BACKGROUND TO THE DEVELOPMENT OF THESE GUIDELINES
These guidelines were developed in response to a resolution from the United Nations Economic and Social Council (ECOSOC), which invited the World Health Organization (WHO), in collaboration with the United Nations Office on Drugs and Crime (UNODC), “to develop and publish minimum requirements and international guidelines on psychosocially assisted pharmacological treatment of persons dependent on opioids” [1]. In accordance with WHO policy, the recommendations in these guidelines are based on systematic reviews of the available literature and consultation with a range of experts from different regions of the world. The GRADE evidence tables summarizing these reviews are contained in Annex 1 of this document.
INTENDED READERSHIP OF THESE GUIDELINES
These guidelines are intended to be read by those involved in providing psychosocially assisted pharmacological treatments at any level. The readership falls into three broad groups:
policy makers and administrators who make decisions on the availability of medicines and the structure and funding of services in countries or in subnational health administrative regions
managers and clinical leaders responsible for the organization of specific health-care services, and for the clinical care those services provide
health-care workers treating patients within the health-care system.
EPIDEMIOLOGY OF OPIOID DEPENDENCE
UNODC estimates that there are 25 million problem drug users in world, of whom 15.6 are problem opioid users and 11.1 problem heroin users (approximately 0.3% of the global population) [2].1
The global epidemic of HIV and acquired immune deficiency syndrome (AIDS) is often fuelled and maintained by unsafe injection practices, with an estimated 30% of new cases of HIV outside sub-Saharan Africa due to unsafe injecting, [5] particularly unsafe opioid injecting. The cost of this epidemic is counted in the millions of lives lost each year and the billions of dollars spent [6]. A comprehensive package of interventions to prevent the transmission of HIV must include measures to reduce unsafe injecting of opioids, including the treatment of opioid dependence [7,11].
As with other chronic conditions, opioid dependence tends mostly to follow a relapsing and remitting course.
PSYCHOSOCIALLY ASSISTED PHARMACOLOGICAL TREATMENTS
Psychosocially assisted pharmacological treatment refers to the combination of specific pharmacological and psychosocial measures used to reduce both illicit opioid use and harms related to opioid use and improve quality of life. While the psychosocial measures are varied, only a few specific medications are used for the treatment of opioid dependence.
Opioid agonist maintenance treatment is defined as the administration of thoroughly evaluated opioid agonists, by accredited professionals, in the framework of recognized medical practice, to people with opioid dependence, for achieving defined treatment aims [8,9,10. Both methadone and buprenorphine are sufficiently long acting to be taken once daily under supervision, if necessary. When taken on a daily basis they do not produce the cycles of intoxication and withdrawal seen with shorter acting opioids, such as heroin. Both methadone and buprenorphine can also be used in reducing doses to assist in withdrawal from opioids, a process also referred to as opioid detoxification. Methadone and buprenorphine have a strong evidence base for their use, and have been placed on the WHO model list of essential medicines [8].
A different approach is that of assisting people dependent on opioids to withdraw from opioids completely, a process also referred to as opioid detoxification. Both methadone and buprenorphine can also be used in reducing doses to assist in withdrawal from opioids. Alpha-2 adrenergic agonists – such as clonidine – can also be used for opioid detoxification, to reduce the severity of opioid withdrawal symptoms.
Following detoxification, the long-acting opioid antagonist naltrexone can be used to prevent relapse to opioids. Naltrexone produces no opioid effects itself, and blocks the effects of opioids for 24–48 hours.
The short-acting opioid antagonist naloxone can be used to reverse the effects of opioid intoxication and overdose.
SUMMARY OF EVIDENCE AND RECOMMENDATIONS OF THESE GUIDELINES
Opioid agonist maintenance treatment
Of the treatment options examined, opioid agonist maintenance treatment, combined with psychosocial assistance, was found to be the most effective.
Oral methadone liquid and sublingual buprenorphine tablets are the medications most widely used for opioid agonist maintenance treatment. In the context of high-quality, supervised and well-organized treatment services, these medications interrupt the cycle of intoxication and withdrawal, greatly reducing heroin and other illicit opioid use, crime and the risk of death through overdose.
Compared to detoxification or no treatment, methadone maintenance treatment (using mostly supervised administration of the liquid methadone formulation) significantly reduces opioid and other drug use, criminal activity, HIV risk behaviours and transmission, opioid overdose and all-cause mortality; it also helps to retain people in treatment.
Compared to detoxification or no treatment, buprenorphine also significantly reduces drug use and improves treatment retention.
Methadone compared to buprenorphine for opioid agonist maintenance treatment
Comparing the evidence from clinical trials on the effectiveness of methadone and buprenorphine for opioid agonist maintenance treatment, both medications provide good outcomes in most cases. In general, methadone is recommended over buprenorphine, because it is more effective and costs less. However, buprenorphine has a slightly different pharmacological action; thus, making both medications available may attract greater numbers of people to treatment and may improve treatment matching.
Use of methadone in maintenance treatment
The initial methadone dose should be 20mg or less, depending on the level of opioid tolerance, allowing a high margin of safety to reduce inadvertent overdose. The dosage should be then quickly adjusted upwards if there are ongoing opioid withdrawal symptoms and downwards if there is any sedation. From there, the dose should be gradually increased to the point where illicit opioid use ceases; this is likely to be in the range of 60–120 mg methadone per day. Methadone use should be supervised initially. The degree of supervision should be individually tailored, and in accordance with local regulations; it should balance the benefits of reduced dosing frequency in stable patients with the risks of injection and diversion of methadone to the illicit drug market. Patients should be monitored with clinical assessment and drug testing. Psychosocial assistance should be offered to all patients.
Use of buprenorphine in maintenance treatment
Buprenorphine maintenance treatment should commence with a dose that is tailored to the pattern of opioid use, including the level of tolerance, the duration of action of opioids used and the timing of most recent opioid use (usually 4mg). From there, the dose should be rapidly increased (i.e. over days) to one that produces stable effects for 24 hours; this is generally in the range of 8–24 mg buprenorphine per day. Generally, if there is continuing opioid use, the dose should be increased. Dosing supervision and other aspects of treatment should be determined on an individual basis, using the same criteria as for methadone maintenance treatment.
Treatment for withdrawal and prevention of relapse
Opioid withdrawal (rather than maintenance treatment) results in poor outcomes in the long term; however, patients should be helped to withdraw from opioids if it is their informed choice to do so. Withdrawal from opioids can be conducted either on an outpatient or an inpatient basis, using reducing doses of methadone or buprenorphine, or alpha-2 agonists. Methadone and buprenorphine are the preferred treatments for opioid withdrawal, because they are effective and can be used in a supervised fashion in both inpatient and outpatient settings. Inpatient treatment is more effective, but it is also more expensive and is recommended only for a minority of patients (e.g. those with polysubstance dependence, or medical or psychiatric comorbidity). Accelerated withdrawal techniques using opioid antagonists in combination with heavy sedation are not recommended because of safety concerns.
Use of naltrexone to prevent relapse
Naltrexone can be useful in preventing relapse in those who have withdrawn from opioids, particularly in those who are already motivated to abstain from opioid use. Following opioid withdrawal, patients who are motivated to abstain from opioid use should be advised to consider naltrexone to prevent relapse.
PSYCHOSOCIAL TREATMENT
Psychosocial interventions – including cognitive and behavioural approaches and contingency management techniques – can add to the effectiveness of treatment, if combined with agonist maintenance treatment and medications for assisting opioid withdrawal. Psychosocial services should be made available to all patients, although those who do not take up the offer should not be denied effective pharmacological treatment.
TREATMENT SYSTEMS
In planning treatment systems, resources should be distributed in a way that delivers effective treatment to as many people as possible. Opioid agonist maintenance treatment appears to be the most cost-effective treatment, and should therefore form the backbone of the treatment system for opioid dependence. Countries with established opioid agonist maintenance programmes usually attract 40–50% of dependent opioid users into such programmes, with higher rates in some urban environments. Because of their cost, inpatient facilities should be reserved for those with specific needs, and most patients wanting to withdraw from opioids should be encouraged to attempt opioid withdrawal as outpatients.
ETHICAL PRINCIPLES OF CARE
When treating people with opioid dependence, ethical principles should be considered, together with evidence from clinical trials; the human rights of opioid-dependent individuals should always be respected. Treatment decisions should be based on standard principles of medical-care ethics – providing equitable access to treatment and psychosocial support that best meets the needs of the individual patient. Treatment should respect and validate the autonomy of the individual, with patients being fully informed about the risks and benefits of treatment choices. Furthermore, programmes should create supportive environments and relationships to facilitate treatment, provide coordinated treatment of comorbid mental and physical disorders, and address relevant psychosocial factors.
RECOMMENDATIONS
This section lists all the recommendations contained in these guidelines.
Recommendations for action at policy or health-system levels are marked as either marked “minimal” or “best practice”:
minimal recommendations are suggested for adoption in all settings as a minimum standard; these should be considered the minimal requirements for the provision of treatment of opioid dependence
best practice recommendations represent preferred strategies for achieving the optimal public health benefit in the provision of treatment for opioid dependence.
The document contains recommendations based on evidence from systematic reviews and meta-analyses, taking into consideration evidence from other sources, technical considerations, resource implications and the risks and benefits of different alternatives. As recommended in the GRADE system, recommendations were divided into two strengths, here termed as “strong” or “standard” recommendations.
strong recommendations are those for which:
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most individuals should receive the intervention, assuming that they have been informed about and understand its benefits, harms and burdens
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most individuals would want the recommended course of action and only a small proportion would not
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the recommendation could unequivocally be used for policy making
standard recommendations are those for which:
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most individuals would want the suggested course of action, but an appreciable proportion would not
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values and preferences vary widely
policy making will require extensive debates and involvement of many stakeholders.
Some recommendations do not include an indication of strength – this means that the recommendation was ungraded.
Summary of recommendations
Recommendations for health systems at national and subnational levels
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| Minimal requirements | Best practice |
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| Treatment strategy | | A strategy document should be produced outlining the government policy on the treatment of opioid dependence. The strategy should aim for adequate coverage, quality and safety of treatment. |
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| Legal framework | Psychosocially assisted pharmacological treatment should not be compulsory. | |
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| Treatment funding and availability | Treatment should be accessible to disadvantaged populations.
Pharmacological treatment of opioid dependence should be widely accessible; this might include treatment delivery in primary care settings. Patients with comorbidities can be treated in primary health-care settings if there is access to specialist consultation when necessary.
At the time of commencement of a treatment service, there should be a realistic prospect of that service being financially viable.
Essential pharmacological treatment options should consist of opioid agonist maintenance treatment and services for the management of opioid withdrawal. At a minimum, this would include either methadone or buprenorphine for opioid agonist maintenance and outpatient withdrawal management. | To achieve optimal coverage and treatment outcomes, treatment of opioid dependence should be provided free of charge, or covered by public health-care insurance.
Pharmacological treatment of opioid dependence should be accessible to all those in need, including those in prison and other closed settings.
Pharmacological treatment options should consist of both methadone and buprenorphine for opioid agonist maintenance and opioid withdrawal, alpha-2 adrenergic agonists for opioid withdrawal, naltrexone for relapse prevention, and naloxone for the treatment of overdose. |
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Recommendations for treatment programmes
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| Minimal requirements | Best practice |
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| Clinical governance | Treatment services should have a system of clinical governance, with a chain of clinical accountability within the health-care system, to ensure that the minimal standards for provision of opioid dependence treatment are being met. | A process of clinical governance should be established to ensure that treatments for opioid dependence are both safe and effective. The process should be transparent and outlined in a clinical governance document.
Treatment of opioid dependence should be provided within the health-care system. |
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| Consent to treatment | Patients must give informed consent for treatment. | |
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| Training of staff | Treatment of opioid dependence should be carried out by trained health-care personnel. The level of training for specific tasks should be determined by the level of responsibility and national regulations. | Health authorities should ensure that treatment providers have sufficient skills and qualifications to use controlled substances appropriately. These requirements may include postgraduate training and certification, continuing education and licensing, and the setting aside of funding for monitoring and evaluation. |
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| Medical records | Up-to-date medical records should be kept for all patients. These should include, as a minimum, the history, clinical examination, investigations, diagnosis, health and social status, treatment plans and their revisions, referrals, evidence of consent, prescribed drugs and other interventions received.
Confidentiality of patient records should be ensured.
Health-care providers involved in the treatment of an individual should have access to patient data in accordance with national regulations, as should patients themselves.
Health-care providers or other personnel involved in patient treatment should not share information about patients with police and other law enforcement authorities unless a patient approves, or unless required by law.
Patients treated with opioid agonists should be identifiable to treating staff. | |
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| Pharmacy records | Documented processes should be established to ensure the safe and legal procurement, storage, dispensing and dosing of medicines, particularly of methadone and buprenorphine. | |
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| Clinical guidelines | Clinical guidelines for the treatment of opioid dependence should be available to clinical staff. | Clinical guidelines should be detailed, comprehensive, evidence based and developed at a country level or lower, to refect local laws, policies and conditions. |
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| Opioid agonist maintenance dosing policies | To maximize the safety and effectiveness of agonist maintenance treatment programmes, policies and regulations should encourage flexible dosing structures, with low starting doses and high maintenance doses, and without placing restrictions on dose levels and the duration of treatment. | |
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| Detoxification services | | Opioid withdrawal services should be structured such that withdrawal is not a stand-alone service but is integrated with ongoing treatment options. |
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| Take home doses | | Take-home doses can be recommended when the dose and social situation are stable, and when there is a low risk of diversion for illegitimate purposes. |
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| Involuntary discharge | | Involuntary discharge from treatment is justified to ensure the safety of staff and other patients, but noncompliance with programme rules alone should not generally be a reason for involuntary discharge. Before involuntary discharge, reasonable measures to improve the situation should be taken, including re-evaluation of the treatment approach used. |
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| Assessment and choice of treatment | A detailed individual assessment should be conducted which includes: history (past treatment experiences; medical and psychiatric history; living conditions; legal issues; occupational situation; and social and cultural factors, that may influence substance use); clinical examination (assessment of intoxication / withdrawal, injection marks); and, if necessary, investigations (such as urine drug screen, HIV, Hep C, Hep B, TB, liver function).
Urine drug testing should be available for use at initial assessment when a recent history of opioid use cannot be verified by other means (e.g. evidence of opioid withdrawal or intoxication). | The choice of treatment for an individual should be based on a detailed assessment of the treatment needs, appropriateness of treatment to meet those needs (assessment of appropriateness should be evidence based), patient acceptance and treatment availability.
Screening for psychiatric and somatic comorbidity should form part of the initial assessment.
Voluntary testing for HIV and common infectious diseases should be available as part of an individual assessment, accompanied by counselling before and after testing.
Ideally, all patients should be tested at initial assessment for recent drug use.
Treatment plans should take a long-term perspective.
Opioid withdrawal should be planned in conjunction with ongoing treatment. |
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| Range of services to be offered | Essential pharmacological treatment options should consist of opioid agonist maintenance treatment and services for the management of opioid withdrawal.
Naloxone should be available for treating opioid overdose. | Pharmacological treatment options should consist of both methadone and buprenorphine for opioid agonist maintenance and opioid withdrawal, alpha-2 adrenergic agonists for opioid withdrawal, naltrexone for relapse prevention, and naloxone for the treatment of overdose. |
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| Psychosocial support availability | Psychosocial support should be available to all opioid-dependent patients, in association with pharmacological treatments of opioid dependence. At a minimum, this should include assessment of psychosocial needs, supportive counselling and links to existing family and community services. | A variety of structured psychosocial interventions should be available, according to the needs of the patients. Such interventions may include - but are not limited to - different forms of counselling and psychotherapy, and assistance with social needs such as housing, employment, education, welfare and legal problems. |
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| | Onsite psychosocial and psychiatric treatment should be provided for patients with psychiatric comorbidity. |
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| Availability of treatment for comorbid medical conditions | Links to HIV, hepatitis and TB treatment services (where they exist) should be provided. | Where there are significant numbers of opioid-dependent patients with either HIV, hepatitis or TB, treatment of opioid dependence should be integrated with medical services for these conditions.
For patients with TB, hepatitis or HIV and opioid dependence, opioid agonists should be administered in conjunction with medical treatment; there is no need to wait for abstinence from opioids to commence either anti-TB medication, treatment for hepatitis or antiretroviral medication.
Opioid-dependent patients with TB, hepatitis or HIV should have equitable access to treatment for TB, hepatitis, HIV and opioid dependence. |
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| Availability of hepatitis B vaccine | | Treatment services should offer hepatitis B vaccination to all opioid-dependent patients. |
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| Treatment evaluation | There should be a system for monitoring the safety of the treatment service, including the extent of medication diversion. | There should be intermittent or ongoing evaluation of both the process and outcomes of the treatment provided. |
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Recommendations for treatment of the individual patient
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| | Strength of recommendation | Quality of evidence |
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| Choice of treatment | For the pharmacological treatment of opioid dependence, clinicians should offer opioid withdrawal, opioid agonist maintenance and opioid antagonist (naltrexone) treatment, but most patients should be advised to use opioid agonist maintenance treatment. | Strong | Low to moderate |
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| For opioid-dependent patients not commencing opioid agonist maintenance treatment, consider antagonist pharmacotherapy using naltrexone following the completion of opioid withdrawal. | Standard | Low |
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| Opioid agonist maintenance treatment | For opioid agonist maintenance treatment, most patients should be advised to use methadone in adequate doses in preference to buprenorphine. | Strong | High |
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| During methadone induction, the initial daily dose should depend on the level of neuroadaptation; it should generally not be more than 20 mg, and certainly not more than 30mg. | Strong | Very low |
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| On average, methadone maintenance doses should be in the range of 60–120 mg per day. | Strong | low |
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| Average buprenorphine maintenance doses should be at least 8 mg per day. | Standard | Very low |
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| Methadone and buprenorphine doses should be directly supervised in the early phase of treatment. | Strong | Very low |
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| Take-away doses may be provided for patients when the benefits of reduced frequency of attendance are considered to outweigh the risk of diversion, subject to regular review. | Standard | Very low |
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| Psychosocial support should be offered routinely in association with pharmacological treatment for opioid dependence. | Strong | High |
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| Management of opioid withdrawal | For the management of opioid withdrawal, tapered doses of opioid agonists should generally be used, although alpha-2 adrenergic agonists may also be used. | Standard | Moderate |
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| Clinicians should not routinely use the combination of opioid antagonists and minimal sedation in the management of opioid withdrawal. | Standard | Very low |
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| Clinicians should not use the combination of opioid antagonists with heavy sedation in the management of opioid withdrawal. | Strong | low |
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| Psychosocial services should be routinely offered in combination with pharmacological treatment of opioid withdrawal. | Standard | Moderate |
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| Pregnancy | Opioid agonist maintenance treatment should be used for the treatment of opioid dependence in pregnancy. | Strong | Very low |
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| Methadone maintenance should be used in pregnancy in preference to buprenorphine maintenance for the treatment of opioid dependence; although there is less evidence about the safety of buprenorphine, it might also be offered. | Standard | Very low |
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The category of “problem drug user” is generally defined to include both dependent users and non dependent drug injectors.
