The research evidence for methadone

Summary
Introduction
Research methods
Research findings on methadone detoxification
Research findings on methadone maintenance

Summary

Studies are embedded in their social and historical context, and this always needs to be considered.

As with many other pharmacological treatments, there is much more to methadone treatment than methadone: psychological and social components of treatment have strong influences on outcome.

The delivery system of long-term prescribing may act to bring order into the lives of chaotic opiate users - whether this is picking up daily from a chemist or (as in the American way) attending a maintenance programme daily.

Stimson and Oppenheimer made a valid obsevation when they noted that: 'the clinic system, with its ...constraints, the socially organised policies, treatments and controls, enabled some people to lead stable lives. Stabilisation is, then, not just about drugs, but is about being integrated into a socially engineered system for obtaining them.'15

Drug workers, like many clients, can be so locked in to 'chemical thinking' about the drugs themselves that they can ignore or under use non-chemical components of methadone treatment.

Making decisions about the treatment of individual clients has to be based as far as possible on both a thorough assessment of what will work for that person and on reliable information about 'what works' in general.

Research findings can probably be safely generalised to UK practice and can be used to support decision making.

The research supports the conclusion that methadone maintenance is more effective than no treatment or placebo in retaining people in treatment, reducing use of heroin and other illicit drugs and reducing involvement in criminal activity and imprisonment rates.

Detoxification alone is seldom effective in producing long-term change.

Six months after in-patient detoxification and psycho-social treatment in a specialist NHS unit about 50% of opiate addicts are opiate free: treatment in a less expert setting results in poorer outcomes.

In-patient detoxification over 10 days is likely to be more distressing, but equally as successful as 21 day detoxification.

The benefits of methadone maintenance treatment last as long as maintenance lasts. For some people the long-term benefits can be as great as those of residential rehabilitation.

Benefits can be maximised by retaining clients in treatment, prescribing higher rather than lower doses of methadone, orientating programmes towards maintenance rather than abstinence, offering counselling, therapy, and social treatments and the use of contracts and counselling to reduce the use of additional drugs.




Introduction
The research into methadone in the management of opiate use has looked extensively into its uses for detoxification and maintenance.

Methadone has been used for both treatments because it:

Is cross-tolerant with most opiates, and so can be substituted for them

Can be taken orally, helping drug takers to move away from injecting

Is long acting, and therefore needs to be taken only once a day as opposed to the more frequent administrations required by drugs such as heroin.

Care must be taken in drawing lessons from studies carried out in one place and applying them to services in another. In particular it must be remembered that much of the work on methadone maintenance has been carried out in the USA where:

Patients receive their medication in a very different way to patients in the UK

Street heroin has been less pure than in Europe

Cocaine use has been much more prevalent than in Europe.

It is also important to bear in mind the prevailing drug and treatment trends of the time as this can have an influence on the outcomes of a study.

There are different types of research which measure different things in various ways. The methods of research that have been carried out are outlined below, followed by the findings.



Research methods
Randomised controlled trials
The most conclusive method of answering questions about the effectiveness of any treatment is to do a randomised controlled trial in which patients are randomly allocated to different treatments so that differences in outcome can be attributed to differences in treatments.

There have been only a small number of randomised controlled trials in the study of methadone maintenance and detoxification.

The only British randomised controlled trial of maintenance, comparing maintenance treatment using either methadone mixture or heroin was carried out in the early 1970s when heroin maintenance was the norm. They found that heroin maintenance kept more patients in treatment, but caused less change in them than did methadone. This might not be found now, 20 years on, in a different culture where methadone mixture is the norm and offering it is less confrontational.

Social and economic factors have also dramatically changed since then, as evidenced by the authors' comment that:

'... addicts were rarely unemployed for external reasons ... when patients wished, they had little difficulty in obtaining work or training'.16

The value of work for people abandoning opiate use and the associated lifestyle demonstrates the need for judgement in generalising the research from one time and place to that carried out in another.

Descriptive studies
Descriptive studies are interesting and valuable, but their findings cannot establish cause and effect because there is no 'control group' with which to compare the changes in the study group. For example, an American study in 1991 of 633 patients receiving methadone maintenance found that patients on higher doses of methadone were less likely to take heroin.29 From this alone one could not conclude with certainty that higher dosages of methadone caused patients to take less heroin: there are other possible explanations.

Relationship between methadone dose and heroin use: Adapted from Ball and Ross, 1991
Relationship between methadone dose and heroin use.


Descriptive studies such as this are helpful and thought provoking and can suggest questions that can only be answered by experimental studies. In this instance a subsequent double-blind randomised controlled trial which compared 0mg, 20mg and 50mg of methadone daily, found that larger doses were more effective in suppressing heroin use.30, 31 The suggestion that came from descriptive studies was confirmed by a randomised trial.

Descriptive studies are sometimes the only practical way of studying some topics. For example Hubbard et al carried out a very large study of 11750 drug users who entered treatment for drug dependence in 1 of 41 American programmes between 1979 and 1981.32 The study followed them up for three to five years after terminating treatment, in order to compare the outcomes of those receiving three very different treatments:

Methadone maintenance

Drug-free residential programmes

Non-prescribing out-patient programmes.

It would be almost impossible, although invaluable, to carry out such a study as a randomised trial. Nevertheless the results are extremely interesting and suggest further questions to be answered.

The most interesting observations were that in the long run each type of treatment produced very similar results, despite their very different approaches, and that the best predictor of outcome in any of these three approaches was the time spent in treatment. The time spent in treatment was more important than the type of treatment.

Perhaps treatments work by giving people the opportunity (albeit in very different ways) to modify their behaviour whilst in treatment, and the longer the opportunity to abandon old behaviour and develop new patterns of behaving, the more likely it is that these will persist after treatment and unlock further change. So although this study lacked the tight control of a randomised trial to disentangle cause and effect, it provided valuable and thought-provoking findings.



Research findings on methadone detoxification
Isbell and Voge33 published an account of methadone's use in detoxification in 1948. They concluded that it was much safer than many methods of detoxification used since 1900, which included treatments which had significant mortality rates such as:

Belladonna sleep treatment

Bromide sleep treatment

Insulin sleep treatment

Sodium thiocyanate - which triggered psychotic states in some patients.

A review carried out in 193834 had concluded that most treatments were either useless or dangerous or both, and that the best approach was a 10 day gradually-reducing treatment of morphine and codeine. Methadone seemed much safer than all of these.

Much of the British research on methadone detoxification has been carried out on its use with in-patients.



Subjective experience of withdrawal symptoms
In a series of studies at the Bethlem Royal Hospital in Kent, Michael Gossop and colleagues have examined patients' responses to methadone detoxification.35

A study of the effects of a 21-day withdrawal regime on patients' withdrawal symptoms36 found that the intensity of withdrawal symptoms started rising after the 10th day of treatment, and reached a peak on the 20th day, the last day on which patients took methadone. Withdrawal symptoms then started to subside, but it took another 20 days for them to reach a low level. This means that newly detoxified patients are very vulnerable for some time.

A further study showed that the intensity of withdrawal symptoms was determined not by the amount of opiates the person had been taking, but by their level of anxiety.37 Many studies of patients' reactions to unpleasant medical procedures had found that a major cause of anxiety was patients' unclear expectations about what they would experience. The study also found that removing uncertainty, by teaching patients about what they were likely to experience, caused them to be less anxious.

Green and Gossop38 carried out an experiment in which a total of 30 patients were detoxified as usual, but 15 of these patients were also taught in detail about the pattern of symptoms that they were likely to experience over time. Those who received education experienced milder withdrawal symptoms than the others, and were also more likely to complete treatment.



10 and 21 day detoxifications
A further study39 compared completing methadone withdrawal over two periods - 10 days or 21 days. A similar pattern of withdrawal symptoms occurred in each group except that withdrawal symptoms peaked on the 13th day in the shorter treatment, compared with the 20th day in the longer treatment.

Although those receiving the 10 day treatment experienced more intense withdrawal symptoms, just as many (70%) completed detoxification.

Short term detoxification using methadone and heroin
Gossop and Strang40 compared the responses of heroin users and methadone users to a 10 day methadone detoxification treatment. The methadone users experienced more severe withdrawal, especially during the first 10 days (when they took methadone). They experienced much more intense insomnia, muscular tension, weakness, and aches and pains. However despite more painful withdrawal, the methadone users were just as successful as heroin addicts in completing treatment.



Methadone detoxification with out-patients
Considering most detoxes in Britain are carried out in the community there is very little UK research into methadone detoxification with out-patients.

Two treatment trials carried out by the Maudsley Community Drug Team suggest that short-term detoxification is not, in terms of achieving sustained abstinence, very effective.41, 42 A randomised controlled trial comparing out-patient and in-patient detoxification found that only 17% of out-patients and 81% of in-patients completed treatment.

A further study compared two out-patient methadone detoxification programmes. One group of patients were given a fixed dose reduction schedule over 6 weeks. The other group were able to negotiate their rate of reduction, with the aim of reducing to nothing in about 6 weeks.

Those receiving the fixed reduction were three times as likely as the others to complete detoxification. For all patients 40% of urine samples taken during the detox contained evidence of other opiates, but only 28% of patients completed treatment.

Although this sort of out-patient detoxification may not be effective in terms of achieving lasting abstinence it can be a useful tool in helping the client understand the nature of their drug dependence. This can be maximised if clients are carefully assessed and offered support and counselling during and after the detoxification.



Research findings on methadone maintenance
Randomised controlled studies
A study in Bangkok43 compared a 45-day period of methadone maintenance with a 45-day methadone withdrawal. The withdrawal group were 6 times more likely to drop out of treatment than the maintenance group and were 10 times more likely to have an opiate positive urine test result.

A New York study in 199129 compared the effects of methadone alone versus no medication for people on the waiting list for a comprehensive maintenance programme. The methadone group were three times more successful in stopping taking heroin during this period and twice as likely to start on the comprehensive programme at the end of the waiting list.

These studies demonstrate the value of methadone maintenance, even without additional counselling.

Three randomised controlled trials, one each in the USA44, Hong Kong45 and Sweden46, compared methadone maintenance with a no-treatment control group. The trial in each country was carried out soon after the treatment became available there. This meant that the people in the no-treatment control group would not have had access to methadone maintenance so preventing the ethical problem that arises when people are denied treatment that has been shown to be effective.

Each trial used people who:

Were current opiate users

Had at least a 4 year history of opiate use

Had relapsed after at least one previous episode of rehabilitation.

The US study compared methadone maintenance with a no-treatment waiting list and found that at the end of a year the control patients were 97 times more likely to be using heroin daily than the treated group, and 53 times more likely to be in prison.



The Hong Kong study compared methadone maintenance with maintenance prescribing of a placebo medication, under double blind conditions. In this study the placebo group were started on methadone and then had their methadone gradually replaced by a placebo under double blind conditions. All patients received intensive counselling and support, but by the end of three years the placebo group were 63 times more likely to have been discharged from treatment because they had returned to heroin use.

The Swedish study compared methadone maintenance plus vocational rehabilitation with a no-treatment control and found that at the end of two years the treatment group were 38 times more likely to have stopped regular illicit drug use.

These three studies show that methadone maintenance is more effective than no treatment in reducing illicit drug use with its attendant health risks and criminal activity.

Treatment duration and change
In 1989 Hubbard et al carried out a national study of drug treatment effectiveness in the USA.32 They found that the longer people stay in treatment (beyond a minimum of 3 months) the better they do in the long term.

This may reflect self selection of the more motivated patients for longer treatments, or it may show that each treatment is effective and that the longer patients receive it, the more lasting the improvements they make.



Dose level and behaviour change
Nyswander and Dole's pioneering studies used large doses of at least 80mg of methadone daily to establish 'pharmacological blockade'. The theory being that if enough methadone is taken it blocks all of the opiate receptors so that taking heroin in addition would have no effect.

Subsequent implementation of methadone maintenance in the USA often used lower doses. Descriptive studies have repeatedly found larger doses to be associated with less heroin use and the US National Institute on Drug Abuse (NIDA) recommended 60mg of methadone as a minimum effective dose.30

British prescribing has typically used lower doses, with the rationale of giving just enough methadone to abolish withdrawal symptoms, without increasing the level of dependence, or causing other harm, such as accidental overdose or inadvertently feeding the illicit market.

Whether or not Nyswander and Dole's hypothesis about the protection of 'pharmacological blockade' is true in Britain is open to question. Street heroin in Britain has tended to be much purer than in the USA and it may, therefore, be more potent in overcoming any 'pharmacological blockade'.

In 1993 Strain and colleagues reported a double blind trial comparing the effects over 20 weeks of medication containing 0mg, 20mg, or 50mg methadone daily.30,31 The larger the dose the more people stayed in treatment and the more they reduced their heroin use. This shows that methadone dosage does have a real effect on outcome and raises the possibility that doses greater than 50mg would have achieved greater improvements.



Using treatment incentives to help reduce other drug use
A significant problem for methadone prescribing has been that some patients who stop using heroin continue to use non-prescribed drugs such as benzodiazepines and alcohol.

One method of reducing additional drug taking has been to systematically link incentives with reductions in illicit drug use and increased stability. Examples of incentives intrinsic to methadone treatment are the frequency of dispensing from a pharmacist (in the UK) or of 'take-home' doses (in the USA).

In one randomised treatment trial47 half the patients who took additional drugs were given take-home doses of methadone after achieving heroin-free urine samples: the other half received the same number of take-home doses, but on a random basis. Of those receiving the doses linked to improvements, a third improved: hardly any of the others did.

Reducing the use of drugs such as benzodiazepines may well improve peoples' mental state and allow them to make further improvements in functioning. The systematic use of incentives is a cheap, safe way of reducing additional drug use by patients on methadone.



Methadone maintenance programmes: descriptive studies
Studies have tried to examine the differences between programmes to identify whether some are more effective than others. Clearly some are more effective but these studies can suggest, but not prove, factors that may underlie the differences.

A landmark study by Ball and Ross48 looked in detail at 6 methadone programmes and carried out independent assessments of 633 male patients and repeated it on 507 of these patients a year later. They found an overall improvement in patients, but great differences between programmes. For example overall 71% of the patients had stopped injecting drugs but the rates for this in individual programmes varied from 43% to 90%.

Better outcomes came from programmes with better counselling services and an orientation toward maintenance and rehabilitation. Higher doses of methadone were associated with lower levels of heroin use.

These findings suggest, but cannot prove, that psychosocial treatment and methadone dosage are very important; they have been followed up by randomised trials, described above.



Counselling and psychosocial interventions and change
Programmes which offer more of such facilities tend to get better results. Nyswander and Dole's original treatments involved intensive rehabilitative efforts. A trial which compared three levels of psycho-social treatments coupled to methadone maintenance found that more intensive help and counselling led to better results.49 Just 'policing' methadone by urine testing and interviews was inadequate. Adding counselling virtually halved the numbers of urine samples that contained illicit opiates. Adding additional psychological and social services resulted in further reductions in illicit drug use as measured by urine screening, and also brought improvements in:

Alcohol use

Employment

Criminal activity

Mental health.

Since all patients received the same methadone programme, these differences are entirely due to the differences in psycho-social services. Compared with the patients in the counselling condition of this study, British patients maintained on methadone usually receive a rather low level of counselling and support.

Treatment programmes which accept that opiate dependence is a chronic condition, and that methadone treatment is required as long-term stabilisation, tend to produce greater change than those which see it as a short-term treatment leading to abstinence. Also counselling that is compulsory and not client centred is unlikely to be helpful and may even be counter productive.