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 ..

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 ..

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 ..

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 habitués. 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 ..

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

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