DISEASE MANAGEMENT eNS Drugs 1996 Dec; 6 (6): 440-449 1172-7047/96/0012-0440/S05.oo/0

@Ads International Limited. All rights reserved

Methadone Maintenance Therapy for Opioid Dependence A Guide to Appropriate Use

Jeff Ward, James Bell, Richard P. Mattick and Wayne Hall

National Drug and Alcohol Research Centre, University of New South Wales, Sydney, New South Wales, Australia

Contents Summary , , , , , , , , , , , , , , , 1, Opioid Dependence and Opioid Replacement Therapy 2, Pharmacology of Methadone

2,1 Individual Variation , , , , , , , , , , , , , , , 2.2 Drug Interactions

3, Assessment for Methadone Maintenance Therapy 3,1 Assessing Suitability: Opioid Dependence, , , 3,2 Assessing Functioning and Life Circumstances 3,3 Establishing and Defining a Therapeutic Relationship

4, Commencing Methadone Maintenance Therapy 5, Maintenance Dosage , 6, Patient Management , , , ,

6,1 Illicit Drug Use 6,2 Take-Home Medication

7, Ancillary Services, 7,1 Counselling '" 7,2 Medical Care 7,3 Psychiatric Care

8, Duration and Goal of Treatment, 9, Long Term Prospects , , , , ,

9,1 Withdrawal Regimens , , , , 9,2 Medical Maintenance , , , ,

10, Adverse Effects Associated With Methadone Maintenance Therapy 11 ,Conclusions " """""""",

440 441 441 442 442 443 443 443 444 444 444 445 445 445 445 446 446 446 446 446 447 447 447 448

Summary Opioid dependence is a chronic, relapsing condition that is associated with significant morbidity and mortality. Methadone maintenance therapy involves the provision of a controlled supply of an orally administered opioid, thereby stabilising the opioid-dependent patient. Research studies have shown that methadone maintenance reduces illicit opioid use, opioid-related crime, prema­ture mortality and the risk of HIV infection. It is most effective when prescribed at an adequate dosage (usually 60 to 100 mg/day) and when long term mainte­nance on methadone is the goal of treatment rather than detoxification from all drugs including methadone. Successful long term methadone maintenance is

Methadone Maintenance Therapy 441

more likely when it takes place within the context of a well established therapeutic relationship and when the medical, social and psychological needs of patients are met either through direct assistance or referral.

1. Opioid Dependence and Opioid Replacement Therapy

Opioid dependence is a chronic, relapsing syn­drome that has become a characteristic feature of contemporary life in many urban centres around the world. This condition was originally described in people taking medicinal opioids. However, over the past 3 decades, with the advent of dramatically increased supplies of illicit heroin (diamorphine) being distributed and marketed throughout the world, there has been a concomitant increase in the prevalence of this condition among the young, alienated and disadvantaged.l l,21 The failure of criminal sanctions, detoxification and psychother­apy to address this growing problem led to the ac­ceptance of medically supervised opioid substitu­tion programmes. While various opioids have been used for this purpose (e.g. opium, heroin and mor­phine), recently, the most widely accepted regimen has been oral methadone maintenance therapy. This approach was developed initially by Dole and Nyswanderl31 in New York City, US, in the early 1960s.

Providing oral methadone breaks the cycle of income-generating crime, drug seeking and drug use. Methadone is prescribed and dispensed under a range of circumstances. Medical practitioner in­volvement encompasses a number of specialties and may include psychiatrists, general practition­ers, infectious disease specialists responsible for the management of patients who are HIV positive, as well as practitioners who specialise in the treat­ment of addictions. Depending on local regulations and clinical judgment, the patient may attend daily to ingest their methadone or their medication may be dispensed in bottled dosages for consumption at home.

Methadone maintenance treatment has been shown to be effective in a small number of randomised controlled trials and a larger number of

© Adis International Limited. All rights reserved.

observational studies.14-14J These studies have con­sistently shown that methadone treatment leads to substantial reductions in heroin use, premature mortality and drug-related crime. More recent large scale prospective studies have also found that methadone maintenance reduces injection-related risk behaviours associated with HIV infec­tion.l 15,161 It has yet to be demonstrated whether this protective effect extends to hepatitis Band C. Hepatitis C, in particular, appears to be spread more readily than HIV among injecting drug users, which means that most people who present for treatment have already been exposed to the virus.[ 171

2. Pharmacology of Methadone

Methadone is a synthetic opioid receptor ago­nist that has effects in humans that are similar to those observed with morphineJl8] It differs from morphine in that it: (i) has a high level of bioavail­ability when ingested orally (80 to 90% compared with 40%); (ii) is extensively bound to blood pro­teins once absorbed; (iii) is stored in a biological reservoir of body tissue after repeated administra­tion; and (iv) has a long elimination half-life (24 to 36 hours) once steady-state is achieved (usually af­ter 4 to 6 days).

This profile makes methadone an ideal mainte­nance drug for the management of opioid depend­ence. 119,20] The oral route of administration avoids the risks associated with injection, its long half-life allows for a single daily administration schedule, and its accumulation in body tissue means that steady-state plasma concentrations are achieved after repeated administration. Furthermore, meth­adone has no serious long term adverse effects as­sociated with long term administrationf21J and, when administered orally during maintenance therapy, it does not produce the pronounced 'nar­cotic' effects seen with shorter acting opioids such as heroin.120]

eNS Drugs 1996 Dec; 6 (6)

442

2.1 Individual Variation

One of the most notable features of the disposi­tion of methadone in human beings is the marked interindividual variability that has been found in studies of methadone-maintained individuals. Oral bioavailability has been reported to vary from 41 to 99%, half-lives have been reported ranging from 4 to 91 hours, and the rate of clearance from the body has been reported to vary by a factor of almost 100 [from 1.38 to 126 Llh (23 to 2100 mll min)].[22,23] Clinically, these findings suggest that what constitutes an adequate dosage of methadone varies markedly between individuals (see section 5 for a full discussion of dosage),

2.2 Drug Interactions

Interactions with methadone have been reported with a number of drug classes.[22,24,25]

2.2. 1 Enhancers and Inhibitors of HepatiC Enzymes Drugs known to enhance hepatic metabolism

[e.g. phenytoin, rifampicin (rifampin), phenobarbi­tal (phenobarbitone), carbamazepine, etc.] have been reported to reduce plasma methadone con­centrations and provoke a withdrawal syndrome in some patients who are stabilised on methadone. Patients receiving these drugs may require higher than usual or split dosages of methadone to achieve a stable pharmacological profile.

Drugs known to inhibit hepatic metabolism (e.g. cimetidine) may lead to the onset of the opioid withdrawal syndrome when they are discontinued or to methadone toxicity when commenced in methadone-maintenance patients. Such patients may require an increase in methadone dosage on cessation of the enzyme-inhibiting therapy, or a re­duction of their methadone dosage if they show signs of toxicity after commencing such therapy.

2.2.2 eNS Depressants CNS depressants [e.g. benzodiazepines, alcohol

(ethanol), etc.] are often abused by opioid-dependent individuals and may lead to additive CNS depres­sion when administered or ingested with meth ad­one or other opioids. Patients need to be advised of the risk of overdose in such circumstances and CNS

© Adis International Limited. All rights reserved.

Ward et al.

depressants should be prescribed with care during methadone maintenance therapy.

2.2.3 Urinary pH Modifiers Urine acidifiers lead to an increased elimination

of methadone from the body, while urine alkalisers slow this process down. An appropriate dosage ad­justment in such situations may be necessary if pH modification is to continueP61

2.2.4 Antidepressants

Serious interactions have been reported be­tween monoamine oxidase inhibitors and pethidine (meperidine) and may occur with methadone, al­though the probability in the case of methadone is estimated to be very low. [27 I

Serum concentrations of desipramine have been found to be elevated in some patients concurrently maintained on methadone, suggesting that care should be taken to avoid desipramine toxicity in patients undergoing methadone maintenance ther­apyJ28]

Fluvoxamine, a selective serotonin (5-hydroxy­tryptamine; 5-HT) reuptake inhibitor, has recently been reported to be associated with higher than ex­pected blood concentrations of methadone and withdrawal symptoms when discontinued,l29]

2.2.5 Zidovudine Interactions between methadone and zidovud­

ine have been the subject of contradictory case re­ports. While one report suggested that zidovudine enhances the elimination of methadone, [30] another reported that the administration of methadone leads to increased blood concentrations of zido­vudine.l31 ]

2.2.6 Opioid Receptor Antagonists and Partial Agonists

Opioid receptor antagonists and partial ago­nists, such as naloxone and pentazocine, produce a severe opioid withdrawal syndrome in individuals being maintained on methadone. The treatment of choice for acute severe pain in methadone-mainte­nance patients is additional agonist therapy such as morphine or pethidine (meperidine).

eNS Drugs 1996 Dec; 6 (6)

Methadone Maintenance Therapy

3. Assessment for Methadone Maintenance Therapy

Assessing applicants for methadone mainte­nance therapy involves assessing the patient's suitability for therapy and their level of function­ing and life circumstances, and establishing and defining a therapeutic relationship. An additional task is to obtain informed consent for the com­mencement of treatment.

3.1 Assessing Suitability: Opioid Dependence

Methadone maintenance therapy is suitable for individuals who are opioid-dependent, or who have been opioid-dependent and are at risk of re­lapsing (e.g. just released from prison). A proper assessment of opioid dependence is essential to avoid the induction of an iatrogenic methadone de­pendence. Generally, opioid dependence is charac­terised by 3 or more of the criteria summarised in table V321 These must have occurred together for at least 1 month, or, if for less than 1 month, have occurred repeatedly together over the past 12 months.

The key components of the dependence syn­drome can be assessed by taking a careful history that documents the extent and duration of opioid use and the extent to which it has influenced the patient's life.l l •51 This can be confirmed by corrob­orative evidence such as: (i) the patient's history of treatments for their opioid problem; (ii) arrests for drug offences; (iii) medical complications of op­ioid use, such as overdosing; and (iv) exposure to injection-related infections (e.g. hepatitis Band C and HIV).

A physical examination should also be carried out for evidence of opioid use, such as recent puncture marks from injecting, and signs of opioid intoxication (e.g. miosis, scratching, 'nodding' / somnolence) or withdrawal (e.g. piloerection, pro­fuse sweating, rhinorrhoea, lacrimation).

© Adis International Umited. All rights reserved.

443

Table I. Criteria for the diagnosis of opioid dependencel321

A strong compulsion to use opioids

Impaired control in the use of opioids, as characterised by taking opioids in larger amounts and for longer than intended, or being unable to stop or control their use

The onset of the opioid withdrawal syndrome when use is reduced or discontinued

Evidence of tolerance to opioids, as indicated by the need to take increasing amounts to achieve the desired effect

Being preoccupied with acquiring and using opioids to the detriment of other interests and life activities of importance to the individual

Persisting with the use of opioids in the face of negative consequences

3,2 Assessing Functioning and Life Circumstances

Opioid dependence is often associated with pro­found effects on all aspects of the lives of affected individuals. Thus, as well as establishing suitabil­ity by determining the presence and severity of op­ioid dependence, it is helpful to comprehensively assess each patient's psychological and social functioning, and their current life circumstances. This activity does not cease at assessment and can be incorporated into periodic reviews of the pa­tient's progress.

It is useful to use a semi-structured approach to assessing and reviewing patients. Important areas for particular attention are: • the nature and extent of non-opioid drug use,

including alcohol • risk and status of exposure to HIV and hepatitis

B andC • history of criminal involvement and imprison-

ment • general physical health • mental health • living circumstances and state of current per­

sonal relationships. Where possible, the prescribing medical practi­

tioner or health facility should meet the patient's needs. Alternatively, they can be met through re­ferral (e.g. psychiatric problems) and/or advocacy (e.g. seeking adequate housing).

eNS Drugs 1996 Dec; 6 (6)

444

3.3 Establishing and Defining a Therapeutic Relationship

The initial assessment interview is important in establishing and defining a therapeutic relationship with the patient, but certain difficulties may need to be surmounted for a therapeutic alliance to be established. I II The prospective patient is often in a state of crisis. During the assessment interview they feel vulnerable and are preoccupied with whether and when they will receive methadone. This focus on access to opioids is to be expected because it is a characteristic feature of opioid de­pendence. A prompt confirmation of opioid de­pendence to establish eligibility for methadone en­ables other issues to be dealt with. In some areas, it is better to wait until trust develops, rather than to try to elicit sensitive information while the pa­tient is anxious to appear compliant. The assess­ment interview is not a time for getting to know people well, it is a time for initiating contact and setting the ground rules for future interactions.

4. Commencing Methadone Maintenance Therapy

The initial goal in commencing methadone maintenance therapy is to reliev~, or prevent, with­drawal symptoms and to safely achieve an ade­quate maintenance dosage as quickly as possible. The initial dose of oral methadone should be in the range of 20 to 40mgJI,33] The actual dose adminis­tered should be based on an assessment of the quantity, frequency and route of administration of heroin that the patient has been using. For patients who are currently physically dependent on opioids, a dose in the range of 30 to 40mg should be chosen. For patients who have a history of dependence but who have not recently used opioids, 20mg should be sufficient. In patients in whom severe physical dependence is suspected, a further dose of 10 to 20mg may be administered, if withdrawal signs are still present 4 to 6 hours after administration (when peak plasma methadone concentrations should be achieved).

([) Adis International Limited. All rights reserved.

Ward et al.

While it is likely to vary from individual to in­dividual, a toxic dose of methadone for a non-tol­erant adult is in the vicinity of 40 to 60mg)18] Doses in this range have resulted in fatalities in minimally tolerant individuals within a few days of commencing methadone maintenance therapy.134]

Peak plasma concentrations gradually increase during the first week of treatment with methadone. This may mean that some patients may not experi­ence the full benefit of therapy until 3 to 4 days after commencing medication. Unless there are clear signs of withdrawal, the dosage may be raised at weekly intervals by I Omg increments until a sat­isfactory maintenance dosage is achieved, which is usually in the 60 to 100 mg/day range.

5. Maintenance Dosage

There is abundant research evidence to support the use of comparatively high maintenance dosages of methadone, in the range of 60 to 100 mg/ day.14,5,33] Dosages in this range are associated with less heroin use and less attrition from treatment than lower dosages.

In the past, there has been a tendency to under­dose patients receiving methadone maintenance therapy in the belief that they only require suffi­cient methadone to prevent the onset of withdrawal symptoms, and that it will be easier to withdraw methadone if lower dosages are used. Both of these beliefs are contradicted by research evidence. 14,S,33] The wide variability that has been observed in half­life and clearance rates of methadone between in­dividuals (see section 2.1) suggests that there will be a similar variability in optimal dosage. While most patients can be successfully maintained on dosages in the 60 to 100 mg/day range, some may require higher (i.e. >100 mg/day) or lower (e.g. 30 to 40 mg/day) dosages of methadone. 13S]

Many patients remain ambivalent about being in methadone maintenance therapy and worry about adverse effects and the extent of their de­pendence on methadone. Such patients tend to re­main on less than adequate dosages of methadone and continue to use heroin. Other patients enter treatment to control rather than eliminate their use

eNS Drugs 1996 Dec: 6 (6)

Methadone Maintenance Therapy

of heroin, and wish to stay on lower dosages so that they can continue to use heroin with some econ­omy by keeping their opioid tolerance to a rela­tively low level. The challenge with the former pa­tients is to encourage and support their desire to stop using heroin, and with the latter, to assess whether there is benefit in assisting them to control their heroin use. Many patients in the latter cate­gory significantly reduce their heroin use and ben­efit substantially from their contact with healthcare professionals.

6. Patient Management

Patients in methadone maintenance therapy should be managed according to the same princi­ples of good patient care found in other areas of medicine. Their use of methadone and their re­sponse to treatment need to be monitored. Two areas of particular importance are illicit drug use and the dispensing of take-home methadone dos­ages.

6.1 Illicit Drug Use

Patients in methadone maintenance therapy often use drugs other than opioids (e.g. alcohol, benzodiazepines, amphetamines, cocaine). Pa­tients with alcohol-use problems can be offered the same treatment as those alcohol-dependent pa­tients who are not also opioid-dependent, and those dependent on benzodiazepines can be detoxified as outpatients. However, on the whole, it has to be acknowledged that non-opioid drug use is difficult to respond to because there are as yet no known specific effective interventions. Punitive approaches that attempt to control patients with rules and threats are especially ineffective and should be avoidedp6]

The traditional method for monitoring drug use in methadone clinics has been the testing of urine samples for the presence of illicit drugs and their metabolites. Compliance with methadone inges­tion is also commonly assessed by this method. However, the presence of urine surveillance does not, by itself, lead to reductions in illicit drug use.l5]

Urine testing is costly and in many situations, such

© Adis International limited, All rights reserved,

445

as a general practitioner's surgery, may be imprac­tical. Moreover, in a situation where patients are accepted from the outset as people who use drugs and where they feel they can talk readily with staff about their drug problems, urine testing may be unnecessary for most patients. Clinical experience over the past 3 decades has shown that it is impor­tant to ensure that urine testing does not become a substitute for talking with patients) I]

6,2 Take-Home Medication

Attending a clinic or pharmacy every day to re­ceive methadone proves onerous for many pa­tients. One alternative is to dispense one or more doses per week as take-home doses to be ingested in the privacy of the patient's home. The adminis­tration of methadone is often controlled by govern­ment legislation and regulatory bodies, and the extent to which this is an option for treatment pro­viders varies from jurisdiction to jurisdiction.

Where it is possible, take-home medication is usually dispensed to patients who have responded well to treatment. When methadone is used in this manner, it has been shown to assist some patients in reducing and abstaining from illicit drug use.[37] However, the benefits of take-home methadone have to be weighed against the risk of methadone diversion, which may have adverse consequences for the methadone treatment system. Diverted methadone can be sold like other illicit drugs, and deaths from overdose may occur among persons not enrolled in methadone maintenance therapy (see section 10).

7. Ancillary Services

As well as administering methadone, medical practitioners and clinic staff may off~r a range of services to deal with the predisposing causes and consequences of opioid dependence. The most common services are counselling, medical care and psychiatric treatment.

eNS Drugs 1996 Dec; 6 (6)

446

7.1 Counselling

The role of counselling in methadone mainte­nance therapy is best viewed in terms of the overall therapeutic relationship that is established between the patient and the staffJI] While formal counsel­ling may be of use to some patients, many are un­willing to participate and should not be compelled to do so. However, patients attending for meth­adone maintenance therapy often present in a dis­tressed state owing to crises in their lives, and pro­viding support and assisting in problem solving to such patients is appropriate.

Patients who are experiencing interpersonal dif­ficulties or who have psychiatric problems should be encouraged to seek formal counselling or psy­chotherapy. Some patients might request assist­ance on their own. They can be referred to a psycho­logist, social worker or psychiatrist, if staff with the requisite skills are not employed at the methadone treatment agency.

7.2 Medical Care

Patients in methadone maintenance therapy may have a range of medical complaints that are a consequence of injecting drugs and the lifestyle as­sociated with it (see table II). The provision of medical care for these problems in methadone clin­ics is attractive to patients and has been associated with a better response to methadone maintenance therapyJ38-40] Where this is not possible, patients' medical needs should be met by referral.

7.3 Psychiatric Care

In opioid-dependent individuals who present for methadone maintenance therapy, comorbid psychiatric disorders occur at a much higher rate than that observed in the general population. These include personality, mood and alcohol-use disor­dersJ41-43] Treating methadone-maintained pa­tients who have depression with psychotherapy has been shown to enhance the response to methadone maintenance therapy.[44,45] For patients who seek assistance with these problems, treatment should

© Adis International Limited. All rights reserved.

Ward et al.

Table II. Medical disorders that may be observed in patients who are on methadone maintenance therapy

Liver disease resulting from hepatitis infections and alcohol (ethanol) abuse

HIV infection, resulting from sharing injecting equipment

Sexual health problems

Range of infections, resulting from unsterile injections (abscesses, granulomata, thrombophlebitis, etc.)

be delivered or arranged by referral as would occur in other cases.

8. Duration and Goal of Treatment

There is no optimum duration for methadone maintenance therapy. There has been considerable debate about whether maintenance on methadone, rather than abstinence from all drugs including methadone, is a worthwhile treatment goal. Re­search suggests that once dependence develops, abstinence from opioids is difficult to achieve and that most patients relapse when they leave methadone maintenance therapy. [38] Because of the potential adverse consequences associated with re­lapsing to injection opioid use (e.g. imprisonment, HIV and/or hepatitis Band C infection, overdose, etc.), there is widespread support in the clinical and research literature for the goal of long term methadone maintenance rather than complete ab­stinence. [4.5, 14,38]

9. Long Term Prospects

After being successfully maintained on meth­adone for some time, the question often arises: should the patient consider detoxification? While some patients can successfully detoxify from methadone, others cannot. For patients who wish to detoxify, a planned withdrawal regimen is ap­propriate. For patients who are functioning well otherwise, but who may relapse if they stopped re­ceiving methadone, ongoing 'medical' mainte­nance should be considered. The term 'medical' is used to indicate that such patients can be treated in a general practice as would other patients with chronic conditions such as diabetes and epilepsy, and have their medication managed in a similar fashion.

eNS Drugs 1996 Dec; 6 (6)

Methadone Maintenance Therapy

9.1 Withdrawal Regimens

The most effective and humane procedure for withdrawing methadone from patients maintained on the drug is to slowly reduce their methadone dosage. Research suggests that the slower the pace of the reduction, the better the response,[461 al­though clinically the pace is best set in consultation with the patientJ1.51 For patients maintained on dosages in excess of 80 mg/day, dosage reductions of 10 mg/week are well tolerated. For patients on dosages in the 40 to 80 mg/day range, a reduction of 5 mg/week is recommended.

Once the dosage has been reduced to 40 mg/day the likelihood of the patient experiencing with­drawal symptoms increases and the reduction schedule should be slowed to 2.5 mg/week. If the patient experiences withdrawal distress or relapses to heroin use, the reduction should be stopped and the dosage raised. In such patients, it is important to remain supportive and avoid communicating to the patient that they have failed.

Supportive counselling or psychotherapy im­prove success rates for patients detoxifying from methadone maintenance therapy.l47] Some patients experience an abstinence or detoxification 'pho­bia', which impedes any attempt at detoxification. They may require more intensive counsellingJ481 Success after detoxification has been found to be enhanced by continued counselling, relapse pre­vention training and attendance at self-help groups.1491

9.2 Medical Maintenance

For some patients, long term methadone main­tenance may be the best option. Such patients may no longer require the structure of daily clinic atten­dance that is necessary in patients who are at an earlier stage of their treatment careers. One option for continuing therapy is medical maintenance.[SO] A patient attending for medical maintenance has their methadone prescription managed by their general practitioner and attends for methadone ad­ministration at a local community pharmacy.

(0 Adis International Limited All rights reserved.

10. Adverse Effects Associated With Methadone Maintenance Therapy

447

Although methadone maintenance is associated with significant advantages for most individuals, there are disadvantages and potential adverse con­sequences associated with this approach. [51]

For the patient, this treatment is associated with costs in terms of time and a loss of freedom and mobility that is associated with attending a clinic or pharmacy on a regular basis. Being registered as a patient receiving methadone maintenance ther­apy also entails a loss of privacy and submission to the rules of the administration facility, which may involve the requirement of regular, observed urination.

The dispensing of methadone for ingestion at home carries the risk of accidental poisoning if some other adult or a child unwittingly drinks one of the prepared doses. The use of child-proof bot­tles for take-home methadone doses and advising patients to store their methadone in a safe place reduces this risk.

If take-home methadone is dispensed too liber­ally, the drug may be diverted and used by other individuals for intoxication or to self-medicate opioid withdrawaJ.ls2] Diversion can be reduced by dispensing take-home methadone only to pa­tients who respond well to treatment.

Another potential adverse effect is the risk of inducing or prolonging an iatrogenic opioid de­pendence. The former can be prevented by employ­ing adequate assessment and screening procedures (see section 3), while the latter concern has to be placed in the context of what would happen in the absence of treatment. Studies of the life-histories of opioid-dependent individuals suggest that a mi­nority recover in the short term without treatment, but are at an increased risk of opioid-related mor­bidity and mortality compared with those who en­ter and remain in methadone maintenance ther­apy.[33] Furthermore, in comparison with patients treated in drug-free treatment programmes (e.g. therapeutic communities), patients receiving methadone are no less likely to become abstinent than their drug-free counterparts.[S3] This suggests

eNS Drugs 1996 Dec; 6 (6)

448

that by remaining in therapy, patients are not sub­jected to a dependence that they would otherwise not experience, are not exposed to the adverse con­sequences of being dependent on illicit opioids, and are no less likely to achieve abstinence than patients treated without methadone.

11. Conclusions

Methadone maintenance therapy is a well tol­erated and effective response to the problem of op­ioid dependence. It is most effective when deliv­ered at an adequate dosage in the context of a therapeutic relationship aimed at stabilising pa­tients' drug use and overcoming the difficulties that either led to or have arisen as a consequence of their opioid dependence. While some patients are able to make significant gains during treatment and eventually withdraw from methadone without re­lapsing, many require long term methadone main­tenance.

Acknowledgements

The authors would like to thank Patricia Ward for helpful comments on a draft of this article. Jeff Ward was supported during the writing of this paper by a grant from the New South Wales Department of Health.

References I. Bell 1. O'Connor D. New South Wales methadone prescribers'

manual. Sydney: Australian Professional Society on Alcohol and Other Drugs. 1994

2. Hartnoll RL. Opiates: prevalence and demographic factors. Ad­diction 1994; 89: 1377-83

3. Dole VP, Nyswander M. A medical treatment for diacetylmor­phine (heroin) addiction: a clinical trial with methadone hy­drochloride. lAMA 1965; 193: 80-4

4. Gerstein DR, Harwood Hl, editors. Treating drug problems. Vol. I. A study of the evolution, effectiveness. and financing of public and private drug treatment systems. Washington, DC: National Academy Press, 1990

5. Ward 1, Mattick RP, Hall W. Key issues in methadone mainte­nance treatment. Sydney: New South Wales University Press, 1992

6. Gunne L-M, Gronbladh L. The Swedish methadone mainte­nance programme: a controlled study. Drug Alcohol Depend 1981; 7: 249-56

7. Dole VP, Robinson lW, Orraca 1, et al. Methadone treatment of randomly selected criminal addicts. N Engl 1 Med 1969: 280: 1372-5

8. Newman RG, Whitehill WB. Double-blind comparison of methadone and placebo maintenance treatments of narcotic addicts in Hong Kong. Lancet 1979 Sep: 8: 485-8

'5::) Adis International Limited. All rights reserved

Ward ct al.

9. Strain EC, Stitzer ML, Liebson lA, et aI. Dose-response effects of methadone in the treatment of opioid dependence. Ann Intern Med 1993; 119: 23-7

10. Vanichseni S, Wongsuwan B, Staff of the BMA Narcotics Clinic No.6, et al. A controlled trial of methadone maintenance in a population of intravenous drug users in Bangkok: implica­tions for prevention of HIY. Int 1 Addict 1991; 26: 1313-20

II. Yancovitz SR, Des larlais DC. Peyser NP, et al. A randomised trial of an interim methadone maintenance clinic. Am 1 Public Health 1991: 81: 1185-91

12. Ball lC, Ross A. The effectiveness of methadone maintenance treatment: patients, programs, services, and outcome. New York: Springer-Verlag, 1991

13. Simpson DO. Sells SB. Effectiveness of treatment for drug abuse: an overview of the DARP research program. Adv Al­cohol Subst Abuse 1982; 2: 7-29

14. Hubbard RL, Marsden ME, Rachal lY. et al. Drug abuse treat­ment: a national study of effectiveness. Chapel Hill: Univer­sity of North Carolina Press, 1989

15. Caplehorn lRM, Ross M. Methadone maintenance and the like­lihood of risky needle sharing. Int 1 Addict 1995; 30: 685-98

16. Moss AR, Vranizan K, Gorter R, et al. HIV seroconversion in intravenous drug users in San Francisco 1985-1990. AIDS 1994; 8: 223-31

17. Crofts N. Hopper lL, Milner R. et al. Blood-borne virus infec­tions among Australian injection drug users: implications for spread of HIY. Eur 1 Epidemiol 1994; 10: 687-94

18. laffe lH, Martin WR. Opioid analgesics and antagonists. In: Gilman AG. Rail TW. Nies AS, et aI., editors. The pharmaco­logical basis of therapeutics. 7th ed. New York: Pergamon, 1990: 485-52\

19. Dole VP. Implications of methadone maintenance for theories of narcotic addiction. lAMA 1988; 260: 3025-9

20. Krcck MJ. Using methadone etfectively: achieving goals by application of laboratory, clinical, and evaluation research and by development of innovative programs. In: Pickens RW, Leukefeld CG, Schuster CR, editors. Improving drug abuse treatment. NIDA Research Monograph 106. Rockville (MD): National Institute on Drug Abuse, 1991: 245-66

21. Novick DM, Richman BL, Friedman 1M, et al. The medical status of methadone maintenance patients in treatment for 11-18 years. Drug Alcohol Depend 1993; 33: 235-45

22. Henderson GL. Harkey MR. The use of therapeutic drug mon­itoring to improve the effectiveness of methadone treatment programs. Sacramento (CA): Department of Alcohol and Drug Programs. 1990

23. Sawe 1. High-dose morphine and methadone in cancer patients: cI inical pharmacokinetic considerations of oral treatment. Clin Pharmacokinet 1986; II: 87-106

24. Stockley IH. Drug interactions. 3rd ed. London: Blackwell Sci­entific, 1994

25. Kreek Ml. Factors modifying the pharmacological effective­ness of methadone. In: Cooper lR, Altman F. Brown BS, ed­itors. Research on the treatment of narcotic addiction: state of the art. Rockville (MD): NIDA, US Department of Health and Human Services. 1983: 95-114

26. Nilsson MI, Meresaar U, Angaard E. Clinical pharmacokinetics of methadone. Acta Anaesthesiol Scand Suppl 1982; 74: 66-9

27. Dollery C. editor. Therapeutic drugs. London: Churchill Living­stone. 1991

28. Maany I, Dhopesh V, Arndt 10, et al. Increase in desipramine serum levels associated with methadone treatment. Am 1 Psy­chiatry 1989; 146: 1611-3

eNS Drugs 1996 Dec; 6 (6)

Methadone Maintenance Therapy

29. Perucca E, Gatti G, Spina E. Clinical pharmacokinetics of fluvoxamine. Clin Pharmacokinet 1994; 27: 175-90

30. Brockmeyer NH, Mertins L, Goos M. Pharmacokinetic inter­action of antimicrobial agents with levomethadon in drug-ad­dicted AIDS patients. Klin Wochenschr 1991; 69: 16-8

31. Burger DM, Meenhorst PL, ten Napel CHH, et a!. Pharmaco­kinetic variahility of zidovudine in HIV-infected individuals: subgroup analysis and drug interactions. AIDS 1994; 8: 1683-9

32. WHO. The ICD-IO classification of mental and behavioural disorders: clinical descriptions and diagnostic guidelines. Ge­neva: World Health Organization, 1992

33. Institute of Medicine. Federal regulation of methadone treat­ment. Washington, DC: National Academy Press, 1995

34. Drummer OH, Opeskin K, Syrjanen M, et al. Methadone tox­icity causing death in ten subjects starting on a methadone maintenance program. Am J Forensic Med Pathol 1992; 13: 346-50

35. Ward J. Methadone doses: adequate and otherwise lcomment]. Drug Alcohol Depend 1994; 36: 73-5

36. Zweben JE. Review of clinical issues. In: Parrino MW, editor. State methadone treatment guidelines. Rockville (MD): Cen­tre for Substance Abuse Treatment, US Department of Health and Human Services, 1993: 25-32

37. Stitzer ML, Iguchi MY, Kidorf M, et a!. Contingency manage­ment in methadone treatment: the case for positive incentives. In: Onken LS, Blaine JD, Boren JJ, editors. Behavioral treat­ments for drug abuse and dependence. NIDA Research Monograph 137. Rockville (MD): National Institute on Drug Abuse, 1993: 19-35

38. Ball JC, Ross A. The effectiveness of methadone maintenance treatment: patients, programs, services, and outcome. New York: Springer Verlag, 199 I

39. McLellan AT, Alterman AI, Metzger DS, et al. Similarity of outcome predictors across opiate. cocaine. and alcohol treat­ments: role of treatment services. J Consult Clin Psychol 1994; 62: 1141-58

40. Umbricht-Schneiter A, Ginn DH, Pabst KM, et a!. Providing medical care to methadone clinic patients: referral \'s on-site carc. Am J Public Health 1994; 84: 207-10

4 I. Strain EC, Stitzer ML, Bigelow GE. Early treatment time course of depressive symptoms in opiate addicts. J Nerv Ment Dis 1991; 179: 215-21

Ads International Limited. All rights reserved.

449

42. Regier DA, Farmer ME, Rae DS, et al. Comorbidity of mental disorders with alcohol and other drug abuse: results from the Epidemiologic Catchment Area (ECA) study. JAMA 1990: 264: 2511-8

43. Kosten TR, Rounsaville BJ, Kleber HD. DSM-1Il personality disorders in opiate addicts. Compr Psychiatry 1982; 23: 572-81

44. Woody GE, McLellan AT, Luborsky L, et al. Psychotherapy in community methadone programs: a validation study. Am J Psychiatry 1995; 152: 1302-8

45. Woody GE, Luborsky L. McLellan AT. et al. Psychotherapy for opiate addicts: does it help') Arch Gen Psychiatry 1983: 40: 639-45

46. Senay EC, Dorus W, Goldberg F, et al. Withdrawal from methadone maintenance: rate of withdrawal and expectation. Arch Gen Psychiatry 1977; 34: 361-7

47. Milby JB. Methadone maintenance to abstinence: how many make if) J Nerv Ment Dis 1988; 176: 409-22

48. Milby JB, Hohmann AA, Gentile M, et al. Methadone mainte­nance outcome as a function of detoxification phobia. Am J Psychiatry 1994; 15 I: 103 1-7

49. McAuliffe WE. A randomized controlled trial of recovery train­ing and self-help for opioid addicts in New England and Hong Kong. J Psychoactive Drugs 1990; 22: 197-209

50. Novick DM, Joseph H. Medical maintenance: the treatment of chronic opiate dependence in general medical practice. J Subst Abuse Treat 199 I: 8: 233-9

51. Mattick RP, Hall W, editors. A treatment outline for approaches to opioid dependence. Canberra: Australian Government Publishing Service, 1993

52. Spunt B, Hunt DE, Lipton DS, et a!. Methadone diversion: a new look. J Drug Issues 1986; 16: 569-83

53. Maddux JF, Desmond DP. Methadone maintenance and recov­ery from opioid dependence. Am J Drug Alcohol Abuse 1992: 18: 63-74

Correspondence and reprints: Dr Jeff Ward, National Drug and Alcohol Research Centre, University of New South Wales, Sydney, NSW 2052, Australia.

eNS Drugs 1996 Dec: 6 (6)