31 December 2003

To crush or not to crush - buprenorphine tablet administration

Drug and Alcohol Review (2003) 22;4:471-2


Muhleisen P, Spence J, Nielsen S. Crushing buprenorphine tablets.



In Australia, as in most of the research reports, buprenorphine is generally given under supervision of the nurse or pharmacist. As with methadone, there is more supervision for new and unstable patients with take-away dosing permitted to some degree for stable patients after periods in treatment. For example in South Australia up to 5 days may be dispensed in a week with 2 supervised doses after 18 months in stable treatment. In NSW up to two doses may be given per week for those needing daily doses under certain conditions, and for emergencies, travel, etc. Reports from France show that a proportion of doses there are also given under supervision although this is not by regulation but just �good practice�. The issue of whether tablets should be given whole, bisected or crushed is debated.

A report in this month's Drug and Alcohol Review covers this area from a practical perspective from a team which has been using the drug for over 5 years (originally running a trial). This group in Melbourne initially crushed tablets for some patients who they suspected were diverting the drug. Others requested crushed tablets to reduce administration time. Then the Victorian Health authorities, who are not known for their liberal attitudes, nor strong evidence base, advised all buprenorphine to be 'substantially broken or crushed'. Too fine crushing, however, is reported by these authors to sometimes result in a 'powder' which may be swallowed and thus remain largely unabsorbed. Thus crushing can cause problems in the attempt to avoid them.

These authors quote reports of about a quarter of buprenorphine patients attempting to inject their drug on at least one occasion but only less than 5% continuing to do so when they could. This is probably not too different from rates of injecting of methadone syrup.

"Merely crushing doses does not stop diversion or injecting..." <snip>

"Adequate supervision is still the basis of good treatment in this field, and is not replaced by dose-crushing. All professionals involved in the treatment should be diligent in their responsibilities in ensuring that the treatment is safe and effective. Clients who continue to misuse their buprenorphine could be considered unsuitable for treatment with this more expensive and time-consuming drug and an option to minimize potential harm to the client and the treatment itself is to suggest transfer to dosing with methadone, which is still the gold standard opioid substitution treatment."

My personal feeling is that the drug was approved by the TGA in the current tablet forms and most patients should receive the doses in that form. The tablets should only be crushed for good clinical reasons, and then only with the consent and understanding of the patients involved. Otherwise it could be seen as another paternalistic manoeuvre perpetuating the 'them and us' attitude so prevalent in drug clinics around the world.

comments by Andrew Byrne ..

12 December 2003

60 year follow-up of Boston drinkers.

Vaillant GE. A 60-year follow-up of alcoholic men. Addiction 2003 98:1043-1051

Dear Colleagues,

In a staggering feat, veteran alcohol researcher George Vaillant has followed the classic Boston study groups of Glueck & Glueck for up to 60 years from enrolment. These two groups included over 700 citizens either from poor inner city areas or from Harvard University undergraduates, most born in the 1920s. There are significant findings on the natural histories of alcohol abuse, dependence, abstinence and controlled drinking in relation to other medical problems, employment, self-help and mortality. Most importantly there is information on the onset of alcohol problems since the subjects were chosen young and at random. There is some bias since alcoholics are less likely to comply with such research but the differences in responses were not significant in this case.

There is more in this paper than could be included in a brief review. However, the main finding given by Vaillant in his abstract is that despite major differences in the groups in terms of IQ, social background and ethnicity, the main outcomes were very similar in four important domains by age 70. As also found by Drew, chronic alcohol dependence was rare in the older age groups. Controlled drinking was exceptional (1%). Just over half the subjects had died in both groups and around 10% were abusing alcohol (but not dependent) with most of the remainder abstinent.

‘Surprisingly, in both samples, alcohol abuse could persist for decades without remission, death or progression to dependency.’ [of 29 college alcohol abusers 13 surviv(ed) to age 80]. But there were some differences between the groups: ‘The average age of onset of alcohol abuse was a decade later for the college men (40 vs. 30) than it was for the core city men.’

I felt very proud when I completed a ten year follow-up of opiate dependent patients a few years ago. But my achievement is dwarfed by this monumental piece of work in the case of alcohol since Vaillant has now carefully examined outcomes over more than an average adult lifetime of three score years and ten.

comments by Andrew Byrne ..

Oral lofexidine versus naloxone injections for detox. American Journal of Addiction.

The Effectiveness of Combined Naloxone/Lofexidine in Opiate Detoxification: Results from a Double-blind Randomized and Placebo-controlled Trial. Beswick T, Best D, Bearn J, Gossop M, Rees S, Strang J. American Journal of Addiction 2003 12;4:295-305

Dear Colleagues,

This intriguing trial from a London based group gave frequent injections of naloxone to addicts in a detoxification ward.

The authors state that methadone ‘has been the standard treatment for in-patient opioid detoxification’. This may be the case in England but not necessarily elsewhere. There seems to be an assumption that lofexidine (and/or clonidine) are safe and effective in outcomes of opioid withdrawal episodes. Although there are apparently fewer hypotensive side effects with lofexidine (‘Brit-Lofex), a recent study from England, a generation of experience and the absence of a reported black market would seem to cast some doubt on their efficacy in successful heroin withdrawals. Next comes the rather controversial and little-researched use of naloxone in drug withdrawal. These researchers gave most subjects over 30 hypodermic injections, a behaviour which most of us are actively trying to discourage.

After finding that there were no significant differences in overall outcomes in those randomised to receive the antagonist naloxone, the authors come to the surprising conclusion that more research is needed on this treatment modality for those trying to quit heroin. With the increasing use of buprenorphine for detoxification, it would seem almost outlandish to support the use of injectable, short acting antagonists like naloxone.

About half of the 33 references are from the authors themselves which may indicate their pre-eminence in the field of opioid detoxification.

Comments by Andrew Byrne ..

Article on inheritance of addiction in Iran. One in 15 offspring opioid-dependent.

Ahmadi J, Arabi H, Mansouri Y. Prevalence of substance abuse among offspring of opioid addicts. Addictive Behaviors (2003) 28:591-595

Dear Colleagues,

This fascinating study from Iran tells us some basic facts about drug use and inheritance in that population. With major differences with western experience in drug and alcohol use there, the significance for our own populations is somewhat limited.

The authors interviewed 500 randomly chosen adult offspring of 2000 addicts in treatment in Shiraz, Iran. Evidently the average age of those in treatment is much higher than our patients since 28% of their offspring were over 40 years of age and 80% married (but still living under the one roof, a condition of the survey).

The authors remind us of the ‘old tradition of drug use’ in Persia, including opium which is used for pleasure as well as as a medicine. While all these drugs are currently illegal, and penalties severe, drug use and dependency are still common. Even alcohol, which is ‘both religiously and legally prohibited’ has significant reported use and dependency. In the first degree relatives of opioid addicts there was substantial ‘ever used’, ‘current use’ and ‘dependency’. There was no reported use of cocaine or psychodelics. Stimulants were not mentioned.

In short, the findings were that among the offspring of opioid addicts in Iran, 20% had ‘ever used’ opium or heroin and 6.4% were currently opiate dependent. Tobacco was ‘ever used’ by 36% with 24% being currently dependent by DSM-IV criteria. In 95% of the opioid used was opium and 5% heroin. Males greatly outnumbered females for most forms of drug use by up to 9:1. The survey was evenly split, however.

Alcohol was ‘ever used’ by 18.2% and cannabis products by only 4.2%. Thus over half of the population had used a psychoactive drug (56.4%) excluding caffeine.

These researchers asked the respondents the reason for their drug use. ‘Enjoyment’ was the prime answer (57%). Next came ‘modeling’ (50%) [which I take to be something akin to ‘peer pressure’] and then ‘release of tension’ (34%).

In our own patient population in Redfern we have a median age of 37 years. On cursory exmination, we could identify only twelve patients out of 328 from the past three years who had adult children and only two of these had a known drug dependency history. Hence, while this paper shows distinct differences between drug use in different countries, drug use can certainly run in families as with other habits, partially as a result of genetics and partly environmentally induced (see elegant twin studies from Minneapolis St Paul).

Comments by Andrew Byrne ..

Australian national opioid treatment guideline publications August 2003.

Commonwealth Department of Health and Aging. Australian national treatment guidelines (full citations and internet address below) published Aug 03

Dear Colleagues,

Below are the web contacts for the Australian National treatment guidelines which were distributed in December 2003 by the Department of Health and Aged Care in Canberra. There are four volumes, a full and abbreviated version for both methadone and naltrexone. The authors are to be congratulated on a 'generic' set of instructions for the basic approaches to maintenance treatments, regardless of where this may be given.

http://www.healthyactive.gov.au/internet/main/publishing.nsf/Content/phd-illicit-methadone-treatment (old 1997 version)

http://www.health.gov.au/internet/main/publishing.nsf/Content/phd-illicit-methadone-cguide-s (abbreviated version 2003)

http://www.health.gov.au/internet/drugstrategy/publishing.nsf/Content/pharmacotherapy
(link to other guidelines available for buprenorphine, naltrexone, methadone, etc)

Australia’s eight different jurisdictions have eight different sets of treatment rules, from quite liberal (South Australia) to almost barbaric (Northern Territory). However, doctors do not normally have the liberty of giving sub-standard treatment because of the jurisdiction they practice in. According to the British Medical Journal, where there is clear research evidence, doctors are normally required to follow it. Hence, as these Guidelines point out, all Australian opioid dependent residents should have access to appropriate dose levels of the right drug in the right setting. Also, in all community treatment settings there should be some level of take-away dosing available for stable patients as this improves compliance and retention rates, according to these Guidelines. In the absence of regular take-away doses one of the most important ‘incentives’ of supervised methadone treatment is lost and patients may feel condemned to almost daily attendance indefinitely (as apparently sometimes happens in Victoria as well as the NSW public sector clinics). If local rules should impinge on appropriate dosing, they should be addressed and overcome in the interests of making treatment safe, effective and humane (for example the ACT rules on daily methadone doses of over 100mg; the Victorian DOH will allow waivers for take-home doses under certain circumstances if doctors apply appropriately).

An area of major difficulty in these and other guidelines remains induction protocol for methadone. Mortality from overdose in the first week has caused a knee-jerk reduction in starting doses from 40mg to 20mg in some settings. However, there has been no evaluation of this rather dramatic change and it may well have caused an increase in treatment drop-outs. Despite the stated wide variations in methadone metabolism in these guidelines, no clinical protocol is given for determining who is a fast metaboliser and thus may need higher doses. In one paper it is stated that due to variable absorption and metabolism of methadone, “the rate of clearance from the body has been reported to vary by a factor of almost 100” [Ward J, Bell J, Mattick RP, Hall W. Methadone Maintenance Therapy for Opioid Dependence. A guide to appropriate use. (1996) CNS Drugs. 6;6:440-449]. Thus increasing doses by only 10mg per week may take many months to reach optimal levels in some folk who may need 200mg or even more to achieve ‘normal’ or therapeutic blood levels.

There is no substitute for careful clinical assessment and gradual dose adjustments for this drug, as with insulin, digoxin or Dilantin in unstable folk at the commencement of treatment. Perhaps somebody should describe a ‘sliding scale’ for methadone inductions. The American Health Department “TIP” protocols allow up to 60mg on the first day in three divided doses under very close clinical supervision. Few clinics can support the clinical supervision necessary for this, hence 40mg is the usual starting dose in many cases in the USA. Most Australian drug services now apparently use a standard 30mg starting dose in the great majority of cases.

I hope this is of assistance for colleagues involved in methadone and buprenorphine treatments. Naltrexone should only be prescribed for opioid dependency in specialist settings, whereas for alcoholism all primary care physicians should be familiar with it.

Andrew Byrne ..

Clinical guidelines and procedures for the use of methadone in the maintenance treatment of opioid dependence - Abbreviated version (pdf file 176Kb) Date Published: 2003 ISBN: 0 642 82263 8
Author: National Drug Strategy Australian Government Department of Health and Ageing.

19 November 2003

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 ..

18 November 2003

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 ..

17 November 2003

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 ..

11 November 2003

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 ..

5 November 2003

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).

10 October 2003

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.

1 October 2003

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 ..

23 September 2003

Smoking cessation in dependency patients / Therapeutic thresholds in methadone maintenance

Tues 23 Sept 03

Presenters:
Professor Robyn Richmond. "Smoking cessation in dependency patients. What is best practice?"

Dr Richard Hallinan "Therapeutic thresholds in methadone maintenance: resolving the debate over blood levels".



Chair - Dr Bob Elliott.



Dear Colleagues,

We had another informative session at the September Concord dependency seminar when Professor Robyn Richmond from UNSW gave us a preview of the new general practice smoking cessation guidelines and their genesis. She reminded us of the prevalence of smoking in Australians at around 20% of the population, one of the lowest rates in the world. Despite very high smoking rates in the 1950s to 1960s, Australia succeeded in reductions with a combination of advertising bans, education, price policy and treatment availability. Yet smoking is still the biggest cause of preventable pathology and premature deaths in our population.

Around a third of smokers do not want to address their dependency and are 'pre-contemplators' regarding abstinence programs. But this still leaves a substantial proportion of smokers who are amenable to intervention. We now know from careful research that 'brief interventions' actually succeed in terms of yielding more non-smokers in 6 to 12 months, especially when there is active follow-up (see this week's MJA on the subject). General practice is one of the few places where 'opportunistic' interventions such as this can be done when smokers attend for a variety of other reasons, usually unrelated to tobacco addiction.

Professor Richmond told us that good statistics are now available for tobacco use as well as responses to the various evidence based interventions which are being promulgated in the new National Guidelines. On average, about 40% of 'successful' quitters will have taken up the habit again by one year. This emphasises the importance of follow up and preventive measures. We were told that although they may help some people, non-evidence based treatments such as acupuncture or hypnotherapy will not be included in the current guidelines.

As doctors, pharmacists and other health care workers, we were encouraged to inform all our smokers that help was available when they were ready to quit using nicotine replacement therapy (gums and patches) and buproprion tablets (Zyban). Professor Richmond said that there are some new 'commercial in confidence' drugs on the way and we should have even more modalities in the coming years. Nicotine patches can become a longer-term habit in about 10% of cases but this was thought to be overshadowed by the great benefits of the others who often manage to become abstinent for long periods, or even permanently.

We were advised to address smoking from the individual's perspective and ask what people actually found positive and pleasurable about smoking and what they found negative such a cost, health consequences, halitosis, etc. This allowed the patient to focus and reflect on their own habit and its consequences. Some anatomical photographs of lung cancer cases, blocked arteries, etc made good theatrical props and will be included in the package to GPs which are now being trialled.

In the second half Dr Richard Hallinan spoke of taking a history, examination and, occasionally, blood testing for detecting fast metabolizers in methadone maintenance therapy. He spoke of Professor Chin Eap's masterly review of the subject and his finding of a 'threshold' for blood levels which was consistent at around 0.4mg/l. Above this level regular heroin use is exceptional, making dose increases a serious option for those with lower levels, given that there is no clinical toxicity.

Dr Hallinan brought us face to face with a large group of published research relating to the absorption, portal availability, protein binding, hepatic and other metabolism and excretion of methadone. He pointed out the differences between methadone and many other drugs we use in medical practice as well as some of the similarities. He is presently working on a study of left and right stereoisomers of methadone (to use outdated terminology) and will bring us up to speed on that subject, including the new terms at the next seminar.

Summary by Andrew Byrne ..

3 September 2003

Supervised injecting room called for in Redfern

Dear Colleagues,

On Sunday a public meeting was held in Redfern to discuss the need for an injecting room in the area. It was chaired by South Sydney Mayor Tony Pooley and had speakers Dr Ingrid van Beek, Rev Ray Richmond, Rev Bill Crewes and Councillor Shayne Mallard. There were 45 people in attendance including representatives of the communities, Aboriginal Medical Service, local pharmacy, housing and local residents from Waterloo, Redfern and 'the block'.

There appeared to be no opposition to the concept of an injecting room but some lively debate occurred on where it might be located and how the police might react to it all. Police Service support for the Kings Cross injecting facility has been instrumental in its success.

Dr van Beek and other speakers were at pains to state that the lessons from Kings Cross did not necessarily translate directly to other areas where needs may be different. They had proved that such a service could operate successfully without disrupting the local community or business. Support had actually risen significantly during the 2 years of the trial according to independent polling (from 68 to 78% among residents and 58 to 63% for businesses). Apparently, only 1% of over 200 businesses polled reported adverse effects due to the injecting centre.

A resident from Eveleigh Street spoke passionately of the 'village' atmosphere which is potentially poisoned by the constant visible drug dealing and using. A man from Wilson Street also supported the injecting room concept to 'disconnect' the 'normal' use of needles seen by local children all around them. It was stated that there had been over 100 deaths in the Eveleigh-Abercrombie-Cleveland Street triangle in the past 3 years. It was debated just how many of the users were locals and what proportion were from Aboriginal backgrounds. Then it was generally agreed that they were all using drugs in our area and thus a local facility stood to help both the users and the local community, regardless of the backgrounds or origins of the users involved.

Most informed discussion since the release of the independent report into the Kings Cross "MSIC" has been very positive and it has been granted almost permanent status with another 4 year licence extension this week. Some debate has occurred on just how many deaths were prevented and at what cost. Such debate should focus on how to save more lives and how to be more cost effective in service delivery, yet some commentators have taken the consistent stand that it should be closed forthwith! Gross differences between the 'average' Australian drug user and the folk who use the trial injecting facility would seem to invalidate simple statistical comparisons.

I visit the Kings Cross injecting centre each week and have been struck by the 'ordinary' nature of its operation. Despite the rather brutal and potentially dangerous injecting behaviour which goes on in private in the 'middle' room, the entry assessment and waiting areas are always pleasant and businesslike with an almost complete lack of tension, high spirits or confrontation. The staff are invariably patient and yet firm with the assessment process which takes between two and ten minutes. After declaring what drugs they intend to use and when their last injection was, patients/clients may inject under supervision of nursing staff. The staff may give advice on injecting practices, vein care or other health matters, but they may NOT assist with actual injecting. Drug 'sharing' in the facility it not permitted.

The results speak for themselves and it is to be hoped that a consensus will be found for an injecting facility for the many people at risk as well as the community of Redfern and adjacent suburbs in the very near future. There seemed to be a general agreement at the public meeting on 31 August that such a medically supervised service should be within easy walking distance of 'the block' but probably not on 'the block' itself. This leaves the streets close to busy Redfern Station (10 tracks plus subway) as the most likely contenders. It would be no coincidence that a successful injecting facility would again be close to a hub of transport where it seems to disrupt other business less than the drug dealing and public using which is already going on, almost unchecked. I live one short block from the Kings Cross facility and it has improved matters for local residents here without doubt.

It is no longer possible to argue against the concept of injecting facilities without undervaluing the lives of drug users. They have been used for up to 15 years in several countries and they constitute one useful strategy to stem the toll from drug use in our society. Some of the victims of drug overdose are occasional or relatively recent users who may not be amenable to any other intervention and some may not even be addicted. Overdose death is the most recognisable complication of drug use but for every overdose death, we know that there is a proportionate number of non-fatal yet serious complications as well as viral infections from unclean injecting practices and the crime, poverty and ill health which accompanies street drug use.

Comments by Andrew Byrne ..

8 August 2003

Smoking cessation randomised controlled trial using gums, clonidine or naltrexone

Ahmadi J, Ashkani H, Ahmadi M, Ahmadi N. Twenty-four week maintenance treatment of cigarette smoking with nicotine gum, clonidine and naltrexone. J Subst Abuse Treat (2003) 24;3:251-255

Dear Colleagues,

This paper describes a simple three-way pharmacotherapeutic intervention for smoking cessation using nicotine gums, clonidine or naltrexone. In three randomised groups each of 60 would-be quitters, these researchers gave double blind treatments to see how many folk dropped out and how many managed to abstain from smoked nicotine over a six month period.

The results are of great interest and relevance to clinical practice, confirming some things we believed and showing some other novel findings. After 24 weeks of the study, abstinence rates were 37% for the nicotine gum group, 19% for the clonidine group and 5% for those given naltrexone, each finding being significantly different from the others.

The authors state that this supports the use of NRT (nicotine replacement therapy) and at the same time questions the utility of naltrexone for smoking cessation, which had mixed reports from previous literature reports.

The rate of significant side effects was 42% in those on NRT, 32% for clonidine and 84% for those taking naltrexone tablets (50mg daily). These were largely headache, GI upset, and sleep disturbances. Some of the 'side effects' may have been nicotine withdrawals.

It would seem that naltrexone has been tried for many conditions including anorexia and bulimia. I have prescribed it with consent for severe cannabis dependence patients with mixed results. Despite its consistently good results with alcoholism, other substance or behavioural disturbances seem less amenable to its antagonist effects.

comments by Andrew Byrne ..

Heroin trials - old and new.

HEROIN TRIALS - AN ABRIDGED HISTORY - AND A DUTCH ADDITION.

van den Brink W, Hendriks VM, Blanken P, Koeter MWJ, van Zwieten BJ, van Ree JM. Medical prescription of heroin to treatment resistant heroin addicts: two randomised controlled trials. BMJ 2003;327 310-0

Dear Colleagues,

It is fascinating to track the history of heroin prescription over the past 25 years. We first find an English report in an American journal. Next, almost 20 years later came another English description in an Australian journal. After that the major Swiss trials were reported in Anglo-American journals while this latest Dutch trial is in the BritishMedical Journal. It is indeed a global problem.

Most of these trials took treatment resistant heroin addicts and permitted pharmaceutical heroin to be injected with supervision under trial conditions. Some used comparisons with methadone but one used a six month delay as a 'chronological control' group. Patients were permitted realistically high doses of heroin, consistent with their pre-treatment street use, up to one gram daily. There were small trials of 30 to 50 patients such as Perneger and Hartnoll, while the main Swiss trial enrolled 1146 subjects.

There was a practice of prescribing morphine and heroin to addicted patients in the US, England and probably Australia prior to the 1940s but records have been lost and details are mired in history and even mythology. The Swedish prescribing of stimulants in the 1960s was similar in some ways. There appeared to be no prominence of adverse reports from coroners or others at the time but little else can be gleaned from a scientific stand point. There were reports of rapid opiate detoxification (bromides) under sedation from Hong Kong in the British Medical Journal of 1899 and at least one death was reported from that era.

The report by van der Brink and colleagues in the British Medical Journal describes 550 methadone patients who were still using illicit heroin in 6 Dutch cities. They were randomised either to remain in methadone treatment or to receive heroin (injectable if they usually injected, inhaled powder if they normally inhaled - making two separate trials). Despite being allowed up to a gram per day in three divided doses, patients chose to take only half that in an average of 2 daily supervised doses. The mean methadone dose was around 70mg daily, with a maximum permitted of 150mg. Although higher than average doses in some areas, this was probably still inadequate, just as occurs with methadone patients in every country.

Follow-up rates were as high as 95%. Outcomes of numerous aspects of social, mental and physical integration were examined by independent researchers using a modified Addiction Severity Index (ASI). Improvements were marked in both groups but almost twice as much in the groups permitted heroin as well as methadone (~45% vs. ~25% 'response' rate = 40% improvement in ASI). The differences were significant. The rather unfortunate end to the trial was a compulsory 2 months without prescribed heroin, during which the good progress was reversed.

Those decrying a heroin trial in Australia are just delaying the inevitable while the consequences of unchecked drug use cause untold damage to the security and prosperity of our community. There has been no report of increased drug addiction or other adverse sequelae of drug use in regions where heroin has been prescribed. Also, in the largest and longest controlled trial in Switzerland, only a small expansion has occurred, disproving any 'floodgates' effect. Politicians should note that a referendum on such policies was resoundingly successful, especially in the older age groups.

Comments by Andrew Byrne ..

Hartnoll RL, Mitchelson MC, Battersby A, Brown G, Ellis M, Fleming P, HedleyN. Evaluation of Heroin Maintenance in Controlled Trial. Arch Gen Psychiatry1980 37:877-84.

Metrebian N, Shanahan W, Wells B, Stimson GV. Feasibility of prescribinginjectable heroin and methadone to opiate-dependent drug users: associatedhealth gains and harm reductions. 1998 Med J Aust 168:596-600

Perneger TV, Giner F, del Rio M, Mino A. Randomised trial of heroinmaintenance programme for addicts who fail in conventional drugtreatments. BMJ 1998;317:13-18

Ali R, Auriacombe M, Casas M, Cottler L, Farrel M, Kleiber D, et al.Report of the external panel on the evaluation of the swiss scientificstudies of medically prescribed narcotics to drug addicts. Sucht1999;45: 160-70

Rehm J, Gschwend P, Steffen T, Gutzwiller F, Dobler-Mikola A,Uchtenhagen A. Feasibility, safety, and efficacy of injectable heroinprescription for refractory opioid addicts: a follow-up study. Lancet2001;358: 1417-20

Haemmig RB, Tschacher W. Effects of high-dose heroin versus morphine inintravenous drug users: a randomised double-blind crossover study. JPsychoactive Drugs 2001 Apr-Jun;33(2):105-10

Spanish group's experience with naltrexone implants.

Spanish group's experience with naltrexone implants. 'AddictionBiology' report.

Maintenance treatment with depot opioid antagonists in subcutaneousimplants: an alternative in the treatment of opioid dependence. Carren JE,Alvarez CE, San Narciso GI, Bascaran MT, Diaz M, Bobes J. Addiction Biology(2003) 8, 429-438

Dear Colleagues,

In this paper a group of Spanish naltrexone enthusiasts report on 156patients, nearly all male, who were treated with a rapid opioiddetoxification process followed by a naltrexone implant. It is due to the‘open’ policies of the editors of Addiction Biology that they are preparedto publish such papers. Research of this nature would be unlikely tosurvive the strict new ‘Farmington’ editorial rigours of the NAC ‘sister’journal, Addiction, edited by Griffith Edwards.

These researchers’ main finding is a two year follow-up with 4 six-monthlyretention rates of 80%, 65%, 55% and 21% “all of them remaining abstinent toopioids.” “It is concluded that the programme is safe for the patients andshows a better retention index than programmes using oral antagonists, withan improved compliance (negative urine analysis) compared to the latter.”Thus, although 80% of patients are lost to follow-up the authors seemconfident to report comparative results.

The authors also allow us to compare these naltrexone treated patients withthose prescribed methadone. Their reported statistics show only very minordifferences in social, drug use and other demographics over the 24 monthsfrom starting the treatment. This is in stark contrast to methadone andbuprenorphine patients who generally report dramatic and sustainedimprovements in employment, housing, drug use and criminal statistics afterjoining treatment. Indeed, despite finding a worrying increase in alcoholconsumption (mean 50%) over the period, the Spanish authors do not address this.It is also unfortunate that the authors of this naltrexone study do not givetheir specific clinical indications for the use of an experimental treatmentin preference to methadone or buprenorphine treatments which are the normal ‘gold standards’ for unstable opiate addiction in most western countries. At one point they give the feeble and almost embarrassing information thatnaltrexone is beneficial over methadone because it has no drug interactions,apart from the obvious one (the effects of opioids are negated in patients on naltrexone).

In our practice we have prescribed naltrexone to many patients over the years with a small number doing well for limited periods taking the oral formulation. Our indication for the use of naltrexone is for stronglymotivated patients seeking abstinence and who have faired poorly on agonist treatments. There is also a proportion of addicts who refuse to takemethadone and buprenorphine but their success rates on naltrexone do not seem to be any better than the others, the majority relapsing after stopping the medication, whether oral or implanted.
There may be sub-groups who do well with naltrexone but as long as research is done by ‘enthusiasts’ for the treatment in an undiscriminating manner, we will never learn what those subgroups are. Only randomised controlled research can resolve this question and the few such trials that there are to date using naltrexone are not encouraging for its use in non-selected opioid dependent patients.

Comments by Andrew Byrne ..

BMJ report on less methadone ampoules/tablets but more oral liquid prescribed over 12 years

Strang J, Sheridan J. Effect of national guidelines on prescription of methadone: analysis of NHS prescription data, England 1990-2001 BMJ (2003) 327: 321 - 322

Dear Colleagues,

This intriguing item claims to examine the results of published English clinical guidelines yet it only examines 2 minor outcomes, and then not how these were achieved. On examining NHS prescriptions the authors found that the use of methadone tablets and ampoules had dropped by around 50% in a decade. Without examining clinical details, they assume that both of these outcomes were favourable, and that further, the changes were necessarily a result of their own published dependency guidelines which were circulated to GPs in 1996 and in 1999 (see title of article). The number of prescriptions for methadone overall increased, each year, albeit unevenly, tripling over a 12 year period to 2001. We are not told the duration of such prescriptions, nor what proportion of patients were in continuous maintenance treatment or detoxification regimens.

The same issue of BMJ contains a positive descriptive item on prescribed heroin from Holland, so injectable methadone may equally have a place in legitimate clinical practice. It was reported that less than 10% of all treatment in England utilises injectables. Methadone tablets, likewise, may have a useful if small place in dependency treatment where other measures have failed. Hence a blanket edict against such treatment may not be appropriate, despite neither tablets nor ampoules being standard, evidence-based approaches.

It is disappointing that these veteran researchers, while giving a small glimmer of potentially good news, ignored an examination of the dose levels on these prescriptions as well as the degree of supervision given, or not given. Their own guidelines recommend 60mg as a minimum effective daily dose for most patients, yet it is said that *average* doses in England are below 50mg daily. Very little methadone in England is taken under supervision, although the words ‘supervise’ or ‘supervision’ are used up to 50 times in the ‘Orange Guidelines’, written by a panel chaired by Strang.

Many pharmacists in Scotland now regularly supervise methadone doses as recommended in Strang’s highly regarded guidelines. It is possible that the Scots even go ‘too far’ in daily dose supervision, just as English pharmacists seem to avoid it altogether for obscure reasons. The nature of addiction involves a lack of control over drug use, thus making supervision an important plank of any treatment strategy. It is disappointing that the originators of these impressive dependency guidelines have still not stated in unequivocal terms that their many English colleagues are systematically undermining good clinical work by ignoring evidence and giving poor quality treatment to their patients. In certain cases it may be worse than giving no treatment at all. Improved treatment would simply require endorsing prescriptions with a careful but adequate dosing schedule - and a request for a certain proportion of doses to be ‘supervised’.

Comments by Andrew Byrne ..

7 July 2003

Benzodiazepine dependence - randomised reduction study.

In-patient benzodiazepine withdrawal: comparison of fixed and symptom triggered taper methods. McGregor C, Machin A, White JM. Drug and Alcohol Review (2003) 22:175-180

Dear Colleagues,

This group from Adelaide University has come up with yet another instructive study of great clinical relevance. Benzodiazepine dependence has been neglected for too long. Considering the substantial profits made by drug companies it is disappointing (cynics may say predictable) that so little funding has been given to the potential for harm from benzodiazepines in vulnerable populations such as the elderly and recreational drug users.

The authors remind us that although many treatment agencies give supervised tapering doses of diazepam, this procedure has not been systematically evaluated. As with nicotine, opiates and even stimulants, such therapeutic substitutions and subsequent reductions can be a feasible way of addressing dependency management. Longer term drug maintenance is a 'fall back' position, generally using long acting, oral forms with low toxicity, in cases where reductions repeatedly result in relapse.

This study showed no significant differences between those given fixed reductions versus symptom initiated dosing with diazepam. The intervention demonstrated numerous positive outcomes at one month follow-up in such poly-drug users up to a month after treatment. Patients had used a spectacular daily mean 'Valium-equivalent' of 115mg or 23 tablets! Two thirds were using more than one type of sedative on the week of admission. At least half of the 44 subjects were also opioid habitu├ęs. The mean hospital stay was 5 days, with subsequent tapering doses offered as outpatient treatment. At the end of one month, sedative use had declined dramatically from previous levels.

We know from the British 'NTORS' research and other opioid studies that even poor quality, non-evidence-based treatments can yield positive outcomes. Hence there still needs to be much more comparative work with benzodiazepine addiction. In the meantime, either of the treatments offered in this study would seem to be appropriate, safe and effective, at least in the short term. The fixed dose regimen started with an estimated equivalent up to 80mg diazepam daily in four divided doses, reducing at 10mg daily down to 40mg and by 5mg daily thereafter. Although supervised consumption is preferable, excessive supervision may cause patients to drop out. Also, hospital admission is neither acceptable nor necessary for the majority in community practice.

In our own practice, we have found that daily attendance with supervised dosing is suitable for patients whose drug use is chaotic. Later, second or third daily attendance can suffice as patients demonstrate features of stability. A small proportion seem to need to continue daily doses of diazepam indefinitely. Some may have pre-existing anxiety or panic disorders and a proportion may have unacceptable withdrawal symptoms. This distinction may become blurred with time, but the required treatment may be the same for either diagnosis.

comments by Andrew Byrne ..

Buprenorphine comparison office-based vs. clinic no differences!

A comparison of buprenorphine treatment in clinic and primary care settings: a randomised trial. Gibson AE, Doran CM, Bell JR, Ryan A, Lintzeris N. MJA 2003 179;1:38-42

Dear Colleagues,

This trial of buprenorphine for heroin addiction has shown for the first time, to my knowledge, that agonist treatment can be given in primary care settings with results equivalent to those obtained in specialist clinics when patients are randomised at enrolment.

These researchers randomised 115 consenting heroin addicts who were seeking detoxification and offered them a 5 day course of buprenorphine in community practice or clinic practice. After two days without medication (days 6 and 7), they were given an option to transfer to maintenance therapy on day 8.

About 75% of patients returned at day 8, and one third of them chose to have no further drug treatment. Of the other two thirds, all but 4 chose buprenorphine maintenance (2 went onto methadone while another 2 chose naltrexone). It is to the credit of these researchers that of the 64/115 (56% of original group) who started maintenance, 40 (35%) remained in treatment at 3 months. This is a derived retention rate of 62% for continuing patients by my calculations.
There were no significant differences in any of the measures between the primary care group and the clinic group. Costs were also similar. The medication was administered in the doctors' offices for the primary care cases and at the clinic dispensary for the clinic patients during the detoxification phase (doctors are permitted to administer S8 drugs 'in the normal course of medical practice' as long as they comply with appropriate local legislative requirements for documentation, etc). For the maintenance phase, prescriptions were filled at community pharmacies where patients paid $25 per week, contrasting with the clinics which were free of charge, making the outcomes for primary care even more impressive. There must be some doubt about some of the authors' derived conclusions regarding comparative costings owing to the necessarily approximate nature of the figures between private and public sectors.

The nature of this trial was rather unusual as it offered subjects the prospect of one thing (opioid detoxification) but ended up by giving most subjects quite the opposite (opioid maintenance). The rationale behind this 'ruse' was not discussed although the consent included the possibility of maintenance if detox was not succeeding. It meant that although, by definition, all maintenance patients had 'failed' at their initial goal, their maintenance treatment was evidence based and very likely life-saving, unlike detoxification. Further, maintenance is, or should be, a flexible treatment which can be given by GPs and community pharmacists.
http://www.mja.com.au/public/issues/179_01_070703/gib10877_fm.html

comments by Andrew Byrne ..

6 June 2003

Twin study fails to prove 'gateway' hypothesis. Australian researcher in JAMA lead article.

Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls. Lynskey MT, Heath AC et al. JAMA 2003 289:427-433

Dear Colleagues,

Twin studies can be informative in causation theories. These authors state that in addition to having close or identical genetic make-up: ".. twin pairs, having been reared in the same household, would be expected to be highly concordant for environmental experiences." Thus most twins are exposed to alcohol, tobacco and other drugs at much the same age.

In their lead item in JAMA, Lynskey et al. find that for the exceptional minority of twin pairs (~300 out of 4000) in whom 'cannabis use before age 17' was discordant, that subsequent reported drug abuse/dependency was 2 to 5 times more prevalent in the early cannabis users. The authors find that this association lends weight to causation while admitting it is 'not possible to draw strong causal conclusions' of the 'gateway' theory. It is intriguing that they would address causation when this is a retrospective, cross-sectional study, a design which is not able to determine causation.

Since twins who used cannabis in the same year were eliminated, conclusions based on their similarities of upbringing must be guarded. These twins demonstrated at least one major difference in their environment and/or decision making on at least one occasion during adolescence. Whatever caused this may also explain the higher reported rates of other drug use, quite independent of any theoretical 'chemical priming' or 'gateway' effect.

These results are all derived single follow-up telephone interviews with an unknown party over matters relating to illegal drug use, child sex abuse and other personal issues up to 15 years earlier. Some may have chosen to (falsely) deny childhood cannabis use and then to also deny adult abuse or dependency. Others may have had faulty recollection for such distant events, making the findings less secure.

A certain minority of young people use hard drugs prior to using cannabis (around 1 - 2% from household surveys). Such subjects should be of considerable interest to those addressing the so-called 'gateway' theory. Lynskey et al. however, having found that up to 17 of their subjects used hard drugs before being exposed to cannabis, chose to exclude them from their study.

Another problem with this study is that the drug abuse/dependence findings are so high that they may indicate an atypical sample. For 'any illicit drug abuse/dependence' the prevalence was 33-48%; for 'alcohol dependence' it was 30-43% ['non cannabis by age 17' group first percentage followed by 'early users group' %]. Alcoholism is only thought to affect around 5% of adult males in the general population.

The authors state that their findings "..were consistent with early cannabis use having a causal role as a risk factor for other drug use and for any drug abuse or dependence." But further, they state: "While the findings of this study indicate that early cannabis use is associated with increased risks of progression to other illicit drug use and drug abuse/dependence, it is not possible to draw strong causal conclusions solely on the basis of the associations shown in this study." A 'causal' link between early cannabis use and later hard drug use remains unlikely on balance (National Academy of Science review) - and it is hard to imagine that a study of this nature could clarify the issue, no matter how well it was performed and analysed.

An associated editorial by Kandel teases some of the matters out while still seeming to assume that all cannabis use is problematic and needs to be discouraged by any effective means. Her own work from 19 years ago showed the strong association between alcohol/tobacco and illicit drug use.

Kandel indicates three factors necessary to prove the gateway hypothesis: (1) sequencing, (2) association and (3) causation. As she points out, the third is the hardest to prove.
In discussing the modern calls for prescribed cannabis, Kandel states that there is no empirical knowledge on whether medical cannabis will lead to problems. But cannabis products were widely prescribed in the first half of the 20th century without apparent problems arising (eg. tincture of cannabis). She says that it is a 'curious phenomenon' that morphine used for medical purposes 'does not lead to addiction'. Could it be equally 'curious' that medical cannabis does not do so either?

And unlike Lynskey et al., Kandel does not address the known non-chemical associations between cannabis and hard drug use. Having found from personal experience that drug education about cannabis was unreliable, young people may then reason that information about heroin and cocaine being dangerous is also unreliable. Similarly, having broken the law on cannabis, they may then have less compunction about breaking laws relating to other drugs. There is at least anecdotal evidence that some heroin addicts first used heroin when their dealer could not supply cannabis, amphetamine or other drugs of current choice. To his credit, Lynskey writes: ".. access to cannabis use may provide individuals with access to other drugs as they come into contact with drug dealers. ... [Dutch decriminalization of cannabis] may have been partially successful as rates of cocaine use among those who have used cannabis are lower in the Netherlands than in the United States." [One wonders what criteria the authors would need for 'complete' success of Dutch cannabis policy!]

Comments by Andrew Byrne ..

Citations:

Lynskey MT, Heath AC, Bucholz KK, Slutske WS, Madden PAF, Nelson EC, Statham DJ, Martin NG. Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls. JAMA (2003) 289:427-433

Kandel DB. Does Marijuana Use Cause the Use of Other Drugs? JAMA (2003) 289; 4: Editorial

5 June 2003

Flumazenil infusion for benzo addiction - still experimental but promising.

Intravenous flumazenil versus oxazepam tapering in the treatment ofbenzodiazepine withdrawal: a randomized, placebo-controlled study. Gerra G,Zaimovic A, Guisti F, Moi G, Brewer C. Addiction Biology 2002 7:385-395

This small randomized, placebo controlled study lends weight to the use ofintravenous flumazenil in the reversal of tolerance to benzodiazepines. Ina well designed study involving 50 patients addicted to benzodiazepines theauthors infused 2mg of flumazenil over 8 hours each day for 8 days in a daycare hospital setting. Twenty such patients were compared with another 20given oxazepam taper with saline placebo and another 10 given placebos ofboth.

Some of the effects of benzodiazepines were reversed almost immediately (eg.balance test performed each day on the subjects) while the modest dosesgiven for night-time sedation (15mg oxazepam) for 3 days were very effectivein inducing sleep, unlike the patients' previous experience which hadinvolved very much higher doses of flunitrazepam, bromazepam, etc. It appeared that the flumazenil reversed the tolerance to benzodiazepines evenfrom day one. There was no increase in anxiety symptoms and convulsions didnot eventuate, perhaps due to some intrinsic agonist activity of the drug.A previous study had shown re-emergence of panic symptoms in some patientswith a previous history but this involved the drug being infused over 5minutes and not 8 hours.

Most impressive, the patients all appeared to be fully detoxified whilerelapse occurred in only half the patients given the flumazenil whencompared with those on oxazepam taper. The relapse rates at days 15, 23 and30 were 25/55%, 30/60% and 40/70% in flumazenil vs. oxazepam taper groups.These results are impressive but need to be confirmed before being accepted.More research is certainly warranted in this difficult area as there iscurrently no single accepted management strategy for benzodiazepineaddiction.

The authors make much of receptors and GABA allosteric effects in theirdiscussion. However, this is a clinical paper and such speculation probablybelongs elsewhere. However interesting they may find it, the authors reallyhave no idea why the drug did what it did as far as I can read and themechanisms are only of distant relevance to the patients involved.

There is a very comprehensive list of references relating to the use offlumazenil for benzodiazepine addiction, from 1986 with animal studies andto controlled studies, observational work and opinion pieces since.

comments by Andrew Byrne ..

other reference:Mintzer MZ, Stoller KB, Griffiths RR. A controlled study offlumazanil-precipitated withdrawal in chronic low-dose benzodiazepine users.Psychopharmacology (Berlin) (1999) 147:146-50