10 December 2005

BMJ editorial on whether methadone is outdated and ought to be replaced by buprenorphine

Is methadone too dangerous for opiate addiction? Luty J, O'Gara C, and Sessay M. BMJ 2005; 331: 1352-1353

Dear Colleagues,

This contentious editorial by Luty, O'Gara and Sessay

(full text requires login)

raised much interest in the "rapid response" pages of the web BMJ in late December. There had been 25 replies up to Februrary, which is remarkable.

While a few have agreed with the premise that buprenorphine (pure) should be the drug of choice now for newly presenting heroin addicts, there was a stronger sentiment that methadone is still the best first line drug, with buprenorphine an excellent alternative. Methadone is also much cheaper at present, but this may change as generics are reportedly being introduced (in France and possibly elsewhere) since the patent has expired on high-dose buprenorphine for addiction treatments.

Perhaps as a gesture to the many responses, the journal published two of the early responses in their hard-copy edition only 4 weeks following the original (including one from Byrne Surgery). Numerous specialists have been involved in this BMJ 'debate' - and it is a pity that some of them were not chosen by the BMJ to review this manuscript long before it was published, with its controversial and unsubstantiated suggestions. There were letters from Andrew Ashworth, Chris Ford, Adam Bakker, Richard Hallinan, Gordon Morse, Matthew Hickman, Pier Paolo Pani, Colin Drummond and Jenny Keen.

I hope these reflections are of interest. There is hardly any mention of combination buprenorphine, which seems to be almost off the radar in Europe.

Comments by Andrew Byrne ..

1 December 2005

China: Eye-opening activity and impressive progress

Andrew Byrne's trip to China Nov 05. Eye-opening activity and impressive progress.

Although largely on a private visit, I was invited to visit a harm reduction centre in Beijing as well as spending some time with an American public health consultant who works for both Chinese and foreign NGO's. I was also able to interview one of the first methadone patients in China and view a harm reduction centre.

On a related subject, last Friday's English language China Daily had two articles on the HIV problems in Henan province, Central China (pages 1&5). Despite quoting figures of affected local citizens in one small region (29,000 'carriers' and 16,000 with AIDS), neither addressed any continuing problem, reporting nothing but good news. They stated that 100% of the farmers who had donated blood in the past had been tested for HIV and that those who were positive were receiving anti-viral treatments paid for by the government. There was also another 'good news' story describing a mayoral official who was 'moved to tears' watching an operatic performance based on "the story of an HIV carrier that went from being in despair after suffering discrimination to regaining confidence with the support of neighbours, official and health workers" in Zhumadian city, Henan province.

It is disappointing but perhaps predictable that the People's Republic of China is still not prepared to be open about injecting drug use and homosexual transmission of HIV. To read their reports in the weekend official press one would think that the HIV problem had been solved! Yet WHO reports show otherwise and Koffe Annan himself was present when the first Beijing harm reduction centre was opened, along with high ranking Chinese officials. Nevertheless, it is clear that this sovereign country must address these matters in a manner which is effective, socially acceptable and sustainable - hence my own outsider's observations remain very much tentative.

My host and I were given a presentation by the manager of the first harm reduction centre in Beijing near one of the main trunk railway stations. They do most of their education and other work by use of outreach workers since people are very reluctant to attend in person. China is still a highly policed state (I saw three separate seemingly banal situations over two weeks where people were apparently apprehended, searched and detained).

The harm reduction centre has over a dozen education brochures on various related topics from the simple in cartoon style (which is very popular in China) to the more detailed on health issues. Needles and syringes were given out in lots of approximately 6 although more were permitted if old needles are returned. Some may be re-sold in what Americans term 'secondary needle services'. This is likely to extend the usefulness of the service in a society where there is a very major stigma and sanctions attached to drug use. Initially the centre was only distributing a few dozen syringes per day but this has risen dramatically in recent months to numbers in the hundreds per day.

We were told that since opening in May this year the centre had performed about 50 blood tests on injecting drug users. Of these about 6 were positive for HIV and 3 had AIDS clinically. Another 50-70% were positive for hepatitis C virus. We were told that at any hour of the day or night one could see dozens of injecting drugs users at one of the large railway stations in the capital.

The methadone patient who I interviewed appeared to be receiving high quality treatment. He drank his medicine under supervision on a daily basis after having a comprehensive assessment with on-going counselling. His dose had been increased to 90mg already, but a higher dose of up to 120mg was discussed. Following careful negotiation involving his case worker, as a result of his good progress his dose remained at 90mg daily. This is close to the average dose found in most well run treatment services. The patient appeared to be coping well with treatment. He was open and frank with his descriptions (via my host, who interpreted from the Pu-tong-hua or Mandarin, a language which every Australian child should be taught these days). The patient had pathology testing promptly and regularly (details unclear) and stated that he was satisfied with his treatment. Indeed, he said that he was delighted to be able to avoid heroin at last after a long drug use history with frequent relapses. I was intrigued to find out that the methadone treatment service was overseen by the police department (who also run the compulsory detoxification services in China).

Despite an apparent slowness to respond to some public health issues, it is clear that the 'new China' is moving ahead rapidly in many other respects. It is only a matter of time, I believe, before public health measures are put in place to address the above matters, considering the long history this country has of communal action for community needs. The Chinese have a strong historical record . starting with dams, bridges, 'walls' and other major works by successive dynasties. Already there are signs that pollution is being addressed (two of the days I was in Beijing were crystal clear with some haze, mist and possibly smog on others). The capital's tap water looks, smells and tastes pure, although we were advised to drink bottled water. Drainage is improving and even public conveniences around the city, while variable, are mostly clean and hygienic from what I saw in Beijing and Shanghai.

It has been a privilege to spend 2 weeks in China. I look forward to more news of this power-house society which has so much to offer (and gain from) the rest of the world. We also look forward to news on the 'second methadone clinic' and beyond (see Rachel Humeniuk and Robert Ali's article 'The first methadone clinic in Beijing' D&A Review, May 2005 issue).

Comments by Andrew Byrne ..

The neurobiology of addictive behaviours.

For those of you who weren't at Royal North Shore Hospital on Thursday1st December, 2005 for the 2nd Annual Macquarie Hospital conference:

�DOUBLE TROUBLE � TWICE THE FUN� co-morbid mentalillness and substance misuse, DVDs are now available.

The first speaker was Dr Stephen Jurd, Medical Director Northern AreaDrug & Alcohol Services, who have us a brilliant synthesis on the theme Addiction Biology 2005.

Brain plasticity, the dopaminergic reward/reinforcement pathway, "weighing up" and �rationalising and deciding� versus automatic behaviours, the risky period of synaptic pruning, changing addictive behaviours by enhancing frontal lobe activity or by reducing craving - with these ideas Dr Jurd gave us a solid basis for understanding the development and management of addictive behaviours.

Dr Jurd cautioned us not to think of our brains as hard-wired black boxes. Acknowledging the work of neuropsychologist Aleksandr Romanovich Luria (1902-1977) who identified the functional purpose of various parts of the brain (eg auditory and visual cortex) in a model of fixed structural inter-relations, Dr Jurd warned: only one thing is wrong with this model: everything!
In truth, the brain as an active organ, "a living breathing organ", of "highly dynamic synaptic structures", which is constantly reinventing itself. If we remembered anything of the day�s talk, it would be structurally encoded in our brains. It takes about 20 minutes to build a new synapse; synapses the structural substrates of learning. Each nerve cell body in the brain has thousands of synapses. On average a child's brain has 2,500 synapses per cell-body, increasing to 15,000synapses per cell-body in a child, and dropping to 7,500 per cell-body in the adult, during the "time of pruning". Unused synapses are cutback: "use them or lose them".

�Brain plasticity' also exists in mature brains, which are capable of regenerating damaged neurones (making new neurones?) and where neurones are capable of migration within the brain, after injuries like stroke, and after exercise.

Why do we do silly things again and again? Everyone knows from their own experience: most of us have experienced automatic driving - on a Saturday morning, the car somehow automatically takes the turn to work instead of the shopping centre.... With this question Dr Jurd turned to models of drug dependence.

It is easy to produce substance dependence in animals, and to show that not all drugs are the same in addiction liability. For example, primates will become addicted to low-dose alcohol, high-dose alcohol, barbiturates, and cocaine, in ascending order of addiction liability. Some animals will resist low-dose alcohol, high-dose alcohol, and barbiturates, but become addicted to cocaine (however, having become addicted to cocaine, these resilient animals will, when exposed to low-dose alcohol, use it in a dependent fashion).

Animals, once addicted, will neglect food, and neglect even their favoured mate. Dr Jurd described the image of a limp mouse, lying dead over the cocaine lever, having given its last gasp trying to get a shot. He described the anthropomorphic image of a mouse pressing the 'bar' which delivers alcohol every ten presses, leaning down to gulp the alcohol without taking its paw off the bar, bringing to mind the attachment of the drinker to their glass (or indeed that other 'bar').

Experimental models where the number of bar presses is increased progressively to test the strength of the addiction - "racking up the bar" - show that animals will go to 30, 40 or 50 presses for a "drop of booze", but there is a limit. This limit is about halved by the anticraving agents acamprosate, naltrexone and rimonabant. We can therefore expect relative but not absolute reductions in drinking from these drugs, which are more like a "blanket in the cold" than a "magic bullet".

The dopamine hypothesis has been around for a long time and is familiar to all those who treat psychosis. Dr Jurd stressed that dopamine is not just a "vector for psychosis" but has a lot of functions elsewhere in the brain. It is important in models of 'reward' in addiction: from dopaminergic neurones in the ventral tegmental area of the brain we get a little squirt of dopamine in limbic areas of the brain, in the "feeling parts" of the brain, such as the shell of the nucleus accumbens.

However the idea of 'reward', though easy to grasp (and communicate to our patients) is better expressed as 'reinforcement': dopamine is not just about 'feel-good' sensations but attention, memory and learning; noticing, remembering and valuing something: "I remember that, that was good".

Addiction can be thought of as subsuming this basic and, in evolutionary terms, very old mechanism, which is essential for our survival. Animals have to be reinforced in certain their actions for survival. An animal will make the effort to peck through a mango skin if it has a fond memory of the pleasure of the fruit within. The lizard with a fond memory makes the effort to chase the other lizard for some 'hanky panky', rather than eating the food. This has its homologue in "euphoric recall" in the drug user.

Dr Jurd raised the paradox in understanding addictions - that such different drugs as stimulants and sedatives are both addictive. The dopaminergic reward/reinforcement pathway provides an explanation. Dopaminergic neurones arising in the ventral tegmental area release dopamine in the shell of the nucleus accumbens, in the "feeling parts"of the brain. Stimulants like cocaine and amphetamine-like drugs work directly to release dopamine, acting as "accelerators" of the reward pathway. �Downers' like opiates and alcohol �inhibit the inhibitors� of this pathway - they "disable the brake".

Dr Jurd moved on to decision making: say whether or not to buy a chocolate bar or a pair of shoes. The process of "weighing up" a decision is associated with activity in the anterior cingulate/orbitofrontal complex, and the final step of �rationalising and deciding� is associated with activity if the dorsolateral prefrontal cortex (DLFRC for short). By contrast, posterior structures including the striatum and thalamus are associated with more automatic activities and are also more strongly activated in decision-making in stress situations, in situations of craving, and generally in addicts, whether presented with drug- or non drug-related decision making scenarios.

Decision making processes can be tested using the STROOP: a test which requires a kind of mental effort that "lights up the decision making parts of the brain". An example is the word red printed in green colour, the task being to say what colour the word is printed in.

This is surprisingly difficult, as the audience could testify. Cocaine and heroin users have less anterior and more posterior activity on the STROOP, showing that they think differently, using more automatic and less rational areas of the brain, even in non drug-related scenarios. This might be because they more habitually decide in this way, or are subject to more stress than other people.

Dr Jurd turned to animal models of craving and relapse in addiction, mentioning that 30 years ago the talk was all of stress, cues and triggers, and priming effects, old ideas which were then generally known to be untrue for the next 20 years until the behavioural/psychologists rediscovered them. Alcohol dependent rodents whose habits have been 'extinguished' (for example by cutting off the reward of alcohol from 'pressing the bar' until the rodent loses interest and resumes normal behaviours, like paying attention to food and to its mate) can be shown to resume drug-seeking behaviour by exposure to cues (eg a red light previously flashed when alcohol is supplied),stress (typically and charmingly produced by applying foot-shocks to the animal) or priming (for example, giving a small amount of uncued alcohol).

Moving back to the idea of synaptic pruning, SJ observed that adolescence, the time of maximum synaptic pruning, is a risky period in terms of addiction. Nicotine is both neurotoxic and reinforcing in adolescent rats, but is neither in mature rats.

Adolescent rats become intoxicated with alcohol more slowly than mature rats. (If this is true in humans, do adolescents' more active brains fight back more effectively against sedative substances?) Resilience against intoxication and vulnerability to reinforcement and neurotoxicity combine to create higher risk in adolescence. Adolescence is the "time when you make decisions about what sort of person you're going to be".People exposed to alcohol in adolescence develop a smaller hippocampus, and have about 15% fewer frontal neurones than other people.

Human frontal lobes continue to mature well into the 20s; itis no wonder that tobacco companies want to reach people before this happens. Think of Joe Camel.

Dr Jurd referred to Australia's epidemic use of stimulants, Australia having the highest rates of MDMA use in the world and the second highest rates of amphetamine use. He put in a plea for the use of the term MDMA (methylene deoxy methamphetamine), which sounds like a chemical that distorts brain function, rather than the trade name 'ecstasy', a name that invites us to think it "wasn't made in a bathtub by a bunch of bikies just wanting to make money".

He then moved to some of the applications of this neuroscience.

Essentially there are two ways to change addictive behaviours:1. enhance frontal lobe activity (cognitive behavioural or other therapies might work this way)2. reduce the unconscious drive to use, which is craving.

Naltrexone blocks opioid pathway mediated reinforcement from alcoholin the brain, and seems to work best in 'positive reinforcers', people who drink to feel good, rather than to stave off the consequences of not drinking. These are people who drink for episodic high blood alcohol levels. In reducing opioid mediated reinforcement from alcohol (experienced drinkers will recognise that 'glow') naltrexone has a place for those who are not ready to stop drinking altogether, and aim to control their drinking.

Acamprosate may be more appropriate for "steady state top-up drinkers", who drink to maintain blood alcohol levels and avoid negative consequences when blood alcohol levels fall. The appalling animal model is "alcoholised rats" who live in an alcohol vapour chamber: in this model acamprosate is very effective.

Naltrexone is contraindicated in people taking opioids and will cause goose flesh even in moderate opioid users, like the regular drinkerusing paracetamol/codeine for hangovers - they really won't like it.Unlike naltrexone, acamprosate can be used in people on methadone orbuprenorphine, and can be used in the presence of all but the most terminal liver disease (a bit of yellow in the sclera and puffy ankles are OK) whereas naltrexone should not be used if the liver function tests are more than 3 times normal. Naltrexone has the advantage ofonce daily dosing (50mg) where acamprosate needs to be taken 3 times daily (666mg tds).

Ondansetron, a serotonin 5HT-3 blocker, best known as a very effectiveand expensive antiemetic, has been shown in well conducted trials toreduce relapse in abstinent drinkers who developed alcohol dependence early in life (Early Onset Alcoholics, who also often have a strong family history, and antisocial behaviours) but to have no benefit inother alcoholics compared with placebo. This might be explained by serotonergic abnormality in EOA, with increased mood disturbance predisposing them to drink, and/or increased activation of 5-HT3receptors in alcohol-induced reward.Therefore selective serotonin reuptake inhibitors (SSRIs) might not be effective treatment for alcoholics and could even make things worse insome cases -which is borne out by a number of studies. Dr Jurd suggests SSRIs be used with care - for true comorbid major depression, not just the alcoholic who is feeling a bit sad.

Topiramate is an antiepileptic medication used for partial seizures. It has an anti-dopaminergic action (possibly mediated by increased activity of GABA, and reduced action of glutamate). It reduces the reinforcing effects of alcohol and tobacco in dependent people and reduces both craving and relapse.

Studies of combinations of anticraving agents for alcohol are going on, such as naltrexone+acamprosate, naltrexone+ondansetron. We were advised to watch for the results of the large NIAAA study, coming out soon....

Rimonabant, a cannabinoid receptor CB-1 blocker, is showing promise as an anticraving agent in surprising ways: it seems to be effective for smoking cessation and weight loss, Rimonabant, a cannabinoid receptorCB-1 blocker, is showing promise as an anticraving agent in surprising ways: it seems to be effective for smoking cessation and weight loss, as well as blocking reward from cannabis smoking. It might be the first true anticraving agent. Paradoxically, it might be too effective to be a useful treatment for cannabis dependency, in the same way that naltrexone is �too effective for opiate dependency: people simply won�t take it. It is likely the pharmaceutical industry will targetthis new medicine at cardiologists, representing a potentially huge market, rather than addiction doctors.

Dr Jurd summarised with these critical points: addiction is a disease; craving is physical; addicts reward themselves chemically; multiple neurotransmitters are involved in addiction; there may be pharmacological subtypes of alcoholism, allowing matching alcoholics to medications based upon their different biological natures; and combination treatments may be appropriate - they work in animals.

And returning to the idea of brain plasticity, Dr Jurd assured us: Recovery is Real. Citing George Vaillant's "Natural History of Alcoholism" , Global Assessment of Functioning (GAF) scores in abstinent drinkers are as good as those in never-alcoholics. Well worth remembering if your patient or client, like mine today, receives a dismissal notice claiming a "medical report provided (sic) that your condition of substance abuse is considered permanent".

R. Hallinan summary.

22 November 2005

Dependency issues in Aboriginal people

Tue 22 Nov 2005

Dr John Daniels, director of health services and research
at Redfern Aboriginal Medical Service (AMS).

Mr Maurice Shipp, public health co-ordinator at Redfern AMS.

Case Histories: Dr Yianni Faros and Michael Englert, nurse unit manager, AMS.

This meeting began with an overview of the link between indigenous culture and health. Regardless of lifestyle choice in either a more traditional setting or westernised urban area, Aboriginal people are a separate cultural group linked by a sense of belonging to a specific locality or extended family. The three widely accepted components of Aboriginal cultural identity were outlined. These are self-identity as an Aboriginal person, being the descendant of an Aboriginal person and being accepted by a particular Aboriginal community as belonging to that community. Maurice Shipp emphasised how the latter point underlines the seamless continuity between the individual person and their community. He discussed how the traditional kinship systems continue to have a powerful influence over contemporary family structures. An example of this would be how the children of two brothers may call each other brother and sister, rather than cousin, and that a person could therefore have several mothers and fathers. For an Aboriginal person, their mother's sister is their mother, but their father's sister is not their mother, but their aunt. Various rights and obligations may be expressed by these relationships and, with regard to any one individual, involve many members of the family and community.

It was pointed out that all of the world's indigenous peoples have a legally enforceable power to obtain and protect their human rights, via the Universal declaration of Human Rights to which Australia is a signatory. However, there are significant anomalies between the Articles within this Declaration and the current situation of Aboriginal and Torres Strait Islander (ATSI) people.

Maurice Shipp talked about various aspects of Aboriginal culture that are shared by different Aboriginal groups. These commonalities include a "world view" that expresses itself in religion, art, dance, music, language and kinship, and individuals within different Aboriginal communities will share these links, though they may differ from one community to another. However, common to all Aboriginal communities is the regard that is given to custodianship, in which all aspects of Aboriginal knowledge are sacred. Certain types of knowledge may only be permitted to be transmitted by certain people. Within particular communities young people may be picked to go through law, even as young as thirteen. Kinship within community is central to Aboriginal conceptions of identity and Maurice Shipp emphasised that Aboriginal people know who their families are. Even cousins, "sixth removed" by western definition, are regarded as close. Historical continuity is another commonality linking all Aboriginal people together, and Australia's indigenous people have at least a 60,000 year history here, ie something like 2400 generations of family living in Australia of which 2392 passed before European settlement. This gives a very deep sense of attachment to family and land; a powerful sense of ancestry. Another commonality between Aboriginal communities is the preservation and renewal of culture, the emotional and spiritual development that has continued to evolve up to and including this present day.

It was pointed out that there are about 70 different Aboriginal language groups in NSW and about 600 nationally. There are even more dialects, around 1,500. They are all absolutely distinct from one another and stem from different root structures. They are grammatically very complex and difficult to learn. For example, the beginning, middle or end of a word may change according to its context, and the meaning of words change according to who is talking to who. There are several languages still spoken in their full context particularly in remote Australia, and urban Aboriginal people often pepper their speech with Aboriginal words from their particular community group. This Aboriginal English is formally recognised by linguists as a distinct form of English and is an important means of expressing Aboriginal identity. It has a distinctive range of accents, incorporates local Aboriginal words, and shows unique grammatical features.

Dr John Daniels outlined some of Australia's shame in his summary of current mortality facts pertaining to Aboriginal people. The life expectancy of Aboriginal men is only 56 years, almost 21 years less than their non-indigenous Australian counterparts. For Aboriginal women the life expectancy is 63 years, about 19 years less than their non-indigenous counterparts. Dr Daniels contrasted the causes of death for Aboriginal people versus non-Aboriginal people.

Circulatory diseases account for 27% of Aboriginal deaths, and this compares with 36% for non-Aboriginal. Aboriginal people between the ages of 25 and 44 have ten times the death rate from circulatory disease. External causes of death (self-harm assault, murder) account for 20% of all ATSI deaths, and for non-indigenous people this figure is 6%. Neoplasms account for 14% of Aboriginal deaths, compared to 29% in non-indigenous people. It was emphasised that Aboriginal health data is very similar between rural and urban communities, and that life expectancy is also the same. Disease patterns are also largely similar, with some variations between remote and urban settings noted for particular diseases. Trends in these patterns can only be assessed over a very long time-frame, and whilst the current situation is a national emergency, Dr Daniels did point out that better access to health promotion and health care services are at least positive influences.

There was some discussion of the current situation with regard to blood-borne viruses in Aboriginal people. There are 190 notifications of HIV nationally in Aboriginal people, and 68% of these are in men. Two-thirds of the positive people live in Sydney and there have been about 19 notifications per annum since 1995. The overall prevalence of the HIV is therefore similar to that seen in the non-indigenous population, however whilst Aboriginal people are not over-represented nationally in HIV statistics, this obscures the experience of Aboriginal communities and health service providers in the focal outbreaks that have occurred. Dr Daniels gave an example of this when mentioning a cluster that occurred in Redfern in 1984. It is also important to understand that the pattern of occurrence of HIV in indigenous people is different. Heterosexual transmission is three times higher among Aboriginal people than non-Aboriginal people and 32% of people who are positive are women (compared to 11% for non-indigenous women.) 14% of Aboriginal people who are HIV positive are IVDU compared to only 3% in the non-indigenous population. Between 1995-2004 there were 22 cases where IVDU was the sole method of transmission, and an additional 12 cases where IVDU was a co-risk factor with sexual transmission.

Collection of data on incidence and prevalence of hepatitis C in Aboriginal communities needs to be improved, as many reports don't comment on Aboriginal status. However, Dr Daniels told us that there is almost certainly a higher prevalence of hepatitis C in the Aboriginal community, and that we are yet to see the real burden of disease.

The session finished with some excellent case presentations by Dr Yianni Faros with commentary also from Michael Englert (see below). Optimism for the future was inspired by the creative and thorough way in which the Redfern team deliver health care to the ATSI people who visit their dependency service.

Summary written by Dr Jenny James. Daruk AMS.

Case Studies

Dr Yianni Faros presented three case studies from the Aboriginal Medical Centre at Redfern.

The first was a 29yo man with a history of IDU since his teens, and large heroin habit, whose buprenorphine treatment was unsuccessful owing to poor attendance. Despite accepting only low dose methadone, which he supplemented with heroin, his attendance improved. He later experienced symptoms of withdrawal and received inadequate analgesia when hospitalised for gunshot wounds, due to loss of this illicit opiate intake, his partner bringing in Buscopan for his symptoms. He and his partner perceived suspicion and hostility by hospital staff which they attributed to racism and his being "already on methadone".

The next case was a 34yo woman, homeless with two children, yet also looking after the children of her sister. She had been injecting for ten years and had a $250 per day heroin habit. After being stabilised on methadone, she changed to buprenorphine because of the stigma of methadone. With a coordinated team approach to her care, over 4 years she established housing away from area of drug use, dosing at a community pharmacy, developed improved parenting skills through contact with local community health centre, received instruction in financial planning skills, hepatitis B immunization and hepatitis C assessment, formed a new stable relationship, and managed to move back to the area she grew up in and remain abstinent.

The last case study was a 29yo man with bipolar disorder, renal impairment secondary to lithium toxicity and $200/day heroin dependency. After unsuccessful methadone treatment, he received buprenorphine with variable periods of abstinence following. Written reports were provided for Section 32 applications in relation to outstanding warrants, and he spent reduced time involved with the Justice System. A drop-in service was negotiated for care after many failed attempts for psychiatry appointments. After four years, his drug use was down to once a week, he was compliant with psychiatric medications, and was talking of getting a job as a gardener.

These case studies illustrated points of particular relevance to Aboriginal people, such as the importance of unpressured, respectful communication, the importance of extended family ties, and the value of coordinated approaches to health based in culture and community. There were also lessons applying to all people on opioid replacement treatment, such as the need for adequate analgesia, and the differing sorts of treatment retention and compliance issues with methadone and buprenorphine.

Next year's program is being finalised presently. We will start on Tues Jan 31 with Dr Adam Winstock speaking about drugs, alcohol and driving. "Do we have to inform authorities about such matters?" (eg. RTA as well as DOCS, Medical/Nursing Boards, etc?).

9 November 2005

APSAD annual scientific conference, 2005

9th November 2005

APSAD annual scientific conference. Melbourne, Victoria, Australia. Day three.

The third day of the East Melbourne addiction meeting started with an up-date by Keith Humphreys on the place of Alcoholics Anonymous and other self-help groups in managing addictions. He quoted the estimated staggering numbers of such groups as AA, NA, Alanon, Alateen, Cocaine Anon, etc, across the world. While accepting that scientific proof of the benefits of such social interventions are not possible, he stated that numerous high quality studies showed that health budgets saved large sums from those who chose to use self-help rather than traditional medical services such as counselling, cognitive behavioural approaches and pharmacotherapies. He also quoted one of the most convincing studies from 1981 in which not one patient who was 'passively' referred to AA actually attended a meeting. This compared with 100% who had a personal telephone referral from an AA sponsor. This is consistent with my own experience in simply recommending AA by handing a leaflet with dates, time and addresses of local meetings.

The next talk was by Annie Madden who spoke eloquently about ethics of research on subjects with drug and alcohol issues. Ms Madden was commended for her work in various capacities with and for drug users in NSW and Canberra over many years. This was backed up later by Adam Winstock who praised the Intravenous League for their cooperation and assistance in some of his novel research on drug diversion in South West Sydney. In this parallel session he and his colleague Tony Jackson showed that in their diverse Health Service cohort both methadone and buprenorphine were diverted for numerous reasons. Their findings indicated that about 5 per 1000 doses of buprenorphine were diverted. This was more commonly reported from those treated in community pharmacies where time and other factors make effective direct supervision less practicable. He said that one public clinic stated that they have had absolutely NO diversion yet his confidential questionnaire showed that the clinic had dozens of such instances reported by patients. Dr Winstock takes a non-judgemental line in addressing diversion, treating each case individually and working on the issues leading to the apparent misuse of the prescribed medication. He reminded us of two ways buprenorphine can be diverted, (1) obscuring the drug within the mouth and (2) secreting it elsewhere during administration. These were reported to be equally prevalent in western Sydney. 'Cracking' the tablets to coarse granules was probably an effective strategy both in aiding absorption and preventing diversion. However if tablets are pulverised to powder this can defeat both aims by creating either a milky solution which is swallowed or else forming a paste which is not absorbed at all well either. [In our own service we usually break the tablets in two and to observe them 'in situ' at least twice before they have gone.]

The reasons respondents gave for diverting their medication included: (1) to take later in the day (2) to inject (3) to sell (4) to take a lower dose (5) to store (or 'squirrel' as Dr Bell terms it). Dr Winstock speculated on the 'big picture' reasons for such diversion as being: (1) the continued shortage of treatment positions (2) constraints on such treatment (3) desire for lower maintenance doses (4) as a replacement for street heroin (ie for illicit purposes). Overall he felt that diversion itself was prima facie evidence for a breakdown in the therapeutic relationship, rather than just a lack of understanding of motivations behind it. He pointed out that especially since the 'heroin drought' buprenorphine and methadone can be excellent value on the streets, being cheap and longer acting.

Another important contribution on day three was Winstock's other paper described three means of starting buprenorphine in an attempt to avoid early drop-outs. His own elegant longitudinal study showed in a variety of community patients, those who were given over 17mg in the first three days of treatment had almost twice the chances of still being in treatment at 6 months as those given 17mg or less (54% vs. 29%). He also found heavy heroin users had higher drop-out rates. We were told that whether methadone or buprenorphine, the first few weeks are crucial since inadequate dosing may be the reason for some to drop-out. The risk of early toxicity with methadone is far lower when using buprenorphine . hence his and others' suggestion at this conference that we move away from the 'start low - go slow' approach and move to a 'new paradigm' for a 'new drug'. His preference was for 8mg on the first morning with an option for an extra 2-8mg later that day if desired. Some follow on day 2 with 12mg or more if cravings, insomnia or drug use persist. In our surgery we usually start with 4mg and repeat later in the day if needed (which it often is).

Nick Lintzeris then told us about his study from London (with Ridge, Gossop, Strang and Witton) looking at a large number of maintenance treatment starts (or re-starts) as to preference, experience of and actual prescription for four drugs: methadone, buprenorphine, lofexidine and dihydrocodeine. He suggested that lofexidine 'is hardly used any more in England' and that 'it is virtually the same as clonidine, except much more expensive'. He showed many comparative figures, reflecting much work from his team, but which overall showed that most patients eventually got what they had expressed a preference for initially. Because of the longer duration of action of (pure) buprenorphine, sufficient dose can be given to last 24 hours without causing the sedation which sometimes occurs with methadone. This gives rise to the 'clear-headed' reports from some patients. However, he also reminded us that many patients feel better on methadone, hence the need for individual choices, the only real other issue being pregnancy where buprenorphine is relatively contraindicated and the combination drugs completely contraindicated.

Nico Clark gave an illuminating talk on transferring in-patients from high dose methadone (between 40 and 100mg) to buprenorphine using clonidine and Valium. While all were patients wishing to try buprenorphine, several had to return to methadone dissatisfied within 2 weeks of the transfer. A significant proportion were only slightly uncomfortable and some had no withdrawal symptoms at all. The methadone was stopped for a full 24 hours and where possible for 48 hours while close observations were done in the detoxification centre being used.

Suzi Nielsen spoke about the Melbourne experience with buprenorphine and benzodiazepines. It was one of several descriptions during the conference which all seemed to be quite consistent. A majority of opioid maintenance patients (up to two thirds) have used benzodiazepines in the past 6 months and about 10-20% are dependent at any one time. One strategy was given from the Adelaide group presented by Kate Morefield on how to deal with this problem. Following on the work of Rickells, they tested a protocol to put long-term dependent patients onto 40 weeks stepped reduction doses of long acting benzodiazepine, in this case clonazepam. They used 5 weeks slow reductions by 25%, followed by 5 weeks plateau doses which was repeated in steps. The final reductions were more individually tailored. The drug was to be taken supervised on the same regimen as the opioid, from the same dispensary. Matched benzo users in parallel and "usual" treatment were used as controls and at the end of 12 months, despite numerous relapses, far less benzodiazepine (about 75% less) was being consumed by the trial patients. Such interventions are unlikely to eliminate benzo use but should enable substantial reduction in overall use of the drug, consistent with harm reduction principles. It is probably the responsibility of maintenance prescribers to address benzodiazepine use in their patients - yet many clinics and pharmacies still do not have a protocol of dispensing or administering for such dual dependencies. Poisons regulations are not attuned to this in some states. Community pharmacy may not be ideal for such treatment in new or unstable patients where there is a choice of a specialist clinic. It may be that a subsidised PBS item number for 'administration' of a small quantity of diazepam could solve the major conundrum that when we prescribe less than 50 tablets it costs our patients more money.

Presentations on hepatitis C reminded us that 90% of such infections occur in drug users and it is the responsibility of every maintenance prescriber to address this disease. Greg Dore and his group described early results of a multicentre trial of the treatment of 'acute' (or at least recently acquired) HCV using 24 weeks pegylated interferon. The treatment looks promising in HCV but may not be effective in HIV co-infected patients. Nick Walsh and Turning Point team are up-beat about a dependency clinic as a 'one stop shop' for addressing blood borne viruses (BBV). Their abstract described the use of a peer counsellor to facilitate regular in-house blood testing to monitor the need for vaccination (HBV, HAV) and/or referral for biopsy. They also dispense anti-virals at the clinic. In the same bracket Ian Chaussivert points to the enormity of the problem by describing early numbers from their 'clinic within a clinic' started in January. Out of an estimated 550 HCV carriers who have been in contact with their service, up to 200 may benefit from treatment. In the first 5 months, they assessed 32 patients and two have commenced therapy while 4 await biopsy. While these models may be very useful for New South Wales where a large proportion of patients are treated in clinics, other strategies are needed for other states and territories where community pharmacies deliver most opioid maintenance treatment. A more traditional medical referral system requires that doctors ensure that their maintenance prescription patients have blood tests ordered and referred as appropriate. A useful model might be Pap smears for cervical cancer which are now standard practice. Ian Kronborg and colleagues related a slightly larger pilot study of 23 methadone patients prescribed 'standard' antiviral treatment of 24 or 48 weeks (40% genotype 1, 55% genotype 3, 16% already with cirrhosis). We await further results after the full 50 outcomes have been tabulated.

I apologise if these summaries seem to be biased towards my own 'medical' interests. In fact many other fascinating subjects were covered in this conference. These included stimulant use and abuse, performance enhancing drugs, policy issues, injecting rooms, Aboriginal health, ethics, drugs and driving, alcohol "Interlock" ignition lock program, designer party drugs, withdrawal practices, drugs in pregnancy, specialist College policies, pain management and more.

It was disappointing that despite just receiving Commonwealth funding of up to 2 million dollars, those utilising naltrexone implants and performing rapid detoxification did not present any of their experimental findings. We could sure use funding like that in Redfern where our patients often have to pay $2000 or more per year out of their own pockets for pharmacy dispensing of their medication.

Melbourne is a beautiful city and it is a good time of year to visit. It was a frustration to have to stay indoors for the conference. I hope most delegates from out of town managed to enjoy some of the city's pleasures aside from the meeting. Congratulations to the conference organisers and presenters. The ever-present Walter Ling from California has said that he believes our annual APSAD conference is probably the worlds second largest and certainly most diverse dependency 'talkfest' (after the AATOD meeting which is held every 18 months in North America - next is April 2006 in Atlanta).

Comments by Andrew Byrne ..

8 November 2005

APSAD 2005 Conference - Melbourne 7-9 November

8th November 2005

APSAD Conference 2005. 'Australian Professional Society on Alcohol and other Drugs' scientific meeting

The 2005 APSAD conference has all the hallmarks of a great meeting. While I missed day one, having been in China, evidently there was a full program of diverse subjects covered by well qualified folk. I understand that there was a 'full and frank' discussion in a large plenary session on the origins of the Australian 'heroin drought' (so-called - and it may NOT be JUST Australia involved). One view was that 'new' law-and-order initiatives had meant drugs were less available in Australia. Another was that other factors such as poor seasons in the opium growing countries as well as increased consumer demand from an expanding Asian market led to less heroin for the relatively small Australian market. Much has been written since 2001 and many statistics examined and interpreted. It is agreed by all that the price of heroin increased dramatically and purity dropped while annual overdose deaths dropped from over 800 to under 300 in Australia overall. We should remember that even with capital punishment possible for traffickers, compulsory detoxification for users and a shortage (or absence) of effective treatment options, opium and heroin are readily available in most countries in Asia, showing that 'Tough on Drugs' is probably more a slogan than a policy. It is a shame that so many criminology experts are salaried and thus under certain constraints not to 'rock boats'.

Tuesday's proceedings started with Tim Rhodes discussing issues from the UK on 'The social structure production of drug-related harm'. He suggested that we go further than simple harm reduction techniques and examine the whole "risk environment" including political, social, economic and geographic factors in drug use. He then brought together much of what we know about the origins and exacerbators of drug dependency in our societies including poverty, homelessness, depression, etc.

Rajita Sinha then spoke on 'the role of stress and cues in addiction - how does it relate to clinical practice?' She reminded us of the role of stress in relapse in drug and alcohol addiction. Her talk was largely based on the American abstinence model. She showed some PET scans, quoting Dr N. Volkow's demonstration of the physiological basis of stress and certain specific changes in the brain's reward circuits. Hippocrates described similar sentiments over 2000 years ago, needing little electro-science but just his own learning and experience. Her two video clips of two recent patients describing why they relapsed were hardly novel for the gathered audience. She said that the patients, recorded in September this year, had given permission for the use of their recorded interviews.

Eric Strain from Johns Hopkins told us of the importance of choices in treatment and that oral supervised methadone was, for about 25 years, the only treatment for opioid addiction. Even in the US, LAAM was used, while dihydrocodeine, heroin prescription and parenteral methadone have been used quietly in certain countries for a generation or more. He said that the past 15 years was 'a golden age' of drug development, stressing that we not lose sight of the three complementary factors in the addicts progress, only one of which is medication. He then went in rapid succession through a series of newer drugs for alcohol, cocaine and opiate addiction. He said that the US funding agencies would only allow research on non-opiates, which for some reason included tramadol, the only 'non-scheduled' opiate on the US market. Tramadol may be a step down from buprenorphine and methadone for progressively lower levels of opiate dependency. While not having the ring of scientific language, it is probably an area worthy of more research.

He then discussed naltrexone, acamprosate and even combinations of the two for alcoholism, quoting all the relevant studies. He did not cover the monumental disinterest of the medical profession in using such drugs (as stressed by the next speaker, also American). Ondansetron and topiramate were also mentioned. In the next 15 minutes he mentioned over a dozen approaches including current mooted FDA approval for rimonabant in obesity treatment. The manufacturers seem reluctant to become involved in drug addiction trials although there is already quite a degree of promise in this cannabinoid receptor blocker. Dr Strain gave some of his own preliminary results in a pilot study of lofexidine for opioid cravings. His results were mixed at best, yet he felt positive about further research. It would be extraordinary that if lofexidine actually reduced cravings that it never developed a black market in England where it has been used freely for many years. At the conference, a UK speaker spoke disparagingly about his experience with lofexidine in opioid addiction.

Next we heard Dr H. Westley Clark describe (at some speed) 'The art and science of knowledge transfer'. Early on he gave a 'plug' for the 'Addiction Technology Transfer Center' and its web site: http://csat.samhsa.gov/ This is one way that his organisation the 'Substance Abuse and Mental Health Services Administration' (SAMHSA) uses to raise clinical standards. He sounded unduly pessimistic, quoting an average of 15 years for advances in research to be implemented clinically (although in some places is seems to take forever!). While his organisation was "committed" to the field, one wonders what all the other medical bodies are doing in the intervening years. We know that with help from drug companies and the media, some advances can be made within weeks (eg. Viagara). His group has produced high quality clinical guidelines for many years. They are available in print and electronically at TIP (Treatment Improvement Protocols or see http://www.kap.samhsa.gov/products/manuals/) which are also available on the SAMHSA web site above (as long as you express an affinity with Uncle Sam). He comes from the only western country where community pharmacists are banned from administering methadone for addiction purposes just as American doctors are banned from prescribing it. Don't they trust their own professionals? He explained that buprenorphine was made available, not by an authority but through a 'waiver' system. It used to be the British 'system' which 'waived the rules', now it seems to be American!

In the course of a wide-ranging talk on recent innovations, Dr Clark also made some intriguing and seemingly inconsistent remarks. He said that in many parts of the USA now, pain killers (mostly taken orally) rather than street heroin (often injected) are the main reason for admission to opioid addiction treatment (as also found in Tasmania and N.T.). Apparently these prescription tablets are prescribed by avaricious or simply naïve doctors - and the tablets readily find a street market from unscrupulous (or perhaps desperate) 'consumers'. Yet in almost the same (very long) breath Dr Clark stated his confidence in the lack of diversion of the buprenorphine combination in the US, although he did not cite any sources. Is it hard to imagine that this drug could be so successful for addicts in treatment and NOT command a place on the black or 'grey' market, especially in America where treatment positions are often either in short supply or else very expensive. We were told elsewhere in the conference that substantial buprenorphine diversion had been reported in the past from Perth, New Zealand, Finland and Scotland - and some speakers even quoted recent street prices for methadone and buprenorphine as if they were high street commodities (which they probably are). Dr Clark also said that out of 600,000 US doctors, only 1000 are addiction specialists and only another 2000 others have expressed an interest in prescribing buprenorphine (by doing a short course in dependency treatment). This he pointed out was woefully inadequate for the needs of his country where less than 1% of doctors are prepared to be involved in addiction treatment.

It seemed odd that this conference had broken with a number of long standing 'conventions', including timing of the James Rankin oration which was ably given again by Ian Webster on the second mornings. He said that either the management had forgotten that he spoke a couple of years ago, or else they were so impressed that they wanted more of the same! He did not disappoint, painting a generous verbal 'picture' of his colleagues, Australia's successes and some gaps needing attention in the dependency landscape.

The poster displays this year were not just a side-show but were given a 90 minute section when their authors stood by and explained their work. This was largely successful but also caused some congestion as so many people were interested (I was reminded of the fowl pavilion at the Easter Show). The prize for lateral thinking should probably go to the enterprising group from Perth who showed that keeping an animal (a bunny rabbit in this case) makes detoxification more manageable and successful. We sometimes forget that for some drug addicts, attending the clinic, self-help group or dispensary is sometimes the most interesting thing they do all day. Hence a chat or a 'pat' may not go astray.

In a session on pharmacotherapies after lunch James Bell described his recent excellent study with Dr Batey from Sydney on the combination buprenorphine product. This may be the first time in the world that the combination product has been prescribed as a weekly dispensed medication in a parallel comparison with traditional daily clinic treatment. It appears that this drug combination was approved in the US, NZ and now Australia despite not one single trial of this kind (Fudala's study did not compare with traditional supervised addiction treatment). After consent and randomisation, patients had 3 months of either 'dispensed' or 'supervised' treatment and after that time were 'streamed' into dispensed or supervised medication. This was done largely according to self report and/or urine testing, although we were told that these two were quite inconsistent at times. The trial, performed in a socially deprived part of inner Sydney, somehow attracted a group of patients with a mean of 12+ years of schooling and were 70% in paid work. Dr Bell said that employment rates in patients presenting to his clinic had been rising over the years even though this seemed surprising to him (and to some of the audience). He described in detail the similarities between the groups for demographic and drug use characteristics. He then gave their findings of psychological testing, pathology results and self reported drug use � with no significant difference in outcomes apart from one aspect of 'stress' (but not 'anxiety', interestingly). Dr Bell reminded us that the main difference between the groups was daily attendance for one and weekly for the other, and that less stress in the weekly group was hardly surprising. Dr Bell agreed with one suggestion from the audience that pure buprenorphine may well have delivered the same results. In response to my question about evidence of diversion, we were told that some diversion was expected and that this had occurred, but it was not quantified any further. Despite enormous interest in the field and heavy sponsorship by the manufacturers, this was the only session which addressed the use of this drug combination which was approved only a couple of months ago by the TGA in Canberra (and is yet to be marketed). I was approached by numerous colleagues on this point and can only suppose that it is because there is so little evidence on the subject, despite the combination drug having been used in America for several years in community practice.

Nick Lintzeris then revisited the serious dangers of buprenorphine in combination with other depressants. He first reminded us that in opiate na�ve individuals, buprenorphine can be very toxic, citing 4 reports of overdoses from the anaesthetic literature. He then said that 27 out of 43 buprenorphine related deaths in the UK had involved benzodiazepines in addition. Following old animal reports (which he reported to APSAD in past years), he has since performed an excellent study on volunteer subjects in London. Some initial problems with ethics approval were overcome by using two separate groups. However, this made direct comparisons less rigorous. Stable maintenance patients were given 50% extra methadone (or placebo) and/or 20 or 40mg diazepam (ie. 4 groups) and then perform detailed psychometric testing, most importantly, at peak (3 hours). His conclusion was that 50% extra methadone given with placebo or even 20mg Valium had little effect on sedation, respiratory rate or other measurable domains. However, 40mg had substantial effects on all factors measured. His conclusion was that despite relative safety when used on its own, buprenorphine in combination with other drugs is unpredictable and can even be lethal.

Jason White then gave a summary of his and others' work on methadone metabolism in relation to 2 important genetic markers. He also said that although the observed equivalence ratio of 1:2 of levo methadone to racemic (R,S) methadone seemed relevant to most situation, there may be a subgroup of patients who are sensitive to levels of the inactive enantiomer (dextro or 'S' form) and who may benefit from receiving half the dose of the (double strength) active (or levo, or R) form. This theory should be easy enough to test in practice if the drug could be sourced. Also administering the S form might also be a way to test it. Dr Kreek at Rockefeller tells an amusing if pathetic anecdote of the world's entire supply of inactive (S) methadone being used up by an inexperienced research assistant in a small animal experiment at her lab some years back.

Eric Strain then discussed the 20 year history of consistent buprenorphine research. For some reason his group examined the QT cardiographic changes in some methadone patients, despite it not being a high profile problem after 40 years of experience. While he made passing reference to the serious complication of torsades which has also happened with LAAM and numerous other common medications (Yap, 2000), he did not report that the mean dose level of almost 300mg in those developing such complications (Krantz, 2000), nor the fact that buprenorphine is widely believed to be less effective than methadone in those with high opioid requirements or severe pain management problems.

The rates of two different cut-offs of prolongation of the QT segment in the standard ECG was shown to be more prominent in methadone then buprenorphine cases. While this is reassuring for the legal department of the manufacturers of the latter, it is not clear whether it has any clinical significance. It was disappointing that LAAM was taken off the shelves by its manufacturer supposedly in a response to cardiotoxicity when it should be the clinician who makes the decision balancing risk versus benefit in the individual. The same logic might see methadone withdrawn except that this would probably cause a revolution. Also, there is more than one manufacturer which is healthy for all including consumers.

Paul Cassadonte then told us about his work with long-acting naltrexone injections (Vivitrex) in alcoholism and a more recent trial which included both alcoholics and drug addicts. His group found that monthly injections, while large and in some cases uncomfortable, had substantial positive effects on alcohol-free days and overall alcohol consumption. One wonders if they could be combined with acamprosate tablets to improve results.

The next bracket saw Paul Haber report a controlled comparison of these two latter medications. A session on inhalants was chaired by Jane Maxwell from Texas. Wendy Loxley introduced 5 speakers on early and brief interventions for harm prevention. Other parallel sessions were on prison populations, court diversion, illicit drug market economies and cannabis harms.

The Melbourne organizers should be congratulated on an excellent venue, great service in the 'old lady' hotel Hilton on the Park (next to the MCG) and fine scientific papers from a range of invited and local speakers. Alison Ritter and her colleagues should get a medal for their preparation and hard work.

The conference dinner was another 'first' for this conference, and I hope a 'last'. Rather than a sit-down meal with colleagues, this was held in the tennis centre. Only after serious urging from folk with sore legs they finally produced some chairs for what was otherwise a stand up 'entertainment' starting with the Tivoli lady dancers whose average age was over 70. Initial mirth was not maintained for these proud and ambitious senior citizens. A stand-up comedian and flame thrower (the smoke detectors had to be turned off) did not encourage collegial discussions, reminiscences or new introductions which is what a conference dinner should be all about. Also a loud band producing aggressive, amplified modern music is not my idea of a good night out either. While I approve of paying for drinks individually, I find it most annoying that, with 2 friends, I ordered 3 glasses of white wine without being told that a whole bottle would cost much the same price (which others learned quickly). The food was either finger food or else served in boxes with sauces to dip. In order to consume the boxes, one had to put one's drink down, but there were few tables on which to do so. Glasses which were put down were quickly taken away by attentive staff. All in all a disaster with only the 'fresh air' for us to 'smoke' and retreat from the din within. I vote for a string quartet next time and a sit-down dinner featuring Queensland seafood and tropical fruits for dessert in Cairns.

Comments by Andrew Byrne ..

22 September 2005

Naltrexone implants: Claims and counter claims: None so blind

Addiction Biology 2005 10:201-204

Letters to the Editor

Naltrexone implants as treatment for heroin dependence:

Contents of this post

Part I of letter

There are a number of important methodological problems with this recent study of naltrexone implants (Hulse et al., 2004a). The selection of patients was opportunistic. No inclusion and exclusion patient selection criteria are provided. The authors do not state exactly how many specimens were obtained from each of the patients with either the 1.7g or the 3.4g implant, and the testing was not done according to any fixed protocol.
The most serious problem is the presentation of the data. Only blood concentrations �standardised� to 70kg body weight are reported, apparently to compare the two sizes of implant. It is, however, misleading to use plasma concentrations standardised to 70kg bodyweight in discussing the minimum effective concentration (2ng/ml). In the examination of kinetic data, relationships between plasma concentrations and body weight can be assessed, but actual plasma concentrations should have been reported, as has been done in the other reported studies on sustained release naltrexone preparations (Comer et al., 2002; Olsen et al., 2004). Concentrations �standardised� for bodyweight are not a useful clinical measure, and this study provides no helpful information into how to adjust the implantation protocols for bodyweight.
A high proportion of bodyweight-standardised blood concentrations reported in this study were below 2 ng/ml. Further, in a second study of sequential naltrexone implants (Hulse et al., 2004b), two out of five patients are reported as having plasma concentrations, standardised to 70kg body-weight, below 1ng ml for at least some of the time. Based upon the data presented in these studies it appears likely that blood concentrations were inadequate in several patients. Without actual concentration data, however, these studies allow no conclusions to be drawn about the proportion of subjects who had naltrexone �above therapeutic levels�.
These flaws, especially in the data analysis, make it very difficult to draw conclusions about the clinical performance of naltrexone implants in these studies.

Dr Andrew Byrne* MB BS FAChAM, Professor Garry Graham�, Dr Richard Hallinan* B, Dr Bridin Murnion BSc, MBChB

* Dependency physicians, 75 Redfern St, Redfern, New South Wales, Australia

# Department of Clinical Pharmacology and Toxicology, St Vincent�s Hospital, Sydney, Australia


Hulse GK, Arnold-Reed DE, O�Neil G, Chan C,T, Hansson R, O�Neil P. (2004a) Blood naltrexone and 6-�-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology 9:59-65
Hulse GK, Arnold-Reed DE, O�NeiI G, Chan C-T, Hansson R. (2004b) Achieving long-term continuous blood naltrexone and 6-�-naltrexol coverage following sequential naltrexone implants. Addiction Biology 9:67 72
Comer SD, Collins ED, Kleber HD, Nuwayser ES, Kerrigan JH, Fischman MW. (2002) Depot naltrexone: long-lasting antagonism of the effects of heroin in humans. Psychopharmacology (Berl) 159:351 60
Olsen L, Christophersen AS, Frogopsahl G, Waal H, Morland J. (2004) Plasma concentrations during naltrexone implant treatment of opiate-dependent patients. BrJ Clin Pharmacol 58:219

Reply to Part I:

I write in response to Dr Byrne et al�s letter commenting on our recent publication (Hulse et al., 2004) in Addiction Biology. First, Dr Byrne comments on the vagueness of patient selection and study design. This is despite the methods section clearly stating that the study was a retrospective review of blood sample results from clinical records with subject selection, data inclusion criteria and number of samples collected per patient also delineated in the manuscript.
Secondly, with regard to Dr Byrne�s comments on the "serious" flaws regarding the validity of using body-weight standardised blood concentrations of naltrexone, we feel that this is open to interpretation. Our original manuscript submitted to Addiction Biology reported non-standard blood levels (as advocated by Dr Byrne). However, the standardisation was made in response to the journal reviewer�s comments on our paper. The rationale of the reviewer and journal was that as all subjects received a fixed quantity of naltrexone in their implant, if non standardised values were used then we would have to reconcile larger body mass (male) subjects with a lower circulating blood naltrexone concentration with smaller body mass (female) subjects with a higher blood naltrexone concentration when estimating longevity of implants. To overcome this we standardised blood concentrations to a body weight of 70kg. Exponential curves were fitted to the standardised values based on a least squares best fit method. These calculations take into account the variation in blood naltrexone levels between subjects.
Lastly, this paper is a research article and was not written to provide a clinical framework for the use of implants. It is therefore erroneous to attempt its use as such.

Prof G K Hulse, Dr D E Arnold-Reed

School of Psychiatry and Clinical Neurosciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia


Hulse GK, Arnold-Reed DE, O�Neil G, Chan C,T, Hansson R, O�Neil P. (2004) Blood naltrexone and 6-�-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology 9:59-65

Part II of letter

We have serious ethical concerns about a recent paper (Hulse et al., 2004) reporting naltrexone and 6-�-naltrexol levels following naltrexone implant.
In this paper, the authors have not followed the generally accepted sequence of studies in drug development. They have commenced a Phase II study before they (or others) have reported Phase I studies. Researchers in Phase I clinical trials test a new drug in a small group of people (generally 20�80) for the first time to evaluate the safety and likely safe dosage range and to identify side effects. In contrast, researchers in Phase II clinical trials give the study drug to a larger group of people (100�300) to see if it is effective and to further evaluate the safety of the drug.
Phase II studies of disulfiram implants were also conducted before Phase I studies had been undertaken (Johnson and Morland, 1991; Konoplitskaya et al., 1991). The Phase II trials were unsuccessful because extensive fibrosis sealed off the implants. Had Phase I studies been conducted first, this would have been detected and ineffective Phase II studies would have been thus avoided. Ideally, Phase I trials should always be prospective and this is a retrospective study.
There were other methodological problems including opportunistic selection of patients, no published inclusion and exclusion patient selection criteria and lack of clarity about the number of specimens obtained from each of the patients with either the 1.7g or the 3.4g implant.
The authors state that they have ethics committee permission to review patient records and to perform the study. However, they do not state explicitly that they have ethics committee approval for the novel naltrexone implant itself. The authors do not refer to any protocol to detect, record and consider adverse effects. The lack of such a protocol may well have led to an underestimation of adverse effects. Serious adverse events with implanted naltrexone have been reported (Hamilton et al., 2002). The authors do not provide or refer to any plan of action in the case of disease or trauma that would normally require standard opioid agonist therapy.
The treatment in this study has been approved by the Therapeutic Goods Administration (TGA), Australian Government Department of Health and Ageing, under the Special Access Scheme (SAS) (http: www.tga.gov.au does html sasinfo.htm). This scheme enables medical practitioners to supply unapproved medications to some very seriously ill patients under clearly specified conditions on a case-by-case basis. However for trial purposes, use of this therapy should properly be approved under the Clinical Trial Exemption Scheme (CTX) or the Clinical Trial Notification Scheme (CTN) under the Australian NHMRC guidelines (http: www.tga.gov.au does html clintrials.htm). In Australia, naltrexone-implants are required to be stamped with a notice in large print warning against use in human subjects. It is not clear if patients enrolled in this study have been informed about this notice.
The declaration of interest states that �one of the authors (G.O�N.) is a director of GoMedical, the medical device company which manufactures the implants�. Yet this declaration states that this author only �would be expected to receive pecuniary benefit (amount unspecified) from GoMedical in his role as surgeon performing the implants�. The declaration does not state whether or not any of the authors stand to gain from marketing the devices.
Studies of naltrexone implants should meet the same high and scientific standards as other studies evaluating novel medical treatments for the same condition. We believe that this paper does not meet the same standards now accepted for the evaluation of substitution treatment for heroin dependence.

Dr. Alex Wodak, Dr Robert Graham

Alcohol and Drug Service, St. Vincent�s Hospital, Darlinghurst, NSW, 2010, Australia


Hulse GK, Arnold-Reed DE, O�Neil G, Chan C-T, Hansson R, O�Neil P. (2004) Blood naltrexone and 6-�-naltrexol levels following naltrexone implant: comparing two naltrexone implants. Addiction Biology 9:59-65
Konoplitskaya KL. Pkhakadze GA. Narazayko LF. (1991) Biocompatibility of a prolonged-action anti-alcohol preparation. Biomaterials 12:701 704
Johnsen J. Morland J. (1991) Disulfiram implant: a double-blind placebo controlled follow-up on treatment outcome. Alcoholism: Clinical & Experimental Research 15:532 536
Hamilton RJ, Olmedo RE, Shah S, Hung OL, Howland MA, Perrone J, Nelson LS, Lewin NL, Hoffman RS. (2002) Complications of Ultrarapid Opioid Detoxification with Subcutaneous Naltrexone Pellets. Academic Emergency Medicine 9:63 68

Reply to Part II:

Doctors Wodak and Graham are correct in their assertion that the development and registration of pharmaceutical drugs commonly involves the successive testing of the drugs in phase I prior to phase II and subsequently phase III trials. There is however, within many countries, the ability for physicians under clearly specified conditions on a case-by-case basis to prescribe or use non-approved pharmaceuticals for some seriously ill patients. Legislation that allows this commonly holds that prescribing of non-registered pharmaceuticals can occur where there is a high risk of mortality associated with the morbidity under treatment. Perhaps the most recognised instances of this supplement use is oncology, where use of cancer treatment drugs, which have been successfully used overseas, but not registered in the practitioner�s country, might be used by the practitioner to treat a cancer. Clearly where this takes place, it is important to evaluate outcomes associated with these treatments.
As noted by Drs Wodak and Graham, this legislation in Australia is known as the Special Access System (SAS) and administered by the Commonwealth Therapeutic Goods Administration (TGA). Given increased risk of mortality amongst heroin users, this SAS has been used by a number of Australian community and hospital based physicians in at least 4 of the 6 Australian States to administer sustained release naltrexone preparations. These preparations have included a number of those developed in the US with a likely clinical pharmacokinetic life of 6-8 weeks and the locally Australian produced GoMedical implant. For the last 5 years the TGA in Australia has continued to allow naltrexone implants to be administered under SAS. It is estimated that in the past few years, in excess of 3,000 heroin dependent persons have been treated by this method in the States of Victoria, New South Wales, Queensland and Western Australia.
Clearly, as with the cancer scenario, it would be foolhardy and I suggest irresponsible not to superimpose some type of monitoring and evaluation on these patients. The result of analysing naltrexone blood samples from a cohort of SAS treated patients was in fact the basis for the two papers published in Addiction Biology. As such, this was not a phase II drug development study. This is made clear in the paper, in that Drs Wodak and Graham should seek to suggest otherwise is misleading. Lack of methodological clarity raised by the two doctors is also misleading, given that this again this is clearly delineated in the paper. Clearly an international journal such as Addiction Biology has in place checks and balances to ensure that this type of information is made available to the readers and they and the paper�s separate and independent assessors found it adequate.
Drs Wodak and Graham refer to the lack of protocol to detect, record and consider adverse events. This is the type of protocol that would be required where a randomised clinical trial was in place, yet these were SAS not clinical trial treated patients. In the context of SAS patients, monitoring of adverse outcomes is the responsibility of the treating physician, and I would hasten to note that the TGA has mechanisms for collecting this adverse information from SAS treated patients. In making their case the doctors refer to "serious adverse events associated with implant naltrexone." (Hamilton et al., 2002). Of course those who are familiar with this literature will recognise that this article refers to morbidity and mortality in the US resulting from the use of implants to precipitate rapid opiate detoxification and not sustained release naltrexone for the purposes of naltrexone maintenance. This typifies Drs Wodak and Graham�s letter with subtle non-truths to create illusion to support a fictitious case; words " twisted by knaves to make a trap for fools". There is no place for this type of misrepresentation and Drs Wodak and Graham stand reprimanded for this deceptive behaviour. This includes both the misrepresentation of the aforementioned article and the attempt to present SAS patient data collection as a clinical trial.
Questions are also raised about the statement of declaration and pecuniary interests of the authors in marketing the implant. I would hasten to note that the wording of this disclaimer was superimposed by the Journal and perhaps any issues of concern should be raised with them. However, for the record, we state categorically that neither I nor any member of my research team has, or will receive pecuniary interest in marketing of this implant product. We are a University clinical research facility and our sole objective is the unbiased reporting and evaluation on clinical activities. For Drs Wodak and Graham to suggest otherwise is both disturbing and a personal affront.
Of course, the reader could be forgiven for believing that all this information will be new to Drs Wodak and Graham, but alas, I understand they are already conversant with all the facts. That these two doctors suggest that evaluation of SAS patients treated with naltrexone implants should not take place is to me not only abhorrent, but lacking in vision. In fact the opportunity to monitor and access valuable information from SAS treated patients with implant naltrexone in Australia has been recognised by the Commonwealth Department of Health and Human Services, who in consultation with the TGA (a subsection of this Branch) identified additional funding and identified areas of information to be garnished from these SAS patients. This includes histological information on tissue reactivity around the site of implant, ultrasound to assess biodegradability and I might add additional pharmacokinetic blood collected similarly to that published in Addiction Biology. Similarly, the National Health and Research Medical Council (NH&MRC) has recently funded for hospital morbidity, mortality and mental health data to be collated from a large cohort of these SAS treated patients. Ultimately, this information, coupled with more data collected from randomised double blind clinical trials will be used to assess the viability of the Australian implant for transTasman registration. I also understand from the Australian Commonwealth Department of Health that as part of this assessment, the National Drug and Alcohol Centre in Sydney, of which Dr Wodak is an adjunct senior lecturer, has been or will be funded to garnish morbidity and mortality data from similarly treated SAS patients. This would put Dr Wodak�s facility in exactly the same position as my research team, yet Dr Wodak makes no reference to this.
It would appear that Drs Wodak and Graham are not only at odds with myself, but also the Commonwealth Department of Health, the Therapeutic Goods Administration and the NH & MRC in their objection of data being sought from SAS treated patients. For clinical researchers to not garnish valuable information from patients treated by new methods under the SAS legislation would be a tragedy, yet for some, this simple concept seems incomprehensible. "There are none so blind as those who will not see."

Prof G K Hulse

School of Psychiatry and Clinical Neurosciences, University of Western Australia, 35 Stirling Highway, Crawley, WA 6009, Australia


Hamilton RJ, Olmedo RE, Shah S, Hung OL, Howland MA, Perrone J, Nelson LS, Lewin NL, Hoffman RS. (2002) Complications of Ultrarapid Opioid detoxification with Subcutaneous Naltrexone Pellets. Academic Emergency Medicine 9:63 68

20 September 2005

Drugs in pregnancy

Tuesday 20th September, 2005

Associate Professor Paul Haber and Christine Stephens, Nurse Manager Drug Health, RPAH.

This seminar gave us an overview of the Drugs in Pregnancy Service (DIPS*) at RPA Hospital, covering issues around drug use in pregnancy, followed by some case histories to illustrate approaches to various management dilemmas. Christine Stephens outlined the general approach DIPS used over time, stressing the change to a family unit focus that happened after their 1994 review. 'DIPS' aims to build relationships between the patient, her family and the various service providers before the baby is born, and they to try to be as inclusive as possible in their approach to team management. Early intervention is of prime importance. They also aim to build up supports for the family that are needed in the baby's first two years of life, and stress the value of having health care providers involved who are committed for the long-term. Liaison is done with GPs, Redfern Aboriginal Medical Service, family support units, DOCS, Benevolent Society, Early Childhood Centres and other relevant groups from as early in the pregnancy as possible. As well as this focus on the multi-disciplinary approach to pregnancy and post natal care, 'DIPS' tries to foster inter-agency collaboration between such groups, being very aware of the difficulties inherent in inter-agency communication. Comprehensive discharge plans with clear assignment of responsibilities and GP attendance at case conferences are examples of two methods used to achieve this.

DIPS do a comprehensive assessment of the family unit, and explore the psycho-social circumstances of extended family members and whether any family members also have drug dependency problems. As well as making sure appropriate supports are in place, DIPS will also ensure a family is not over-serviced, as this can be a hindrance to a family developing independent coping skills. DIPS are pro-active with regards to child protection case planning, always being upfront and willing to assist families in making the necessary changes. They aim to identify potential risks, eg finding out about safe storage of take-away methadone. They provide a lot of education about what to expect post discharge. As an example Christine outlined the importance of explaining to parents the changes that take place in babies who have been on morphine and are relatively settled, and become less settled when the morphine is ceased. In this scenario it is important to teach parents settling techniques before they are discharged and give them information about the spectrum of normal newborn behaviour.

DIPS aim to get women to attend a minimum of 5 antenatal visits as research has shown this to be the minimum number of visits needed to positively influence outcomes. They provide alcohol and other drug assessments and treatments including provision of inpatient withdrawal programmes and provide beds for women with intractable pregnancy-related vomiting. They do a lot of their ante-natal care on a one-on-one basis as their patient population tend not to go to parenting classes. They address nutritional and dental issues, social, lifestyle and pregnancy related issues, ever with a family-centred approach. 38% of their patients are of Aboriginal and Torres Strait Islander background, are often on a temporary Centrelink benefit and most are not alone, with partners, friends and relatives usually around. There are 20% of referrals which come from "out of area", most coming from the ante-natal clinic, GPs and other clients.

Presentations of women with untreated drug dependency into labour ward are now only 4.2%, a vast improvement, we were told, from the early 90s. DIPS staff have learnt that it is important not to just have one mode of operation but to be flexible and cut down barriers to access as much as possible.

The principle drugs of concern used by patients at this service are heroin, benzodiazepines, cocaine and alcohol. It was noted that alcohol is often less likely to be acknowledged by the patient to be a problem. Paul Haber told us that there is no evidence that light and infrequent drinking causes foetal harm, and outlined the NHMRC guidelines that suggest women consider not drinking at all whilst pregnant or otherwise limit intake to 1 or 2 drinks once or twice a week. Heavy drinking in pregnancy is clearly linked with the development of the foetal alcohol syndrome, where alcohol kills the cells that should form the midline structures in the brain and the face. It was acknowledged that many women with alcohol dependency are never seen at all by drug and alcohol services.

The effects of some other drugs in pregnancy were outlined. Because cannabis is usually used with tobacco it is not easy to look at its effects in isolation. Tobacco is known to increase the chance of low birth weight babies and decrease the length and head circumference of newborns (also can cause microcephaly). A Canadian study (Fried, 2000) was quoted in which heavy use in the mother was associated with adverse long-term effects on the offspring. These involved subtle changes in some finer points of global functioning but not intelligence. Tobacco use, on the other hand, was shown to be associated with lower IQ in a dose dependent manner in the same review of outcomes, some going for up to mid-teenage years.

Use of hydroponic cannabis (assuming it is stronger) was said to be more harmful to the foetus than 'bush' THC. Some believe the opposite to be the case as higher THC concentrations, if associated with less raw cannabis use, may limit exposure to other more dangerous burnt products in the smoking process (personal communication G. Chesher, retired associate professor of pharmacology, Sydney University).

The increased risk of SIDS among babies born to mothers who smoke is thought to be related to tobacco use rather than cannabis. Some women now 'cook' with cannabis to avoid using it with nicotine (eg. 'cannabis/hash cookies'). There was discussion about contradictory information that cannabis can cause nausea as well as treat it at different times. Because of the lack of evidence surrounding foetal safety and cannabis use in the mother, as with most other drugs, we should advise women not to use cannabis during pregnancy.

Cocaine use in pregnancy was also discussed and in this case there is no doubt of the deleterious effects to both mother and foetus. It is associated with maternal hypertension and increased chances of miscarriage, stillbirth and placental abruption. Babies are often born small for their gestational age and neonates experience a significant withdrawal syndrome. It is now recommended that all neonates born to mothers who have used cocaine have a scan done to detect cerebral infarcts, as there is a significantly increased risk of this occurring. Cocaine is harmful throughout all stages of pregnancy and many perinatal deaths are associated with maternal cocaine use.

There was a brief discussion of ecstasy use in pregnancy and Prof. Haber told us that the risks to the foetus were comparable to amphetamines. It was stated that about one third of "ecstasy" tablets have no psychoactive component, one third have a variable quantity of MDMA and one third contain other psychoactive drugs. This should be born in mind when monitoring the pregnancy of women who give a history of ecstasy use, although the strength may be more reliable in some circles.

Four interesting case histories were discussed to help guide us in our management of common scenarios. The first case involved a woman on methadone maintenance with intractable vomiting. Firstly it was recommended that she be advised not to have a methadone dose on an empty stomach and not to run or exercise straight after a dose. Both prochlorperazine (Stemetil) and metoclopramide (Maxalon) tablets or injection can be used, the former being also available in suppository form. The role of ondansetron (Zofran) is increasing, with obstetricians using it as a second line agent, especially as buccal �wafer�. It is not suitable for long-term use and is quite costly with a potential for side effects in pregnancy.

A change between formulations may help some women (Biodone sugar-free versus the syrup). In women on high dose methadone (and some others who are sensitive) split dosing (half morning and night) may be helpful. Take-away methadone may be increased for the period of vomiting so women can sip their doses at home.

A second case history also looked at the problem of pregnancy related vomiting, this time associated with weight loss. It was pointed out that many women lose weight in the first trimester of pregnancy and that this in itself is not a concern. What is important is to assess the fundal height to check that the nutritional status of the mother has not affected the well being of the foetus. The woman may need detailed information about nutrition and diet. Most antenatal clinics now only do a baseline weight of the mother at first presentation, as it is the fundal height that reflects intrauterine growth, and frequent maternal weighing may cause unnecessary worry.

The third case history brought up the issue of buprenorphine use in pregnancy. Whilst it is a �category C� drug, it was pointed out that so is methadone. There is limited local research into the effects of buprenorphine in pregnancy and on neonates. However, worldwide there are now greater than 250 published cases of buprenorphine use in pregnancy and most have reported safe outcomes. Currently pregnant women are advised to transfer over to methadone maintenance treatment, and this should ideally occur as an in-patient. There was much audience debate about this issue, but it was generally agreed that it is wise to get a second opinion if considering prescribing buprenorphine to a pregnant woman. If a woman is unable to take methadone, then the outcome following buprenorphine treatment is likely to be much better than having no prescribed treatment. Christine touched on the similarities and differences between babies experiencing neonatal abstinence syndrome according to whether their mother was on methadone or buprenorphine. The duration of total treatment time with morphine is much the same for babies coming from either situation, though indications are that for buprenorphine there are fewer needing morphine and for shorter periods. It was also emphasised that not all babies of mothers on MMT or buprenorphine require morphine, and that the chances of a baby developing NAS are not strongly dose-related.

The final case history promoted a discussion about child protection issues. In this particular case, a mother on MMT was found to have morphine metabolites in her urine at 3 weeks post-partum. Her baby was healthy and had not required any morphine post delivery. The importance of setting up frequent reviews with this patient was emphasised. A urinary drug screen result in isolation is not so much a reason to notify DOCS, but is certainly an indication to see the patient more often and explore what is happening in her life. Relevant issues to explore include whether the procurement of drugs is impacting on the family's finances, and whether drug use interferes with the mother's ability to attend to the needs of her newborn. We should ask about who else cares for the baby, and who else comes to the house. Do any drug dealers visit the house, or does the mother take her baby with her to procure drugs? Is she in a stable relationship or does she have several partners? We were reminded of the fact that two-thirds of deaths of babies occur in households where there are significant problems with drug and alcohol use, so we must always satisfy ourselves with regard to the safety of children.

Written by Jenny James, Daruk AMS (edited by Andrew Byrne).

*Note that the hospital DIPS has now been renamed the Perinatal and Family Drug Health Service (PFDHS).


Fried, PA. Pregnancy & effects on offspring from birth through adolescence. In: Cannabis and cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. Haworth Press, New York (2000). Eds Grotenhermenl F, Russo E.

Fried PA, Smith AM. A literature review of the consequences of prenatal marihuana exposure: An emerging theme of a deficiency in aspects of executive function. Neurotoxicology and Teratology (2001) 23;1:1-11 [The Ottawa Prenatal Prospective Study (OPPS)]

Weinberg DS, Inturrisi CE, Reidenberg B, Moulin DE, Nip TJ, Wallenstein S, Houde RW, Foley KM. Sublingual absorption of selected opioid analgesics. Clin Pharmacol Ther (1988) 44(3):335-42

Finnegan LP. Women, pregnancy and methadone. Heroin Addiction and related clinical problems 2000: 2 (1): 1� 8

Fischer G, Jagsch R, Eder H, Gombas W, Etzersdorfer P, Schmidl-Mohl K, Schatten C, Weninger M, Aschauer HN. Comparison of methadone and slow-release morphine maintenance in pregnant addicts. Addiction (1999) 94(2) 231-239

Fischer G, Johnson RE et al. Treatment of opioid-dependent pregnant women with buprenorphine. Addiction (2000) 95; 2: 239-244

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Hulse GK, O'Neill G. A possible role for implantable naltrexone in the management of the high-risk pregnant heroin user. Aust NZ Journal of Obstet Gyn. (2002) 42:93-94

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13 September 2005

Addiction summaries: LAAM, morphine, personality disorders.

Addiction August 2005 edition.

Dear Colleagues,

Despite the disappointing results of naltrexone in opioid treatments, Addiction's August edition includes three other items on retention rates and reduced heroin use in maintenance therapies in various situations (LAAM, long-acting oral morphine and in subjects with borderline personality disorders taking methadone treatment).

The group from Vienna headed by Dr Fischer reports a rigorous 14-week double blind, cross-over study of long acting morphine versus methadone. They find comparable results for retention and illicit drug use, with particular benefits to general health in the oral morphine group. The doses may explain some of the differences: morphine (mean 680mg daily, max 800mg) and methadone (mean 85mg daily, max 100mg).

A veteran team from California has belatedly demonstrated not only that LAAM (l-alpha methadyl acetate) is free from detected cardiac complications, but it has certain benefits over methadone for some subjects. It is disappointing that this drug has now been withdrawn by its manufacturers, probably for spurious reasons. The reported cardiac events are extremely rare, and they have never been shown to be due to LAAM. Indeed, it is still possible that LAAM actually reduces the likelihood of coronary abnormalities, especially if stimulants and/or alcohol are implicated.

Those with antisocial personality traits (45% of a large, mixed addict cohort were classified as 'borderline type') were found to have responded just as well to treatments, yet still displayed higher rates risk and harm across a range of domains. Nothing surprising here, but nice to see common observations documented scientifically in a well conducted longitudinal study ('ATOS').

Nancy Petry from Farmington, Connecticut presents another study comparing pathological gamblers with and without antisocial personalities, also finding worse parameters, younger subjects and, interestingly, a link with illicit drug use.

Citations: Eder H, Jagsch R, Kraigher D, Primorac A, Ebner N, Fischer G. Comparative study of the effectiveness of slow-release morphine and methadone for opioid maintenance therapy. Addiction (2005) 100:1101-09

Longshore D, Annon J, Anglin MD, Rawson RA. Levo-alpha-acetylmethadol (LAAM) versus methadone treatment retention and opiate use. Addiction (2005) 100:1131-39

Darke S, Ross J, Williamson A, Teesson M. The impact of borderline personality disorder on 12-month outcomes for the treatment of heroin dependence. Addiction (2005) 100:1121-30

Pietrzak RH, Petry NM. Antisocial personality disorder is associated with increased severity of gambling, medical, drug and psychiatric problems among treatment-seeking pathological gamblers. Addiction (2005) 100:1183-1193

Comments by Andrew Byrne ..