Alcohol in Iran. Some move to opium in preference says New York Times

Dear Colleagues,

The New York Times ran an interesting story about alcohol in Iran and the conflict between Persian wine traditions and modern enforcement of Islamic prohibitions on drinking. As with all blanket bans on popular pastimes, there are black markets, inequalities, arbitrary punishments, tainted alcohol, poisonings, deaths and, according to this item, a move towards other drug use such as opium. Is this "harm maximization" at work?

If certain patterns of alcohol consumption are beneficial (which has recently been questioned), do citizens have a 'right' to access as they should for medicine, education, etc? As a drug and alcohol physician, I always feel obliged to encourage reduced alcohol consumption, just as with tobacco or other harmful drugs. Excepts below. (Registration (free) is required with NYT to read the full article.)

The New York Times

3 April 2006

Tehran Journal "As Liquor Business Booms, Bootleggers Risk the Lash"

Photo caption: 'Pure alcohol, sold in many stores for under $3. The common recipe is one shot mixed with two shots of juice' By NAZILA FATHI Published: April 4, 2006

TEHRAN, April 3 - For more than 27 years, Iran's Islamic leaders have waged an uphill battle to cleanse the country of bootleg liquor.

Since the revolution in 1979, the government has banned alcoholic drinks and frequently flogged those who drank them. The small community of Christians and Jews was exempted, but could not sell alcohol to Muslims.

<snip> ... Parliament recently increased the punishment for selling or drinking it. Offenders still get 74 lashes, but now also receive a hefty fine and from three months to a year in prison, twice the maximum sentence than under the old law.

<snip> ... Every month, newspapers report that tens of thousands of bottles of illicit liquor are confiscated by the police .

Despite the crackdown, there is no sense of an alcohol shortage. .

The Iranian grape is so good for making spicy wine that Australian Shiraz, sometimes known as Syrah, is made from the same grape that grows in Iran's southern city of Shiraz, which gave the wine its name. .

... Islam forbids the consumption of alcohol ... But drinking and wine are integral parts of Persian culture. ... poems by Iran's popular 14th-century poet, Shamsudin Mohammad Hafiz, who was from Shiraz, revolve around wine. "A rose without the glow of a lover bears no joy," he wrote. "Without wine to drink the spring brings no joy."

... earliest evidence of wine making dates from 5400 B.C., in Haji Firuz Hills, near Western Azerbaijan Province, south of where the city of Orumieh is today.

... more than 40 factories, some of which have imported machinery from China and Europe, are competing in the market. A thin plastic bottle of 600 milliliters, known here as pocket size, has few indications of medical use, but is available in stores for under $3. The common recipe is to mix one shot of alcohol with two shots of juice, preferably pineapple. ... pure alcohol is still widely available.

... the decision to permit such widespread production of alcohol was made to limit the number of deaths and casualties caused by illegal drinks. Some 19 people were killed in 2004 after drinking bad bootleg liquor. "A lot of people had turned to drugs such as opium because they were cheaper and more accessible," said the official.

Comments by Andrew Byrne ..

Suboxone Sydney launch

April 5 2006

Product launch by Reckitt Benckiser. Suboxone combination drugs containing buprenorphine and naloxone 8mg/2mg and 2mg/0.5mg approved in Australia from April 1 2006.

Dear Colleagues,

This was an auspicious evening put on by the plush Rydges Jamison Hotel at Wynyard in central Sydney. After elegant canap�s of Beijing duck, sushi and bonsai pies with tomato sauce, Eric Strain from Johns Hopkins Medical Center gave a comprehensive description of the development of the combination drug. He showed numerous slides of his own pharmacokinetic and pharmacodynamic studies. He started by asserting that adding naloxone to opioids was an effective and time-honoured practice. Apart from the New Zealand experience (which resulted in the combination drug's eventual withdrawal), he quoted previous 'successful' uses with pentazocine (Fortral/Talwin), methadone (patented in the 1970s) and tilidine (Valeron) as having stemmed abuse. We were given neither criteria nor references for this conclusion.

Dr Strain emphasised that the withdrawal reaction to injected buprenorphine and naloxone in those already dependent on other opioids is 'very unpleasant' but GENERALLY (my emphasis) not harmful. He did not cite the reports of serious adverse events, including sudden death from injected naloxone in the literature (Osterwalder 1996; Andree 1980). We were also told of a trial (corroborated by some data on blood levels) showing that subjective effects of three types of buprenorphine were maximal in the liquid preparation, medium in the pure sublingual product and least in the combination tablet at a given dose level (the first differences were significant but the second trend did not reach statistical significance). We were then told by Dr Strain, supported by Chris Chapleo of Reckitts, that the formulation type had little effect on absorption. Surprisingly, Dr Strain seemed unaware of the common practice of using 'granulated' (semi-crushed) tablets in Australia. He speculated as to whether the citrus flavour of the newer preparation increased salivary flow, facilitating absorption (it might just do the opposite - but studies are limited). Some blood level studies showed higher levels in the combination product, others lower or the same. I was surprised that none of the speakers covered the only published clinical trial comparing the new product with other modalities (Fudala 2003).

Next we had a choice of grilled salmon tranches on mash or ox cheek braised in red wine with turnip, baby carrot resting on artichoke or chestnut puree and jus. Joining the 'coalition of the willing', Dr Mike McDonough then gave an eclectic account of his unit's contribution to a multi-centre study of 130 patients treated with unsupervised combination buprenorphine. He described having to deal with many unexpected occurrences, each involving a new learning curve in randomised subjects taking weekly non-supervised (dispensed) treatment. We heard of scenarios where patients who were originally assessed as being 'stable' subsequently revealing worrying and unpredicted problems. One had taken a mixed drug overdose needing emergency resuscitation. Another patient reported that cutting their own dose by half, leaving sufficient tablets for a trip to Perth but with some unpleasantness on return to Melbourne. So even in very experienced hands stability is hard to gauge.

Dr McDonough then quoted Robinson's paper from Wellington, NZ from 1993 [their finding was that after pure buprenorphine was banned and almost entirely replaced with the combination product due to abuse, 63% of new dependency patients were still using the drug, most by injection. Subjects also stated that it was 'easier to obtain' and that the black market price was lower a year after the change to combination product. And the drug was subsequently withdrawn completely]. We were also reminded of James Bell's study but were reassured that the finding of 50% dose increases reported on changing from pure to combination product was probably due to "anxiety" (no references) and that the doses 'returned back to previous levels after a while' (which is not my reading of the paper - they did decrease, but not back to original levels on pure buprenorphine). We all await publication of further data on the fundamental issue of dose equivalence.

Ms Susan McGuckin, the representative from NUAA (a NSW consumer advocacy group) spoke eloquently about the frustrations of being a consumer is such a volatile field. She also supported more choices for doctors and patients.

Next we had the arrival of Professor Bob Batey, breathlessly brandishing hot-off-the-press copies of a 'draft' set of NSW guidelines on buprenorphine/naloxone prescription for addiction. He reminded us of the inevitable diversion which can be expected and the fact that it is not just take-away policy which drives such markets. His words were more of basic clinical common sense than revealing any brave new frontiers. It was the first time in my experience that a new health department policy was announced at a drug company event.

We were told that questions would only be taken at the end from written submissions on cards supplied to each of the dozen or more round tables. They were to be addressed to a panel in the final session during coffee by the chairperson.

Following bread and butter pudding with summer berries and clotted cream, question time was not very encouraging as Dr Strain was asked to predict events if the combination drug is injected. He gave likely outcomes in the various scenarios, apologising for the length of his reply. He seemed to have difficulty responding to a more specific query about whether a current buprenorphine patient would get a withdrawal reaction if they injected the combination product. Others have stated that such patients can inject buprenorphine 'with impunity' and a withdrawal reaction is highly unlikely (one called it a "best kept secret"). Dr Strain, on the other hand stated that it was a difficult matter to predict but that on balance, he thought that the situation would probably be 'dose related' and that under 8mg would probably cause euphoria while higher doses would be likely to cause withdrawals. These uncertainties may reflect the limited research in the area, making it all the more difficult for regular clinicians to make decisions.

One public sector member of the audience asked if the combination product was being pushed for reasons of patent or 'evergreening' to secure market share. Dr (PhD) Chris Chapleo of Reckitts told the audience that his company had no patent over either product, although he said later that there were 'exclusive licence' agreements in some countries 'in return for the company's input into research and development' but that these did not apply in Australia or New Zealand.

A further question was read out by chair Dr Alison Ritter as to whether the combination product could be chemically converted into its constituents by enterprising amateur chemists. Chris Chapleo stated that short of having a complicated chemistry equipment and knowledge this was most unlikely, and his company had tested several proposed amateur methods, finding that they did not work (one tried to oxidation of the naloxone with potassium permanganate). My own reading of the manufacturer's prescribing instructions indicates that the two drugs have quite different solubility properties. Hence by adjusting temperature, granulation and simple dissolution and filtration, an enterprising kitchen 'cooker' might find this quite simple, as many do with mixed analgesics currently. Dr Charles R (Bob) Schuster, who is doing post marketing surveillance of buprenorphine in America, wrote recently in Drug and Alcohol Dependence: "It is unlikely, however, that any formulation can be developed that cannot be altered by 'street chemists' into a more abusable form."

A final card was read out, questioning if we were all "missing something". Were we all 'ignoring the elephant in the room?' This was put to the silent audience but after such generous hospitality (although not a drop of alcohol) it may have seemed unfair on our hosts to ask the clinical questions:

1. Can we be sure of dose equivalence between pure and combination product?


2. Are there clinical studies to show that the combination product is safe and effective? Fudala's 28 day comparative study - the only one of its kind - was not dealt with by any of the speakers on the night, but it did have some data for up to 11 months.


3. Why is there no 0.4mg tablet for the new product? Thus at a common dose level of 4mg daily the only possible reduction is 50%. For methadone (or insulin, or warfarin) this would be considered inappropriate or at best a 'courageous' reduction.


4. Why are the new products not 'scored' like the pure ones which are easy to break in half? As stated in the NSW guidelines on combination buprenorphine presented on the night, it is acceptable for patients to take half doses morning and night to avoid sedation or other side effects.


5. There appear to be TWO quite different concepts arising out of the new product: (a) combination buprenorphine may have a lower abuse potential and (b) a totally new claim that unsupervised use is safe and effective for addiction treatment. While we would all hope both of these will be true, to date, neither has been subject of more than one or two limited preliminary studies. Hence claims for their appropriateness would seem premature, especially considering pure buprenorphine and pure methadone have stood the test of time when given in traditional medical settings.


6. Can injecting naloxone be dangerous? In what ways? Can we be held responsible if the drugs we prescribe are used contrary to our instructions? Can we reduce the harms?


7. Should women of child bearing age be prescribed this drug combination, given the lack of safety data for naloxone in pregnancy?


8. Since it is agreed that partial antagonists like buprenorphine and pentazocine already cause precipitated withdrawals when used (injected or otherwise) by subjects who are currently using other opioids such as heroin or methadone, one may ask what is the point of adding naloxone? We also do not know if the new product is safer for injecting than the existing pure product with regard to 'chalk', 'filler' or other non-active constituents?


9. And we should not forget: this treatment is generally less effective and less cost-effective that methadone. Combination buprenorphine does not have long-term safety data like methadone. If methadone is considered better for pregnant women, why not also for others?

James Bell had the last word of the evening, saying that the combination product is not a 'third drug' as another participant had stated. It is still the buprenorphine we are all used to, only now being used under a different 'paradigm'. He said that taking the focus away from supervised treatment and back towards other more important clinical matters would be a great challenge to everyone in the room. [He had told another meeting recently that unsupervised treatment may be shown by experience to be completely unworkable and we might have to be withdrawn entirely ... 'only time will tell'. It seems odd to me to take such risks in peace time.]

We should all be grateful to Dr Strain and his colleagues for their pioneering studies on the combination drug, although from the questions, this audience was still anxious for more direct clinical information on the new drug and its possibilities.

Reckitt Benckiser is to be congratulated for taking the risk on this new formulation in an attempt to improved dependency treatments in Australia. We could not expect this launch to be an update on all opiate treatments, a subject which is being left to the College of Physicians with a new series of regular workshops generously sponsored by Reckitts.

Comments by Andrew Byrne ..

Refernces:

Osterwalder JJ. Naloxone for intoxications with intravenous heroin and heroin mixtures - harmless or hazardous? A prospective clinical study. J Toxicol Clin Toxicol. (1996) 34;4:409-416

Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784

Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN et al. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

Methadone comparison with buprenorphine (pure) from Norway.

Tidsskr Nor Laegeforen 2005 125;2:148-151

A randomised clinical trial of methadone vs. buprenorphine to opioid dependants. Kristensen O, Espegren O, Asland R, Jakobsen E, Lie O, Seiler S.

Dear Colleagues,

After decades of denial in Norway, methadone was finally introduced in 1998 and buprenorphine in 2000 for opioid dependence. These researchers set out to compare the effects of the two maintenance therapies in their own drug using population.

There were 50 long term (>10 years) opioid dependent subjects randomised to receive 16mg fixed dose buprenorphine or variable dose methadone (mean daily dose 106mg, range 80-160mg) over 6 months observation. Patient retention rate was 85% in the methadone group and 36% for those prescribed buprenorphine. Opiate positive urine tests were slightly lower in the methadone group (20% vs. 24%). Importantly, the methadone subjects reported less high risk behaviour. For some reason, only the buprenorphine group (or the minority who remained in the trial) reported significant improvements in general health.

This small study should be the last to compare methadone and buprenorphine in this way. Their results were predictable, adding little more than Scandinavian corroboration to 20 years of preceding research. The fixed dose buprenorphine dosing schedule here was probably based on a successful Swedish model (Kakko, 2003) but patients were moved automatically onto second daily double doses after 2 months. This may have caused some of the excess drop-outs. Also, fixed dose schedules are unlikely to be as effective as flexible ones.

Methadone and buprenorphine should both be prescribed in tailored doses according to clinical need, using appropriate increments (eg 5mg for methadone, 0.4mg for buprenorphine). It is likely that some buprenorphine patients in this trial dropped out because they received too little or too much of the drug (32mg is the maximum recommended dose).

There is no longer any doubt that both methadone and buprenorphine are effective for substantial numbers of heroin addicted subjects treated with adequate supervised (and flexible) doses along with psychosocial supports.

From a body of research, including numerous RCT�s, we know that when compared to buprenorphine: (1) methadone generally suits a higher proportion of the total and (2) it reduces the use of other opiates to a greater degree and (3) whilst in treatment, such patients are less likely to be involved in high risk behaviours. Methadone is also considered to be safe in pregnancy and is much cheaper and easier to administer. Thus methadone should probably still be our preferred first option and buprenorphine kept in reserve for particular indications. If there are concerns about patients misusing methadone then take-away doses should be limited until stability has been demonstrated. It may be that long-term users are less likely to fare well on buprenorphine, as shown in this study.

It is unfortunate that decisions for physicians and especially for patients are frequently dictated not by clinical considerations as much as by regulatory constraints. In some countries (and for no logical reason) these are far more onerous and odious for methadone, while others artificially restrict or even ban the use of buprenorphine for addiction treatment, despite almost 20 years of favourable research.

My feeling is that buprenorphine should be available as an option to all patients who report problems taking methadone. Such patients, however, should be carefully monitored since a high proportion relapse (in this case 74% within 6 months) and may need to transfer back to methadone or to consider other alternatives such as detoxification. These authors are not the first to use the term �gold standard� for methadone maintenance treatment.

There is no indication that combination formulation of buprenorphine (with naloxone) will be any more effective than the pure product. Some evidence points towards lowered efficacy (50% higher doses were required in Bell�s pilot study). While some have stated that sublingual naloxone is not relevant clinically, others have found objective changes and significant absorption (10% or more). Naloxone has a rapid serum clearance time (~5 minute half life) but its serum half life following distribution is just over one hour. While one hopes for less diversion with this formulation, Charles (Bob) Schuster writes: "It is unlikely, however, that any formulation can be developed that cannot be altered by �street chemists� into a more abusable form." Dr Bell�s pilot study of seventeen stable subjects had four who did not attend for their random call-backs for medication count, raising the possibility of non-compliance and/or diversion.

Comments by Andrew Byrne ..

References:

Harris DS, Jones RT, Welm S, Upton RA, Lin E, Mendelson J. Buprenorphine and naloxone co-administration in opiate-dependent patients stabilized on sublingual buprenorphine. 2000 Drug and Alcohol Dependence 61:85-94

Berkowitz BA. The relationship of pharmacokinetic to pharmacological activity: morphine, methadone and naloxone. Clin Pharmacokinet. 1976 1;3:219-30

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

Schuster CR. History and current perspectives on the use of drug formulations to decrease the abuse of prescription drugs. Drug and Alcohol Dependence (2006 in press, pre-publication version, accessed 28/2/06)

Patterns of methadone treatment in NSW: only one in seven is 'long-term'

Drug and Alcohol Dependence 2006 81;1:55-61

Cycling in and out of treatment; participation in methadone treatment in NSW, 1990-2002. Bell J, Burrell T, Indig D, Gilmour S.

Dear Colleagues,

In New South Wales doctors fill out various coloured forms every time a patient starts, stops or transfers opioid maintenance treatment. The Health Department used to release statistics regularly yet little has appeared in recent years. Here, the hard work of Bell et al. pays off with a useful analysis of some of the details of sample cohorts of all patients starting their first treatment episode during February 1990, 1995 and 2000 (n = 477). February was chosen since it is the first 'normal' month after the summer holiday season.

Retention at 3, 6 and 12 months is tabulated for public [free to the patient] and private [typical cost to patient A$40 (~US$30) per week] systems. There was no significant difference between the sectors and retention rates were 64%, 51%, 38% at 3, 6 and 12 months with 12% of the first two cohorts still remaining in their initial episode at 5 years.

Five years from admission, 45% of original entrants were still registered for maintenance treatment and 75% of these had been continuous or had one break in treatment. 25% had between 3 and 9 treatment episodes.

Overall about two thirds of discharged patients re-entered treatment, the majority within 2 years from discharge. Those more likely to be re-admitted to treatment were young patients as well as those who had a short initial treatment episode (< 3 months). Overall the number discharged after 'successful dose reductions' was 68 (17%) and these patients had been in treatment an average of 2 years at discharge.

The initial cohort from 1990 had an average treatment period of 4.8 years during 2.6 episodes over the 12 year follow-up possible in this study.

Also, 67% dropped out for unspecified reasons. The rest reportedly 'transferred' (8%), were discharged involuntarily (1.5%) or died (1%). Another 69 patients remained in their initial treatment episode (14% of original total).

There were 342 subjects commencing treatment in private clinics while 135 started in public settings (only exceptionally are new entrants started in pharmacies in NSW).

This is a fine demonstration of the natural history of citizens' opiate use as well as their interaction with a mature and flexible medical maintenance service (available in hospitals, pharmacies, private clinics, public clinics and all jails). It is also consistent with Thorley's old review: "over a seven year period, something over a third of dependent subjects will cease opiate use and a very small number will have moved to intermittent use. Approximately 2% will die each year, and after seven years, around 5% will be in prison and 80% will be divided almost equally into a group attending drug clinics and [therefore] in receipt of a legal prescription, and a group not attending clinics and in the community".

Comments by Andrew Byrne ..

Thorley A. Longitudinal Studies of Drug Dependence. In: Drug Problems in Britain: A review of ten years. Eds: Edwards G, Busch C. 1981, Academic Press. p162

Bell J, Burrell T, Indig D, Gilmour S. Cycling in and out of treatment; participation in methadone treatment in NSW, 1990-2002. Drug and Alcohol Dependence 2006 81;1:55-61

Cannabis and psychosis: some references for readers

Dear Colleagues,

This very "debate" proves that if cannabis causes psychosis, it does not cause very much of it, very often (see references below). According to widely published expert Professor Fergusson of Christchurch, the jury is still �out� on causation, but there probably is a small group whose numbers are hard to measure considering schizophrenia is relatively common and cannabis smoking is rife in our society.

Stringent laws against cannabis have never been shown to reduce the use of cannabis or its complications. Even in places like Jamaica and Nimbin (NSW) where cannabis is used rather heavily, no evidence has ever been produced that schizophrenia is more commonly diagnosed. Comparisons of areas with decriminalisation such as Canberra, Adelaide and Amsterdam against places using severe law enforcement (eg. Bali and San Francisco) has never shown either higher rates of cannabis use, nor higher rates of psychosis to my best knowledge.

An important finding in recent years is that the younger one starts using cannabis (or probably any other drug), the more likely one is to develop serious and perhaps permanent complications. A strong reliance on law enforcement in drug control may well encourage more children to become involved as happened in the American alcohol prohibition period last century.

I hope these references are useful for readers.

References

Reinarman C, Cohen PDA, Kaal HL. The Limited Relevance of Drug Policy: Cannabis in Amsterdam and in San Francisco. Am J Public Health. (2004) 94:836 842

Fergusson DM, Horwood LJ, Swain-Campbell N. Cannabis use and psychological adjustment in adolescence and young adulthood. Addiction (2002) 97:1123-35

Lynskey MT, Heath AC, Bucholz KK, Slutske WS, Madden PAF, Nelson EC, Statham DJ, Martin NG. Escalation of Drug Use in Early-Onset Cannabis Users vs Co-twin Controls. JAMA (2003) 289:427-433

van Os J, Bak M, Hanssen M, Bijl V, de Graaf R, Verdoux H. Cannabis Use and Psychosis: A Longitudinal Population-based Study. Am J Epidemiol 2002; 156:319-327

Rey JM, Sawyer MG, Rafael B, Patton GC, Lynskey M. Mental health of teenagers who use cannabis: Results of an Australian survey The British Journal of Psychiatry (2002) 180: 216-221

Comments by Andrew Byrne ..

RCT of buprenorphine versus methadone in pregnancy reassuring

Addiction 2006 101;2:275-281

Methadone versus buprenorphine in pregnant addicts: a double-blind, double-dummy comparison study. Fischer G, Ortner R, Rohrmeister K, Jagsch R, Baewert A, Langer M, Aschauer H.

Dear Colleagues,

This small but meaningful study from Vienna gives us further confidence in the safety and effectiveness of (pure) buprenorphine in pregnancy when compared with traditional methadone treatment. These authors performed a randomised, double dummy trial using flexible dosing, daily attendance and psychosocial supports for 18 patients.

They used flexible doses of 8-24mg buprenorphine and 40-100mg methadone in women at 24-29 weeks of pregnancy.

There was a still birth at 38 weeks in a woman who had been abusing opioids, cocaine and benzodiazepines. Another had a late spontaneous abortion at 28 weeks. Both were methadone subjects. Another two patients were withdrawn from the study due to non-compliance (one buprenorphine and one methadone patient).

Of the remaining subjects who went to term, neonatal abstinence syndrome (NAS) was equal across the two groups. Only about 50% of babies needed treatment for NAS (for an average of 5 days in both groups). The signs were noted slightly earlier in the methadone subjects (60 hours; versus 72 hours after birth for buprenorphine). Intercurrent drug use, determined from urine toxicology, was significantly less in the methadone subjects. Retention rates were not significantly different, possibly owing to the low numbers.

Again, these researchers have provided further evidence of the safety and effectiveness of buprenorphine in pregnancy. With a lack of adverse reports and widespread use in many countries, we can probably now prescribe buprenorphine with more confidence for pregnant women in whom methadone has proven unsatisfactory. It is still not 'first line' in my view, but an excellent alternative when indicated. It also is an indirect reminder that the combination drug should never be used in pregnancy or during lactation (and probably ought not to be used in women who are at risk of becoming pregnant since safety data are absent).

Comments by Andrew Byrne ..

The use of combination buprenorphine naloxone in clinical practice

Email/Medline exercises examining use of combination buprenorphine naloxone in clinical practice.

Dear Colleagues,

The combination buprenorphine product is due for release in Australia in April, as 2mg and 8mg buprenorphine with 0.5mg and 2mg naloxone. Australian states and territories have been using the pure product (0.4mg, 2mg and 8mg sublingual tablets) for almost 6 years and it now accounts for between 10 and 50% of the opioid maintenance 'markets'.

There have been claims that the combination is clinically equi-potent and that it is subject to significantly less abuse. While sublingual naloxone is only partially absorbed (~10%) it may still have side effects in the longer term. It might also be the reason why some patients request a higher dose when taking the combination product (see Bell et al 2004 in which a mean increase of about 50% was required). While research on (pure) buprenorphine is extensive and consistent for addiction, work on the naloxone combination is scanty and conflicting. We need to consider that some of the prescribed combination drug will be injected (in Wellington, NZ, more than 50% of addicts presenting for treatment in 1992 were reportedly doing so). This will predictably cause toxic reactions in some users for which we need to be cognisant.

For these reasons we performed a literature search of naloxone using Medline and find that it is not always benign when used intravenously. Below we list some citations which seem relevant (note that none relates directly to maintenance treatments). We also sent an email request to American colleagues on their experience after nearly 4 years of clinical use of the drug using office based (non-supervised) prescription in that country. This is a summary of the findings.

Methods:

An email request was sent to 184 US colleagues (see wording below). The recipients were drug and alcohol workers who had indicated an interest in the field and who received regular journal summaries sent by email from our surgery. Some details of respondents and responses are tabulated here, along with some selected quotes. The recipients included substantial numbers of university professors, clinicians, drug users, advocates, policy makers and researchers, many of whom responded.

Results:

There were 44 responses received, 5 being from 'secondary' recipients making crude response rate of 24% in the busy weeks between Thanksgiving and Christmas, 2005. Of those who felt that they could comment on the issue, 16 responses came from New York, 5 from Massachusetts, 3 from California, 3 from Maryland, and one each for Connecticut, Illinois, Maine, Minnesota, New Jersey, Vermont and Puerto Rico (omits those unable to comment).

Twenty five of the 44 (57%) reported that they were personally aware of at least one case of diversion and 9 of these (20%) cited the existence of a black market with 5 (11%) quoting a street price. There was one report of primary buprenorphine addiction. A further 10 (23%) stated that they had not seen any diversion in their own practices. Two respondents no longer worked in the field. Another 7 could not answer the question from their own experience.

Analysis:

Most replies were brief but some were quite detailed. Some of the most definitive replies came from Puerto Rico and the North East of the USA. The most worrying replies came from two experienced respondents who stated that virtually all of their detox and/or maintenance patients (in three different states) had tried buprenorphine on the street in the weeks before admission. [See below for sample replies].

Conclusion and discussion:

It appears that despite reportedly low uptake of buprenorphine in America generally, in some regions doctors are prescribing the drug to the extent that a secondary 'grey' market is being reported (Cicero, 2005). Some of the street drugs reported may be 'Temgesic' obtained from Canada, Mexico, the internet or elsewhere. However, the majority would appear to be the local 2mg and 8mg combination tablets from the reports detailing the type of drug diverted. While pure buprenorphine is now available in many countries, the combination drug is currently only used widely in the US. It is also used in medical trials elsewhere (eg. Australia and ?Finland ?New Zealand - see Bell 2004).

The use of buprenorphine and buprenorphine-naloxone combination tablets in an office setting without dose supervision was introduced into the United States in unique and difficult circumstances (see Jaffe 2003) and in spite of very little published research on the intervention (Fudala 2003). Events subsequent to marketing do not appear to have been well monitored/reported as I have yet to find any meaningful data relating to the extent, safety and effectiveness of the intervention in America. There are indications of diversion (Cicero, NEJM, 2005) but these appear to be in isolated areas.

The email survey we have performed has serious limitations, being restricted to a sample of correspondents who have self-identified as being interested in dependency medicine. A true random sample of American prescribers would give more rigorous results. We believe that such a study should be performed as a matter of urgency to ascertain if indeed buprenorphine or buprenorphine-naloxone products are being diverted to a street market at a rate which is of concern.

In my view, until more is known, non-supervised opiate maintenance treatment should generally be used in the context of increasing access to take-away doses ['take-homes' or 'carries' in US parlance] in a structured, 'stepped' or 'streamed' treatment setting. This should be based on traditional indicators of stability and progress in treatment. Another use would be in research trials comparing office based treatment with existing clinic treatment. Extended unsupervised periods (more than ~3 days) have been shown to be satisfactory for 6, 13 and up to 27 doses at a time in highly selected long-term patients after stabilisation in a clinic setting (Senay; Schwartz; Novick; Rhoades).

Appended: [1] wording of email request, [2] selections of responses, [3] references.

[1] Quoted request in buprenorphine diversion survey.

Subject: 'Use and abuse of buprenorphine (Subutex/Suboxone) query'.

Dear Colleague,

Can you let me know if you have any knowledge of the mis-use or 'diversion' of these drugs in the American community since their widespread use began about 4 years ago. They appear to be very safe and well tolerated yet we have little information to date.

Best regards for the holiday season.

Andrew Byrne .. (Sydney, Australia)

[2] Quotes

The following are selected quotes [most direct quotes, some paraphrased for clarity] of responses received:

no significant reports of misuse or diversion ... <snip> ... few serious adverse events reported

someone on the street sold him two 8mg bup/nal tablets (50 cents per mg).

I'm certainly not aware of any, but you folks might know better.

We see virtually none of it at either my clinics in [W Coast]

'remarkably little'

'expensive' [on street]

all my patients have tried bup on the street ... at $25 for 8mg ... plenty of docs give a month's supply of 32mg at the first visit and hasta luego.

regarding safety and illicit bup use in the United States. ... We are generating many anececdotal stories...

Most diversion seems to be ... from a someone for cash to abate withdrawal symptoms.

there is an illicit market for these drugs with an 8mg tab going for as much as $50.

Several .. patients .. [say] .. suboxone is available at street black market very early since its approval. ... patients have poor compliance ... almost all need supervision of medicine ... in stabilization ...

there is some diversion in NY but it is very small ... diverted buprenorphine was reported in a shelter and use by heroin addicted shelter residents

ONE of our patients in [Tri-state area] got a subutex from a "friend" and put themselves in withdrawal

there has been evidence of diversion of Buprenorphine ...mostly anecdotal.

It didn't do nothin' for me doc!

only heard of one case of street use.

'unpopular with addicts, not just due to naloxone'.

no real abuse or problems thus far.

[bup] has a bad street reputation for getting high ... [but] ... a good reputation if an addict wants to stop withdrawal.

Increasingly patients are telling me of instances where they have purchased a few pills

'little evidence of clear diversion'

one of [20 treated patients] diverted his medication, and that was to his wife

I have to get my medication from the street. The doctors here are charging ridiculous prices ... [I pay] $30 for 3 x 8mg suboxones which .. last for 2-3 weeks.

rumours .. from patient advocate group members, regarding the [New England] area. There is no question that diversion occurs...but it has not hit the papers, yet.

I've had patients report they have used bup (suboxone) provided by others

$30 for 8mg Boston

one patient ... taking extra doses of his suboxone

we ... do unscheduled "call backs" for pill counts [for] detection of diversion ... .

anecdotal reports from needle exchange customers who have used or plan to use street-acquired buprenorphine

addicted unable to get bupe elsewhere

some anecdotal reports suggesting that the little diversion ... for the purpose of trying out the treatment.

[3] References:

Cicero TJ, Inciardi JA. Potential for Abuse of Buprenorphine in Office-Based Treatment of Opioid Dependence. NEJM (2005) 353;17:1863-5

Jaffe JH, O'Keeffe C. From morphine clinics to buprenorphine: regulating opioid agonist treatment of addiction in the United States. Drug and Alcohol Dependence 2003 70 (supp) 2:

Osterwalder JJ. Naloxone -- for intoxications with intravenous heroin and heroin mixtures: harmless or hazardous? A prospective clinical study. Clin Toxicol 1996; 34: 409-416.

Hsu W, Rao RB, Nelson LS. Naloxone hazards overstated. Clin Toxicol 1997; 35: 215-217

Andree RA. Sudden death following naloxone administration. Anesth Analg 1980; 59: 782-784.

Jasinski DR, Martin WR, Haertzen CA. The human pharmacology and abuse potential of N-allylnoroxymorphone (naloxone). J Pharmacol Exp Ther 1967; 157: 420-426.

Schwartz JA, Koenigsberg MD. Naloxone-induced pulmonary edema. Ann Emerg Med 1987; 16: 1294-1296.

Kanof PD, Handelsman L, Aronson MJ, et al. Clinical characteristics of naloxone-precipitated withdrawal in human opioid-dependent subjects. J Pharmacol Exp Ther 1992; 260: 355-363.

Bell J, Byron G, Gibson A, Morris A. A pilot study of buprenorphine-naloxone combination tablet (Suboxone®) in treatment of opioid dependence. Drug Alcohol Rev (2004) 23;3:311-318

Fudala PJ, Bridge TP, Herbert S, Williford WO, Chiang CN et al. Office-Based Treatment of Opiate Addiction with a Sublingual-Tablet Formulation of Buprenorphine and Naloxone. NEJM (2003) 349:949-958

Senay EC, Barthwell A, Marks R, Bokos PJ. Medical Maintenance: An Interim Report. Journal of Addictive Diseases. 1994;13(3):65-9.

Schwartz RP, Brooner RK, Bontoya ID, Currens M, Hayes M. A 12-year Follow-Up of a Methadone Medical Maintenance Program. American Journal on Addictions 1999 8;4:293-299

Novick DM, Joseph H, Salsitz EA, Kalin MF, Keefe JB, Miller EL, Richman BL. Outcomes of Treatment of Socially Rehabilitated Methadone Maintenance Patients in Physician's Offices (Medical Maintenance). J Gen Intern Med. 1994;9:127-30.

Barsan WG, Olinger CP, Adams HP, et al. Use of high dose naloxone in acute stroke: Possible side-effects. Crit Care Med 1989; 17: 762-767.

Reisine T, Pasternak G. Opioid analgesics and antagonists. In: Hardman JG, Limbird LE, Molinoff PB, et al, editors. Goodman & Gilman's the pharmacological basis of therapeutics. 9th edition. New York: McGraw Hill, 1996: 549-551.

Gaddis GM, Watson WA. Naloxone-associated patient violence: an overlooked toxicity? Ann Pharmacother 1992; 26: 196-198.

Neal JM. Complications of naloxone. Ann Emerg Med 1988; 17: 765-766.

Ward S, Corall IM. Hypertension after naloxone. Anaesthesia 1983; 38: 1000-1001.

Azar I, Turndorf H. Severe hypertension and multiple atrial premature contractions following naloxone administration. Anesth Analg 1979; 58: 524-525.

Flacke JW, Flacke WE, Williams GD. Acute pulmonary edema following naloxone reversal of high-dose morphine anesthesia. Anesthesiology 1977; 47: 376-378.

Brimacombe J, Archdeacon J, Newell S, Martin J. Two cases of naloxone-induced pulmonary oedema -- the possible use of phentolamine in management. Anaesth Intensive Care 1991; 19: 578-580.

Harrington LW. Acute pulmonary edema following use of naloxone: a case study. Crit Care Nurse 1988; 8: 69-73.

This report was written by Andrew Byrne. With thanks to all those who generously gave their time in responding to my email request on this issue.

Rapid detox trial shows no long term benefit

Drug and Alcohol Dependence 2006 81;2:109-116

Opioid antagonist detoxification under anaesthesia versus traditional clonidine detoxification combined with an additional week of psychosocial support: A randomised clinical trial. Favrat B, Zimmermann G et al.

Dear Colleagues,
February's D&A Dependence journal has a feast of items including a randomised trial of rapid versus traditional detox from Switzerland. While there is a trend for more rapid detox patients to be abstinent at 3 months, by 6 and 12 months there is no difference and the relapse rate is over 95% for both groups. This is consistent with a similar trial from Adelaide some years ago.

But this item tells us more about rapid detox than just abstinence outcomes. Of the 70 "mono-dependence" patients who sought detoxification in the trial only 26 out of 36 (72%) randomised to rapid detox actually took the procedure, despite it being free and performed in a general hospital. And of the remaining 34 who were randomised to 'classical clonidine' detoxification, only 21 were included in the trial (62%). In each group between 4 and 8 patients just did not turn up on the appointed day while a similar number were excluded because they showed up non-opiates in the pre-treatment urine screen and this trial excluded those using drug other than opiates.

The compliance with oral naltrexone was shown to be very poor despite being offered to all patients. In the clonidine group only 2 started naltrexone, compared to 24/36 in the anaesthesia-assisted patients. Yet the drug was so unpopular that it was only taken for an average of 10.8 days in this latter group, where the company recommends 6 months.

There was a death in the rapid detox group at the 3 month follow-up. The authors state this was probably not related to the treatment, however the treatment obviously did not help this subject. We now know that the choice of detoxification is a risk in itself, regardless of how it is achieved. However, in these low-risk, 'mono-addicted' subjects, rapid detox had no benefit except in the short term. It is invasive, costly and in this as other reports, there is a mortality (see ABC link below in which 80 deaths have apparently been reported from a single 'naltrexone' clinic).

Comments by Andrew Byrne ..

The ABC had a very revealing naltrexone item on the 7.30 Report on Friday 13th. See http://www.abc.net.au/7.30/content/2006/s1547424.htm

Developments in buprenorphine, methadone and hepatitis in France

Dear Colleagues,

"Le Flyer" is a French dependency newsletter (circ 10,000, also on internet www.rvh-synergie.org/) edited by the director of an addiction centre in Paris. The latest issue (no.23) has a provocative editorial predicting that 2006 will be a year of big changes for drug treatments in France.

We are told that a company called 'Arrow' specialising in generics will market a new brand of buprenorphine while the current French supplier, Schering Plough, intends to introduce a quick dissolving tablet or wafer. This has been talked about for several years by Reckitts staffers and would be most welcomed in Australia too. The editorial also predicts the introduction of the combination product with naloxone - which they term 'non-injectable' - at the risk of 'a bad quarter hour' - meaning withdrawals, I presume, in translation.

The proposal appears to be the same as in the US where the current guidelines recommend using pure buprenorphine for initiation but that continuing maintenance be done with the combination product (except in pregnant women or those who are sensitive to the combination). It is hard to imagine how the French authorities will convince doctors and patients to move from pure buprenorphine to a combination after so many years of apparently successful experience with the treatment using 'Subutex' in the community.

There is a press release on "H�patite C: Xavier Bertrand (French Health Minister) souhaite que les patients soient majoritairement pris en charge en ville. PARIS, 8 d�cembre 2005 (APM)" [this calls for hepatitis treatment to be largely undertaken in the community in the future.]

"Le Flyer" also covers a comprehensive report by a committee of French experts on the prevention of both hepatitis B and C. It is pointed out that methadone has a better track record in several respects (reducing needle sharing; less illicit drug use; better retention). They therefore recommend that methadone become the treatment of first choice for people who are sero-negative (to keep them that way, I suppose is their logic). In my own view, it is also the treatment of choice for those who are sero-positive to prevent them passing it on.

In France buprenorphine can be prescribed in a community setting where methadone maintenance treatment (MMT) can only be commenced in a specialist clinic (as in New South Wales). This does not prevent gradual increases in methadone numbers in France or Australia since once stable, GPs can take over prescribing of methadone, just as might occur with insulin, warfarin, etc. In the US, methadone 'slots' are frozen by the number of clinics and the ban on GPs or pharmacies being involved. This is all the more tragic since America still has such a large unmet need for addiction services while these are relatively cheap and simple treatments with major benefits for individuals and society.

I have been sent some interesting old papers from the 1970s regarding the combination methadone and naloxone. Although it never really 'caught on', this may have seemed a logical concept considering methadone can be so toxic in overdose. One of the comparative studies showed that the addition of naloxone caused a significant reduction in the initial methadone peak on serial blood levels (the paper was way ahead of its time!). I wonder if this could explain the dose increases requested by nearly all 17 subjects in Bell's study when changed from pure buprenorphine to the combination product.

Comments by Andrew Byrne ..

More about the Byrne Surgery practice

Extract from a recent publication (Drug and Alcohol Dependence) relating to methadone dose levels and metabolism.

The study practice has been treating drug and alcohol dependent patients for 15 years (Byrne and Wodak, 1996). Patients are referred by local doctors or other drug services and at any one time up to 150 patients are treated with opioid pharmacotherapy. Most patients live or work in the area and attend the practice for supervised dispensing for which they pay a fee, others attending public or private clinics, or pharmacies, for dosing.

There is no maximum methadone dose, although doses above 200 mg/day must be approved by a committee of the New South Wales Department of Health. Mean methadone doses calculated periodically in recent years at this practice have ranged between 89 and 107 mg/day.

Patients are seen regularly by a doctor for counselling and dose review, one- to four-weekly as their stability in treatment is demonstrated, and a doctor is available to see patients whenever the clinic is open. Dose changes are made in consultation with the patient, in response to any symptoms of opiate withdrawal, mood disturbance, continuing use of illicit opioids, or other prescribed and non-prescribed substances including alcohol, benzodiazepines and cannabis.

The practice uses an enzyme immunoassay (Microgenics CEDIA®, Fremont, CA, USA) for urine toxicology, which includes a test for opiates, sensitive to 300 ng/ml of morphine/monoacetyl morphine and having similar sensitivity for metabolites of morphine (glucuronides), for codeine and a range of other opiates. In our experience, the opiate screen remains positive for up to five days after heroin use. If the opiate screen is positive, specific thin paper chromatography is performed which has a sensitivity of 300-500 ng/ml for morphine/monoacetyl morphine.

Supervised urinary drug toxicology is performed every one to four weeks depending on the patient's progress in treatment. Patients newly in treatment are tested more frequently while those patients with consistent evidence of abstinence from illicit drugs over a period of time are tested less frequently. The testing protocol is random but is varied by the doctor or dispensing nurse on duty in response to clinical indicators of drug use (such as intoxicated presentations) and prior urine toxicology results. Urine testing is encouraged but not compulsory, and patients receiving takeaway doses are seldom asked to provide urine specimens on days when they would not otherwise attend the practice. Positive urine drug screens do not lead to forced withdrawal regimens or withholding of treatment, and do not disqualify a patient from receiving take-away doses, but are indicators for more intensive supervision including more frequent urine tests. Typically several negative opiate screens are required before a patient qualifies for less frequent urine tests.

Taken from: Hallinan R, Ray J, Byrne A, Agho K, Attia J. Therapeutic thresholds in methadone maintenance treatment: A receiver operating characteristic analysis. Drug and Alcohol Dependence 2006 81;2:129-136