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 ..

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 ..

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: Byrne, Graham, Hallinan and Murinon


• Reply to Part I: from Hulse and Arnold-Reed


• Part II: Wodak and Graham


• Reply to Part II: from Hulse

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

References

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

Reference

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

References

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

Reference

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

Drugs in pregnancy

Tuesday 20th September, 2005

Presenters:
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).

References:

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

Hulse GK, O'Neill G. Methadone and the pregnant user: a matter for careful clinical consideration. ANZJ Obst & Gyn (2001) 41;3:329-332

Hulse GK, O'Neill G, Pereira C, Brewer C. Obstetric and neonatal outcomes associated with maternal naltrexone exposure. ANZJ Obst & Gyn (2001) 41;4:424-8

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

Jones HE, Johnson RE, Jasinski DR, O�Grady KE, Chisholm CA, Choo RE, Crocetti M, Dudas R, Harrow C, Huestis MA, Jansson LM, Lantz M, Lester BM, Milio L. Buprenorphine versus methadone in the treatment of pregnant opioid-dependent patients: effects on the neonatal abstinence syndrome. Drug and Alcohol Dependence (2005) 79;1:1-10

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 ..

Benefits of LAAM demonstrated after its withdrawal from market!

The effects of racemic D,L-methadone and L-methadone in substituted patients - a randomized controlled study. Verthein U, Ullmann R et al. Drug and Alcohol Dependence 2005 80;2:267-271

Dear Colleagues,

This interesting and definitive study from Hamburg informs us that pure 'levomethadone' and racemic (mixed levo-dextro 50:50) methadone are clinically equivalent in the expected ratio of 1:2 with no significant difference in withdrawal symptoms or other clinical aspects of maintenance treatment. The pure enantiomer is more expensive and thus should probably be phased out in Germany, the only country where it had widespread use.

Despite no real evidence, some have speculated that certain methadone side effects might be due by the inactive L or 'dextro' component. This careful, cross-over, randomised trial with 75 subjects has only found mild, transient differences in sudden experimental substitutions of medication. These did not reach significance and confirm what was done by Judson in 1976.

Comments from Andrew Byrne ..

Is rapid detox followed by oral naltrexone effective?

JAMA 2005; 294:903-913

Collins ED, Kleber HD, Whittington RA, Heitler NE. Anesthesia-Assisted vs Buprenorphine- or Clonidine-Assisted Heroin Detoxification and Naltrexone Induction - A Randomized Trial.

Dear Colleagues, The current [August 2005] JAMA home page features this item with the caption: "Anesthesia-Assisted Heroin Detoxification: Collins and colleagues randomly assigned treatment-seeking heroin-dependent patients to anaesthesia-assisted rapid detoxification with naltrexone induction, buprenorphine-assisted rapid detoxification with naltrexone induction, or clonidine-assisted opioid detoxification with delayed naltrexone induction. They found that withdrawal severity, treatment completion and retention, and proportions of opioid-positive urine specimens during 12 weeks of outpatient treatment were comparable across the 3 methods of detoxification."

In fact, there are five items in this edition mentioning naltrexone, two being letters to the editor on a long acting injectable form for alcoholism. The current feature has a commentary by Patrick O'Connor on the role of detoxification. There is also is a glowing historical tribute to Vincent P. Dole and colleagues whose seminal methadone report was published in this same summer holiday edition of JAMA 40 years ago.

With veteran researcher Herbert Kleber, this group from Columbia describe a randomised comparison of naltrexone induction in heroin addicts using three methods: (1) rapid detox under 4-6 hour anaesthetic (2) buprenorphine bolus and (3) clonidine with traditional in-patient detoxification.

The study raises several important ethical questions while also giving perhaps the last word on rapid detoxification from opioids, a century after the first report [MacLeod, N. Cure of morphine, chloral, and cocaine habits by sodium bromide. BMJ (1899) 15/4/1899 p896]. The main results are unremarkable: viz (a) that almost 100% of anaesthetised patients successfully take their first dose of naltrexone, (b) that rapid detox is hazardous, (c), that the naltrexone "treatment" is of very limited benefit (75-90% of subjects dropped out by 12 weeks) and (d) that the particular method of detoxification has no significant impact on rates of medium-term abstinence.

It is possible that some side effects in the anaesthesia group (n=35) may reflect this team's lack of experience as well as their limited ability to elicit a clear history from their patients. All three subjects who developed major anaesthetic complications are said to have had "concealed" histories (of diabetic ketoacidosis, bipolar disorder, pneumonia and sleep apnoea) from the researchers. To ascribe each anaesthetic complication to deceitful subjects is rather unusual and there may be alternative views. Others have reported lower complication rates, yet there is no doubt that such treatment can be hazardous in this population, especially if they come directly from street heroin habits.

Prescription of naltrexone for opioid addiction as a 'treatment' has only little limited scientific support in unselected candidates in community treatment. Some believe that it may have benefits in carefully selected subjects (as stated by O'Brien in the same issue p888). So why did these authors go to so much trouble to 'induct' addicts into an ineffective treatment? I note that some providers now give very frank details about the expected success rates of their treatments. Yet others have claimed '100% success' rates and call their detoxification treatments 'painless'.

It is predictable that those taking pure buprenorphine were retained for slightly longer than those given clonidine, which may be little more than a placebo in this situation. And it is self-evident that the anaesthesia patients were more likely to take their first dose of naltrexone which is given while they are still unconscious.

In his accompanying editorial Patrick O'Connor tells us that over 3 million Americans have used heroin and ten times that number prescribed opioids. Even more worrying is that over 1% of school children in the US had used heroin in 2004. Thus we are dealing with an epidemic in anyone's terms.

As with McGregor and Ali's randomised study from Adelaide (D&A Rev) rapid detox shows no significant benefits over traditional detoxification in the medium term (3, 6 or 12 months). In view of the high risks and poor results, there should probably be no further studies of rapid detoxification in unselected subjects. It is still possible that longer acting forms of naltrexone may yet prove effective for those seeking abstinence. Formal research on the safety and effectiveness of such novel delivery methods is awaited.

comments by Andrew Byrne ..

Pain management and dependency

North Sydney, Mon 22 Aug 2005

Dr Doug Gourlay

During the International Pain Conference, a meeting for 'locals' was convened by Professor Robert Batey of NSW Health at North Sydney on Monday 22 Aug 2005. We had an illuminating talk from one of the few specialists with expertise in BOTH pain management AND dependency, Dr Doug Gourlay of Mount Sinai Hospital, Toronto, Canada.
Our renowned speaker started with some definitions of addiction, physical dependency, tolerance, pseudo-addiction, with some prevalence figures in the general population.
We were given a logical approach to 'universal precautions' in opiate prescription patients. Infectious disease and dependency have some parallels: rather than isolating those already infected (eg. hepatitis, TB, leprosy) modern practice is to assume that all patients could harbour (or be victim to) infections just as all opioid recipients can sometimes demonstrate features of dependency. Thus we need to be alert and to respond with appropriate measures when needed.
Dr Gourlay reminded us of the difficulties in detecting high-risk patients on first consultation. While an accurate diagnosis is crucial to appropriate treatment, on-the-spot diagnoses are not always necessary or indeed possible in pain management and dependency. We have the benefit of seeing our patients' progress over time which allows a prospective diagnosis after accumulating more details of the patient's habits, history, examination and special tests. Predictors of progress in our field can be notoriously unreliable with some seemingly low risk patients displaying the most manipulative behaviour.
While most dependency diagnoses are made prospectively, one diagnosis we can only make retrospectively is 'pseudo-addiction'. In this, all the apparent features of addiction abate once the patient's pain has been addressed, whether physically, chemically and/or mentally. [If we postulate a 'psychic pain' and self-medication, this might be true of many dependency cases as well, since once they receive appropriate management any DSM criteria of addiction regress or even vanish.]
The items Dr Gourlay recommended we use in diagnosis included the CAGE features -Have you tried to Cut down? Do you get Annoyed by using too much medication? Do you suffer from Guilt? Have you taken medications early? 'Eye-opener' - as well as a number of other 'tell-tale' characteristics involving finances, work, drug seeking (eg. early requests for prescriptions), criminal behaviour and urine test results.
The 'tools' we have to use in dependency patients include (1) limiting quantities of medications ie. the frequency of pharmacy attendance (2) increasing doses of medications (3) utilising longer-acting forms of the appropriate medication (4) direct supervision of medication (5) supervised urine testing (6) treatment agreements � a drug diary. Dr Gourlay also reminded us not to stop opiates or benzodiazepines suddenly and that even high doses of one class of drugs will never suppress withdrawals from the other, although a transient improvement in symptoms might result. He gave a telling example of a new methadone patient denied benzodiazepines in early treatment despite a large habit. Most of our dependency patients have more than one drug habit.
Dr Gourlay has no hesitation in ordering urine tests on all his dependency patients. This includes pain management patients who have developed features of dependency - usually a small proportion, perhaps 10%. He reminded us that such testing needs to be done in a climate of trust and mutual respect. Results should never be used as a "gotcha!" manner nor used punitively. Like all pathology testing the results must only be used directly in the patient's interests. Direct observation, we were told, is not necessary in all cases but that some supervision, eg temperature testing or randomisation, is reasonable for compliance checking. We were given a compassionate and practical way to approach unexpected results. "Now I wonder if you can help me explain some unusual results we received on your recent urine specimen".
Another tool Dr Gourlay uses is a 'treatment agreement' ('never a contract') where the patient agrees to be frank about their drug use and that they will not use other sources of drugs, including prescribed medication, over-the-counter drugs or street drugs. Where they do, this should be discussed openly rather than be treated in a 'cat and mouse' manner in the therapeutic environment.
We were confronted with the statement that "no drug is addicting". Addiction requires an interaction between the drug, environment and individual. The vast majority of patients prescribed opioids never develop addiction. Dr Gourlay also said that opioids were often successful for patients with chronic non-cancer or neuropathic pain and always worth a 'trial' when other means had failed.
We were honoured to have the presence of Dr Joyce Lowinson and Dr Herman Joseph who were both associated with the early evaluation of methadone treatment at Rockefeller University in Manhattan from the 1970s.
After the main feature, we has a discussion of three complex case histories with comments from an expert panel comprising Bob Batey, James Bell, Peter Cox, John Currie, John Ditton, Paul Haber, Robert Graham and Adam Winstock. There was lively discussion over various difficulties in diagnosis and management in special circumstances, dependency, disabilities, children, alcohol, infectious disease, prejudice and other matters of mutual interest. The ethics and practicalities of urine testing was also covered.
Each case demonstrated some failings in early treatment despite warning signs being present. Each contained lessons in communications, diagnosis and a multidisciplinary, approach. There seemed some divergence of views from the panellists, but agreement with Dr Winstock that methadone is not a panacea and that psychological trauma also needs to be addressed.
For a poly-drug user on methadone for 18 years, it was surprising that with continued use of multiple opioids (pethidine and street heroin) she still was not prescribed sufficient methadone to suppress opioid use. She had also been drinking to excess and using benzodiazepines. Already taking 145mg, consideration of dose increases were not advised by all panellists. One even cautioned against consideration of blood level monitoring. It seems that some take the issue of high dose methadone in such cases to be potentially mischievous, even 'sending the wrong message' to the patient. Yet while no cure-all, we might expect that an appropriate methadone dose might reasonably be expected to suppress illicit opioid use after so long on treatment.
Dr Gourlay also stressed that in such cases, stabilising the substance dependency issues was essential before being able to deal with all the psychosocial issues that panel members had brought up ('setting boundaries'). Calling a 'case conference' is not much help if the patient cannot keep an appointment.
Dr Cox suggested admitting such complex patients to hospital as a strategy to sort matters out. Another panel member took the view that such efforts might just waste hospital resources and DG reminded us of the behavioural difficulties of such unstable cases in a general hospital setting, potentially creating resentment among staff.
Some implied a need to accept that certain situations are just not amenable to interventions. Yet in dependency practice, we often come across patients who used to be like these unhappy, unstable cases, and in whom various ministrations and time (especially the latter) have yielded stable, productive citizens in the long run.
Persistence on our part can reinforce the old saying that "when the student is ready, the teacher will appear" ... change is a process that occurs over time.

Summary of meeting by Andrew Byrne .. [final sentence and several other corrections with thanks to Dr Gourlay]

Two deaths; few other surprises; bup-combo vs clonidine for opioid detoxification.

Addiction (2005) 100: 1090-1100

A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Ling W, Amass L, Shoptaw S, et al.

Dear Readers,

This 14 day trial showed buprenorphine-naloxone prescribed patients significantly more likely to stay in treatment and stop using street drugs than those taking clonidine. It also found much better completion rates for in-patients (77%; 22%; n = 77; 36) compared with out-patients (29%; 5%; n = 157; 74) prescribed the opioid versus clonidine. Considering the buprenorphine was given in therapeutic doses of 2mg daily up to the last day, these results are not surprising.

However, it is intriguing that there are so many inconsistencies in this report from such highly respected authors. Most useful randomised trials compare an intervention of known utility with a protocol of promising but uncertain benefit - using parallel protocols and clearly defined, positive end points regarding the subjects' health. There are usually equal numbers of participants but it appears this trial was halted early by a pre-determined protocol due to the poor outcomes of the clonidine group. Unusual for 'Addiction', this multi-centre trial does not appear to have a statement concerning the funding (although the buprenorphine combination tablets were supplied by the manufacturer). Nor could I see a statement on conflict of interest. In-patients and out-patients are included but selection criteria are not given, nor are they randomised. Also unusual for Addiction, there is more than half a page of acknowledgements containing 85 names and up to 20 institutions. Several aspects of the article remind me of the sort of item contained in sponsored journal 'supplements'. One wonders if the normal peer-review process occurred, so numerous are the inconsistencies, omissions and questions concerning a lack of specific clinical aims/focus in the piece.

As above, most of the findings are predictable from the literature. The study involved a comparison of two non-evidence based 'treatments', being clonidine for detoxification and buprenorphine combination for 'detoxification'. Both 'treatments' have been shown to be ineffective in trials with over 90% failure rates on conservative criteria at medium term follow-up (1 to 3 months). Thus this study, whatever its findings, is unlikely to add to the scientific literature or knowledge base. We know that prescribing buprenorphine in standard doses to heroin addicts attracts and retains subjects while also reducing heroin use. We also know that clonidine does not do any of the above to any measurable or consistent extent although its use still has supporters and there is some promise of its chemical cousin, lofexidine (Brit-Lofex) for withdrawal symptoms. As yet, we still do not know whether the buprenorphine combination (bup-combo) drug is as effective as pure buprenorphine. There are indications that it is less efficacious (Bell) although another paper (Strain) showed contrary-wise that the combination drug caused consistently higher blood levels of 10-40% and thus might be expected to yield a better response. Thus readers may ask why use a combination drug rather than the pure drug, especially when the combination drug is not approved for commencement of treatment. The combination drug's only claimed benefit is reduced attractiveness to the street market. Yet dose diversion would not seem to be an issue here, being largely supervised and only short-term.

Unsurprisingly, the authors find that a higher proportion of bup-combo opioid dependent patients remained in 14 days of prescribed "detox" than those given no opioids. Also, and most importantly, they found that in-patients fared much better than out-patients in all respects (apart from hapless pair who perished in the in-patient group).

The authors fail to clearly define 'opioid detoxification'. Some might find the prescribing of opioids during 'detoxification' incongruous. Opioid detoxification cannot really commence until the patient ceases all significant intake of opioids. Even on day 13, these patients were offered 2mg of buprenorphine, still ten times the standard analgesic dose of 0.2mg sublingual (the maximum dose given - on day 3 - was 16mg). A further period of 14 days follow-up for the bup group might have allowed a fairer comparison of the two approaches in this case.

Either way, the authors have not clearly defined what they mean by detoxification, nor have they explained their statement in the abstract that 'success' involved an 'opioid-free urine sample on the last day of clinic attendance'. Perhaps their pathologist was unable to detect buprenorphine. Later in the article they state this must be free of *illicit* opioids, without defining *illicit*. Buprenorphine, like methadone, morphine or codeine can be licit or illicit. Indeed, it was to address the issue of diversion that the combination drug was introduced into the USA. Yet we now know that it can be abused, and that there is little if any evidence of less diversion than for other prescribed opioids.

In several countries now, even heroin can be legally prescribed and it is possible that, prescribed in decreasing doses, it might have comparable or better results than buprenorphine reductions. The very next item in Addiction is, in fact, a favourable comparison of oral morphine with methadone from experienced researchers in Austria.

Adverse events: The section on side effects starts out with a long, confusing, 'de Quincey-esque' sentence of 62 words. In the following 57 lines comes a tedious and confusing 'lecture' to the reader on the technical difference between 'serious adverse events' and 'adverse events'. Only at line 37, and after the reassuring statement 'Few serious adverse events occurred in either protocol' do we first learn of two deaths in this 14 day, 344-subject study. This implies a very high average mortality and requires some detailed explanation. All we are told is that one death (in the bup-combo group) was due to 'respiratory failure' (could this be 'code' for drug overdose?) and one was from the clonidine treated group ('bacterial endocarditis' - usually a slow or sub-acute disease in drug addicts). We are told (without coronial references) that 'neither death was attributed to study medication'. However, we are also told that patients in both groups took an average of three other medications during the trial, including 'OTC' acetaminophen (paracetamol), ibuprofen, loperamide and diphenhydramine as well as prescribed oxazepam, lorazepam, phenobarbital, hydroxyzine, methocarbamol, trimethobenzamide, Donnatal (containing phenobarb), zolpidem, trazadone and doxepin.

I have never heard of a patient dying whilst undergoing supervised detoxification from opioids, so these mortality reports need to be taken very seriously, especially when the patients were in a NIDA approved treatment protocol in registered and (presumably) accredited medical facilities. I can only speculate (as the authors do not) that this was a trial which attracted the most severely ill American addicts and/or may not have provided the best means to rehabilitation for their condition. Neither trial protocol is an 'evidence based' or proven modality for heroin addiction, even though both may be reasonable choices for subjects as long as they also have the option of more effective avenues such as traditional methadone maintenance. In many American (and Australian) cities there are still long waiting lists and/or methadone is beyond the financial reach of many addicts.

The authors state "In the out-patient group, 18 serious events occurred, with 14 in the bup-nx group and four in the clonidine group." Equal numbers of serious events occurred in the in-patient groups, including two with suicidal behaviour and one with persistent vomiting in those receiving bup-nx. I am mystified how an in-patient can have a 'motor accident' whilst under treatment, yet, along with 'spine surgery' we are offered this as an 'adverse event' without further explanation. It is also hard to understand how a patient who was assessed as suitable for detoxification could have died so quickly of sub-acute bacterial endocarditis. Detoxification is highly unwise in those with active septicaemia. One patient dropped out due to 'sensitivity to a study medication' (unspecified). This 'unfortunate' omission becomes a 'serious' one if buprenorphine were implicated.

The most important finding of this trial is probably that in-patient detoxification was so much more efficacious than community treatment (despite there being no randomisation). The differences were dramatic and they point up the inappropriate decisions made by successive administrations to close down drug and alcohol detoxification wards in New South Wales and elsewhere. Much of this was based on claims by so-called experts of their services not being 'cost-effective' or 'evidence based'. This trial shows that by using counselling and the Californian "Matrix" protocols and a 'placebo' such as clonidine, excellent in-patient detox results can be obtained in selected patients.

Comments by Andrew Byrne ..

Conflict of interest: Dr Byrne earns a proportion of his income dispensing methadone and buprenorphine to registered dependency patients.

Please note that Professor Charles O'Brien has written an excellent editorial in this 'Addiction' pointing out many of the above problems. Were he or I a reviewer, this month's edition might have been thinner.

Ling W, Amass L, Shoptaw S, et al. A multi-center randomized trial of buprenorphine-naloxone versus clonidine for opioid detoxification: findings from the National Institute on Drug Abuse Clinical Trials Network. Addiction (2005) 100: 1090-1100

Encourage hepatitis B vaccination in those at risk

Aust N Z J Public Health (2005) 29;4:305-7

Rogers N, Lubman DI. An accelerated hepatitis B vaccination schedule for young drug users.

Dear Colleagues, This study offered a free 3-week hepatitis B vaccination schedule to drug users under 23 years of age who were attending an outreach service. Out of a total patient population of around 500, 90 young people were recruited to the trial, of whom 71% completed all three injections. A further 11% had 2 injections. This enviable rate is much higher than other reports quoted.

This trial shows that drug users are often willing to be involved in preventive health measures when these are offered. Since drug users are at high risk for viral diseases, we should be encouraging all involved to ensure that they have maximum protection. The Sydney injecting room might be another place where a strategy like this could yield enormous benefits.

comments by Andrew Byrne ..