Opioid receptors, addiction and beyond

Inter-Institutional Narcotic and Ethanol Group Lecture
1:00pm Tuesday, May 2, 2006 - Caspary Hall 1B, Rockefeller University, York Avenue, NYC.

Professor Brigitte Kieffer, Ph.D.,
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, Université de Strasbourg, France

Dear Colleagues,

In little over an hour, this informative presentation brought us up to date on the state of the art regarding cloned opioid receptors, rat experiments, fluorescent antibodies and cellular changes associated with opioids. Clinically in opioid addiction, these involve: initiation, maintenance, dependency, habituation, withdrawal, abstinence and relapse to drug use.

Dr Kieffer started with the simplest description of drug use and the inevitable brain changes which occur with tolerance at the receptor level. As she pointed out, all of the consequences of drug use are mediated by such receptors and can be understood in terms of old pharmacology research with corroboration from more recent work on the defined receptors themselves. Dr Kieffer's group in Strasbourg was the first to clone the opioid receptor, which was also done independently at the same time by Evans' group in California.

We were told about behavioural experiments in mice cloned to have one, two or three gene 'knock-outs' being mu, kappa or delta opioid receptors. The first and most important finding was that such animals (even triple 'knock-outs') are still viable, proving that (some) mammals do not require the opioid system for survival and procreation.

Such receptors were predicted long before they were specifically isolated and such rats were bred in the late 1980s. The experiments with mu receptors were all completely predictable based on previous pharmacology but this was not the case with delta or kappa receptors. To examine analgesic and euphoric effects, they used tests of self administration ('press the lever'), tail immersion, dark room, bright lights, place preference, preferred routes, maternal smell recognition and a number of other interesting tests on the cloned and 'wild type' rodents. Consistent with some of the pharmacology, similar results were found in relation to alcohol and cannabis, demonstrating that some of their properties are mediated by the mu system as well. Dr Kieffer's particular interest seemed to be the delta receptors which she feels are related to learning, stress and even mood alterations such as anxiety and depression.

Much of the second part of the talk went over my head, dealing with sub-cellular and membrane changes, much amazingly documented visually.

A fascinating power point clip showed a 20 minute neuron clip speeded up to just 8 seconds showing fluorescence for delta-receptors. In this time, smooth layers of visible glowing membrane-bound receptor rapidly became clumps of granulated intracellular material, altering the cell dramatically. I was told that this was not depolarisation, but a much slower response to other stimuli, some of which may have regulated sensitivities. Most impressive of all, perhaps, were several 3-D representations of the actual receptor molecule with neat little indentations where opioid molecules could trigger pre-determined responses for depolarisation or blocking of the neurone involved or in some cases, movement of dopamine and other neuro-transmitters. So the old 'key in lock' analogy is also valid on a physical molecular level!

Finally there were some questions about the fine points of her field of cloning, obtaining antibodies, etc. It is always a delight to return to Rockefeller University in York Avenue on the East River. Its gardens are quite spectacular and the modern paintings hanging in the dining area are a pleasure and an education. All are on loan from the Rockefeller family collections (see sample below). Dr Kreek's office has a fine view of Brooklyn and Queens across the elegant Queensborough Bridge. Just three blocks away on York Avenue, Sotherby's Auctions were previewing some important French impressionist to be sold in London later in the year (see below). Several had reserves over a million dollars. The only sadness this year is that Dr Vincent P. Dole, aged 94, is quite unwell and no longer able to contribute actively to the field although he did sign the award certificates and send a greeting to the AATOD conference in Atlanta in April.

Comments by Andrew Byrne ..

Please don't mention the real HIV issues - CNN viewers may not like it!

In the US, CNN aired a prime-time program on HIV on Saturday 29th April 2006. Its topic was world eradication of this epidemic yet the content was surprisingly thin and limited. Hosts were the long-serving CNN (and New York Times) doctor-at-large Sanjay Gupta and Bill Clinton, who has taken a high-profile and personal interest in the subject.

Any hopes of this program being a useful contribution were quickly dashed. Even with the involvement of a committed and informed person of President Clinton's status, the facts were glossed over and the entire program had an air of unreality. It was held in a church with gospel singers, an odd decision in my view for a supposedly serious presentation on public health and epidemiology. Even more distressing is that at least one mainstream church has contributed to the extent of the epidemic by banning condom use, even in marriage. And a church spokesman had the effrontery to address this audience on the 'benefits of abstinence'.

The use of a particular church for the program's venue may also have offended some sensitive Christians, Jews, Moslems and even atheists, many of whom must feel strongly about the subject but not be too keen to be associated with formalities of other faiths.

The program looked as if random people stood from the audience to speak yet it would appear that each was carefully chosen. One of the first was a spokesman for the pharmaceutical industry which is telling. Mr Clinton had already said some 'softly' things including the gratifying reduction of the price of some antiviral drug courses from $400 to $300 in response to humanitarian calls. Mention was made of the enormous commitment of the industry to research. No mention was made of running treatment trials using placebos for some subjects in the third world, nor of why treatment in Canada and Mexico is so much cheaper. A young female victim stood to tell us about the futility of telling young people in impoverished regions about the benefits of sexual abstinence. She explained that it was 'fun' and 'for free', and hence the need for education and protection for all young people.

Some alarming statistics were given by President Clinton and it was pointed out that there are still much HIV transmission in the United States every year. Yet the words 'needles', 'syringe', 'gay', 'methadone' were strenuously avoided in over an hour of palaver. While it is an on-going tragedy, no mention was made of the ability of simple public health measures to prevent transmission of HIV. The US uniquely spends large sums on banning needles and syringes, a policy which neither reduces drug use while at the same time facilitating continued spread of contagious diseases benefiting nobody except drug companies and funeral homes.

This television 'special', far from informing the American public or overseas CNN listeners, clearly resulted in keeping its audience in the dark about the basic facts of this modern epidemic. It would seem that 'freedom of the press' gives unique immunity in the US. It ensures neither balance nor truth.

Numbers of Swiss opiate users decline while harm reduction measures introduced. Lancet article.

Nordt C, Stohler R. Incidence of heroin use in Zurich, Switzerland: a treatment case register analysis. The Lancet 2006 367:1830-1834

Dear Colleagues,

This definitive study succinctly refutes the last remaining criticism of harm reduction: whether it encourages drug use. It appears to do precisely the opposite, as these authors report.

Switzerland’s ‘cantons’ have registers of drug treatment approvals going back to the 1970s. It is therefore possible to derive statistically valid measures of the rate of addiction of its citizens over the period when needle services, injecting rooms, methadone treatment, heroin prescription and most recently, buprenorphine treatment were being introduced. Such data reflect the natural history of opiate use through interactions with treatment services such as methadone maintenance treatment (MMT), withdrawal from such treatments, mortality and other demographics.

The canton of Zurich has 1.2 million people (a fifth of the Swiss population) over half being rural. Between 1991 and 2005 about 10,000 patients underwent 24,000 episodes of opiate prescribed treatment (2.4 per person). By 2005 there were 3000 still in treatment and 7000 who had been discharged.

Of those who left treatment in Zurich in 1991-1993, 33% never re-entered treatment, 66% rejoined treatment within 10 years, only 1% returning after a decade. The authors derived a long-term annual abstinence rate of 4%, comparing this with an Australian report of 5% along with others. Each year, the mean age of those in current treatment increased by 9 months, reflecting fewer new entrants and high retention rates.

Importantly, about 50% of Swiss subjects entered methadone treatment within 2 years of starting to use heroin with only small differences depending on sex, age and injector status. This contrasted with an average of 4 years to enter treatment in Italy and probably longer in some other countries. The authors further estimate that at any one time, about 50% of those with problem opioid use are on MMT. With fewer new initiates in Switzerland, they project this figure will rise to 64% by 2010. These figures are comparable with reports from Amsterdam in the 1990s.

Perhaps most crucial are the findings regarding the numbers of Zurich canton citizens taking up heroin for the first time. From around 80 people in 1975, this increased progressively to ~850 new users annually by 1990, only to drop again to ~150 by 2002 at the height of the harm reduction interventions. These included prescription heroin to a small but consistent proportion of maintenance cases.

So we can now quote reliable knowledge that in a modern western country which advocates and practises harm reduction in its most progressive form (apart from decriminalized cannabis) there are not more, but fewer young people availing themselves of the opiate class of drugs. Indeed, we can now say with confidence that harm reduction measures do not “send a message” encouraging drug use. The authors believe that by ‘medicalizing’ addiction, an impression is created that it is unpleasant and undesirable, to be avoided, which is just what has happened.


Comments by Andrew Byrne ..

Atlanta AATOD 2006 conference report

"Treating people with dignity"

April 22-26 2006, Hyatt Regency Hotel, Atlanta, Georgia

This year's AATOD meeting seemed more bland than usual with fewer scientific papers but more emphasis on areas of special need such as social equality, dignity, criminal justice, housing, recovery, etc. Few of the scientific sessions had patient representatives involved.
There were education sessions for health care professionals as well as patient representatives on the Saturday and Sunday prior to the conference proper. There was also a European session, as usual, on the Sunday afternoon, including Swiss, French, Italian, Slovakian, Bulgarian, Ukrainian and other representatives.

Monday 24th:

With fog in Washington (is that an omen?) and airline delays I missed the early sessions on Monday. Afternoon workshops included "Medical Aspects of Methadone: What Counselors Need to Know about the Medication". Judith Martin spoke clearly about the intrinsic benefits of methadone and the need to emphasise to patients why they 'should prefer it' to heroin (or other opioid).
In a parallel session we had James Carleton speaking about his experience with the Rhode Island penal system where there is one large jail for men and two smaller ones for women. When inmates had been on methadone prior to incarceration, this could be continued whilst in holding cells, but only for a limited period. We were told that primary medical care of inmates was quite separate and only those who were already on treatment were able to receive the methadone, albeit on reducing doses, on the authority or their original legal prescription. When pressed, Dr Carleton said that 30 to 60 and sometimes to 90 days treatment could be arranged in that state's lock-ups.
A perceptive participant asked whether a person who developed or redeveloped an opioid habit in jail could be treated by his team in this way. He told us that the prison administration would probably not physically allow such a person to attend for methadone treatment, but that indeed drugs were available in Rhode Island jails. Very recently there had been an overdose leading to hosptialization of the inmate, with a stay in intensive care, presumably at the jail's expense. It would appear that all around the world a drug-free jail is just about as realistic as a drug-free society. Yet US jails allowing methadone are still exceptional (see Tuesday plenary on the subject below).
Andrew Rosenblum from New York spoke about opioid prescription abuse in OTP patients in 70 centers across the country. Data were presented from the past 12 months on over 8000 subjects enrolled in OTP's across the country. The findings show a dramatic difference between whose whose primary drug of choice was heroin or prescribed analgesics. Big-city and metropolitan residents were far more likely to be heroin users while small town people were more often pill takers in their study. The former were 75% injecting while only one third of the pill takers reported injecting. Most of the latter (~80%) reported accessing their drugs primarily from 'dealers', while other sources were from friends, doctors prescription, emergency room, theft and internet or forged prescription (~3%). The prescription drug users were twice as likely to be in work and half as likely to be on public benefits. They were also younger (32 vs. 37) than heroin users and 97% were Caucasian (cf. 54% for heroin users in treatment). Pill takers were also more likely to report chronic pain (>6 months >5/10 severity pain). Prescription drug users were predictably more likely than heroin users to have used more than one drug.
Paul Bowman, NAMA advocate from Massachusetts was billed to speak to "Patient and Provider Groups: Methods and Models". This was one of only a few sessions with consumer input.
There was also a presentation by Randy Seewald on methadone and overdose prevention. Research shows that just being in treatment (of any kind) reduces overdose likelihood. The antagonist naloxone is being distributed in some areas with instructions on emergency resuscitation. Apparently it is available without prescription in Italy. In what seems to be an American habit, in some states naloxone supply has been 'waivered' from medical malpractice action, despite no evidence of its benefits over potential harms in drug overdose treatment by non-medically trained drug users and their associates. Consistent experience from legal injecting rooms shows that only a small minority of 'early diagnosed' observed and confirmed overdoses require naloxone, and that just supportive treatment is sufficient for most.
This New York research group was brave enough to use the "harm reduction" term in their slides, in opposition to the American federal policy against this wording, despite the issue being 'routine' or even 'motherhood' in many countries. They further reminded their audience of the intrusive and unnecessary regulation on methadone prescription.

Tuesday 25th:

The morning plenary was on treatment in the penal system, chaired by Paul Samuels, a long time advocate for rational approaches to the field of addictions and crime.
We heard at length from the Atlanta District Attorney, Paul Howard, about the incarceration statistics, progress with the need for treatment and prevention programs.
Our host lawyer said that for those outside the deep south should take something back home and offered us a local expression: 'lazy as a rigid mule'.
On any one day, 4-7% of prisoners in New York City are getting high on drugs. When he was commissioner in Pennsylvania, the rate was allegedly 10% which dropped to 1% after a concerted effort at interdiction.
Various parts of the country are now moving to allow limited methadone treatment in jails. These include San Francisco; Orange County, Seattle; Orlando, Florida; New York City (not up-state where most prisoners are housed); Rhode Island.
Timothy Ryan spoke eloquently about their implementation of a system of methadone in Florida which gave methadone to existing patients under certain strict rules. He pointed out that one needs to tread lightly as there are 'no absolutes in this area'. I countered afterward to him privately that surely giving correct treatment to all inmates is an appropriate absolute goal. And since drug use is such a high priority issue and methadone treatment is so cheap and effective, there is no excuse for denying such treatment to prisoners on any basis except to punish them twice (like solitary cells and interstate transfers). As Commissioner Martin Horn from New York pointed out to the audience, they work for the Department of Corrections, not the department of punishment.


The morning workshops included the interactions between pharmacotherapy providers and homeless mental patients who are incarcerated; culturally sensitive treatments; older patients in drug treatments; child protection issues and linkages between recovery community and pharmacotherapy providers. Beth Israel New York is the oldest and largest methadone treatment service in the country having over 7,000 patients of whom 20% are over the age of 55 (max 84 years) while in clinics generally the proportion is about 6% and growing each year. There were already 2% over 75 years. The issues addressed included multiple medications for other illnesses more common in older age - this includes possible drug interactions. Arthritis can make 'child-resistant' bottle lids into 'adult-resistant' which may be the bane of life for some, needing attention. Also eye sight issues and mental state may require simpler labelling in some cases. Nursing homes, hospice care, third party drug collections by registered family members or associates, social services and legal issues were addressed. Just as there may be a place for adolescent dependency services, a clinic for older adults may have advantages so a trial is being run in New York presently.

On the Tuesday afternoon we were presented with the so-called Matrix model of evidence based stimulant abuser treatment (despite there being no scientific evidence of its effects over other treatments or placebo/no treatment as far as I am aware). There was another session on details of implementing drug treatments in the prison system. There were also talks on recovery, technology transfer (is this modern term for education?) and the role of the family, work mates and others beyond the drug dependent subject. A web site for family members is being developed by the daughter of a patient.

Poster displays:

As seems to be the trend, rather than just having poster displays passively available in the 'intermissions', there was a designated 'author session' on Tuesday afternoon which was very well attended. There was the full range of dependency issues, including domestic violence, abstinence based treatments, buprenorphine, viral diseases, PTSD, jails, policy, mothers and drugs, alcohol co-morbidity, childhood methadone overdoses, internet data gathering, methadone mortality, client surveys, office based treatments, oxycodone use and abuse.
I will mention two outstanding posters, the first from a Canadian group from Alberta who describe their completely logical system of treatment involving shared care between community physician, specialist clinic, pharmacist and their liaison. Importantly, the Canadian pharmacists are involved in administering methadone to those who need it while also 'dispensing' take-home doses when ordered for suitable stable cases.
Next was an excellent if depressing description of how clinics across the US are addressing hepatitis C virus infection (HCV) by Sheila Strauss and NDRI colleague Janetta Astone. They have on-going studies of staff awareness and other aspects of HCV in dependency clinics. After piloting their survey in a number of clinics around the country including Florida, there is still much room for improvement. Little or no education is given in 16% of clinics and no testing in 30% in their sample. Yet we are told that there are 4 million HCV patients in the country (and one million with HIV) and the largest single group are potentially attending government registered and accredited clinics and thus are ideally placed for education, testing and referral.

Wednesday 26th:

Morning sessions included motivational interviewing, women in jails, drug interactions with dependency medications, measuring cost effectiveness and lastly, suicide, depression and overdose in pharmacotherapy patients.
The final plenary session was given by General Barry McCaffrey, popular drug advisor for the Clinton White House. He gave a most captivating and realistic presentation, starting with some facts on drug use in America. About one million Americans were regular heroin users and about 3.4 million had used the drug ('lifetime exposure'). Another 2.8 million had abused a prescribed ('synthetic') opiate which he labelled "the new heroin". He pointed out that it was a growing and changing problem. McCaffrey punctuated his comments with dramatic and clearly well-sourced statistics. An untreated heroin addict costs society about US$48,000. In jail, they might 'cost' $27,000 annually, but that the average prison stay is only measured in weeks, even in America. The USA, we were told, incarcerates more of it population than almost any other country (Russia and South Africa are the exceptions).
The much decorated general then reminded his audience that this was the ideal opportunity to introduce mandated treatment as in the drug court program which has been so successful in many jurisdictions. He said that there were 241,000 patients on methadone treatment in the US currently. He quoted MMT as being associated with 70% less heroin use, 57% less crime committed and 24% increase in employment rates (these figures are probably quite conservative in my view). He has no hesitation in saying that 'coercion works' (as with drug courts and contingency measures). That same week, Mexico announced that it was introducing decriminalization of all drugs for personal use, like Portugal did some years ago. Along with freeing access to treatment, this would seem a more logical approach than the traditional prohibition tactics instigated by the US after the second world war.
McCaffrey, who did not frame the current laws and has done much to counter their negative effects, quoted the famous line from 'Trainspotting': "If you have got heroin, who needs friends?!" He also gave a hilarious scenario of a person lost in a hot air balloon who found himself lost in a fog 30 feet above a man tending a garden ... "Can you tell me where I am?" ... "You are in a hot air balloon, 30 feet in the air!" ... "Thanks very much, I see you are a scientist!". (Gulp!) "However did you know?" ... "Well, what you have told me is technically correct ... but is of no use whatever, to anyone!" ... "Well, it seems you must be a government policy officer" ... "However could you tell?" ... "You do not have your feet on the ground, your head is in the clouds and despite your best efforts, you have no idea where you have been, where you are, nor where you are going". [my memory may be imperfect]

Comments by Andrew Byrne ..

Combination Therapy for Alcohol Dependence

From: JAMA Vol. 295 No. 17, May 3, 2006

Dr Byrne has suggested the following is an important research study. He will consider doing a more formal summary of it in future to ascertain its relevance to regular medical practice and alcohol dependent citizens seeking treatment. We still need to accept that the more effective options we have, the more subjects we can help.

"The efficacies of medication and behavioral therapies, alone or in combination, for treating alcohol dependence were assessed in the multicenter randomized Combined Pharmacotherapies and Behavioral Interventions (COMBINE) study, in which study participants were randomly assigned to 1 of 9 treatment groups. Anton and colleagues report that patients in all groups had an increased number of days of abstinence. However, patients receiving naltrexone, CBI, or both along with medical management had more days of abstinence and fewer heavy drinking days than patients in other treatment groups."

Link to abstract (full text is available for JAMA subscribers only).

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 ..