Addiction Treatment in Metamorphosis: Paradigm Shift in Theory & Practice

New York State Psychological Association Division on Addictions

April 28, 2006.

The New School, Wollman Hall, 65 W 11th St, NYC, 10003

Dear Colleagues, This conference opened with respected veteran researcher Thomas McLellan who spoke at length about his recent realisation that addiction is indeed a chronic disorder and that his and others' research over the years had missed often this essential fact. He said that it shows the futility of treating a chronic disorder with a variety of short term interventions, hoping to get different outcomes where nearly every trialled treatment for dependency found much the same (disappointing) results in the medium term. He emphasised the many consequent benefits of on-going treatment rather than 'black box' interventions lasting weeks or months. He came close to candidly conceding that much previous dependency research by himself and others was worthless, using the term 'mea culpa' at one point (see some citations below). Some people, such as Dr Vincent P. Dole, have been pointing in this direction for many years.

We were shown outcomes of various trials on diabetes, hypertension and addiction, including Project MATCH. McLellan pointed out that reports of medication compliance (now termed 'adherence') had often shown less than 50% of general medical patients actually take their medication as prescribed (eg. for asthma, arthritis, etc). We were shown other close similarities between dependency and general medical research trials. However, there was often the rather major difference was that addiction trials usually examined short periods of active treatment, reporting limited outcomes after a defined treatment had ceased.

We were also led through one 'rationale' to dispense with detoxification treatments which are expensive and 'largely ineffective'. The goals of such treatments, however, need to be more clearly defined. Crude cost benefit examinations may look negative, but with the added benefits of conduits into on-going treatment, abstinence or otherwise, far more positive figures resulted. In fact, the government of Delaware had introduced novel legislation reducing funds for open-ended detoxification but increasing payments for proven higher retention rates in treatment (any documented treatment). While only a small state, such successful interventions could pave the way for larger jurisdictions in the Union and elsewhere.

Dr McLellan's final point was that like other 'disorders', 'diseases' or 'conditions', addiction should normally be addressed by primary care doctors and their usual staff in a community setting. Difficult or complex cases should be referred to multidisciplinary specialist services which should be able to instil a degree of 'self management' after acute problems are addressed. He pointed to the parallel with new diabetic patients being taught about diet, skin care, sugar measurement, medication, etcetera. The patient should then be returned to primary care for on-going management, reviews, prescribing and follow-up.

Dr McLellan spoke privately about the somewhat discomforting challenge of being in a room full of psychologists (!). I questioned the use of 'contingency management' in view of his espousing the use of 'normal' medical interventions for addiction treatment. He replied that these were used in normal practice as well (but he gave no examples apart from general encouragement of good progress - see below for details of 'contingency' manglement).

Following, there was a series of 4 workshops after the plenaries of which I chose 'mandated addiction treatment issues' with Professor Barbara Wallace. To a packed room, she alluded to her numerous books while confronting the audience with numerous anecdotal cases. For some reason, she avoided mention of pharmacotherapies which are the mainstay of most drug court decisions in some jurisdictions. Her "menu" of treatment options read like a dozen ways of describing the same thing from my untaught medical perspective.

Next, prior to lunch, Andrew Tatarsky spoke eloquently about psychological and psychoanalytic approaches using principles of harm reduction. He has also written a book on the subject and feels passionately that such principles are consistent with good practice. He went so far as to say that the Alcoholics Anonymous "Big Book" was the original 'bible of harm reduction', although it has been hijacked recently by fundamentalists. Dr Tatarsky had been invited to give a talk to a group on addiction related topics but because of federal rules, he was asked to change the name and nature of his talk as it contained the words 'harm reduction'. This shows Dr Tatarsky's perseverance in the face of blind prejudice and ignorance, perpetuated, it would appear, by official White House policy.

We then had Dr Tatarsky and Dr McLellan taking questions from the audience. One woman challenged Dr Tatarsky on the acceptance of 'controlled drinking' by the use of an anecdote with untoward outcomes. The questioner invoked her own case of sugar, food, heroin and alcohol addiction and being tempted by occasional cakes. We were reminded by Dr Tatarsky that harm reduction was not a back-door method of legalisation, but quite the opposite.

This conference was convened by Professor Scott Kellogg and Dr Andrew Tatarsky who are both office bearers in the Association and were also both speakers. It was a sell-out with standing room only at times.

After lunch we were exposed to the chief draw-card of the sell-out conference, "Pleasure and Addiction" "Sex Addiction 101" by Sharon Nathan, followed by an update on 'The Pleasure Project" from the South Bronx by Joyce Rivera, including her own experience introducing needle exchange in the area. We were told about the internet being "the crack cocaine of pornography" with over 300,000 sites for all manner of sex images. In addition, we were reminded that sex addiction was not a DSM III or IV diagnosis but may be in the next version. 'Frottage' equally did not rate a DSM mention although it is a widely known condition here in America (it was explained to this ignorant foreigner that it is people who rub up against others in packed subway trains or buses). While there may be females involved, nearly all cases of sex addiction referred to Dr Nathan were men. It involved numerous aspects of sex including masturbation, pornography, voyeurism, quick liaisons, prostitution and fantasies. Invariably there were negative aspects on the person's regular partner(s) and relationships.

We were given an example of her first case who, although he lived in a typical New York apartment, it seemed to him to look out onto multiple sex scenes beyond uncovered windows in neighbouring apartments. In addition, the patient/victim had once crawled down a ventilation shaft to view a women's dressing room nearby. Telephone sex was the order of the day in the 1990s when this case arose, but internet, webcams and video telephones are what we were told were the norm in the modern era.

It was interesting in this advanced city that several of the presenters were unfamiliar with power point presentations (I thought that I was old fashioned!). One workshop presenter refused to use any such modern audio-visual aids at all. Another was only familiar with Mac's and could not find the slide show button! But help was at hand.

Afternoon workshops were held on eating disorders, 'altered states and creativity' and psychoanalysis and drug abuse treatment.

The final session was on the use of contingencies in opioid maintenance and non-opioid treatment settings by Professor Scott Kellogg. Entitled "Keeping it Positive: Contingency Management In Substance Abuse Treatment", his own summary gave what he called a somewhat panoramic overview of this extremely effective, if somewhat controversial, treatment approach. Beginning with examples from history, he spoke about Alexander Maconochie's humanistic work in the penal institutions in Australia in the mid-19th century, and Charles Dickens' and Angela Georgina Burdett-Coutts' work with prostitutes in England, shortly thereafter. Both of these projects utilized early forms of token economies based on positive reinforcement. This was then followed by a review of classic alcohol studies in sixties and seventies and the more recent work by Stitzer, Higgins, Silverman, and Petry, as well as the results of the NIDA Clinical Trials Network study. After a review of the 7 core principles, he spoke of his own work with the New York Health and Hospitals Corporation - which has been the largest adoption of contingency management anywhere in the world. This project has provided contingencies to thousands of patients. Dr. Kellogg somewhat boldly closed by stating that positive reinforcement systems are the most effective psychosocial intervention in the addictions treatment field, and he spoke about his hope that treatment providers can find ways to integrate the principles and practice of positive reinforcement into their work.

Comments by Andrew Byrne (last paragraph by Scott Kellogg since Dr Byrne missed the session and also remains seriously sceptical of the whole area of 'contingency management') ..

Selected citations of Dr McLellan:

Cornish JW, Metzger D, Woody GE, Wilson D, McLellan AT, Vandergrift B, O'Brien CP. Naltrexone Pharmacotherapy for Opioid Dependent Federal Probationers. 1997 Journal of Substance Abuse Treatment 14;6:529-534

Kraft MK, Bothbard AB, Hadley TR, McLellan AT, Asch DA. Are Supplementary Services Provided During Methadone Maintenance Really Cost-Effective? Am J Psychiatry (1997) 154;9:1214-19.

McLellan AT, Arndt IO, Metzger DS, Woody GE, O'Brien CP. The Effects of Psychosocial Services in Substance Abuse Treatment. JAMA. 1993;269:1953-1959.

McLellan AT, Carise D, Kleber HD. Can the national addiction treatment infrastructure support the public's demand for quality care? Journal of Substance Abuse Treatment (2003) 25:117-121

Take-aways in opioid replacement treatment - Case Studies & Discussion

Tuesday March 28, 2006

Presenters:
Professor James Bell, Director, The Langton Centre, Surry Hills.

Professor Bob Batey, Hunter New England Area Health Service.

Chaired by Dr Richard Hallinan, Redfern Dependency Practice.

Case Studies

Click here for summary of main presentation
Professor James Bell had indicated in his presentation that the therapeutic relationship in opioid replacement treatment was not based on trust, but rather on clarity and transparency of boundaries and decisions. Asked if there was any place for trust at all, he gave the thought-provoking answer "None". In response it was suggested that a case given of the folly of trust actually showed want of discretion. Another view was that a therapeutic relationship where trust had been lost ought to be ended. However the point was made that clear guidlelines can protect staff against manipulation and pressure from patients, and also provide a level of reassurance and protection to patients against arbitrary decisions, or the the appearance of them.

Asked whether Takeaway Guidelines were in fact rules, Professor Bell replied, perhaps tongue in cheek, that they were "Commandments". However in the case studies which followed, opinion differed on how to implement even Commandments.

Setting the scene, there was a tale from the prisons: a 35 year old male, intermittently on MMT over 15 years, currently getting 180mg daily with 4 takeaway doses/week. After 10 days in custody on daily supervised doses, prison staff became concerned at his level of sedation.

No-one in the room needed the obvious pointed out: the possibility that this man had not been consuming his takeaways as directed. The doctor who submitted this case suggested the corollary that some patients actually cope quite well on second daily methadone dosing, while others considered that this was unusual. It was also possible that this man had been consuming part but not all of each takeaway dose.

It was suggested that period of daily supervised dosing may help establish compliance with daily dosing, provided the patient is examined 3-4 hours post dose during this time.

Next came a simple case illustrating basic issues: a 31 year old woman on MMT for 3 years, daily dose 140mg and 4 weekly takeaways, returned a series of urine drug screens positive for benzodiazepines but denied taking these drugs.

A major concern was that she had felt the need to deny benzodiazepine use. On the basis that ongoing use of benzodiazepines was a clear contraindication to giving any takeaway doses, one expert opinion was that takeaways should be stopped until she could submit a clear urine drug screen, which she would probably do with this incentive. Others suggested examining the patient 3-4 hours post dose, and restricting but not stopping takeaways. All were agreed on the need to go into the reasons for her benzodiazepine use.

It was asked whether there was any evidence that self-report of substance use was inproved where no punitive consequences were expected. While no-one was aware of such evidence, there is good evidence that the possibility of urine toxicology being required improves self-report.

The third case involved methadone injecting: a 41 year old man working part time, on MMT for 10 years, currently 75mg/day dispensed from a pharmacy, with 5 takeaways/week. After the patient admitted buying and injecting extra black market methadone, he was offered and agreed to an increased methadone dose and a period of suspended takeaways. On the dose of 110mg/day his 24 hour trough methadone concentration was 0.37 ng/ml.

As he reported having ceased injecting, and had taken up full-time work, takeaways were gradually returned . However a year later, after being in hospital with severe cellulitis of the leg, he admitted having resumed injecting methadone months before.

Although he agreed again to daily supervised dosing and more frequent consultations, he dropped out of treatment, blaming the onorous attendance requirements and complaining about his increased dose which made it harder to jump off. The doctor received information that he was surviving on black market methadone.

Discussion centred on the need to balance supervised dosing with retention in treatment and the benefits of a person working. It was agreed that this man might have been offered injectable methadone in some jurisdictions. The benefits of providing methadone takeaway doses in an additive-free formulation to reduce injecting harms, or diluting them with orange juice to prevent injection were discussed: it was noted that diluted methadone is not an approved formulation in NSW but is mandatory in Victoria. The importance of examining veins was pointed out, as well as the difficulties of examining femoral veins � in this case the injection site was old and hollowed out, making evidence of current injecting difficult to find.

Although increasing methadone dose is one suggested response to methadone injecting (Eap et al 2003), it was not helpful in this case.

In a fourth case, a "concerned relative" had written to the Health Department claiming the children of a couple on MMT "may be at risk from exposure to methadone and/or illicit drugs" as the parents were "polydrug users and misusing take-aways" and there was "current Department of Community Services involvement with the family."

The prescriber received an official letter reminding of the guidelines about children under the age of 4: with current DOCS involvement there should be no takeaway methadone.

The team involved requested the original letter and noted it included a request that "methadone contain some sort of contraceptive." They established there was no current DOCS involvement, and previous involvement had been only brief, over the matter of the electricity being cut off. Subsequent review by the team concluded as before that the parents were suitable for takeaway doses.

Opinions varied as to whether the advice from the Health Department had been high handed, and whether credence should ever be given to complaints of this kind. It was argued out that the staff had acted properly and the result had been a good one, that they should not have felt threatened by the official letter; and nor should parents feels threatened by DOCS officers who had a serious responsibility and generally avoided draconian actions. It was suggested that having the electricity cut off was not a trivial matter, and indicated a serious level of disorganisation.

The final case was of a 34 yo man: on disability support pension, and 10 yrs MMT with a current dose 80mg/day, and 4 takeaways per week. He had been prescribed dexamphetamine years ago for ADHD. After urine toxicology showed amphetamines, he admitted injecting about twice a month. He said he needed takeaways for part time work and was often called at short notice.

With reduced takeaways and future takeaways contingent on amphetamine-free urine tests, he produced a series of clear urine drug screens. However he was unable to bring payslip evidence of his work as he was working for cash and said his employers would sack him if he they found out about his methadone. The dispensing pharmacist confirmed that he appeared regularly dressed in work clothes, and never intoxicated

On one occasion he admitted that a urine test that day would show amphetamines, and on this occasion was allowed to continue 4 takeaways for his honesty, and given an opportunity to "redeem himself" in 2 weeks.

Issues raised included: the difficulties for some people in the 'fringe' economy demonstrating their need for takeaways;, the importance of liaison with staff at the dosing point; the implications for a person's frankness in future if they were 'punished' for admitting illicit drug. This case showed a "carrot and stick" approach. An ambiguity was pointed to in the current NSW takeaway guidelines which refer to stability defined in terms of amphetamine use in times per month - this might refer to single 'shots' or episodes (which might include several 'shots' or 'smokes' ).

A useful draft document reminds us that NSW takeaway guidelines emphasize "process and documentation", including assessment , monitoring and review, and that "the essence of a therapeutic relationship is the capacity to set limits, to withstand manipulative behaviour and to decline to prescribe inappropriately, without becoming angry or judgmental. This is the critical skill at the heart of methadone prescribing."

At the same time we might remember to keep an eye out for manipulative behaviour in our mass media, politicians, pharmaceutical companies and perhaps even .... ourselves.

Summary by Richard Hallinan

Ref: Eap CB, Felder C, Golay KP, Uehlinger C. Increase of oral methadone dose in methadone injecting patients: a pilot study. J Addict Dis. 2003;22(3):7-17.

Take-aways in opioid replacement treatment - guidelines, safety and ethical issues

Tuesday March 28, 2006

Presenters:
Professor James Bell, Director, The Langton Centre, Surry Hills.

Professor Bob Batey, Hunter New England Area Health Service.

Chaired by Dr Richard Hallinan, Redfern Dependency Practice.


Professor Bell started with an overview of some issues and principles relating to opioid maintenance therapy. Over the last twenty years in Australia there has been an increase in the number of people on opiate treatment programs ('OTP'), but this rate of growth is slowing. Up to 2001 there was a rising availability of heroin and the increase in numbers of people on OTP reflect this. Following the "heroin drought" some heroin users changed their illicit drug use to other drugs, which may be related to a slow-down in the expansion of OTPs.
We were told that there are three measures useful in assessing the effectiveness of OTPs. They are:
1) stabilisation (ie decreased drug use and what he termed 'distress')
2) retention rates
3) minimisation of diversion
In terms of stabilisation of people on OTP in NSW, it is known that greater than 90% of people decrease their heroin use whilst on methadone maintenance treatment. Ongoing drug use is common, and persisting distress and health care seeking behaviour is three times the state average in this group of patients. Patients on MMT see a lot of doctors other than their prescriber and two factors are predictive of this. The first is the level of benzodiazepine use and the other factor is the level of psychological distress. As prescribers we have an important role in helping to contain the degree of distress by being empathic and genuine listeners and ensuring we allow enough time to review our patients.
James Bell showed us results of a study looking at retention rates of people on MMT over the period 1990 to 2006. He found that people on MMT in 1990 cycled in and out of treatment an average of four times up to the current year. He also found that retention rates of people on MMT diminished as the program expanded, so that people who entered MMT in 1990 stayed on the treatment longer than those who began MMT 10 years later in 2000. With increased numbers of places available on NSW programs in later years, this may have reflected an "easy-come-easy-go" attitude to treatment, from both patients and prescribers. His results also showed that longer episodes of treatment on MM were predictive of a decreased likelihood of return to MMT at a later date and that this perhaps suggests a "cure" among those people who no longer seek treatment programs.
A study by Lintzeris from Melbourne in 1999 showed that diversion and injecting among those on MMT was common. Another (NSW) study showed that 88% of black market methadone comes from take-aways that have been diverted. It is pertinent to note that two-thirds of the deaths associated with MMT are the result of diversion (ie fully one third come from other sources such as analgesic tablet prescription). Within the group studied, there was poor compliance of take-away guidelines.
Results from a Western Australian survey were presented, firstly to illustrate why people buy take-away methadone. The four reasons given by people were:
1) reluctance to get registered on a formal MMT programme so that privacy was protected
2) to detox for a short period of time (usually days)
3) because it was too hard to access a clinic due to working away eg on boats and in mines
4) to "get wasted."
The same survey asked people why they sold take-aways and three reasons were cited:
1) because they are asked.
2) to subsidise the cost of treatment.
3) to supply their partner.
The success of OTP in Australia is seen to be partly due to the distinctive model of care under which these programmes operate. OTPs are funded through our national health system of Medicare and this has allowed an expansion of access to occur. The treatment is seen as part of mainstream healthcare, and is office-based with the doctor being the primary care-giver and the doctor and pharmacist acting as a "team." It was emphasised that continued improvements to this model rely on an awareness that issues of opioid prescribing are relevant to all doctors who see patients, and not just the authorised prescribers.
A Melbourne study by Martyres in 2004 looked at the circumstances surrounding the cases of 203 fatal overdoses in young people. It was found that among this group there were high levels of doctor shopping (6 times the state average) and multiple prescriptions for opioids (eg. Panadeine forte, oxycodone, long-acting morphine) and benzodiazepines. In fact prescribed drugs were present at autopsy in greater than 90% of these people. Only a small percentage of people in this study died as a result of heroin overdose with no other drug present.
The presenters then went on to discuss the principles of opioid prescribing (and in fact this is relevant to any psychotropic drug). This revolves around:
1) information,
2) structure,
3) the therapeutic relationship
4) symptom relief.
Information involves assessment and formulation of a diagnosis, an exploration of expectations and goals of treatment, a treatment plan and ongoing monitoring and feedback. Assets, strengths and liabilities should be discussed between prescriber and patient, and it is important to ask the patient what their expectations of treatment are. It is very useful to give a full and honest explanation first-off of dosing arrangements and take-away rules to avoid subsequent haggling and negotiations in later consultations. Monitoring includes taking a drug use history, looking for track marks, and performing urinary drug screens. The analogy of not taking a blood pressure but assuring the patient that the medication is working well was given to emphasise the importance of careful follow-up.
Imposing some external structure on a patient's MMT regime may be therapeutically useful which of course includes being very thoughtful about how the dispensing should be done. In situations where people have lost a lot of control from their lives, take-away methadone can be very problematic, and lead to further destabilisation within the patient's life. Structure involves ensuring adequate frequency of patient review, understanding the physical and mental health symptoms of the patient, and monitoring the patient for any signs of continuing drug use. It was pointed out that if a prescriber regularly checks for signs like track marks and regularly performs urinary drug screens, the patient will not regard such monitoring as strange and will come to expect it as part and parcel of the routine MMT review. Dispensing arrangements should be reviewed as well, including setting up good communication between the prescriber and pharmacist, eg making sure the pharmacy is clear about what days the patient must attend for dosing and asking the pharmacy to let the prescriber know if the patient is missing doses.
Many opioid users have interpersonal difficulties and the "secondary gain" of acting out conflict with authority figures ("pushing the limits") is common. Managing this requires forethought and skill. Professor Bell outlined his philosophy that the doctor-patient relationship in this instance be based on skepticism, clarification and professionalism and that clear guidelines be set up from the beginning. The rules for take-aways should be absolutely transparent. Hasty decisions about take-aways should never be made; if more information is needed then more information should be sought and this should be made clear to the patient. This may be particularly important with regards to combination buprenorphine, where increased numbers of take-aways will be legally available to patients.
Professor Bell outlined guidelines for take-away prescription for those on MMT. People who are regularly injecting drugs, or are dependent on alcohol, BZD or stimulants are not suitable for take-away doses. Again he suggested this be assessed by clinical presentation, presence of track marks and results of urinary drug screens. Results of a risk assessment should also be considered when deciding whether a patient is suitable for take-away methadone or not. If someone is homeless it is a bad time to prescribe take-aways, similarly if a patient is psychotic or "at risk". Take-away opioids are contra-indicated in people with unstable psychosocial or mental health status, and we should all be aware of the dangers of take-away opioids to children who are inadvertently exposed.
We were informed that the new NSW Dept Health take-away guidelines will be available soon. The recent (as of April 1st 2006) availability of combination buprenorphine has triggered a review of all take-away processes attached not only to combination buprenorphine but also to methadone and buprenorphine. There is a lack of good literature on what take-away doses achieve, but there is a lot said about them.
Professor Batey presented us with the spectrum of views of which we would all be familiar. These include seeing take-aways as a privilege, as dangerous, as inevitably being diverted by some patients, as over-utilised, as necessary to gain freedom from daily clinic visits, and as a process that should be more strongly regulated. It is generally accepted that most patients want more take-aways, that take-away guidelines are not always followed, and that no particular policy guarantees a particular outcome for a particular patient or community. Professor Batey teased out the "facts" from this list to tell us that with or without take-aways, opioid replacement therapies will be diverted. He also emphasised that untimely provision of take-away doses can destabilise a patient, as can an overly strict adherence to take-away policies. Patients are ultimately human beings and unpredictable.
Prof Batey also told us that the more liberal a take-away policy, the more likely a drug is to be diverted. He reminded us that patients divert all sorts of medication (eg proton pump inhibitors, Ventolin etc) and that we ultimately cannot prevent diversion. We should perhaps be aiming for a process that seriously addresses the patient's need to grow whilst also aiming for a practice that is able to be adhered to and sets limits on both the patient and on ourselves as prescribers. There was some debate as to whether take-aways should be regarded as a right or a privilege. The characteristics of a good doctor-patient relationship in the context of methadone prescribing received some attention and the importance of an explicit contract was emphasised, as well as the need for transparency of all criteria for take-aways clarified right from the outset. This can prevent a lot of subsequent "argy-bargy" around the issue of take-away increases, and allows more empathy and connection to develop within the professional relationship when this "argy-bargy" is out of the way.
The issue of take-aways in combination buprenorphine prescribing were touched on near the end of the presentation. It is hoped that this drug combination will be diverted less, and that clinically stable patients may be able to have many more take-away doses in the future. The two contradictions to combination buprenorphine remain being pregnant or being allergic to naloxone.
The evening ended with presentations of five case studies sent in from the seminar participants. They illustrated many of the dilemmas faced by prescribers in deciding what appropriate and safe prescribing actually is. Dr Hallinan will summarise these and Dr Byrne will give a brief overview on clinical practicalities on another posting shortly.

Dr Jenny James. Daruk (NSW) Aboriginal Medical Service.

Diversion of buprenorphine in India: 29% addicted to pain medication

Dear Colleagues,

The 'The Hindu' newspaper on April 5 has a front page story on the widespread abuse of buprenorphine in Kerala State which has apparently been increasing over a number of years. The current publicity surrounds a heist of 20,000 ampoules (see selected quotes and url below). Not unconnected may be an indication that India has experienced a 'heroin drought' similar to Australia (see excerpts below).

The situation seems comparable with Wellington, New Zealand in 1991 when the drug was being used widely for pain management but found a large niche with addicts. In a careful comparison before and a year after the national switch to a combination formula, the addition of naloxone was associated with twin effects of reducing the proportion of addicts injecting the drug from 80% to 60% but was also associated with reportedly easier access to the drug and a lower street price. I would still consider this wholesale abuse, especially considering the drug was ostensibly only for analgesic indications. The drug was withdrawn shortly afterwards.

There have been sporadic items from France, Finland, Western Australia, Melbourne, United States and India about the abuse of buprenorphine. The most obvious way of avoiding these problems is to increase access to supervised, evidence based addiction treatments as well as limiting access of young, healthy people to uncontrolled quantities of opioids from na�ve or unscrupulous doctors.

"The Hindu"

Online edition of India's National Newspaper

Wednesday, Apr 05, 2006

"Illegal diversion of buprenorphine to State" Reporter: G. Anand

"The drug is cheaper compared with heroin in the market"

Thiruvananthapuram: A particular brand of medicine containing opium is being illegally diverted to Kerala in large quantities for sale in the street as a substitute for heroin, Narcotic Control Bureau (NCB) officials said.

An indication of the trend came last year when the NCB investigated a case relating to the delivery of 20,000 ampoules of the medicine, buprenorphine, to a stockist of pharmaceutical products in Perinthalmanna in Malappuram district.

The buprenorphine was sourced from a medicine factory in Gujarat. During investigation it was found that the stockist in Perinthalmanna had not placed the order for the drug. The NCB revealed <snip>

... two persons were arrested ... sale as a narcotic substance in the black market. The ampoules had already reached the hands of drug peddlers by the time the agency got to the bottom of the case, an NCB official said.

The decreased availability of heroin, owing to a drastic reduction of illegal opium production in Afghanistan, is a crucial factor that has resulted in the increased availability of buprenorphine in the illegal market, according to the NCB.

Buprenorphine has been used widely in heroin de-addiction therapy for reducing the craving for the drug and easing the withdrawal symptoms of `brown sugar' addicts. The drug, having a street price of Rs.100 for an ampoule, is relatively cheap compared to heroin.

... there had been instances of medical prescription forms ... being stolen or forged to procure buprenorphine ...

... only few medical shops in the State have the licence to stock and sell buprenorphine.

... Alcohol and Drug Information Centre-India, said that a random assessment of drug abuse conducted in 14 urban centres in India had found that at least 29 per cent of injectable drug abusers in Thiruvananthapuram were addicted to buprenorphine.

<snip>

Comments by Andrew Byrne ..

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