatment with generous take-home provisions.

Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN, Jones K, Collins K. Raisch D, Casadonte P, Goldsmith RJ, Ling W, Malkerneker U, McNicholas L, Renner J, Stine S, Tusel D. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

Dear Colleagues,

This study randomised consenting heroin dependent subjects to receive one month’s treatment with (i) buprenorphine, (ii) buprenorphine/naloxone or (iii) placebo. For a further 11 months, surviving (sic) patients were followed in an open-label manner for primary outcome measure of 'percentage of urine drug screens negative for opiates' as well as for safety.

The double blind treatment was given for one month, supervised for weekdays with take-home doses for weekends. Doses were fixed at 16mg buprenorphine, 4mg naloxone. In the open label study there were more liberties with up to 10 consecutive doses being dispensed for home consumption.

The authors seem to have been surprised that results (retention and drug screens) for the placebo group quickly became more than 3 standard deviations away from those in the active treatment groups. Under their agreed protocol this triggered abandonment of the placebo arm of the trial, but not before a substantial excess of treatment drop outs and relapses to illicit drugs.

The paper leaves many questions unanswered. What was the 12 month retention rate? Significant numbers of late drop-outs must have occurred as there is a shortage of urine drug screens reported from the open label study. We are not told whether the patients with abnormalities to liver function tests thought to be ‘possibly’ or ‘probably’ related to the treatment (7 cases) were prescribed pure buprenorphine or the combination product.

These subjects were presumably told that they had a one in three chance of being given no active drug and would thus may have had to face opiate detoxification.

The ethics of researchers offering placebos for serious conditions has been dealt with in detail since this paper’s genesis in 1996. These authors may be reluctant to be associated with such a practice today.

This trial is only of very limited relevance since it did not compare office based practice with standard US clinic treatment. Nor were the conditions the same as current licence arrangements in the US (no supervised doses are required!). In essence, the trial patients on bup/naloxone combination showed slightly more side effects (?significance) but comparable reductions in illicit drug use .. and similar early retention rates compared with those taking the pure sublingual tablet without the naloxone. Hence the combination drug conferred no particular advantage for the patient and, being a mixed drug, may have some disadvantages over the pure drug. Thus there would seem to be no proof that the combination drug is either better for the patient, nor that it is necessarily better for the public health situation in America. This lack of good scientific evidence favouring the use of the combination product provides yet another challenge for American doctors. It is to be hoped that this trial will, however, give strong support for allowing more unsupervised buprenorphine doses in Australian settings where such dispensed doses are still the exception. For 8 years in France most doses of the pure drug buprenorphine have been unsupervised and most indications are positive.

Comments by Andrew Byrne ..

Some opiate antagonist therapy 'escaped the usual process of therapeutic controls'.

Streel E, Verbanck P. Ultra-rapid opiate detoxification: from clinical application to basic science. Addiction Biology (2003) 8:141-146

Dear Colleagues,

This ‘Invited Review’ from Brussels describes the rise of opiate antagonist therapy over the past 20 years, much of which has ‘escaped the usual process of therapeutic controls’. We are told that most new treatments should start with animal studies - yet with antagonists the reverse has happened. These two Belgian authors quote some of their own recent work on addicted rats given anaesthetics and antagonists to quell the symptoms and signs of opiate withdrawal. Objective findings are hard enough to find (ever tried to detect pin-point pupils in a rat?) - but subjective withdrawal effects are necessarily even more elusive (where is the Pied Piper when you need him?). The authors quote a number of studies showing contradictory effects on withdrawals from anaesthetics, sedatives and antagonists. Some even concluded that animal modelling, at least with rats, was not applicable for rapid opiate detoxification (‘ROD‘).

The article contains two major misconceptions, starting with the first line that rapid detoxification ‘has become increasingly popular in both private and public addiction centres’ (no reference). The treatment has never been ‘popular’ in public treatment agencies I am aware of, nor is its use necessarily still increasing in the for-profit sector. Secondly, the authors seem to have been persuaded that naltrexone maintenance therapy leads to long-term abstinence in a substantial proportion of those who are prescribed it. The evidence I have read is otherwise, with reported compliance as low as 10% at 6 to 12 months. Promising outcomes were reported in only three of the many well conducted trials - and two of these three utilised enforced supervision in the prison or probation system (Chan 1996; Cornish 1997). The encouraging outcomes of Gerra (1995) were never replicated by other researchers. Excess deaths and self harm were reported in one trial (Miotto 1997). Australian studies have been equally disappointing (Foy 1998) although mortality was not specifically sought from official sources so final outcomes remain uncertain for those who were lost to the authors’ follow up.

Like certain other authors on the subject, Streel and Verbanck state that the process is probably best conceptualised as ‘rapid antagonist induction’ and not ‘rapid detoxification’. This almost sounds like a ‘mantra’ from some. In fact, the process is both of these, and the problem is not conceptualisation, but whether the overall treatment is actually both ‘safe and effective’ for addicted patients who receive it.

It is to the credit of Addiction Biology that, like Lancet, it is prepared to publish items at the ‘edge’ of medical practice, some of which would be rejected by more ‘purist‘ journals. Rapid detoxification under anaesthetic/sedation and naltrexone implants are still not evidence-based modalities and some of these reports may not fit all aspects of the ‘Farmington consensus’ introduced by NAC sister journal, Addiction.

The list of 43 references in this invited review is a who’s who of the field, including Loimer, Brewer, Resnick, Kleber, Strang, Seoane, Legarda, Currie, O’Neil and Hulse. The article emphasises the need to do animal studies and ‘basic science’ prior to introducing treatments into clinical practice. The authors thus regret the situation where the use of naltrexone implants and long acting depot preparations are not always first used in appropriate laboratory experiments. The article makes persuasive reading.

Comments by Andrew Byrne ..

Transfer to buprenorphine from methadone - another approach.

Transfer to buprenorphine from methadone - another approach.

Greenwald MK, Schuh KJ, Stine SM. Transferring Methadone-maintained Outpatients to the Buprenorphine Sublingual Tablet: A Preliminary Study. Am J Addict (2003) 12:365-374

This study shows that it is possible to transfer patients from methadone to buprenorphine after being stabilized on a dose level of 60mg daily. A single dose of 45mg and commencement of buprenorphine 8mg the next day was acceptable to most of the 5 volunteers on the several 'blinded' transfers accomplished. Another method was tested using 3 days of 30mg which was equally effective.

The authors state: "It may be feasible to transfer outpatients on methadone 60 mg/day to buprenorphine 8 mg/day s.l. tablet, although this pilot protocol needs refinements to improve tolerability and clinical efficacy."

There is a major conference on buprenorphine taking place this month at the New York Academy of Medicine, sponsored by the Edmund de Rothschild Institute of Chemical Dependency. It is entitled "Voices of Experience" Nov 17 and 18 details from: http://opiateaddictionrx.info/buprenorphine.html

Like all new drugs introduced, buprenorphine has several advantages as well as some disadvantages over existing agonist treatments, largely methadone. For most patients who are stable and content on methadone there is probably little reason to transfer to the new drug. However, for those with side effects, continued drug use, altered mood or other negative aspects, a second opinion is always worthwhile. This may involve dose alteration, changes to pick-up point, changes to take-away provisions or addition of antidepressants or other medications. In some cases it may entail a change to buprenorphine, sometimes with dramatic and gratifying results. Others may have to return to methadone which can be easily accomplished without delay in most settings (exception is the US where artificial regulations, exemptions and 'waivers' prevent doctors giving appropriate treatment in some instances).Comments by Andrew Byrne ..

Hong Kong WHO methadone workshop for prevention of HIV in Asia

Training Workshop on Methadone Treatment for HIV Prevention.
UNAIDS - UNICEF - UNDP - UNCCP - UNESCO - WHO - World Bank.
Hong Kong Baptist University, Kowlong Tong

22-24 October 2003

Dear Colleagues,

This very successful event attracted over 100 doctors and other health care workers from China, Viet Nam, Nepal, India, Bangladesh, Indonesia, Thailand, Burma (Myanmar) and the Phillipines.

The HIV epidemic has brought renewed interest in methadone treatment as a means of reducing needle use and avoiding the spread of viral diseases. There is a dramatic contrast in HIV rates between countries with and without harm reduction measures such as methadone treatment and needle services. Like Australia, Hong Kong has had 'easy-access' (aka 'low threshold') methadone treatment for 30 years. The HIV rate among Hong Kong injectors is around 1%, in stark contrast to neighbouring regions with much higher rates. For example, in Viet Nam it has been estimated that around 35% are HIV positive. Despite the difficulties in reporting on the prevalence of HIV infection amongst drug users, over 60% of HIV infections in Burma (Myanmar), China, Malaysia and Viet Nam are thought to be directly related to IV drug use. In prisons, the prevalence is up to 50% among injectors. Medication for prisoners in Hong Kong is still very restricted, as in most other countries. It would appear that New South Wales, Australia is one of the few jurisdictions with methadone traditionally available in its prisons.

The prominence accorded to the subjects of HIV and drug treatment was demonstrated with the event's formal opening ceremony by Director of Health, Dr PY Lam, Mr Sandro Calvani (UNAIDS), Mrs Rosanna Ure, Narcotics Commissioner, Mr Gray Sattler (WHO) and Conference Convenor Dr S.S. Lee (Red Ribbon Centre).

Over the next three days Dr Robert Newman (US), Dr C.N. Chen (HK), Dr DSW Wong (HK), Gray Sattler (Aust/WHO), Dr Y.W Mak and Dr S.S. Lee (HK) joined by myself and the organisers, interpreters and support staff to produce what should make a seeding of harm reduction for the delegates in their countries of origin. Originally delayed by finances and then the SARS epidemic, this conference/workshop had lately become of increased interest to mainland Chinese authorities which is most gratifying. The HIV problem needs to be confronted using all effective means, including needle programs and methadone treatment.

It is to the credit of Dr S.S. Lee that the program was comprehensive, utilizing lectures and workshops to complement separate methadone and harm reduction clinic visits locally. It was an old colonial administration almost 30 years ago which engaged Dr R.G. Newman from New York to advise on setting up a series of methadone clinics across the territory. Mr Peter Lee, the ex-Commissioner for Narcotics, now aged 87, was reintroduced to Dr Newman. Together they deserve credit for averting an epidemic in the territory and thus improving the lives of countless individuals over the years.

A dinner was given by Director of Health, Dr PY Lam at the Hong Kong Academy of Medicine to honour Dr R.G. Newman in recognition of his services to Hong Kong. He continues to be a vocal advocate for humane and effective treatment interventions, including detoxification facilities, buprenorphine, mental health measures, etc for all who need them.

The three day conference/workshop was highly successful by all reports. The final day was as well attended as the first. The main message of the conference was that methadone treatment can be implemented in a variety of ways using both dedicated facilities as well as existing services. The more diverse and flexible the approaches, the more effective the overall outcomes will be in reducing or eliminating injecting behaviour.

The issues occupying most time were: dose levels, inductions, degree of supervision, staffing, provision of take-home doses as well as psychosocial supports. There was also some discussion of the place of substitution treatment and the need to be clearly focussed on the need for drug dependence to be correctly placed and dealt with as a medical condition, requiring treatment. In countries that are now looking at the need for drug treatment, in the face of explosive growths in HIV infection, this issue is again being played out.

On the Thursday evening there was a reception for all delegates, hosted by Dr Homer Tso of the Advisory Council on AIDS. There were also two sessions at the nearby 'Red Ribbon Centre', one on an on-going media campaign in HIV prevention and the other on outreach experiences. The center has designed attractive information brochures for safe injecting messages. These messages of prevention of overdose and viral infection these have been translated into several other languages including Nepali and Thai.

Congratulations to the organisers of this seminal workshop.

Comments by Andrew Byrne .. (who was a paid delegate to this event . and found modern Hong Kong to be fast, stylish and a good-value destination for the traveller).

Cost effectiveness of buprenorphine versus methadone. Both 'winners'.

Buprenorphine versus methadone maintenance: a cost-effectiveness analysis. Doran CM, Shanahan M, Mattick RP, Ali R, White J, Bell J. Drug Alc Dependence 2003 71;3:295-302

Dear Colleagues,

This monumental study was one of the steps required in the licensing of buprenorphine in Australia. It is a credit to the authors who went against almost all previous studies of comparative opioid addiction treatments in keeping the randomised interventions 'naturalistic' rather than arbitrary, fixed or even placebo. Doses were not capped and the initial period was double blind. Pregnant women, dual diagnosis folk and those currently in agonist treatment were exluded.

This analysis is of the costs versus benefits and has a brief but important literature review of the subject. The summaries are worth quoting: "The most comprehensive cost-benefit analysis to date … by Gerstein [CALDATA study] … found that for each modality of treatment the summed benefits significantly exceeded the cost of delivering the episode of care. For residential treatment the ratio of benefits to costs was 4.8. Comparable ratios were obtained for social model treatment and for continuing methadone. Much higher ratios of 11 to 1 and 12.6 to 1 were estimated for outpatient and discharged methadone participants."

[In this study:] "Treatment with methadone was found to be both less expensive and more effective than treatment with buprenorphine, which suggests methadone dominates buprenorphine. However, [this may not be] statistically significant. The results of this study . indicate that buprenorphine provides a viable alternative to methadone in the treatment of opioid dependence."

The authors could not directly test the cost of those opioid dependent patients who do not do well on methadone treatment. Other studies indicate that they are more likely to die and to be involved in high risk behaviours. Hence an alternative as effective as methadone must be a boon and would increase the cost-efficiency even further, even in the case of slightly higher costs of buprenorphine and its delivery.

Comments by Andrew Byrne ..

Reference: Gerstein DR, Johnson RA, Harwood HJ, Fountain D, Suter N, Mallow K. 1994 Evaluating Recovery Services: The California Drug and Alcohol Treatment Assessment (CALDATA). Report by NORC at University of Chicago and Lewin-VHI Inc, Fairfax Virginia.

Heavy drinking and illicit drug use in London methadone patients.

Heavy drinking and illicit drug use common in London methadone patients - were doses adequate? Research summary by Dr Richard Hallinan.

Excessive alcohol consumption and drinking expectations among clients in methadone maintenance. Hillebrand J, Marsden J, Finch E, Strang J. Journal of Substance Abuse Treatment 2001 21;3:155-60

Dear Colleagues

This study investigated the prevalence and psychological determinants of alcohol consumption in 66 MMT clients in South London in 1999, using the framework of the Theory of Reasoned Behaviour (Ajzen and Fishbein, 1980). By a sensitive criterion of 3 or more of 8 DSM-IV markers of alcohol dependence, 54% of surveyed clients were alcohol dependent in the previous 12 months. In some cases this period could have preceded the time in MMT, which together with the sensitive criterion of alcohol dependence may have given a liberal estimate of this problem in MMT clients, however the results are consistent with many previous studies showing a high prevalence of alcohol dependency in MMT clients in the US and UK.

The study participants had been in treatment at least a month (mean 28.4 months), and were dosed at community pharmacies with a mean dose of 49mg (SD 27mg). There were also high levels of recent use of heroin (62%), stimulants (47%) and benzodiazepines (32%).

The researchers examined the clients' perceived functions for alcohol use, and found 84% used it to relax, 68% to relieve boredom, 66% to improve low mood, 64% to forget problems, 54% to help them sleep and 30% to increase the effect of methadone; 28% to get going in the morning; 24% to stop feeling sick in the morning. 24% used it to calm down after using other drugs.

The strongest predictor of clients' expectation of change in their own drinking was 'subjective norms', suggesting their susceptibility to the views of 'important others' around them, potentially including MMT staff. The use of alcohol to perform particular functions was also a strong predictor of low expectation of change, suggesting that if these specific functions could be served in other ways, clients may be more susceptible of change in their drinking behaviour. The dose of methadone was significantly and negatively related to expectation of change in drinking.

The mechanism for determination of methadone doses in this client group is not specified in the report; in particular it is not apparent whether there were actual or perceived ceilings to methadone dosing.

The MMT clients reported in this study apparently received a considerable range of doses but the mean dose was lower than the minimum 60mg daily recommended by the US National Institutes of Health consensus panel guidelines (1997). Only 35.5% of MMT clients in the US were receiving doses less than 60mg daily in 2000, down from 79.5% in 1988 (D'Aunno and Pollack 2000). Ball and Ross (1991) found that prevalence of heroin use fell to under 10% only with MMT doses higher than 50mg daily. In a study of 211 MMT patients Eap et al (2000) found a trough R,S- methadone level of 400 ng/ml was a significant therapeutic threshold with an 81% specificity for absence of heroin use, a level achievable with a mean dose of circa 80mg daily (Wolff et al 1991).

Hillebrand et al's study should thus be examined through the prism of possible underdosing, which is strongly suggested by the high prevalence of continuing heroin use. Most of the specific perceived functions of alcohol use which they identified (viz to relax, relieve low mood, get to sleep, get going or stop feeling sick in the morning, to augment the effect of methadone) could be interpreted as self medication of symptoms of abstinence. Borg et al 1995 found methadone levels under 150 ng/ml in 9 of 10 patients with such symptoms, and reported "Early opioid withdrawal, requiring a higher dose of methadone, is often difficult to diagnose because many of the symptoms are also symptoms of other syndromes common in the methadone maintenance population."

The authors identified a negative correlation of dose of methadone with expectation of change in drinking behaviour, which they speculate may reflect a greater 'attachment' to their drinking behaviour in higher dose clients. This finding needs scrutiny considering the limited information given about dosing practices. On the figures given, at least 95% of the clients had doses less than 103 mg daily (ie mean+2xSD). In a situation where there is considerable dosing flexibility within actual or perceived limits, higher dose clients are more likely to include those limited by a 'ceiling'. Thus, paradoxically, higher doses could be associated with a greater likelihood of underdosing, explaining the greater 'attachment' of some higher dose clients to their drinking. The fact that the association of high dose with lower expectation of change was independent of perceived functions of alcohol, need only imply that the function of alcohol in alleviating symptoms of abstinence is not always perceived as such.

The strongest positive predictor of expectations was found to be subjective norms, evidence of the importance of the MMT environment in addressing problematic alcohol consumption. The power of subjective norms also suggests a mechanism by which clients might limit their own doses to 'acceptable' limits and fail to perceive the extent to which alcohol is used to alleviate symptoms.

Clients who felt they were using alcohol for specific functions were less likely to expect change in their drinking. The simplest alternative to alcohol for many of the functions identified by the researchers might be methadone dose titration.

In contrast to the good evidence that adequate doses of methadone can reduce cocaine use, there is only a modest literature of observational studies suggesting the same for alcohol and benzodiazepines Byrne 1998 Maxwell and Shinderman 1999, Tennant 1987, Stimmel et al 1982, Gelkopf et al 1999. Recently Lubrano et al 2002 et al have described high levels of craving for alcohol in MMT patients receiving low doses. Hillebrand et al's simple and elegant study highlights the need for further research to evaluate the issue of adequacy of methadone dose in dealing with the important problem of alcohol use in MMT.

Comments by Dr Richard Hallinan, 75 Redfern St, Redfern, 2016


Refs:

Ajzen, I., and Fishbein, M. (1980) Understanding attitudes and predicting social behaviour. London: Prentice-Hall International.

Ball, J.C., and Ross, A. The effectiveness of Methadone Maintenance Treatment. New York: Springer-Verlag, 1991.

Borg L, Ho A, Peters JE, Kreek MJ. Availability of reliable serum methadone
determination for management of symptomatic patients. J Addict Dis 1995;14(3):83-96

Byrne, A. Use of serum levels for optimising doses in methadone maintenance treatment. J Main Addict 1998; 1: 13-4.

D'Aunno T, Pollack HA. Changes in methadone treatment practices: results from a national panel study, 1988-2000. JAMA. 2002 Aug 21;288(7):850-6.

Eap CB, Bourquin M, Martin J, Spagnoli J, Livoti S, Powell K, Baumann P, Deglon J. Plasma concentrations of the enantiomers of methadone and therapeutic response in methadone maintenance treatment. Drug Alcohol Depend. 2000 Dec 22;61(1):47-54.

Gelkopf M, Bleich A, Hayward R, Bodner G, Adelson M. Characteristics of benzodiazepine abuse in methadone maintenance treatment patients: a 1 year prospective study in an Israeli clinic. Drug Alcohol Depend. 1999 Jun 1;55(1-2):63-

Maxwell S, Shinderman M. Optimizing response to methadone maintenance treatment: use of higher-dose methadone. J Psychoactive Drugs. 1999 Apr-Jun;31(2):95-102.

Stimmel B, Hanbury R, Sturiano V, Korts D, Jackson G, Cohen M. Alcoholism as a risk factor in methadone maintenance. A randomized controlled trial. Am J Med 1982 Nov;73(5):631-6

Tennant FS Jr. Inadequate plasma concentrations in some high-dose methadone maintenance patients. Am J Psychiatry. 1987 Oct;144(10):1349-50.

Hillebrand J, Marsden J, Finch E, Strang J. Excessive alcohol consumption and drinking expectations among clients in methadone maintenance. J Subst Abuse Treat. (2001) 21(3):155-60

National Addiction Centre Institute of Psychiatry, Maudsley Hospital 4, Windsor Walk, London SE5 8AF, UK.

Pharmacokinetics of high-dose buprenorphine

Drug Alc Depend (2003) 72; 1:75-83

Pharmacokinetics of high-dose buprenorphine following single administration of sublingual tablet formulations in opioid naïve healthy male volunteers under a naltrexone block. McAleer SD, Mills RJ, Polack T, Hussain T, Rolan PE, Gibbs AD, Mullins FGP, Hussein Z.

Dear Colleagues,

At last we have some real data on buprenorphine half lives, absorption and effects from healthy volunteer studies. These researchers, who were working for the manufacturers, have taken 35 healthy males and given substantial doses of buprenorphine after 50-150mg naltrexone 'block'. They then measured clinical and blood parameters at regular intervals for up to 3 days in an in-patient setting. Techniques for measuring blood levels of buprenorphine are still being developed and are not generally available in clinical practice. This makes patient history and clinical observation even more important than otherwise. A liquid chromatographic tandem mass spectrometric (LC-MS/MS) assay was developed by these researchers and it was validated for the measurement of buprenorphine and nor-buprenorphine, its metabolite, in blood.

Mean half life was found to be 26 hours with a wide range from 9 to 69. Interestingly, these authors have confirmed some observations in clinical practice including highly variable half lives and the 'bi-exponential' decay sometimes reported by patients. Some had a 'secondary peak' at about 10 hours from dosing. The authors report that some had higher levels following meals and propose 'entero-hepatic recirculation' in some cases. Maximum or 'peak' levels occurred between 30 minutes and 3 hours.

The addition of naloxone in the sublingual preparation made no difference to blood levels. The time taken for the tablets to dissolve were similar for all dose levels from 2 to 16mg (range 6-12 min) and were no different for the combination product. It is worrying that the American FDA has approved the marketing of the combination product even before research of this nature had been established. One wonders if they have different standards for drugs used in the treatment of addiction.

The authors confusingly claim to have shown that the two formulations of buprenorphine - naloxone were 'bioequivalent'. This should not be read as their being bioequivalent to the pure product which for some reason they did not test or else did not report if they did. Also, and importantly, these patients had already been given a large dose of naltrexone, a close chemical cousin of naloxone. Unsurprisingly, they found approximately half the blood levels when half the buprenorphine dose was administered. To demonstrate bioequivelence between the old pure sublingual product and a new formulation will take specific research which is yet to be done to my knowledge. The manufacturers have sponsored numerous experts who have stated that for practical clinical purposes the pure product is bio-equivalent yet this is not based on any research to my knowledge and is also very unlikely based on the small amount of research there is out there.

Thus a major weakness of the present study is that it did not examine levels in on-going treatment, but just individual single doses. Thus is it more relevant to the initiation period, which is still a major problem for some patients and is thus a helpful contribution to the scientific literature. There were no opioid effects using the naltrexone block at between 50 and 150mg doses 4 hours prior to opioid administration. This is also helpful information for those using blocking therapies, despite their limited place in normal clinical practice.

comments by Andrew Byrne ..