The Pharmaceutical Journal Vol 267 No 7162 p260
25 August 2001

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Naltrexone implants for opiate addiction: new life for a middle-aged drug

By Colin Brewer

Addiction may or may not be a disease but is often treated by psychiatrists. So, here is a challenging statement. Naltrexone, a pure opiate antagonist, is psychiatry’s most effective drug. Not all depression is banished by antidepressants. Many schizophrenic patients remain floridly psychotic despite generous doses of every known neuroleptic. Valium is still mother’s little comforter but it does not comfort all mothers. Naltrexone, in contrast, will unfailingly block the effects of any conventionally abusable opiates by any route and in any dose likely to be used by the most determined addict.

Naltrexone (synthesised circa 1965) has had a full British product licence since 1988 and a United States one since 1983. It is an obvious alternative to methadone, especially for the many patients who have successfully stabilised on methadone and want to move to the next stage, which means both becoming and remaining opiate-free. Yet naltrexone is not often prescribed in Britain. In good randomised controlled studies, naltrexone considerably increases the likelihood of being opiate-free six months after withdrawal, but it is not even a treatment option in many NHS drug dependency units.

There are two problems with naltrexone. The first is that the official advice is to start naltrexone only when the patient has been opiate-free for at least a week. Sadly, many patients never quite manage to get clean during detoxification. Failure rates are typically at least 20 to 30 per cent even for inpatients, and patients who have had clean urine for a week can still experience significant withdrawal symptoms. The first dose of naltrexone can make patients, briefly, feel even worse, so that first dose may be their last. To avoid this, one must either do a naloxone challenge, which is time consuming and can still be quite uncomfortable, or be prepared to medicate patients quite generously before or after the first naltrexone dose.

Secondly, if patients are just given a bottle of tablets and advised to take them regularly, most will discontinue naltrexone within a few weeks or sooner. This is because, almost by definition, people seeking help for drug dependence are highly ambivalent about giving up the drug in question. If they were not ambivalent, they would not need treatment. Ambivalence means that some days, they will resolutely resist temptation and take naltrexone to bolster their resolve; on other days they will do neither. In this respect, naltrexone is similar to disulfiram, another drug which helps people to stop doing something which they admit is damaging them, though by the threat of an unpleasant reaction rather than simple blockade. There are far more studies of disulfiram than there are of naltrexone and they show that unless disulfiram is supervised by a third party, few patients take it for longer than a short period. In contrast, programmes using supervised disulfiram consistently give results that are clinically and statistically much better compared with results from programmes that do not use supervised disulfiram, even if they also include intensive counselling.¹

Virtually every study of supervised disulfiram has a positive outcome, many with P values of less than 0.02. One obvious solution to the problem of supervision and compliance was to produce depot preparations. Disulfiram implants were briefly in vogue and can sometimes seem remarkably effective, but when blood-levels were measured, they turned out to be very erratic. So most of the effects appeared to be a matter of suggestion.

Recently, naltrexone implants have been developed for the same reason. They are different from disulfiram implants because they do give effective blood levels. This is important because many alcoholics do not test out their disulfiram implants whereas heroin addicts, being more sceptical and experimental by nature, often test out naltrexone implants. If they did not block heroin, there would be a risk of serious overdoses, because addicts lose their tolerance to heroin when they have been opiate-free for a while.

As long ago as the early 1970s, US studies showed that workable naltrexone implants could be produced. For some reason, nobody took the research any further and it was left to a small US private pharmacist, in response to requests from various doctors using oral naltrexone, to produce the first crude naltrexone implants in 1997. The current model contains 1g of naltrexone, 10mg of triamcinolone to reduce tissue reaction and a small proportion of magnesium stearate as a binding agent. Because naltrexone is such a powerful drug, even low blood levels can block a large amount of opiates. In 1998, Professor David Gastfriend and I published a short report on a patient who had been implanted two weeks previously.² We injected him with 50µg of fentanyl every minute for 20 minutes. This is equivalent to about 0.67g of street heroin, but no subjective or objective effects were noted.

An independent follow-up study of 50 consecutive implanted patients showed that none had relapsed in the first month after detoxification and 80 per cent were still opiate-free three months later.³ The current implants seem to last an average of about six weeks and almost half the patients who have an implant go on to have at least one further implant. This means that for the first time in the history of the treatment of opiate-dependence, one can give something approaching a guarantee. When it is considered that, even at the National Addiction Centre, according to its own published results, about 20 per cent of patients fail to complete detoxification and about half of those who do are using opiates again within a few days of discharge, naltrexone implants are clearly a useful addition to treatment.

Although all implants produced so far are unofficial and have no product licence, any doctor can import them for use with his own patients, provided that he takes full personal responsibility. I know of at least one NHS GP who has been using them to treat his own NHS patients without any clinical or bureaucratic difficulties. In a bureaucracy-infested NHS, innovation is not always popular but at least one respected drug-dependency unit plans to start a controlled clinical trial of oral versus implanted naltrexone.

It is seven years since I wrote an article in The Independent, urging British drug companies to produce a naltrexone implant. The technology is not complex and we are already seeing a second generation of implants based on biodegradable plastic-coated microspheres, providing effective opiate blockade for six months.

Naltrexone implants makes treatment easier for both parties. Knowing that they cannot use opiates for a substantial period, patients usually stop thinking about whether or not to score heroin and simply get on with their lives. Implants do not make counselling unnecessary but they make it less important and counsellors can concentrate on ordinary life problems rather than on helping people to resist the lure of heroin. Thanks to monoclonal antibody techniques, we may soon have the equivalents of naltrexone implants for most of the other drugs of abuse, including nicotine. In short, we are entering a completely new world of addiction treatment.

Colin Brewer, MRCPsych, is medical director of the Stapleford Centre (e-mail cb@stap-cen.demon.co.uk)