Alcohol anti-craving drugs

Tue 3rd Feb 2004

Presenters:
Prof John Saunders,

A/Prof Kate Conigrave (case histories).

Convened by Dr Richard Hallinan.

"The latest in pharmacotherapies for alcohol dependency: alcohol and the opiate dependent patient."

John Saunders gave us a scholarly and comprehensive overview of the state of play in the field of alcohol dependency and its treatment in our society today. It is estimated that there are over 500,000 alcohol dependent people in Australia of whom a meagre 10% are in some form of treatment (including self-help groups) while only a minuscule 1% are being prescribed anti-craving drugs at any one time. This contrasted dramatically with an estimated 50% of opioid dependent citizens who were in treatment.

The facts and figures on the consequences of alcohol related harms are profound, affecting driving, drowning, suicide, liver disease, domestic violence and beyond. About 90% of the adult population drink (at least occasionally) and up to 20% are engaged in some degree of hazardous drinking. Young men are over represented, especially those from lower socio-economic groups, indigenous communities and other disadvantaged minorities such as mental health patients.

Professor Saunders described alcohol's effects on a range of neurotransmitters including actions on both GABA and glutamate receptors and how it acts through both dopaminergic and endogenous opioid reward pathways. Thus drugs from a variety of quite different classes have been found to have benefits for alcohol dependency. But with limited effects from single drugs, he predicted the possible wider future use of more effective combination therapies. Parallel moves have happened over the years with certain oncology and antiviral treatments, with substantial benefits for their recipients.

Both naltrexone and acamprosate are approved medications for alcohol cravings in Australia. According to metanalysis of numerous placebo controlled trials both treatments work well in preventing relapse and reducing intercurrent drinking. But we were reminded of the draw-backs of metanalyses which may include studies with very different protocols. Controlled research can only ever determine whether one drug is better than another (or placebo) in given circumstances. The studies he quoted seemed to agree that, when taken according to directions, either drug can double the proportion of subjects who are abstinent at 3, 6 and 12 months after commencing treatment. Australian experience seems to confirm the utility of these treatments in the out-patient setting.

There are a number of factors in choosing between these two first line drugs. As a guide, Professor Saunders cited evidence that naltrexone is indicated especially in people who experience strong craving for alcohol after a priming dose. It seems to reduce the likelihood of a lapse progressing to a relapse. On the other hand, acamprosate is indicated especially in those who are susceptible to 'cueing' by their environment or emotions, or whose drinking is triggered by true withdrawal symptoms. Clearly naltrexone in not suitable in those taking opioid or in whom opioid prescription is likely.

Newer work, case reports and single series have shown some promise for using other agents including the 5HT3 antagonist ondansetron (Zofran). In addition, it appears that the use of naltrexone in combination with acamprosate and other drugs can be safe and effective in appropriate cases.

SSRI antidepressants have been found to be unhelpful in alcoholism and they should be reserved for patients who have stopped drinking but still manifest signs of clinical depression. Buspirone was mentioned as having a place in alcohol dependent people with disabling social phobia.

The use of Antabuse (disulfiram) has waned in recent years and as a single agent there would appear to be little favouring its use. According to Professor Saunders it may still have a place an adjunct with other treatments where adequate supervision of doses is always desirable.

It was stressed by both speakers that medication should always be given in the context of a supportive clinical setting with psychosocial interventions, counselling and 'suggested' but not 'obligatory' self help group attendance.

Case Histories

Two interesting case histories were presented by Professor Kate Conigrave regarding alcohol problems in regular methadone patients. Both cases stimulated discussion regarding how to deal with intoxicated patients who present for methadone dosing, and whether it was appropriate to continue treatment at all with its attendant risks. Some clinicians used breath testing kits while others used clinical measures while all clinicians in the audience either refused to give medication or else reduced doses in such patients when intoxication had reached a certain degree.

In one of the cases Professor Saunders raised the possibility of rapid methadone metabolism possibly requiring split-dosing. This was taken up by Kate Conigrave regarding her suggested physical examination 3 and 24 hours after dosing to determine waxing and waning of the opioid effects.

A lack of time prevented further discussion of the place of measuring methadone blood levels in unstable patients, a subject which was covered in previous seminars. However, some clinicians never order methadone levels, stressing the primary importance of clinical assessment in dependent patients who are drinking excessively.

Comments and summary by Andrew Byrne and Richard Hallinan from lecture given and material provided by the above two speakers (JB Saunders, K Conigrave).

Next meeting:

Tuesday 6/04/2004 Chair Dr Gary Swift

Session 1 "At their peril: Cocaine-related deaths in NSW."

Prof Shane Darke, National Drug and Alcohol Research Centre

Session 2 "Forum on takeaway doses."

Prof James Bell, The Langton Centre.

Injecting rooms need support from experts, not alarmist doubts.

The case for piloting supervised injecting centres in the United Kingdom is strong. Wright NMJ, Tompkins CNE. BMJ 2004 328:100-102

Dear Colleagues,

With continuing high rates of drug related deaths in the UK, the BMJ is
right to again give prominence to the issue. The report by Wright and
Tompkins [ref 1] clearly demonstrates that there are new and promising
ways to address the current UK epidemic of overdose deaths from street
drugs, including medically supervised injecting facilities. Overseas
experience with injecting centres over 15 years has been uniformly
positive. Over one million injections occur each year in such centres
where deaths and serious complications almost unknown. Nearly all such
injections would otherwise take place in less savoury and thus less safe
environs. Such services also bring large number of addicts into contact
with health care workers, some for the fist time.

It is thus disappointing that in their following commentary [ref 2],
rather than unequivocally supporting such moves, Strang and Fortson
raise the canard of the differences between prescribed heroin for
dependency and injecting facilities (which they pejoratively call
'fixing rooms').

As a leading dependency expert, Strang knows the reassuring reports of
such centres in Europe, Australia and, most recently, Canada. The
concept has worked effectively elsewhere [ref 3], including apparently
unofficial experience in London. Strang and Fortson give no realistic
alternative strategy for the UK's high rates of overdose, HIV and
hepatitis C. They write that heroin prescription would only ever be a
'tertiary service', while injecting rooms a primary one.

These authors compare injecting centres to pubs, adding to the confusion
they are trying to address. Licensed premises, like Swiss heroin
prescription trials, supply the patrons' drug of choice in a safe
environment, while injecting centres only provide the supervised
environment for consumption of illicit drugs. Injecting centres are
perhaps more like patrolled beaches where people do risky, even
foolhardy things, while professional life-guards move into action if
needed in a non-judgemental manner.

Strang and co-author cannot know how insensitive their petty
reservations on injecting rooms must sound to grieving relatives when
every overdose death is potentially preventable. Rather than refuting
them, these authors raise old issues such as injecting rooms 'fostering
.. more .. drug use', drug dealing and operational protocols after over
a decade of positive experience. Their perfunctory dealing with 'harm
reduction' in the first sentence belies its being the foundation of good
medical and public health practice since the time of Hippocrates. It is
also official government health policy in some countries and has
prevented an HIV epidemic in Australia and Hong Kong.

Like heroin prescription, on current evidence we probably need a small
number of injecting rooms in drug 'hot-spots', as well as simultaneous
improved access to traditional drug treatments, detox services, harm
reduction measures and education.

Yours faithfully,

Andrew Byrne ..

References:

[1] Wright NMJ, Tompkins CNE. Supervised injecting centres. BMJ (2004)
328:100-102
http://bmj.bmjjournals.com/cgi/content/full/328/7431/100

[2] Strang J, Fortson R. Supervised fixing rooms, supervised injectable
maintenance clinics-understanding the difference. BMJ (2004) 328:102-103
http://bmj.bmjjournals.com/cgi/content/full/328/7431/102

[3] Burton, B. Supervised drug injecting room trial considered a
success. BMJ (2003) 327:122
http://bmj.com/cgi/content/full/327/7407/122-a


Extracts:
BMJ 2004 328:100-102 (10 January)

Wright NMJ, Tompkins CNE.

The case for piloting supervised injecting centres in the United Kingdom
is strong.

Medically supervised injecting centres are "legally sanctioned and
supervised facilities designed to reduce the health and public order
problems associated with illegal injection drug use." Their purpose is
to enable the consumption of pre-obtained drugs under hygienic, low risk
conditions. They differ from illegal "shooting galleries," where
users pay to inject on site. Worldwide, medically supervised injecting
centres (also referred to as health rooms, supervised injecting rooms,
drug consumption rooms, and safer injecting rooms or facilities) are
receiving renewed attention. In 2001, the first medically supervised
injecting centre in recent times was opened in Sydney, Australia.




BMJ 2004 328:102-103 (10 January)
Strang J, Fortson R.

Supervised fixing rooms, supervised injectable maintenance
Clinics - understanding the difference.

John Strang (psychiatrist), Rudi Fortson (barrister)

Harm reduction policies and practices (where anything goes, if it
actually reduces harm) have fundamentally altered our approach to the
drugs problem. Two innovations were recently considered by the Home
Affairs Select Committee-supervised injecting centres and supervised
injectable maintenance clinics-but with unhelpful confusion between the
two. They have different target populations, potential benefits, and
legal obstacles.




http://bmj.com/

Three fine French papers on methadone/buprenorphine (community, pregnancy, HIV).

Illicit drug use and injection practices among drug users on methadone and buprenorphine maintenance treatment in France. Guichard A, Lert F, Calderon C, Gaigi H, Maguet O, Soletti J, Brodeur J-M, Richard L, Zunzunegui M-V. Addiction (2003) 98: 1585-1597

The November Addiction starts with a rather gauche exercise by Griffith Edwards et al. in which a hand-picked group of sub-editors, chosen for ‘their insight into Addiction’s ways of working’, are asked their suggestions for future directions in publication. It will come as no surprise to the reader that it is to be more of the same. While these distinguished folk come up with numerous worthy suggestions, the ‘uncomfortable’ issues are not raised to any level of prominence. These include the standard of opioid treatments; heroin prescription trials; controlled drinking; injecting centres; views direct from ‘consumers’; urine testing protocols; rapid opioid detoxification; naltrexone implants; medicinal uses of cannabis; the effects of criminal sanctions on the use of drugs, aka ‘drug law reform’; harm reduction philosophy and practice.

The authors congratulate themselves in advance by writing “the exercise has fulfilled its intentions”. They then concede that at some time in the future such an exercise may be repeated ‘with a wider sample’ and from ‘a younger generation’. We can only hope.

In spite of its current management, Addiction still attracts leading researchers, publishing key items of interest. An important item in this journal comes from France where in a three-city study, 340 addicts in maintenance treatment for at least 6 months were interviewed regarding illicit drug use, treatment characteristics and demographics. There were 200 on methadone while 140 were prescribed buprenorphine. About half the methadone patients and 80% of buprenorphine patients were treated in general practice, the remainder in specialist dependency treatment units.

The authors write that in France methadone can only be started in formal dependency treatment units. After stabilization, patients may attend pharmacies and receive up to a week’s supply of methadone on a GP prescription. In contrast, buprenorphine tablets (‘pure’, sub-lingual) can be prescribed for up to 28 days by any physician. Thus the latter has had a rather broader uptake even though both were introduced around the same time in France. This is especially so in regions without specialist units. The authors state that buprenorphine was generally considered the ‘first line’ drug in France.

This study found that methadone patients had been using drugs for longer and had been in treatment slightly longer than the buprenorphine recipients.

Mean daily dose for methadone was 67mg (SD 30) and for buprenorphine 10mg (SD 9).
The important finding of this study was a low rate of illicit drug use of around 35% of subjects (18% heroin, 25% cocaine, 7% crack). There was little significant difference between patients being cared for in specialist clinics or by GPs. It was noteworthy that 40% of the buprenorphine patients had injected their own substitution drug (ever) while only 15% of the methadone patients had done so. In addition, the higher dose buprenorphine cases were more likely to have injected, a trend which was not seen with the methadone patients.

About 80% of methadone patients received a prescription for two weeks or less. Two thirds of buprenorphine prescriptions were for 3 weeks or more.

About half of the subjects had a jail history. About 90% of patients had been tested for HCV and HIV. Around 50% were HCV positive while 22% HIV positive. These figures may relate to the late introduction of harm reduction measures in France compared with experience elsewhere (eg. Australia and Hong Kong). It is partly as a result of increasing HIV and overdoses that France took the bold step of making buprenorphine so widely available.

My ‘theory’ on the buprenorphine injecting is that a proportion of patients who do not do well initially on buprenorphine doses may increase their dose, still without suppressing cravings. Such unstable and unhappy patients may tend to inject their buprenorphine, thus defeating one of the main purposes of the treatment. Whether relapse to heroin use or buprenorphine injecting, such behaviour should indicate a consideration of transfer to methadone or another agonist drug such as long acting morphine if available.

With arbitrary regulations in some jurisdictions these options are not always available in the same treatment settings. This would be unlikely to occur in other fields, rather like banning some doctors or pharmacists from using certain antibiotics. The principles governing methadone treatment should be parallel to those for buprenorphine with emphasis on real risks and benefits, not implied or theoretical ones. Historical regulatory anomalies should be removed in the interests of all involved since agonist treatments are evidence based, cost-effective and can be simply delivered using existing resources and facilities. Fortunately, all Australian jurisdictions now permit (limited) take-away provisions for buprenorphine, including New South Wales (up to two per week as well as for emergencies and travel in suitably approved patients). South Australia allows up to 5 dispensed doses per week in stable patients who have been in treatment for over 18 months. Such dosing encourages retention and is recommended by the new Australian treatment guidelines. Intriguingly, both France and the US allow unlimited unsupervised doses even though these have not been researched to any degree. Such are the anomalies of our field.

This Addiction edition also has some largely reassuring information on buprenorphine in pregnancy with 13 cases reported from France. The authors state that no teratogenic effects have been reported, and that their cases had variable neonatal abstinence syndrome but of shorter duration than with methadone. Two cases (15%) had some motor abnormalities which did not resolve completely at follow-up. [Kayemba-Kay’s S et al.]

Another important recent comparative description is: Carrieri M-P, Reya D, Loundoua A, Lepeuc G, Sobeld A, Obadia Y .Evaluation of buprenorphine maintenance treatment in a French cohort of HIV-infected injecting drug users. Drug Alc Depend (2003) 72; 1:13-21

comments by Andrew Byrne ..

Do cannabis withdrawals need drug therapy? Controlled trial from America.

Pharmacotherapy for Marijuana Dependence: A Double-blind, Placebo-controlled Pilot Study of Divalproex Sodium. Levin FR, McDowell D, Evans SM, Nunes E, Akerele E, Donovan S, Vosburg SK. American J Addiction 2004 13:21-32

Dear Colleagues,

Negative research findings can be just as important as positive ones. This is especially so in well conducted placebo-controlled, randomised intervention trials. A recently published trial from the group at Columbia University in Manhattan has shown no significant effects using a mood-stabilising anti-convulsant, divalproex, in cannabis withdrawal subjects.

Despite finding no effect from the drug treated group, for some reason these veteran researchers do not say as much in their abstract. One has to read this sentence in the abstract to glean the important message of the article: “Regardless of treatment group, patients reported a significant reduction in their frequency and amount of marijuana use as well as a reduction in irritability.”

These researchers stress their positive findings, corroborating other reports regarding cannabis: (1) There are many members of western communities who perceive that they have cannabis dependency, (2) many such citizens are interested in treatment options, (3) such subjects will attend and comply well with recommended treatment and (4) most will reduce (or cease) their drug consumption during such interventions, regardless of their nature.

Any drug used to counteract cravings or withdrawals must have a safety profile which is in measure with the safety profile of the drug of dependence being treated. As well as such safety, such a drug must also be effective. This trial shows convincingly that divalproex, although a drug with some promise for cocaine withdrawals, is not a useful drug for symptoms of cannabis withdrawal. Cannabis is a harmful drug, causing dependence in a proportion of users and causing damage to the upper respiratory tract if smoked. The scope for harm appears to be low for most users, and is much lower than the harm which occurs in the ‘average’ tobacco smoker.

These authors (or the journal’s editors) use the lay term marijuana for some reason, only rarely using the correct scientific term, cannabis, in their text.

There is also a problem with the formal DSM criteria for cannabis dependency in the USA. The definitions (304.30 and 305.20) involve (1) the time spent acquiring the drug, (2) interference with family, schooling, work or 'recreation' (sic!) and (3) legal consequences of possession and consumption of the drug. Thus some of the subjects in this trial, if given access to cheap, unadulterated cannabis as in Holland, may not have satisfied the same criteria and thus been categorized as having cannabis ‘problems’ rather than cannabis ‘dependency’.

Levin FR, McDowell D, Evans SM, Nunes E, Akerele E, Donovan S, Vosburg SK. Pharmacotherapy for Marijuana Dependence: A Double-blind, Placebo-controlled Pilot Study of Divalproex Sodium. American J Addiction (2004)13:21-32

comments by Andrew Byrne ..