Rapid detox trial shows no long term benefit

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

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

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

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

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

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

Comments by Andrew Byrne ..

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

Developments in buprenorphine, methadone and hepatitis in France

Dear Colleagues,

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

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

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

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

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

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

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

Comments by Andrew Byrne ..

More about the Byrne Surgery practice

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

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

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

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

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

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

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

Drugs, alcohol and driving: Do we have to inform authorities about such matters?

Tue 31 Jan 2006

Presenter:
Dr Adam Winstock, who also presented on this subject at the recent APSAD conference in November in Melbourne.

A whistlestop tour through the epidemiology of self-reported recent substance-affected driving in Australia showed prevalence to range from 3-9%, varying depending on such factors as substance availability, availability of other transport, and the age group and cultural mores. Preferred substances vary greatly, MDMA, cannabis and alcohol being most commonly used by clubbers, and stimulants by truck drivers. Illicit opioids are generally the least commonly used by drivers. Not surprisingly, young men are the group most likely to engage in substance-affected driving.
The risk of substance affected driving is not only due to intoxication, but also to more subtle effects such as altered judgement and risk perception, and post-use effects such as the alcohol 'hangover'. Other important factors include the behaviour of passengers (even when the designated driver is not substance affected), driver inexperience, road and vehicle conditions. Such factors tend to aggregate, as in ......a group of drunken teenage males in a rickety car hooning on a dirt road on a dark and stormy night.....
The legal concept of the 'culpability' of certain substances was defined: "If drugs contribute to road accidents then drivers found culpable for crashes will be more likely to have drugs in their bodies than drivers deemed non culpable". Culpability is clearly demonstrated with benzodiazepines and alcohol, but not for cannabis, opioids and stimulants.
The 'culpability' of alcohol is striking, with a dose-related risk of accidents with rising blood alcohol level (BAL). Permissible blood alcohol concentrations vary from zero (Bulgaria, Turkey), 0.02 = 20 mg/L (Sweden) and 0.08 = 80mg/L (UK, Austria, Spain). Dr Winstock deplored this high permitted level in the UK.
Driving under the influence of alcohol is strongly associated with other alcohol related problems, particularly dependence with rate of accidents being 0.5/year for all drivers, 2.5 for binge drinkers and over 3/year for those with alcohol dependence. Further, there is an overrepresentation of alcohol dependent drivers who are caught with very high BAL .
Driving simulator studies show impairment of driving skills by cannabis, however there is a wide variation between individuals. The impairment appears to be less in true on-road conditions, possibly because cannabis affected drivers are capable of adapting by driving more carefully. There is some evidence that chronic use of cannabis causes impairment of driving unrelated to current intoxication.
Gamma hydroxybutyrate (GHB), like alcohol, produces dose-related psychomotor impairment. It is especially prone to cause gross impairment (including vomiting and amnesia) owing to the narrow 'therapeutic window' of its desired effects. Testing for this drug is difficult as it may be detected in small amounts in the body as a normal metabolic product. We were told that it is used therapeutically in some countries for alcohol withdrawal management.
Stimulants such as amphetamines may possibly improve some aspects of driving by increasing vigilance and stamina, and reducing fatigue. However judgement may be impaired at higher doses, with over-confidence, risky or reckless behaviour. Depending on the dose and a person's reaction to the substance, stimulants may have other risks, including altered vision from dilated pupils, the possibility of perceptual disturbance or paranoia. MDMA has been shown to increase the rate of accidents on a driving simulator (De Waard 2002).
Given that Attention Deficit Disorder (ADD) is itself a risk for driving accidents, it is an interesting question whether people with this condition ought to be provided with stimulant drugs that might in some cases improve their safety on the road.
With prescription medicines, both the underlying condition as well as the effects of the medicine need to be considered, as well as interactions with other substances. An example is opioids, where the stabilised opioid-tolerant person will generally show no signs of psychomotor impairment from their medication. However there may be increased impairment when combined with alcohol or other sedative-hypnotics, and one needs also to consider any associated personality or other psychiatric disorders.
In Germany, it was reported, a patient on opioid replacement is considered impaired until proven otherwise and facilities exist for formal testing. In New South Wales, the situation is rather complicated, and Dr Winstock took us step by step through his experience of trying to achieve clarity about legal and professional responsibilities of the health professionals. A useful website for understanding these is Austroad's Information for Health Professionals section.
In general it is, in the first instance, a driver's responsibility to report to the relevant Drivers Licensing Authority (DLA) any medical condition which may impair their ability to drive. In NSW, for example, the DLA is the Roads and Traffic Authority.
If a patient is "unable to appreciate the impact of their condition, or to take notice of the health professional's recommendations due to cognitive impairment or if driving continues despite appropriate counselling and is likely to endanger the public, the health professional should consider reporting directly to the Driver Licensing Authority" and "in the Australian Capital Territory, New South Wales, Queensland, Tasmania and Victoria ..... health professionals who make such ....without the patients consent but in good faith that a patient is unfit to drive, are protected from civil and criminal liability ".
This leaves the health professional with flexibility and at the same time a grey area of legal responsibility. It was pointed out that a family doctor may have very detailed knowledge of a person's psychosocial situation which may help making differentiated judgements but might also involve a conflict between the interests of their patient and society at large.
In general situations involving imminent risk and involving commercial drivers call for more decisive action from health professionals.
In determining whether to report someone to the Driver Licensing Authority, Dr Winstock advised considering:

• the risks associated with disclosure without the individual's consent or knowledge, balanced against the implications of non-disclosure;


• whether the circumstances indicate a serious and imminent treat to the health, life or safety of any person.

He reminded us of the formula: Risk = (likelihood of the event) x (the severity of consequences).
Unfortunately, anomalies do arise. Dr Winstock was advised by a NSW Roads and Traffic Authority spokesperson that a driver need only self-report a medical condition that was chronic, therefore the commencement of methadone treatment need not automatically be notified. However, if a person stayed on methadone treatment for over 12 months, notification would be appropriate. This is exactly the opposite of what an experienced clinician would advise - a patient early in methadone treatment should be advised not to drive until the dose is stabilised, a person stable on methadone maintenance can be expected to be perfectly fit to drive. In cases where illicit use compromises driving safety (regardless of the treatment status of the patient) notification by the patient should be recommended.
Dr Winstock's algorithm "What should do we do in practice ?" is based on the need to protect ourselves, the patient and the community where a driver has an impairment to driving.

1. Give feedback to the patient on the legal and financial obligations and implications for them, as well as your own legal/professional responsibility.


2. Invite the patient to notify the DLA, or inform them of your intention before you do so yourself.


3. Document your advice, including that you have told patient what they should do.


4. Request feedback and document patient's reported action/inaction re-driving at next appointment.


5. Assess immediate risk if patients continue to drive.


6. Document and seek second opinion from colleague/DLA.


7. Advise patient that unless they notify the DLA you will.

The case studies illustrated how these principles might be applied in practice.
In the first case, a patient on methadone maintenance developed psychotic depression and was commenced on risperidone and citalopram. The patient was notified to the DLA, and a subsequent medical report was that her akathisia did not affect her psychomotor skills and she was fit to drive. However, another doctor started her on large doses of diazepam for the akathisia. Interest centred on the inappropriateness of using diazepam for akathisia, but also the question of how a doctor best determine whether there was any impairment from this combination of medications. Suggestions included examination 3-4 hours after supervised methadone and diazepam dosing.
A second case study dealt with a patient on methadone maintenance known to use benzodiazepines who was observed to stop on the wrong side of the road then reverse across double lines to park on the correct side. He claimed that he did not usually drive as he was unlicensed and his car unregistered. Although the patient showed no signs of benzodiazepine intoxication, the behaviour could reasonably be described as disinhibited, and the responsible doctor chose to deal with this by giving very firm warnings, including a future possible notification of police or the Department of Community Services (responsible for the safety of children in NSW). Debate centred on whether the doctor should have confiscated the car keys, immediately informed the police, notified the DLA (even though it has no powers over unlicensed drivers) and the question of how best to follow up the patient for compliance with acceptable standards.
In another case a patient using a cocktail of medications including sedative hypnotics, tricyclic antidepressants, opioids and a major tranquilliser, was offered inpatient management of her problems. She agreed to be admitted but insisted she had first to drive home to cook dinner. In the face of this woman's signs of current intoxication, the doctor acted firmly to take her car keys (which the patient accepted in good spirit), justified by the immediate and serious risk to her and the public.
This led to discussion of possible protocols such as requiring anyone entering an alcohol detoxification treatment to agree to notify the DLA of their impairment. It was pointed out that draconian measures by health professionals could push a person out of the therapeutic relationship, losing the opportunity for constructive engagement.
Finally, some public health challenges including road side drug testing were discussed:

• Legal status of drugs is unrelated to driving risk.


• Nor does the mere presence of drugs imply impairment.


• Limitations of road side testing, including the number of false negatives.


• Visible, frequent, random testing may maximise exposure to enforcement and testing may alter perception of risk and lead to a positive impact on people's decision whether to drive.

Office tests such as heel-toe, past-pointing, Rombergs and examination for lateral gaze nystagmus are good for alcohol but much less good for other causes of impairment (the latter is a good party trick as well). Dr Winstock briefly described other more sensitive measures of impairment such as head sway measures that may become more widely used in the future.
A telling note was struck when Dr Winstock asked how many participants at the seminar routinely asked about driving in every clinical drug and alcohol assessment. At the end of the seminar participants were left with a heightened awareness of this need and a practical framework for acting to protect themselves, the patient and the public.

Summary by Richard Hallinan, with contributions from Adam Winstock and Andrew Byrne.

Combination buprenorphine widely abused in New Zealand in early 1990s

Drug Alcohol Dependence (1993) 33;1:81-6

The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN.

Dear Colleagues,

This 1993 study from Wellington, New Zealand, has relevance to us today with the recent approval of the buprenorphine combination product containing naloxone. According to my reading there have only been two published comparative studies of the combination product in recent years and neither compared unsupervised combination treatment with traditional methadone treatment. Nor did either examine community diversion in any systematic way. After TGA approval and PBS funding process, the States and Territories are responsible for introducing the combination into clinical practice (we are told from April 2006). An absence of good research evidence on the product led me to look into older literature for knowledge about the subject.

To his great credit, Dr Robinson saw an opportunity in 1991 to monitor a naturalistic experiment in Wellington, New Zealand when pure buprenorphine tablets were withdrawn and replaced with a combination product due to reports of abuse. The replacement combination product contained approximately the same quantity of naloxone (the modern version has only one quarter of this proportion). Owing to the widespread abuse of prescribed analgesics (and almost absence of heroin) in New Zealand in the early 1990s, the combination product was introduced in an attempt to make it unpopular with addicts. Although the analgesic tablet was only one tenth of the strength of the common 2mg tablet used for maintenance, it was dispensed in quantities of 50 in a pack (10mg total � 8.5mg naloxone).

What the article does NOT say is that shortly after publication, the combination drug was also withdrawn by the company after the widespread abuse including injecting reported here. After years in the 'therapeutic wilderness', I understand that NZ authorities have licensed the drug(s) again for addiction treatment, presumably with more formal assessments, structure and supervision this time around.

Robinson interviewed a sample of new methadone treatment applicants 12 months apart during which the pure product was withdrawn and replaced with the combination. This revealed the surprising original rate of 81% of patients had abused buprenorphine in the previous 4 weeks. The rate was still 57% 12 months later when only combination product was available in New Zealand (nearly all of these had used the combination drug intravenously). Both figures were corroborated with consistent urine tests, a testimony to Robinson�s thoroughness (it is not easy to get buprenorphine toxicology performed even now). At the same time, between the two surveys it apparently became easier to obtain the prescribed Reckitts' tablets, the proportion stating it was 'easy' rising from 35% to 52%.

Two thirds of patients who had injected the combination product reported no withdrawal reactions. One third reported possible withdrawals after injecting, yet this experience did not appear to discourage injecting generally and the drug was subsequently withdrawn. Thus the combination product appears to have been less popular with addicts but was still widely abused, albeit at lower levels. The lower street price reported may be been due to the naloxone, increased supply or lower demand (or a combination of the three factors).

There is now a burgeoning literature on diversion of prescribed opiates, both from Australia and overseas. Cicero writes in October�s New England Journal of Medicine that, after numerous provisos, �� its [buprenorphine combinations] availability as new product lines led to an almost immediate increase in buprenorphine use for nontherapeutic purposes.�). In recent cross-jurisdictional comparisons, both Ritter et al. from Australia and EMC from Europe found that there was little correlation between �take-away� policy and the extent of methadone or buprenorphine diversion reported across borders.

Clearly one way for us as dependency workers to address the issue of diversion is to ensure addicted citizens have access to appropriate, flexible treatments of high quality, including detoxification, maintenance as well as attention to other medical and social problems.

Comments by Andrew Byrne ..

References:

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

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

Cicero T, Inciardi J, Mu�oz A. Trends in Abuse of OxyContin� and Other Opioid Analgesics in the United States: 2002-2004. The Journal of Pain 2005 6;10:662-672

Inciadi JA, Surratt HL, Kurtz SP, Burke JJ. The Diversion of Prescription Drugs by Health Care Workers in Cincinnati, Ohio. Substance Use & Misuse 2005 41:255-264

Jenkinson RA, Clark NC, Fry CL, Dobbin M. Buprenorphine diversion and injection in Melbourne, Australia: an emerging issue? Addiction (2005) 100;2:197-205

Ritter A, Di Natale R. The relationship between take-away methadone policies and methadone diversion. Drug Alcohol Rev (2005) 24;4:347-352

Robinson GM, Dukes PD, Robinson BJ, Cooke RR, Mahoney GN. The misuse of buprenorphine and a buprenorphine-naloxone combination in Wellington, New Zealand. Drug Alcohol Dependence (1993) 33;1:81-6

Prevalence of buprenorphine misuse. EMCDDA2005 (web site accessed 22-1-06)

Naltrexone and buprenorphine combination in the treatment of opioid dependence (after rapid detoxification).

J Psychopharmacol. 2006 Jan 9; [Epub ahead of print]

Naltrexone and buprenorphine combination in the treatment of opioid dependence. Gerra G, Fantoma A, Zaimovic A.

Dear Colleagues,

Out of 60 trial patients given rapid detoxification using naltrexone, 34 (57%) completed a 12 week follow-up. These researchers state that due to 'very poor' compliance with oral naltrexone for relapse prevention, they decided to add buprenorphine to the naltrexone. Half of the sixty were given the buprenorphine (4mg daily) in addition to naltrexone 50mg daily. Three month retention was almost double in the experimental group at 73% versus 40% in the pure naltrexone patients, which was highly significant statistically.

The authors propound their theory that adding these drugs leaves kappa opioid receptor antagonism as the major medication effect. This may be a simplistic view, being "on-off" logic, as it ignores the variable absorption of both drugs, different receptor affinity and other unknown factors including the degree of partial antagonism of buprenorphine on mu and/or kappa receptors. While it is said to be this speculation which led to the trial, it may be more productive to speculate on the actual outcomes of this most unusual clinical study.

It appears that buprenorphine is able to breach the block of naltrexone at certain dose levels. This would explain why more patients continued in treatment when it included buprenorphine. [It may also explain the reported large black market in buprenorphine in Perth, WA.]

The conclusion seems contradictory: "The combination of buprenorphine and naltrexone may significantly improve the outcome of opioid antagonists treatment in terms of retention, negative urinalyses, and reduced dysphoria, mood symptoms and craving."

Gerra wrote up a successful report of oral naltrexone over ten years ago. His very positive abstinence outcomes were never replicated by the many similar trials since then.

I cannot see the benefit in trying to compare a treatment which is known from many trials to be relatively ineffective (oral naltrexone for relapse prevention has very low retention rates) with an experimental one. Here, buprenorphine is from the very class of drugs being avoided in this population seeking abstinence. The results are therefore almost meaningless, except to show yet again that oral naltrexone has limited results following rapid detoxification.

My conclusion is that there is now abundant evidence that oral prescribed naltrexone has little if any benefit in opioid addiction treatment in unselected patients. This may be why enthusiasts are currently treating patients with unlicensed naltrexone implants, a practice which should only be done, in my view, under controlled trial conditions with ethics approvals and appropriate funding.

Comments by Andrew Byrne ..

Supplying alcohol to alcoholics may help reduce harms (and total consumption)

Canadian Medical Association Journal 2006 174;1:45-49

Podymow T, Turnbull J, Coyle D, Yetisir E, Wells G. Shelter-based managed alcohol administration to chronically homeless people addicted to alcohol.

Dear Colleagues,

This remarkable report is necessarily modest in its aims and its claims, yet it shows that giving alcohol in a supervised manner to homeless heavy drinkers can yield positive outcomes both for the subject and the community.  This was a pilot study of 17 subjects in Toronto (15 men, mean age 51, alcoholic for mean period 35 years) who had been registered at a funded city shelter for over a year. 

 The study used a ‘chronological’ control, looking at annualised use of alcohol and treatment/social services before and after the study which lasted for up to three years before and two years after registering in the study. 

 There were significantly fewer primary interactions (up to 50%) with medical and police officers after enrolment in this study.  And paradoxically, supplying supervised alcohol on request in the shelter (13.6g alcohol beverage hourly from 7pm to 10pm) was reportedly associated with substantially reduced consumption from 46 standard (US) drinks to 8 (excluding the 3 subjects who died, one refusal and 3 others for whom paired data were unavailable). 

 The lack of a parallel control group and small size of the study do not detract from the thrust of the findings which are highly significant. 

 The authors explain the study’s genesis: “After an inquest into the freezing deaths of homeless alcoholic men, a pattern was noted of heavy alcohol consumption before shelter entry to achieve in-shelter abstinence, followed by early-morning alcohol-seeking to avoid the symptoms of withdrawal.”

 Predictably there was a journal response requesting tax-payer alcohol for all.  While he may have his tongue in his cheek, CMAJ correspondent Dr Monczak seems unaware of the enormous potential savings if these findings were translated across entire communities. 

 While this group is already severely damaged and rehabilitation options limited, one can still be simultaneously pragmatic and humane in dealing with them, just as the Swiss dealt with heroin addiction over the past 20 years (using needle rooms, detoxification services, heroin prescription, methadone, etc). 

 Comments by Andrew Byrne ..

Comments by Andrew Byrne ..

BMJ editorial on whether methadone is outdated and ought to be replaced by buprenorphine

Is methadone too dangerous for opiate addiction? Luty J, O'Gara C, and Sessay M. BMJ 2005; 331: 1352-1353

Dear Colleagues,

This contentious editorial by Luty, O'Gara and Sessay

(extract)
(full text requires login)

raised much interest in the "rapid response" pages of the web BMJ in late December. There had been 25 replies up to Februrary, which is remarkable.

While a few have agreed with the premise that buprenorphine (pure) should be the drug of choice now for newly presenting heroin addicts, there was a stronger sentiment that methadone is still the best first line drug, with buprenorphine an excellent alternative. Methadone is also much cheaper at present, but this may change as generics are reportedly being introduced (in France and possibly elsewhere) since the patent has expired on high-dose buprenorphine for addiction treatments.

Perhaps as a gesture to the many responses, the journal published two of the early responses in their hard-copy edition only 4 weeks following the original (including one from Byrne Surgery). Numerous specialists have been involved in this BMJ 'debate' - and it is a pity that some of them were not chosen by the BMJ to review this manuscript long before it was published, with its controversial and unsubstantiated suggestions. There were letters from Andrew Ashworth, Chris Ford, Adam Bakker, Richard Hallinan, Gordon Morse, Matthew Hickman, Pier Paolo Pani, Colin Drummond and Jenny Keen.

I hope these reflections are of interest. There is hardly any mention of combination buprenorphine, which seems to be almost off the radar in Europe.

Comments by Andrew Byrne ..

China: Eye-opening activity and impressive progress

Andrew Byrne's trip to China Nov 05. Eye-opening activity and impressive progress.

Although largely on a private visit, I was invited to visit a harm reduction centre in Beijing as well as spending some time with an American public health consultant who works for both Chinese and foreign NGO's. I was also able to interview one of the first methadone patients in China and view a harm reduction centre.

On a related subject, last Friday's English language China Daily had two articles on the HIV problems in Henan province, Central China (pages 1&5). Despite quoting figures of affected local citizens in one small region (29,000 'carriers' and 16,000 with AIDS), neither addressed any continuing problem, reporting nothing but good news. They stated that 100% of the farmers who had donated blood in the past had been tested for HIV and that those who were positive were receiving anti-viral treatments paid for by the government. There was also another 'good news' story describing a mayoral official who was 'moved to tears' watching an operatic performance based on "the story of an HIV carrier that went from being in despair after suffering discrimination to regaining confidence with the support of neighbours, official and health workers" in Zhumadian city, Henan province.

It is disappointing but perhaps predictable that the People's Republic of China is still not prepared to be open about injecting drug use and homosexual transmission of HIV. To read their reports in the weekend official press one would think that the HIV problem had been solved! Yet WHO reports show otherwise and Koffe Annan himself was present when the first Beijing harm reduction centre was opened, along with high ranking Chinese officials. Nevertheless, it is clear that this sovereign country must address these matters in a manner which is effective, socially acceptable and sustainable - hence my own outsider's observations remain very much tentative.

My host and I were given a presentation by the manager of the first harm reduction centre in Beijing near one of the main trunk railway stations. They do most of their education and other work by use of outreach workers since people are very reluctant to attend in person. China is still a highly policed state (I saw three separate seemingly banal situations over two weeks where people were apparently apprehended, searched and detained).

The harm reduction centre has over a dozen education brochures on various related topics from the simple in cartoon style (which is very popular in China) to the more detailed on health issues. Needles and syringes were given out in lots of approximately 6 although more were permitted if old needles are returned. Some may be re-sold in what Americans term 'secondary needle services'. This is likely to extend the usefulness of the service in a society where there is a very major stigma and sanctions attached to drug use. Initially the centre was only distributing a few dozen syringes per day but this has risen dramatically in recent months to numbers in the hundreds per day.

We were told that since opening in May this year the centre had performed about 50 blood tests on injecting drug users. Of these about 6 were positive for HIV and 3 had AIDS clinically. Another 50-70% were positive for hepatitis C virus. We were told that at any hour of the day or night one could see dozens of injecting drugs users at one of the large railway stations in the capital.

The methadone patient who I interviewed appeared to be receiving high quality treatment. He drank his medicine under supervision on a daily basis after having a comprehensive assessment with on-going counselling. His dose had been increased to 90mg already, but a higher dose of up to 120mg was discussed. Following careful negotiation involving his case worker, as a result of his good progress his dose remained at 90mg daily. This is close to the average dose found in most well run treatment services. The patient appeared to be coping well with treatment. He was open and frank with his descriptions (via my host, who interpreted from the Pu-tong-hua or Mandarin, a language which every Australian child should be taught these days). The patient had pathology testing promptly and regularly (details unclear) and stated that he was satisfied with his treatment. Indeed, he said that he was delighted to be able to avoid heroin at last after a long drug use history with frequent relapses. I was intrigued to find out that the methadone treatment service was overseen by the police department (who also run the compulsory detoxification services in China).

Despite an apparent slowness to respond to some public health issues, it is clear that the 'new China' is moving ahead rapidly in many other respects. It is only a matter of time, I believe, before public health measures are put in place to address the above matters, considering the long history this country has of communal action for community needs. The Chinese have a strong historical record . starting with dams, bridges, 'walls' and other major works by successive dynasties. Already there are signs that pollution is being addressed (two of the days I was in Beijing were crystal clear with some haze, mist and possibly smog on others). The capital's tap water looks, smells and tastes pure, although we were advised to drink bottled water. Drainage is improving and even public conveniences around the city, while variable, are mostly clean and hygienic from what I saw in Beijing and Shanghai.

It has been a privilege to spend 2 weeks in China. I look forward to more news of this power-house society which has so much to offer (and gain from) the rest of the world. We also look forward to news on the 'second methadone clinic' and beyond (see Rachel Humeniuk and Robert Ali's article 'The first methadone clinic in Beijing' D&A Review, May 2005 issue).

Comments by Andrew Byrne ..

The neurobiology of addictive behaviours.

For those of you who weren't at Royal North Shore Hospital on Thursday1st December, 2005 for the 2nd Annual Macquarie Hospital conference:

�DOUBLE TROUBLE � TWICE THE FUN� co-morbid mentalillness and substance misuse, DVDs are now available.


The first speaker was Dr Stephen Jurd, Medical Director Northern AreaDrug & Alcohol Services, who have us a brilliant synthesis on the theme Addiction Biology 2005.

Brain plasticity, the dopaminergic reward/reinforcement pathway, "weighing up" and �rationalising and deciding� versus automatic behaviours, the risky period of synaptic pruning, changing addictive behaviours by enhancing frontal lobe activity or by reducing craving - with these ideas Dr Jurd gave us a solid basis for understanding the development and management of addictive behaviours.

Dr Jurd cautioned us not to think of our brains as hard-wired black boxes. Acknowledging the work of neuropsychologist Aleksandr Romanovich Luria (1902-1977) who identified the functional purpose of various parts of the brain (eg auditory and visual cortex) in a model of fixed structural inter-relations, Dr Jurd warned: only one thing is wrong with this model: everything!
In truth, the brain as an active organ, "a living breathing organ", of "highly dynamic synaptic structures", which is constantly reinventing itself. If we remembered anything of the day�s talk, it would be structurally encoded in our brains. It takes about 20 minutes to build a new synapse; synapses the structural substrates of learning. Each nerve cell body in the brain has thousands of synapses. On average a child's brain has 2,500 synapses per cell-body, increasing to 15,000synapses per cell-body in a child, and dropping to 7,500 per cell-body in the adult, during the "time of pruning". Unused synapses are cutback: "use them or lose them".

�Brain plasticity' also exists in mature brains, which are capable of regenerating damaged neurones (making new neurones?) and where neurones are capable of migration within the brain, after injuries like stroke, and after exercise.

Why do we do silly things again and again? Everyone knows from their own experience: most of us have experienced automatic driving - on a Saturday morning, the car somehow automatically takes the turn to work instead of the shopping centre.... With this question Dr Jurd turned to models of drug dependence.

It is easy to produce substance dependence in animals, and to show that not all drugs are the same in addiction liability. For example, primates will become addicted to low-dose alcohol, high-dose alcohol, barbiturates, and cocaine, in ascending order of addiction liability. Some animals will resist low-dose alcohol, high-dose alcohol, and barbiturates, but become addicted to cocaine (however, having become addicted to cocaine, these resilient animals will, when exposed to low-dose alcohol, use it in a dependent fashion).

Animals, once addicted, will neglect food, and neglect even their favoured mate. Dr Jurd described the image of a limp mouse, lying dead over the cocaine lever, having given its last gasp trying to get a shot. He described the anthropomorphic image of a mouse pressing the 'bar' which delivers alcohol every ten presses, leaning down to gulp the alcohol without taking its paw off the bar, bringing to mind the attachment of the drinker to their glass (or indeed that other 'bar').

Experimental models where the number of bar presses is increased progressively to test the strength of the addiction - "racking up the bar" - show that animals will go to 30, 40 or 50 presses for a "drop of booze", but there is a limit. This limit is about halved by the anticraving agents acamprosate, naltrexone and rimonabant. We can therefore expect relative but not absolute reductions in drinking from these drugs, which are more like a "blanket in the cold" than a "magic bullet".

The dopamine hypothesis has been around for a long time and is familiar to all those who treat psychosis. Dr Jurd stressed that dopamine is not just a "vector for psychosis" but has a lot of functions elsewhere in the brain. It is important in models of 'reward' in addiction: from dopaminergic neurones in the ventral tegmental area of the brain we get a little squirt of dopamine in limbic areas of the brain, in the "feeling parts" of the brain, such as the shell of the nucleus accumbens.

However the idea of 'reward', though easy to grasp (and communicate to our patients) is better expressed as 'reinforcement': dopamine is not just about 'feel-good' sensations but attention, memory and learning; noticing, remembering and valuing something: "I remember that, that was good".

Addiction can be thought of as subsuming this basic and, in evolutionary terms, very old mechanism, which is essential for our survival. Animals have to be reinforced in certain their actions for survival. An animal will make the effort to peck through a mango skin if it has a fond memory of the pleasure of the fruit within. The lizard with a fond memory makes the effort to chase the other lizard for some 'hanky panky', rather than eating the food. This has its homologue in "euphoric recall" in the drug user.

Dr Jurd raised the paradox in understanding addictions - that such different drugs as stimulants and sedatives are both addictive. The dopaminergic reward/reinforcement pathway provides an explanation. Dopaminergic neurones arising in the ventral tegmental area release dopamine in the shell of the nucleus accumbens, in the "feeling parts"of the brain. Stimulants like cocaine and amphetamine-like drugs work directly to release dopamine, acting as "accelerators" of the reward pathway. �Downers' like opiates and alcohol �inhibit the inhibitors� of this pathway - they "disable the brake".

Dr Jurd moved on to decision making: say whether or not to buy a chocolate bar or a pair of shoes. The process of "weighing up" a decision is associated with activity in the anterior cingulate/orbitofrontal complex, and the final step of �rationalising and deciding� is associated with activity if the dorsolateral prefrontal cortex (DLFRC for short). By contrast, posterior structures including the striatum and thalamus are associated with more automatic activities and are also more strongly activated in decision-making in stress situations, in situations of craving, and generally in addicts, whether presented with drug- or non drug-related decision making scenarios.

Decision making processes can be tested using the STROOP: a test which requires a kind of mental effort that "lights up the decision making parts of the brain". An example is the word red printed in green colour, the task being to say what colour the word is printed in.

This is surprisingly difficult, as the audience could testify. Cocaine and heroin users have less anterior and more posterior activity on the STROOP, showing that they think differently, using more automatic and less rational areas of the brain, even in non drug-related scenarios. This might be because they more habitually decide in this way, or are subject to more stress than other people.

Dr Jurd turned to animal models of craving and relapse in addiction, mentioning that 30 years ago the talk was all of stress, cues and triggers, and priming effects, old ideas which were then generally known to be untrue for the next 20 years until the behavioural/psychologists rediscovered them. Alcohol dependent rodents whose habits have been 'extinguished' (for example by cutting off the reward of alcohol from 'pressing the bar' until the rodent loses interest and resumes normal behaviours, like paying attention to food and to its mate) can be shown to resume drug-seeking behaviour by exposure to cues (eg a red light previously flashed when alcohol is supplied),stress (typically and charmingly produced by applying foot-shocks to the animal) or priming (for example, giving a small amount of uncued alcohol).

Moving back to the idea of synaptic pruning, SJ observed that adolescence, the time of maximum synaptic pruning, is a risky period in terms of addiction. Nicotine is both neurotoxic and reinforcing in adolescent rats, but is neither in mature rats.

Adolescent rats become intoxicated with alcohol more slowly than mature rats. (If this is true in humans, do adolescents' more active brains fight back more effectively against sedative substances?) Resilience against intoxication and vulnerability to reinforcement and neurotoxicity combine to create higher risk in adolescence. Adolescence is the "time when you make decisions about what sort of person you're going to be".People exposed to alcohol in adolescence develop a smaller hippocampus, and have about 15% fewer frontal neurones than other people.

Human frontal lobes continue to mature well into the 20s; itis no wonder that tobacco companies want to reach people before this happens. Think of Joe Camel.

Dr Jurd referred to Australia's epidemic use of stimulants, Australia having the highest rates of MDMA use in the world and the second highest rates of amphetamine use. He put in a plea for the use of the term MDMA (methylene deoxy methamphetamine), which sounds like a chemical that distorts brain function, rather than the trade name 'ecstasy', a name that invites us to think it "wasn't made in a bathtub by a bunch of bikies just wanting to make money".

He then moved to some of the applications of this neuroscience.

Essentially there are two ways to change addictive behaviours:1. enhance frontal lobe activity (cognitive behavioural or other therapies might work this way)2. reduce the unconscious drive to use, which is craving.

Naltrexone blocks opioid pathway mediated reinforcement from alcoholin the brain, and seems to work best in 'positive reinforcers', people who drink to feel good, rather than to stave off the consequences of not drinking. These are people who drink for episodic high blood alcohol levels. In reducing opioid mediated reinforcement from alcohol (experienced drinkers will recognise that 'glow') naltrexone has a place for those who are not ready to stop drinking altogether, and aim to control their drinking.

Acamprosate may be more appropriate for "steady state top-up drinkers", who drink to maintain blood alcohol levels and avoid negative consequences when blood alcohol levels fall. The appalling animal model is "alcoholised rats" who live in an alcohol vapour chamber: in this model acamprosate is very effective.

Naltrexone is contraindicated in people taking opioids and will cause goose flesh even in moderate opioid users, like the regular drinkerusing paracetamol/codeine for hangovers - they really won't like it.Unlike naltrexone, acamprosate can be used in people on methadone orbuprenorphine, and can be used in the presence of all but the most terminal liver disease (a bit of yellow in the sclera and puffy ankles are OK) whereas naltrexone should not be used if the liver function tests are more than 3 times normal. Naltrexone has the advantage ofonce daily dosing (50mg) where acamprosate needs to be taken 3 times daily (666mg tds).

Ondansetron, a serotonin 5HT-3 blocker, best known as a very effectiveand expensive antiemetic, has been shown in well conducted trials toreduce relapse in abstinent drinkers who developed alcohol dependence early in life (Early Onset Alcoholics, who also often have a strong family history, and antisocial behaviours) but to have no benefit inother alcoholics compared with placebo. This might be explained by serotonergic abnormality in EOA, with increased mood disturbance predisposing them to drink, and/or increased activation of 5-HT3receptors in alcohol-induced reward.Therefore selective serotonin reuptake inhibitors (SSRIs) might not be effective treatment for alcoholics and could even make things worse insome cases -which is borne out by a number of studies. Dr Jurd suggests SSRIs be used with care - for true comorbid major depression, not just the alcoholic who is feeling a bit sad.

Topiramate is an antiepileptic medication used for partial seizures. It has an anti-dopaminergic action (possibly mediated by increased activity of GABA, and reduced action of glutamate). It reduces the reinforcing effects of alcohol and tobacco in dependent people and reduces both craving and relapse.

Studies of combinations of anticraving agents for alcohol are going on, such as naltrexone+acamprosate, naltrexone+ondansetron. We were advised to watch for the results of the large NIAAA study, coming out soon....

Rimonabant, a cannabinoid receptor CB-1 blocker, is showing promise as an anticraving agent in surprising ways: it seems to be effective for smoking cessation and weight loss, Rimonabant, a cannabinoid receptorCB-1 blocker, is showing promise as an anticraving agent in surprising ways: it seems to be effective for smoking cessation and weight loss, as well as blocking reward from cannabis smoking. It might be the first true anticraving agent. Paradoxically, it might be too effective to be a useful treatment for cannabis dependency, in the same way that naltrexone is �too effective for opiate dependency: people simply won�t take it. It is likely the pharmaceutical industry will targetthis new medicine at cardiologists, representing a potentially huge market, rather than addiction doctors.

Dr Jurd summarised with these critical points: addiction is a disease; craving is physical; addicts reward themselves chemically; multiple neurotransmitters are involved in addiction; there may be pharmacological subtypes of alcoholism, allowing matching alcoholics to medications based upon their different biological natures; and combination treatments may be appropriate - they work in animals.

And returning to the idea of brain plasticity, Dr Jurd assured us: Recovery is Real. Citing George Vaillant's "Natural History of Alcoholism" , Global Assessment of Functioning (GAF) scores in abstinent drinkers are as good as those in never-alcoholics. Well worth remembering if your patient or client, like mine today, receives a dismissal notice claiming a "medical report provided (sic) that your condition of substance abuse is considered permanent".

R. Hallinan summary.