21 November 2004

How to get the most from methadone treatment - better treatment practices can help patients and staff.

Abstract: This article presents strategies to improve the results of methadone treatment which currently are very variable. Dose levels and take-away provisions can have profound effects on the effectiveness of methadone treatment. Here we have some practical approaches to the patient who is not doing well in treatment.

Patients need sufficient doses and adequate psychosocial support.

A large and consistent body of research evidence gives us clear indications how to optimise the use of methadone in treating heroin addiction. Doses need to be sufficient in order to retain patients in treatment, reduce needle sharing and keep illicit drug use to a minimum. In addition, the regimen of dosing, supervision, urine testing and psychosocial supports need to be appropriate and acceptable to the patient population.

Some may be surprised at the statement that "95% of opioid dependent patients can achieve abstinence from injected drugs while in treatment". This is a quote from Dr Vincent P. Dole who originated methadone maintenance treatment. He said that to maximise outcomes in this way, methadone needs to be given in sufficient doses, in the right clinical circumstances and with adequate psychosocial supports [ref 1].

Clinical recommendations in several countries recommend doses in the range 60mg to 120mg daily for the majority of patients [ref 2] However, for a variety of reasons, many patients are still taking lower doses with correspondingly unsatisfactory results [ref 3.].

The initial methadone study in 1964 employed doses up to 180mg daily with a mean of 103mg (range 10-180mg) [ref 4.].

Cross tolerance between heroin and methadone.

Since there is cross tolerance with other opioids, patients who continue to use heroin regularly should be candidates for additional methadone. If heroin use has been sporadic and small in quantity, patients may well be advised to persist with the current dose. However, when heroin use has become regular such as several times weekly, a dose increase should be considered, usually of 5 to 10mg daily. This assumes that there is not excessive sedation from the dose and if there is any doubt an examination 3 hours after a supervised dose is often instructive and reassuring for both clinician and patients.

Inadequate doses of methadone can also be associated with increased cocaine use [ref 5]. Patients on inadequate methadone doses may also find it more difficult to stop drinking or to detoxify from benzodiazepines. Most importantly, they drop out of treatment and return to illicit drug use.

The patient's dose should be sufficient to abolish cravings for 24 hours. Sometimes the patient may not describe cravings, but will have other symptoms indicative of an inadequate dose. These can include a general malaise or frank depression. Patients will have one or two responses to such a situation, either suffer in silence or resort to illicit opioid use. Either way the patient is likely to be less than fully functional.

Patients needing more than 120mg may be rapid metabolisers and/or they may have had higher than average tolerance. Only a small proportion, perhaps a fifth of the total, need high dose (>120mg daily) and some only for short periods. Metabolism is a function of the patient's cytochrome enzyme characteristics and has little to do with how much drug they used or to their 'degree of addiction', etc. There is also a substantial minority, perhaps another 20%, who fare perfectly well on doses of less than 60mg daily.

There have been isolated reports of doses up to 300mg daily but these should only be used in specialist centres in clinical research settings. This may be due to altered opioid tolerance and/or metabolism and can be due to drug interactions or pregnancy. (see blood levels, below).
There may be a resistance to high doses from both patients and staff. This may be due to a natural conservatism or misunderstanding of the treatment. On occasions, genuine side effects can limit the usefulness of methadone. Some patients will tolerate such side effects, while others will reduce their dose or drop out. Doctors are used to this 'balancing act' with side effects caused by many other drugs. The patient is the final judge and will decide based on benefits versus adverse effects. Where outcomes are unsatisfactory despite dose adjustment then alternatives should be looked at such as adding an antidepressant or even changing the patient to buprenorphine.

Apart from some sedation in the first days of treatment, there are few side effects reported with methadone. Sweating and constipation are the only common side effects and these are rarely dose limiting. Impotence and menstrual irregularities are common with heroin and usual improve on methadone. The improvements following appropriate dose adjustments are usually very gratifying. Any side effect can be addressed by graduated dose reductions.

Strategies to encourage appropriate dosing.

It is often helpful for the prescriber to engage an unstable patient more intensively. While there is continued use of illicit opioids and/or stimulants there should probably be regular weekly consultations with the treating doctor. Such visits need be no more than 20 minutes in most cases. It is helpful to discuss a range of related issues such as general health, dose levels, side effects, supplementary drug or alcohol use, 'track' marks, vein care, finances, employment and family matters. Not all of these matters need to be broached at each visit.
It may then be helpful to focus on the person's major particular presenting problem or nominated goal. For example: 'I've just got to save some money for rent'; 'I really need to get away from the needle'; 'My liver pain is getting worse and worse'; 'I should take less time off work or else I might lose my job'; 'I need to spend more time with the family'. Any one of these would be a useful starting point as there is often intercurrent drug use contributing to the problem and making the goal less achievable. A notation should always be made in the medical records for future reference.

After these practical problems have been identified, it is then useful to assess the patient's responses to treatment, including current dose level and past history of MMT. It may be helpful to place the patient's treatment into perspective by pointing out the wide range of methadone doses used, even up to 300mg or more. Such "high-pointing" may have a reassuring effect in itself by taking the emphasis away from 'minor' dose adjustments.

It is then useful to discuss the benefits and drawbacks of a higher dose in the individual case. Side effects are usually minor when compared with the consequences of continued illicit drug use.
The patient may have been on higher doses previously with good results. Experience has shown that the majority of patients who have a relapse tend to have to return to their own maximum "plateau" dose before regaining control.

Some patients will volunteer that they have taken large doses of 'street' methadone and can report the results. "Have you ever taken extra methadone?" "What happened when you did?" "How much did you take?" "Did you get 'stoned'?" "Did you use other drugs or alcohol afterwards?" This is all taken in the strictest medical confidence, and it is worthwhile saying so, even to the point of not writing actual details in the regular medical records if the patient prefers.
Fear of eventual reductions.

There is often a resistance to higher doses because of a fear of 'coming down again' and 'how hard it will be'. We need to reassure patients that reductions from 100mg to 50mg are the easy part and can often be done within a month or two. However, the major effort is needed for the lower steps of reductions such as from 50 to 25, or 25 to zero, according to most patients. Such drops usually take months and sometimes even years.

Fear of methadone in pregnancy.

Some women state that pregnancy is a good reason for not increasing doses. But in a setting of continued heroin use it is more important than ever. It is much safer to take a little more methadone and eliminate extraneous street drug or alcohol use wherever possible. While abstinence is doubtless preferable, there is also a high risk of foetal complication from relapse during the stressful episodes which inevitably occur, even in normal pregnancies.

Fear of incarceration.

Another common piece of 'home logic' from the patient may be: "I might be arrested and then I will hang out in the cells". Patients who give false names for minor infringements or 'warrants' cannot very well request methadone in their own name. We can reassure such anxious patients on two accounts. Those fearing arrest should also be reminded that when taking adequate doses of methadone they are far less likely to be apprehended. And if arrested, a stable patient on higher doses is more likely to be able to provide a good record of attendance and progress, thus making bail or acquittal more likely.

But patients who are taken into custodial care should receive every endeavour by their doctor to have their medication continued by some means or other. All prisons have medical services with access to appropriate medications. Methadone and even buprenorphine are becoming more routine in jails around the world. It works as well and may be even more important than in the community due to the higher risks in prison.

Fear of termination of treatment.

We should also reassure patients that their treatment will not be terminated arbitrarily. It is no longer acceptable to cease treatment abruptly, especially as a 'punishment' for continued illicit drug use. If there are serious behavioural problems, patients may sometimes be transferred to another service, but they should always have some realistic medicated option, even though it may not be as convenient.

Intolerance of methadone additives.

Another barrier to correct dosing may be the various constituents of prescribed methadone. Sorbitol, alcohol, preservatives, flavouring, colouring and other ingredients appear to affect some people adversely. Sugar-free solution is now available in Australia and its release has revealed a substantial proportion of patients are much better off without the additives in the older preparation. Considering the poor dental health of many methadone patients it may be that the pure solution should be use first-line.

In summary, unstable and unhappy patients should carefully consider the matter of dose for a reasonable period before deciding on an increase. The dose can always be reduced again if desired. It is very important that the patient does not feel forced into higher doses without consent. It is the patient who must bear the consequences of higher or lower doses. And there is often excess sweating and constipation. Research shows added benefits when patients have a direct input into their dose level. This happens with other forms of therapeutics such as analgesic, antidepressant, antipsychotic and anxiolytic treatment.

Blood 'trough' levels for guidance and reassurance.

Another strategy in some cases is to order a 'trough' blood methadone level, 24 hours after a supervised dose. This is advisable for patients taking doses above 120mg daily, at least once, to demonstrate their rapid metabolism. It is a safeguard for both patient and doctor. In those who are still using other drugs, the level is very often in the low range, indicating the scope for substantial dose increases. This information always helps patients and their doctors to know that they are not having the drug 'build up' in the body, nor that it is 'getting into the bones' or cause other residual side effects. It is very rare to find levels in the 'toxic' range (>1.0mg/l) but a small number may have very high tolerance and require such levels under specialist treatment. It is clear that those in the range 0.2 to 0.6mg/l do better than those with levels below that range. Most patients are quite happy and stable in the lower end of that range. Dose increases should only be implemented with patient consent and for clinical reasons such as illicit drug use, cravings, insomnia, depression, etc, and only when these symptoms do not resolve with simple measures and the passage of some time.

Ref 1. Dole VP. In Ball J, Ross A: The Effectiveness of Methadone Maintenance Treatment. Springer-Verlag, New York 1986. Foreword p viii.

Ref 2. Drug Misuse and Dependence - Guidelines on Clinical Management. 1999 The Stationary Office. Working Group Chair: Strang J.

Ref 3. D'Aunno T, Folz-Murphy N, Lin X. Changes in Methadone Treatment Practices: Results from a Panel Study, 1988 - 1995. American Journal of Drug and Alcohol Abuse 1999 25;4:681-700

Ref 4. Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50 '193(8) 80-84'

Ref 5. Hartel DM, Schoenbaum EE, Selwyn PA, Kline J, Davenny K, Klein RS, Friedland GH. Heroin use during Methadone Maintenance Treatment: The Importance of Methadone Dose and Cocaine Use. Am J Public Health. 1995;85:83-88.

written by Dr Andrew Byrne and Dr Richard Hallinan

Sincere thanks are due to Dr Stefan Goldfeder who suggested the exercise originally and gave useful comments on the manuscripts at several points during its gestation.

17 November 2004

APSAD Conference, Fremantle, Western Australia - Day 3

Wednesday 17th November 2004

Day Three

Dear Colleagues,

The third full day of this conference found some delegates somewhat jaded after the conference dinner the night before. A relief then at 9am to find that every chair in the plenary hall attended by a box labelled "Hangover recovery kit"! With my aversion to advertising of almost all kinds I had to pass it up.

Straight to business, however, with a brilliant talk by Thomas Stopka from California describing numerous studies on "secondary needle exchange". For Australians this is a rather odd concept, although it does happen to some extent, even in Australia. In places where there is major difficulty obtaining clean needles and syringes, there are retail intermediaries, entrepreneurs or unofficial purveyors of clean "works". Some may be diabetics with legal access to injecting equipment. Others are non-drug users (incorrectly termed 'alcoholics' by injectors interviewed in the US). But the majority as described by Dr Stopka are unemployed drug users who make a small income out of a restricted market [another overlooked benefit of prohibition!].

An example was a group of people living close by, converting a two-hours-per-day needle program into a 24 hour program, albeit with limited stock each day - and at a premium price. An inducement used in some areas is the provision of additional clean needles for each old one returned. Thus, as in the case of aluminium cans, people can be found 'cleaning' back lanes and stairways, ridding them of discarded 'works', in order to profit (even though the equipment provided has a commercial value of only a few cents).

It is a sign of the drastic toll which continues to be exacted by the American public due to its own laws that serious discussions regarding extraordinary research such as this exists. Only in recent months were Californian pharmacies permitted (under certain restricted circumstances) to sell syringes to drug users. I understand that up to 8000 people annually contract HIV from contaminated syringes in California. It is to be hoped that this figure can be reduced towards zero as new policies are gradually incorporated into the scene.

Next we heard from Paul Gruenwald on the important subject of alcohol policy - from global to local approaches. It was a wide ranging and very logical description of what can be done, what has been done (and undone) and what SHOULD be done for the future. There seems little controversy on the basics. While prohibition does not work (introduced as 'another Californian', Dr Gruenwald should know), age limits, differential taxation, venue licence conditions, law enforcement, labelling, drink driving strategies and education all have a place in reducing consumption and therefore, resulting harms. We were told that a 10% increase in price causes a 7.5% decrease in consumption and this in known to include the most heavy drinkers. Age limit changes also have potential benefits but these can hardly continue into middle age! Venue regulation enforcement, server responsibility and other details can also reduce consumption and harms.

After morning tea we heard from Kate Conigrave on alcohol screening in pre-operative cases in a large teaching hospital. She pointed out that previous work from Scandinavia published in the BMJ shows that it is possible to reduce post-operative complications dramatically by simply diagnosing and acting upon alcohol excess in the weeks before surgery (they used disulfiram 'Antabuse' as well as other measures). She pointed out how difficult it was from their own attempts at Sydney's Prince Alfred Hospital to co-opt anaesthetists, surgeons, secretaries, etc, due to all the other presumably necessary 'fuss' entailed in getting to surgery. In their own pilot study, only dedicated research assistants working in pre-admission clinics could reach sufficient numbers of patients, yet their efforts even then were often fruitless because operations were scheduled for the next day or two, long before any useful alcohol intervention such as disulfiram (Antabuse), counselling et cetera could be instituted.

There were parallel sessions on stimulant use, party drugs, policy, harm reduction and aboriginal issues. For the remaining stoics, the afternoon sessions comprised some innovative areas for APSAD. These included a study of rat mortality using buprenorphine and benzodiazepines which had been mentioned by Nick Lintzeris at last year's meeting but here was presented in person by Suzanne Nielsen. She had measured the breathing rates of variously drugged rodents, no mean feat in my book, and pointed out that buprenorphine is no benign drug when used in combination with other drugs, especially alcohol or benzodiazepines.

Robert Ali gave an enlightened presentation on why official doctors' groups should be involved in policy activism. He pointed out that many common causes of death were related to obesity, drugs, behaviours, life-style choices, diet, etc. Many of these were amenable to changes with simple measures. Likewise, regarding alcohol, tobacco and illicit drugs we should be able to give expert advice on what is best for our patients and for society generally [and this might balance in some small way what is best for breweries, tobacco industry, their shareholders and the 'sleaze' factor in lobbying]. All attending were given a copy of the booklet "Illicit Drugs Policy" published by the RACP, RANZCP and GROW (Self Help).

This conference has been a high point of the year for those of us up to our necks in dependency work. The convenors Simon Lenton, Steve Allsop and other Perth colleagues are to be congratulated for getting together a group of interested and interesting folk from all around the country (and the world) in a congenial venue. We were fortunate to have some of the most important players in research and clinical matters in our field present at the conference. Walter Ling (bup, ntx and other fields), John Grabowski (who first 'proved' that take-away doses improve outcomes), S. S. Lee who is running harm minimisation in Hong Kong and workshops for China; Robert Ali (multitude of inputs from clinical science to policy and administration); Nick Crofts (Asian Harm Reduction Network and many other contributions); Alex Wodak who almost single-handed 'invented' needle programs almost 20 years ago (to name just a few of the 'notables').

We look forward to the next APSAD conference in Melbourne, 2005.

comments by Andrew Byrne ..

16 November 2004

APSAD Conference, Fremantle, Western Australia - Day 2

Tuesday 15th November 2004

Day Two

Dear Colleagues,

The second formal day of proceedings had an emphasis on prisons and law enforcement. Michael Farrell's talk was entitled "Tackling problem drug users before, during and after prison. Dealing with a high risk environment". He reminded us of the problems of suicides in jail as well as deaths in recently released prisoners, citing numerous studies showing the greatly increased risks of overdose in the days after release. It was for this reason that methadone was introduced into all prisons in New South Wales almost 2 decades ago. It appears that methadone treatment is still not routine in British jails and indeed, most other countries' jails, despite the evident need and benefits.

Next we heard from Heino Stoever on drug use in German prisons. He quoted numerous trials of needle/syringe availability, which is known to reduce rates of blood borne diseases. None of the trials had been associated with reported problems such as prisoners threatening other inmates or staff with officially provided syringes. Since one cannot stop drugs entering jails, it would seem illogical to ban needle/syringe provision for their safer use.

Brian Watters launched the new ANCD (Australian National Council on Drugs) compilation of the research on custodial matters. He was remarkably frank about the value of harm reduction measures of all kinds in the prison system, including needle/syringe programs. Copies were available for delegates.

The meeting then split into 6 streams of which I was involved in 'pharmacotherapies'.

Tim Mitchell spoke on the potential advantages of using the active enantiomer ('R') of methadone in preference to the cheaper racemic version ('RS') generally available. He had searched the literature, especially from Germany where this has been used in clinical practice for many years for historical reasons. While there were some negative effects noted from the inactive form, these appeared mild in most people, except at high dose levels. It was shown that the metabolism of the two forms could be quite different and one might induce the metabolism of the other. The best information might be obtained from those who have transferred regularly from the German program to other European locations where doses have to be doubled to yield the same agonist effect.

Ian Kronborg gave in interesting talk on sleep disturbances in methadone maintained patients, pointing out how complex this field has become. There are dozens of specific sleep pathologies recognised and now, a particular one associated with opioid maintenance. All practitioners should remind those with insomnia about regular 'sleep hygiene' as some methadone patients were found to require only simple advice to improve disturbed sleep patterns.

Lula Kamal gave a disturbing account of the reasons English patients had left maintenance treatment in past episodes. Methadone doses had been 'too low' with 'cravings', 'withdrawals' and 'continued heroin use' given as the reasons in many of her confidential questionnaire subjects in London. A question from the audience confirmed that poor quality treatment appears to be rife in London with little patient involvement in decision making about dose levels. It is still a mystery why the mean methadone dose in England remains reportedly below 40mg (where it probably should be double this for optimising benefits) . and no wonder that as a consequence methadone has a bad name amongst patients, doctors, journalists and the community generally. It is most surprising that the major Addiction journals, Colleges, NAC and NHS have not conceded the existence of this parlous state of affairs, nor have they done anything to rectify it. Comparisons with other European countries show an ongoing spate of adverse consequences from overdoses to HIV and hepatitis. The matter is so grave that even quite conservative people are now calling for heroin prescription for addicts.

Richard Hallinan from our own surgery then presented evidence of hypogonadism and sexual dysfunction in opioid treated men. He recommended that practitioners include these issues in clinical assessments and in monitoring of on-going opioid replacement treatment.

In a second paper, Dr Hallinan then described the use of receiver operating characteristic (ROC) analysis to define statistically optimal thresholds for methadone dose and plasma concentrations (100mg daily; 250ng/ml R-methadone; 300-400ng/ml for racemic methadone) in relation to continuing heroin use in MMT. Measuring plasma concentrations apparently did not help to predict continuing heroin use in MMT.

Dr Comer spoke about her work with long acting depot naltrexone for heroin relapse prevention. Her own study from Columbia University used ~200mg and ~400mg doses, measuring blood levels and responses to injected heroin in the 6 weeks following (yes, an American heroin trial!). Some developed skin irritation at the naltrexone injection site and one attempted suicide during the trial. This is consistent with Miotto and Ling's findings and might be associated with an accompanying depression although Comer said that it was not thought to be a result of the treatment.

After lunch we heard a series of speakers on the increasing problems with psychostimulants. Robert Ali implied that following an epidemic of stimulant popularity, there may have been some reductions of late, with some high quality heroin 'flooding' back onto the market. He had done the ground work for a trial of treatment for amphetamine psychosis but now there seemed to be fewer presentations for this diagnosis at the two centres proposed for the trial. Drugs such as benzodiazepines and anti-psychotics were discussed, along with their various advantages and disadvantages including the stigma of a 'schizophrenia' diagnosis and the addictive nature of the 'minor' tranquillizers.

Parallel sessions then addressed alcohol use in the older person, prison issues, general practice, youth and cannabis law reform.

The James Rankin oration was given this year by Jason White in the presence of Professor Rankin himself. We were given a succinct but detailed overview of the subcellular neural mechanisms for the actions of many of the substances people use as well as the treatments we institute. We then heard from Dr Comer again on naltrexone in relapse prevention using the long acting depot form.

Finally, Frank Hansen from the NSW Drug Squad gave the constabulary's view of the stimulant epidemic, followed by the police approach to harm minimization and some difficulties which can arise.

It is impossible to get a completely fair overview of such a large meeting and my apologies to all those who contributed who I have not mentioned. There was a camaraderie in all of the coffee and meal breaks in which sometimes quite disparate people found common ground and enjoyed each others' company. While the company was superlative, the conference dinner was not really worth $75 (food review on application). However, I approve of the principle of individual bar service rather than 'unlimited poor quality grog' which has sometimes been the case in the past.

comments by Andrew Byrne ..

15 November 2004

APSAD Conference, Fremantle, Western Australia - Day 1

Monday 15th November 2004

Day One

Dear Colleagues,

Health Minister McGinty, despite being the local member for Fremantle, was not able to attend to open the conference so his upper house Parliamentary Secretary said a few brief but very pertinent words in his absence as she declared the conference open.

Aboriginal elder Mr Wilkes spoke about his Nunga people and their land as well as some negative interactions with drugs and alcohol. His grandson, also Mr Wilkes, then played the didgeridoo, albeit with permission from the traditional owners of the pipe far to the north. Both were widely appreciated and complimented by the first key-note speaker Dr Tracy Westerman. She spoke eloquently and effectively about the cultural differences with Koori/Nunga and other indigenous family structures from the European. Her talk came as a breathe of fresh air from a caring, insightful and productive professional who spoke her part with conviction - minus 'attitude'. She also had a team of like-minded psychologists who were involved in spreading the word about interventions, local control and the use of beneficial, self sustaining programs to address drug and alcohol abuse in indigenous communities across the country.

Next the Professor Michael Farrell from London revealed some worrying but sadly unsurprising statistics from London. He showed some slides of depressed neighbourhoods in his once great city. Sorry inhabitants, poor living conditions and the availability of very cheap alcohol were a shock to some in the audience. He gave some figures for tobacco, alcohol and illicit drug use amongst such folk. Despite being worldly and knowledgeable about the field, he stopped short of definitive advice on how to address the multiple problems he described.

The day progressed with 6 'strands' of parallel lectures/workshops covering a multitude of topics.

Initially I heard Robyn Richmond speak about her randomised controlled trial of smoking interventions in schizophrenic patients. Her rigorous evaluation showed significant benefits in the early phase but with waning effects by 12 months. She also addressed smoking in prison populations in another session and described the outcomes of the new GP anti-smoking guidelines. There were also talks on hepatitis C rates and injecting behaviours, indigenous issues, rehabilitation and peer support, co-morbidity and South-east Asian perspectives.

In the afternoon we heard from Dr Tim Mitchell about a new titanium canister being trialled in London to dispense methadone take-away doses by remote control. The tamper-proof unit has an electronic dispenser which only responds to an optical recognition such as a finger-print. The pharmacist would also have a 'key' using finger prints as well to refill the thing. He pointed out that it only monitors methadone usage and does not prevent the patient on-selling or injecting the drug. I am still surprised as to why we use liquid methadone for take-away doses rather than tablets. Liquids can be an invitation to injecting for some unstable or unhappy patients. This would seem like an English response to their situation, being unable to address the abysmal quality of MMT. But there is a risk that this system could stigmatize our patients even more than they are already.

Pier Paolo Pani from Italy went to some trouble next to document his efforts to define which patients are more likely to do well with methadone and (pure) buprenorphine respectively. Even from their wide experience in Italy and his close attention to numerous clinical factors, it still came down to personal preference or trial and error in most cases. Leslie Amass repeated some of her figures from the Sunday meeting, emphasising the bio-equivalence of Suboxone and Subutex and the obvious advantages of take-home doses. I was surprised that despite an enormous experience in the US over the past few years (up to 50,000 individual patients) that there have been no further published studies to support the continuing safety and effectiveness of the combination product, especially whether it can be diverted to the black or 'grey' markets. Professor Walter Ling spoke about opioids and pain, alluding to the possible development of non-addictive drugs which were still effective for pain management. This has long been a 'wish' for those in the field and each drug company claim of a lower addiction potential has been followed by disappointment (including heroin itself!). He cited evidence for the existence and relevance of the 'orphan' receptor which may compliment the mu and other opioid receptors in the brain.

Don Weatherburn gave a talk about reduced detected crime amongst those in the criminal justice system who chose to go onto methadone treatment. The reductions did not seem dramatic but he assured us that they were significant, elaborating details of unreported crimes and low clear-up rates as low as 6% for some types.

Michael Tedeschi gave a fascinating talk on his findings in a survey of patients and prescribers on their reasons for preferring buprenorphine or methadone. Doctors were more impressed with the safety angle while patients were more interested in the convenience of a longer acting drug which is more flexible that methadone in some respects. Some also cited the illusory 'less addictive' nature of buprenorphine, despite a lack of evidence that it is more likely to result in abstinence than methadone or traditional detoxification from heroin. Side effects seem less with buprenorphine in a proportion of those who responded.

Jane Maxwell spoke of her experience with mortality in methadone patients in Texas.

Sue Hailstone described a NSW Health Department initiative aimed at detecting and dealing with doctors who prescribed more than the 'guideline' maximum 4 take-away doses weekly from an audit conducted in May 2001. While the follow-up audit showed better compliance, there was still no attempt to determine if actual clinical practice had improved as a result of the audit. I understand that some experienced doctors left the field at the time, possibly partly as a result of the intrusive nature of this intervention.

A senior Victorian doctor questioned the whole subject when 'guidelines' are 'just that'. 'Mandatory guidelines' is something of an oxymoron. The NSW authorities no longer have the means to vet individual clinical requests to go outside these maximums and doctors are caught in the uncomfortable position of either giving inappropriate treatment or breaking these rules in their patients' interests. It is gratifying that the new draft guidelines do not apply the same restrictions to those taking less than 40mg daily.

Many areas are still sadly lacking in on-going education for front-line health workers to raise the standard of care of patients with alcohol and drug problems.

Next we heard from Suzanne Fraser and Kylie Valentine on their new project comparing the take-away policies in Australia's two most populous states. Their pilot interviews quoted many interesting views from patients on the (obvious) benefits of dispensed doses. One went along the lines: "Urgh . I might not trust myself with doses for a whole week, but a few days of take-aways make all the difference!" The Victorian and NSW studies will make interesting reading in due course.

All in all a fascinating and productive day hosted by the Perth-based APSAD team.

comments by Andrew Byrne ..

14 November 2004

Australasian Professional Society on Alcohol and Other Drugs (APSAD) Conference, Fremantle, Western Australia

Sunday 14th November 2004

Pre-conference symposium

Prior to the APSAD conference proper the Reckitt Benckiser drug company had booked the conference centre for a symposium on buprenorphine. For the entire Sunday afternoon those attending discussed, learned, absorbed and almost 'breathed' partial agonists.

Leslie Amass PhD gave a talk on Suboxone versus Subutex, quoting initially from Fudala's NEJM paper from 2003. She showed some outcome markers, including the percentage of clear urine screens at ~22% for the pure drug versus ~18% for the combination with ~6% for 'controls' (actually 'placebo' cases!). While Amass stated that there was 'no difference', someone in the audience pointed to the apparently better results in the pure buprenorphine subjects (I said it looked like a 'trend'). We were told that this difference was not significant, yet such a trend would be consistent with other research presented by Dr Bell regarding the need for higher doses in the combination cases.

All delegates were given copies of the excellent pilot study by Professor James Bell and colleagues from Sydney published in D&A Review. In an expansive presentation he described the 17 stable consenting patients who were transferred from Subutex to Suboxone and also moved from daily to weekly attendance schedules. Most outcome results were gratifying (self report, urine toxicology weekly) as in other trials of stable folk given increased take-home doses (termed 'medical maintenance' in the US). Bell alluded to the random call-back provisions of his trial to count tablets for compliance. It would have been good if we had heard further details of 4 out of 17 who declined to attend when requested, and of the patient who had a stroke during the Suboxone trial, both mentioned in the accompanying published paper. The fact that 4 'stable' patients (25%) could not account for their remaining medication constitutes prima facie evidence of diversion. Professor Bell also told us that one patient "squirreled away" medication for up to 6 months. This is also a form of 'diversion' to my mind as the drug was clearly not taken as prescribed in the trial protocol. I recall an intriguing reference of measures to protect the good standing of a 'new drug', which ideally might have been discussed in more detail. There seemed to be an inconsistency between a projected slide showing dose increases averaging 50%, and the reference to a "slight" increase (needed in those who transferred from pure buprenorphine to the combination product, Suboxone).

As part of the same study, next we had Professor Bell's colleague, Amanda Morris, who spoke about the qualitative effects of changing daily attendances for stable, employed long-term folk into once per week or even fortnight attendances with the combination buprenorphine product. Unsurprisingly, the patients were uniformly grateful. They were almost grovelling in their praise for the new system, rather damning the previous daily attendance. We were shown dozens of quotes in which patients were almost religious in their support for the change wrought upon them. The staff also found it gratifying to have patients attending less often. No real surprises here to my mind. People were given treatment which was almost a 'cruel and unusual punishment' (daily attendance) and then moved to a liberal and tolerable management regimen so there is little surprise that everyone was pleased about it. The exact same would probably have happened using methadone or pure buprenorphine, simply by following established take-away schedules.

Andrea Gordon then spoke about buprenorphine in pregnancy, describing over 40 cases of controls and methadone patients followed from about 19 weeks gestation. She compared these with comparable numbers of women taking the combination product. There were no miscarriages in the methadone or control groups but 3 in the buprenorphine group. She stated that these were 'not significant' without qualifying herself. Even though this was a study in progress, I think more needs to be sought about the miscarriages. Other studies of buprenorphine in pregnancy have mostly be reassuring and many physicians now believe that it is safe to use in pregnancy. I still believe it should be a second line drug, albeit but an excellent one at that.

Andrea Gordon's other figures from Adelaide showed that methadone and buprenorphine patients had slightly smaller babies who were delivered slightly earlier but with few other differences. Some buprenorphine figures appeared to be slightly better on trend regarding neonatal withdrawals. Although buprenorphine is not yet approved for use in pregnancy it appears that some of these women were prescribed the drug as their choice and for others, their doctor's choice.

Walter Ling gave his usual witty and insightful talk, describing pain syndromes versus dependency diagnosis and the intersection of the two. He also covered the very practical subject of what to do for opioid maintained patients with severe pain, acute and chronic. He started by describing simple manoeuvres such as paracetamol and anti-inflammatories to additional methadone/buprenorphine (eg. one sixth dose increase as a start) or a simple addition of morphine which he said was practical and simple, even in inpatients having operations, transferring straight back to the maintenance medication afterwards.

Next (in Italian) we heard Dr Claudio Leonardi speak about the Roman and Neapolitan experience with buprenorphine (pure). He was gregarious and beautifully spoken with a broadly positive impression of their experience. He appeared to be supportive of the use of buprenorphine in preference to methadone in some cases or even more widely but did not give his reasons. He did however quote a paper he heard in Paris recently in which 5000 women on buprenorphine delivered babies apparently with safety. He stated that his group routinely transfers people on as much as 80mg methadone to buprenorphine. He alluded to the use of anti-diarrhoeals, anti-spasmodics and sedatives in such patients who I presume were in-patients. Our experience with high dose (up to 50mg) transfers has been uniformly unpleasant. I was unable to reconcile the difference as the first buprenorphine dose was given at least 24 hours after the last dose of methadone in all cases. Dr Leonardi did make the point that they never given more than 2mg to such high dose transfer cases on the first day, but afterwards they rack up the dose very quickly (eg. 8mg, 12mg, 16mg). He also mentioned much higher doses in some cases as high as 48 or 56mg which would present something of a challenge to consume just because of its bulk, not to mention the extremely high cost.

Fremantle is beautiful at this time of year and we are fortunate thus far to have clear, warm weather also blessed by the afternoon Indian Ocean "doctor" sea breeze each afternoon. The conference venue is the Fremantle Esplanade which is a large old rambling hotel which has been rebuilt with large, modern facilities maintaining the charming old façade facing the park, Norfolk pines, etc. It is a short stroll to the port, station and restaurant area.

comments by Andrew Byrne ..