Evidenciar la problemática que ha tenido el sector lechero en los últimos cinco años debido a

Should agonist maintenance therapy (i.e. methadone or

buprenorphine maintenance) be used in preference to withdrawal and oral antagonist therapy (naltrexone) or withdrawal alone?

See evidence profiles in Annex 1 in:

Sections A1.1 and A1.2 for methadone versus withdrawal Section A1.3 for buprenorphine versus withdrawal or placebo Section A1.11 for naltrexone versus placebo.

Efficacy

Methadone versus withdrawal

The recently updated Cochrane review^[105] of methadone maintenance therapy versus no opioid replacement therapy identified three randomized controlled trials (RCTs) that compared methadone with opioid withdrawal followed by placebo[106, 107, 108]. These studies show that, compared to opioid withdrawal or placebo, methadone maintenance treatment dramatically reduces levels of illicit opioid use (relative risk [RR] 0.32; 95% confidence interval [CI] 0.23 to 0.44, high quality evidence) and increases retention in treatment (RR 3.05; 95%CI 1.75 to 5.35). Observational studies demonstrate that the mortality rate in methadone treatment is approximately one third the rate out of treatment (RR 0.37; 95%CI 0.29 to 0.48, low-quality evidence).

Methadone appears to reduce the risk of HIV injection by approximately 50% (RR 0.45, 95%CI 0.35 to 0.59, moderate-quality evidence) and there is a similar reduction in seroconversion rates (RR 0.36, 95%CI 0.19 to 0.66, low-quality evidence) compared to withdrawal or no treatment. No studies were found that compare methadone with naltrexone treatment.

Buprenorphine versus withdrawal or placebo

The Cochrane review of buprenorphine identified one study comparing buprenorphine with placebo^[109], and one study comparing 1 mg per day with higher doses^[110]. Compared to placebo (including 1 mg dose as placebo), buprenorphine leads to a dose-responsive reduction in heroin use and improved retention in treatment. A dose of 16 mg buprenorphine results in higher rates of retention in treatment (RR 1.52, 95%CI 1.23 to 1.88) and less morphine-positive urines (standardized mean

27 Patient level guidelines – for clinicians

difference (SMD) –0.65, 95%CI –0.86 to –0.44) than placebo.

Naltrexone versus placebo

The Cochrane review of naltrexone for prevention of relapse in opioid dependence identified 6 studies, with a total of 249 patients ^[170]. In detoxified patients, naltrexone was more effective than placebo in reducing heroin use (RR 0.72, 95%CI 0.58 to 0.90, low-quality evidence), but did not affect retention in treatment (RR 1.08, 95%CI 0.74 to 1.57) or relapse at follow-up post treatment (RR 0.94, 95%CI 0.67 to 1.34).

Safety

Methadone maintenance is associated with an increase in mortality during the first two weeks of treatment compared to pretreatment levels, due to respiratory depression^[111]. After that time, there is a reduction in mortality that remains until treatment stops. Most patients will resume opioid use at some stage, and the reduction in tolerance associated with the completion of opioid withdrawal can increase the risk of opioid overdose.

Pharmacology studies suggest that buprenorphine probably has less risk of overdose than methadone, but fatal overdoses of buprenorphine combined with other sedatives can still occur.

Treatment with naltrexone may increase the risk of sedative overdose in the period following the cessation of naltrexone. Some accelerated opioid withdrawal techniques that are used to start patients on naltrexone – in particular the use of antagonists in combination with heavy sedation – also appear to increase the risk of fatal complications.

A significant proportion of patients in opioid agonist therapy develop adverse effects (see Section 6.5).

Methadone leads to a slight increase in the QT interval (i.e. the time between the start of the Q wave and the end of the T wave in the heart’s electrical cycle), possibly resulting in a slightly increased chance of life-threatening cardiac arrhythmias, although it is difficult to make a precise estimate of any increased risk.

Buprenorphine and naltrexone do not prolong the QT interval.

Contraindications to the use of opioid agonist maintenance treatment, and precautions for use of the treatment, include decompensated liver disease (such as with jaundice and ascites) – because in this context opioids may precipitate hepatic encephalopathy – and acute asthma and other causes of respiratory insufficiency.

Precautions for both opioid agonist treatment and opioid detoxification include high-risk polydrug use, mental illness, low levels of neuroadaptation to opioids (e.g. in recent incarceration, because many people who are incarcerated do not use opioids with the frequency required to maintain their levels of tolerance to opioids) and significant concomitant medical problems.

Precautions to the use of opioid withdrawal over agonist maintenance therapy include pregnancy (because withdrawal can lead to miscarriage), and serious acute physical or psychiatric conditions (because withdrawal may worsen or complicate management of the underlying conditions).

Cost effectiveness

In a recent study of opioid substitution therapy in different countries^[112], resource-use and cost data relating to methadone and buprenorphine maintenance treatment were collected in selected WHO member states (Indonesia, Iran, Lithuania and Poland).

The total monthly cost of providing long-term methadone and buprenorphine maintenance treatment (including an initial induction phase) ranged from as little as US$26–36 in Indonesia and the Islamic Republic of Iran (approximately US$1/day) to US$296 in Poland (approximately US$10/day). This provides an indicative range within which to locate the expected investment needed to provide methadone maintenance treatment to a service user in a low or middle-income country.

In high-income countries, costs for methadone and buprenorphine maintenance treatment are generally estimated to be US$5000 per year, or US$15 per day^[113].

Estimation of the cost of providing medication is not an adequate basis for budgetary planning, because it may represent only a fraction of total service costs (e.g. <20%

in the Islamic Republic of Iran). Studies in Australia, Canada, the United States and United Kingdom have estimated the impact of treatment on total health-care costs, social security costs, lost productivity and crime.

Thus, these studies estimate the economic “return on investment” in opioid-dependence treatment^{[62, 114]}. They show that treatment of opioid dependence pays for itself, because savings in social costs are greater than the expenditure in treatment. It is difficult to extrapolate the results of these studies to lower income countries.

Estimates of cost effectiveness in high income countries countries have found that both methadone and buprenorphine maintenance are cost effective, being well below accepted thresholds for cost–benefit analysis of treatment^{[115, 116]}.

The cost of a “one off” episode of opioid withdrawal varies significantly between settings; it depends on the method of withdrawal, the length of treatment, the medication used and staff resources.

Because of differences between maintenance and withdrawal, it is difficult to estimate the long-term cost implications of choosing between:

opioid agonist maintenance treatment, which is low

•

intensity and long term, and has a low relapse rate opioid withdrawal, which is high intensity and short

•

term, and has a relatively high relapse rate.

Limitations of the data

No studies were found that directly compared the three different treatment approaches using a randomized design. It may be difficult to investigate this question using RCTs because patients may be reluctant to relinquish their right to choose a treatment modality. The clinical trials that were found compared the decision to attempt opioid withdrawal at one point in time versus methadone maintenance. In practice, an attempted opioid withdrawal that fails is usually followed by repeated attempts until the patient either succeeds, or stops trying to withdraw from opioids. This review found no RCTs comparing repeated attempts at opioid

withdrawal with opioid agonist maintenance treatment.

Also lacking were studies comparing methadone and buprenorphine maintenance treatment with opioid withdrawal and relapse prevention using naltrexone.

Treatment considerations

In practice, there is often a blurring between opioid agonist maintenance and opioid withdrawal using tapered doses of methadone or buprenorphine. Patients often start with tapering doses of agonist while trying to cease their heroin use, and increase their agonist dose temporarily whenever they relapse.

Benefits of opioid agonist maintenance treatment

The most significant benefit of opioid agonist maintenance treatment is that it has a much lower mortality rate than treatments based on opioid abstinence (the evidence for this effect is stronger for methadone than for buprenorphine). Opioid agonist maintenance treatment results in less heroin use for most patients, and better retention in drug treatment in general.

Undesirable effects and consequences

Many patients find the burden of supervised dosing every day onerous, and some patients experience adverse effects (including opioid withdrawal symptoms between doses) with methadone. Patients on methadone and buprenorphine can still experience opioid effects if they use illicit opioids; although the effects are diminished, they are not blocked completely as they would be with naltrexone. This results in good rates of retention in opioid agonist maintenance treatment, even for those people with ongoing heroin use, but it may delay the progression to long-term abstinence.

Travel can be difficult for patients on methadone and buprenorphine if they are required to have their doses supervised. Unsupervised administration results in increased rates of misuse of opioid agonist medication, and diversion to illicit drug markets; also, take-home doses are occasionally consumed by children and opioid-naive adults, with fatal consequences. Cessation of methadone and buprenorphine can result in a withdrawal syndrome that is more prolonged and

29 Patient level guidelines – for clinicians

sometimes more severe than withdrawal from heroin.

Also, many patients resume heroin use after cessation of methadone, even after long-term treatment.

Conclusion

For most patients, opioid agonist maintenance