LONG-TERM PHARMACOTHERAPY

MANUAL FOR LONG-TERM PHARMACOTHERAPY

Anju Dhawan, Sonali Jhanjee

        

Published by

National Drug Dependence Treatment Centre All India Institute of Medical Sciences, New Delhi

Developed under
WHO (India) and Ministry of Health and Family Welfare, Government of India

Collaborative Programme

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Additional Professor

First Edition : May 2007 Revised Edition : February 2013

Public Printing (Delhi) Service

C-80, Okhla, Industrial Area, Phase-I, New Delhi-110020 Tel: 26811431, 26816775

This manual is not for sale. No part may be used for commercial purposes.

We would like to acknowledge the financial support extended by the Ministry of Finance, Department of Revenue for the reprint and distribution of the manual.

Methadone Maintenance Treatment 38-54 Atul Ambekar, Shrigopal Goyal

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Introduction

METHADONE MAINTENANCE TREATMENT

Atul Ambekar, Shrigopal Goyal

As seen in the previous chapters, substitution or maintenance on an agonist drug is well accepted and effective treatment and harm-reduction strategy. The basic philosophy of agonist maintenance treatment is to substitute illicit, medically unsafe, short acting and more reinforcing drugs with a medically safer, long acting agonist of known purity, potency and dosage .

Methadone is a synthetic narcotic analgesic compound developed in Germany just prior to World War II. Dole and Nyswander (1965) proposed methadone as an effective maintenance agent. In 1972 Food and Drug Administration (FDA) in US approved its use as maintenance agent for opioid. Since then methadone has gained widespread popularity and is currently being used as treatment for opioid dependence in a number of countries throughout the world. In India, Methadone has been launched rather recently (in early 2012).

Methadone maintenance treatment reduces illicit opioid use, criminal activity, mortality and morbidity (including risk of HIV infection) and improves psychosocial functioning.

Rationale for use

Methadone maintenance treatment (a) eliminates drug hunger, (b) induce a cross-tolerance i.e. blockade of the effectsofillicitopioidsand(c)suppressopioidwithdrawalsymptoms.Thespecificobjectivesof methadone maintenance treatment should be to reduce illegal and other harmful drug use, improve the patient’s health and well-being, reduce the transmission of blood-borne infectious diseases, reduce deaths associated with opioid use, reduce crime committed by patients, facilitate an improvement in the patient’s occupational and social functioning, improve the economic status of patients and their families. The ultimate goal could also include achievement of abstinence from drug use, including cessation of the opioid substitution treatment, though with a harm-reduction perspective this should not be insisted upon.

Pharmacology

Mechanism of Action

Upon acute administration, methadone acts as a typical μ receptor agonist and produces euphoria, analgesia, and other typical morphine-like effects. However, upon long-term oral administration, methadone displays several interesting properties making it a very useful maintenance agent. These properties include

(i) its reliable absorption and bioavailability after oral administration,
(ii) thedelayofpeakplasmalevelsuntil2to6hoursafteringestion,and
(iii) the binding to tissues that creates a large reservoir of methadone in the body.

This large reservoir, along with slow action, protects patients against sharp peaks in euphoria. The reservoir also results in minimum withdrawal. Thus, this makes it possible to administer with a once-a-day regime. Minor variations in dosage over short periods do not induce major changes in biological effects. The mean plasma half-life ranges from 22 to 56 hours in methadone-maintained patients.

Pharmacokinetics

Methadone is rapidly absorbed after oral administration. It is highly plasma protein bound, with an 38

approximate volume of distribution of 4 L/kg. Methadone is demethylated in the liver by several cytochrome P450 (CYP) enzymes, primarily 3A4, and its metabolite is excreted in the urine. Of interest, women may metabolize methadone more rapidly than men. After oral administration, methadone has a biexponential half- life with an initial phase range of 12 to 24 hours and a secondary phase of 55 hours

.

Effectiveness

Many studies have consistently demonstrated that methadone treatment reduces mortality, and decreases illicit drug use, criminal activity, health-care cost, unemployment and accidental overdoses among opioid dependent individuals. Certain program features tend to make some programs more effective than others.

Retention in treatment

The average retention rate for a group of methadone clinics participating in a national prospective study in USA was 81 percent at 1 month, 67 percent at 3 months, and 52 percent at 6 months (Strain et al, 2009).

Illicit drug use

Evidenceindicatesthatmethadoneprogrammedecreasesillicitdruguse andpreventsmanyopioidinjectors from getting HIV (Ball et al, 1988; Novick et al, 1990). Overall methadone maintenance is cost-beneficial (Barnett, 1999). Methadone maintenance treatment is cost-effective and beneficial to society.

Furthermore, MMT has been shown to decrease mortality among opioid-dependent patients. Mortality estimates indicate that heroin-dependent individuals in MMT are one fourth as likely to die as dependent individuals not in treatment.

Methadone has shown to be better able to suppress heroin use than buprenorphine, especially if high-dose methadone is used. Similar conclusions have been reached by other recent meta-analytic reviews of agonist maintenance treatments.

Methadone maintenance treatment: Experience from India

Considerable amount of experience and expertise exists in India, with using Buprenorphine as a maintenance agent for treatment of opioid dependence. Many practice guidelines are also available for the same. Methadone, though similar in many respects, is still a new drug for the medical practitioners in India. However, as a pilot project, MMT is being provided at five diverse sites in the country: Delhi, Mumbai, Bathinda, Kapurthala and Imphal. The early experiences have indicated that MMT is effective, safe and acceptable to the patients

Indications

As mentioned in the chapter on buprenorphine the selection criteria for inclusion of patients in maintenance treatment may vary, but essentially include as a pre-requisite – a confirmed diagnosis of opioid dependence. Thus a comprehensive history and physical examination to clearly document Opioid dependence are essential aspectsofassessment. Certainothercriteriaforagonist(methadone)maintenancetreatmentmayinclude:

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·  Above 18 years of age: (though age less than 18 years in not a contra indication)

·  Minimum 1-year history of opioid dependence

·  Failed abstinence attempt with short-term treatment or with other agonists (Buprenorphine or SROM)

·  High amount of heroin use

·  Feeling withdrawal symptoms on buprenorphine

·  Willingness to comply with the programme requirements

·  Additionally, there is much larger evidence-base with safety of Methadone (as opposed to
buprenorphine) in case of opioid dependent pregnant females. Side Effects
Methadone shares the adverse effects and toxic potential of other opioid agonists. Hence, the usual precautions of opioid agonist therapy should be observed. Common side effects of opioids include sedation, constipation, sweating, nausea, dizziness, and hypotension. During methadone maintenance, most adverse effects disappear over the course of several weeks. However, constipation and excessive sweating often persist even with long-term methadone administration. Methadone in moderate to high doses can impair cardiac conduction, prolong the QT interval, and, in rare instances, lead to torsades de pointes. Some patients would also complain of decreased libido; and sexual dysfunction. A Post-marketing Surveillance study of Methadone in India is currently underway, which is likely to produce Indian data regarding side-effect profile Methadone.
Toxicity
Severe intoxication or overdose with methadone constitutes a medical emergency. Opioid overdose leads to potentially fatal respiratory depression from direct suppression of respiratory centers in the midbrain and medulla. For severe cases, the administration of the pure opioid antagonist naloxone in combination with general supportive measures is indicated. Owing to the long half-life of methadone, repeat administration of naloxone may be necessary.
Drug interaction
Variety of therapeutic agents can cause a decrease in plasma levels of methadone by inducing hepatic enzymes that metabolize methadone (CYP3A4). Among those are rifampin, phenytoin, barbiturates, carbamazepine, and ethyl alcohol. Agents that can inhibit methadone metabolism include erythromycin, cimetidine, and ketoconazole. Valproic acid does not alter methadone metabolism.More methadone is excreted when urinary pH is low rather than when it is high; stress and other factors that lower urinary pH can result in lower plasma levels of methadone.
Interaction with antiretrovirals
Zidovudine does not alter methadone metabolism, but patients on methadone tend to have higher zidovudine levels than do controls. Nevirapine and Ritonavir increases methadone metabolism and decrease methadone level in blood. Other protease inhibitors may raise or lower methadone plasma level.

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In general, none of the drug-drug interactions are clinically severe enough to warrant a discontinuation of treatment, but may just need dose adjustments.

Contraindications

Drug reactions

A person with an established history of side effects (hypersensitivity) to methadone should not be put on methadone maintenance.

Incapable of providing informed consent

Methadone maintenance should not be considered if a person couldn’t provide informed consent to treatment due to a psychiatric condition such as acute psychosis and cognitive impairment.

Primary dependence on non Opioid drugs

Methadone maintenance is not appropriate for people who are primarily dependent on non-opioid drugs such as alcohol, benzodiazepines, amphetamines, or combinations of these.

Concomitant use of other drugs

Concurrent use of high dose of hypnotic, sedative or alcohol leads to risk of aggravation of respiratory depression.

Severe medical illness

It should be used cautiously in patients suffering from bronchial asthma. Severe respiratory impairment, hepatic impairment, pheochromocytoma, inflammatory bowel disease, hypothyroidism and severe prostatic hypertrophy are contraindications to methadone treatment.

Special population

Pregnant Women

Illicit opioid use during pregnancy is associated with many adverse effects for both the pregnant woman and thefetusincludingnotreceiving prenatalcare,havepoornutritionalstatus,engageinriskysexualanddrug- related behaviors that are associated with infectious diseases (e.g., HIV) and other medical complications. Pregnant illicit opioid users are at risk for infections, pre-eclampsia, miscarriage, premature rupture of membranes, and premature labor and also at risk for having stillbirths, premature infants, and infants with low birth weight and neonatal opioid withdrawal.

Methadone maintenance remains the current standard of care for treatment of the pregnant opioid- dependent woman. Methadone maintenance significantly improves infant outcomes compared to pregnant women not on methadone maintenance that continue to use heroin. Methadone maintenance dose increases may be needed for the pregnant woman because

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of changes in blood volume and metabolism as the pregnancy progresses, and split methadone dosing may be useful in the third trimester (when methadone metabolism and clearance increases). Babies born to mothers who have been maintained on methadone usually have evidence of the neonatal abstinence syndrome, and various effective treatment interventions have been advocated for the neonate.

Young or very young subjects

The data on use methadone maintenance in adolescent drug users is limited. Due to the short duration of drug use in this age group, a drug free approach or other modality of treatment should be attempted. However, after weighing the risks and benefits of treatment, should a physician believe MMT to be the most suitable treatment for an adolescent opioid dependent, patient, it should be not be withheld.

People with HIV/AIDS

Drug users who are living with HIV have a variety of reactions and needs. In principle, methadone treatment options are the same, regardless of their HIV status. Methadone treatment can reduce risk behaviours that could further damage the immune system. It can reduce stress and improve the general health of the patient by helping to live a regular life. Methadone maintenance treatment is an exceptionally good tool to improve retention in treatment (for HIV/AIDS). Liaison with specialist care, particularly with the HIV physician, is strongly recommended. Prescribing should be done in collaboration with the HIV specialist to avoid potential risk of interactions between methadone and HIV medications. Attention should be paid to specific issues, such as the reduction of tolerance on account of periods of illness and the risk of overdose.

People with Hepatitis

It is strongly recommended that all people in treatment should be tested for Hepatitis B and those without protective antibodies, should be vaccinated. Hepatitis C is a serious health problem for injecting drug users, both in terms of prevalence and its clinical effects. There is a great need for improved methods of diagnosis and management of people with hepatitis C. The dose of methadone will have to be reviewed and analysed, according to the liver function of the patient. Specialist referral should be managed for assessment and possible treatment of HCV. People who are stable on methadone can be very compliant with HCV treatment. Finally, as in the case of people with HIV, it is important to reiterate the importance of avoiding any sharing of injecting equipment.

Dependence and abuse potential

Methadone is an abusable compound which may lead to physical dependence. Withdrawal syndrome develops following abrupt cessation of treatment.

Preparation of methadone

It is available in tablet and liquid preparation. Usual formulations are 5mg/ml of liquid but is also available in 1mg/ml, 10 mg/ml, 20 mg/ml and 5 mg / 10 mg / 20 mg tablets. Methadone liquid is vicous and hence very difficult to inject. Tablets can however, be injected and hence extra precautions are warranted in case, non- supervised administration is being considered.

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Induction

After assessment for suitability of methadone treatment, patient should be supplied with verbal and written information about all aspects of the maintenance treatment. The dose should be titrated according to the clinical effect in the individual patient.

Methadone can be initiated in an individual with well-established current physiological dependence at a dose of 20 to 30 mg. If there is doubt regarding degree of an individual’s tolerance to opioids, an initial dose of 10 mg is indicated. The maximum allowable first dose is usually 30 mg, and the maximum total dose for the first day of treatment is 40 mg. Dose escalation should be done in small increments (usually 5 to 10 mg at a time) under close physician supervision until an optimum maintenance dose is achieved. Given methadone’s long half- life, it is advisable to observe the patient for at least 3 to 4 days before an additional dose increase is provided.

Thus, in the first week of treatment, the prescription may appear something like this:

—  Methadone 10 to 20 mg/day

—  Methadone 25 mg/day

—  Methadone 30 mg/day

—  Maximum dose at the end of 1st week < 40 mg/day
The key to initiating methadone dosing is to start low and go slow. In other words, on day 2 and 3 of treatment, a temptation to increase the dose should be avoided even if the patient reports incomplete control of withdrawals. Every dose increase should be carried out only at the interval of 3-4 days.
Clinical signs and patient-reported symptoms of either overmedication or withdrawal, along with drug craving and/or continuing illicit-opioid use, are vital indicators for achieving dose adequacy. Finally, patient education is an essential component of safety in MMT. This should be combined with efforts to foster open, trusting relationships between patients and clinic staff, which will produce the most successful treatment outcomes.
The optimum dose is considered to be achieved when

. (1)  the patient evidences no withdrawal signs or symptoms throughout the 24-hour dosing period,

. (2)  the patient reports an absence of craving for opioids,

. (3)  adequate tolerance is obtained such that the patient experiences little or no reinforcement from use of
other opioids, and

. (4)  self-report and urine testing indicate the absence of illicit opioid use.

X day 1 to day 3 X day 4 to day 6 X day 7 to day 9

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Table 1: Induction of Methadone with the principle: Start low, Go slow

Phases of MMTO

Phase

Objective

Initial Induction

Relieve withdrawal (abstinence) symptoms

Early Induction

Reach tolerance level, reduce craving.

Late Induction Stabilization

Establish adequate dose (physical and emotional well-being)

Maintenance

Preserve desired effects (steady-state occupation of opioid receptors)

Table 2: Signs/Symptoms of Opioid Withdrawal and overmedication

Overmedication Signs and Symptoms,

Sedation (“nodding-off,” drowsy), miosis (pinpoint pupils), itching/scratching, hypotension, respiratory depression (severe in overdose), depressed mental status, flushing, spasticity. Also, mild

Euphoria (temporary).

Therapeutic Comfort Range

No withdrawal or overmedication. Ultimately, no craving or illicit opioid use.

Withdrawal Subjective Symptoms

Drug craving, anxious feelings, depression, dysphoria irritability, fatigue, insomnia, hot/cold flashes, myalgia/arthralgia (aching muscles/joints), anorexia, nausea, abdominal cramps, restlessness

Withdrawal Objective Signs

Illicit opioid use, mydriasis (dilated pupils), piloerection (“goose flesh”), diaphoresis (perspiring), muscle tremors/twitching (shaking), diarrhea, vomiting, lacrimation, rhinorrhea, sneezing, yawning, anxiety (outward signs), fever, tachycardia,

Safety/ Precautions during methadone treatment

·  All pharmacies / clinics offering methadone maintenance treatment must ensure that they have adequate arrangement for safety for methadone storage to prevent theft.

·  The major hazard associated with methadone is the risk of overdose. This risk is particularly high at the time of induction and when methadone is used in combination with other sedative drugs. The relatively slow onset of action and long half-life mean that methadone overdose may not be obvious and may only become life threatening many hours after ingestion.

·  Cardiac vigilance recommended for methadone: There are risks of QT prolongation and torsades de pointes with methadone, particularly high doses. It is recommended that ECG monitoring should be undertaken in patients prescribed methadone > 150 mg/day and in those with risk factors for QT prolongation or symptoms that may be attributable to arrhythmia.

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Dosage and Administration

Minimum effective dose found in the western studies is 60 mg / day (oral). A dose below 50 mg enhances the risk of patient drop-out. In a study of six clinics in the United States, there was an inverse relation between methadone dosage (over the range from 20 to 80 mg daily) and the percentage of patients using heroin. Although some programs persist in using low doses that have been shown to correlate with high dropout rates and continued heroin use, their number has decreased as data on the importance of adequate dosage have become more generally accepted. While the adequate dose is yet to be determined because of inadequate experiencewiththedrug InIndia,itappearsthatmostclientswouldrequiredoserangingbetween40and 80mg/day.

Duration of treatment is also important as treatments lasting less than 90 days usually have little or no impact; consequently, retention in treatment is critical. In general longer the duration of treatment and retention in treatment, better the outcome.

Higherdosesontheotherhandleadtolongerretentionandgreaterreductioninillicitopioiduse. Thereare wide variations in rates of methadone metabolism. Indeed, some experts also suggest measuring methadone plasma levels to determine daily dosage. It appears that an average methadone serum level of 400 ng/mL is adequate, and that levels of less than 150 ng/mL are likely to be associated with withdrawal or drug hunger. However because of its resource-intensive nature, most treatment guidelines do not recommend routine monitoring of serum methadone levels.

Responding to Special issues regarding Methadone Dosing

Missed doses

Methadone is a respiratory depressant. Patients on daily dosing become tolerant to this effect, but on missing doses there is variable and unpredictable loss of this tolerance. Missed doses are fairly common in MMT for many reasons. Once a patient turns up in the clinic after missing his doses for some days, the prescribing physician must assess the situation and determine the correct dose. Patients should be assessed for signs of intoxication and withdrawal before dosing is recommenced.

In general the following schedule can be presumed to be safe and effective. If the patient has missed,

If the dose has not been collected for 3 or more consecutive days the dose should be withheld or reduced until the patient has been assessed by the prescriber.

· · · · ·

One day: No change in dose.
Two days: If no evidence of intoxication administer normal dose. Threedays:Administerhalfdose indiscussionwiththeprescriber.
Four days: Patient must see prescriber. Recommence at 40mg or half dose whichever is the lower . Five days or more: regard as a new induction.

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Thus, if a patient on a daily dispensing regimen misses a pickup from the pharmacy, the patient should return the next day as usual for their next dose. The missed dose should not be replaced. Three days missed consecutively should lead to a dose review and possible reduction in dose. Five days or more missed consecutively should lead to re-assessment and re-titration.

Deferred dispensing

Patients should not receive Methadone if they appear to be intoxicated, particularly with alcohol; patients may be asked to wait to be reassessed some hours later prior to administration of Methadone.

Replacement of vomited doses

A physician or pharmacist may replace a vomited dose provided the vomiting was observed by a responsible individual e.g.: pharmacist or nurse. The following schedule must be followed:

·  The vomiting occurred less than 15 minutes after ingestion: full replacement

·  The vomiting occurred between 15 and 30 minutes: 1⁄2 the dose would be replaced

·  The vomiting occurred after 30 minutes: no replacement is to be given
Partial consumption of doses
If a patient refuses to consume their full dose, the pharmacist must not insist that they ingest the total amount. The unconsumed portion however cannot be given as a take-home dose. Reason for partial consumption of doses must be documented
Length of maintenance treatment / Completion and Termination
Patients should remain in treatment for the minimum time it takes to achieve their agreed treatment goals. The length of time required for treatment will vary amongst individuals. Regular reviews will assist in determining need for continued treatment. There is no optimal duration of methadone treatment and removing people from treatment too early may result in very poor outcomes, including high rates of relapse into illicit opioid use and a consequent increased risk of overdose. Setting an arbitrary duration of treatment and withdrawing treatment at that endpoint is not recommended. The treatment approach should include working towards goals, that when achieved, prepare a patient to live well without methadone. In most situations stabilization on methadone for at least one year would be required before withdrawal from it is considered, although most patients need about two years of treatment. An important objective of methadone treatment is the successful withdrawal from methadone combined with continued good functioning, including good health and social functioning. Planning for successful withdrawal from methadone should commence from the initiation of treatment. The decision to withdraw voluntarily from methadone should be a joint decision of the patient and the prescribing doctor, with information contributed by the social worker or nursing staff, who may be evaluating the psychosocial functioning of the patient. When all agree about the

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timing and method of withdrawal from methadone, patients tend to be more successful in their methadone reduction. It remains, however, the patient’s right to withdraw from medication at any time.
Forcing a patient off methadone when they do not feel capable of coping without the treatment may result in return to opioid use and related problems. Unless there is a specific reason for involuntary termination from treatment, this approach is not recommended.

Dose

A flexible approach to dose reduction, individualizing reduction regimens is best. A slower rate of reduction is required if relapse is likely, or the patient is not coping.

Increased psychosocial support during withdrawal

More frequent supportive, skills oriented and relapse prevention counselling, more frequent monitoring and review, access to residential programme if necessary (residential withdrawal or rehabilitation programme) and involvement of significant others (including family) in providing support should be explored.

Aftercare services

Counseling, continuing case management and structured group programme are all likely to assist outcome after completion of withdrawal from buprenorphine. The staff should remain involved in the care of patients who have voluntarily withdrawn from maintenance treatment for at least a few months after completion of withdrawal. In case of relapse, the patient should have easy access back into treatment. Treatment should be offered quickly and without recrimination.

Involuntary termination of treatment

At the beginning of treatment, patients should be informed about the conditions in which the treatment may be temporarily suspended or terminated. These may include violence or threat of violence against staff or other patients, property damage or theft from the service centre, drug dealing on or near the service premises, diversion of medication and unacceptable disruption in the locality. If the patient is to be involuntarily withdrawn from methadone treatment, reduction in dosage should be gradual.

The patient should be advised regarding other treatment options, including detoxification. He should also be warned of the increased risk of overdose after completion of withdrawal.

Transfer to other medications

Certain situations may warrant shifting patients from one modality of treatment for opioid dependence to another. These may be, individual preferences, intolerable side effects, an inadequate treatment response, the lack of availability of a particular agent in an area into which a patient has moved, and complications associated with drug interactions etc.

Transfer from methadone to buprenorphine

The dose of methadone should be reduced to and stabilised on 30 mg or less. The first dose of buprenorphine 47

should be administered at least 24 to 36 hours after the last use of methadone and preferably with mild to moderate withdrawals. Increasing the time interval between the last dose of methadone and the first dose of buprenorphine reduces the incidence and severity of precipitated withdrawal. The starting dose of buprenorphine is around 4mg on day one to be increased to 6 to 8 mg on day two for those receiving 20 to 30 mg methadone. Similarly, for those receiving less than 10mg of methadone the dose of buprenorphine on day 1 is 2 mg, to be increased to 6 mg on day 2. Subsequently the dose should be titrated as usual.

For induction from methadone doses between 30 to 60 mg, the methadone dose should be reduced as far as possible without the patient becoming unstable or chaotic, and then abruptly stopped. The first buprenorphine dose should be delayed until the patient displays clear signs of withdrawal, which is generally longer than 24 to 36 hours but may be as long as 48 to 96 hours, after the last methadone dose. An initial dose of 4 mg of buprenorphine should be given and following this the patient should be reviewed 2 to 3 hours later. If withdrawal has been precipitated, further symptomatic medication can be prescribed. If there has been no precipitation or worsening of withdrawal, an additional 2 to 4 mg of buprenorphine can be dispensed on the same day. The patient should be reviewed the following day at which point the dose should be increased to between 8 to 12 mg.

Transferring from methadone to naltrexone after detoxification

If the patient maintained on methadone wishes to shift to the antagonist in the form of naltrexone the dose of methadone should be reduced gradually at the rate of 5 mg/ week for dose more than 50 mg, 2.5 mg/week for dose between 30 -50 mg and 1-2 mg/ week for doses less than 30 mg per day.

Transfer from buprenorphine to methadone

To shift the patient receiving buprenorphine to methadone a gap of around 24 hours since the last dose of buprenorphine is usually sufficient to introduce methadone. The initial dose of methadone should be up to 40 mg per day for those been stabalised at 8 mg or more of buprenorphine per day. The initial dose of methadone could be 20 mg and 10 mg for those on 4 mg and 2 mg buprenorphine, respectively. Appropriate dosage levels vary according to the dose of buprenorphine and individual factors.

Summary and Conclusions

Opioid dependence is a relapsing disorder. Agonist maintenance treatment is associated with reduced drug use, improved psychosocial functioning, reduced risk of transmission of blood borne infections such as HIV and reduced mortality. Methadone as an agonist maintenance agent is an important treatment option to treat opioid dependence. Data from clinical trials generally indicate that moderate doses of methadone has comparable efficacy to buprenorphine but high doses of methadone is superior to buprenorphine. Adequate doses of methadone with adequate duration of treatment are required for better outcome of opioid dependent patients.

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Treatment algorithm for methadone maintenance for opioid dependent patients

DETERMINATION OF DAILY DOSE REQUIREMENT

Frequently asked questions
Q1. Ismethadoneeasilyavailableformaintenancetreatment?

Ans. Methadoneisnotavailableinmarket.Methadonecanbeobtainedonlyatfewspecialiseddrugtreatment clinics. Additionally, regulatory framework in India, allows only hospitals to stock and dispense, medications such as Methadone. Thus, Methadone is likely to be available only at selected centres in the country.

Q2. Whoarethesuitablecandidatesformethadonemaintenance?bThesuitabilitycriteriaforinclusionof patients in methadone maintenance treatment may vary. However, a confirmed diagnosis of opioid dependence is a pre-requisite; thus patients need to be evaluated for dependence on opioids. Besides a confirmed diagnosis of opioid dependence, other criteria may be considered such as at least 1 years of regular opioid use, failed abstinence attempt on other maintenance agents, high dose of heroin user and feeling withdrawal symptoms on other agonists maintenance.

Q3. Canmethadonemaintenancebeadvisedduringpregnancy?
Ans.
Methadone maintenance remains the current standard of care for treatment of the pregnant opioid-

dependent woman. Methadone maintenance significantly improves infant outcomes compared to pregnant women not on methadone maintenance that continue to use heroin. Methadone maintenance dose increases may be needed for the pregnant woman because of changes in blood volume and metabolism as the pregnancy progresses, and split methadone dosing may be useful in the third trimester (when methadone metabolism and clearance increases).

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Q4. Whatshouldbedoneifapatientmissesadoseofmethadone?
Ans.
Insuchcases,ifpatientmissesadoseforoneortwodaysthenshouldbegiventheusualdailydoseof

methadone. There is no point in adding the missed dose with the next dose. However, the reason for missing the dose needs to be enquired properly with the counselling of the patient if required. If patient misses doses for five days or more then new induction required.

Q5. Whatshouldbedoneifapatientdidnotcomefortreatmentfor3-4days?
Ans.
These situations are not infrequent in the methadone maintenance programmes. However, in such

circumstances, it is important to enquire the reason for absenteeism, ask for emergence of opioid withdrawal symptoms and their management along with the clinical examination of the patient for features of recent opioid use or withdrawal symptoms. If the facility of urine screening for psychoactive substances is available, this should be done. After assessing the patient, maintenance treatment should be reinducted and issues related to compliance should be addressed.

Q6. Whatwillhappenifthepatientstopsusingmethadoneabruptly?
Ans.
Severe withdrawal syndrome develops after 24 hours following abrupt methadone and lasts for 1-2

weeks.

Q7. How do I determine that the patient is not using any illicit opioids along with methadone maintenance?

Ans. It is important to understand that when the patient uses illicit opoids, he develops complications in all the spheres of life. Thus, information needs to be obtained from the family members regarding use of illicit opioids and psychosocial as well as occupational recovery of the patient. Apart from this, the patient needs to be examined for the evidence of recent opioid use such as recent injection mark, pupillary constriction along with other evidence of overdose/intoxication. If facilities for urinary screening of psychoactive substances are available, this should be done regularly for the presence of illicit opioids.

Q8. What should be done if the patient is found using illicit opioids while on methadone maintenance treatment?

Ans. If the patient is found using illicit opioids while on methadone maintenance treatment, he should not be incriminated. Rather, assessment of the cause for the same is required. Afterwards, the cause needs to be addressed by the joint decision of the doctor, and counselor / social worker / clinical psychologist along with the patient and family member so that treatment goals can be achieved. The dose of methadone may often have to be increased in such a case as it indicates inadequate blockade of acute effects of the illicit drug that is consumed.

Q9. Whatshouldbedoneifthepatientisusingalcoholconcurrentlywhileonmethadonemaintenance? Ans. This is not an infrequent situation in patients with polydrug dependence. In such situations, the patient

needs to be told about the risk of respiratory depression with the concomitant use of alcohol. This opportunity should also be used to motivate the patient to seek treatment for alcohol use as well if he is a problem drinker.

Q10. Whatmeasuresarerequiredtopreventdiversionofmethadonefromthetreatmentcentre?
Ans.
Itisimportanttosupervisethedispensingofmethadonetopreventdiversionfromthetreatmentcentre

(directly observed therapy). Additionally, care should be taken to maintain the stocks and records. 50

Q11. Whatshouldbetheadequatedurationofmaintenancetreatmentwithmethadone?
Ans.
Patients should remain in treatment for the minimum time it takes to achieve their agreed treatment goals

which is usually about 1-2 years. The length of time required for treatment will vary amongst individuals. Regular reviews will assist in determining the need for continued treatment. There is no fixed optimal duration of methadone treatment and removing people from treatment too early may result in very poor outcomes, including high rates of relapse into illicit opioid use and a consequent increased risk of overdose. Setting an arbitrary duration of treatment and withdrawing treatment at that endpoint is not recommended. The treatment approach should include working towards goals, that when achieved, prepare a patient to live well without methadone. In most situations stabilization on methadone for about two years would be required before withdrawal from it. An important objective of methadone treatment is the successful withdrawal from methadone combined with continued good functioning, including good health and social functioning.

Q12. How should successful withdrawal of a patient from methadone maintenance treatment be carried out?

Ans. Planning for successful withdrawal from methadone should commence from the initiation of treatment. The decision to withdraw voluntarily from methadone should be a joint decision of the patient and the prescribing doctor, with information contributed by the social worker or nursing staff, who may be evaluating the psychosocial functioning of the patient. When all agree about the timing and method of withdrawal from methadone patients tend to be more successful in their methadone reduction. It remains however, the patient’s right to withdraw from medication at any time. Forcing a patient off methadone when they do not feel capable of coping without the treatment may result in return to opioid use and related problems. The elements of treatment that assist patients to complete withdrawal successfully are flexible approach to dose reduction, increased psychosocial support during withdrawal and provision of aftercare services. Other options are shifting to Buprenorphine- Naloxone combination or naltrexone.

Q13. Whendoesthemethadonemaintenancetreatmentneedtobeterminatedinvoluntarily?
Ans.
At the beginning of treatment, patients should be informed about the conditions in which the treatment

may be temporarily suspended or terminated. These may include violence or threat of violence against staff or other patients, property damage or theft from the service centre, drug dealing on or near the service premises, diversion of medication and unacceptable disruption in the locality. If the patient is to be involuntarily withdrawn from methadone treatment, reduction in dosage should be gradual. Rapid dose reduction or abrupt cessation of treatment is warranted only in cases of violence, assault or threatened assault. In general, involuntary withdrawal from methadone should not take less than 14 days. The patient should be advised regarding other treatment options, including detoxification. He should also be warned of the increased risk of overdose after completion of withdrawal. A plan for subsequent readmission into treatment for each patient involuntarily withdrawn from the programme should be made and documented in the patient’s case record.

Q14 Whycan’tmydoctorincreasemydosemorequickly?
Ans.
When you first start methadone, you want to get on the right dose as soon as possible. But your doctor has

to increase your dose slowly over several weeks, because your body takes time to adjust to methadone, and (unlike other narcotics), methadone builds up slowly in your bloodstream over several days. A dose that may feel like too little on a Monday could put you in hospital for treatment of overdose by Thursday.

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Q15 What can I take to relieve withdrawal and help me sleep until the methadone begins to work?
Ans.
Only take medications that are prescribed by your methadone doctor. If you’re on a medication

prescribed by another doctor, your methadone doctor needs to approve it because it could interact with methadone. Substances that make you relaxed or sleepy can be dangerous. This includes alcohol, opioids, benzodiazepines, antihistamines and certain types of antidepressants and tranquilizers. Even certain antibiotics can be dangerous, by blocking the breakdown of methadone in the body. So make sure to check all medications with your methadone physician.

Q16 Isn’tmethadonesupposedtomakeyousleepy?
Ans.
No. You are supposed to feel normal on methadone, not high or sleepy. Methadone builds up so slowly

that someone can feel a bit sleepy during the day, lie down for a nap and not wake up. So please take the following precautions:

· · ·

Q17

· · · ·

Only take your methadone in the morning.
See your doctor twice a week for the first two weeks.
Discuss your methadone treatment with a close friend or family member. If they see that you’re drowsy, they must call your methadone doctor or an ambulance.

What are some of the symptoms if my methadone dose is too high?

You may feel sleepy, and nod off several times during the day.
You may be forgetful.
You may be difficult to wake up from your sleep.
You may experience slurred speech, stumbling walk, or appear drunk.

If these things are occurring you must call your doctor immediately or go to Emergency as you may be overdosing.

Q18 I’vebeenofferedasmallamountofmethadonebyamethadonepatientatthepharmacy.Thiscan’t hurt—IknowIneed80mg!

Ans. Above all, don’t take any extra methadone. It’s probably safe for your friend, but could be lethal for you. You took 80 mg once and were okay. If you had taken 80 mg every day for three or four days, you might have died. Remember, it takes five days for a certain dose to build up in your blood.

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References and further reading

• Ray R (2004) “The Extent, Pattern and Trends of drug abuse in India” UNODC, Regional Office for South Asia and Ministry of Social Justice and Empowerment, Government of India.

• Strain EC, Lofwall MR, Jaffe JH (2009). Opioid-related disorders. In: Sadock BJ, Sadock VA, Ruiz P. (Eds). Kaplan & Sadock’s Comprehensive Textbook of Psychiatry, 9th Edition, Lippincott Williams and Wilkins, Philadelphia.

• Ambekar A, Rao, R, Mukherjee D, Kedia S, “Counselling in Targeted Interventions for Injecting Drug Users: A Counsellor’s Training Module”, 2011, United Nations Office on Drugs and Crime, Regional office for South Asia, New Delhi

• Dole VP, Nyswander ME (1965). A medical treatment for diacetyl morphine (heroin) addiction: a clinical trial with methadone hydrochloride. JAMA.193:80-4.

• Ward J, Waynett, Mattick RP (1999). Role of maintenance treatment in opioid dependence. Lancet.353 : 221-26.

• Ling W, Wesson DR, Charuvastra C, Klett CJ (1996). A controlled trial comparing buprenorphine and methadone maintenance in opioid dependence. Arch Gen Psychiatry.53: 401-07.

• Farre M, Mas A, Torrens M et al (2002). Retention rate and illicit opioid use during methadone maintenance intervention: a meta-analysis. Drug Alcohol Depend. 65: 283-90.

• World Health Organisation. Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, 2009, World Health Organisation, Geneva

• Ball JC, Lange WR, Myers CP, Friedman SR (1988). Reducing the risk of AIDS through methadone maintenance treatment. Journal of Health and Social Behaviour. 29: 214-26.

• Novick DM, Joseph H, Croxson TS, Salsitz EA, Wang G, Richman BL, Poretsky L, Keefe JB (1990). Absence of antibody to human immunodeficiency virus in long term, socially rehabilitated methadone maintenance patients. Archives of Internal Medicine. 150: 97-9.

• Gossop M, Marsden J, Stewart D et al (2002). Reduced injection risk and sexual risk behaviours after drug misuse treatment : Result from the National Treatment Outcome Research Study. AIDS Care.14: 77-93.

• Metzger DS, Woody GE, De Philippis D, McLellan AT, O’Brien CP, Platt JJ (1991). Risk factors for needle sharing among methadone-treated patients. Am J Psychiatry.148:636-40.

• Esteban J, Gimeno C, Bassil J (2003). Survival study of Opioid addicts in relation to its adherence in methadone maintenance treatment. Drug Alcohol Depend. 70 :193-200.

• Rufener BL, Rachal JV, Cruze AM (1977). Management effectiveness measures for NIDA drug abuse treatment programs. Cost benefit analysis. Rockville, MD: National Institute on Drug Abuse.

• Harwood HJ, Hubbard RL, Collins JJ, et al (1988). The costs of crime and the benefits of drug abuse treatment: a cost-benefit analysis using TOPS data. NIDA Res Monogr;86:209-235.

• MattickRP ·, Breen C, Kimber J, Davoli M. (2009)Methadonemaintenancetherapyversus no opioid replacementtherapyfor opioid dependence. Cochrane Database Syst Rev.8;3

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• Mattick RP·, Kimber J, Breen C, Davoli M.(2008) Buprenorphinemaintenanceversus placebo ormethadonemaintenancefor opioid dependence. Cochrane Database Syst Rev.16;2

• Lal R (2005). Substance use disorder, manual for physicians. New Delhi: National Drug Dependence Treatment Centre, All India Institute of Medical Sciences.

• Lowinson JH, Marion I, Joseph H, Langrod J, Salsitz EA, Payte JT, Dole VP (2005).Methadone maintenance. Lowinson JH, Ruiz P,Millamen RB,Langrod JG (Eds). Substance Abuse: A Comprehensive Textbook. 4th edition.

• WHO (2009). Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence, WHO, Geneva

• WHO (2008). Operational Guidelines for the Management of Opioid Dependence in the South-East Asia Region, WHO, SEARO, New Delhi

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