10 December 2005

BMJ editorial on whether methadone is outdated and ought to be replaced by buprenorphine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

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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 ..

1 December 2005

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.