4.1 Rationale for methadone maintenance therapy
4.2 Harm reduction and treatment goals
4.3 Effects of methadone on drug use, crime and social functioning
4.4 Effects on health
4.5 Treatment characteristics predictive of good outcome
4.6 Alternatives to methadone
4.1 Rationale for methadone maintenance therapyCurrently, the major form of opioid substitution therapy internationally involves orally administered methadone. Methadone hydrochloride is a synthetic opioid pain-killer. In New York in the 1960s, Dole and Nyswander [1, 2] examined the ability of different prescribed opioids to manage heroin dependence, and reported that they found that methadone was most suitable to the task. They believed that long-term heroin use caused a permanent metabolic deficiency in the central nervous system and an associated physiological disease, which required regular administration of opiates to correct the metabolic deficiency . They believed that maintenance/retention was a major goal of treatment, and used the analogy of diabetes mellitus to explain the need for ongoing, indefinite dosing. Methadone maintenance thereby became a treatment option for opiate dependence. It involves the daily substitution of one opioid drug with a long half-life (methadone), for a short-acting and usually injected opioid drug (heroin).
The aspects of methadone that have led to its use as a substitute drug for heroin include the following:
- At the basis of methadone maintenance treatment (MMT), and all opioid replacement therapy, is the observation that opioid analgesics can be substituted for one another. The cross-tolerance between methadone and heroin means that a person tolerant to heroin will also be tolerant to a dose-equivalent amount of methadone .
- Cross-suppression between heroin and methadone allows methadone to prevent or reverse withdrawal symptoms, and thus reduce the need for the person to use illegal heroin .
- Orally administered methadone remains effective for approximately 24 hours, requiring a single daily dose rather than the more frequent administration of three to four times daily which occurs with the shorter-acting heroin .
- Methadone accumulates in body tissues, being released as the blood concentration falls, apparently buffering serum levels and minimising withdrawal and sedative effects .
- Higher doses of methadone can "block" the euphoric effects of heroin, discouraging illicit use and thereby relieving the user of the need or desire to seek heroin . This allows the opportunity to engage in normative activities, and "rehabilitation" if necessary.
- Methadone is typically administered orally, reducing the health risks associated with injecting. It is quite a safe drug when administered in correct doses, and the side-effects are not significant , especially when compared to the adverse effects of continued illicit drug use.
Methadone maintenance treatment is differentiated from methadone-assisted detoxification, as maintenance implies long-term stabilised dosing of methadone. It is recognised that the long-term dosing may be for an indefinite period or for a substantial number of years with the view of eventual abstinence, although this is not a necessary goal. The differing conceptualisations of the use of methadone maintenance have differing underlying rationales for use. Where an abstinence goal is seen to be appropriate, conceptually the mechanism whereby methadone maintenance exerts its effects is that it allows the user to develop a life free of the need to seek opiates (allowing the development of a social network, employment, etc.), at which time methadone can be reduced and eventually ceased. Where long-term maintenance is the goal, methadone is considered by some to act to correct a permanent underlying pathology, in much the same fashion that insulin is used in the case of diabetes mellitus.
Top of page
4.2 Harm reduction and treatment goalsThe use of methadone as a maintenance agent has been affected by the adoption of harm reduction as an appropriate goal for treatments of drug dependence by the National Drug Strategy (NDS). The adoption of harm reduction as a goal has also had an effect on the goals of methadone maintenance treatment. This has been reinforced by the advent of epidemic human immunodeficiency virus (HIV) infection rates among injecting drug users in some parts of the world . Accordingly, the national methadone policy has incorporated harm reduction as a major goal of methadone maintenance. More recently, the recognition of the high prevalence of other infectious diseases such as hepatitis B and hepatitis C has come to be seen as an important issue in the care of injecting drug users.
It is clear that there are a number of goals that treatment might attempt to achieve (sometimes to differing degrees) depending upon a number of factors including the type of intervention involved and the perspective on drug use (whether the user, the clinician, the community or the health bureaucrat). Listed below are the major goals of treatment/intervention for opiate dependence.
4.2.1 Reduced drug useThe promotion of life-long abstinence from illicit drugs has traditionally been regarded as the principal aim of treatment for persons with illicit drug-related problems, with a concomitant reduction in level of drug dependence. There has been a recent tendency in the prevention and treatment of alcohol-related problems to accept more limited and realistic goals of treatment such as limiting consumption below agreed levels or reducing the degree of risk of certain patterns of illicit drug consumption by aiming to change only the mode of administration. To date, the status of these more limited goals remains controversial within the alcohol field. However, the achievement of more limited objectives may be tolerated in the context of persons with serious drug problems provided that other treatment goals have been met satisfactorily.
Sometimes the goal of total abstinence from all opioid drugs will be unattainable, as in the case of those on long-term methadone maintenance, where the use of methadone is criticised and where a small proportion of users who enter the treatment will continue to use illicit drugs occasionally. Even for those in drug-free treatment it is likely that there will be continued drug use among some of these individuals, albeit at a reduced rate. The choice of goal must be realistic in terms of what is achievable with the opioid dependent.
4.2.2 Reduced risk of human immunodeficiency virus (HIV)Because of the danger of HIV spreading widely in the injecting drug using community, the reduction (or elimination) of needle sharing associated with the injection of opiates and other illicit drugs (as well as unsafe sexual practices) is an additional goal of illicit drug treatment which has only been accepted relatively recently. An associated objective is the reduction of vertical transmission among HIV infected injecting drug users. HIV risk reduction as a treatment objective often explicitly emphasises public health benefits although not at the cost of a beneficial outcome for the individuals involved. Clearly the reduction of the spread of HIV is important to all sectors of the community. A hierarchy of HIV risk reduction objectives has been accepted. Variations on this hierarchy exist, but essentially the hierarchy is as follows (from least to most desired):
- sharing injection equipment but injecting less frequently;
- sharing injection equipment but decontaminating (sterilising) it effectively;
- using only clean needles and syringes for injection;
- administering drugs by means other than injection; and
4.2.3 Improved physical healthPhysical health of drug users often improves following commencement of drug treatment but the measurement of changes in physical health is difficult. Most scales available for measuring physical health are designed for severely disabled clients and do not apply well to this population, although there is a scale recently developed in Australia for the estimation of the health status of opioid users . Illicit drug users more frequently have infectious diseases including respiratory illness, skin disease, sexually transmitted diseases, and chronic liver disease, hepatitis B, C and D, HIV, infective endocarditis, osteomyelitis, and septicaemia. A reduction in the transmission of viral infections closely associated with injecting drug use, such as hepatitis B, C, D, or HIV, is clearly of benefit to individuals as well as the broader society. Additionally, associated with drug use are problems such as poor nutrition, dental caries, menstrual irregularities, complications of injection as a mode of administration, and accidents occurring while intoxicated. Specific conditions include pulmonary emboli, cellulitis, thrombophlebitis, and nephrotic syndrome .
Top of page
4.2.4 Improved psychological healthThere is a range of psychological problems ranging into serious psychiatric disorders that are likely to occur in those who are entering treatment for opiate dependence. Disturbances of mood and personality disorders are said to be extremely common in injecting drug users. Although psychiatric morbidity is common in injecting drug users receiving drug treatment, the extent to which psychiatric problems are a cause or a consequence of illicit drug use remains unclear. Whether cause or consequence, these states must be detected via routine screening of those in treatment. Treatment should reduce these problems and promote psychological good health or at least leave the individual no worse off than before in terms of subjective well-being. There is evidence that for the more severe psychiatric disorders such as serious anxiety disorders, depressive disorders, and psychotic disorders, it is necessary to use well-researched psychiatric interventions.
4.2.5 Reduced criminal behaviourAlthough some regard a reduction in criminal behaviour among injecting drug users as an inappropriate goal for drug treatment, arguing that this constitutes "social control", there can be little doubt that injecting drug users who are incarcerated as a result of criminal activity can suffer negative consequences which are associated with imprisonment. Therefore, it is quite legitimate to include a reduction in criminal behaviour as an important goal of drug treatment. The relationship between drug use and crime is complex. Although reduced drug use is likely to be accompanied by reduced criminal behaviour, this is not necessarily the case.
4.2.6 Improved social adjustment and functioningA return to gainful employment, part- or full-time study, successful parenting, improved relationships with spouse, parents, family and friends, and increased residential stability are all desirable goals for treatment. With improved social functioning, clients should also become more financially independent and, ultimately, detached from the criminal drug-using milieu. The extent to which drug treatment may improve the quality of parenting is an important but relatively neglected field of research.
4.3 Effects of methadone on drug use, crime and social functioning
4.3.1 Randomised controlled researchMethadone maintenance treatment is without competitor as the best researched of all of the treatments for opioid dependence [12-16]. It is the only treatment for opioid dependence which has been clearly demonstrated to reduce illicit opiate use more than either no-treatment [17, 18], drug-free treatment , placebo medication [20, 21, 22], and detoxification  in randomised controlled trials. These trials have been conducted by different research groups in markedly differing cultural settings, yet have converged to provide similar results, suggesting a robust effect.
4.3.2 Observational studiesThe evidence from other forms of research on the effects of methadone maintenance treatment, such as quasi-experimental and large-scale cohort studies, supports the results of the randomised controlled clinical trials [15, 16].
There are three major single group observational studies of MMT effectiveness which involved monitoring client progress, but which included no comparison group [24, 25, 26]. They have all shown benefits accruing from MMT, and the convergence of the data from randomised research, quasi-experimental comparative studies and these large scale single group studies provides a level of confidence that MMT possesses robust and replicable beneficial effects.
4.4 Effects on healthInjecting drug use is associated with a high risk of premature death [29-33]. Deaths from overdosage of methadone have occurred and these are reviewed below. Although precise estimates of the contribution of drug use to mortality are difficult to provide , the major causes of premature morbidity and mortality include accidental overdosage, and infectious disease.
Top of page
4.4.1 Effects on drug-related death ratesCompared to untreated opioid users, those in MMT have a much reduced risk of dying.
- Gearing and Schweitzer , in a study of 17,500 clients in the New York methadone program from 1964-1971, found that the mortality rate for methadone maintained clients (7.6 deaths per 1000) was not significantly different from the general population for their age group (6.6 deaths per 1000), and was lower than therates observed among both methadone clients who had left treatment (28.2 deaths per 1000) and heroin users requesting detoxification (82.5 deaths per 1000). The deaths that occurred among those in MMT were less likely to be associated with continued drug use than those which occurred among those who had left MMT or requested detoxification.
- Swedish researchers  followed a cohort of 368 heroin-dependent individuals, and assessed mortality over five to eight years. The yearly death rates showed:
- for those enrolled in methadone maintenance treatment, 1.40% died, a rate 8.4 times the population-based expectation
- for those "successful" graduates from methadone maintenance treatment, 1.65% died
- for those involuntarily discharged from methadone maintenance treatment, 6.91% died, 55.3 times greater than the population-based expectation and
- for those who were provided "intermittent detoxification and participated in drug-free treatment", 7.20% died annually, 63.1 times greater the population-based expectation.
- More recently, Italian research has confirmed the protective effect of MMT. In a case-control study of overdose deaths, Davoli and colleagues  found that among a cohort of 4200 clients in MMT in Rome from 1980 to 1988, those who left MMT were 8 times more likely to die of overdose in the first 12 months after they left compared to those who remained in MMT (odds ratio = 7.98, 95% confidence interval = 3.40-18.73). The effect continued; after a year those who had left MMT were twice as likely to die of an overdose than those who remained (odds ratio = 2.54, 95% confidence interval = 1.25-5.15).
- Australian research has examined the outcome of 307 heroin addicts and confirmed that their relative risk of dying in MMT was one-third that when not in MMT (odds ratio = 0.35, 95% confidence interval = 0.18-0.69) .
4.4.2 Effects on infectious disease risk behavioursAs noted above, MMT produces a decrease in injecting drug use and thereby reduces the risk of spreading infectious disease (human immunodeficiency virus, hepatitis B virus, hepatitis C virus). There is also increasing evidence showing that there is an association between being in MMT and lower rates of sharing of injecting equipment, compared to those opioid dependent individuals not in MMT [25, 27, 28]. For example, Ball and Ross  showed that injecting drug use and sharing of injecting equipment were significantly reduced after commencement of MMT. Longshore  reported that MMT reduced the likelihood of sharing significantly (odds ratio = 0.43).
Top of page
4.4.3 Effects on rates of infectious diseaseWhile it has been usual for drug abuse treatments to be evaluated in terms of their ability to reduce illicit drug use, reduce criminal behaviour, and improve psychosocial functioning, the advent of the human immunodeficiency virus (HIV) has broadened the focus. It is now commonplace to assess drug dependence treatments in terms of their ability to prevent or interrupt this epidemic. In addition, the high prevalence of hepatitis B virus (HBV) and the hepatitis C virus (HCV) has been noted  among injecting drug users. Unfortunately, the effect of MMT on these diseases has been poorly documented to date, so by necessity the following section focuses on HIV.
The available evidence suggests that being in methadone maintenance treatment is associated with lower rates of HIV infection and risk behaviours associated with injecting (sharing used injecting equipment) compared with not being in methadone maintenance [25, 38-42]. The results of the research are consistent across setting and research groups. In New York, clients entering methadone maintenance treatment prior to 1982, were subsequently found to be less likely to be HIV positive than those who entered treatment after that year . Also in New York, there has been an inverse relationship observed between months in MMT and HIV seropositivity . Clients in MMT were less likely to be HIV positive that those in detoxification treatment , and those not yet receiving MMT . Most recently, U.S. research has further confirmed the beneficial protective effects of methadone maintenance treatment on HIV infection rates .
According to Ward and his colleagues [15, 46], this evidence, in combination with the existing evidence for the effectiveness of methadone maintenance in reducing injecting opiate use, leads to the conclusion that methadone maintenance is an important component of any overall strategy to contain the spread of HIV among injecting drug users, a view that is supported by other influential reviewers of the extant evidence [9, 47].
4.5 Treatment characteristics predictive of good outcome
4.5.1 Methadone doseProbably the single most influential determinant of outcome in MMT is the adequacy of the dose level, with doses in the range 50-120 mgs resulting in better retention and less illicit opioid use than those in the lower range of 20-40 mgs [21, 22, 25, 48-53]. The original model developed by Dole and Nyswander [1, 6] used doses of 50-150 mgs sufficient to block both the withdrawal symptoms and the euphoria from continued illicit use (and doses were often above 80 mgs per day). These doses appear sufficient. There is absolutely no evidence to support the use of extremely high doses (>1000 mgs) mentioned by some practitioners .
Doses in the U.S.A. and Australia were lowered after some researchers and clinicians advocated low dose MMT (range 30-40 mgs) [55, 56]. Research on doses lower than 50 mgs produced equivocal results, despite the enthusiastic conclusions of some authors that these low doses were adequate for most clients [57, 58]. A careful reading of the research involved reveals that the higher doses are associated with a better outcome . Additionally, recent research clearly shows the inferiority of low-dose methadone maintenance, compared to moderate doses in terms of heroin use and retention in treatment [21, 22, 25, 50, 59, 60]. It seems counter-therapeutic that dose level should be kept low, when it is the single best predictor of continued opiate use; the lower the dose the more likely continued unsanctioned opioid use will occur. Doses should be tailored, and arbitrary rules about low (or high) doses removed. Client control of dose seems unproblematic [61, 62, 63].
Top of page
4.5.2 Methadone formulation and distributionThere is little comparative research on the formulation of methadone. Some agencies use tablets, others hypertonic syrup, and some mix methadone in orange juice. Diversion is a risk with syrup and tablets, and these preparations can be injected, and there has long been evidence that diversion does occur .
Methadone can be diverted for several reasons. It can be sold illicitly to supplement illicit opiate users' supplies of heroin, to function as a primary drug of dependence, or to supplement the doses of methadone maintenance clients whose prescribed dose is insufficient. In the latter case diverted methadone would appear to be dealing with an unmet demand. Of course, diversion which functions to meet a legitimate (albeit illicit) demand is an argument for ensuring that prescribed doses are adequate to meet clients' needs, and that methadone maintenance treatment is readily available, so that additional opioids are not required to stave off withdrawal symptoms. Research from the United States  with 145 subjects who admitted using illegal methadone indicated that diverted methadone was primarily used to "kick a heroin habit", to "reduce a heroin habit" or "to avoid withdrawal" in the majority of cases. Methadone was also used when "other narcotics were unavailable", and because it was cheap and easily procured. The extent to which methadone is diverted elsewhere is unclear, as are the reasons for whatever diversion that occurs. However, there is no evidence to suggest that it is a major problem, and it is possible that the uses of any methadone that is diverted are similar to those reported by Inciardi (1977) for his sample.
Methods that may reduce the problems of diversion, while normalising clients' lives, include the use of long-acting opioids such as LAAM or buprenorphine, or the use of pharmacy outlet dosing. For unstable clients or where diversion is suspected daily clinic or doctor supervised clinic may be helpful. Research is sparse on these issues.
4.5.3 Treatment durationThe next most influential determinant factor in MMT is the duration of treatment, which is partly related to ensuring the adequacy of daily dose levels. A number of studies have provided evidence that longer retention in MMT is associated with higher doses [21, 22, 25, 50]. Research studies converge to show that retention in treatment is an important goal and result of successful MMT, and that premature termination of MMT is associated with a return to drug use [24, 65, 66]. There is some relevant research on the effects of the sudden termination of methadone treatment from natural experiments [66, 67]. The research has shown that the ongoing benefits of terminated methadone maintenance treatment are not impressive (reinforcing the maintenance aspect of treatment), as there appears to be a high relapse rate to illicit opioid use.
The notion of "curing" the addiction after some arbitrary period of time for the majority of dependent persons is not supported by research. However, a small proportion of opioid dependent clients will leave methadone treatment successfully, and remain opioid free. They do so at their own behest, usually with the approval and sanction of clinical staff, and have the option of returning to maintenance dosing, if necessary. These successful "graduates" from methadone maintenance programs do appear to achieve a satisfactory outcome. It is thought that the rate of successful graduation is about the same as successfully ceasing illicit opioid use [68, 69]. A useful analogy here is that of schizophrenia, wherein maintenance anti-psychotic neuroleptic medication is associated with reduction in florid psychotic symptoms, and the cessation of medication results in prompt relapse.
The results of other research are consistent, with the bulk of studies from diverse research groups showing that length of time spent in MMT is a good predictor of outcome; the longer the time spent in MMT the better the result in terms of reduced illicit drug use and psychosocial adjustment [70-78]. The benefit from longer periods in methadone does not appear to be a statistical artifact of poor performing clients dropping out, and "good" clients continuing treatment .
The minimum length of time that is required to reap benefits from being in methadone treatment has been less well studied. It does appear that clients can benefit from the first day of dosing, as there is an immediate drug effect from methadone and therefore heroin does not need to be sought. There is a clinical "stabilisation" period of some three month duration during which marked changes can be observed. However, the research suggests that two to three years of methadone treatment is necessary before maximal behaviour change is observed.
Top of page
4.5.4 The role of ancillary servicesThe early studies of MMT incorporated extensive ancillary services in MMT (drug counselling, psychiatric care, medical care, vocational rehabilitation, regular urine screens, etc.) [17, 19, 20]. Since then, a number of correlational studies have suggested a better result is achieved from methadone maintenance treatment if ancillary services are provided [25, 79-83].
It is noteworthy that these studies have found a benefit from ancillary services in a country where social security, social welfare, medical and psychiatric services are not easily available to the target group. It remains unclear whether the results can be generalised to other countries where universal health care exists and where social services are more easily available. A second problem with the research on ancillary services, is that it suggests that involvement in ancillary services brings about a better outcome, but this effect cannot be easily disentangled from the motivational factors associated with clients who wish to do well. It may be that the apparent benefits have more to do with client motivation than with a direct effect of additional services.
The randomised research on the impact of ancillary services has been equivocal, with only one randomised controlled trial showing a benefit from enhanced ancillary services in methadone treatment . The role of ancillary services, especially counselling, in MMT has become a focus of attention in recent research in the U.S.A., but the bulk of randomised research shows little benefit from enhanced psychosocial services .
Nonetheless, it is clear that there are a number of problems associated with drug misuse, and that ancillary services should be available to misusers to address these specific problems. It is also apparent that the drug misuser is often poorly dealt with by many sectors of the health/welfare system wherein the personal views of professionals enter into the encounter. We know, for example, that there is a very high rate of physical morbidity associated with illicit drug use , and medical services need to be freely available. Psychiatric morbidity is prevalent [83, 85-89], especially the affective and anxiety disorders, and these appear to negatively impact on outcome [83, 90, 91, 92], although some studies have failed to find any relationship . Psychiatric treatment should be available to address these comorbid states for affected clients who wish to receive assistance. Many drug misusers will need assistance with social welfare and housing, and this should be provided either within treatment or via referral to appropriate agencies.
There is a view that urine analyses are a relevant ancillary service, and that regular random screens assist in reducing illicit drug use. Reviewers in the area could find no evidence that regular urine screens were effective in reducing illicit drug use . The costs of the procedure must be weighed up against the potential benefits, especially in a harm-reduction environment.
4.5.5 The role of aftercareRelated to ancillary services is aftercare. Although the literature is not extensive, there is reasonable evidence that additional support and aftercare at the cessation of methadone maintenance treatment enhances post-treatment success rates. In randomised controlled research, comparisons have been conducted of "structured aftercare" against "assistance on request" for persons who were opiate dependent and had been treated in methadone maintenance programs, therapeutic communities, and detoxification programs [93, 94]. The aftercare program used was a combination of relapse prevention procedures and self-help. The study found that, compared to the assistance on request, the structured approach significantly reduced the risk of relapse, decreased self-reported crime, and assisted unemployed persons to find employment. Similar results are reported for alcohol dependent clients . The research suggests that structured aftercare is an important component of treatment.
4.6 Alternatives to methadoneIt is important to recognise that there are a number of alternatives to methadone as a substitute for heroin. Most research has focussed on long-acting opioids. Two in particular are considered here: buprenorphine and LAAM. Both of these medications are being extensively assessed in the U.S.A. and will be presented for approval for use in the near future .
Top of page
4.6.1 BuprenorphineOf special additional interest as a maintenance opioid drug is the opiate agonist-antagonist buprenorphine (Temgesic ®), which is a potent opioid analgesic which also has the action of blocking opioid receptor sites. This mixed action appears to make buprenorphine safer in overdose, less likely to be diverted, and may offer an easier withdrawal phase. It was the subject of some research in the past. Much recent research has occurred, and applications for approval for use of the drug in the U.S.A.  and in European countries are in train. It is apparent that the drug is as effective as methadone as a maintenance agent [59, 97-106].
4.6.2 Levomethadyl acetate (LAAM)LAAM (levomethadyl acetate) is a synthetic opioid analgesic which has been investigated as a pharmacological alternative to methadone [107-110]. Its major advantage is that it has a half-life of 92 hours compared with the 24-36 hour half-life of methadone. It is being considered for use in the U.S.A. It has been shown to be as effective as methadone in a number of trials [107-110].
Early research compared LAAM, methadone and a wait-list control group  and found LAAM to be as effective as methadone. In a large, multi-site double blind, randomised controlled trial, LAAM (80 mgs thrice weekly) was as effective as daily high-dose (100 mgs) methadone, and both were more effective than low dose methadone (50 mgs) administered daily . Freedman and Czertko  compared low-dose daily methadone (mean = 26 mgs) with a thrice weekly low-dose LAAM (mean = 24 mgs), and found that the LAAM subjects used illicit drugs less and had better retention in treatment than the daily methadone subjects. Others  report LAAM is as effective as methadone and that both were safe treatment procedures.
Top of page