Benzodiazepine use in dependency patients

26th July 2005

Presenters:

Richard Hallinan and Andrew Byrne, Redfern Dependency Practice

Richard Hallinan and Andrew Byrne, who are both committed to best practice in dependency medicine, presented this useful seminar on benzodiazepine use. The session began with an overview of the pharmacology of benzodiazepines, and some relevant comparisons were made with alcohol, opiates and major tranquillisers. Differences between the various benzodiazepines particularly in relation to half-lives were outlined, and indications, side effects, tolerance and withdrawal were all discussed. A handout was available detailing all of these points.

Special mention was made of benzodiazepine (BZD) use by patients on methadone maintenance treatment (MMT) and it was noted that this group of people often have particularly high levels of psychopathology and psychosocial distress, including higher rates of unemployment, incarceration, HCV, and HIV/HCV risk-taking behaviour. BDZ users on MMT also tend to be on higher methadone doses and to have higher blood levels, although methadone concentrations adjusted for dose are actually lower in this group. The reason for this is unclear as there is no evidence that diazepam increases the clearance of methadone. One hypothesis is that there is a tendency for rapid methadone metabolisers to seek BZDs, in which case split methadone dosing might be useful. It may also be that these people are self-medicating, or "just can't get enough of a 'good' thing".

An approach to BZD abuse in MMT patients was outlined. It was suggested we make sure that psychopathology (eg anxiety and depression) is adequately treated, alcohol problems are addressed and information obtained from the Doctor Shoppers Hotline in appropriate cases. Consideration should be given to moving from short to long acting forms of which diazepam is the most common. Also, supervised dispensing should be considered where 'control' or impulsivity are problems. It is also essential to optimise the methadone dose, being flexible about dosing times or, occasionally, split-dosing (which needs prior approval from the PSB).

Reasons for BZD use were outlined, and are important to understand when looking at treatment options. People take BZD for many reasons, including alleviation of anxiety and insomnia, self-medication of depression, self-medication of withdrawal from opiates and BZDs, to come down off stimulants, and to get an increased "buzz". So-called "Poly-drug users" swap from one drug like speed or heroin to another such as BZD, and may simply do this because BZDs are the cheapest or most available drug at the time. It was noted that BZDs in Australia are subsidised on the PBS, whereas they are very expensive and hard to obtain in the U.S. so it is no surprise that their use amongst the marginalized in the USA is far less.

Aims of treatment of BZD dependence were clarified within the overall context of harm reduction goals. This includes abstinence and it was pointed out that harm reduction has sometimes erroneously been seen to include legalizing drugs, which while worthy of discussion, is quite a separate issue. Our first dictum should be "Do No Harm" and we shouldn't forget that an important part of this is just saying "no" when appropriate.

When assessing a patient for treatment we need to understand their personal history of abstinence, by asking questions such as "when were you last abstinent?", "how many times have you achieved abstinence?", "how did you become abstinent?", and "what did it feel like when you were abstinent?". We need to understand that previous abstinence may not necessarily have been a happy and stable time for every patient.

It was pointed out that the statistics regarding measurement of harm relating to BZD use are limited, but nonetheless worrying. Doctors must weigh the harms and benefits of BZDs both in the community and in individuals (as we do with all other prescribing). PBS prescribing figures reached a peak in 1988 and have fallen since then. It is well accepted that some people function well on a small dose of diazepam, so this drug may have a useful place in legitimate treatment plans. It is gratifying that in Australia, appropriate regulation has seen the end of temazepam capsules, along with Mandrax (methaqualone and diphenhydramine), meprobamate (Miltown), bromides, barbiturates and high dose flunitrazepam, which have all vanished from scene.

Harm from BZD dependency was discussed, and includes an array of physical, social and behavioural disturbances. Special mention was made of the damage to nerves and blood supply when subjected to pressure for prolonged periods of time. This scenario can occur with overdose and increased use which leads to long periods of reduced consciousness in fixed positions. Nerve palsies, skin necrosis and the compartment syndrome can occur. Thrombosis and infections from injecting, criminal activity including prescription fraud, convulsions from withdrawals, and deepening of depression are all possible consequences of BZD use. Rates of domestic violence are probably parallel with alcohol abuse.

Treatment approaches to BZD use rely on an accurate diagnosis, which should depend on a detailed history with relevant physical examination. Urinary drug screening can be useful, along with information from pharmacists and reports from HIC services. Some unusual features of benzodiazepine users were noted, including possession of a Medicare card with a high terminal digit (8 or 9), fiddling with the position of furniture within the consulting room, talking to the GP with great familiarity and requesting the drug by specific name. The assessment of BZD use should parallel that which is done for opiate users, including the level of dependence and addressing resultant medical and social harms. Co-existent mental health issues should be treated and methadone treatment at optimal dosage. As with all other drug use, there is a spectrum of patterns of use, including non-dependent occasional use, irregular binge use, dual dependency (eg with opiates) and "pure" BZD dependency. It may be useful for the patient to keep a drug diary, as memory may fail in this patient group.

If considering regular prescribing of BZD with a view to abstinence, there are some useful "check-list" questions we can all ask ourselves. They include: "What alternative strategies has the patient tried?", "have I seen their drug diary?", "what is their motivation for abstinence?", "have I seen a UDS result?", "have I sought information from the HIC hotline?", "are they on optimum doses of methadone or pain treatment?", "is treatment for mental health conditions adequate?"

Prescribed BZD must be tailored for the individual, but it was emphasized that slow reductions in doses may take months in established dependency. It is unrealistic to expect a patient with long-term BZD dependency to be able to maintain abstinence following a 2-4 week reduction regime. Diazepam is the preferred BZD to use for reduction regimes owing to its long action and familiarity. Several case histories were discussed to help illustrate management plans.

Australian Health Insurance Commission (HIC) services were also discussed. There are two separate services: firstly, "Prescription Shopping Information Service". Doctors must first register if they wish to access any information. Doctors are given a PIN number, and can find out information on numbers of BZD PBS prescriptions and numbers of doctors seen, above a certain threshold. No information is kept on private prescriptions. Toll-free phone is 1800 631181. The second HIC service is a "voluntary agreement" print-out of PBS items available after the patient signs the consent form. Forms available from 1800 420074. These services may be useful not only because of the information they provide, but because patients know their doctors can access certain information about their BZD use.

The meeting ended after some complex but somehow familiar case histories with lively discussion about the various possible approaches.

Dr Jenny James. Daruk AMS.

Hep C in dependency patients: prevalence and outcomes

Hepatitis C virus prevalence and outcomes among injecting drug users on opioid replacement therapy. Hallinan R, Byrne A, Amin J, Dore GJ. J Gastro Hepatology 2005 20;7:1082-1086

Dear Colleagues,

This item from our own surgery shows that of 178 injectors on methadone/buprenorphine maintenance treatment, 75% tested positive for hepatitis C (HCV) antibodies. Of 130 untreated HCV cases, 53% had normal ALT enzyme levels and half of these were HCV-RNA negative, indicating probable viral clearance.

Older patients on methadone/buprenorphine were significantly more likely to have normal ALT levels and to be HCV-RNA negative. This might be explained by low levels of injecting and hepatitis C re-infection in this group.

Younger patients were less likely to have hepatitis B (HBV) immunity through vaccination or exposure, pointing to the need to target this at-risk group effectively for catch-up vaccination.

Of 58 active hepatitis cases meeting pre-liver biopsy criteria for subsidised HCV treatment, 34 had relative contraindications to antiviral treatment, including drug and alcohol/psychiatric reasons. There were 11 whose only contraindication was continuing to inject. Recent studies show that patients with active injecting drug use can still be successfully treated with HCV antivirals.

At the time of this clinical audit only 6 patients had ever been referred for specialist HCV assessment, however since the end of the study the rate of referral has increased considerably and several patients have completed or commenced HCV treatment, some in the primary care interferon prescribers project of the Australasian Society for HIV Medicine (ASHM).

This study emphasises a unique public health opportunity. The emerging epidemic of hepatitis C is occurring predominantly in the drug using population, thus detection and referral should be possible at methadone clinics, GPs, pharmacies, needle services and injecting rooms frequented by this population. Hence, despite the enormous looming problem of active hepatitis, liver failure and cancer, it is possible that early detection and treatment could avert many of the consequences and save health funds in the long term.

We believe that it is incumbent on all those who treat drug addicts to ensure that their patients have HIV and HCV testing at least annually, and recommend HBV vaccination where appropriate. This is as fundamental as doctors doing cervical cancer smears at certain intervals in appropriate women in the course of normal community practice.

Comments by Andrew Byrne ..

Buprenorphine, heroin drought, heroin prescription.

Foetal withdrawals with buprenorphine; uptake of buprenorphine in America; Australia's heroin 'drought' revisited; Barcelona death rates confirm protective effects from methadone;

Dear Colleagues,

From the plethora of publications on dependency recently I report on a number of items below so that readers may pick what might be relevant to their own practices, starting with a RCT of buprenorphine (pure) in pregnant women and results of foetal withdrawals.

Jones HE, Johnson RE, et al. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug and Alcohol Dependence (2005) 79;1:1-10 (Ref 1)

This shows favourable outcomes in 10 women and their babies on buprenorphine compared with 11 on methadone (randomised, double dummy trial). The proportion receiving medication for neonatal abstinence syndrome was lower in the buprenorphine and the doses used were lower (neither significantly due to the small numbers). Hospitalization period was significantly shorter in the buprenorphine treated subjects/offspring. This is yet another report showing the safety of buprenorphine in pregnancy. It is sensible that the combination drug was not used in these women. The best 'evidence' for the safety of buprenorphine in pregnancy comes probably from a lack of reports of serious foetal or maternal problems from France where the drug has been freely available from GPs for a decade.

Sullivan L, Chawarski M, O'Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Drug and Alcohol Dependence (2005) 79;1:113-116 (Ref 2)

This piece attempts to categorize some characteristics of 96 buprenorphine prescribed addicts in America in comparison with 94 entering methadone maintenance at the same period. While not a piece of controlled research, it does indicate that methadone is more likely to attract previous methadone recipients while buprenorphine attracts a higher proportion who have never had methadone (or other maintenance) treatment.

Degenhardt L, Day C, Dietze P, Pointer S, Conroy E, Collins L. et al. Effects of a sustained heroin shortage in three Australian States. Addiction (2005) 100, 908-920 (Ref 3)

This is the latest and probably most comprehensive description of the so-called heroin 'drought' or shortage starting in early 2001 in Australia. There are detailed figures for crime, treatment entries, street prices, etc from three states. While NSW saw a temporary increase in crime, this was not seen in other states. The most dramatic effect was on overdoses which dropped by up to 75% from their high points around 1999. There appeared to be less injecting as shown by fewer syringes distributed. Treatment places were increased at the same time as the 'drought' began while Sydney's highest overdose area saw the opening of an injecting room which attracted thousands of injectors.

Most interesting are commentaries from 6 or 7 experts, each agreeing that a sustained drug shortage of this nature has never been reported before and that the cause was not an obvious alteration in drug policies (although some mention a 'tough on drug' strategy without documenting any substantial changes in customs, policing, treatment, etc).

Gossop points to police crackdowns in Canada and London resulting in enormous drug seizures and arrests, neither of which had any reported effect on illicit markets. None of the wise commentators speculates on China 'opening up' and causing opiates to be diverted from the relatively much smaller Australian market. The 'drought' began within weeks of the start of the so-called 'Chinese century' in January 2001. Ironically a commentator from the People's Republic writes in critical terms about 'harm reductionists' as though they were a pest to be eradicated. He is apparently proud that China 'has experienced a drug-free society for more than 30 years' without mentioning how this was achieved by the deprivation of civil liberties, travel, etc! And then he has the temerity to suggest that methadone and needle services should only be used as a last resort! Does he mean only when the HIV rates exceed 10% of the population? Or 20%? Hao then quotes a proverb using cats and mice to describe the drug war! His views, which some term 'zero tolerance', are so nauseating that they well plead the contrary case!

Brugal MT, Domingo-Salvany A et al. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and AIDS in a cohort of heroin users in Spain. Addiction (2005) 100:981-989 (Ref 4)

This study followed over 5000 heroin users in a variety of treatment settings in Barcelona over a 6 year period, looking at mortality, HIV and other demographics. In 23,000 patient years of treatment there were just over 1000 deaths, one third from overdose, one third from HIV and another third from 'all other causes'. Only 11 overdose deaths occurred in patients currently receiving methadone treatment (50% were on MMT during the study period - mean dose 71mg daily). Being in methadone treatment conferred a 'protection' reducing the risk of death by a factor of 7. This also reduced the risk of contracting HIV.

Reported death rates dropped from 3.1/100 to 0.6/100 between 1992 and 1999 and the authors state: "the protective effects of methadone treatment was proved to have played a significant role." The overall decline is similar to that reported for France during the late '90s, where the drop in overdose deaths is attributed to massive increase in buprenorphine availability. Further, they estimate "that 86% of the overdoses and 38% of the AIDS deaths occurring among non-methadone users could have been avoided had they been in treatment."

This is not to say that all addicts should be on methadone for life. However, only a very experienced professional, after a complete assessment and probably knowing the patient for a time, should ever recommend a course of abstinence based treatments over supervised medical maintenance with psychosocial supports.

Despite containing possibly some of the most valuable lessons in the 40 years of methadone treatment, Addiction, true to type, gives this Spanish item no particular prominence. No editorial appears on the anniversary this month of this life-saving treatment. Methadone (along with related public health measures) has probably saved Australia from the HIV epidemic suffered in most other comparable countries. It also addresses addictions in a humanitarian manner for those unable or unwilling to go directly down the abstinence pathway. Even Australians who express disapproval of methadone treatment can still share in the multi-million dollar savings they have from its use in this country. Most New South Wales patients who were approved for methadone treatment are now off treatment (over 50,000 approved, ~17,000 currently).

Rehm J, Frick U, Hartwig C, Gutzwiller F, Gschwend P, Uchtenhagen A. Mortality in heroin-assisted treatment in Switzerland 1994-2000. Drug and Alcohol Dependence (2005) 79;2:137-144 (ref 5)

These authors report on the continuing success of the heroin prescription trial in Switzerland. Death rates have declined to rates comparable with other drug treatment subjects at around 1% per year, having been over 2.5% in the 1990s across the spectrum of drug users. This is all the more remarkable, they say, because only 'treatment refractory' subjects were admitted for heroin prescription, and these probably had a much higher expected mortality than the 2.5% estimated for opioid users generally in Switzerland in the 1990s.

Comments by Andrew Byrne ..

References

(1) Jones HE, Johnson RE, et al. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug and Alcohol Dependence 2005 79;1:1-10

(2) Sullivan L, Chawarski M, O'Connor PG, Schottenfeld RS, Fiellin DA. The practice of office-based buprenorphine treatment of opioid dependence: is it associated with new patients entering into treatment? Drug and Alcohol Dependence 2005 79;1:113-116

(3) Degenhardt L, Day C, Dietze P, Pointer S, Conroy E, Collins L. et al. Effects of a sustained heroin shortage in three Australian States. Addiction 2005 100, 908-920

(4) Brugal MT, Domingo-Salvany A et al. Evaluating the impact of methadone maintenance programmes on mortality due to overdose and AIDS in a cohort of heroin users in Spain. Addiction 2005 100:981-989

(5) Rehm J, Frick U, Hartwig C, Gutzwiller F, Gschwend P, Uchtenhagen A. Mortality in heroin-assisted treatment in Switzerland 1994-2000. Drug and Alcohol Dependence 2005 79;2:137-144

Psychiatric co-morbidity in drug and alcohol dependence - with focus on anxiety symptoms

31st May 2005

Presenters:
Dr Glenys Dore, Psychiatrist and
Dr Lisa Juckes, Senior Registrar & Fellow in Psychiatry from Macquarie Hospital.

This session focused on anxiety disorders and their management, from both a pharmacological and non-pharmacological (eg: CBT) perspective. We were given a very complete hand-out which summarised, among other things, the diagnostic features of various anxiety disorders. These can also be accessed through the DSM-IV and good mental health texts.

Attention was drawn to the high rates of anxiety disorders in people with drug and alcohol dependence problem. The lifetime prevalence of anxiety disorders in the general population is between 10-20%, yet around 32% of people with an opiate use disorder will experience at least one of these disorders in their lifetime. The various anxiety disorders often co-exist both with substance misuse and other mental health disorders such as depression. A person may also have more than one anxiety disorder; the co-existence of panic disorder and agoraphobia being particularly common.

We were reminded that people with anxiety disorders, particularly generalised anxiety disorder (GAD), will often present with physical symptoms. Whilst there is a short list of medical conditions that it may be pertinent to screen for, these symptoms are usually the result of physiological arousal. There were a lot of questions about post-traumatic stress disorder (PTSD), and Dr Dore noted that opiate users score highly on both PTSD and depression scores. These two diagnoses can be difficult to sort out from each other when they co-exist and can be so intertwined that knowing what symptom belongs to which is impossible. However at the heart of PTSD is a life-threatening trauma to which the patient can usually direct us. We were reminded of the intense horror and fear felt by many victims of sexual assault, and how important the work of feminists has been in bringing this trauma under the PTSD umbrella of life-threatening events. Acute stress disorder was alluded to briefly, and can sometimes be a predecessor of PTSD, though it resolves in 60% of cases. On the other hand, some people may have no immediate anxiety following a life-threatening event, but over time begin to exhibit symptoms.

There was an interesting debate involving the audience about the extent to which D and A specialist doctors should manage the psychological issues. It was noted that some patients on methadone have a separate GP, and that in some cases it may be feasible for the drug and alcohol issues and psychological issues to be dealt with by two different doctors or other health professionals. However this was seen to be very situation specific, for example in rural areas the lack of availability of GPs can make separation of care impossible, and in other cases prescribers of methadone may find that they are in fact the only regular medical/counselling contact a patient attends.

Dr Dore pointed out that the "post-withdrawal syndrome" from alcohol can last 3 to 12 months, and that in that time there may be some unmasking of anxiety disorders which seem to apparently prolong this state. The link between excess alcohol consumption and anxiety was emphasised, and the difficulties of knowing whether excess anxiety causes excess drinking or vice versa was discussed. However the inability to be sure which is the chicken and which the egg should not prevent treatment. Dr Dore told us that the best management through this phase is CBT, and that medicating was not recommended unless the anxiety symptoms pre-dated the heavy drinking . and therefore appeared to indicate an independent anxiety disorder.

The post-withdrawal syndrome relating to opiates was also discussed and the importance of educating patients about this before they come off their opiates was emphasised. The first few months off opiates is often the time when psycho-social pressures build up strongly. There can be an expectation, either from the patient's community or even from the patient themselves, that mental health is linked wholly and solely to being opiate-free. Since factors influencing mental health are far more complex than that, it is crucial to support the patient through this ~6 month period. The major toxicological differences between alcohol and opiates was pointed out with reference to management in the post-withdrawal syndrome phase. Because of the direct toxic effects of alcohol on several organ systems, once the patient is over the acute withdrawal from alcohol they may start to feel better much sooner than the patient who has come off opiates. This in turn may have implications for the issue of medical management through the post-withdrawal syndrome phase.

The two main arms of treatment for both anxiety disorders and post-withdrawal syndromes are CBT and pharmacological. Cognitive behavioural therapy starts with the provision of information to the patient about the nature of their condition; how and why it occurs and what can be done about it. There is an emphasis on promoting active participation from the patient. The principles of CBT apply to all anxiety disorders, so that whilst management is fine-tuned to suit the patient overall strategies and aims are similar.

Patients can be encouraged to self-monitor their treatment by keeping diaries, noting what works and when. Structured problem solving can be taught, and slow breathing (the "six-second cycle") is a very useful technique to teach the patient. Relaxation therapies such as muscle relaxation or meditation can be taught. Assertiveness and social skills training is also part of CBT. Other important CBT strategies include graded exposure to the feared situations and cognitive challenge work.

Dr Dore noted that most of the anti-depressants are also excellent anti-anxiety agents. Her handout gave details of the various groups of anti-depressants that are useful. Special attention was paid to SSRIs, and Dr Dore reminded us of the interaction between fluvoxamine and methadone. This particular SSRI, when used with methadone, can cause methadone toxicity by elevating methadone blood levels and is thus best avoided. Dr Dore also noted that it is wise to commence the SSRI's at a very low dose in anxiety states (eg 25mg sertraline) as the SSRIs can cause an initial increase in anxiety which can be prevented with a "start low" approach. While venlafaxine is useful for anxiety disorders, it can be problematic when patients stop it abruptly because of unpleasant rebound symptoms including increased anxiety. It was noted that patients on methadone maintenance therapy may be more likely to "stop/start" anti-anxiety medication, which adds weight to Dr Dore's advice.

Special mention was made of the RIMAs (such as moclobemide) and their excellent anti-anxiety properties. Tri-cyclics tend to be avoided these days due to their side effect profile and toxicity in overdose. Mirtazapine was also noted to be effective in this group of patients, though weight gain can be a major problem. Interestingly, mirtazapine has a greater sedative effect at a dose of 15mg compared to 30mg. Reboxetine ('Edronax', an SNRI) needs to be carefully titrated against the patient's response: Dr Dore mentioned that she starts very low and usually "trickles in" 2mg every few days. Reboxetine can be effective in increasing patients' motivation, but this effect can trip over into agitation if not monitored carefully.

The atypical anti-psychotics can be used as second-line medication for anxiety disorders, but in much lower doses than are used for treatment of psychoses eg sometimes 25 - 50mg of quetiapine (Seroquel) is a large enough dose to maintain an anti-anxiety effect, while other patients may need 100 - 200 mg. Anti-convulsants were also briefly mentioned as possibilities if anxiety is refractory to other treatments. Sodium valproate (Epilim) is best avoided in women of child-bearing age due to its deleterious effects on the foetus. Complex anxiety states requiring more complex medication regimes are best managed in partnership with a psychiatrist. Also, PBS rules must be carefully observed as not all of these drugs are covered for general use.

Finally, Dr Dore told us that benzodiazepines are best avoided in patients with a history of substance abuse, though she outlined some exceptions to this. The beginnings of a lively debate about the role of benzodiazepines came from the audience, and we look forward to a future seminar on this important and complex topic.

Written by Dr Jenny James, Daruk Aboriginal Medical Service.

Recent advances in the treatment of alcoholism

Charles O'Brien, MD, PhD.

Uris Auditorium, Cornell Medical School, York Ave, New York City

11am Wednesday 13th April 2005. Summary by Andrew Byrne

Dear Colleagues,

I was privileged to attend this grand rounds presentation in which world expert Dr Charles O'Brien addressed 'recent developments in the treatment of alcoholism'. He separated his talk into three sections: What is addition? Is drug treatment necessary for alcoholism? What treatment should be chosen? Newcomer acamprosate (Campral) has recently joined naltrexone ('Trexan', 'Re-via', now generic) and disulfiram (Antabuse), making three FDA approved medications for alcoholism. Each acts by a different mechanism.

This group of senior psychiatrists at Cornell Medical School was told that Dr O'Brien helped formulate DSM IIIR criteria for alcohol and other dependencies and had worked on the new DSM IV. He said that it was unfortunate that he and his colleagues had originally chosen the term 'dependency' since 'addiction' was more descriptive and was the commonly understood and still accurate scientific term. Rather than the old understanding of tolerance and withdrawals, addiction needed a much more comprehensive delineation. Some people treated for pain over a short period, even conceivably following a single dose of morphine, may develop tolerance and withdrawal, but clearly this is not 'addiction'. Also, some people who are profoundly addicted may show neither tolerance nor withdrawal at certain times. Hence the DSM committee arrived at the modern definitions involving compulsive self-administration of drugs/alcohol despite attempts to avoid them, involving continued harms AND/OR defined detrimental consequences resulting from issues of time spent in drug acquisition, legal, financial, family and vocational matters. Addiction thus involves the drug, person and their community setting.

Dr O'Brien reminded us of the permanent brain changes which occur with all human experience, each potentially involving actual physical, molecular changes as well as synaptic and dendritic alterations. He detailed some of the known sub-cellular mechanisms which end in the common 'reward' pathway for substances whose primary actions are on opioid, GABA or NMDA receptors. They involve the nucleus accumbens, amygdala and connections with the anterior cyngulate gyrus, pre-frontal cortex, etc. As well as for substance use, these pathways operate for other pleasurable behaviors such as gambling and eating. Dr O'Brien showed a number of 'in vivo' PET and other vascular scans showing increased blood flow in both hind-brain and anterior cortex in subjects who were shown pornographic or drug use related images while actually within the imaging machines. He also detailed the close links between alcohol, other drugs and the opioid system.

Likewise, we learned that when measured in rats, the continuously monitored brain dopamine changes in response to drugs such as cocaine or morphine were far greater than the responses found during sex or other pleasurable behavior. This finding exemplifies the intensity of the reward pathways for drugs as well as the 'learned' behaviours which are so hard to change. As a comparison, Dr O'Brien likened it to learned activities � and the younger it is learned, the less likely it is to be forgotten, such as learning to ride a bicycle in childhood. Despite the best will, it is impossible to 'unlearn' this, just as an alcoholic cannot 'unlearn' the experience of drinking to excess (or a hangover, presumably).

We were then told about new findings of 25 discrete alleles of the gene for the �-opiate receptor that have been found at a frequency of 1% or more. One such allele which is functional to the extent that its affinity for �-endorphin in vitro is significantly higher than other alleles and is associated with a higher frequency of alcoholism in a single Swedish study. At least one copy of this allele is found in 30% of European Americans and in a retrospective study of clinical trials of alcoholics with this allele, those randomized to placebo did very poorly but those randomized to naltrexone did very well. The difference was significant and could indicate that alcoholics with this genotype do particularly well on naltrexone. Dr O�Brien emphasized that alcohol is �just another drug� and alcoholism should not be seen as fundamentally different from addiction to illicit drugs or nicotine. He also reminded the audience that it was for �political reasons� that alcohol research in America was funded by a separate authority from illicit drugs.

The speaker then detailed some illuminating Japanese work on alcohol dehydrogenase deficiency which is quite prevalent amongst Asian populations. All homozygous subjects develop severe flushing and distress on consuming alcohol and their incidence of use, abuse and addiction is near zero. However, heterozygous subjects can overcome the similar but less severe effects. And despite some negative effects, some of them nevertheless become regular users, excessive users and/or dependent users of alcohol. This again emphasized the equally strong inputs from each of three domains: (1) drug, (2) host and (3) environment in the causation of addictions.

We were then quoted some figures from a 1994 study by Dr Anthony in which 'ever used' prevalence of addictive drugs was compared with 'became dependent'. For tobacco users 32% became addicted, for alcohol, 15%, and likewise for cocaine 16% heroin 23%, cannabis 9%. These figures are very important for parents and medical people, showing that a highly variable minority of all drug users later become dependent. These figures might be further refined in future research according to at what age subjects were first exposed to the particular drugs.

Next we were given the latest research on naltrexone and acamprosate, both of which reduce alcohol use significantly in 3 to 12 month follow-ups with low rates of side effects and good retention rates. When the total amount of alcohol consumed is compared between placebo and active groups the difference is quite dramatic. Most of the trials used standard psychotherapy, cognitive behavioural or group therapy in addition to drug treatment. Dr O'Brien implied that these therapies were considered essential if not sufficient in some cases yet he did not cite studies showing the effectiveness of such 'talking' therapies for alcoholism. He did quote one study (nearly all were positive) in which the anti-craving drug was given successfully in the absence of any focused psychotherapy (from community practice in Australia).

Such research both in the US and overseas shows similar results despite slightly different criteria for lapse/relapse end points ('just one drink' versus consecutive drinking days). Because these two drugs work by different mechanisms they have been used together by some groups with potentiated effects and minimal side effects. Theoretically at least, disulfiram (Antabuse) could be used as well, comprising a third strand to therapy, although such an approach has apparently not yet been researched.

Topirimate and ondansetron are other drugs with apparent beneficial effects in alcoholics. Thus they might be used "off-label" in certain circumstances. Neurological side effects have limited the use of topirimate, an anticonvulsant. A small randomised trial by Bankole Johnson showed benefits with ondansetron in 'genetic' or life-long alcoholics but no effect in the later onset 'acquired' type. Presently these may be considered promising but still experimental.

We were then told of the intriguing possibilities of the French drug �rimonabant�, a CB-1 (cannabinoid) antagonist. It is currently being promoted for obesity and for nicotine addiction, but animal models suggest that it should benefit alcoholics and cocaine addicts. One experiment showed that it does indeed block the effects of cannabis in human smokers.

Following replies to several diverse questions from the audience, Dr O'Brien was thanked by Dr Robert Millman and his staff. The meeting then broke up as we exited to the warmth and sunlight of York Avenue, East Side of New York City. I walked the block to Sotherby's Auctions where there was a boring showing of antique Rolex watches on the first level with a more engaging sale upstairs entitled "A celebration of the English Country House". There were paintings, brown furniture, rugs, silver, glass and other household meubles and trinkets to turn the eye � and the budget, one suspects.

Comments by Andrew Byrne .. (with some help from and thanks to the speaker)

Peer support for dependency problems: 12-step and CBT-based approaches

29th March 2005

Presenters:

Dr Stephen Jurd, Ms Josette Freeman, Dr Alex Wodak, Ms Lyn Roberts.

This session focussed on non-pharmacological management approaches to substance abuse. Stephen Jurd, director of D&A services at RNSH began the session by giving an overview of Alcoholics Anonymous ('AA'). He first presented us with the evidence for a genetic proclivity to alcohol dependence. He defined the dependence syndrome with reference to alcohol. This syndrome includes narrowing of the behavioural repertoire, salience of drinking, increased tolerance to alcohol, subjective awareness of the compulsion to drink, increased frequency and severity of withdrawal symptoms as dependence on alcohol increases and the seeking of relief from withdrawal symptoms by drinking more alcohol. There is also often a rapid return to pre-abstinence levels of drinking after a period of abstinence. He pointed out that controlled drinking for someone with an alcohol dependent syndrome would be very difficult to achieve, and that the two most likely outcomes for heavy drinkers were either a move to abstinence or eventual death from the complications of alcohol overuse.

AA, a 12-step approach, is not just about attending meetings, but a comprehensive philosophy. It does not tell people to "stop drinking" and has no opinion on any outside issues. We were told about the importance of the AA facilitators in encouraging people to attend meetings and connect with people. If people are just told the time and place of a meeting, it is not very likely that they will turn up, so the facilitators ring the prospective attendees to remind them of the upcoming AA events. This demonstrates the emphasis on personal contact that is integral to AA or the 'fellowship'.

Reference was made to the "clichés" used by AA, but Stephen Jurd asserted that if used skilfully they can change people's thinking. Some of these clichés include: "one day at a time", "live and let live", "easy does it", "let it begin with me". The literature that AA produces includes 3 major arms: 1) the AA big book 2) Living Sober, 3) the 12-steps and 12 traditions manual. The "Living Sober" book contains a lot of very practical advice to commonly asked questions such as should I avoid parties? How to I approach sex when I'm not drunk? and what do I do if I can't sleep? The AA groups require regular attendance, and there is usually a group task that is done each session to facilitate the sense of community and aid motivation. There is a group "conscience" whereby particular issues may need to be voted upon and a consensus reached. The 12-steps are the actual AA "program" and the meetings are centred around these 12 steps. Workbooks are available (eg at the Sydney 'Feminist' bookshop). A group member will often have a "sponsor" whose task it is to go through certain steps with the attendee. Sometimes it is required that these steps are written down (step 4). It is up to the attendee as to whether they want their sponsor to be temporary to cover certain steps, or long-term. A sponsor's role can include such things as ringing the person at a certain time each day to see how they are going.

There were questions about whether AA was religious, and though it did originally have Christian roots (the 'Oxford group'), it is now regarded in Australia as having no religious aims or affiliations. The term "God", as mentioned in AA literature, can be taken religiously or in any other way, eg as an acronym for "gathering of drunks" (!). It was noted by Alex Wodak that there is no hard evidence to prove that AA works, but he felt that as AA is a community organisation there should be no onus on it to have to prove its mettle. He believed it would be a difficult thing to assess scientifically, particularly for reasons of confidentiality and privacy. Stephen Jurd pointed out that there are currently about 2 million members of AA worldwide, and that it draws no outside funding yet has continued to exist for many years. He considers this to be suggestive of its merit. He said there is a bit of scant evidence for AA, but you have to scratch around for the data, and it's not "level 1" evidence. (ie double blind randomised control studies.)

Josette Freeman spoke to us about the SMART Recovery programme of which she is the co-ordinator, based at St Vincent's Hospital. They have a grant to establish 20 SMART recovery groups across NSW. SMART ("self management and recovery training") originated in the 1990's in the USA and is based on cognitive behavioural therapy (CBT) principles. The groups are peer-run. One of the principal objectives is to help foster motivation within people so that they are self-propelled towards recovery. The programme cultivates self-help and problem solving skills. People learn how to identify and manage their urges to use their drug of dependence. They work towards achieving a balanced lifestyle. The programme's CBT approach teaches people to challenge unhelpful automatic thoughts that surround their drug use. It is a time-limited commitment of a minimum of five weeks, though some people attend for up to 18 months.

In SMART, members are encouraged to do a cost/benefit analysis of their drug use. Relapses are looked at by the group and studied to see what has lead up to them. Analysing relapses is seen as part of the group's learning curve. Looking at the here and now is important, and meetings encourage people to study what has worked and not worked for them during the past week. Facilitators are encouraged to network with each other and share ideas about the running of their groups. SMART can complement adjunctive pharmacotherapies being used to treat substance misuse. It is not a substitution or competitor to the 12-step programme and members can attend both programmes if they wish. Group attendees may use different drugs of dependence, like alcohol and opiates, so in this sense the groups are "mixed". Josette described SMART as being an abstinence programme with latitude. The programme has not been evaluated, though discussions regarding this are currently happening with NDARC.

Alex Wodak commented that SMART, like AA, is a community resource and therefore shouldn't have to be evidence-based, though a positive evaluation would encourage health professionals to refer to it. Josette explained that for a client to be suitable for SMART, they must want to go. She said it offers an alternative to those people who don't like the 12-step approach, including the 'higher power' and 'disease concept', thus opening up more options for those with drug and alcohol dependency problems.

Lyn Roberts spoke to us about the therapeutic community model of treatment. She is manager of WHOS MTAR. This acronym stands for 'we help ourselves' and 'methadone to abstinence residential'. It is a residential service for those wishing to withdraw from methadone maintenance therapy. The methadone reduction regime is managed by external GPs as well as being externally dosed at the Langton Centre. There is a recommended protocol of dose reduction of methadone, but clients have the right to delay the reduction. Lyn Roberts stressed that conceptually it is important to understand that MTAR is not a "detox", but clients are undergoing their reduction while they are going through their rehabilitation program. Therapeutic community staff primarily utilise facilitation as a means of engagement as opposed to traditional medical models of treatment. Clients are referred to as residents, not patients, with the expectation that they will take responsibility for their own recovery. They are encouraged to support staff with the orientation of new clients, and the maintenance of the program schedule. They celebrate achievement of goals. MTAR came about after networking with USA TCs, but the Australian approach is modified and more flexible than a traditional American TC. Clients are not required to do as many functions as in a traditional TC and if a client prematurely discharges themselves, they are allowed back into the program within a 3 day time span if assessed as appropriate for readmission. Peer support is an integral part of the TC model and utilises privileges as part of its programme. Insight is gained through group and one-on-one interaction. Clients have access to harm minimisation programmes at MTAR eg educational sessions on hep C and HIV, drug overdose, infection control, etc. There is provision for safe injecting equipment and safe sex supplies throughout all WHOS facilities including MTAR. The recommended length of stay is 4-6 months. Lyn explained that MTAR is in the process of doing follow-up studies on its clients, but felt already that the high retention rates of clients in the programme provided some evidence of its success.

Summary written by Dr Jenny James, Aboriginal Medical Service, Daruk, NSW.

Buprenorphine diversion prevalent in Victoria, rare in other states

Buprenorphine diversion and injection in Melbourne, Australia: an emerging issue? Jenkinson RA, Clark NC, Fry CL, Dobbin M. Addiction (2005) 100;2:197-205

Dear Colleagues,

When prescribed according to established guidelines, buprenorphine is very effective in retaining addicted subjects in treatment and in suppressing heroin use. This paper looks at buprenorphine from the 'grey' market perspective when supply does not meet demand by interviewing attendees at city needle exchanges in Melbourne.

We are told that of 156 subjects 57% had 'ever' used buprenorphine (53% in the previous 6 months). Of those reporting buprenorphine use, 37% reported obtaining the drug illicitly (i.e. not from their own prescription) at least once during that period with one quarter (26%) reporting 'mostly' using illicitly obtained buprenorphine (ie. not on their own prescription).

Of the 156, 37% had 'ever' injected buprenorphine (33% in the previous 6 months). Around half of these injectors had obtained sublingual tablets from illicit sources at least once and in one third of cases reported 'mostly using illicitly obtained buprenorphine'. Injectors were more likely to be poly drug users, to be in treatment (mostly bup), to be unemployed and to have a prison history (50%).

From these figures it would appear that for the previous 6 months for the 156 subjects, 31 (20%) had used illicit buprenorphine and 24 (15%) had injected illicitly obtained buprenorphine. Hence a quarter of the subjects involved in diversion had obtained illicit buprenorphine and NOT used it by injection. Thus Jenkinson, Clark, Fry, and Dobbin have demonstrated clearly that the mooted combination buprenorphine product (with naloxone to discourage injecting) cannot address this major aspect of diversion (illicit oral use). In addition, despite nearly 100% 'supervised' administration of this sublingual product there still appears to have been widespread 'leakage' to the community near these 5 needle programs. Take-home doses are apparently only allowed in exceptional circumstances in Victoria.

It is reassuring that 58% of these subjects who attended a needle exchange had been involved in some treatment in the previous 6 months. However, it may concern Victorian authorities that only 38% remained in treatment at the time of the questionnaire, implying that two thirds of these high-risk users had dropped out. Of those still in treatment, two thirds were taking buprenorphine, one third methadone and 3% drug-free treatment ('counselling').

This survey shows that even when there is widespread availability of buprenorphine from pharmacies, as in Melbourne, there is still a market for the diverted drug. This must be at least partly consumer driven and might reflect inadequate dose levels prescribed locally, inadequate dispensary opening hours, travelling, fees and/or other constraints in accessing prescribed buprenorphine.

From a purely public health perspective, this report might be seen as demonstrating a reduction in dependence on illicit, unhygienic and impure heroin for a pharmaceutical with quality control, labelling and predictability. However, some of the tablets may have been diverted after being in the oral cavity and thus could represent a serious infection risk. This might be termed a 'secondary treatment program' as in the concept of secondary needle programs which were reported recently. As with needles, it is still disappointing that the tablets were not available legally to those who needed them, when they need them (eg. before work for unskilled people starting at 7am; in lunch hours; evening doses for those doing overtime). While buprenorphine can last for 48 hours or longer in some situations, for new patients, reductions, pregnancy (not approved as yet) and fast metabolisers (half life as short as 9 hours in some - ref on request) it is not realistic to expect such people to work and function normally without having their daily medication first.

In response to the high rates of diversion, the authors remind us of the challenge to busy community pharmacists to strictly supervise the sub-lingual administration of the drug which can take over ten minutes in some cases. They even suggest the possibility of formal clinic treatment for some patients or else transferring to methadone to prevent diversion (a liquid is much easier to supervise).

The authors inform us that of the other five Australian jurisdictions for which comparable figures were taken for recent buprenorphine injecting, each was less than 5% (cf. 33% for this Melbourne sample). This is all the more remarkable since both Queensland and South Australia have allowed take-away dosing in parallel to methadone for stable patients for a number of years (up to 4 per week for those NOT on second daily dosing already). I understand that, apart from Perth, WA, the reported figures for subsequent years have not risen significantly. I have asked the Sydney injecting room staff about buprenorphine injecting and they say it is almost unheard of with heroin and cocaine making up the bulk (~95%) of their patients' dealings, in 'oscillating' proportions. Some Kings Cross police I have interviewed had never heard of the drug. Currently, there are about 2500 patients taking buprenorphine in New South Wales (pop ~ 6 million).

Congratulations to these authors for their vital seminal work. Thanks also to RAJ for her helpful suggestions and corrections for an earlier draft of this summary.

Comments by Andrew Byrne ..

Reference

Jenkinson RA, Clark NC, Fry CL, Dobbin M. Buprenorphine diversion and injection in Melbourne, Australia: an emerging issue? Addiction (2005) 100;2:197-205

Internet drugs 'more expensive' than from pharmacy ... but no doctor needed

Sydney Morning Herald 3/3/05. "Online sales of mind-altering drugs surges: UN."

In a slightly confusing article on drugs AFP reports on the International Narcotic Control Board's chief Hamid Ghodse and his 'panel' warning about increased supply of narcotics and other psychoactive drugs from the internet.

Ghodse mentions the serious worry of children having access to internet supplies. But he then appears to contradict himself regarding how to address the situation. He states that policing was difficult (or impossible) as internet supply companies 'can easily be relocated' across borders to avoid tighter laws. But his final quote is to call for governments to 'act urgently'. This is usually 'code' for increasing restrictions and raising penalties which he has already pointed out only serve to drive suppliers off-shore. Can he mean the opposite?

On a seemingly separate issue, the report then moves to Afghan opium production which is nearing peak levels again (4600 tons per year).

Clearly only a radical re-think of current policies will have any impact. Citizens deserve access to good medical care at affordable prices. At the same time community demand for drugs in non-medical settings such as alcohol, tobacco, cannabis, ecstasy, cocaine, steroids, etc should be met with more enlightened policies than ineffective and expensive bans as at present. This does not mean 'legalising' everything, however!

My calculations of 4600 tons of opium (which may be flawed), based on 20% morphine equivalent approximation, yields 100,000 million standard 10mg doses of morphine. If dependent people used an average of half a gram per day, this comes to just under 200 grams per year. Thus the Afghan crop estimate above could support 50 million addicts. This may, however, include a larger numbers of non-addicted, occasional drug users.

A Sydney TV news bulletin on Sat 5/3/03 dealing with these matters stated that Afghanistan has now eclipsed Burma by 17-fold in opium poppy production. It may be no coincidence that both of these countries lie in close proximity to potentially the world's biggest opium market after Europe and America, China. Places like Australia and New Zealand must look like tiny 'niche' markets in such a world.

comments by Andrew Byrne ..

Fewer methadone deaths reported from UK. Female drug users at higher risk.

Dear Colleagues,

The March 5 2005 British Medical Journal has a reassuring news report about reductions in most poisoning cases for the year 2003. The exception was for female drug users whose rate had climbed to 346, the highest on record (compared to 1042 men, the lowest since 1997).

Notably, Ms Brock of the Office for National Statistics stated that "...deaths involving methadone fell to their lowest number recorded..." Further: "We do not have information or an indication that people are taking fewer drugs."

They report further that there was an increase in the number of deaths involving antidepressants-from 392 in 2002 to 424 in 2003. These were mostly selective serotonin reuptake inhibitors such as Prozac and related drugs, although these are widely thought of as safer alternatives to older antidepressants.

I commend readers to the BMJ site for
the full article.

Comments by Andrew Byrne ..

January 2005 National Geographic cover article on caffeine

Dear Colleagues,

January 2005 edition of the National Geographic Magazine has a 30 page cover story on caffeine which makes fascinating reading. Caffeine is the world’s most popular drug, even eclipsing tobacco and alcohol.

The history of beverages, nuts and confection containing caffeine makes quite a story, paralleling civilisation itself. Prior to the industrial revolution there was little to be gained in keeping awake after dark. Since caffeine increases alertness, improves reflexes and reduces fatigue, it is an ideal accompaniment to round-the-clock factory work. With few proven side effects at normal doses, it would thus appear to be the ideal drug for the modern era.

After tea, coffee and cocoa, the latest incarnation is in ‘energy drinks’. We are told that “Red Bull” was an Austrian invention which is now copied all around the world. I recall seeing "Jolt" cola when in Japan over ten years ago. Strangely, it is compulsory in many countries to state contents details on the label of most products, but tea, coffee and cola often still remain exempt from this requirement.

We are informed that dark chocolate contains up to three times as much caffeine as milk chocolate and 12mg is a typical dose contained in a small block. The article quotes a cup of brewed tea at 50mg, about the same as a single shot of espresso coffee. A 20oz (US) bottle of Coca-Cola has 57mg caffeine while a small tin of Red Bull contains 80mg.

There is an exhaustive discussion of the benefits versus the potential side effects of the drug, including its use in pregnancy and in children. The author’s conclusion on balance is parallel with the FDA, that the drug is ‘generally recognized as safe’ in doses of up to 300mg daily. However they sound a warning that ‘people who consume caffeine have higher rates of kidney and bladder cancer, fibrocystic breast disease, pancreatic cancer and osteoporosis’ even if these are not necessarily causative. Nervousness, panic attacks and temporary increases in blood pressure are also occasional associations of caffeine consumption.

Other interesting quotes: “The caffeine extracted from coffee beans to make ‘decaf’ is sold to drug and soft drink manufacturers”. “Military studies of subjects who had not slept for 48 hours showed that 600mg of caffeine improved alertness and mood as much as 20mg of amphetamine”. “The robusta coffee beans used in less expensive brands contain almost twice as much caffeine as the arabica beans favored by connoisseurs”. “Going without caffeine for a day and a half increases blood flow in the brain which may explain why people get headaches when they first give it up”. “Cigarette smoking nearly doubles the rate at which the body metabolises caffeine”. “Vietnam is now the world’s second largest coffee producer, yet is largely a nation of tea drinkers”.

comments by Andrew Byrne ..