American Association for the Treatment of Opioid Dependence (AATOD) National Conference

Integrating Evidence-Based Practices Within Opioid Treatment

Sun 13th to Wed 16th April 2003

I was privileged to attend the AATOD conference in the Renaissance Washington DC Hotel along with many of our field's eclipsing luminaries. Over 1000 health workers came from all over the US and overseas. Much was said in the formal lectures and workshops, but face-to-face meetings with long-time, long-distance colleagues, in some cases for the first time, was a unique pleasure.

On the Saturday there were pre-conference courses on buprenorphine prescribing in office based practice and another for 'methadone advocates' (NAMA). On the Sunday afternoon, two further parallel 'strands' took place, one for local policy folk, the other involving overseas researchers and clinicians. The latter described experiences in a variety of settings in Switzerland, Italy, Israel, Bulgaria, Ukraine, Slovakia and Slovenia. Two additional American collaborations included talks of neonatal abstinence syndrome (Dr Loretta Finnegan) and high dose methadone prescribing (Dr M. Shinderman). The Canadians and Europeans at the meeting added a much needed bredth of experience. This conference which was pervaded by reaction to the uniquely American antagonism to logical drug policies. This includes regulations preventing doctors from treating their dependent patients in accordance with long-standing concordant research, mostly performed in this country.

On Monday morning we were addressed by Association President Mark Parrino, Washington D.C. Mayor Williams, D.C. Health Director James Buford, DEA Diversion Administrator Laura Nagel and SAMSA Officer Charles Curie. Surveys showed that 7% of Americans interviewed had used an illicit drug in the previous month and it was estimated that 16,000,000 were regular drug users. Surprisingly, this was not used as evidence that current policies fail to protect US families against drug problems. We were, however, reminded that 'treatment works', despite common mythology to the contrary. The virtues and proven benefits of intensive psychosocial supports for maintenance patients were extolled. The speakers quoted from the few good studies which confirm scientifically what Hippocrates described over 2000 years ago (additional services improve medical outcomes).

Parrino and his knowledgeable presenters dwelt on the 'crucial' role of these psychosocial supports. Indeed, as with diabetes and other conditions, such services can significantly improve numerous treatment outcome measures. But we know that even with minimal services, dependent folk can attain positive results in many or even most cases. Nobody would suggest denying such services if they were available, but equally, to deny methadone or other medication in adequate supervised doses, because of a lack of counselors, funding, real estate, etc, would be unacceptable in other fields. The latest moves on buprenorphine prescribing may redress some of the calcification in US policies which continue to deny simple and effective treatments to most American addicts who cannot realistically advocate on their own behalves.

The morning workshops included 'ethnic considerations', smoking cessation, 'harm reduction' integration, office based prescribing and benzo abuse. It was disappointing to me that the conference organisers did not have more practising clinicians among the 14 plenary speakers, most of whom were administrators.

I attended a workshop on a needle exchange information initiative in New York City's Bronx, given by Dr Jennifer McNeely of the Albert Einstein Medical School. She pointed out just how difficult it was to get simple practical information to patients. She had to deal with various levels of administration just to be able to pass on the contact details of 3 Bronx pharmacies selling clean needles and syringes under the new Sate legislation. It would seem that a graffito on the washroom door with the phone contacts would have had the same effect. However, by going through the correct channels, McNeely has wisely ensured that in other states with similar waivers clinics will now be able to do the same thing, thus reducing viral transmission and ultimately saving lives. This in turn may reduce the hysteria in this country over issues such as needle availability. 'Harm reduction' and needle services were under the conference heading of "hot topics". This is intriguing since each is just so uncontroversial as to be official government policy in numerous other countries.

In the Q&A session, I mentioned some details of the Sydney medically supervised injecting center where 69,000 injecting episodes occurred over 2 years with no deaths or other significant problems. One clinic manager from Pennsylvania said that she cannot even get minor changes to her clinic approved and was very pessimistic about a syringe program opening in her state. And a legal injecting room seemed light years away.

Other workshops covered cardiac rhythms in opioid users, Federal Regulation, counselors eduction, 'recovery', addiction nursing, residential care and community transfers. Another was "Administrative Withdrawal: Ethics, Implementation, and Alternatives". Apparently in various places across the country currently there are hundreds or even thousands of patients experiencing this callous indignity for reasons I could not comprehend, considering the this country's abundance of resources.

Next we had an interesting session on the introduction of buprenorphine into practice in the US. Dr Laura McNicholas gave a brief overview of the pharmacology and therapeutics, then Dr David Feillin related a number of trials of the sub-lingual combination drug including naloxone. Most of these trials involved supervised administration of the drug as distinct from the current waiver arrangements to dispense up to a month's supply at a time without supervision. Also, most of the extensive buprenorphine literature has been performed with pure buprenorphine, yet the recommendation is for American physicians to use mainly the combination product with naloxone. The claims that this is safe and effective in both treatment and avoiding diversion are not based on much scientific evidence. This shows that the drug can be abused by novice or occasional users and further, that the naloxone is absorbed up to 10% and has some clinical effects such as pupil changes. In the Q&A session mention was made of a twelve month Swedish/American study which compared buprenorphine maintenance with detox. The detox group had near zero retention rates at 2 months and, worryingly, 20% of the subjects had died. One must question the ethics of giving a virtual placebo treatment to half of such trial cases without some formal safety net.

On the Tuesday morning there were 4 papers delivered at the first plenary session. Before introducing Marc Gourevitch of the Bronx in New York City, Andrea Barthwell alluded to a concept I have always avoided: "conquering addiction". The term "brain disease" was also used in the plenaries, reflecting official policy edicts from the 1990s. The problem is that if drug addiction is a brain disease, then about 90% of us have it! I feel on safer ground calling drug dependency a 'condition'. Then, like dandruff, pregnancy, obesity or baldness, it is the sufferers who can decide if and when it becomes a 'disease' (and there were numerous user representatives present at the meeting). Dr Gourevitch spoke modestly and authoritatively about co-existing disorders in dependent patients.

Dr Leonard Seeff was ill and at short notice Dr Larry Brown spoke well on the difficult subject of HIV in dependent patients. Dr George Woody then dealt with non drug related symptoms in dependent patients. He quoted DSM IV and even later definitions of the various presentations (mentioning that the DSM V was due out in 2010!). Symptoms from a number of pre-treatment surveys found high rates of anxiety, phobic disorders, ASPD, auditory hallucinations, etc. We were also told that just as drug users suffer from a wide variety of psychiatric disorders, equally, up to 50% of mental patients can present with co-existing substance abuse problems. When the primary condition is treated the other symptoms will resolve spontaneously in a proportion of cases. We were told that two weeks was a good interval in new methadone patients to reassess such problems which may need specific interventions such as antidepressants. It would appear that MMT can improve depression, anxiety and in some cases paranoid symptoms. It has long been believed that opioids have some anti-psychotic properties.

Regarding hepatitis and HIV infections, "prevention is better than cure" is an old maxim which was apparently NOT emphasised. Needle availability was an unpardonable omission in these plenaries. It is disappointing when respected scientific experts fail to say what needs to be said. Needle availability prevents viral disease transmission and does NOT encourage drug use. Several US states have introduced 'waivers' against the bans on pharmacies selling injecting equipment (see workshop above).

After the morning plenaries there were workshops on a variety of issues: dual diagnosis, homelessness, pregnant patients. In a well attended session, Dr Peter DeMaria spoke about 'Optimizing methadone doses'. He used a number of case histories to show that dose manipulation, splitting, increases, etc can turn around a 'failure' in treatment. One case history was a MMT patient who had used heroin continuously for 12 months in treatment while on 120mg daily. While it was helpful to examine the methadone level and a dose increase, it might also be questioned why the patient was treated for twelve months in this clearly unstable state, and all the attendant risks (but better late than never!).

DeMaria also took us back to the basic pharmacology of methadone to explain withdrawal symptoms with a helpful graph of methadone levels over 48 hours and thus two doses. He reminded us of the words of Sir William Osler: "Listen to the patient, he's telling you what's wrong with him". [I seem to recall that Osler continued: "... and if you listen hard enough he may also tell you the treatment"].

DeMaria stated that daily doses of 80 to 120mg are adequate for about three quarters of patients, but that others, some with aberrant metabolism need extra, split doses or alternative drug or non-drug treatments. Drug interactions were covered in detail, including phenytoin, fluvoxamine, antiretrovirals (three of them only), anti-fit meds etc. It was gratifying that the hall was packed with attentive clinicians from all over the US since one major consistent finding of surveys of clinics is inadequate dose levels across the board (this also occurs in Australia, Great Britain and elsewhere). Then we had mention of the stereoisomers of methadone and cytochrome metabolism ... rather too complex and speculative for us front-line workers perhaps, unlike the rest of this practical presentation.

Another session, by researcher and editorialist Stewart Leavitt, was entitled "Can Addiction Research be Trusted?" He helped us with just how to assess the clinical significance of particular studies from the anecdotal ('n=1') to RCT to the hallowed 'metanalysis'. But he warned that some such studies may be "gigo" (garbage in, garbage out) since overall conclusions are only as reliable as the data they are based on. Leavitt also gave us a timely lesson on the two common ways of interpreting studies over time (1) ITT or 'intention to treat' and (2) PP 'per protocol' (analysis of only those who finish the intervention). Both have pros and cons depending on the proportion of drop outs. He introduced the terms "PLUS-cebo" (for positive effects) and "NOCI-bo" (harm causing) for the more usual term for 'dummy' treatments which do often have apparent effects in trial subjects.

Leavitt then shattered the illusion of the "Farmington consensus" (which may not be a 'consensus' at all) that all research associated with 'inappropriate' sponsorship should be rejected for publication. This ban, largely aimed at tobacco and alcohol sponsorship, could also be levelled at drug companies, health authorities, policing interest, drug cartels, etc. Dr Leavitt pointed out that all research is biased by the nature of the authors, their background, ethnicity, funding, etc. Thus it is the reader who should look at what is disclosed regarding possibly conflicts of interest, who is writing/funding the research and then decide for themselves its 'rigour' and/or relevance for their practices. 'Publication bias' was also covered in which studies which have positive outcomes are more likely to be completed and published. Laura McNicholas MD from Philadelphia VA questioned some details from the floor concerning research samples - which were clarified. Extensive references and comprehensive handouts were given on a number of clinical and ethical matters of interest and the declaration that Leavitt's service is sponsored by a manufacturer of methadone and naltrexone.

The Tuesday evening dinner included 13 awards in honour of Vincent P. Dole and Marie Nyswander who together pioneered methadone treatment. While I have no objection to credit being recognised when it is due, Washington DC is hardly the place for accolades over drug treatment or policy in the centre of these continuing epidemics (addition, HIV, hepatitis C). Hence to avoid any ill feeling, I avoided this part of the proceedings and retired back to my lodgings early to gather my thoughts. It had been a marvellous three days meeting up with dozens of colleagues from all over the US as well as further afield.

I have great admiration for all these dedicated and hard working front-line professionals, some of whom operate in situations of poor funding, dangerous work environments and limited scope for professional advancement. Even simple advocacy can be hazardous in America. But one remains in hope of improvements, and that conferences like this might seed some such positive moves.

The above is not intended to be a comprehensive summary of the conference which also had 22 diverse poster displays and many other workshops, plenaries and 'round table' discussions I could not get to.

comments by Andrew Byrne ..

Addiction summaries: methadone versus buprenorphine. Does clonidine work?

'Addiction' journal, April 2003.

# Randomized, controlled comparison of methadone vs. 'bup'.
# Methadone syrup injection in 1996/7 in Adelaide.
# Does methadone kill more people than heroin?
# Poor quality of agonist treatments in England/Wales.
# Does clonidine work for withdrawal symptoms?
# 'Reductions' of bup popular but 90% need repeat treatment.

Dear Colleagues,

This edition reveals an extraordinary wealth of clinically relevant research material ... but also shows an intriguing reversal of health priorities by the editors. Some truly 'landmark' research is 'buried', while the first two reports and their related editorials are on subjects of modest, local and/or historical moment. The injecting of methadone syrup in Adelaide from 1996/7 and opiate deaths in England 1993-98 are both subjects deserving of clarification. But as is so often the case with Addiction, the tenor seems to be to question whether methadone treatment is a valid intervention rather than how to use it more effectively. After 35 years of positive research, Addiction should abandon its persistently negative focus on methadone treatment. Agonist treatments are not perfect, but they are now used by most western health authorities as one helpful approach to opioid addiction.

As a lead research journal, Addiction's main focus should be how to maximise the benefits of this proven treatment, not to question its very existence. The first page of the April edition in entitled: "Methadone syrup injection in Australia: a sentinel finding?" The writers state that there is a lack of reports of methadone injecting outside of Australasia. They relate some alarming consequences of methadone injecting, each being potentially paralleled for street heroin injecting, yet neither the nature nor extent of the problem is backed up by references. In fact, one of their suggested solutions is to examine introducing a type of methadone which is suitable for injection. In fact, since this study was completed, a safer water solution of methadone has begun replacing the older 'syrup' mixture. It is disappointing that the Adelaide researchers only had 2 questions: had subjects 'ever injected' and 'was there any injecting in the previous 6 months?' Thus the story lacked quantitation. Hardly fodder for the lead research paper in the world's most venerable dependency journal!

'Addiction' might care to ask a guest writer to look at why agonist treatments are still so restricted and why so much is of such poor quality, especially in England, where Addiction is published. Established guidelines are almost completely ignored by doctors to the cost of their patients and the UK community. Professor Dole, who originated the use of agonist treatments in New York, states that injecting behaviour (and therefore its complications) can be almost completely eliminated in up to 95% of subjects by using adequate doses of methadone with appropriate supervision and sufficient support services. All treatment should be judged according to whether it is in accordance with established treatment guidelines (eg. Strang's UK guidelines). Maintenance treatments save the health care system more per dollar invested than most other interventions. They reduce crime, prevent HIV infection and probably also hepatitis C yet they are still maligned in a way which is not based on logic.

Amongst the plethora of clinical material, the April edition has two important items on subjects after my own heart. Mattick et al. have published their three-city study of double blind methadone versus buprenorphine maintenance (see my detailed review elsewhere). At 3 months they found only minor differences in retention, drug use and side effects between these two drugs. This trial is very important scientifically and of substantial clinical relevance. It probably should have been the first item in Addiction and certainly deserves an editorial, considering buprenorphine was released in the USA recently. This may seem a small criticism, but not so the fact that Hickman's study of opiate deaths in England gives text references as numbers, while the actual list is alphabetical, making the article incomprehensible to the reader. The author was kind enough to send me an earlier draft with his own numbered references. I am bemused by the lack of editorial control at Addiction which led to this error. One wonders that the proper peer review process did not prevent such an error. The management at Addiction owe Hickman and colleagues an apology for this humiliating error.

The content of Hickman's article relates to an issue into which I had a personal input back in 1997: that 'methadone kills more people than heroin'. It is a sad fact that the issue is still being debated rather than being acted upon. In fact the last time Addiction published my name unrelated to some gossip or ridicule from house writers, was on the issue raised by Newcombe. The item by Hickman shows that there are still many (possibly unnecessary) deaths from methadone in England and Wales, but not as many as caused by heroin, and the number is still increasing. Both Hickman and the editorialist touch on clinical practice in England, but neither seems able to state that there is strong anecdotal evidence pointing to abysmal compliance with clinical guidelines in England and Wales. The drug is usually prescribed by doctors with no training in addiction medicine, without supervision of the medication and at dose levels which are often inadequate to quell cravings for 24 hours. Such deficiencies are inconsistent with Strang's detailed official UK Dependency Treatment Guidelines (1999). There appears to be no coherent plan either by professional groups, the NHS nor the National Addiction Centre to address these failings, despite them probably leading to the deaths of many people annually. This edition would have been an ideal place to address the issue. I offered to write such a piece but editor Edwards, while conceding the need, has not followed up on the matter it would appear.

Another item, from the group at Johns Hopkins, gave trial subjects on 30mg daily doses of methadone injections of naloxone and medicated them with clonidine or lofexidine without placebo control. Approval was granted by The Johns Hopkins Bayview Medical Center Institutional Review Board and individual consent given. We are not told if this is a properly constituted ethics committee, but it is gratifying that subjects were offered either a 90 day reduction course of methadone and/or assistance with referral to a long term maintenance facility in Baltimore after their services in this somewhat brutal trial (for which they were paid volunteers). It is a moot point as to whether currently addicted individuals can consent to a single option, especially one which is not an appropriate treatment for addiction (fixed 30mg of methadone daily). Unsurprisingly, 6 subjects who agreed to participate dropped out at the prospect of naloxone injections. However, 8 of 14 who completed the twice weekly experimental in-patient protocol effectively showed that neither lofexidine nor clonidine did anything significant in reducing withdrawal symptoms. My patients have told me for years that clonidine does little for withdrawal symptoms. Now here at last is proof!

In yet another item from Baltimore 120 subjects were offered a three day course of buprenorphine using 'high' (4mg) or 'low' (2mg) dose. This can hardly rate as 'reduction treatment' since the drug takes at least 5 days just to stabilize. It is not stated which professional protocol this 'treatment' is taken from. One wonders at the wisdom of giving a "treatment" which has little if any scientifically proven benefit and then reporting near 90% failure rates in an international journal. There was apparently no safety net reported by these researchers who noted frequent relapses in their patients. At 1, 3 and 6 months there were progressively fewer patients were contacted (80%, 55%, 47%). The authors' first statistics do not take lost subjects into account and their 6 month abstinence figure of 62% (self report) and 25% (clear urine test) are then translated for clarity to 35 and 14 subjects out of the original 119 (29%, 12%). A proportion of those lost to follow up may have been dead but this is not addressed by the Gandhi and co-authors. Their conclusion that there was 'reduced frequency and intensity of drug use' following their "intervention" is based on respondents only and is thus of limited validity, like their 'treatment'. All patients deserve appropriate treatment and this means regular assessments and if agonist prescription is appropriate on one day, like insulin, lithium or Prozac, it is nearly always appropriate on the next. Discharge from treatment should never be arbitrary as it was for all of these patients.

comments by Andrew Byrne ..

How does buprenorphine compare with methadone? A rigorous multi-centre study from Australia.

Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients. Mattick RP, Ali R, White JM, O'Brien S, Wolk S, Danz C. Addiction 2003 98:441-452

Dear Colleagues,

This vital multicentre trial comparing 3 months maintenance treatment gives us invaluable information on the use of buprenorphine for heroin addicts. Unlike some other fixed dose studies, the patients in both groups here were treated in a clinical, 'naturalistic' manner with flexible doses supervised with true 'blinding' of medications (each started with active/dummy). Inductions and dosing practices were in broad accordance with established guidelines, such as those from the UK (Strang, 1999) and the various Australian clinical guidelines. In the second month of treatment daily doses of up to 150mg of methadone and 32mg of buprenorphine were used (means 57mg and 11mg respectively). Dose increases were in response to patient reports of cravings, illicit drug use and doses just 'not holding' them.

If the overall numbers randomized to each treatment are considered (205 and 200), the retention rates at 13 weeks can be calculated at 58.5% for methadone and 48% for buprenorphine. My amateur statistical estimation sees this as reaching significance. However, in their own calculations, these authors exclude the patients who did not receive an initial dose (significantly, 3 for methadone and 8 for buprenorphine, a drug with more clinical limitations on starting) making their retention rates 59.4% and 50.0% (p=0.06). While this may seem picky, the authors also spend some effort looking at this significance. Regarding (1) the mean length of stay, 59 vs. 67 days and (2) evidently by applying a survival analysis across the 13 weeks there was a significant difference between the groups (but not at 6 weeks). The authors speculate about a possible 'type I error' since there were some parallel questions with possible 'overlapping' factors.

The overall findings are that this study again confirms that in the normal clinical context buprenorphine is almost as good as methadone at retaining opioid-dependent patients in treatment. It also showed equal benefits regarding reduced illicit heroin use and equal side effect profile for those remaining in treatment. This profile is much more extensive that my own experience: up to two dozen significant side effects suffered by patients in both groups (eg. nausea 16-17%; vomiting 8%; 'flu symptoms 7-10%; headache 11-13%). In my own practice I have seen virtually no side effects with buprenorphine and only sweating, constipation and some sexual dysfunction as prominent problems in some methadone patients. I understand that these researchers spared no effort in regularly canvassing for reports of side effects, some of which just might have been from withdrawals or other causes, hence a possibility of over-reporting compared to other research.

The question seemingly posed originally by these researchers, "is buprenorphine better than methadone" is no longer a useful question to my mind. We now known from years of research that buprenorphine works well as an outpatient treatment for opioid addiction, in many ways comparable with methadone prescription. Now we need to implement the treatment in a logical fashion for those who may benefit from it. The drug is much more expensive than methadone. It has limited long term safety data, although that which exists is reassuring. Buprenorphine is not proven safe in pregnancy although there too, early studies indicate no problem in many pregnancies studied while the drug was continued.

Hence, like the second antibiotic introduced after penicillin, buprenorphine should be used initially for those unable or unwilling to take methadone. It may be that it will become a first line drug at some stage but in my book it is currently an excellent alternative in cases where there are problems with methadone. My own practice has 15% of our maintenance patients taking buprenorphine. The state of NSW has 1,600 out of 16,000 on the newer drug 2 years after its introduction under the same general conditions as for methadone maintenance (but fewer take-home provisions).

Comments by Andrew Byrne ..

Lancet article - strong science but serious ethical issues.

1-year retention and social function after buprenorphine-associated relapse prevention treatment for heroin dependence in Sweden: a randomised, placebo-controlled trial. Kakko J, Svanborg KD, Kreek MJ, Heilig M. (2003) Lancet 361:662-668

Dear Colleagues,

The Swedes have produced some of the most quoted data showing the life saving properties of methadone maintenance, partly because this treatment is so severely restricted in Sweden. Thus trial candidates who are randomized not to receive prescription treatment, or who are discharged from treatment, rarely receive agonist maintenance therapy which might be available in the normal course of medical practice in other ‘normal’ countries.

From work performed in the 1980s, Grönbladh and colleagues showed a very high mortality in those rejected from methadone treatment - almost 8% per year. In an even more rigorous and controlled study using sublingual buprenorphine, Kakko et al. have found what the accompanying Lancet editorial calls: "massive 20% mortality at one year in the placebo group versus 0% in the buprenorphine group [which] is immensely concerning". Indeed, a trial using placebo in heroin addiction treatment would be considered unethical in Australia.

This trial provides strong support for buprenorphine maintenance since at a fixed dose of 16mg daily it had a 12 month retention rate of 75% and no deaths, compared with placebo: 0% retention at 2 months and four out of twenty being dead from overdose by 12 months. All 'placebo' (actually '6 day reduction') cases had access to intensive levels of psychosocial supports, some of which were reported to have induced paradoxical cravings. I understand that one of the 5 buprenorphine drop-outs has also since died.

The mortality rate is even more worrying considering that these candidates were chosen from over 400 applicants based on less severe dependency and less poly drug/alcohol use. Thus none of the chosen candidates was suitable for the stringent Swedish criteria for methadone prescription (4 years hospital-documented multiple daily heroin use). All but one were injectors.
All of the placebo patients showed positive urine tests for opiates before dropping out of treatment. Thus none was an early abstinence success - despite this being the consented aim of the trial. About 75% of urine tests of the buprenorphine patients were negative for illicit substances tested for. Thus despite continued if less frequent drug use was still associated with good retention and reduced health problems measured in a variety of ways by these researchers.

Swedish drug policy is based on the belief that all drug addicts can and should stop using certain proscribed drugs immediately (abstinence orientated, or 'zero tolerance'). While this has been long abandoned in most other countries, Sweden continues despite their own research showing excess deaths, continued drug use and high rates of viral disease transmission when such policies are pursued. One fails to understand how in such a modern democracy such ill-founded policies are used.

Yet the world's two most persuasive studies are from their own country showing that if heroin addicts are left untreated (or "treated" in the compulsory manner used in Sweden) then the result is a high mortality of young Swedes from a totally preventable and treatable cause, drug overdose.

For related editorial commentary: Law FD, Nutt DJ. Maintenance buprenorphine for opioid users. Editorial. Lancet (2003) 361:634-5

comments by Andrew Byrne ..

Methamphetamine addiction: review article.

Journal of Substance Abuse Treatment (2003) 24:267-277

Cretzmeyer M, Vaughan Sarrazin M, Huber DL, Block RI, Hall JA. Treatment of methamphetamine abuse: research findings and clinical directions.

Dear Colleagues,

This 'review article' looks at the modern stimulant epidemic from a clinical standpoint. On searching the literature, these authors found some treatment protocols, each of limited if any proven value in stimulant addiction, but each describing some 'promise' for methamphetamine dependency. Unlike the treatment of opioid and nicotine dependency, none involved prescribing of stimulants as either maintenance or reduction regimens as is used in the UK and in trials in Australia.

Amphetamine analogues are regularly prescribed by doctors and, unlike in the case of opioids for pain, there seems to be no 'grey area' between this and 'recreational' use despite some similarities in the expectations of both types of consumer. Like alcohol, opiates and other drugs, it is clear that stimulants have benefits and risks. Indeed, they are apparently dispensed to US Air Force pilots to increase attention and reduce fatigue. Yet current bans have never stopped many long-haul truck drivers claiming the same benefits from regular but completely unsupervised and unresearched stimulant use.

The first treatment protocol quoted by these authors, remarkably, involves the almost completely discredited 'aversion therapy'. It was used in the most clumsy and misguided manner using stand-in drugs for the stimulants and emetics or low voltage electrocution as the 'punishment'. Despite the absence of a control group and no valid scientific outcome data, these authors accept the treatment as 'promising'. And this was not in Abu Graid prison, but America in the 1990s.

The second was using first-generation antidepressants which the authors claim were successful or 'promising' based upon an improvement from 17 to 34 days retention with active imipramine over placebo, proving little except that these drug-users could detect placebos. 34 days in the life of a drug user is not exactly long-term.

The Californian 'Matrix' program is a psychosocial treatment model funded by the US drug agency, NIDA. It may be that the name 'matrix' is the most important component of its 'success' or 'promise'. The quoted trial here, with or without desipramine, only had 13 subjects who were amphetamine dependent. They were randomised three ways and ethnic differences confounded the already insignificant outcomes at 6 and 12 months. Why such a trial was quoted in a scientific paper I cannot tell.

'Case management' is examined next and it was found, unsurprisingly, that giving high quality vocational counselling improved employment outcomes and decreased depression levels. Case management did not reduce drug use compared with controls and thus it cannot be considered a 'treatment' for stimulant dependency on this evidence.

This review by a group of eminent experts seems to indicate an unwillingness on their part in the current US political climate to examine medical dependency problems from a purely scientific viewpoint. If patient outcome is paramount, it is essential to look beyond our own jurisdiction to see what is being done elsewhere. No promising modality should be 'off limits'. Substitute prescribing is not mentioned by these researchers for unstated reasons and when I wrote to them, I was asked to explain what I meant! As long as US researchers feel unable to write freely about harm reduction measures, and while needle services are not available in most areas, American citizens, including non-drug users, will continue to be exposed to high risks of HIV/AIDS, hepatitis C and the enormous social costs of unchecked non-medical drug use.

comments by Andrew Byrne ..

Citations:

Cooper D, Souther L, et al. Public Health Consequences Among First Responders to Emergency Events Associated With Illicit Methamphetamine Laboratories - Selected States, 1996-1999. JAMA (2000) 284; 21

Volkow ND, Chang L et al. Association of Dopamine Transport Reduction With Psychomotor Impairment in Methamphetamine Abusers. Am J Psychiatry 2001;158:377-382

What causes addiction / Practical issues in prison entries and exits / S8 approvals

Tues 25 March 2003

"What causes addiction - and does it matter?" Dr Richard Matthews.

"Practical issues in prison entries and exits - a new scheme is trialed" Dr Gilbert Whitton.

"Proposed new on-line, web based interface for S8 approvals". Ms Kanan Gandecha, Pharmaceutical Services Branch, NSW Health.

Chair Dr Andrew Byrne.

Dear Colleagues, Dr Richard Matthews has a wealth of knowledge about the history of drug use as well as the philosophy and attendant mayhem in attempts to control it. He reminded us that despite the popularity of drugs over the centuries, only the last 100 years have seen a variety of psychoactive drugs available to most citizens in western countries. For the first time in history the poor could be well fed and have excess income for mind altering drugs which are now major world trade commodities.

We were reminded of the history of the 'big three' legal drugs: caffeine, alcohol and tobacco, followed by the 'big three' illicits stimulants, opiates and cannabis. It is only when three factors coincide that drug use 'takes off': availability, low price and peer pressure. This appears to apply to illicits as much as legal drugs. Dr Matthews pointed out the interesting history of futile attempts to ban the various drugs including tobacco and coffee. Even draconian efforts such as decapitation did not prevent their use! Only today, with taxation, education, warnings and restricted places where smoking is allowed, we have seen substantial reductions in consumption. John Mills essay "On Liberty" was quoted in which sane adults were said to have the sovereign rights over their bodies (and thus what they consumed).

We were told the Coca Cola story in context of the temperance movement from the mid-1800s which saw alcohol as the major evil, ignoring patent medicines and tonics such as cola. Various combinations of caffeine, cocaine, alcohol and other drugs were purveyed to the delectation of Victorian era consumers. The caffeine was originally obtained from the coca nut but subsequently using more economical 'sweepings' from tea processing plants.

Following the Madame Butterfly story, US troops were encouraged to take Coca Cola wherever they went including world wars and other regional conflicts, often selling the drink at a loss (a 'nickel' or 5 cents per bottle).

We also had a lesson in the meaning of the term 'addiction' from the Latin 'ad' meaning 'to' or 'towards' and 'dicere' the verb 'to declare'. From the word's origin we glean the element of a lack of control as the individual is "declared towards" consuming the drug, despite other dissuading factors. This term could be applied equally to behaviours such as gambling, sex or shopping. We know that the ancients were familiar with the addictive properties of opium from the writings of Galen and others.

Keats, Byron, King George IV, William Wilberforce, Thomas de Qunicey were just a few of the 19th century notables who used opiates, largely laudanum. It was only with the invention of the hypodermic syringe that the major acute dangers of opiates (morphine) became evident. Yet, still at high prices, intravenous opioids did not become generally popular for another 100 years.

Regards drug use generally, Dr Matthews used a graph of two parallel alcohol studies to show that three groups emerge of (1) dabblers, (2) 'accelerators' and (3) heavy users. It is this last group consumes 80% of the total drug supply and also has most of the morbidity. Why this occurs is speculative, but its significance is obvious regarding harm reduction interventions such as needle services, methadone treatment, injecting rooms etcetera. The final conclusion was that we do not know the full story of the cause of addiction, but that its quest probably DOES matter.

Rather than just looking at drug use in prison entrants, Dr Matthews started with psychiatric symptomatology. He showed elegantly from a large study that anxiety, psychosis, depression and mental defection were each greatly over represented when compared with community findings. Predictably we also saw drug and alcohol use/dependency far more common and especially polydrug use in prison inmates. Several of the figures were more than 100-fold the community prevalence! Dr Matthews questioned whether prison was always the right place for such folk who in a previous age may have not used drugs at all, and if they did, may not have been subject to the risks attended by the illicit market.

Next, and on the same topic, Dr Gilbert Whitton let us know about a new scheme to facilitate prison inmates moving to community methadone, buprenorphine [and ?naltrexone] prescription on discharge. The new scheme will operate in regional areas rather than the current centralised system. Area coordinators will liaise with GPs, clinics and hospital to attempt to facilitate transfers without interrupting treatment which is so often a cause of relapse, reoffending and reincarceration. We were told by the PSB representative that any GP in NSW can prescribe temporarily for such a patient if appropriate authority is obtained (Tel 02 9879 5246). This would require that the patient is already on stable treatment and this is to be continued in a supervised manner with a 'mentor' arrangement either with another community specialist or the original prison prescriber. Presumably take-home doses would be very limited if available at all in such cases initially.

Ms Kanan Gandecha next told us to expect major changes in PSB approvals in the next few months as web-based application trials come to the field. Security will be similar to that used for internet banking with a 'user name' and ID number for prescribers (the current prescriber number will be used to avoid duplication). Access will be strictly limited to the doctor's own patients, or to clinic patients for clinic managers. Prison medical authorities will be considered as one special group, allowing information to be shared more easily in this special case.

Numerous questions were raised concerning privacy, out of hours access, changing addresses, doses, pick up points, etc. All applications will still need individual pharmacist approval for patient, doctor AND pick up point. This will simplify transfers from methadone to buprenorphine (or vice versa for those unhappy with buprenorphine). PSB processes up to 100 applications per day and attempts to keep to a 24 hours turn around time. These include methadone, buprenorphine, stimulants (for ADD) and opioids for chronic pain which are all handled by only 6 pharmacists. Urgent applications, such as priority cases of pregnancy, HIV are always processed first, sometimes within 2 hours or even less.

comments by Andrew Byrne ..

Anticraving drugs - boring or breakthrough?

Anticraving drugs - boring or breakthrough?" Dr Stephen Jurd at Concord Seminar Series 4th Feb 2003.


Dr Stephen Jurd spoke eloquently about the use of anti-craving drugs foralcohol dependence at our first Concord Dependency Seminar for 2003.

We were reminded of the history of this field and the poor uptake of the two approved drugs, acamprosate and naltrexone both in Australia and overseas. Well under 5% of target subjects are currently being prescribed the drugs for reasons which are not at all clear.

Our speaker detailed the now copious research data on these medications individually as well as one very recent trial using both together, a non-approved but promising innovation.
Dr Jurd described his own personal way of choosing whether to try acamprosate or naltrexone initially. He feels that one can score most alcoholics between two extremes, one end tending to drink to get the blood levels up to high levels and attain pleasurable experiences, the other end drinking to maintain a blood level, thereby avoiding unpleasant and negative feelings, including physical/mental withdrawals. From opiate research we know quite a deal about the pleasure centres, opioid receptors, naltrexone blockers, etcetera, which probably dominate as a causal mechanism in the first type of alcohol dependent subjects. The GABA and glutamate systems are in a rough balance, modulating the level of arousal in the CNS. Acamprosate is active at both GABA and glutamate receptors, in an opposite way to alcohol (decreasing glutamate activity and increasing GABA activity). Thus naltrexone decreases the positive feelings associated with alcohol and acamprosate reduces the negative feelings associated with the lack ofalcohol. Naltrexone decreases positive reinforcement and caproate probably decreases negative reinforcement.

The research on naltrexone and acamprosate has been performed in numerous ways in different countries. A common end point in American studies was 'time to relapse' where this was defined as '5 standard drinks on one day' or '5 drinking days' (of any quantity). [And to confuse further, an American 'standard' drink has 15g alcohol, not 10!]

Some European acamprosate research used 'time to first drink' (ANY drink) which made interpretation and comparison more difficult but all trials showed substantially higher numbers retained in treatment and abstinent at 3 months with approximately double the numbers being retained. Graphs of treatment population 'decay' are most impressive, showing an even greater response to both drugs used simultaneously. Outcomes have varied widely in different studies, but there have been so many positive studies that it is beyond doubt that these drugs exert an active effect, presumably on cravings.

The Concord audience was also reminded of the definition of the "intention to treat" research principle: It is a preferable way to analyse outcomes in research studies to include the results from all subjects included in the study, not just those who complete the study. In this way, the survival curve displaying the decay of sobriety over the months will have different sample sizes at each point on the graph. Starting say, with 50 subjects in each of the active and placebo group, after a week 4 may have dropped out of the placebo group and 5 may have dropped out the active drug group. What is compared in the graphing of the results is the PROPORTION of sober subjects at 1 week, say 40 out of 45 (or .89) and the PROPORTION of sober subjects in the placebo group, say 35 out of 46 (or .76). Thus at each point on the graph, all available data are used. As each subject drops out, the denominator decreases.

The anti-serotonin (5HT) drug ondansetron (Zofran) seems to act in a manner opposite to SSRI drugs (which had negative effects in alcoholics in the small number of trials so far performed). Ondansetron doses are modest, being only a fraction of the usual anti-emetic dose of 4mg (300µg taken twice daily). Further studies on this are needed before it could be accepted as a standard alcoholism treatment. The drug appears to be more effective for the "genetic" type of alcoholism rather than the later onset 'reactive' type.

'Rimonabant' is a French-developed cannabis receptor blocker. It seems to have some effect on alcohol cravings in animals but human research is still quite limited.

General practice was the ideal setting to implement these new drug treatments. Both naltrexone and acamprosate are available on the PBS for alcohol dependence when the patient is 'in a treatment program' (such as a general practice setting) - one month supply and repeats allowed. Naltrexone is a simple once daily administration with few side effects in alcoholics. It is contraindicated with opioid analgesics, unlike acamprosate which needs to be taken as two tablets, three times daily. Acamprosate equally has a low side effect profile and few significant drug interactions. The important issue of when to stop therapy was also broached - without a general consensus. Since most relapses occurin the first 2 to 3 months, by 6-12 months it is probably safe to rely on non-drug means to maintain abstinence in most patients.

We should always remember to utilise support services such as self help groups, counselling and psychological services and liver clinics when appropriate.

comments by Andrew Byrne ..

Urine testing in drug treatments: Is it effective? Is it ethical? Is it necessary?

re: Goldstein A, Brown BW. Urine testing in methadone maintenance treatment: applications and limitations. J Substance Abuse Treatment 2003 25; 2: 61-63

Commentaries by Coppola; Dupont; Heaps and Lurigio; Parrino.

In addressing urine testing in methadone treatment, these authors seem to have forgotten that methadone prescription by doctors is a time-honoured practice in which compulsory urine testing is not only unnecessary, but also possibly unethical. There is no scientific evidence cited by them or anyone else to my knowledge to show that such testing reduces drug use or improves treatment outcomes in other respects. Indeed, the concept runs contrary to behavioural theory as well as to Hippocratic principles. That is not to say urine testing should not be done. It should. But it should be voluntary. Urine testing may be a valuable measure of outcome for practitioners in evaluating their own practices, rather than necessarily judging their patients. Further, it might be reasonable to suppose that testing improves outcomes if it is part of an environment that promotes communication with patients, even if there is no evidence currently. In this way, urine testing may be a better judge of treatment programs than of the patients in them.

The article by veteran researchers Goldstein and Brown and the series of commentaries published with it show the complete ‘divide’ which exists between good medical treatment and American drug treatment program protocols. Rather than a considered description of the subject, these authors write an ‘introduction’ followed immediately by ‘conclusions’. Neither the authors, nor their commentators give a clear description of how the use of such testing fits into the ethical framework of addiction treatment. We treat obesity and weigh people. We treat diabetes and measure the patients’ sugar levels. We treat tobacco addiction and alcoholism with a variety of means and outcome measures. A treatise on when and how to order these measures would be based on practical experience with the modalities available and their costs/effectiveness. Nobody would suggest withholding or altering treatment substantially if a patient declined to submit to testing on one or two occasions. At the same time, treatment would be fraught if there were no outcome measures.

Each of these authors appears to assume that urine testing reduces drug use and that to be effective, urine testing must be random and frequent, with an implication that it must be compulsory. None of them seriously broach the sensitive but important subject of ‘supervision’ or ‘witnessing’ of urine samples for accuracy and to prevent substitution. This should be implemented in close cooperation with consumer groups, needing scrupulous care in maximising privacy while maintaining the integrity of the process. In some American states it is considered illegal to ‘witness’ such testing. Patients who refuse testing should not be denied treatment although other means need to be sought to demonstrate their progress.

A senior colleague once said to me that the only unquestioned purposes of urine testing is in the course of research and practice evaluation, as well as to make money for pathologists. This should involve consent of the subjects. Most authorities would probably agree that a full dependency assessment also includes urine toxicology. Indeed, it is probably as fundamental as taking the blood pressure and urine test as components of a full cardiovascular assessment. But patients should never be forced to do such testing and the results should only ever be used in their direct best interests.

From the two misconceptions above, these learned American experts delve ever deeper into the realm of speculation, moving further away from science and ethics. How can we justify doctors ordering compulsory expensive and intrusive tests which have never been proven to be of any benefit? Indeed, in many programs the results may directly cause patients to be deprived of take-away doses … and this is lauded by one of the commentators as a ‘benefit’ to the long suffering patient! Such actions could lead to the loss of a job or prevent children getting to school on time. Take-home dosing should only be denied in cases where is it is causing greater risks than benefits, and it should never be withdrawn based on an individual urine test result. It is clear that with improved education that American treatment programs can respond to evidence and improve the quality of the treatment given (d’Aunno 1999). It is difficult to do so, however, when state mandated practice guidelines conflict with the evidence, as with take-home dose provisions, dose levels, counselling and urine testing frequency in some jurisdictions.
These authors seem to be learning things well known to every young medical student, yet they ignore some of the refinements of urine testing which can indeed be very useful for patient care. Results can be wrong for a variety of reasons such as labelling, storage, substitution, ‘inhibitors’, lab errors etc. Doctors’ usual response to unexpected results is to have them repeated. Such testing usually takes 24 hours. While some clinics now do them on site, few can provide a result and a medical opinion in the short time a patient is present for medication. Dupont seems to have realised that urine testing is not ‘delivering’ what we might like, has suggested the role for hair or saliva or sweat tests. These research tools are of interest, but are hardly near implementation, being without a solid research base nor current clinical guidelines.

These authors all seem to believe that a positive methadone result is an important finding to confirm compliance with treatment. Yet these patients are nearly all receiving one or two doses per week under supervision, making such testing superfluous as methadone remains detectable in the body for several days. Indeed, a negative test result is far more likely to be from a tampered urine sample or a lab error than a case of a patient not taking their medicine in my experience. Another unusual but interesting finding is a specimen which is positive for methadone but negative for methadone metabolites. This usually indicates a substituted specimen from a non-methadone patient with a soupcon of medicinal methadone added to the urine. Such unusual but worrisome results should be used with the utmost sensitivity and in the patient’s best interests. Why would patients be driven to do such things in a caring treatment program? How can there be a productive outcome to such a seemingly distrusting environment? Obviously repeated episodes would indicate a change of treatment, but a single such event may lead to a watershed if it leads to improved communication and/or more frank discussion in the therapeutic milieu.

Goldstein and Brown’s response to poor outcomes with standard testing is to do it more frequently and introduce true randomisation so clients could be urine tested on ANY day (even two days in a row). Also recognising the limitations of urine testing, Dupont suggests that hair testing is ‘impervious to cheating’, although goes on to say it is not without problems, as well. We have heard similar claims for drugs in sport or the workplace, equally without any serious evidence of safety nor effectiveness of the intervention.

My own attitude is that urine testing can and should be used by patients to demonstrate their progress in treatment. This should be used, along with evidence of employment or education, a drug ‘diary’, rent receipts, healed veins and other indicators of stability in order to qualify for less supervision in treatment, and thus more ‘normalisation’ of their lives.

Patients should be able to volunteer for a supervised (witnessed) urine test at a point when they wish to have it known that they are moving away from illicit drug use. In my experience, a person who uses a significant quantity of street heroin has a positive ‘EMIT’ opiate test (Syva Corporation, California) for at least 5 and often 6 days. Such a positive test may, however, equally indicate the use of codeine, cough suppressants or even poppy seeds. Hence a positive test is less ‘useful’ than negative one or the negative predictive value of the test is higher than its positive predictive value for heroin use. A confirmed test for morphine is suggestive of, but not proof of illicit heroin use. And in some countries heroin is not always illicit. The use of buprenorphine is directly parallel to methadone maintenance and urine testing principles should be the same in nearly all respects. To date most tests cannot detect buprenorphine, but this does not reduce their utility significantly unless there is no supervision of doses. Even in America, doctors may request pharmacists to supervise some buprenorphine sublingual doses - although for unknown reasons this has not been widely recommended, despite nearly all the excellent American research on buprenorphine using dose supervision.

I have discussed the effect of urine testing on treatment outcomes with an Australian expert who has confirmed that there is no good evidence in his experience and reading either for or against it. He pointed out further, that ‘punishment’ rarely has a beneficial affect on behaviour. On the other hand, there is ample evidence in the literature that ‘reward’ mechanisms do have a positive effect on outcomes. It is a tragedy that so many modern experts appear to be convinced of the utility of unproven modalities and that many such practices which may be outmoded, expensive and even dangerous are persisted with, despite the evidence.

An enquiry of the corresponding author about these matters yielded a reminder that the main thrust of the article was to point out that the probability of detecting a "dirty" urine is ‘vanishingly small’ in most cases of illicit drug use. This rather simplistic piece of mathematics was based on the unreferenced premise that negative tests only indicate an absence of heroin use in the previous 24 hours. The one area we seem to agree on is that most patients, even long term, stable people, should have up to 8 urine tests per year as a part of their normal treatment. But in my view such testing should be patient-initiated and the results should only be used as a guide to the patients’ level of stability along with other clinical indicators.

There is also a political reality that in most countries where addiction treatment is state-funded, community expectations are that urine testing, along with other safeguards and supports, be used as part of a strict and effective system of ethical health care delivery for those addicted to drug and alcohol.

While it can sometimes be disheartening to read superficial and unscientific research in our field, it is always uplifting and reassuring to receive feedback from so many caring and intelligent colleagues who are working effectively with dependent patients in their practices, clinics, hospitals, etc in many different parts of the world. More strength to you all!

Comments by Andrew Byrne ..

Methadone syrup vs. sugar-free solution, buprenorphine availability in pharmacies and clinics.

Dear Esteemed Colleagues,

After over a decade of being almost a "one product shop", our addiction practice has moved to try each new form of opiate pharmacotherapy as it was made available. In most cases initial reservations were dispelled by the positive feedback regarding patient acceptability, stability and retention from the new drugs. We have also noted a proportion withdrawing successfully from all opioids. Professor Vincent P. Dole suggests that addiction pharmacotherapy should be considered the same as any other prescription medicine.

Thus the first patients to be considered for any new modalities might best be those who are unhappy with current options (usually moderate-dose methadone 'syrup'). While staff considerations are important, patient considerations should be paramount. Hence despite our reticence, we have tried each new product in patients who seemed appropriate. I now believe that buprenorphine and 'Biodone' (and probably diazepam and naltrexone) should be available in every addiction treatment service dispensary. And they should be available during the same hours, and from the same experienced staff as other supervised pharmacotherapies (and if possible, at the same price). To do otherwise is unduly disruptive to couples or associates who may be on different treatments, of for those changing from one to another. It also adds to the stigmatisation of addiction treatments and may increase congestion.

Staff may feel reluctant to introduce new medications in addiction treatment but they can yield enormous rewards for both patients and staff. I recommend starting with the most frustrating and unhappy cases and one may find that with some manipulation of the medication such folk can become the most devoted and grateful patients, and they often attain stability surprisingly rapidly. We thought that having buprenorphine cases would take longer but in fact it now saves us time. People are more likely to be getting what they need and are thus less likely to be in the 'unstable' category who take up so much of our time.

In our practice (~150 patients) about 75% now choose 'Biodone' sugar-free solution of methadone. About 10% are grateful that we still supply the old 'syrup' being as yet unable to tolerate the sugar-free medicine. And we have about 20 patients on buprenorphine currently, nearly all previously unhappy with methadone. There are also a number on methadone who were very unhappy with buprenorphine, which is no surprise considering personal preferences.

Some say that it is more difficult to dose different medications but I remember the frustrating cases who previously took time to 'gag down' their medicine - as well as those with nausea and vomiting who needed reassessments, anti-emetic injections, supplementary dosing and other time-consuming consultations and procedures. In community pharmacies, hospital wards, ambulance and psychiatric crisis teams, the staff members dispense and administer a variety of different medications without difficulty, sometimes to large numbers of patients.

With some places being still "one product" establishments, I hope that we can "normalize" these pharmacotherapies since what is happening at present is less than satisfactory for a great many patients and is certainly no good for staff morale. My staff and I have found the new options have made our lives easier and more rewarding professionally. I estimate that the proportion we can retain in treatment has increased substantially to perhaps 85%.

Andrew Byrne ..

Sugar-free methadone acceptable to a majority of patients

Byrne A. Methadone ‘solution’ (Biodone) survey. APSAD Annual Conference, Wesley Centre, Sydney. October 2001 p41 (published conference abstract)

METHADONE 'SOLUTION' (BIODONE) SURVEY

INTRODUCTION: In November 2000 a new formulation of methadone became available in Australia, a red coloured, solution without the sugars, preservative, gum and alcohol of the current syrup. Patient responses have shown a low level of satisfaction with the existing product and it is not necessarily safe from a dental point of view. Comments on the flavour such as 'disgusting' and 'foul' have been made.

In some patients, side effects such as dyspepsia, vomiting and reflux are given as reasons for patients either dropping out of treatment or taking inadequate doses to abolish cravings for 24 hours. Such patients may be assisted by an alternative formulation.

METHODS: We offered the new methadone 'solution' to 125 patients (31 female, 82 male) who had been receiving the 'syrup' prescribed at an inner city dependency practice. Most patients received their medication at the Redfern practice while 14 (11%) attended a variety of pharmacies and clinics. Patients were surveyed about whether it was preferred and if any changes were noted after taking the new preparation.

RESULTS: The new 'solution' was tried by 116 (93%) at least once. The preparation was preferred by 57 (46%) patients with a further 24 (19%) having no preference. Thirty five patients (28%) sought to return to the 'syrup' product, finding the solution unacceptable, largely because of the foul taste. Many patients described the taste as being unpleasant, but that it went away more rapidly than with the syrup.

For those on high dose (>150mg daily, n = 30) the acceptance rate was higher, 60% favouring the new formulation. For those on less than 80mg, the rates were almost evenly divided into thirds: (1) favouring the Biodone solution, (2) favouring the Glaxo syrup and (3) no preference.
Reports from 6 patients indicated that clinically significant side effects from the syrup were either completely or largely abolished with the solution. These included morning sickness, reflux, dyspepsia and a 'heavy' feeling in the upper abdomen after dosing.

Four patients (3%) reported that the new solution did not seem to last as long and withdrawal symptoms occurred prior to 24 hours. This was addressed by increased dose in one case, splitting doses in another, returning to the syrup in one case. The fourth case persevered with the symptoms which settled after a number of weeks.

DISCUSSION: It is possible that sorbitol, alcohol and the other constituents of the 'syrup' may impede absorption in some cases. The 'non-core' constituents may be responsible for reducing gastric emptying time, thus increasing the effective half-life. The simple 'solution' thus may be absorbed faster in some cases and its elimination slightly faster. The syrup is thought to induce nausea and vomiting in some cases since changing to the simple solution caused such symptoms to cease in several cases.

CONCLUSIONS: It is recommended that all patients who have symptoms from the current formulation are given access to the new water based solution ('Biodone Forte'). If experience proves positive in practice, the benefits of a sugar-free medicine should be a consideration for all patients.