Method of formulating recommendations 2.1 Conventions for reporting clinical trial data 3 Background 3.1 Opioid dependence 3.2 Neurobiological aspects of opioid dependence 3.3 Epidemiology of illicit opioid use and dependence 3.4 Harms associated with opioid use 3.5 Economic consequences of opioid use 3.6 Natural history of opioid dependence 3.7 Opioid dependence as a medical condition 3.8 Treatment of opioid dependence 3.8.1 Management of opioid withdrawal 3.8.2 Agonist maintenance treatment 3.8.4 Psychosocial assistance 4 Guidelines for health systems at national and subnational levels 4.1 International regulations 4.2 Opioid dependence as a health-care issue 4.3 National treatment policy 4.4 Ethical issues 4.4.1 Compulsory and coerced treatment 4.4.2 Central registration of patients 4.5 Funding 4.6 Coverage 4.6.1 Primary care 4.6.2 Prisons 4.7 What treatments should be available? 4.8 Supervision of dosing for methadone and buprenorphine maintenance 5 Programme level guidelines -for programme managers and clinical leaders 5#
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" . 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) . 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,  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 . 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 .
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 .
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.
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: most individuals should receive the intervention, assuming that they have been informed about and understand its benefits, harms and burdens most individuals would want the recommended course of action and only a small proportion would not the recommendation could unequivocally be used for policy making - standard recommendations are those for which: most individuals would want the suggested course of action, but an appreciable proportion would not 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.

# 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.
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.

# 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.

# 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 reflect local laws, policies and conditions.

# 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.
Recommendations for treatment programmes

# Minimal requirements Best practice

# Detoxification services
Opioid withdrawal services should be structured such that withdrawal is not a stand-alone service but is integrated with ongoing treatment options.

# 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.

# 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.

# 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.
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.

# Psychosocial support availability
Psychosocial support should be available to all opioiddependent 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.

# Executive summary
Recommendations for treatment programmes

# Minimal requirements Best practice
Onsite psychosocial and psychiatric treatment should be provided for patients with psychiatric comorbidity.

# 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 opioiddependent 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.

# Availability of hepatitis B vaccine
Treatment services should offer hepatitis B vaccination to all opioid-dependent patients.
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.
Recommendations for treatment of the individual patient

# Strength of recommendation

# Quality of evidence

# 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
For opioid-dependent patients not commencing opioid agonist maintenance treatment, consider antagonist pharmacotherapy using naltrexone following the completion of opioid withdrawal.

# Standard low

# 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
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
On average, methadone maintenance doses should be in the range of 60-120 mg per day.

# Strong low
Average buprenorphine maintenance doses should be at least 8 mg per day. Standard Very low
Methadone and buprenorphine doses should be directly supervised in the early phase of treatment.

# Strong Very low
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
Psychosocial support should be offered routinely in association with pharmacological treatment for opioid dependence.

# Strong High

# 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
Clinicians should not routinely use the combination of opioid antagonists and minimal sedation in the management of opioid withdrawal.

# Standard Very low
Clinicians should not use the combination of opioid antagonists with heavy sedation in the management of opioid withdrawal.

# Strong low
Psychosocial services should be routinely offered in combination with pharmacological treatment of opioid withdrawal.

# Standard Moderate
Opioid agonist maintenance treatment should be used for the treatment of opioid dependence in pregnancy.

# Strong Very low
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
These guidelines have been developed in response to the resolution Guidelines for psychosocially assisted pharmacological treatment of persons dependent on opioids of the United Nations Economic and Social Council (ECOSOC). The resolution invited the World Health Organization (WHO), in collaboration with 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, taking into account regional developments in the field, in order to assist the member states concerned" .
These guidelines are intended to be read by those involved in providing psychosocially assisted pharmacological treatment of opioid dependence at any level. Chapter 2 explains how the guidelines were formulated, and Chapter 3 provides background information on opioid dependence. Chapters 4-6 are directed, respectively, at the three broad groups for whom this document is intended: policy makers and administrators who make
- decisions on the availability of medicines, and on 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. National and regional programmes, and treatment guideline groups may wish to use this document to assist in the development of locally adapted guidelines.
The clinical questions addressed by these guidelines were developed in consultation with clinicians and academics from various countries involved in the management of opioid dependence. The questions addressed by these guidelines can be summarized briefly as: What medications should be used for the - management of opioid dependence and withdrawal? Further questions related to this issue are: Should preference be given to opioid agonist maintenance treatment, detoxification or antagonist treatment?
Which medications should be used for each approach? How should medications be administered (optimal dose, level of dosing supervision, etc.)? What level and type of psychosocial support should - be provided to opioid-dependent patients? What specific treatment should be offered The recommendations in the guidelines operate at three levels:
treatment systems at national and subnational
- levels (policy, legislation, funding, regional and country planning) (see Chapter 4) treatment programmes (methods of organization The medications considered in these guidelines are methadone, buprenorphine, naltrexone and adrenergic alpha-2 agonists (clonidine, lofexidine and guanfacine).
Although other medications show promise in the treatment of opioid dependence, they have not been included in these guidelines because there is insufficient evidence to make a full analysis of their effectiveness; thus, including them would significantly increase the complexity of the guidelines. A brief description of the pharmacology of these medications is included in Annex 4.
The aims of these guidelines are to: reduce global barriers to the effective treatment of The guidelines cover not only opioid dependence, but also treatment of opioid overdose and opioid withdrawal.
The WHO Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence were prepared according to the WHO Guidelines for WHO Guidelines (2003)  modified as necessary to provide advice: on many complex clinical questions for which
- evidence is lacking even in the absence of high-quality evidence.
- A group of technical experts -international scientists with expertise in opioid dependence and clinical guidelines development -was convened in 2005, and again in 2006 and 2007. The membership of this group is detailed in the acknowledgements section. In their first meeting, the group defined the key questions to be addressed by the guidelines. For each key clinical question, the literature was searched for recent systematic reviews on the topic. Where a Cochrane review 2 existed, that review was used in preference to other reviews. Where no suitable systematic review existed, a review was conducted.
At its meeting in 2006, the group assessed the evidence and formulated recommendations. The quality of the evidence was assessed according to the methodology described by the GRADE working group . This approach involves assessing the quality of evidence on a particular question, taking into consideration the magnitude of the effect, the relevance of the data to the clinical question being asked, the sample size in the relevant trials, the methodology of the trials and the consistency of the findings. At the start of this process, each health outcome was rated from 1 to 9, according to its importance. The GRADE convention on the rating of outcomes is as follows: ratings of 7-9 are for critical health outcomes
- ratings of 4-6 are for outcomes that are considered
- important but not critical to the decision; they should be used in judgements about tradeoffs and recommendations, but not in judgements about the overall quality of evidence across critical outcomes ratings of 1-3 are generally removed from
- the evidence profile and are not considered in 2 / judgements about the overall quality of evidence, tradeoffs or recommendations.
In some instances, additional meta-analyses were conducted from the systematic review data: to exclude non-randomized controlled trials (non-
- RCTs) (where Cochrane reviews had included nonrandomized trials) to reverse some outcomes and thus maintain
- outcome consistency (e.g. using "drop out" as the primary outcome measure of retention rather than "still in treatment") to reverse the order of the comparisons, where
- necessary (e.g. methadone versus buprenorphine instead of buprenorphine versus methadone). to examine an additional outcome of interest (e.g.
- the addition of seroconversion as an outcome measure in the review of opioid agonist treatment and HIV).
In the GRADE system, evidence is classified as "high", "moderate", "low" or "very low". Definitions are as follows: High
- -Further research is very unlikely to change confidence in the estimate of effect. Moderate
- -Further research is likely to have an important impact on confidence in the estimate of effect and may change the estimate. Low
- -Further research is very likely to have an important impact on confidence in the estimate of effect and is likely to change the estimate.

# Very low
- -Any estimate of effect is very uncertain.
The resulting evidence profiles are listed in Annex 1.
To produce a series of recommendations, the technical experts considered the evidence from these reviews and meta-analyses, taking into consideration evidence from other sources, technical considerations, resource implications and the risks and benefits of different alternatives.
The strength of each recommendation is based on considerations of the effectiveness of the intervention, the strength of the evidence, the resource implications, 2 Method of formulating recommendations the balance between benefits and harms, and a consideration of ethical implications. As recommended in the GRADE system, recommendations are divided into two strengths, here termed as "strong" or "standard" recommendations.
"Strong" recommendations can be interpreted as follows:
Most individuals should receive the intervention,
- assuming that they have been informed about and understand its benefits, harms and burdens. Most individuals would want the recommended
- course of action and only a small proportion would not.
The recommendation could unequivocally be used
- for policy making.
"Standard" recommendations can be interpreted as follows:
Most individuals would want the suggested course
- of action, but an appreciable proportion would not.
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 is ungraded.
A draft of the guidelines was circulated for feedback in July 2007 to selected organizations, WHO departments and regional offices, and WHO collaborating centres; it was also provided to individuals on request. This draft, along with received submissions, was considered at the third meeting in September 2007.
These guidelines are likely to require updating in the near future, given the pace of research in this field, the multitude of alternative treatments not considered here and the relatively scant published experience to date in less resourced countries. The recommendations are therefore expected to remain valid for the next three years only.
The WHO Department of Mental Health and Substance Abuse will take responsibility for updating these guidelines.
Policy and programme-level recommendations are based on the evidence from the GRADE process, combined with other evidence not reviewed systematically, including the opinion of the members of the technical expert group. Consequently, there are no GRADE tables corresponding to the recommendations in these sections.

# Conventions for reporting clinical trial data
Clinical trial data are summarized in these guidelines. When comparing outcomes classed as categorical variables (e.g. mortality, retention in treatment or abstinence from opioids), the relative risk is used (RR). The relative risk is the ratio of the probability of a particular outcome in the population exposed to a particular intervention or risk factor, compared to the probability of that outcome occurring without exposure to the risk factor or intervention. For example, if an RCT compared a group of heroin users on methadone with a group assigned to detoxification, and found that those in the methadone group had a relative risk of heroin use of 0.32, this would mean that, on average, people with opioid dependence are approximately one third as likely to be using heroin if they are treated with methadone than if they undergo opioid detoxification.
For continuous variables (e.g. the severity of opioid withdrawal, or the number of opioid-positive urine tests for each study participant), the standardized mean difference (SMD) or weighted mean difference is used with a meta-analysis. The standardised mean difference, used for non-comparable scales, is the difference between two means, divided by an estimate of the within-group standard deviation. The weighted mean difference is used for comparable scales.
The 95% confidence interval (CI) for a relative risk or mean difference expresses the range that is highly likely (i.e. 19 times out of 20) to contain the true relative risk or mean difference, based on the data available. For example, the 95% confidence interval for the relative risk of dying in the follow-up period if randomly allocated to methadone compared to detoxification is 0.29 to 0.48; this implies that there is a 95% chance that the true relative risk lies in this range.

# Opioid dependence
Opioid dependence is characterized by a cluster of cognitive, behavioural and physiological features. The International Classification of Diseases, 10 th edition (ICD-10)  identifies six such features: a strong desire or sense of compulsion to take
- opioids difficulties in controlling opioid use ICD-10 defines opioid dependence as the "presence of three of more  present simultaneously at any one time in the preceding year" (see Annex 3 for more details).
Opioid dependence does not develop without a period of regular use, although regular use alone is not sufficient to induce dependence.

# Neurobiological aspects of opioid dependence
Repeated opioid use induces a series of neuroadaptations in various neuronal circuits in the brain that are involved in motivation, memory, behaviour control and disinhibition. The result is an increased and long-lasting reward value associated with the use of opioids and the environmental cues associated with such use, and a decreased reward value associated with natural reinforcers encountered in everyday life events .
Recent decades have seen a substantial increase in our understanding of the neurobiological aspects of substance dependence . We now know that certain parts of the brain have an important role in regulating pleasurable behaviours, and that neuronal pathways to and from these areas form so-called "reward circuits". They are located within the mesocorticolimbic dopamine systems originating in the ventral tegmental area, projecting to the nucleus accumbens, amygdala, and prefrontal cortex area .
In the 1970s and 1980s, the existence of multiple opioid receptors was reported, and further pharmacological research suggested the classification of opioid binding sites into three receptor classes, referred to as mu, delta and kappa receptors . Since then, our understanding has further developed and we now know that opioid receptors belong to the family of G-protein coupled receptors, and that each receptor class has several subtypes .
The opioid effects of analgesia, euphoria and sedation are mediated primarily by the mu receptor. Opioids induce dopamine release indirectly by decreasing gamma-aminobutyric acid (GABA) inhibition via mu receptors in the ventral tegmental area . They also induce dopamine release directly, by interacting with opioid receptors in the nucleus accumbens .
The effect of chronic opioid exposure on opioid receptor levels has not been well defined in humans. Tolerance develops through multiple mechanisms, including an acute desensitization of the opioid receptor (which develops within minutes of opioid use and resolves within hours after use), and a long-term desensitization of the opioid receptor (which persists for several days after removal of opioid agonists). Changes also occur in the number of opioid receptors  and there is compensatory up-regulation of the cyclic adenosine monophosphate (cAMP) producing enzymes. When the opioid is withdrawn, the cAMP cascade becomes overactive, leading to the "noradrenergic storm" seen clinically as opioid withdrawal, which may create a drive to reinstate substance use. The intensely dysphoric withdrawal syndrome is characterized by watery eyes, runny nose, yawning, sweating, restlessness, irritability, tremor, nausea, vomiting, diarrhoea, increased blood pressure, chills, cramps and muscles aches; it can last seven days or even longer.
Long-term changes in neuronal circuitry, similar to those seen in learning and memory, can occur as a result of repeated opioid use. This effect creates a high risk of relapse to opioid use even after long periods of abstinence .

# Epidemiology of illicit opioid use and dependence
Opioid dependence is a worldwide health problem that has enormous economic, personal and public health consequences. There are an estimated 15.6 million illicit opioid users in the world, of whom 11 million use heroin . Opioids are the main drugs of abuse in Asia, Europe and much of Oceania, and it is estimated that globally the consumption of the opioid class of drugs is increasing .

# Harms associated with opioid use
Injecting drug use has been strongly associated with HIV, accounting for 30% of HIV infections outside sub-Saharan Africa, and up to 80% of cases in some countries in eastern Europe and central Asia . Once it enters a drug-using population, HIV can spread rapidly, and new epidemics of HIV infection mediated by intravenous drug use are occurring in sub-Saharan Africa . Despite this situation, measures that prevent the spread of HIV in IDU, including opioid agonist maintenance treatment, have less than 5% coverage worldwide .
Unsafe injecting practices associated with injecting drug use have also led to a global epidemic of hepatitis C. An estimated 130 million people are infected with hepatitis C, with 3-4 million people newly infected each year . Unsafe injection practices are the main route of transmission, accounting for an estimated 90% of new hepatitis C infections.
In countries with a low prevalence of HIV, opioiddependent individuals have been found to have an annual mortality of 2-4% per annum, or 13 times that of their peers . This increased mortality is primarily due to overdoses, violence, suicide, and smoking and alcohol-related causes . In countries with high HIV prevalence, acquired immunodeficiency syndrome (AIDS) also makes a significant contribution to mortality .
Opioid dependence per se is associated with a significant reduction in quality of life as meaningful activities become replaced by time spent intoxicated or seeking opioids . In addition to medical comorbidity associated with injecting drug use and violence, illicit opioid users have high rates of psychiatric comorbidity -in particular, depression and post-traumatic stress disorder .

# Economic consequences of opioid use
Opioid dependence imposes a significant economic burden on society, not only in terms of directly attributable health-care costs (e.g. treatment and prevention services, and other health-care use), but also in terms of its impact on other budgets (notably social welfare and criminal justice services). Opioid dependence also has an effect on productivity, due to unemployment, absenteeism, and premature mortality.
Studies in industrialized countries have attempted to place an economic value on the aggregate impact of these consequences, with findings of from 0.2 to 2% of a country's gross domestic product (GDP) .

# Natural history of opioid dependence
Cohort studies of dependent illicit opioid users show that although a significant proportion (10-40%) are abstinent at follow-up, most continue to use illicit opioids . Contact with treatment is one factor associated with recovery from opioid dependence; other factors include personal motivation, religion, spirituality, family and employment .

# Opioid dependence as a medical condition
Historically, opioid dependence was often seen as a disorder of willpower, reflecting poorly on the character of an individual. However, with recent advances in the understanding of the biological mechanism behind dependence and its implications, it has now been widely accepted that, regardless of the reasons for opioid use, the neurological changes that occur with opioid dependence constitute a brain disorder. Therefore, opioid dependence can be considered as a medical condition, with complex sociological and individual determinants. Opioid dependence is characterized by a series of symptoms that have long-term prognostic implications, and for which treatment options now exist .

# Treatment of opioid dependence
Treatment of opioid dependence is a set of pharmacological and psychosocial interventions aimed at: reducing or ceasing opioid use
- preventing future harms associated with opioid use
- improving quality of life and well-being of the
- opioid-dependent patient.
Treatment of drug dependence can serve a multitude of purposes. Beyond reductions in drug usage, it can help the drug user to see his or her problems from a different perspective, improve self-reliance, and empower the individual to seek and effect changes in their life; it can even confer self-esteem and give hope. At the same time, it can provide access to physical and psychiatric care and social assistance, and provide for the needs of the patient's family as well as those of the patient.
In most cases, treatment will be required in the long term or even throughout life. The aim of treatment services in such instances is not only to reduce or stop opioid use, but also to improve health and social functioning, and to help patients avoid some of the more serious consequences of drug use. Such long-term treatment, common for many medical conditions, should not be seen as treatment failure, but rather as a cost-effective way of prolonging life and improving quality of life, supporting the natural and long-term process of change and recovery.
Broadly speaking, there are two pharmacological approaches to opioid dependence treatment -those based on opioid withdrawal and those based on agonist maintenance.

# MAnAGeMenT OF OPIOID WITHDRAWAl
Pharmacological management of opioid withdrawal is usually by one of the following: gradual cessation of an opioid agonist (i.e.
short-term use of a partial agonist (i.e.
- buprenorphine) sudden opioid cessation and use of alpha-2
- adrenergic agonists to relieve withdrawal symptoms.
In practice, most patients resume opioid use within six months of commencing opioid withdrawal  ; the implication being that a single detoxification episode should not be promoted as effective treatment.

# AGOnIST MAInTenAnCe TReATMenT
Agonist maintenance treatment usually consists of daily administration of an opioid agonist (e.g. methadone) or a partial agonist (e.g. buprenorphine). The resulting stable level of opioid effect is experienced by the dependent user as neither intoxication nor withdrawal, but more as "normal". The aims of agonist maintenance treatment include: reduction or cessation of illicit opioids
- reduction or cessation of injecting and associated
- risk of bloodborne virus transmission reduction of overdose risk
- reduction of criminal activity
- improvement in psychological and physical health.
In practice, most patients commencing opioid agonist treatment will cease heroin or use it infrequently, with only 20-30% reporting ongoing regular heroin use . However, relapse to heroin use following the cessation of agonist maintenance treatment is common  and research is lacking on when, who and how to withdraw from opioid agonist maintenance treatment.

# PSYCHOSOCIAl ASSISTAnCe
Psychosocial assistance in the treatment of opioid dependence refers to the many ways in which professional and non-professional members of society can support the psychological health and the social environment of the opioid user, to help improve both the quality and duration of life. Assistance can range from the simple (e.g. provision of food and shelter) to the complex (e.g. structured psychotherapy); this topic is discussed in Chapter 6.
The WHO constitution  defines health as "a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity". It goes on to state that the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being, without distinction of race, religion, political belief, economic or social condition.
The constitution also states that the health of all peoples is fundamental to the attainment of peace and security, and is dependent upon the fullest cooperation of individuals and states. Similarly, the Ottawa charter  outlines the link between health and broader social policy and health systems, highlighting the importance of actions at the health-system level.
These guidelines contain two levels of recommendations for action at the health-system level -"minimal" and "optimal". Recommendations marked "minimal" are suggested for adoption in all settings as a minimum standard; they should be considered the minimal requirements for the provision of treatment of opioid dependence. Recommendations marked "optimal" represent best practice strategies for achieving the maximal public health benefit in the provision of treatment for opioid dependence.

# International regulations
Nations operate within an international regulatory framework; and methadone and buprenorphine are medicines under international control. The Single Convention on Narcotic Drugs, 1961 (as revised by the 1972 protocol) and the Convention on Psychotropic Substances, 1971, outline specific control requirements for those substances (details of requirements of these conventions are given in Annex 7). The conventions also include the requirement to make treatment available for people who are dependent upon narcotic drugs or psychotropic substances. The two main objectives of these conventions are to make narcotic drugs and psychotropic substances (including opioids) available for medical and scientific purposes, and to prevent their diversion for other purposes.
Responsible authorities should familiarise themselves with the international and legal regulations for the procurement, distribution, storage and prescription of opioids. If a country does not have regulations concerning the dispensing of agonist maintenance medications and provision of interventions, then these should be developed in accordance with the relevant conventions. The laws and regulations should enable prescribed methadone and buprenorphine to be dispensed -either under supervision or as takehome doses -from accessible dispensing points, while preventing diversion for non-medical use.
Treatment providers should familiarize themselves with the national and subnational requirements, and ensure that the treatment provided is consistent with relevant laws and regulations.
International agreements that outline responsibilities for the protection of human rights are also relevant to opioid treatment (see ethical issues, below).

# Opioid dependence as a healthcare issue
Substance dependence per se should be regarded as a health problem and not a legal one. Given the multiple medical problems associated with opioid dependence and the nature of pharmacological treatment, provision of pharmacological treatment for opioid dependence should be a health-care priority. This is encouraged in the Single Convention on Narcotic Drugs, 1961, which encourages parties to give special attention to, and take all practicable measures for, the prevention and treatment of the abuse of narcotic drugs. The convention also stipulates that treatment may be made available as an alternative to conviction or punishment (or in addition to them) to those people with substance-use disorders who have committed punishable offences.

# National treatment policy
When a treatment system is developed in any country, it should be planned as part of the community's overall resources for dealing with health and social problems (WHO Expert Committee 30th Report).  The policy should outline the approach to preventing and treating the problems of opioid dependence. It 4 Guidelines for health systems at national and subnational levels should be based on epidemiological data, the evidence for effectiveness of interventions, the resources of the country and the values of the society.
Estimating treatment need is important for planning treatment services, and for reviewing the accessibility of services to different population groups. Estimating the number of opioid-dependent people in a population from household surveys is difficult due to their under representation in largescale epidemiological surveys. Alternative techniques that can be more effective are capture-recapture, back projection and multiplier methods . WHO has produced guidance on how to estimate the number of opioid-dependent people .
Treatment need can also be estimated using systems that monitor treatment, including the demand for first-time treatment. However, some populations may be underrepresented in estimates of those seeking treatment; such groups include women, the young, street children, refugees, the poor and minority ethnic and religious groups.
Collecting data on the number of patients treated with each type of treatment can be useful. Data on numbers in opioid agonist maintenance treatment can be gathered from treatment centres or pharmacies dispensing methadone and buprenorphine, either in real time or on an intermittent basis. Gathering data on numbers of people treated for opioid withdrawal is more difficult, and requires coordination of data from residential facilities, outpatient specialist services and primary care. A relatively inexpensive way to evaluate long-term outcomes is to link data records with population registries (mortality).
A needs assessment is a formal systematic attempt to determine important gaps between what services are needed and those that are currently being provided. The assessment involves documenting important gaps between current and desired outcomes, and then deciding in which order those gaps should be closed.
When planning and developing pharmacological treatment for people with opioid dependence, the scope of present and potential public health problems associated with opioid dependence and current treatment coverage should be considered.

# Recommendation (Best Practice)
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.

# Ethical issues

# COMPUlSORY AnD COeRCeD TReATMenT
In line with the principle of autonomy, patients should be free to choose whether to participate in treatment, unless another ethical principle overrides this. The principle of autonomy may be overridden, for example, when a person is incapacitated by a mental illness and can no longer care for themselves, or when a person poses a risk to others. Most countries have mental health legislation to this effect, which can be applied to patients with opioid dependence if necessary. However, in most cases, those who have lost control over opioid use are not necessarily considered to have lost the ability to care for themselves in other ways.
In situations where opioid-dependent individuals are convicted of crimes related to their opioid use, they may be offered treatment for their opioid dependence as an alternative to a penal sanction. Such treatment would not be considered compulsory unless the punishment for refusing or failing treatment were more severe than the penal sanction it replaced. Similarly, legal proceedings can be a delayed until after a period of treatment, so that the effects of treatment can be taken into account. Such programmes, which divert opioid-dependent patients away from the criminal justice system, can also be implemented on arrest or before trial. These programmes are sometimes called diversion programmes (the use of the term "diversion" here should not be confused with its use in "diversion of treatment medication", which is described elsewhere). Evaluations of diversion programmes show high rates of successful treatment and low rates of recidivism .

# Recommendation (Minimum standard)
Psychosocially assisted pharmacological treatment should not be compulsory.
In each national situation, funding and equitable access to treatment should be assured for the treatment approaches that are appropriate. In general, this means making the most cost-effective treatment widely available and accessible.
The cost to patients of treatment for opioid dependence also influences the outcomes of treatment. If costs are excessive, treatment will not be accessible to disadvantaged populations. Many opioid-dependent patients have difficulty paying for treatment and are not covered by health-insurance schemes. Where patients have to pay for treatment, retention rates and health outcomes are worse than where treatment is free . Even small financial costs for treatment can be a significant disincentive.
Costing mechanisms for treatment can have unintended consequences. For example, if higher doses of methadone and buprenorphine cost more than lower doses, patients may opt for too low a dose, resulting in poorer outcomes. In contrast, if patients pay the same price regardless of the dose, they may overstate their needs and sell their excess supply, which in turn may make staff reluctant to increase the medication dose when patients request it.
The cost of dispensing the medication is also relevant.
If patients pay a dispensing fee to a pharmacist or clinic each time they collect their medication, they may collect their medication less frequently.
Although it is impossible to avoid all perverse incentives (i.e. those that have unintended and undesirable effects), making treatment both free and accessible will minimize them.
Where a country has a public universal health-care system, this should include access to opioid dependence treatment. Where a country has an insurance system, this should again include access to opioid dependence treatment, recognizing that long-term treatment will be needed in many cases.
Another aspect of treatment funding is sustainability. In many cases, pilot funding is used to launch treatment of opioid dependence. However, it is not appropriate to use short-term funding for long-term agonist maintenance treatment without a realistic prospect of people in treatment being able to access continuing pharmacotherapy at the end of the pilot phase.
The development and maintenance of opioid treatment services evidently needs to take place within the broader system of health-care financing and provision in a given country. An understanding of the way that health funds are raised and allocated in a country is therefore important for the appropriate planning of opioid treatment services. One particularly important potential barrier to treatment in many countries with relatively low resources is the reliance on private, out-of-pocket spending by households as the primary mechanism for paying for health care. Tax-based public health-insurance schemes provide a more equitable mechanism for paying for health services, as well as a more suitable basis for developing and sustaining opioid treatment services at the population level.
Determining the total resources and associated costs needed to initiate and maintain a treatment service for opioid dependence should be a key element of strategic planning. Although cost estimates have been produced for a range of opioid-dependence treatment programmes  they are largely restricted to the context of high-income countries, where costs and levels of funding for health may differ markedly from those found in low and middle-income countries. For example, although estimates of required staff will figure prominently in any resource-planning exercise, the costs of this labour may not represent such a large component of total cost in low and middle-income countries (due to lower salary levels); in contrast, the costs of purchasing and distributing medication, and of fuel, utilities and equipment may take up a relatively greater share of costs in such countries. WHO has methods and tools that can be used to assist such resource planning and programme costing at the national level .

# Recommendation (Minimum standard)
Treatment should be accessible to disadvantaged populations.

# Recommendation (Minimum standard)
At the time of commencement of treatment services, there should be a realistic prospect of the service being financially viable.

# Recommendation (Best Practice)
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 (the efficacy of opioid agonist maintenance treatment is well documented in this setting) and other closed settings . Interruptions to opioid agonist maintenance treatment while patients are moving in and out of custodial settings should be avoided. Pharmacological treatment of opioid dependence should be widely accessible; this might include treatment delivery in primary care settings. Comorbid patients can be treated in primary health-care settings if there is access to specialist consultation when necessary.

# Recommendation (Best Practice)
Pharmacological treatment of opioid dependence should be accessible to all those in need, including those in prison and other closed settings.

# PRIMARY CARe
Integration of opioid dependence treatment into primary care is one way to increase accessibility, although it may not be possible in all settings. Primary care practitioners will usually need support from the specialist system, through mentoring, training, consultation and referral. With such support, patients with quite complex comorbidity can be safely managed in primary care.
Opioid agonist maintenance treatment, opioid withdrawal services and relapse prevention services can all be provided in primary care settings, given the right conditions.
Several clinical trials of opioid agonist maintenance treatment have been conducted in primary care settings . Use of general practitioners for opioid agonist maintenance treatment significantly increases the capacity of the service, and treatment numbers have increased rapidly in countries that have adopted this approach . Treatment in primary care also has the advantage of integrating addiction medical and psychiatric services into mainstream services, reducing the stigma of addiction and the professional isolation of medical staff. Integration also reduces some of the problems that clinics can develop when large numbers of patients on opioid agonist maintenance are aggregated. Within the clinic setting, interaction between patients can lead to drug dealing and an antitherapeutic milieu.
Outside the clinic, the congregation of drug users can become a visible target for members of the public who do not approve of opioid agonist maintenance treatment.
Opioid withdrawal and relapse prevention services can also be provided in primary care, with similar efficacy as specialist clinics but at lower cost .
Prisoners should not be denied adequate health care because of their imprisonment. This would normally imply that the treatment options available outside prison should also be available in prison. Opioid withdrawal, agonist maintenance and naltrexone treatment should all be available in prison settings, and prisoners should not be forced to accept any particular treatment.

# Opioid agonist treatment in prisons
The benefits of opioid agonist maintenance in prisons include less injecting drug use while in prison, increase in uptake of treatment on leaving prison, and reduction of rates of return to prison. Potential harms include diversion of medication, and spread of HIV through injection of diverted medication using contaminated injecting equipment. Because of these potential harms, unsupervised doses are generally not appropriate in prison settings. Rates of diversion of methadone are low, even in prison settings, and can be reduced further by diluting the methadone and by keeping methadone patients separate from other prisoners for 30 minutes after dosing. Because it is a sublingual tablet that can take up to 15 minutes to dissolve, buprenorphine is difficult to supervise in prison settings, sometimes resulting in pressure on patients from other prisoners to divert their medication for injection . Methods to increase the effectiveness of supervision include crushing the tablet, filming dosing, ensuring the hands remain behind the back of the patient during dosing and inspecting the mouth after dosing. If effective supervision of buprenorphine is difficult, it may be better to use methadone instead.
Policy makers and prison administrators should ensure appropriate links between prison health services and agonist maintenance treatment outside prison. Even small gaps in the continuity of treatment are distressing for the patient and risk the person relapsing to illicit opioid use. Therefore, opioid agonist maintenance treatment should be continuous on leaving prison. This means coordinating the day of discharge from prison with the day of commencement of opioid agonist treatment outside prison.
Patients not in treatment in prison should be given the opportunity to start methadone or buprenorphine in prison, even if they have only a short period of their sentence left to complete. Commencement of opioid agonist maintenance treatment in prison reduces the high risk of overdose and death on leaving prison, and reduces reincarceration rates.

# What treatments should be available?
If countries are able to afford it, it is best to have both methadone and buprenorphine available for opioid agonist maintenance treatment. Having both treatments means that patients who experience adverse effects from one of the medications, or fail to respond, can try the alternative. This situation may increase the proportion of people with opioid dependence staying in opioid agonist treatment; it may also increase the effectiveness of treatment, through better matching of treatment and patient. The additional availability of alpha-2 adrenergic agonists for opioid withdrawal increases the options for those who wish to withdraw as quickly as possible or who wish to commence naltrexone after withdrawal. The availability of naltrexone after withdrawal is also a valuable additional option, because it gives a lower rate of relapse.

# Recommendation (Minimum standard)
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.

# Recommendation (Best Practice)
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.

# Supervision of dosing for methadone and buprenorphine maintenance
This section should be read with the section on opioid agonist maintenance treatment (Section 6.4). Without supervision of dosing, methadone and buprenorphine are likely to be diverted for illicit use, giving rise to problems of overdose, injection and spread of bloodborne viruses.
However, supervision of every dose is severely restrictive to patients, and limits the acceptability of treatment. Supervision of most doses is still onerous for patients, but is not necessarily detrimental to the individual in treatment; on the contrary, it may be of benefit in the early phases of treatment.
Regulations and laws describing the degree of supervision of methadone and buprenorphine maintenance should be in accordance with the relevant international treaties and reflect the balance between treatment acceptability and risk of diversion that is acceptable to the community. Programmes in which medicine is being diverted to the street market are not beneficial to patients and often not tolerated outside the health-care sector either.
With guidance, treatment staff can select patients at lower risk of diversion, who can receive a lower level of supervision of dosing (Section 4.6).
In most cases, staff training, adequate take-home policies and normal legal restrictions on illicitly procured opioids can minimize diversion without the need for specific legislation. Programmes will be more sustainable if there are systems to prevent or minimize diversion of pharmacotherapy, and to monitor the benefits of treatment. As a minimum, this would include systems that monitor the extent of diversion (Section 5.7).
This section is primarily aimed at clinical leaders and health administrators responsible for the organization and delivery of opioid dependence treatment, and the standards of care involved.

# Clinical governance
Clinical governance refers to the mechanism of accountability for clinical outcomes. Normally, this role falls to a clinical leader or health administrator, or is shared by both. Responsibilities include ensuring that: staff are adequately selected, trained and supervised
- adequate clinical protocols and procedures are in
- place for determining the structure of the treatment service developing and maintaining mechanisms of quality assessment and improvement ensuring that practices comply with relevant laws and professional requirements.
As a minimum, a process of clinical governance should be established to ensure that minimal standards for provision of opioid dependence treatment are being met. Ideally, the process of clinical governance should be well developed, so that treatments for opioid dependence are both safe and effective.
Where treatment is delivered outside the health-care system (e.g. in prisons) and not primarily under the responsibility of health authorities, there should still be a documented chain of accountability for health outcomes.
It is best to have the primary responsibility for treatment within the health-care system, even in diverse settings, because clinical accountability is then easier to establish and maintain.

# Recommendation (Minimum standard)
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.

# Recommendation (Best Practice)
Treatment of opioid dependence should be provided within the health-care system.

# Recommendation (Best Practice)
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.

# Ethical principles and consent
In line with the rights to autonomy and the highest attainable standard of health enshrined in Article 12 of the International Covenant on Economic, Social and Cultural Rights  people should be free to chose whether or not they participate in treatment.
The WHO Resource Book on Mental Health, Human Rights and Legislation  says that, to be valid, consent must satisfy the following criteria: "The person/patient giving consent must be having the capacity to give consent, then refusal of such consent must also be respected."
One of the implications for provision of informed consent in opioid-dependent patients is that patients may not be in an adequate state to provide informed consent when they are intoxicated or in opioid withdrawal. In this case, treatment may commence and patients may be asked to confirm their consent to treatment after treatment has commenced, as soon as the patient is neither intoxicated nor in opioid withdrawal. On occasion, this may mean a change in treatment direction from opioid agonist maintenance to opioid withdrawal, or the reverse.
When considering what risks to include in the informed consent process for patients commencing opioid agonist maintenance treatment, it is important to include the increased risk of overdose during the first weeks of treatment, and the likely opioid withdrawal symptoms that will be experienced when stopping opioid agonist treatment. Patients commencing opioid withdrawal and abstinence-based treatments should be specifically warned about the increased risk of overdose on relapse to opioid use compared to opioid agonist maintenance treatment.

# Recommendation (Minimum standard)
Patients must give informed consent for treatment.

# Staff and training
The support and training of health-care personnel requires a continuous effort, and special attention is needed to develop and maintain a competent workforce.
Training should include (as a minimum) an understanding of the nature of opioid dependence, assessment and diagnosis, pharmacological and psychosocial treatments, and management of intoxication, overdose and difficult behaviours.

# Recommendation (Minimum standard)
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.

# Recommendation (Best Practice)
Health authorities should ensure that treatment providers have sufficient skill 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.

# MeDICAl STAFF
In most settings, medical staff will be required for the treatment of opioid dependence, both for clinical assessment and for prescription of pharmacotherapy. In some settings, due to a shortage of medical staff, these responsibilities may fall on nursing or other health-care staff. Also, medical staff may delegate some of their responsibilities to nursing and other health-care staff, in accordance with local regulations.
In specialist clinics, medical staff should be supervised by a physician or psychiatrist specializing in the treatment of substance dependence.
In generalist settings, general practitioners and other medical staff should have a basic level of training in the diagnosis and treatment of opioid dependence. Because of the potential for methadone and buprenorphine to do harm if prescribed inappropriately, many countries have a system of licensing medical staff to prescribe opioid agonist maintenance treatment. Each service should ensure that its own training programmes incorporate local clinical guidelines and regulations.
All medical staff working in the field of substance abuse should have some avenue for clinical supervision, be it from peers, senior colleagues or professional supervisors. This helps to guard against inappropriate prescribing and to maintain the professionalism of medical staff in their dealings with patients.

# PHARMACY STAFF
Staff dispensing methadone and buprenorphine are generally pharmacists, although medical and nursing staff may also be able to dispense medication, depending on national laws. Staff dispensing methadone and buprenorphine should have specific training in opioid-dependence treatment. This should include the nature of opioid dependence, the goals of treatment, therapeutic rapport, recognition of opioid withdrawal and intoxication, and responses to difficult behaviours. This should include proper storage of controlled medicines, the nature of opioid dependence, the goals of treatment, therapeutic rapport, recognition of opioid withdrawal and intoxication, methods to minimize diversion of medication, and responses to difficult behaviours.

# PSYCHOSOCIAl SUPPORT STAFF
To ensure professionalism and consistency of service delivery, basic training in treatment of substance dependence is recommended. Further training requirements will depend on the nature of the psychosocial intervention being offered.
Staff should be provided with supervision, adequate support, and standardized operational instructions on the management of intoxication, difficult behaviours and other emergency conditions.

# Clinical records
Every contact between the health service and the patient should be recorded in the medical record. The record should be up to date and clearly legible. Each entry should be signed and dated.
Sometimes police may ask to see medical records; they should not be given access to medical records against the wishes of the patient unless appropriate legal requirements and procedures have been met.
In some circumstances, professional standards may warrant a breach of confidentiality; for example, if the safety of a child is at risk. In these situations, professional staff should balance the patient's right to privacy against the duty to protect, and should seek advice from their professional body if unsure. Such breaches of confidentiality are generally allowed under law; indeed, in some cases they may be required by law.
As a general rule, patients should have access to their own medical records. This may be limited in some situations if it is not in the patient's best interest to view all of his or her own records.
If there are national systems of identification, such as identity cards, bank cards or social security cards, these should be used when necessary to confirm the identity of patients. In the absence of such systems, treatment providers should find alternative ways to establish patient identity. The main reason for this is to avoid giving potentially lethal doses of opioids to the wrong patient.
If there is a system of central registration (Section 4.2), the system will require accurate identification of participants if it is to be effective.

# Recommendation (Minimum standard)
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.

# Recommendation (Minimum standard)
Confidentiality of patient records should be ensured.

# Recommendation (Minimum standard)
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.

# Recommendation (Minimum standard)
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.

# Recommendation (Minimum standard)
Patients treated with opioid agonists should be identifiable to treating staff.

# Medication safety
Most countries have regulations that govern the procurement, storage, dispensing and dosing of medicines, and these often contain special provisions for opioids and other medications of abuse and dependence. The regulations usually stipulate storage of methadone and buprenorphine in locked cabinets, with two staff members witnessing any movement of medication. These measures reduce the risk of theft of medication, particularly the risk of diversion by staff members.
Methadone and buprenorphine can be fatal if the wrong dose is dispensed or a dose is dispensed to the wrong patient. Various systems can be used to ensure that the correct dose is being dispensed to the correct patient. Such systems essentially involve checking the identity of the patient and ensuring that the prescription is valid. They can be low technology -for example, having a photo of the patient at the dispensing point and having the patient sign for their dose. Alternatively, systems can be high-technology -for example, commercial systems linking retinal scanning devices to methadone pumps.

# Recommendation (Minimum standard)
Documented processes should be established to ensure the safe and legal procurement, storage, dispensing and dosing of medicines, particularly of methadone and buprenorphine.

# Treatment provision

# ClInICAl GUIDelIneS
Clinical guidelines are one mechanism for improving the quality of treatment. Clear, evidence-based clinical guidelines for the treatment of opioid dependence are available, and at a minimum these should be accessible to treatment staff. Ideally, local guidelines should be developed at a country or subnational level to reflect local laws, policies and conditions. The guidelines will be affected by differences in costs and requirements for supervision of methadone and buprenorphine. Local guidelines should represent the accepted treatment standards in the particular location, reflecting to some extent the values and mores of the society and its professional bodies.

# Recommendation (Minimum standard)
Clinical guidelines for the treatment of opioid dependence should be available to clinical staff.

# Recommendation (Best Practice)
Clinical guidelines should be detailed, comprehensive, evidence based and developed at a country level or lower, to reflect local laws, policies and conditions.

# TReATMenT POlICIeS
Policies on the objectives, indications, settings, dosage schemes and treatment regulations (including reasons for treatment termination) should be developed and clearly communicated to patients and staff. This applies for the management of opioid dependence with opioid detoxification, opioid agonist maintenance and naltrexone treatment.
Access to and networking with medical, psychiatric, social and harm-reduction services is desirable, and should be developed when possible; however, psychosocial interventions, including counselling, may not be necessary onsite.
Men and women can be treated in the same facility, providing that culturally appropriate and gender-specific needs can be taken care of.

# Recommendation (Minimum standard)
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, without placing restrictions on dose levels and the duration of treatment.

# Recommendation (Best Practice)
Opioid withdrawal services should be structured such that withdrawal is not a stand-alone service but is integrated with ongoing treatment options.

# Recommendation (Best Practice)
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.

# Recommendation (Best Practice)
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.

# InVOlUnTARY DISCHARGe AnD OTHeR FORMS OF lIMIT SeTTInG
One of the primary responsibilities of a treatment service is to protect its staff and patients from harm. If a situation arises in which the past behaviour of a patient would indicate that there is a significant risk of harm to other patients or staff, the treatment service must act to reduce that risk, discharging the patient if necessary. Such situations are potentially avoidable if the patient's behaviour is identified and managed at an early stage. An effective treatment service will have clear boundaries on what constitutes acceptable and unacceptable behaviour, and the service will apply the limits consistently and transparently to all patients (sometimes referred to as "limit setting"). To avoid replicating the rejection that patients experience from other parts of society, limit setting should have a graded response, including: positive feedback for "good" behaviour Applying excessive responses for minor breaches of rules will result in many people being discharged when they could have gone on to do well from treatment. At the same time, failure to respond to significant breaches of rules risks harm to other patients and staff, and will not help the patient in question.
Each service will have to decide on its own rules and limits; these will depend on cultural norms, the goals of treatment in that setting and the policy environment that allows the treatment to continue. Treatment rules are likely to be very different for a withdrawal facility or therapeutic community aimed at abstinence, and an opioid agonist maintenance programme aimed at reducing the mortality and morbidity associated with opioid dependence, and at improving quality of life.
Whatever limits are set, they must be consistently applied by all treatment staff. In this way, patients will quickly learn and more readily accept the boundaries of acceptable behaviour. Some patients will push these boundaries when there is a perceived difference in the way that staff apply limits. Sometimes called "splitting", this behaviour risks setting treatment staff against each other, leading to poor outcomes for patients.
Even if an incident is sufficiently serious to warrant abrupt discharge, agencies should use this as an occasion to review whether they have done all they can to avoid provoking or permitting such behaviour.
Treatment services should have a mechanism of reporting incidents when they occur, including "near misses" and unexpected adverse outcomes. The reports should be reviewed regularly by a team that includes someone responsible for the clinical governance of the service.
Initiatives to reduce such incidents might include measures to train staff in non-judgemental and nonconfrontational communication strategies, reducing waiting time for appointments and medication, frequent review of patient treatment, use of family and employment-friendly practices, and presence of security.
If the situation does not warrant immediate discharge for the safety of staff and other patients, then attempts should be made to resolve the situation without discharge, particularly if discharge implies no continuing treatment. Patients should understand what is expected of them, and there should be clear communication when behaviour crosses the boundaries. When alternative options are inappropriate or have been exhausted, attempts should be made to transfer the patient to another treatment service, because outcomes after involuntary discharge from treatment are poor, with relapse to heroin use occurring in 75% of patients .

# InDIVIDUAl TReATMenT PlAnS
The first stage in individualized treatment is a thorough individual assessment that identifies specific psychosocial needs and patient motivations, and confirms the diagnosis of opioid dependence and the response to previous treatments (Section 6.1). Holistic treatment then attempts to meet each of those treatment needs.
Where possible, interventions to address particular needs should be evidence based, incorporating individual preferences and past treatment experiences.
As with other long-term conditions, patients should not be assumed to be "cured" with the first round of treatment, and provisions should be made for followup. Treatment programmes should be structured in such a way that they can support patients in the long term.

# Recommendation (Minimum standard)
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).

# Recommendation (Best Practice)
Screening for psychiatric and somatic comorbidity should form part of the initial assessment.

# Recommendation (Best Practice)
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.

# Recommendation (Best Practice)
Treatment plans should take a long-term perspective.

# Recommendation (Best Practice)
Opioid detoxification should be planned in conjunction with ongoing treatment.

# RAnGe OF SeRVICeS TO Be PROVIDeD
Although different treatment options may be available in different programmes, it is useful for programmes to be able to offer a full range of services, so that they can tailor the services to the needs of the patients.
Each treatment facility with medical staff should ensure that the facility has the capacity to administer the opioid antagonist naloxone to treat opioid overdoses. This includes procedures for maintaining stock and injection equipment. Distribution of naloxone, with training on its use in overdose to opioid users and their families, has been shown to be a feasible approach to reducing overdose mortality in the community . It is similar in concept to the distribution of adrenaline to patients with severe allergic reactions and their families.

# Recommendation (Minimum standard)
Essential pharmacological treatment options should consist of opioid agonist maintenance treatment and services for the management of opioid withdrawal.

# Recommendation (Minimum standard)
Naloxone should be available for treating opioid overdose.

# Recommendation (Best Practice)
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.

# TReATMenT OF COMORBID COnDITIOnS
Opioid-dependent patients often also suffer from other medical and psychiatric conditions, complicated by social problems. The optimal approach is to provide integrated holistic care to address current problems and prevent further problems. In practice, this means being able to detect medical, psychiatric and social issues in the assessment process, and having the means onsite to attend to the issues simultaneously. This may mean having staff with multiple skills, or coordinating the use of staff with different skill sets.

# PSYCHOSOCIAl AnD PSYCHIATRIC SUPPORT
Medications are useful in the treatment of opioid dependence. However, providing medications without offering any psychosocial assistance fails to recognize the complex nature of opioid dependence, loses the opportunity to provide optimal interventions and requires treatment staff to go against their clinical inclination to respond to the total needs of their patients. Treatment services should aim to offer onsite, integrated, comprehensive psychosocial support to every patient. However, treatment services should not deny effective medication if they are unable to provide psychosocial assistance, or if patients refuse it. At a minimum, services should attempt to assess the psychosocial needs of patients, provide whatever support they can, and refer to outside agencies for additional support where necessary.

# Recommendation (Minimum standard)
Psychosocial support should be available to all opioiddependent 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.

# Recommendation (Best Practice)
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.

# Recommendation (Best Practice)
Onsite psychosocial and psychiatric treatment should be provided for patients with psychiatric comorbidity.

# TB, HePATITIS AnD HIV
Despite the large number of opioid-dependent people living with HIV/AIDS, there is considerable evidence that they have less access to antiretroviral medication, and to other HIV/AIDS treatment and care than others who are not substance dependent. Opioid use has been identified as a factor in lack of adherence to antiretroviral treatment, risking the development of viral drug resistance .
On the other hand, observational studies suggest that the impact of highly active antiretroviral therapy on CD4 counts in patients still using heroin and other drugs is reasonable, and is not too dissimilar to the impact of such therapy in patients not using illicit substances . Excellent results can be obtained for patients in opioid agonist maintenance treatment .
The issues for TB and hepatitis treatment are similar, with the exception that clinics with TB patients need to carefully consider the risks of spread of TB from patient to patient, particularly where immunocompromised patients are mixing with TB patients. Given the capacity for overcrowded clinics to spread TB, opioiddependence treatment clinics should consider their response to the issue of TB in combination with local TB experts. Issues of ventilation, overcrowding and management of coughing patients may need to be considered.
Combined treatment of hepatitis C and opioid dependence with opioid agonist maintenance treatment and anti-viral agents can also have excellent results .
A number of RCTs have demonstrated that substancedependent patients are more likely to attend for medical care if the treatment is provided onsite; this can be arranged for minimal additional cost . An alternative approach -providing opioid agonist maintenance treatment at medical clinics  -has also been suggested.
To improve compliance, directly observed treatment of HIV and TB should be integrated with opioid agonist maintenance treatment, and provided in the same location.
There are a number of models for the development of such integrated care.
Existing opioid-dependence programmes may start
- treating medical conditions . Existing medical programmes may start treating
- opioid dependence . New specialized services for drug users may treat
- opioid dependence, TB, HIV and hepatitis. Opioid dependence and HIV/TB can be treated in - primary care .
According to local conditions, mechanisms for treating opioid dependence should be combined with treatment for TB, HIV and hepatitis. The simplest way for this to happen may be for treatment staff to become skilled in treating multiple conditions. Since patients on opioid agonist maintenance treatment already attend a clinic or dispensary daily, integration with HIV treatment provides an efficient mechanism for directly observing HIV treatment and achieving high compliance rates.
Where there is no capacity to provide integrated care, links should be established between services providing drug treatment and services providing treatment for HIV, TB and hepatitis, to increase the success of referral and treatment.
Patients with active TB are highly infective and should be kept separate from other patients as much as possible in the initial stages of treatment, particularly during the first two weeks of anti-TB therapy.
All injecting drug users should have access to measures to reduce the spread of HIV, including access to clean injecting equipment, condoms, antiretroviral drugs and other treatments, psychosocial services and medical care. While patients who have ceased heroin use before treatment have higher rates of adherence to antiretroviral treatment, patients without a drug-free period also have acceptable levels of response to treatment, and there should be no absolute requirement for patients to be drug free before commencing treatment.

# Recommendation (Minimum standard)
Links to HIV, hepatitis and TB treatment services (where they exist) should be provided.

# Recommendation (Best Practice)
Where there are significant numbers of opioid-dependent patients in need of treatment for either HIV, hepatitis or TB, treatment of opioid dependence should be integrated with medical services for these conditions.

# Recommendation (Best Practice)
For opioid-dependent patients with TB, hepatitis or HIV, opioid agonists should be administered in conjunction with other medical treatment; there is no need to wait for abstinence from opioids to commence either anti-TB medication, treatment for hepatitis or antiretroviral medication.

# Recommendation (Best Practice)
Opioid-dependent patients with TB, hepatitis or HIV should have equitable access to treatment for TB, hepatitis, HIV and opioid dependence.

# HePATITIS B VACCInATIOn
Vaccination for hepatitis B is recommended for all opioid-dependent patients . Ideally, hepatitis B vaccines should be given in three doses at least four weeks apart, but other vaccination schedules can also provide acceptable protection. Each treatment service should establish its own vaccination policy, based on the costs of vaccination and serology testing, the ability to maintain a cold chain, the prevalence of hepatitis B and the likelihood that patients will come back for follow-up appointments. Given the difficulty of bringing patients back for follow-up appointments and the relatively low cost of the Vaccine. vaccinating all patients without prior serology testing may be the most effective and the most cost-effective approach, even if completion of the course is not guaranteed. Some studies have shown that provision of free Vaccine. staff training, incentives, onsite vaccination and accelerated schedules can result in higher vaccination rates in this population  On the other hand, it is useful to test levels of postvaccination anti-hepatitis B antibodies, because significant numbers of people do not produce an adequate immune response  ; in these cases, additional doses of vaccination should be given.
Many opioid-dependent patients will also benefit from vaccination against hepatitis A .

# Recommendation (Best Practice)
Treatment services should offer hepatitis B vaccination to all opioid-dependent patients.

# Treatment evaluation
For opioid agonist maintenance treatment programmes, monitoring the potential for harm through diversion, overdose and other adverse events should be the minimum standard of treatment evaluation. Examples of simple evaluation techniques that could be used to detect diversion of drugs from treatment include interviewing key informants about drug diversion and testing levels of the main drugs used in patients presenting for treatment.
A system of detecting and recording adverse events in treatment, followed by regular discussion and implementation of necessary changes, will help to ensure safety. Following-up patients who drop out of treatment is helpful in this regard.
Optimal treatment evaluation examines safety, effectiveness and processes of care. Effectiveness can be measured "in house", through routine collection of outcome measures combined with follow-up of those who have left the service, or "externally", with the assistance of an external evaluation person or team.
Further details on evaluation can be found in the WHO toolkit on the evaluation of opioid substitution programmes .

# Recommendation (Minimum standard)
There should be a system for monitoring the safety of the treatment service, including the extent of medication diversion.

# Recommendation (Best Practice)
There should be intermittent or ongoing evaluation of both the process and the outcomes of the treatment provided.
In recent years, the choice of treatment options for opioid dependence has expanded. Although opioid agonist maintenance treatments (methadone and buprenorphine) are increasingly seen as the most effective management strategies, other options are opioid withdrawal and relapse prevention. In practice, different approaches will suit different patients. Many patients will undergo several episodes of different forms of treatment before finding treatments that work for them. The choice between the treatment options available should be made jointly by the clinician and patient, taking into account the priorities of the patient, the principles of medical ethics and the evidence for effectiveness of the treatments, as well as individual patient factors, such as past treatment history.
The three treatment approaches discussed in this section are: opioid agonist maintenance treatment
- opioid withdrawal
- opioid withdrawal followed by oral naltrexone.
The issues considered in relation to opioid agonist maintenance treatment are: methadone compared to buprenorphine for

# Diagnosis and assessment of opioid dependence
Assessment includes establishing a relationship between the patient and the treatment staff, based on the free exchange of information. Initially, patients may wish to share only information required to start the treatment process. However, as trust develops between the patient and staff, more information may be shared, and treatment staff will be better able to tailor responses to the individual patient.
Determining the physical, psychological and social health-care needs of the patient is an important part of assessment. Assessment should also include factors that may influence drug use, such as past treatment experiences, living conditions, legal issues, occupational situation, and social and cultural factors.
The clinician should take a substance use history to assess: which psychoactive substances have been used in Clinicians should differentiate between substance dependence and nondependent harmful substance use, because these categories have significant implications for the appropriate treatment strategy.

# Patient level guidelines -for clinicians
On examination of the patient, the degree of intoxication or withdrawal should be interpreted in combination with the stated time of last use. 1 If there is a history of injection, the injection sites should be visible and consistent with the stated history (usually both recent and old injection marks will be visible).

# URIne DRUG SCReenInG
Where available and affordable, urine (or other biological sample) drug screening should be routinely conducted at the start of treatment, and should indicate recent opioid use if the person is to be eligible for treatment.
When the cost of urine testing is an issue, urine testing should be used at least when a recent history of opioid use cannot be verified by other means (e.g. evidence of opioid withdrawal or intoxication). A negative urine drug screen combined with absence of withdrawal symptoms excludes current neuroadaptation to opioids; however, it does not exclude dependence on opioids in the past 12 months. Thus, dependence should not be diagnosed on urine drug screening alone, but a negative urine drug screen in the absence withdrawal symptoms should prompt caution in the use of opioids and other sedative medication.
Urine testing is also useful, in combination with the history, to identify other substances that have recently been consumed.
Entry into appropriate treatment programmes should not be delayed by waiting for the result of urine drug screening, unless the other findings in the assessment raise concern about the diagnosis.
Naloxone challenge testing should not be used routinely to confirm the presence of current neuroadaptation, because it can induce significant withdrawal effects. The same information can normally be gathered from the patient's history, examination of the person and interpretation of urine drug test results. Provided the patient is informed of the risk of adverse effects, naloxone challenge testing can be used as an alternative to urine drug screening, to confirm the absence of current neuroadaptation (e.g. when considering giving an opioid antagonist to start maintenance treatment). In this situation, an accidental positive reaction is likely to be significantly milder than the reaction that occurs when the test is used to confirm current neuroadaptation.

# TeSTInG FOR InFeCTIOUS DISeASeS
Voluntary testing for HIV, hepatitis C and common infectious diseases should be offered as part of an individual assessment, accompanied by counselling before and after the test. In areas of high prevalence of HIV, patients should be strongly encouraged to undergo HIV testing. Serology testing and vaccination for hepatitis B is also recommended. As discussed above (Section 5.6), in some circumstances it may be more effective to vaccinate before testing for hepatitis B, and to use accelerated vaccination schedules.
TB and sexually transmitted diseases should also be considered during assessment.
Pregnancy testing should be offered to all women, particularly those contemplating opioid withdrawal, because it may influence the choice of treatment.

# IDenTIFYInG THe PATIenT
In some circumstances, it may be necessary to confirm the identity of the patient, particularly if treatment with controlled medicines is anticipated.
Where patients do not have formal identification, it is advisable to take a photograph and include it in the record signed by the treating clinician, so that the patient can be identified in that clinic. The identity of the patient should be kept private and should not be released without patient consent. When collecting and recording information, the capacity of the service to keep that information private should be discussed with the patient.

# COMPleTInG THe ASSeSSMenT
Sometimes it is not possible to complete the initial assessment in one day; for example, the patient may be intoxicated, in withdrawal or in crisis. In such cases, it may be necessary to make a plan based on the initial assessment, which will then evolve in response to a more comprehensive assessment and the person's response to initial treatment.

# DIAGnOSTIC CRITeRIA
A diagnosis of opioid dependence has important prognostic and treatment implications. Once opioid dependent, the patient has a significant risk of suffering serious health consequences or of dying from behaviours related to their dependence on opioids.
The International Classification of Diseases, 10 th edition (ICD-10) defines opioid dependence as "a cluster of physiological, behavioural, and cognitive phenomena in which the use of opioids takes on a much higher priority for a given individual than other behaviours that once had greater value". A central characteristic of the dependence syndrome is the desire (often strong, sometimes overpowering) to take opioids, which may or may not have been medically prescribed. Once a person is opioid dependent, returning to substance use after a period of abstinence leads to a more rapid reappearance of other features of the syndrome than occurs with nondependent individuals .
The ICD-10 diagnostic criteria for opioid dependence are: a strong desire or sense of compulsion to take opioids overtly harmful consequences, such as depressive mood states consequent to periods of heavy substance use, or drug-related impairment of cognitive functioning (efforts should be made to determine whether the user was actually, or could be expected to be, aware of the nature and extent of the harm).
Narrowing of the personal repertoire of patterns of opioid use has also been described as a characteristic feature of dependence.
Opioid dependence does not develop without a period of regular use, although regular use alone is not sufficient to induce dependence.
A definite diagnosis of dependence should usually be made only if three or more of the diagnostic criteria have been experienced or exhibited at some time during the previous year.

# MAKInG THe DIAGnOSIS
Opioid dependence is essentially diagnosed on the basis of the history provided by the patient. Patients can sometimes be motivated to either overstate or understate their substance use; therefore, it is usually necessary to corroborate the patient history with the results of the physical examination and investigations, and sometime with the history reported by significant others, to be confident of the diagnosis. While any health-care worker can make a provisional diagnosis of opioid dependence provided that they have had appropriate training, the diagnosis should be confirmed by medical staff before opioid agonist treatment is provided.

# Injection sites
Examination of injection sites can provide useful information on the timing and duration of injecting drug use. Recent injection marks are small and red, and are sometimes inflamed or surrounded by slight bruising. Old injection sites are generally not inflamed, but sometimes show pigmentation changes (either lighter or darker), and the skin may have atrophied, giving a sunken impression. A combination of recent and old injection sites would normally be seen in an opioiddependent patient with current neuroadaptation. Many sites can be used for injection, although the cubital fossa (the area on the inside of the elbow joint) and the groin are the most common.

# Interpretation of urine drug screens
Urine drug screens provide evidence of recent drug use; this information can contribute to the assessment. The precise interpretation of a test result will depend on the specific commercial test or reagents used. Generally speaking, a positive test for the opioid class of drugs indicates the use of illicit or prescription opioids in the last few days. However, positive reactions can also be caused by large amounts of poppy seeds. Many commercial opioid drug screens do not recognise buprenorphine, but this situation is changing; therefore, it is best to check with the laboratory. Some tests, such as gaschromatography and mass spectrometry (GCMS), can determine the specific opioid. Heroin is broken down to 6-monoacetylmorphine (6-MAM), then to morphine and then to codeine; thus, the presence of 6-MAM is usually specific for heroin use in the last 24 hours. Morphine, with or without small amounts of codeine, can indicate either heroin or morphine use in the last few days. Small amounts of morphine in the presence of large amounts of codeine can suggest intake of high doses of codeine, since codeine can also be metabolized to morphine although most is metabolized via a different pathway.

# Degree of opioid intoxication and withdrawal
Features of opioid intoxication include drooping eyelids and constricted pupils, sedation, reduced respiratory rate, head nodding, and itching and scratching (due to histamine release).
Features of opioid withdrawal include yawning, anxiety, muscle aches, abdominal cramps, headache, dilated pupils, difficulty sleeping, vomiting, diarrhoea, piloerection (gooseflesh), agitation, myoclonic jerks, restlessness, delirium, seizures and elevated respiratory rate, blood pressure and pulse. Annex 10 provides useful scales for assessing the severity of opioid withdrawal.

# Choice of treatment approach
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.

# Methadone versus withdrawal
The recently updated Cochrane review  of methadone maintenance therapy versus no opioid replacement therapy identified three randomized controlled trials (RCTs) that compared methadone with opioid withdrawal followed by placebo . These studies show that, compared to opioid withdrawal or placebo, methadone maintenance treatment dramatically reduces levels of illicit opioid use (relative risk  0.32; 95% confidence interval  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  and one study comparing 1 mg per day with higher doses . 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 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 . 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).
Methadone maintenance is associated with an increase in mortality during the first two weeks of treatment compared to pretreatment levels, due to respiratory depression . 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 lifethreatening 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 encephalopathyand 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  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 .
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 . 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 .
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 sometimes more severe than withdrawal from heroin. Also, many patients resume heroin use after cessation of methadone, even after long-term treatment.
For most patients, opioid agonist maintenance treatment will result in better outcomes than attempts at withdrawal, with or without the use of naltrexone after withdrawal. In particular, patients on opioid agonist maintenance treatment are more likely than those not undergoing such treatment to stay alive, not use heroin and be in contact with the treatment system.
For  Agonist maintenance treatment is indicated for all patients who are opioid dependent and are able to give informed consent, and for whom there are no specific contraindications. Given the long-term nature of the treatment and the potential for toxicity in the first two weeks, a high degree of certainty of the diagnosis is required before recommending opioid agonist maintenance treatment. If the diagnosis cannot be confirmed by observation of opioid withdrawal, injection sites or confirmation of previous treatment, then treatment should be started carefully and with close monitoring; in this situation, lack of intoxication from opioid agonists will provide direct evidence of opioid tolerance. Staff should be cautious when excluding patients seeking opioid agonist maintenance treatment, because such patients often have poor clinical outcomes if they do not receive treatment .

# CHOICe OF AGOnIST MAInTenAnCe TReATMenT
In patients to be treated with agonist maintenance treatment, should preference be given to methadone or buprenorphine?
See evidence profile in Section A1. 4 of Annex 1
The Cochrane Collaboration conducted a systematic review and meta-analysis on this topic in 2004  and updated it in 2008 (in press). Ten studies compared methadone and buprenorphine, either using flexible dosing, or doses greater than 6 mg buprenorphine or 50 mg methadone.

# Flexible dose buprenorphine versus flexible dose methadone
When using flexible doses, buprenorphine was less likely than methadone to be effective in retaining patients in treatment (6 studies, 837 participants; RR = 0.82, 95%CI: 0.69 to 0.96), but there was no significant difference in heroin use based on results of morphine urinalysis (6 studies, 837 participants; SMD = -0.12, 95%CI: -0.26 to 0.02), or in terms of self-reported heroin use (2 studies, 326 participants; SMD = -0.10, 95%CI: -0.32 to 0.12).

# Moderate dose buprenorphine (6-8 mg/day) versus moderate dose methadone (50-80 mg/day)
When using moderate doses, retention in treatment was better with methadone than with buprenorphine (RR = 0.79, 95%CI 0.64 to 0.99, moderate-quality evidence). Also, there was more heroin use with buprenorphine, as shown by morphine positive urines (3 studies, 314 participants: SMD = 0.27, 95%CI 0.05 to 0.50). There was no difference in self-reported heroin use (2 studies, 74 participants; SMD = -0.02, 95%CI -0.48 to 0.45).

# Safety data
As a partial agonist, buprenorphine has a better pharmacological safety profile than methadone. Data on safety from randomized trials do not show significant differences between methadone and buprenorphine because of the small sample sizes. The strongest data for improved safety of buprenorphine comes from the widespread introduction of buprenorphine in France in 1995, which was followed by a 79% reduction in opioid overdose mortality . From 1994 to 1998, there were an estimated 1.4 times more deaths related to buprenorphine than to methadone, although 14 times more patients received buprenorphine than methadone .
Although deaths have been reported where buprenorphine has been used in combination with other sedatives  the rate of buprenorphine-related deaths is estimated at 0.2 per 1000 patient years  which is much less than the mortality of untreated heroin dependence .
In RCTs, safety data is rarely well collected; however, buprenorphine patients have been found to report more headaches, and methadone patients greater sedation . There is a trend for better psychomotor performance with buprenorphine . When injected, buprenorphine damages veins, and complications of buprenorphine injection are common where buprenorphine is administered to injecting drug users . Methadone appears to prolong the QT interval, and cardiac arrhythmia adverse events have been reported. In clinical trials, the extent to which methadone prolongs the QT interval is minimal; however, there appears to be a small increase in the risk of life-threatening cardiac arrhythmias with methadone that is absent with buprenorphine .
Buprenorphine tablets have a high potential for abuse. Wherever buprenorphine has been prescribed to injecting drug users, there has been an associated epidemic of buprenorphine injecting, with patients presenting for treatment using buprenorphine as their first and primary drug of abuse. While some methadone injection occurs, this is rare -particularly when take-home doses are given diluted to 200 ml per dose -and it can be managed by supervised dosing of methadone.
Supervising the dosing of buprenorphine does not completely remove the problem of abuse because it is difficult to adequately supervise the dosing of a sublingual medication that can take up to 15 minutes to dissolve. Injection of diverted buprenorphine can fuel ongoing dependence, transmit bloodborne viruses and result in fatal overdose when the drug is combined with other sedatives. It has also resulted in hepatitis, local and systemic infections, venous and arterial damage, and other injection-related problems.
Common buprenorphine-related adverse effects include headache, constipation, sleep disorders and anxiety. Buprenorphine does not appear to induce significant QT prolongation.
Overall, while buprenorphine itself is likely to be a safer medication, the difficulty of quantifying these benefits and comparing them with the risks of diversion and injection of buprenorphine mean that no conclusions on safety differences can be drawn.

# Cost effectiveness
The cost of methadone is approximately US0.5-1.0 cents/mg, or US60 cents to US$1.20 per effective dose (see next section). The cost of delivery and associated treatments varies from US$5000 per annum in well-resourced countries to approximately US$500 per annum in less well-resourced countries.
Buprenorphine costs approximately US10 cents to US$1/ mg, or US80 cents to US$8 per minimum recommended dose (see next section). Other costs of treatment are likely to be similar to those for methadone when buprenorphine is supervised.
Methadone is cheaper and more effective than buprenorphine at the doses studied; therefore, it is dominant in cost-effectiveness comparisons in this review.

# Limitations of the data
As methadone and buprenorphine are both dosedependent treatments, adequate comparison depends on doses. Also, because buprenorphine is a partial agonist, it is difficult to directly compare doses with methadone. Pharmacological evidence would suggest that 6-8 mg may not be the optimal buprenorphine dose. Higher doses of buprenorphine will be more effective because they act over a longer time and are more effective in blocking the effects of heroin use. Many studies have not used intention-to-treat analyses, and the patients who drop out of treatment are generally not followed up.

# Treatment considerations
Methadone is available in several forms -injectable, oral solution and tablet. The oral solution form is recommended for the treatment of opioid dependence because its administration is more easily supervised; also, take-home medication is less likely to be injected when it is sufficiently diluted (e.g. to 200 mL) when administered.
Buprenorphine is a sublingual tablet most commonly available in sizes of 2 and 8 mg. Because it takes 5-15 minutes to completely dissolve, its ingestion is difficult to supervise. On the positive side, because of its long duration of action, buprenorphine can be administered every second or third day in about two thirds of patients, reducing the need for daily supervision. A formulation of buprenorphine combined with naloxone in a 4:1 ratio is also now available in Australia, Europe and the United States (see Annex 4 for further discussion).
When patients have a history of injecting buprenorphine (either illicitly obtained or prescribed), methadone maintenance should be used in preference to buprenorphine.

# Other research and basic research findings
The half-life of methadone is highly variable, and a significant minority of patients will not tolerate 24-hourly methadone without withdrawal symptoms between doses . For many of these patients, buprenorphine may be a better option.
In studies to date, methadone at standard doses has been more effective in retaining people in treatment and reducing heroin use than buprenorphine at standard doses; also, methadone is cheaper. This evidence comes from meta-analyses of well conducted clinical trials (moderate-quality evidence); however, use of higher doses of buprenorphine may produce different results. Although buprenorphine treatment might be expected to be safer than methadone treatment, this has not been confirmed by research. Currently, high-quality methadone provision should be considered the optimal treatment, with buprenorphine reserved for second-line therapy for patients in whom methadone is unwanted, inappropriate or ineffective. Patients who inject buprenorphine should be prescribed methadone in preference to buprenorphine. This conclusion places a high value on treatment outcomes over possible safety differences, because of the high mortality from untreated opioid dependence.
For opioid agonist maintenance treatment, most patients should be advised to use methadone in adequate doses in preference to buprenorphine.
Strength of recommendation -strong - Quality of evidence -high - Remarks -Although the general preference may be - for methadone over buprenorphine, some patients may do better with buprenorphine. Reasons for use of buprenorphine may include previous response to buprenorphine or lack of response to methadone, short duration of action of methadone (i.e. withdrawal symptoms between doses), interaction between methadone and other medications taken, specific adverse effects of methadone, treatment availability and patient preference for subjective effects of buprenorphine compared to methadone.
Reasons not to use buprenorphine include a history of buprenorphine injection, buprenorphine-specific adverse effects and failure of buprenorphine treatment in the past.

# InITIAl DOSeS OF OPIOID AGOnIST MAInTenAnCe TReATMenT
What initial doses of methadone or buprenorphine should be used?

# Initial dose of methadone
The initial dose of methadone should be based on a careful assessment of the degree of neuroadaptation of the patient. The first two weeks of methadone treatment is a high-risk period for overdose, because it can be difficult to assess with certainty the level of neuroadaptation. For patients on prescribed opioids, the total daily dose should be converted to an equivalent methadone dose given once daily. For patients using street opioids (e.g. heroin), methadone doses of 20 mg a day will typically be adequate to relieve withdrawal symptoms and retain patients in treatment, while at the same time having a low risk of opioid overdose. Patients with low or uncertain degree of neuroadaptation should start on low doses of methadone and be closely observed. Some patients with high levels of neuroadaptation will experience some discomfort if ceasing heroin and commencing methadone at 20 mg daily. In this group, the use of higher doses (up to 30 mg) to retain patients in treatment and at greater comfort should be balanced against the risk of fatal overdose if the level of neuroadaptation is overestimated. A safer but more labour-intensive strategy is to provide an initial safe dose and review the patient several hours later to assess the response to that dose, adjust the next daily dose and, if necessary, provide a supplementary dose.
Once it has been established that the initial dose is well tolerated, the methadone dose should be gradually increased until the patient is comfortable and not using heroin or other illicit opioids. The rate of increase should be individually assessed, and should generally not be greater than 10 mg every few days.
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.

# Strength of recommendation -strong 
Quality of evidence -very low 

# Initial dose of buprenorphine
The risk of overdose during buprenorphine induction is low. In patients with high neuroadaptation to opioids, however, buprenorphine may precipitate withdrawal symptoms initially, and such patients may benefit from lower initial doses (2 mg). In addition, patients should wait until they are experiencing mild opioid withdrawal before taking the first dose of buprenorphine (generally at least 12 hours since last heroin or other short-acting opioids), to reduce the risk of withdrawal symptoms precipitated by buprenorphine. Patients with moderate levels of neuroadaptation will generally tolerate initial doses of 4-8 mg a day.
Once it has been established that the initial dose is well tolerated, the buprenorphine dose can be increased fairly rapidly to a dose that provides stable effects for 24 hours and is clinically effective.

# FIxeD OR FlexIBle DOSInG In AGOnIST MAInTenAnCe TReATMenT

# Should methadone and buprenorphine doses by fixed or individually tailored?
No studies were identified comparing fixed and flexible doses for methadone or buprenorphine maintenance treatment. Flexible dosing schedules are thought to be preferable because of individual differences in absorption and metabolism, and dose-related differences in clinical response. In general, the dose of methadone and buprenorphine should be increased until illicit opioid use ceases. Thereafter, the dose should be reviewed frequently, without allowing patients to become obsessed with minor changes in their dose. The methadone dose should be reviewed more frequently during induction and dose increases, after missed doses and during dose reduction. In general, the patient should be reviewed at least monthly during the maintenance phase of treatment.

# MAInTenAnCe DOSeS OF MeTHADOne

# What maintenance doses of methadone and buprenorphine should be used?
See evidence profile in Section A1. 5

# of Annex 1
There is moderate-quality evidence that high doses of methadone (>60 mg) result in better retention in treatment and less heroin use than lower doses (<40 mg). Health professionals should prescribe effective doses of methadone and be prepared to increase the dose if patients are still using illicit opioids.
Fixed-dose methadone studies were divided into studies that compared 1-39, 40-59, 60-109 and above 109 mg (patients in this latter category all received 160 mg).

# 60-109 mg versus 1-39 mg
When compared to doses in the range 1-39 mg, 60-109 mg doses resulted in better retention in treatment (RR 1.36, 95%CI 1.13 to 1.63, high-quality evidence) and had higher rates of opioid abstinence (RR 1.59, 95%CI 1.16 to 2.18, low-quality evidence) and cocaine abstinence (RR 1.81, 95%CI 1.15 to 2.85, moderatequality evidence).

# 60-109 mg versus 40-59 mg
When compared to doses in the range 40-59 mg, 60-109 mg doses resulted in better retention in treatment in the long term (RR 1.23, 95%CI 1.05 to 1.45, highquality evidence), and a non-statistically significant reduction in heroin use (RR 1.51, 95%CI 0.63 to 3.61, low-quality evidence).

# 40-59 mg versus 1-39 mg
There was no demonstrable difference between medium (40-59 mg) and low doses (1-39 mg) in terms of retention in treatment (RR 1.26, 95%CI 0.91, 1.75, in favour of medium doses, moderate-quality evidence).

# Doses above 109mg
When compared to doses in the range 60-109 mg, 160 mg per day did not result in better treatment retention (RR 0.96, 95%CI 0.69 to 1.34, low-quality evidence), although this higher dose resulted in better retention in treatment than doses below 60mg (RR 1.67, 95%CI 1.05 to 2.66).

# Non-randomized studies
Numerous non-randomized studies have identified better outcomes for patients on high methadone doses .
High methadone doses may be associated with increased risk of QT prolongation. The precise risk of QT-related adverse effects is difficult to quantity, but it is probably smaller than the benefits of high methadone doses. This is supported by the evidence for lower mortality risk for patients on high methadone doses .

# Cost effectiveness
No studies were found that compared the cost effectiveness of high and low doses of methadone. In well-resourced countries, the cost of methadone is a small part of the overall cost of treatment, and using high doses is likely to increase the cost-effectiveness of methadone. In less well resourced countries, where the cost of methadone may make up a substantial portion of the costs of treatment, the situation is less clear. However, if heroin use is ongoing at any given methadone dose, increasing the methadone dose is likely to be a cost-effective response.

# Limitations of data
The quality of the evidence on this issue is not high. Specifically, there is a lack of research of the impact of methadone doses from RCTs. Although there is a strong association between high methadone doses and good clinical outcomes based on evidence from non-randomized studies, this finding may be biased by patients who respond to methadone staying in treatment longer and on higher doses rather than is the case with those who do not respond.

# Treatment considerations
In clinical practice, doses are individually tailored, based on ongoing heroin use, withdrawal symptoms between doses and adverse effects. Pharmacokinetic studies indicate large differences in methadone absorption and metabolism. In this context, trough methadone levels, measured 24 hours after dosing, are likely to be a better measure of the active dose. Some patients are likely to be adequately treated with low doses; others may need doses above the target dose range.
Doses in the range of 60-109 mg are more effective than lower doses. Clinicians should be encouraged to aim for doses in this range in general. Clinicians should encourage patients to use these high doses and not reduce their dose, particularly when they are still using illicit opioids.
On average, methadone maintenance doses should be in the range of 60-120 mg per day.
Strength of recommendation -strong - Quality of evidence -low 

# MAInTenAnCe DOSeS OF BUPRenORPHIne
No systematic reviews of the effectiveness of buprenorphine at different doses were found. In randomized trials that have been conducted comparing doses, 6 mg has resulted in less heroin use than 2 mg  8 mg/day has been shown to have better retention than 3 mg per day  and 12 mg/day has resulted in less heroin use than 4 mg/day . Two studies examining higher doses have shown a trend (not statistically significant in either study) for 16 mg to be more effective than 8 mg daily .
Buprenorphine dose does not appear to have implications for safety. However, there is a suggestion from one RCT that alanine transaminase (ALT) and aspartate transaminase (AST) levels are more likely to be elevated in patients on higher doses of buprenorphine.

# Cost effectiveness
No studies covering cost effectiveness of different doses of buprenorphine were identified in this review. The cost of buprenorphine is a significant component of buprenorphine treatment and, while higher doses are likely to be more effective, the cost effectiveness is not clear.

# Limitations of the data
There are few data comparing low doses to those above 6 mg.

# Other evidence
High doses of buprenorphine (16-32 mg) block the additional effects of heroin better than lower doses  and last for longer without inducing significant additional sedation.
Although the quality of evidence is low, higher doses are likely to result in better retention and less heroin use than lower doses, with minimal adverse consequences other than cost. On average, doses should be at least 8 mg per day. If patients are continuing to use illicit opioids, consideration should be given to increasing the dose by 4-8 mg, to a limit of 32 mg daily.
Average buprenorphine maintenance doses should be at least 8 mg per day.
Strength of recommendation -standard - Quality of evidence -very low 

# SUPeRVISIOn OF DOSInG In OPIOID AGOnIST MAInTenAnCe TReATMenT

# Should opioid agonist maintenance treatment doses be supervised?
There has been very little systematic research on the supervision of dosing in opioid agonist maintenance treatment. All of the clinical trials demonstrating the efficacy and safety of methadone and buprenorphine against placebo or opioid withdrawal have been conducted using supervised administration, as have trials comparing methadone and buprenorphine. Nonsupervised administration is used in some countries for buprenorphine treatment, most notably France, and some countries have limited supervision of dosing (such as once a week or less) for stable methadone patients. Diversion occurs with both methadone and buprenorphine if they are unsupervised, although there appears to be much greater diversion and injection of buprenorphine, even when combined with naloxone, than of methadone . This is probably due to multiple factors.
Buprenorphine is an attractive drug for injection
- because it produces strong effects, even in low doses, resulting in a group of individuals using buprenorphine as their first and main drug of abuse.
The milder withdrawal symptoms with reduced
- buprenorphine dosing mean that patients can take some of their own buprenorphine and divert the remainder without experiencing strong withdrawal symptoms.
Buprenorphine is difficult to supervise effectively
- because it is sublingually administered, taking 5-15 minutes to dissolve, wheras methadone is swallowed.
Methadone is difficult to divert when dosing is supervised and when given in diluted form (i.e. 200 mL) for takehome use its injection is rare. It has a long duration of action, making it less attractive to inject regularly. People who do purchase methadone illicitly generally use it for self treatment purposes .
The data on diversion and overdose deaths consistently indicate that unsupervised methadone is a hazard, because it results in a substantial number of overdose deaths in people for whom it is not prescribed . Diverted buprenorphine, on the other hand, is less likely to result in death (although deaths have occurred in combination with other sedatives); however, it is likely to be injected. The main problem with buprenorphine diversion is the creation of a group of people primarily dependent on illicit buprenorphine, who are at risk from the problems associated with buprenorphine injection, which can lead to hepatitis C, HIV, endocarditis and local infections. Whether an epidemic of diverted buprenorphine is a net benefit or harm is not easy to ascertain, because it may result in a corresponding drop in heroin use; however, it would not be acceptable in many countries, because it would threaten the viability of the drug treatment system.
These points form the public health argument for supervision of treatment. On the other hand, unsupervised treatment is cheaper to set up and easy to expand. Expansion of treatment is a high priority in many areas where HIV in injecting drug users is a problem and current rates of treatment are low. Rapid expansion of unsupervised buprenorphine is argued to be the most feasible method of meeting the unmet need for treatment in the short term . However, it is not clear whether unsupervised buprenorphine treatment, with its associated problems of buprenorphine injecting, would reduce HIV spread to the extent that has been demonstrated for supervised methadone treatment.
The impact of supervision of treatment on patients themselves must be considered. Opioid dependence implies a lack of control over opioid use; thus, there are strong theoretical reasons why -at the start of treatment at least -supervision of methadone and buprenorphine may be advantageous to the patient. Unfortunately, there is a lack of clinical trial data on this topic. Research has tended to focus on patients who have been in treatment for some time, examining the impact of providing unsupervised treatment to those who meet certain criteria of stability. In this situation, RCTs demonstrate that making unsupervised treatment contingent upon cessation of illicit drug use results in a reduction in illicit opioid use.
On balance, initiating treatment with supervised dosing, assessing response to treatment, and subsequently allowing unsupervised doses to patients who demonstrate stability appears to substantially reduce diversion, probably does not diminish efficacy and is supported by patient groups.
The key elements of "stability" appear to include housing, employment, not being dependent on multiple drugs and ceasing to inject after entering treatment.
It has been argued that because the risk of overdose on buprenorphine is lower then that of methadone, and because unsupervised doses are cheaper to provide and readily accepted by patients, that in places where opioid agonist treatment is not currently available, the greatest public health benefit would occur from the introduction of buprenorphine with unsupervised dosing. It is not possible based on the current data to draw firm conclusions on this proposition. The potential benefits of making treatment more accessible, affordable and possibly more attractive to patients need to be balanced against risk of less effective treatment, creation of an illicit buprenorphine market and potential community antagonism.

# Practical considerations
Supervised methadone dosing involves first dispensing methadone liquid into a clean cup, the liquid is then consumed under the direct observation of a nurse, pharmacist or doctor. Talking to patients after they have consumed their methadone is generally adequate to ensure that the dose has been taken.
Buprenorphine supervision is more difficult, because the tablet can easily be sequestered in a corner of the mouth as it takes up to 15 minutes to dissolve. The tablet should be dispensed into a clean container and tipped into the mouth of the patient, under the tongue. Periodic examination should reveal the tablet in various stages of dissolution.
If no longer needed, for whatever reason, unconsumed unsupervised doses should be returned to the place where they were dispensed.
On balance, initiating treatment with supervised dosing, assessing the response to treatment and subsequently allowing unsupervised doses to patients who demonstrate stability appears to substantially reduce diversion, probably does not diminish treatment efficacy and is supported by patient groups. Routine supervision of dosing with methadone or buprenorphine is recommended for all patients unless they have demonstrated that they meet commonly accepted criteria for take-home doses, developed at a regional or national level.
Methadone and buprenorphine doses should be directly supervised in the early phase of treatment.

# Strength of recommendation -strong 
Quality of evidence -very low - Recommendation 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.
Strength of recommendation -standard - Quality of evidence -very low 

# OPTIMAl DURATIOn OF OPIOID AGOnIST TReATMenT

# What is the optimal duration of opioid agonist treatment?
There is little research on the optimal duration of opioid agonist treatment. Studies comparing short-term opioid agonist treatment (i.e. weeks to months) to longer term treatment (6-12 months) find better results for longer term treatment. This is consistent with opioid dependence being a longer-term disease. No RCTs comparing longer treatment durations were found. Observational studies indicate that those who remain in long-term opioid agonist therapy are more likely to stay alive than those who do not, and that cessation of opioid agonist maintenance treatment is associated with a risk of relapse to opioid use. Given these findings, these guidelines recommend that opioid agonist treatment should be seen as open ended, and should be continued as long as clinically indicated. Patients and clinical staff should not take lightly the decision to terminate opioid agonist maintenance treatment (e.g. for administrative reasons). Factors predicting successful termination of opioid agonist maintenance treatment are not well described, but are likely to include employment or other meaningful activity, abstinence from opioid and other drug use while taking opioid agonists, and changes in the psychosocial environment after starting opioid agonist treatment.

# Practical considerations
The decision to stop opioid substitution therapy can be a difficult one for patients, and they often seek guidance from treatment staff. On the other hand, some patients simply make up their minds that they want to cease opioid agonist treatment. In both situations, patients should be informed of the risks of cessation of the therapy and encouraged to make healthy choices. In patients doing well on opioid substitution therapy, this can also be an occasion to consider the option of more take-home doses as an alternative to cessation of opioid substitution therapy.

# USe OF PSYCHOSOCIAl InTeRVenTIOnS In MAInTenAnCe TReATMenT

# Should psychosocial treatments be used in addition to pharmacological maintenance treatments?
See evidence profile in Section A1.12 of Annex 1
A recent Cochrane Collaboration review identified eight RCTs that addressed the issue of whether psychosocial interventions should be used in addition to pharmacological maintenance treatments. Comparing methadone plus psychosocial treatment to methadone alone, the pooled analysis found no difference in treatment retention (RR 0.94, 95%CI 0.85 to 1.02, high-grade evidence); however, heroin use was significantly reduced with the addition of psychosocial treatment (RR 0.69, 95%CI 0.53 to 0.91, high-grade evidence).

# Cost effectiveness
Cost effectiveness studies in the United States found that methadone with moderate intensity psychosocial services (1-2 hours per week) are more cost effective than methadone either without psychosocial services or with high intensity services (i.e. several hours a day) .

# Limitations of data
Studies have used different techniques, including hypnotherapy, psychotherapy, acceptance and commitment therapy, interpersonal psychotherapy, supportive-expressive psychotherapy, counselling, cognitive behavioural therapy (CBT), contingency management, dialectic behaviour therapy and comprehensive validation therapy. It is difficult to compare these interventions in meta-analyses. Contingency management studies have the most consistently positive findings, regardless of whether vouchers, take-home methadone privileges or prize draw incentives are used. It is not clear whether these interventions can be generalised to settings outside the one in which they were carried out (mainly the United States).
Psychosocial assistance in methadone maintenance can reduce heroin use in methadone maintenance. In the United States, such services are most cost effective if they are of moderate intensity (1-2 hours a week).
Psychosocial support should be offered routinely in association with pharmacological treatment for opioid dependence.
Strength of recommendation -strong - Quality of evidence -high - Remarks -While patients should be offered psychosocial - support, they should not be denied agonist maintenance treatment should they refuse such support.

# Management of opioid withdrawal
Although distressing, the opioid withdrawal syndrome is rarely life threatening; however, pharmacologically assisted management of opioid withdrawal can make withdrawal from opioids more comfortable and more likely to succeed. Given the high rate of relapse, assisted opioid withdrawal is not considered an effective treatment of opioid dependence on its own (see section 6.3).

# SIGnS, SeVeRITY AnD TReATMenT PRInCIPleS
The severity of opioid withdrawal depends on the dose and pharmacological properties of the opioids used, and on the extent of neuroadaptive changes that have taken place in the patient. Drugs with short half-lives will give rise to withdrawal symptoms at an earlier phase than those with long half-lives; the symptoms will also peak and resolve earlier. Untreated heroin or morphine withdrawal typically reaches its peak 36-72 hours after the last dose, and symptoms will have subsided substantially after 5 days. Untreated withdrawal from methadone or other long-acting opiates typically reaches its peak at 4-6 days, and symptoms do not substantially subside for 10-12 days. Untreated buprenorphine withdrawal following the abrupt cessation of long-term buprenorphine treatment emerges within 3-5 days of the last dose, and mild withdrawal features can continue for several weeks.
Opioid antagonists (e.g. naltrexone), which induce rapid changes in receptor activity, can precipitate withdrawal symptoms of greater severity than those normally seen in heroin withdrawal, if administered in close connection with opioid use. Treatment with naltrexone can be started within one week of cessation of short-acting opioids and buprenorphine. By contrast, naltrexone is usually not started until 10-14 days after the cessation of methadone.
The severity of withdrawal is related to the degree and rate of reversal of neuroadaptive changes related to opioid use. The most severe withdrawal occurs with the sudden reversal of significant levels of neuroadaptation; for example, when naltrexone is taken by patients who are taking high doses of methadone. When assessing the patient for planned opioid withdrawal, including admission to a residential detoxification facility or provision of medication to manage withdrawal symptoms, it is important to complete a thorough assessment of the patient (see section 6.1). and, as appropriate, inform the patient of the estimated risks of opioid withdrawal (including the effects of subsequent relapse), as compared to opioid agonist maintenance treatment. Since withdrawal from opioids is associated with higher mortality than opioid agonist maintenance treatment, some indication of the patient's informed consent for opioid detoxification is advised. Precautions for opioid dependence include pregnancy (specifically the first and third trimesters) and current acute comorbid conditions.

# CHOICe OF TReATMenTS FOR ASSISTInG WITHDRAWAl FROM OPIOIDS
Opioid withdrawal can be managed by controlling the rate of cessation of opioids and by providing medication that relieves symptoms, or by a combination of the two.
This analysis focuses on the three approaches to assisting withdrawal from opioids that have been most widely evaluated: tapered oral methadone, tapered sublingual buprenorphine and tapered oral adrenergic alpha-2 agonists.
There are many other alternative treatments; for example: shorter acting oral opioids -these are not Detailed guidance on the use of these medications is beyond the scope of these guidelines.

# What treatments should be used to assist withdrawal from opioids?
See evidence profile in Section A1.6 of Annex 1

# Methadone versus alpha-2 agonists
In the pooled analysis (7 studies, 577 participants), there was no significant difference between methadone and alpha-2 agonists in treatment completion (RR 1.09, 95%CI 0.90 to 1.32, moderate-quality evidence).
There was no difference in rates of relapse at followup (intention-to-treat analysis) (RR 1.06: 95%CI 0.55 to 2.02, low-quality evidence).

# Methadone versus buprenorphine
In the pooled analysis (2 studies, 63 participants), there was no significant difference in completion of treatment between methadone and buprenorphine (RR 0.88: 95%CI 0.67 to 1.15, low-quality evidence).

# Buprenorphine versus alpha-2 agonists
In the pooled analysis (8 studies, 653 participants) comparing buprenorphine to alpha-2 agonists, there were higher completion rates with buprenorphine (RR 1.
Methadone has the greatest risk of over sedation, although this is reduced with the use of lower doses (<20 mg). Buprenorphine, while safer than high doses of methadone, is nonetheless potent even at low doses, and can cause significant respiratory depression when used in combination with other sedatives, including benzodiazepines, alcohol, tricyclic antidepressants, sedating antihistamines and major tranquilizers. A number of deaths have been reported involving the combination of buprenorphine with benzodiazepines and other sedatives. As a partial agonist, buprenorphine can induce precipitated withdrawal if used while heroin is still bound to receptors. This may occur on up to 10% of occasions in which buprenorphine is used for opioid withdrawal. The main adverse effect of buprenorphine is headache. Alpha-2 agonists can cause postural hypotension, which can lead to dizziness and fainting. In overdose, alpha-2 agonists induce profound bradycardia which may require intensive care treatment but is not usually fatal. Lofexidine induces less postural hypotension than clonidine; Cochrane Collaboration reviews of clinical trials detected no difference in safety.

# Cost effectiveness
There are limited data to differentiate the cost effectiveness of these medications when used for opioid withdrawal. Buprenorphine and lofexidine are more expensive than methadone. Despite this, an analysis in Australia found outpatient buprenorphine to be more cost effective than outpatient clonidine .

# Limitations of data
It is difficult to make an assessment of the relative effectiveness of withdrawal treatment from detoxification trials because of variations in practice and because participants often leave withdrawal units on the day of the last dose, before withdrawal symptoms are completed. Data on severity of withdrawal are useful to compare treatments, but are not uniformly collected and are difficult to include in meta-analysis. Furthermore, withdrawal methods vary and few studies use the same techniques.

# Treatment considerations, duration of the treatment
All treatments can be used in inpatient and outpatient withdrawal settings. Methadone and buprenorphine can be administered as once-daily supervised doses, to reduce diversion and increase safety (guanfacine can also be administered once daily, although the need for supervised dosing is less with alpha adrenergic agonists). Gradual reduction of methadone and buprenorphine can reduce the severity and increase the length of opioid withdrawal. Such gradual reductions improve treatment retention but reduce the rate of successful completion of withdrawal .
Buprenorphine is suitable for once-daily - administration; it leads to less severe withdrawal and higher rates of completion than alpha-2 agonists. Methadone is cheaper than buprenorphine and - carries no risk of precipitated withdrawal; it is suitable for use in pregnancy. Alpha-2 agonists can lead to shorter duration - of withdrawal symptoms and shorter time to commencement of naltrexone.
All three medications listed above can be used for opioid withdrawal. Clinical trials clearly show that buprenorphine is more effective than alpha-2 agonists, and clinical experience would suggest that methadone lies somewhere between the two, even though equivalent to both in the Cochrane Collaboration reviews. Choice should depend on the individual situation, capacity to tolerate withdrawal symptoms, timeframe and patient preferences.
For the management of opioid withdrawal, tapered doses of opioid agonists should generally be used, although alpha-2 adrenergic agonists may also be used.
Strength of recommendation -standard - Quality of evidence -moderate - Remarks -Buprenorphine and methadone are both - recommended in the management of opioid withdrawal.
As a partial agonist with slow receptor dissociation, buprenorphine has the best pharmacological profile for use in withdrawal, reducing the risk of rebound withdrawal when opioids are ceased. While buprenorphine is probably slightly more effective, it is more expensive.
continued on next page

# ACCeleRATeD WITHDRAWAl MAnAGeMenT TeCHnIQUeS
Accelerated withdrawal techniques use opioid antagonists to induce withdrawal and thus complete the process more quickly. Here, the techniques are divided depending on whether they co-administer minimal or heavy sedation. Minimal sedation refers to levels that might commonly be prescribed in the management of opioid withdrawal in outpatient or residential settings, because they have a low risk of inducing respiratory depression. Heavy sedation refers to the administration of either oral or parenteral sedatives or anaesthesia that have a significant risk of inducing respiratory depression. The use of heavy sedation requires intensive monitoring and the capacity to assist respiration, such as would be provided in an intensive care setting.

# Should antagonists with minimal sedation be used for opioid withdrawal?
See evidence profile in Section A1.8 of Annex 1
Four studies (394 participants) were found that examined the issue of whether antagonists with minimal sedation should be used for opioid withdrawal. In the pooled analysis, there were no significant differences in rates of completion between different opioid antagonist techniques, (RR 1.26, 95%CI 0.80 to 2.00, moderate-quality evidence). No difference in relapse rates was detected (RR 0.83, 95%CI 0.52 to 1.35, low-quality evidence .
Data from observational studies suggest higher rates of adverse effects with the use of opioid antagonists (RR 3.7, 95%CI 0.65 to 21.32, very low-quality evidence).

# Cost effectiveness
Although the use of opioid antagonists adds to the cost of medications for opioid withdrawal, the overall cost effectiveness may be greater than conventional withdrawal treatment if the duration of withdrawal treatment is reduced .

# Treatment considerations
Naltrexone hydrochloride is available primarily as a solid oral formulation in 25 mg and 50 mg tablets. Naloxone is available as ampoules for injection, at a concentration of 0.4 mg in 1 mL, or as a prefilled syringe.

# Treatment regimens
Dosing regimens used in clinical trials range from a single dose of 50 mg naltrexone daily to a graduated increase of 12.5 mg naltrexone daily. Techniques vary from a single daily dose of naloxone to the use of naloxone infusions. Other than the observation that regimens that use higher initial doses of naltrexone are associated with higher rates of delirium, it is not clear which of these approaches is more effective. Careful and continuous monitoring is necessary during the hours immediately following administration of opioid antagonists, because of the possibility of delirium, vomiting and diarrhoea. To prevent and treat excessive diarrhoea and vomiting, expensive medications, such as ondansetron and octreatide, are often required, combined with intravenous fluid replacement. Opioid antagonist withdrawal techniques should not be undertaken in patients with a history of cardiac disease, psychosis, chronic renal impairment or decompensated liver disease, or current dependence on alcohol, benzodiazepines or stimulants.

# Use of antagonists may reduce the duration of
The duration of the dose taper should be at least 3 days, with a taper over 5 days for buprenorphine and 10 days for methadone resulting in acceptable withdrawal symptoms during treatment and minimal rebound withdrawal symptoms on cessation of the opioid agonist.
Lofexidine should be used in preference to clonidine, particularly in outpatient settings, because it has less adverse effects.
recommendation continued withdrawal; thus reducing the overall severity of withdrawal and increasing the chances of successful completion. In inpatient settings where the cost of the facility is high compared to the cost of medication, this may result in significant cost savings. This technique facilitates commencement of naltrexone treatment.

# Undesirable effects and consequences
Adverse effects of opioid withdrawal treatment may include a higher peak severity of withdrawal symptoms, possibly resulting in dehydration (and resulting complications such as renal failure) and delirium.
Complications from excessive sedation used in managing the increase in peak withdrawal severity could include aspiration pneumonia and respiratory depression.
The small number of clinical trials conducted on treatments for opioid withdrawal have used a variety of approaches, making generalization difficult. Results from these trials suggest that antagonist-induced withdrawal techniques increase the severity of opioid withdrawal initially, and may increase the adverse effects of withdrawal. Given the potential for harm, there is not enough evidence of benefit to recommend the routine use of these techniques.
Clinicians should not routinely use the combination of opioid antagonists and minimal sedation in the management of opioid withdrawal.

# Strength of recommendation -standard 
Quality of evidence -very low - Remarks -This recommendation places a higher value - on the prevention of adverse outcomes due to delirium and dehydration than on any potential for reduced duration or overall severity of withdrawal symptoms. If opioid antagonists are to be used, careful and continuous monitoring is necessary for at least 8 hours following the administration of opioid antagonists, due to the possibility of delirium, vomiting and diarrhoea, and systems should be available for identifying and managing people who become dehydrated or delirious. Opioid antagonist withdrawal should not be undertaken in pregnant women because of the risk of inducing abortion or premature labour.
Should antagonists with heavy sedation or anaesthesia be used for opioid withdrawal?
Opioid withdrawal with opioid antagonists and heavy sedation or anaesthesia is defined as withdrawal that requires monitoring of vital functions such as respiratory rate and oxygen saturation. Such withdrawal usually takes place in intensive care settings.
See evidence profile in Section A1.9 of Annex 1
A recent Cochrane Collaboration review  identified RCTs in which ultra-rapid opioid detoxification (UROD) was compared to: inpatient opioid withdrawal with clonidine (two
- studies  inpatient withdrawal with buprenorphine (one study
) opioid antagonist and minimal sedation techniques - (two studies .

# Completion of treatment and commencement of naltrexone
In the pooled analysis, there was no difference in the rates of completion of treatment of naltrexone compared to either clonidine (RR 1.15, 95%CI 0.79 to 1.68, moderate-quality evidence), or buprenorphine (RR 0.82, 95%CI 0.34 to 1.97, low-quality evidence). The use of antagonists and heavy sedation resulted in higher rates of naltrexone commencement than inpatient clonidine withdrawal (RR 3.40: 95%CI 2.32 to 4.98, moderate-quality evidence), but not inpatient buprenorphine withdrawal (RR 0.97: 95%CI 0.88 to 1.07, low-quality evidence).

# Relapsed at follow-up
Heavy sedation or anaesthesia made no difference in rates of heroin use at the 6 month follow-up (RR 0.97, 95%CI 0.88 to 1.08, moderate-quality evidence).

# Retention in treatment at 12 months
Heavy sedation or anaesthesia made no difference to rates of retention in treatment at 12 months (RR 0.95, 95%CI 0.69 to 1.30, moderate-quality evidence).
Higher rates of adverse effects were seen with techniques involving heavy sedation or anaesthesia (RR 3.21, 95%CI 1.13 to 9.12, moderate-quality evidence).Potential adverse effects include severe opioid withdrawal resulting in dehydration (and resulting complications such as renal failure) and delirium. Potential complications from excessive sedation include aspiration pneumonia and respiratory depression . Three life-threatening adverse events occurred out of 35 participants in the heavy sedation groups, and none out of 71 participants in the non-heavy sedation groups (RR 14, 95%CI 0.74 to 264, low-quality evidence).

# Cost effectiveness
Techniques using heavy sedation and anaesthesia are expensive. In an Australian analysis, these techniques did not offer any cost-effective advantages over techniques using antagonists and minimal sedation .

# Limitations of data
Studies do not have enough numbers to accurately determine safety data. Variations in technique may result in different patterns of safety and efficacy.

# Treatment considerations
At a minimum, techniques involving heavy sedation should be conducted in a setting that is suitable for managing respiratory depression, such as an intensive care or high-dependency unit. A number of patients have died when this technique has been used outside intensive care unit settings .
Compared with use of methadone and alpha-2 adrenergic agonist treatment for opioid detoxification, use of opioid antagonists and heavy sedation may mean that it is possible to start naltrexone earlier. However, use of opioid antagonists and heavy sedation is of little benefit over buprenorphine-assisted withdrawal or use of opioid antagonists with minimal sedation. In addition, the use of opioid antagonists and heavy sedation leads to significantly higher complication rates. Given this balance, techniques combining opioid antagonists and heavy sedation are not recommended.
Clinicians should not use the combination of opioid antagonists with heavy sedation in the management of opioid withdrawal.
Strength of recommendation -strong - Quality of evidence -low 

# TReATMenT SeTTInG FOR OPIOID WITHDRAWAl

# Should withdrawal from opioids be conducted in inpatient or outpatient settings?
See evidence profile in Section A1.10 of Annex 1
A recent Cochrane Collaboration review  identified one RCT that directly addressed the issue of whether withdrawal from opioids should be conducted in inpatient or outpatient settings. The review found better rates of completion of treatment for the inpatient group (RR 1.91, 95%CI 1.03 to 3.55, very low-quality evidence). There were no differences in relapse rates between inpatient and outpatient groups (RR 1.07, 95%CI 0.97 to 1.18).
There were no data to compare the safety of inpatient and outpatient withdrawal. It might be expected that inpatient withdrawal would be safer than outpatient withdrawal, but no data are available on this topic.

# Cost effectiveness
Inpatient opioid detoxification is significantly more expensive than outpatient opioid detoxification.
Australian data suggest that outpatient withdrawal with buprenorphine is significantly more cost effective .

# Limitations of data
The RCT upon which the efficacy data is based has significant flaws; as a result, the grade of evidence is low. It seems that many patients allocated to the inpatient group either refused inpatient treatment or dropped out before opioid withdrawal was arranged.

# Treatment considerations
Inpatient treatment is expensive to administer because it generally requires a secure environment, 24-hour nursing care and daily medical care. Patients in opioid withdrawal are generally restless and irritable, and it can be a challenging environment in which to work. Ensuring the health and safety of the staff in residential withdrawal units requires adequate staffing and training levels.
Opioid withdrawal in residential facilities has higher rates of success and is probably safer.

# Undesirable effects and consequences
Opioid withdrawal in residential facilities is expensive and is inconvenient for many patients.
Inpatient detoxification appears to have higher rates of completion of withdrawal than outpatient detoxification, but there is no demonstrable difference in relapse rates. Data to estimate the relative safety of inpatient and outpatient detoxification are lacking. It is more cost effective to provide most opioid detoxification on an outpatient basis, reserving inpatient opioid detoxification for patients who:
have previously failed to complete outpatient. There were no differences in rates of other substance use during detoxification .

# Treatment considerations
The types of psychological assistance provided in the studies were contingency management, community reinforcement, psychotherapeutic counselling and family therapy. The data show no clear advantage of one technique over the others, although the evidence (from four studies) is strongest for contingency management approaches combined with methadone or buprenorphine.
Psychosocial assistance can: help patients to clarify their goals around their drug
- use increase patients' motivation to stop or reduce their In addition, psychosocial support can help to educate patients about the sort of withdrawal symptoms they will experience, provide them with useful strategies for minimizing withdrawal and help them to interpret the current withdrawal phenomena. It can also facilitate transfer to post-withdrawal treatment options, and assist with reintegration into society.

# Undesirable effects and consequences
There is a theoretical risk that psychosocial interventions to assist people undertaking opioid withdrawal may inadvertently encourage people to continue with opioid detoxification instead of moving to more effective longer term interventions, such as opioid agonist maintenance treatment.
For those who wish to withdraw from opioids, combined psychosocial and pharmacological assistance increases the chance of successfully completing opioid withdrawal. The evidence is strongest for contingency management approaches.
Psychosocial services should be routinely offered in combination with pharmacological treatment of opioid withdrawal.

# Strength of recommendation -standard 
Quality of evidence -moderate 

# Opioid antagonist (naltrexone) treatment

# Should opioid antagonist therapy be used for opioid dependence and, if so, what are the indications for use?
Naltrexone is a highly specific opioid antagonist with a high affinity for opioid receptor sites. It effectively reverses and blocks the opioid effects of lower affinity reversible agonists, such as methadone and heroin. Naltrexone hydrochloride is available by prescription in many countries as 25 and 50 mg tablets; it is also used in the treatment of alcohol dependence.

# InDICATIOnS FOR OPIOID AnTAGOnIST THeRAPY
See evidence profile in Section A1.11 of Annex 1
Naltrexone was compared to placebo for post-opioid withdrawal (with or without psychosocial treatment). There was no effect of naltrexone on retention in treatment (RR 1.08, 95%CI 0.74 to 1.57, moderatequality evidence). There was a reduction in heroin use with naltrexone (RR 0.72, 95%CI 0.58 to 0.90, lowquality evidence). There was no difference in relapse at follow-up (RR 0.94, 95%CI 0.67 to 1.34, very low-quality evidence). There was also a large reduction in criminal behaviour with naltrexone (RR 0.50, 95%CI 0.27 to 0.91, very low-quality evidence).
There was no difference in reported rates of adverse effects (RR 1.21, 95%CI 0.81 to 1.81). However, some observational studies have found high rates of opioid overdose in the period after ceasing naltrexone treatment.

# Limitations of data
Only a small number of studies have examined naltrexone for prevention of relapse in opioid dependence.
Naltrexone treatment results in a reduction in heroin use and criminal behaviour. Family members of opioid addicts often like naltrexone treatment because it is clear that if the patient is taking the naltrexone they are not using heroin. Also, when family members directly observe naltrexone consumption, it gives them an opportunity to become involved in the treatment of the individual. Naltrexone blocks the effects of heroin for approximately 24 hours after each 50mg dose.

# Undesirable effects and consequences
Patients often cease taking naltrexone with the intention of using heroin again, and when they do so it is difficult for them to assess the dose of heroin to use, because the effects of naltrexone are wearing off. In the space of 12 hours, the same dose of heroin can be blocked or can be fatal. This may result in higher rates of unintentional opioid overdose in people ceasing naltrexone therapy.
There is a concern that naltrexone may be used as a coercive treatment. Such coercive pharmacological treatment would be unethical. Furthermore, naltrexone used in this way would not necessarily have the same efficacy as with voluntary participants.

# Treatment considerations
Naltrexone is formulated in 15 and 50 mg tablets. The cost of the medication currently varies from approximately US50 cents to US$5 per tablet. Each tablet blocks the effects of heroin for 24-48 hours. Because it completely blocks the effects of heroin, naltrexone should be prescribed to those who are aiming at complete abstinence from opioids; this limits its use to a subpopulation of more motivated patients.

# Other research and basic research findings
Naltrexone may be more effective when family members are involved in the treatment or directly observe the patient taking naltrexone. Clinical experiences with naltrexone vary considerably between countries, with some countries finding levels of retention similar to opioid agonists and others finding very poor rates of retention. It is possible that cultural and social differences could result in a variable efficacy and acceptability of naltrexone treatment. Clinical experience suggests that naltrexone may be more effective in patients who are motivated to abstain from opioid use -for example, professionals at risk of losing their employment, or patients who have come before the courts and risk incarceration.
The limited evidence available suggests that, in dependent opioid users who have withdrawn from opioids, those who take naltrexone are less likely to use heroin or engage in criminal activity than those who do not take naltrexone. Opioid dependence has a spectrum of severity and early stages of dependence may respond better to naltrexone than more severe dependence.
Retention in treatment is generally likely to be lower than opioid agonist maintenance therapy; nevertheless, in those patients who have withdrawn from opioids and are motivated to cease opioid use completely, relapse prevention efforts with naltrexone are likely to be superior to those without naltrexone.
For opioid-dependent patients not commencing opioid agonist maintenance treatment, antagonist pharmacotherapy using naltrexone should be considered following the completion of opioid withdrawal.
Strength of recommendation -standard - Quality of evidence -low - Remarks -This recommendation is based on evidence from - clinical trials that there is less heroin use with naltrexone, and on clinical experience from some countries of adequate rates of retention in treatment of patients on naltrexone.
There is a concern that naltrexone may be used as a coercive treatment. Such treatment would be unethical.

# InDICATIOnS FOR nAlTRexOne THeRAPY

# Patient selection
Given the potential for overdose after relapse, opioid antagonist therapy is likely to be most useful for those with a reasonable chance of remaining abstinent (this statement is based on expert opinion). Such groups include employed patients, those who have been using drugs for only a short time (e.g. younger patients) and those under threat of legal sanctions.
Naltrexone appears to be most useful when there is a "significant other" to administer and supervise the medication; for example, a family member, close friend or, in some cases, an employer.
Patients with severe opioid dependence should be cautious taking naltrexone; also, naltrexone is not recommended for people with cirrhosis who have a Child's severity rating of C or above.

# Use in pregnancy
There is limited experience of naltrexone in pregnancy, but the likelihood of congenital abnormalities is thought to be low. If a woman taking naltrexone treatment becomes pregnant, the benefits of continuing naltrexone should be weighed against possible unforeseen risks.

# The role of psychosocial therapy in naltrexone treatment
As with other pharmacological treatments, psychosocial treatment should routinely also be offered. There are insufficient data to make recommendations about specific psychosocial approaches for use in combination with naltrexone therapy; however, contingency management with vouchers has been found to be useful in maintaining abstinence and retention in treatment for patients on naltrexone . In a second study, a structured group-counselling approach gave no better outcomes than optional unstructured individual counselling control group . One study comparing individual counselling plus naltrexone to family counselling plus naltrexone found family counselling to be superior both during treatment and at 12 months follow-up .

# Psychosocial interventions
The term "psychosocial support" is used here to refer to a broad range of interventions at a social and psychological level. Interventions at a social level include assistance with basic needs such as food, clothing, accommodation and employment, as well as basic health-care, friendship, community and the pursuit of happiness. Interventions at a psychological level range from unstructured supportive psychotherapy and motivational interviewing techniques, to highly structured psychological techniques. Clinicians and health providers should choose which psychosocial intervention to offer to opioid-dependent patients, based on research evidence, how appropriate a method is to the patient's individual situation, how acceptable it is to the patient, whether trained staff are available, and cultural appropriateness.

# PSYCHOlOGICAl InTeRVenTIOnS
A complete discussion of the range of psychological interventions is beyond the extent of this document; however, two subtypes of therapy dominate the literature -CBT and contingency management.
CBT has become the leading approach in a variety of mental and behavioural disorders including phobias, anxiety and obsessive-compulsive disorders; it can also be effective in depression and eating disorders. CBT in substance dependence is based on the principle that addictions are learned behaviours that can be modified.
Cognitive approaches primarily aim to change addictive behaviours by changing faulty cognitions that serve to maintain behaviour, or by promoting positive cognitions or motivation to change behaviour. Commonly used variants are cognitive therapy and motivationalenhancement therapy.
Behavioural approaches aim primarily to modify behaviours underpinned by conditioned learning; that is, by classical and operant conditioning. They include interventions that aim to extinguish classically conditioned responding (e.g. cue exposure and response prevention), or that are based on instrumental conditioning (e.g. community reinforcement or contingency management) -an approach in which positive non-drug taking behaviours are rewarded.
Behavioural approaches involving aversive conditioning are historically important, mainly in the alcohol treatment field, but their use has ceased, mainly for ethical reasons. CBT requires training of staff in, for example, clinical psychology.
Contingency management rewards or punishes specific types of behaviours using a structured, transparent approach that increases learning of desired behaviours. Most programmes focus on positive behaviours, with reinforcement for the desired behaviour. The elements of a contingency management programme are: clear definitions of the desirable behaviour (e.g.
- opioid abstinence); regular monitoring for the presence or absence
- of the desired behaviour (e.g. regular urine tests); specified rewards for the desired behaviour (e.g.
- money, vouchers, take-home methadone doses or lottery tickets); positive personal feedback from staff for the Counsellors should be aware of links to available social services or other social resources in the community.

# SOCIAl InTeRVenTIOnS

# Vocational training
Vocational training includes a range of programmes designed to help patients find and retain employment.
Vocational training can include skills training, sheltered work environments and monitoring of drug use during employment .
Housing services can vary from group accommodation for the homeless to more stable, affordable, long-term accommodation. The importance of housing is such that assistance with housing may be necessary before cessation of drug use can be attempted. While there may be risks in accommodating drug users together in institutional settings, stable accommodation in a drugfree environment is desirable. The strategies adopted will depend on local resources and norms.
The ability of patients to participate in and enjoy leisure activities of their choice is an important aspect of psychosocial support. Programmes can provide access to a range of healthy leisure activities.

# Self-help groups
In the context of opioid dependence, self-help groups are voluntary, small-group structures formed by peers to assist each other in their struggle with opioid dependence. Usually abstinence oriented, they often provide both material assistance and emotional support, and promulgate an ideology or values through which members may attain a greater sense of personal identity .
Patients receiving pharmacological treatment should be encouraged to participate in self-help groups. Although there has been little research on this form of treatment, observational studies on 12-step groups (e.g. Narcotics Anonymous) are positive, with strong "in-treatment" effects. This form of therapy is inexpensive and provides important psychosocial support.

# Social skills training
Social skills training refers to methods that use the principles of learning theory to promote the acquisition, generalization and durability of skills needed in social and interpersonal situations. Training should take place in the context of real everyday life experiences, not in closed, unrealistic settings.

# Traditional healers
Traditional and spiritual healers may have a role in the provision of psychosocial support, if they are culturally acceptable to the patient. Although the assessment of these methods is beyond the scope of this document, clinical staff might wish to explore what options there are for such support with their patients.

# PROVISIOn OF PSYCHOSOCIAl SUPPORT
Staff and volunteers can provide psychosocial support commensurate with their level of expertise. As a minimum, anyone providing psychosocial support to people with opioid dependence should participate in a brief training programme so that they do not put themselves at risk or inadvertently cause harm. Professional staff without specific psychotherapeutic training might be expected to be able to provide supportive psychotherapy or structured therapy based on an appropriate manual after a brief training period (e.g. 1-2 weeks).

# Treatment of overdose
Opioid overdose is identifiable by a combination of signs and symptoms, including pinpoint pupils and respiratory depression. Dilated pupils suggest an alternative diagnosis. Patients with suspected opioid overdose should be treated if the respiratory rate is less than 10 per minute or if they are hypoxic on pulseoxymetry (oxygen saturation <92%).
Initial treatment of hypoxic patients should include supplemental oxygen and assisted ventilation, as necessary. This would typically include clearing the airway and applying bag and mask ventilation with oxygen.
Naloxone is a non-selective, short-acting opioid receptor antagonist that has a long clinical history of successful use for the treatment of overdose. It is an effective antidote for overdoses of short-acting opiates such as heroin. In managing opioid overdoses, the primary concern should always be respiration and oxygenation. Any respiratory arrest should be managed with assisted ventilation and oxygen while waiting for naloxone to be administered or to take effect. Typically, adequate respiration will resume within 30 seconds of naloxone administration. The ideal dose of naloxone is one that improves ventilation without inducing withdrawal. If in doubt, it is better to err on the side of too high rather than too low a dose. A standard dose for the treatment of suspected heroin overdose is 400 mcg intramuscularly or 800 mcg subcutaneously, repeated 2 minutes later, if necessary. If there is IV access and adequate patient ventilation, small aliquots of 100 mcg can be given in repeated doses until the patient is breathing with a rate of greater than 10 breaths a minute, without inducing opioid withdrawal.
Initial use of doses of naloxone that are too high (>2 mg) can induce severe withdrawal, with the risk of vomiting and aspiration; very high doses (>10 mg) may even be life threatening .
Overdoses of long-acting opioids are more difficult to manage. In this situation, the duration of sedation will outlast the effects of naloxone. The safest method of treating long-acting opioid overdose is likely to be ventilation, if available. Although patients can also be managed with repeated boluses of naloxone or naloxone infusions, death can occur if there is unnoticed interruption to the naloxone infusion, or if the patient wakes up and discharges themselves from medical care.
Ideally, patients should be observed for 2 hours after naloxone administration before they are discharged. In practice, this can be difficult to achieve, but it is most important in patients where overdose is suspected to involve long-acting opioids.
In some countries, prefilled naloxone syringes are distributed to patients and family members, in combination with training in resuscitation . Although the use of naloxone by non-medical personnel is not without risks  and may even be illegal in some countries, such use may prevent overdoses. Evaluation of such distribution systems has been positive  and naloxone distribution is likely to be an affordable approach to the prevention of opioid overdose, particularly where inexpensive prefilled syringes are available.
- 8 Special considerations for specific groups and settings

# PATIenTS WITH HIV/AIDS, HePATITIS AnD TB
As described in section 5.6.8, opioid agonist treatment enhances adherence to treatment with anti-infective agents in patients with opioid dependence (see section 5.6.8 for a more detailed discussion).
When presented with an active drug user with TB and opioid dependence, the first priority of the treatment service should be to treat the active TB without spreading it further. If opioid dependence treatment can be commenced in a way that does not put other patients at risk, then this is ideal. Otherwise, it may be better to delay treatment until the patient is no longer infectious.
When presented with an active drug user with HIV and opioid dependence, it is simpler to delay antiretroviral treatment until the patient is stabilized on opioid substitution treatment than to attempt to start antiretroviral drugs before opioid substitution treatment.
There is no need to delay antibiotic treatments such as co-trimoxazole or isoniazid, if it is indicated.
Adolescents 12-18 years old present to treatment services with the full range of opioid-dependence severity. Some adolescents may be brought to the clinic by their families, who are concerned about recent drug use that may not have reached the level of dependent use. On the other hand, many adolescents presenting to treatment services come from socially disadvantaged backgrounds, are living on the street and may have more severe dependence than many adult patients. In between these two groups is a third with dysfunctional families. Studies suggest that the earlier that substance use commences, the higher the risk of dependence and adverse health consequences .
Working with adolescents requires a sensitivity to the issues pertinent to adolescent health in general, because drug use is often a result of events occurring elsewhere in an adolescent's life. Assessment should be broad and should include medical, psychological, education, family and other aspects of the adolescent's life. Treatment should cover as many aspects of the adolescent's life as possible. Given their special treatment needs, adolescents with opioid dependence often benefit from special health services aimed directly at them.
Treatment approaches should accommodate adolescents, who often have higher levels of risk taking, novelty seeking and responses to peer pressure than older individuals (probably due to incomplete development of brain areas of inhibitory control). Thus, training in self-control, resilience and decision-making should be included in psychosocial interventions. To ensure that treatment is as effective as possible, the treatment programme needs to be individualised and comprehensive, and needs to take into consideration an adolescent's strengths, psychosocial supports, education, legal and medical status and history, and pattern of illicit drug use.
Recent research has provided important information about the clinical profile of opioid-dependent adolescents, and has underscored the high prevalence of comorbid psychiatric disorders among this population. Psychiatric disorders that often accompany opioid dependence include depression, post-traumatic stress disorder, conduct disorder and attention deficit hyperactivity disorder. Some of these disorders (e.g. depressive disorders) are more evident among opioid-dependent female adolescents than among their male counterparts. It is unclear to what extent existing psychiatric disorders lead to "self-medication" with opioids and other drugs among this adolescent population; however, addressing psychiatric comorbidity along with substance use is likely to lead to more effective, comprehensive care.
Adolescents may live with one or more parents, and are likely to still be in the legal custody of one or more parents. Parents may play a central role in the lives of adolescents entering substance abuse treatment, in comparison to adults entering treatment. Adolescents may thus be in need of family counselling, to improve relationships with parents or to help parents learn how to be as supportive as possible of their adolescent while that person is in treatment for their substance use disorder. High levels of parental involvement and low levels of parental detachment protect against opioid use among adolescents.
Experimentation with substance use often starts in adolescence; thus, Addiction. or substance dependence, has frequently been referred to as a developmental disorder. Providing effective interventions early in an adolescent's drug involvement is critical if this progression is to be altered. Early intervention is particularly important in light of emerging research, suggesting that adolescents may progress from substance use to dependence more rapidly than adults. Additionally, substance use among adolescents may interfere with cognitive, social and emotional development .
Effective early intervention for opioid-dependent adolescents -combining pharmacotherapy and psychosocial treatment -can help to prevent adolescents from following a substance-using life trajectory, and from transitioning from intranasal or oral to injecting opioid use. Moreover, early psychosocial intervention with young people who have used heroin but who are not yet opioid dependent can help to prevent young people from becoming dependent on opioids.

# Should pharmacological treatment for adolescents with opioid dependence differ from that for adults?
No systematic reviews addressing this question were found. Some clinical trials were found that supported the use of agonist pharmacotherapy, both for opioid withdrawal and maintenance. One RCT demonstrated that, compared to clonidine patches, 28-day reducing buprenorphine retained more people in treatment (72% versus 39%), and led to higher rates of induction to naltrexone (61% versus 5%) .
The use of agonist pharmacotherapy is still the recommended therapy for adolescent opioid dependence. However, adolescents with a short period of dependence and those living in families may respond to opioid withdrawal with or without naltrexone, and these would be reasonable alternatives. Opioid agonist pharmacotherapy in this population can also be started on an interim or trial basis, and short-term therapy may be all that is required if the response is positive.
A comprehensive treatment programme that addresses this entire clinical profile is more likely to produce better outcomes than a programme that focuses on one clinical problem in isolation.
Women have been found to differ from men in their drug-use patterns, with women using less quantity but advancing more quickly to dependence, and using more prescription sedatives. Women who become opioid dependent are more likely to have less education, fewer financial resources and higher rates of sexual and physical abuse . Often, the needs of women in substance dependence treatment settings are also different. They are more likely to have child-care responsibilities that may limit access to treatment, and they may be reluctant to participate in group psychosocial activities with men. They also report significant rates of sexual harassment by male treatment staff . Data are lacking on the relative efficacy of gender-specific services for women. To retain women, services may need to provide either individual or female-only group counselling, cater for people with small children (e.g. provide childcare facilities), and have measures to guard against sexual harassment of female patients by male staff.

# PReGnAnCY AnD BReASTFeeDInG
For women who are pregnant or breastfeeding, opioid agonist maintenance with methadone is seen as the most appropriate treatment, taking into consideration effects on the fetus, neonatal abstinence syndrome, and impacts on antenatal care and parenting of young children. Opioid-dependent women not in treatment should be encouraged to start opioid agonist maintenance treatment with methadone or buprenorphine. Pregnant women who are taking opioid agonist maintenance treatment should be encouraged not to cease it while they are pregnant. Although many women want to cease using opioids when they find out they are pregnant, opioid withdrawal is a high-risk option because a relapse to heroin use will affect the capacity to care for the child. In addition, severe opioid withdrawal symptoms may induce a spontaneous abortion in the first trimester of pregnancy, or premature labour in the third trimester. Relapse to heroin use during pregnancy can also result in poorer obstetric outcomes. Opioid agonist maintenance is thought to have minimal long-term developmental impacts on children when compared to the risk of maternal heroin use and resulting harms.
Methadone is preferred over buprenorphine because of the longer experience of the safety of methadone in pregnancy compared to buprenorphine, despite the fact that early research with buprenorphine suggests that its use may result in less neonatal abstinence syndrome than occurs with the use of methadone. If women are being successfully treated with buprenorphine, then the benefit of staying with a treatment that is working should also be taken into consideration.
In the second and third trimester, methadone doses may need to be increased, due to increased metabolism and circulating blood volume. Splitting the dose into two 12-hour doses may produce more adequate opioid replacement in this period. After birth, the dose of methadone may also need to be adjusted as some of these changes reverse.
Although methadone and buprenorphine are detectable in breast milk, the levels are low and are not thought to significantly affect the infant. Breastfeeding, on the other hand, has many benefits, including mother-infant bonding, nutrition and prevention of childhood illness. Opioid-dependent mothers should be encouraged to breastfeed, with the possible exception of HIVpositive mothers or those using alcohol or cocaine and amphetamine type drugs; in such cases, specific advice should be sought.
Untreated neonatal abstinence syndrome can cause considerable distress to infants and, in rare cases, can cause seizures. Cochrane Collaboration reviews indicate that opioids and barbiturates are more effective than placebo or benzodiazepines, with opioids probably more effective than barbiturates.
Opioid agonist maintenance treatment should be used for the treatment of opioid dependence in pregnancy.

# Strength of recommendation -strong 

# Quality of evidence -very low 
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.
Strength of recommendation -standard - Quality of evidence -very low 

# OPIUM USeRS
People dependent on opium who are suffering harm as a result can be treated with opioid agonist maintenance treatment, consistent with the approach for dependence on other opioids. Two trials have demonstrated the effectiveness of buprenorphine in this population .
It is important to ensure that opium smokers meet criteria for opium dependence beyond simple tolerance and withdrawal. If unclear, it may be wise for opium smokers to attempt withdrawal first before commencing opioid agonist maintenance treatment.

# DRIVInG AnD OPeRATInG MACHIneRY
Opioid intoxication can occur during induction onto methadone or buprenorphine. Patients should be advised not to drive while sedated. As patients will not know what effect their first few methadone and buprenorphine doses will have on them, they should be advised not to plan to drive at this time.

# PSYCHIATRIC COMORBIDITY WITH OPIOID DePenDenCe
Psychiatric comorbidity with opioid dependence is common; in particular, depression, anxiety, personality and post-traumatic stress disorders should be specifically looked for early in treatment and on a regular basis thereafter. As with medical comorbidity, there is likely to be a greater uptake of treatment if the treatment can be provided by the same medical practitioner or at the same facility in an integrated service. Failing that, strong links with other services should be established to facilitate referral and to establish the framework for joint involvement; such a framework should include clarification about prescribing of psychoactive medication and about giving the patient a consistent therapeutic message.

# POlYSUBSTAnCe DePenDenCe
Annex 12 lists the acute and chronic interactions of opioids, alcohol, benzodiazepines, stimulants and cannabis.
In the treatment of polysubstance dependence, opioid agonist maintenance treatment can be started for the opioid dependence component, in an inpatient facility if necessary, while the person is simultaneously withdrawn from alcohol, benzodiazepines and stimulants.
For withdrawal from high doses of benzodiazepines, gradual withdrawal may be necessary. If benzodiazepines are to be given to outpatients on opioid agonist maintenance treatment, this should be done carefully, because there is little evidence to support the long-term use of these drugs and they increase the risk of sedative overdose. If gradually reducing doses of benzodiazepines are prescribed to facilitate the safe withdrawal from benzodiazepines, the prescription should be from a single practitioner, and the dispensing should occur with administration of the dose of methadone, if possible. Patients should be discouraged from withdrawing from opioid agonist maintenance before ceasing benzodiazepines.
- 9 Management of pain in patients with opioid dependence 6.9.1 ACUTe PAIn Pain in patients with opioid dependence is often exacerbated by the lowering of the pain threshold that tolerance to opioids can induce. Opioid-dependent patients are more resistant to pain management with opioids, due either to their tolerance to opioids or to blocking effects of medications used to treat opioid dependence, including buprenorphine and naltrexone. Patients with opioid dependence have a right to adequate pain relief; however, some patients will try to manipulate the health system to obtain opioids. Measures that can be taken to minimize this include:
managing pain through a single health service
- (hospital or primary care practice -depending on the severity) adequately defining the nature of the painful
- condition resolving acute pain rapidly, and then moving
- quickly to longer acting opioids that have less potential for abuse and produce stable opioid effects (as opposed to cyclical patterns of intoxication and withdrawal).
Clinical assessment should be used to distinguish between opioid withdrawal and opioid intoxication.
Opioids should be titrated to pain response, with close assessment of the clinical features of withdrawal and intoxication, to determine appropriate dose levels.

# Patients not on agonist maintenance treatment
For patients using illicit opioids without opioid agonist maintenance treatment, starting opioid agonist maintenance treatment with methadone allows for combined management of opioid dependence and pain. Inadequate analgesia often contributes to patients self-administering illicit opioids.

# Patients on antagonist medication (naltrexone)
Patients on naltrexone will not respond to opioid analgesics in a regular manner. For mild Pain. non-opioid analgesics (e.g. paracetamol and NSAIDs) should be used. Patients taking naltrexone will not benefit from opioid-containing medicines such as cough, cold and antidiarrhoeal preparations. In an emergency, pain management may consist of regional analgesia; conscious sedation with non-opioids such as benzodiazepines or ketamine; and use of non-opioid techniques of general anaesthesia. For elective surgery pain management in hospital, naltrexone should be discontinued at least 72 hours before elective surgery (including dental surgery), if it is anticipated that opioid analgesia may be required. The treating surgeon or doctor should be informed that the patient has been taking naltrexone. The patient should then be abstinent from opioids for three to seven days -depending on the duration of the opioid use and the half-life of the opioid -before resuming naltrexone treatment. If in doubt, a naloxone challenge test can be administered to determine whether naltrexone can be recommenced without inducing opioid withdrawal.

# Patients on partial agonists (buprenorphine)
Because of the high affinity of buprenorphine for the opioid receptor, patients treated with buprenorphine may need higher effective opioid activity to manage acute pain. The high affinity opioid agonist fentanyl may be more effective than other opioids in this situation. For mild Pain. increasing the dose of buprenorphine or addition of weak opioids (e.g. tramadol) may be effective, although such approaches have not been systematically investigated.
For treatment of acute pain not responding to these measures, the options are to: cease buprenorphine and use full opioid agonists,
- such as methadone or morphine, then switch back to buprenorphine when pain resolves continue buprenorphine with the use of high
- doses of opioids but, as the blocking effect of buprenorphine reduces over time, take care to avoid overdose if buprenorphine is ceased while high doses of opioids are continued continue buprenorphine and use non-opioid
- analgesia such a ketamine infusion; or employ the judicious adjunctive use of clonidine or benzodiazepines.

# Patients on full agonist (methadone)
For mild or acute Pain. consider non-opioid analgesics (e.g. paracetamol). Where parenteral analgesics are required, the NSAID ketorolac should be considered. For elective surgery, pain management in hospital is recommended. Patients on methadone who are experiencing acute pain in hospital often receive inadequate doses of opioids for their pain. For patients in methadone maintenance treatment, the same analgesic techniques should be used in the same way as for other patients; such techniques include the use of injectable and patient-controlled analgesia. Because of their tolerance of opioids, patients taking methadone will require larger doses of opioid analgesia for adequate pain relief.
Partial agonists, such as buprenorphine, should be avoided because they may precipitate withdrawal symptoms. There is evidence of cross-tolerance between methadone and anaesthetic agents; thus, patients on methadone may require higher doses of anaesthetic agents in the event of dental or surgical procedures.
Patients needing methadone for ongoing management of chronic pain benefit from a comprehensive management plan. Specialist advice should be sought regarding such patients.

# CHROnIC PAIn
The recent escalation in the use of opioids for chronic pain in some parts of the world  suggests a significant overlap between treatment of chronic pain and dependence on prescription opioids. This document does not attempt to address the use of opioids in the management of chronic pain; however, patients with chronic pain and patterns of use of their prescribed opioids that fit the criteria for dependence (i.e. more than just tolerance and withdrawal), are often referred (or refer themselves) to opioid-dependence treatment facilities. Typically, they present with problems such as injecting their prescribed opioids, taking rapidly escalating doses of opioids and taking opioids in greater quantities than prescribed (resulting in intoxication or overdose); they may also present with other features that raise suspicions of misuse, which they may deny.
In the management of such patients, the first step could be to determine that there has been a comprehensive assessment of the cause of the Pain. both physical and psychological, with any physical cause found being treated. For patients not on opioid agonist maintenance treatment, the next step would be to provide supervised methadone or buprenorphine in place of unsupervised opioids, to provide stable opioid effects and eliminate cycles of withdrawal and intoxication. For pain persisting despite adequate opioid agonist maintenance treatment, opioid rotation should be considered.
In some cases, it could be that the opioid treatment is no longer useful, either because it is being abused or because it is suspected that pain is being exacerbated by opioid-induced hyperalgaesia . Opioid withdrawal may be considered as an approach to reverse opioidinduced hyperalgaesia, although it may risk relapse to illicitly obtained opioids.
Measures that can be taken to prevent the abuse of prescription opioids include systems that encourage all opioid analgesia to be provided by one doctor, a graded approach to supervision of dosing, prescription of formulations less liable to abuse (e.g. liquid methadone formulations) and careful patient selection.
The following evidence profiles have been produced by applying the GRADE working group approach to determining the quality of evidence to the questions addressed. More information on this approach is contained in Section 2.   ; Bargagli AM et al. (2007) A systematic review of observational studies on treatment of opioid dependence.  (Throughout this annex, -1 is used to indicate that the score has been reduced by one because of a weakness in this area).

# Quality assessment Summary of findings

# Absolute risk (AR) (95% CI)
Use of opiates  (subjective follow-up: 1 month-2 years) Criminal behaviour  (objective follow-up: 1 month-2 years) Mortality from randomized controlled trials  (RCTs) (objective follow-up: 2-3 years) Mortality (any cause) from observational studies  (objective follow-up: 2.5 years-21 years) Mortality (overdose) from observational studies  (objective follow-up: 2.5 years-12 years) Retention in treatment  (objective follow-up: 1 month-2 years) Five studies in an outpatient setting; conducted in Italy, Australia, Sweden, the United States and Spain (one in each).
g Quality of studies using Newcastle-Ottawa Scale: selection, two studies rated 3 and three studies rated 2; comparability, one study rated 3, three studies rated 1 and one study rated 0; outcome, two studies rated 2 and three studies rated 1.
h Five studies in an outpatient setting: two conducted in the Netherlands and one each in Italy, the United States and Spain.
i Quality of studies using Newcastle-Ottawa Scale: selection, four studies rated 3 and one study rated 2; comparability, two studies rated 2 and three studies rated 1; outcome, one study rated 2 and four studies rated 1.  .

# Quality assessment Summary of findings

# Absolute risk (AR) (95% CI)
Injecting behaviour: prevalence of injecting, cohort study  (subjective follow-up: 18 months) Injecting behaviour: prevalence of injecting  (subjective follow-up: 4 months) Injecting behaviour: proportion of patients sharing injecting equipment, observational studies  (subjective follow-up: 0-18 months) Sexual behaviour: commercial sex  (follow-up: 18 months) Sexual behaviour: unprotected sex  (follow-up: 3-6 months) Seroconversion to HIV  (variable follow-up: up to 5 years) One study in an outpatient setting, conducted in the United States (Metzger, 1993) .
b One descriptive study in which the author rated the quality of the study on the basis of six items (description of the population, description of eligibility criteria, adjustment for confounding, less than 20% loss to follow-up, presence of co-intervention, inconsistency in data collection between groups) rated from 0 to 1 where 0 = no bias. On the basis of this rating system the study was rated 1.
c Random effect model.
One study conducted in Australia, in an inpatient setting (in prison).
The study was rated 1 (see footnote 2).
f Opioid-dependent prisoners.
g All three studies were conducted in an outpatient setting, two in the United States and one in Germany.
h Three cohort studies, two rated 1 and one 2 (see footnote 2).
i One cohort study rated 1 (see footnote 2).
j Both outpatient, one conducted in the United States and one in Germany.
k Both rated 1 (see footnote 2).
l Two cohort studies: Metzger (1993)  a non-treatment control group selected by methadone group, and Moss (1994)  a control group selected from contemporaneous entry to opioid withdrawal programme.
A1.3 Is buprenorphine effective for the treatment of opioid dependence? Should buprenorphine maintenance versus placebo be used for opioid addiction? Patient or population:
Opioid dependent Settings:
Outpatient and inpatient Systematic review:
Mattick RP et al. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence (2008, in press) . Retention in treatment: 2-4 mg buprenorphine versus placebo or 1 mg buprenorphine  (objective follow-up: 2-16 weeks d Retention in treatment: 8 mg buprenorphine versus placebo or 1 mg buprenorphine  (objective follow-up: 2-16 weeks d Retention in treatment: 16 mg buprenorphine versus 1 mg buprenorphine  (objective follow-up: 2-16 weeks d.  Quality assessment Summary of findings Retention in treatment flexible doses buprenorphine versus flexible doses methadone  (objective follow-up: 6-48 weeks d Use of opiate during the treatment g  (better indicated by: lower scores) Use of cocaine during the treatment g  (better indicated by: lower scores) Use of benzodiazepine during the treatment g  (better indicated by: lower scores) Criminal behaviour  (better indicated by: lower scores)  .

# Quality assessment Summary of findings

# Quality assessment Summary of findings

# Absolute risk (AR) (95% CI)
Retention in treatment  (follow-up: 17-52 weeks e Use of opiates 7  (better indicated by: lower scores) Use of cocaine 7  (better indicated by: lower scores)  .

# Quality assessment Summary of findings

# Absolute risk (AR) (95% CI)
Retention in treatment  (objective follow-up: 20 weeks) Mortality  (objective follow-up: 6 years)  .  . Retention in treatment at 7-13 weeks  (Objective follow-up: 7-13 weeks) Retention in treatment at 27-40 weeks  (Objective follow-up: 27-40 weeks) Opioid abstinence  (Objective 7, follow-up: 3-4 weeks j Criminal activity  (Objective and subjective l, Range: to. Better indicated by: lower scores) Mortality  (Objective follow-up: 6 years)  . Retention in treatment  (Objective follow-up: 27 weeks) Should tapered methadone versus alpha2 adrenergic agonists be used in opioid users? Patient or population:

# Quality assessment Summary of findings

# Quality assessment Summary of findings

# Quality assessment Summary of findings
any opioid-dependent patients wishing to withdraw from opioids Settings:
Inpatient or outpatient Systematic review:
Gowing L; Alpha-2 adrenergic agonists for the management of opioid withdrawal (CLIB 4, 2004)  ; Amato et al.;
Methadone at tapered doses for the management of opioid withdrawal (CLIB 3, 2005) .   (Objective follow-up: max 30 days e relapsed at 6 months follow-up (intention to treat (ITT) analysis)  (objective follow-up: 6 months)  The quality of reporting was very poor for this outcome. The way to report the results was very heterogeneous and prevented to pool the results in the meta-analysis. Four out of seven studies showed that alpha2 adrenergic agonists have an hypotensive effect more than methadone   ; Amato et al.; Methadone at tapered doses for the management of opioid withdrawal (CLIB 3, 2005) . Completion of treatment  (Objective follow-up: 14 to 30 days h

# Quality assessment Summary of findings

# Quality assessment Summary of findings

#  low
Side effects  (variations in systolic blood pressure Range: to. Better indicated by: lower scores) Should tapered buprenorphine versus alpha-2 adrenergic agonists be used for opioid withdrawal? Patient or population:
Opiate addicts Settings:
Outpatient and Inpatient Systematic review:
Gowing L et al.; Buprenorphine for the management of opioid withdrawal (CLIB 2, 2006) .

# Quality assessment Summary of findings
No of patients Effect Quality Importance

# No. studies

# Design Limitations Consistency Directness Other considerations Buprenorphine Alpha-2 adrenergic agonists
Relative risk (RR) (95% CI)

# Absolute risk (AR) (95% CI)
Completion of treatment  (Objective follow-up)  .

# Quality assessment Summary of findings

# Absolute risk (AR) (95% CI)
Completion of treatment  (Objective follow-up: 3-6 days e Severity and duration of withdrawal symptoms  (Subjective and objective follow-up) Side effects  (Subjective follow-up: 3-6 days e Patients who have relapsed at follow-up  (Subjective follow-up: 6 months opioid-dependent patients undergoing managed withdrawal Settings:
inpatient Systematic review:
Gowing L et al.; Opioid antagonists under heavy sedation or anaesthesia for opioid withdrawal (CLIB 2, 2006) . Completion of treatment 5 (clonidine comparison)  (Objective follow-up: 1-3 days d Completion of treatment e (buprenorphine comparison)  (Objective follow-up: 1-3 days d

# Quality assessment Summary of findings

#  low
Severity and duration of withdrawal  (subjective rating scales follow-up: Life threatening adverse events  (Objective follow-up: 1-4 days d

#  low
Relapsed at follow-up (ITT analysis)  (Objective (urine analysis) follow-up: 12 months) Retention at 12 months  (Objective follow-up: 12 months) The countries in which the 2 studies were conducted are: USA (1), Australia (1), both trials were conducted with inpatients.
In both studies method of allocation concealment was not stated, 1 study was single blind (patients blind) and the other one no blindness A1.10 Should withdrawal from opioids be conducted in inpatient or outpatient settings?  . Completion of treatment  (objective follow-up: 10 days d Relapsed at follow-up  (Objective follow-up: 10 days)  . Retention in treatment  (Objective follow-up: 2-9 months d Use of opioids  (Objective 6 follow-up: 2-9 months d Relapsed at follow-up  ( follow-up: 6 months-1 year) Criminal behaviour  (objective p follow-up: 6-10 months d  .

# Quality assessment Summary of findings

# Quality assessment Summary of findings

# Quality assessment Summary of findings

# Absolute risk (AR) (95% CI)
Retention in treatment  (Objective follow-up: 6-24 weeks d Use of opiates  (Objective g follow-up: 6-32 weeks d Retention in treatment at the end of follow-up  (Objective follow-up: 4-48 weeks) Abstinent at the end of follow-up  ( follow-up: 1-12 months)  . Completion of treatment  (Objective follow-up: average 18 weeks, range 2-52 e Use of primary substance during treatment  (urine samples) (follow-up: average 18 weeks, range 2-52 d Relapsed at follow-up  (Objective :urine test. follow-up: 1 year) Subjects using other substances: barbiturates  (Objective: urine samples) follow-up: 16 weeks e Subjects using other substances: benzodiazepines  (Objective (urine samples) follow-up: 16 weeks e Subjects using other substances: cocaine  (urine test follow-up: 16 weeks e Performing a sensitivity analysis excluding the study with inadequate allocation concealment (class C) from meta-analysis (Robles 2002, 48 participants) . The result did not change, remaining significantly in favour of the associated treatments (RR 0.46 (95% CI 0.27 to 0.79) e

# Quality assessment Summary of findings

# Length of treatment f
All studies with unclear allocation concealment, 2 single blind an 1 not blind g Few patients (109)
The study was conducted in USA, in outpatient setting (Bickel 1997)  i Unclear allocation concealment, single blind Performing a sensitivity analysis excluding the study with inadequate allocation concealment (class C) from meta-analysis (Yandoli 2002, 119 participants) . The result became not statistically significant RR 0. The study was conducted in USA, in an outpatient setting (Yandoli, 2002)  A2.1 Dispensing
Dispensing of methadone and buprenorphine may take place in a variety of clinical and community settings.
In specialist clinical settings, an onsite pharmacy or dispensary can enable observation of patients at the time of each dosing. This observation means that clinic staff can more thoroughly assess patients whom they would normally observe less frequently. In community settings, dispensing may occur at community pharmacies or, in some countries, buprenorphine may be dispensed in a physician's office.
Dispensing staff can make a valuable contribution to multidisciplinary care planning, which is more easily accommodated in the clinic setting. In the community setting, where agonist treatment is dispensed in community pharmacies, medical staff should be encouraged to discuss patients regularly with the dispensing pharmacist, to determine, if applicable, the number of missed doses or the level of intoxication on presentation for dosing. If the pharmacy that is dispensing the methadone or buprenorphine is external to the agency prescribing the methadone or buprenorphine, then patients should be informed, before they commence methadone or buprenorphine, that communication with the external pharmacy is a condition of treatment.
Methadone and buprenorphine should be kept in a secure safe, according to local requirements. The amounts should be checked and witnessed by a second party daily, to ensure the amount used is reconciled with amount dispensed.
Generally, dispensing staff are pharmacists, although in most jurisdictions, medical and nursing staff can also dispense medication. Pharmacists and other dispensing staff should be trained in the issues involved in dispensing methadone and buprenorphine.
Before dispensing methadone and buprenorphine, dispensing staff should: establish the identity of the patient and confirm this with the name on the - prescription confirm that the patient is not intoxicated - check that the prescription is valid and that the current day is a - dosing day (for alternate days or three-times-a-week buprenorphine prescriptions) confirm the dose of the prescription. - To further reduce dosing errors and assist with record keeping, computerized systems are available that confirm the identity of the patient using retinal or iris scanners, and automatically dispense the dose on the prescription (after it has been entered by the pharmacist).
It is vital that methadone or buprenorphine are not dispensed to people who are sedated or intoxicated because this may lead to over sedation. Dispensing staff should be skilled in the assessment of the degree of sedation and confident in refusing doses to intoxicated patients. It can be helpful to test breath alcohol levels if patients have been drinking. Patients who present intoxicated or sedated should be asked to return when the intoxication or sedation has abated.
The dose dispensed should be recorded in accordance with jurisdictional requirements.

# A2.2 Administration of buprenorphine
Buprenorphine tablets should be dispensed in a dry dosing cup after the number and strength of the tablets have been checked. Before administration, a patient should be advised to place the tablets under the tongue and to refrain from swallowing (tablets or saliva) until the tablets have dissolved (5 minutes on average but can take up to 15 minutes). The pharmacist should check a patient's mouth cavity for food or receptacles that might be used to divert buprenorphine. After administration, the pharmacist should check the patient's mouth cavity again, to determine that the buprenorphine has dissolved. The patient should then be offered a drink to rinse the mouth cavity.
To avoid disputes over doses, patients should indicate that they have received a dose in some way, such as by signing a dosing card. If a patient attempts to spit out a dose or to leave the dispensary before the dose has dissolved, the prescribing doctor should be informed. Crushing buprenorphine tablets into course granules has been tried in some places to limit diversion of buprenorphine, but the efficacy of this approach has not been evaluated.

# A2.3 Prescriptions
Legal requirements for prescriptions vary by jurisdiction; however, in general a prescription for opioid agonist maintenance therapy should specify the following:
name, address and telephone number of the prescribing doctor - name of the pharmacy to dispense methadone or buprenorphinename - and address of the patient date of the prescription - preparation to be dispensed (i.e. methadone liquid or buprenorphine - sublingual tablets) dose to be dispensed in milligrams (words and numbers) - frequency of dispensing (daily, twice daily, alternate daily, three times a - week) start and end dates of dosing covered by the prescription - whether doses are to be supervised or if some are to be taken away - (specify the maximum number that can be taken home per week)..
Because of the potential seriousness of dosing error, some jurisdictions ensure that the prescribing medical practitioner endorses a photograph of the patient, which is supplied to the pharmacy or dispensing point. It is a requirement in some jurisdictions for doses of opioids to be written in both words and figures.
To reduce prescription fraud, it can be useful to send a copy of the prescription to the pharmacy by facsimile or secure email.

# Annex 2 Dispensing, dosing and prescriptions
This annex describes the codes from the International Classification of Diseases, 10 th edition (ICD-10) that are relevant to these guidelines .

# F11.0 Intoxication (opioids)
A condition that follows the administration of a psychoactive substance resulting in disturbances in level of consciousness, cognition, perception, affect or behaviour, or other psycho-physiological functions and responses.
The disturbances are directly related to the acute pharmacological effects of the substance and resolve with time, with complete recovery, except where tissue damage or other complications have arisen. Complications may include trauma, inhalation of vomitus, delirium, coma, convulsions, and other medical complications. The nature of these complications depends on the pharmacological class of substance and mode of administration.
Excludes: intoxication meaning poisoning (T36-T50).

# F11.2 Dependence syndrome (opioids)
A cluster of behavioural, cognitive, and physiological phenomena that develop after repeated substance use and that typically include a strong desire to take the drug, difficulties in controlling its use, persisting in its use despite harmful consequences, a higher priority given to drug use than to other activities and obligations, increased tolerance, and sometimes a physical withdrawal state.
The dependence syndrome may be present for a specific psychoactive substance (e.g. tobacco, alcohol, or diazepam), for a class of substances (e.g. opioid drugs), or for a wider range of pharmacologically different psychoactive substances.
The ICD-10 diagnostic criteria for opioid dependence are: a strong desire or sense of compulsion to take opioids - difficulties in controlling opioid-use behaviours in terms of the onset, - termination or levels of use a physiological withdrawal state when opioid use has ceased or been - reduced, as evidenced by one of the following: the characteristic withdrawal syndrome use of opioids (or closely related substances) with the intention of relieving or avoiding withdrawal symptoms evidence of tolerance, such that increased doses of opioids are required - to achieve effects originally produced by lower doses progressive neglect of alternative pleasures or interests because of opioid - use; increased amounts of time spent to obtain opioids or to recover from their effects persisting with opioid use despite clear evidence of overtly harmful - consequences, such as depressive mood states consequent to periods of heavy substance use, or drug-related impairment of cognitive functioning (efforts should be made to determine that the user was actually, or could be expected to be, aware of the nature and extent of the harm).
Narrowing of the personal repertoire of patterns of opioid use has also been described as a characteristic feature of dependence.
Opioid dependence does not develop without a period of regular use, although regular use alone is not sufficient to induce dependence.
A definite diagnosis of dependence should usually be made only if three or more of the diagnostic criteria have been experienced or exhibited concurrently at some time during the previous 12 months.

# F11.3 Withdrawal state (opioids)
A group of symptoms of variable clustering and severity occurring on absolute or relative withdrawal of a psychoactive substance after persistent use of that substance. The onset and course of the withdrawal state are time-limited and are related to the type of psychoactive substance and dose being used immediately before cessation or reduction of use. The withdrawal state may be complicated by convulsions.
Annex 3 ICD-10 codes for conditions covered in these guidelines

# A4.1 Methadone
Methadone is a potent synthetic opioid agonist. It has two oral formulations, a tablet and a solution. The solution is recommended for the treatment of opioid dependence because it is easier to supervise the consumption of a liquid than a tablet and because take-home doses can be diluted to reduce the risk of injection. Both oral formulations have a bitter taste.
In opioid-naive people, the effects of methadone are qualitatively similar to morphine and other opiates; however, in opioid-dependent people, methadone prevents withdrawal symptoms without producing significant sedation or intoxication.
Methadone has a high (85%) oral bioavailability (i.e. the proportion of a therapeutically active drug that reaches the systemic circulation and is available at the site of action after being consumed orally). Peak plasma concentrations are generally 2-4 hours after dosing. Methadone is distributed widely in tissues and protein binding is reported to be 60 to 90%. Methadone is demethylated via hepatic cytochrome P450 3A4 (CYP3A4) and 2D6 (CYP2D6) enzymes to its major metabolite 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP). This inactive metabolite is excreted in the faeces and urine, together with unchanged methadone. Concomitant use of drugs that affect these enzymes may result in clinically significant interactions. Methadone doses should be adjusted accordingly.
Declining plasma concentrations have been reported during methadone maintenance, suggesting that tolerance occurs, possibly as a result of autoinduction of hepatic microsomal enzymes.
Marked inter-individual variations in absorption, distribution, circulation, metabolism or elimination (kinetics) have been observed with methadone. Elimination half-lives vary considerably -a range of 15 to 60 hours has been reported -and careful adjustment of dosage is necessary with repeated administration, after which there is a gradual accumulation in the tissues.
Methadone is included in Schedule I of the Single Convention in Narcotic Drugs, 1961 (see Annex 7).

# A4.2 Buprenorphine
Buprenorphine is a potent synthetic partial opioid agonist with high receptor affinity and slow receptor dissociation. This means that its clinical effects vary both on the level of neuroadaptation of the person consuming the buprenorphine (tolerance) and the level of receptor occupancy at the time of its use (the timing of most recent opioid use). The partial activity of buprenorphine means that it does not induce tolerance to opioids to the same extent as methadone. Its high receptor affinity means that buprenorphine can block the effects of additional opioid use without inducing the same degree of tolerance as methadone. Its slow receptor dissociation and partial activity combined mean that it has a withdrawal syndrome that is milder that methadone.
Under low levels of opioid neuroadaptation, all doses of buprenorphine produce agonist effects, with high doses producing qualitatively similar effects to low doses, but for a longer period of time. However, under high levels of neuroadaptation with recent opioid use, high doses of buprenorphine can displace heroin and other opioids from receptors, leading to a rapid drop in opioid effect, which is experienced as opioid withdrawal.
Low doses of buprenorphine have been used extensively in many countries for the management of acute pain.
The potential advantage of buprenorphine is that it has a very good margin of safety. Its partial agonist activity at the  opioid receptor prevents buprenorphine from causing the potentially fatal respiratory depression that is associated with excessive ingestion of full agonist opioids. This margin of safety also allows higher doses to be used for the purposes of prolonging action, without significantly increasing the opioid effect. In this way a double dose of buprenorphine can be given every second day, with no dose in between.
Buprenorphine is included in Schedule III of the Convention on Psychotropic Substances, 1971.

# A4.3 Buprenorphine-naloxone 4:1 combination product
A combination product of buprenorphine and naloxone in a 4:1 ratio is available in two-dose strengths (2 mg buprenorphine:0.5 mg naloxone and 8 mg buprenorphine:2 mg naloxone). The efficacy of this medication is not reviewed in these guidelines due to the lack of clinical trials; however, as this drug is registered and used in several countries, the pharmacology is reviewed here.
While buprenorphine is absorbed sublingually, naloxone has only a 5-10% sublingual absorption . It is thought that this results in too low a dose to have an effect clinically. As buprenorphine and naloxone have similar affinity for opioid receptors, the buprenorphine effect dominates because it is present in much higher concentrations in the blood. However, if the buprenorphine/ naloxone combination product is injected, the dose of naloxone can induce opioid withdrawal, depending on the circumstances.
In the dependent user of heroin or other opioid agonists, the injection of the buprenorphine-naloxone combination product results in opioid withdrawal . Higher doses of buprenorphine-naloxone induce more significant withdrawal . In the non-dependent opioid user, injection of the buprenorphine-naloxone product does not induce opioid withdrawal, but the opioid effect of buprenorphine is attenuated by the naloxone, resulting in a delayed and reduced opioid effect . For patients in treatment using buprenorphine, or for those using buprenorphine illicitly, injection of the buprenorphine-naloxone product does not appear to induce withdrawal  either because higher doses of naloxone are needed to displace buprenorphine or because the half-life of naloxone is too short in comparison with the slow dissociation of buprenorphine from opioid receptors.

# A4.4 Opioid antagonist medications
Naltrexone is an orally active opioid antagonist, with an effective duration of action of 24-48 hours, making it suitable for use once a day. It has a very high affinity for opioid receptors and will displace heroin and methadone in minutes, and buprenorphine in 1-4 hours. It is used clinically after opioid withdrawal to prevent relapse to opioid dependence.
Naloxone is a short-acting injectable opioid antagonist used in the management of opioid overdose to reverse the effects of opioids. It is poorly absorbed orally and so is used either intramuscularly or intravenously. It has a half-life of approximately one hour but continues to have 50% receptor occupancy at 2 hours after injection due to its receptor binding .

# A4.5 Medication for the management of opioid withdrawal

# Alpha adrenergic agonists
The alpha-2 agonists clonidine, lofexidine and guanfacine act on the central and peripheral autonomic nervous system, reducing the endogenous release Annex 4 Pharmacology of medicines available for the treatment of opioid dependence of adrenaline and noradrenalin, which are in comparative excess in opioid withdrawal. This slows the heart rate, lowers blood pressure, reduces muscle tone and induces sedation. Lofexidine is more specific to peripheral actions and does not induce hypotension to the same extent. Both lofexidine and clonidine are short acting and are taken four times a day. Guanfacine, on the other hand, is taken once a day.
Drug interactions occur because medications have synergistic or antagonistic effects (so-called pharmacodynamic interactions), or because the presence of one medication affects the absorption, distribution, circulation, metabolism or elimination of another medication (so-called pharmacokinetic interactions).

# A5.1 Pharmacodynamic interactions
Any drugs that cause sedation may cause additive sedation with methadone and buprenorphine, increasing the risk of sedative overdose. Such drugs include benzodiazepines, alcohol, other sedative psychotropic medications (e.g. phenothiazines and other antipsychotics), tricyclic and other sedating antidepressants, alpha adrenergic agonists (e.g. clonidine and lofexidine) and sedative antihistamines. Most overdose deaths associated with methadone and buprenorphine are in combination with one or more of these sedatives.

# Opioid withdrawal
Opiate antagonists, such as naltrexone, result in opioid withdrawal for patients on methadone and buprenorphine. Naltrexone cannot be used for the management of alcohol dependence in this population. A combination of agonists and partial agonists can also result in opioid withdrawal. Methadone should generally not be combined with the partial agonists buprenorphine, pentazocine, nalbuphine or butorphanol. Patients on buprenorphine who are also taking opioid agonists for pain may experience incomplete pain relief.

# QT prolongation
A group of medications affect the time it takes cardiac ventricular muscle to depolarize and subsequently repolarize -the QT interval in an electrocardiogram. A prolongation of the QT interval predisposes people to serious cardiac arrhythmias, such as torsades de pointes and other ventricular tachyarrhythmias, which may be fatal if untreated. Methadone is one such medication. Combinations of methadone with other medications that prolong the QT interval should be used with caution, as they may further increase the risk of QT prolongation-associated cardiac arrhythmias. These medications are mainly class I or III antiarrhythmic agents, calcium channel blocking agents, some antipsychotic agents and some antidepressants (see Table A5.1 for a more complete list). Drugs that result in electrolyte disorders (e.g. hypokalaemia and hypomagnesaemia) also result in an increased risk of QT prolongationrelated arrhythmias (i.e. diuretics, laxatives, corticosteroid hormones with mineralocorticoid activity). Buprenorphine does not appear to produce clinically significant prolongation of the QT interval.

# A5.2 Pharmacokinetic interactions
Methadone and buprenorphine are metabolized principally by the cytochrome P450 enzyme pathways. A range of drugs and medication either induce or inhibit cytochrome P450 enzymes. The process of induction is relatively slow as it depends on the synthesis of new enzyme proteins, and occurs over days, whereas inhibition can occur rapidly, depending on the concentration of the inhibiting substance.
Methadone is largely metabolized from active to largely inactive metabolites through CYP3A4 and to a lesser extent CYP1A2, CYP2D6, CYP2B6, CYP2C8 and also possibly CYP2C9 and CYP2C19 . CYP enzyme inducers can result in lower plasma methadone levels and inhibitors can result in higher levels. Because of the potential for sedative overdose, patients on methadone should be observed particularly closely when commencing cytochrome P450 inhibitors, and consideration should be given to simultaneous methadone reduction. After introducing a potentially interacting new medicine, it is important to make careful clinical observations and adjust the dose of methadone if necessary.
Buprenorphine is metabolized in the liver, principally by the CYP3A4 isoenzyme . The active metabolite, nor-buprenorphine is metabolized via a separate pathway. Drugs that inhibit CYP3A4 (e.g. ketoconazole, erythromycin, some protease inhibitors) may result in increases in buprenorphine concentration and the need to reduce the buprenorphine dose. Drugs that induce CYP3A4 (e.g. rifampicin, phenytoin, phenobarbital, carbamazepine) may result in reduced buprenorphine concentrations. Research on drug interactions involving buprenorphine is limited.
A more comprehensive list of drugs that interact on the cytochrome P450 system are listed in Table A5.2 .

# CYP450 inducers
Alcohol Chronic consumption of alcohol has been reported to increase the metabolism of methadone, whereas acute consumption has been reported to increase the area under the curve (AUC) 1 of methadone, resulting in increased potential for adverse effects.
Phenytoin, carbamazepine and phenobarbital are all significant inducers of CYP3A4 and have all resulted in withdrawal symptoms in patients on methadone.
Sertraline, fluoxetine and fluvoxamine are inducers of CYP3A4. Methadone may potentiate the effects of tricyclic antidepressants.
Rifampicin (rifampin) has resulted in clinically significant reductions in methadone levels.
1 Area under the curve is a measure of the bioavailability of a drug or medicine. It is the area under the plasma concentration-time curve for that drug in a particular patient. Increase in this indicates more of the drug has reached the systemic circulation and this is nearly always accompanied by a rise in plasma concentration.   Annexes Antiretrovirals Many antiretroviral medications interact with methadone and buprenorphine, see Table A5.2 and Table A5.3.

# Annex 5 Drug interactions involving methadone and buprenorphine

# Other agents
St John's wort (Hypericum) is also a CYP3A4 inducer.

# CYP450 inhibitors
Azole agents including ketoconazole, fluconazole and itraconazole, are potent inhibitors of CYP3A4 and have increased the effects of both methadone and buprenorphine. Prophylactic dose reductions should be considered.
Many antiretroviral medications interact with methadone and buprenorphine, see Table A6.2 and Table A6.3.

# Macrolide antibiotics
Most macrolides (erythromycin, clarithromycin, dirithromycin, roxithromycin) inhibit CYP3A4. Only azithromycin does not inhibit CYP3A4.

# Other agents
Grapefruit juice is also a significant inhibitor of cytochrome P450 enzymes.   the Liverpool HIV Pharmacology Group web site 2 the 2006 World Health Organization antiretroviral therapy guidelines,  and the Department of Health and Human Services Guidelines for the use of Antiretrovirals Agents in HIV-1-Infected Adults and Adolescents.  2 /   the Liverpool HIV Pharmacology Group web site 3 the 2006 World Health Organization antiretroviral therapy guidelines,  and the Department of Health and Human Services Guidelines for the use of Antiretrovirals Agents in HIV-1-Infected Adults and Adolescents.  A6.1 Heroin maintenance
The limited evidence is inadequate to support any recommendations on heroin maintenance.
A Cochrane review of heroin prescription identified five RCTs comparing heroin with methadone . It was not possible to draw definitive conclusions about the overall effectiveness of heroin prescription because the experimental studies available were not compatible. Heroin use in clinical practice is still a matter of research in most countries. Results favouring heroin treatment over methadone come from studies conducted in patients who have failed previous methadone treatments.

# A6.2 Slow or sustained-release oral morphine
The limited evidence is inadequate to support any recommendations on slow or sustained-release oral morphine.
Recent formulations of morphine can be used in once-daily doses for the treatment of chronic pain  and there have been a number of studies of these formulations in opioid dependence . The results of these trials are promising, demonstrating a long duration of action of morphine and comparable levels of self-reported heroin use to methadone treatment. The use of morphine in the treatment of addiction is complicated by difficulties in assessing heroin use and supervising doses.

# A6.3 Levo-alpha-acetylmethadol
Although still registered in the United States, levo-alpha-acetylmethadol (LAAM) has been withdrawn from the market by the manufacturer, due to the risk of lifethreatening cardiac arrhythmias.
Levo-alpha-acetylmethadol (LAAM) is a long-acting opioid agonist approved for use as a maintenance treatment for opioid dependence. For persons in whom methadone and buprenorphine are not effective, LAAM offers an alternative effective medication. In a Cochrane review and recent RCT, LAAM was found to be better at suppressing heroin use than methadone  but its use is, at present, limited by its effect of QT prolongation . The active metabolite -noracetylmethadol -does not have the same effect on QT prolongation  and may be a promising treatment alternative.

# A6.4 Buprenorphine-naloxone combination
The limited evidence is inadequate to support any recommendations on a buprenorphine-naloxone combination. However, the combination is likely to have similar efficacy to buprenorphine alone.
As with methadone, intravenous abuse of buprenorphine has been reported in many countries . Buprenorphine-naloxone comprises the partial agonist buprenorphine in combination with the opioid antagonist naloxone in a 4:1 ratio. It is hoped that by the addition of naloxone, the resulting product will be less subject to abuse by injection than buprenorphine alone. When the combination is taken sublingually, absorption of naloxone is minimal and the opioid agonist effects of buprenorphine should predominate. However, when buprenorphine-naloxone tablets are injected, naloxone will induce withdrawal in people dependent on opioids other than buprenorphine .
Efficacy of buprenorphine/naloxone in maintenance therapy for opioid dependence is described in three RCTs in comparing the combination with placebo  and clonidine  and comparing stepped combination-based treatment with methadone treatment alone . Three trials investigating the efficacy of the combination with different counselling or medication-dispensing regimens have been published .

# A6.5 Slow-release naltrexone implants and injections
The limited evidence is inadequate to support any recommendations on slow-release naltrexone implants and injections.
Injectable, slow-release naltrexone formulations provide clinically significant opioid blockade for 3-6 weeks (depending on the dose) in early clinical research .
A number of naltrexone implants have been developed that can be inserted subcutaneously using local anaesthesia, either post withdrawal or as part of an antagonist withdrawal treatment. Subsequent implants are inserted at 1-3 months intervals. There are no RCTs to assess the effectiveness of naltrexone implants, although there are some promising reports . Local implant site allergies and infections have been described with implantable formulations.
Annex 6 Alternatives for the treatment of opioid dependence not included in the current guidelines
The Single Convention on Narcotic Drugs, 1961 (as amended by the 1972 Protocol) and the Convention on Psychotropic Substances, 1971 contain specific control provisions for some psychoactive substances . Pursuant to these conventions, the Commission on Narcotic Drugs (CND) has the authority to decide, upon a recommendation from the World Health Organization, whether a substance should be scheduled as a narcotic drug or a psychotropic substance.
Methadone is currently scheduled as a "narcotic drug", falling under the Single Convention on Narcotic Drugs and buprenorphine as a "psychotropic substance", falling under the Convention on Psychotropic Substances.
The International Narcotics Control Board (INCB) is charged with monitoring the compliance by Governments with the above international treaties, ensuring on the one hand that controlled substances are available for medical and scientific use and on the other hand that diversion from licit sources to illicit traffic does not occur .

# A7.1 Single Convention on Narcotic Drugs 1961
The Single Convention on Narcotic Drugs is the principal international treaty regulating the control of opioids. It seeks to limit exclusively to medical and scientific purposes the production, manufacture, export, import, distribution of, trade in, use and possession of narcotic drugs. Heroin, opium, morphine, oxycodone, methadone, and most other potent pharmaceutical opioids (with the exception of buprenorphine) are listed as narcotic drugs under the 1961 Single Convention.
To comply with the convention with regard to methadone, countries must: estimate the annual medical and scientific requirements for methadone - and submit their estimates to the INCB for confirmation limit the total quantities of methadone manufactured and imported to - the relevant estimates, taking into account the quantity exported ensure that methadone remains in the hands of licenced parties from the - point of manufacture or importation to dispensing provide that methadone is dispensed against a medical prescription - report to INCB on the amount of methadone imported, exported, - manufactured and consumed and of stocks held maintain a system of inspection of manufacturers, exporters, importers, - and wholesale and retail distributors of narcotic drugs and of medical and scientific institutions that use such substances; premises, stocks and records should be inspected in addition, a country has a responsibility to ensure that diversion and - abuse of methadone is prevented.

# National estimates of medical need for opioids
Every year, national drug regulatory authorities must prepare estimates of the requirements for methadone of their country during the following year. The estimates must be submitted to the INCB six months in advance of the period for which they apply, but supplementary estimates may be submitted at any time. INCB publishes changes in the estimates received from governments on a monthly basis, as a guide for exporting countries. The responsibility for determining the amounts of opioids necessary to meet the medical and scientific requirements in a country rests entirely with the national governments, but the INCB must be informed of the method used. The INCB establishes estimates of annual requirements for narcotic drugs for countries which fail to do so. In case an estimate is established by INCB, the competent authorities of the country concerned are informed by the Board and requested to review the established estimates.

# Obtaining a supply of methadone
After a country has received confirmation of its estimate from the INCB, it may commence manufacture or import procedures. In both cases, it is vital that the supply is reliable as interruptions to the supply of methadone are distressing for patients and place them at high risk of relapse to illicit opioid use.

# Domestic manufacture
Some, or all of the methadone needed may be manufactured by enterprises in the country itself, under the regulation of the government. Regulation of manufacture of opioids includes licensing, requirements for record keeping and reporting, secure storage, and quality control.

# The import/export system
A specific sequence of steps is stipulated in the convention for the import and export of narcotic drugs, although additional requirements may vary from country to country. Importation and exportation of methadone can only take place with the approval of the national drug regulatory authorities, and within the limits of the total of the estimates for the importing country. A copy of the export authorization must accompany each shipment.
The import and export authorization shall state: the name of the drug - the international non-proprietary name (INN) of the drug, if any - the quantity of the drug to be imported or exported - the name and address of the importer and exporter - the period of validity of the authorization. 
The export authorization shall also state the number and date of the import authorization and the authority by whom it has been issued.

# The steps involved in the import/export process
The import/export process is outlined below in Figure A7.1. Many countries also have an authorization/certification procedure to prevent marketing of pharmaceutical products that are falsely labelled, counterfeit or substandard.
The entity wishing to import a substance controlled under the Single 1.
Convention applies to its regulatory authority for an import authorization. The regulatory authority considers whether the company is properly 2.
licensed and whether the drug and amount are within the national estimate; if approved, an original import authorization and the appropriate number of copies are issued. One copy should be sent to the competent authorities of the exporting country. The original and one copy should be sent to the importer who will send the original to the exporter and will keep one copy for the Customs declaration. One copy should be sent to the Customs authorities of the importing country and an additional copy should be kept in the records of the importing country's competent authority.
The importer sends the original of the import authorization to the 3.
company responsible for the export of the substance. The exporter applies to its drug regulatory authority for an export 4.
The regulatory authority in the exporting country checks that an import 5.
authorization has been issued and that the exporter is properly licensed, and that the estimate of the importing country is sufficient; if the application is approved, an export authorization is issued. The regulatory authority in the exporting country sends a copy of the 6.
export authorization to the regulatory authority in the importing country. Two copies should be provided to the exporter, one of which must accompany the consignment. One copy should be sent to the Customs authorities of the exporting country and an additional copy should be kept in the records of the exporting country's competent authority.
The exporter ships the drugs to the importer, along with the copy of the 7.
Annex 7 Methadone and buprenorphine and international drug control conventions export authorization. The shipment must pass a customs inspection. 8.
The importer sends the export authorization to its regulatory authority. The 9.
regulatory authority of the importing country shall return the accompanying export authorization to the regulatory authority of the exporting country with an endorsement certifying the amount actually imported. Adapted from WHO 1996  The reporting system National drug regulatory authorities must report to the INCB all imports and exports of methadone every quarter. They are also required to make an annual inventory and report the total amount of opioids manufactured, consumed and held in stock. The annual inventory does not include drugs stored in pharmacies, which for official purposes are considered to have been consumed.

# Regulation of health-care workers
The convention recognizes that individual governments must decide the level of regulation of the individuals directly involved in dispensing opioidspharmacists, physicians and nurses. However, it expresses several principles that should be observed: individuals must be authorized to dispense opioids by their professional - licence to practice, or be specially licensed to do so movement of opioids may occur only between duly authorized parties - a medical prescription is required before opioids may be dispensed to a - patient.

# Drug abuse versus patient need
The convention recognizes that governments have the right to impose further restrictions if they consider it necessary, to prevent diversion and misuse of opioids. However, this right must be continually balanced against the responsibility to ensure opioid availability for medical purposes.
In deciding the appropriate level of regulation, governments should bear in mind the dual aims of the convention. The INCB has observed that, in some countries, fear of drug abuse has resulted in laws and regulations, or interpretations of laws and regulations, which make it unnecessarily difficult to obtain opioids for medical use.
"...prevention of availability of many opiates for licit use does not necessarily guarantee the prevention of the abuse of illicitly procured opiates. Thus, an overly restrictive approach to the licit availability of opiates may, in the end, merely result in depriving a majority of the population of access to opiate medications for licit purposes" .

# A7.2 Convention on Psychotropic Substances, 1971
This convention establishes an international control system for psychotropic substances that balances their abuse potential and therapeutic value.
Buprenorphine is listed as a psychotropic substance and is currently included in Schedule III of the convention.
To comply with the convention with regard to buprenorphine, countries must: ensure that buprenorphine remains in the hands of licensed parties from - the point of manufacture or importation to dispensing; provide that buprenorphine is dispensed only with a medical prescription; - prohibit the advertisement of buprenorphine to the general public; - request that all operators manufacturing, trading or distributing - buprenorphine keep records on each acquisition and disposal for at least two years; report to INCB on the amount of buprenorphine imported, exported and - manufactured on an annual basis; maintain a system to inspect manufacturers, exporters, importers, and - wholesale and retail distributors of psychotropic substances and of medical and scientific institutions that use such substances; premises, stocks and records should be inspected; ensure diversion and abuse of buprenorphine is prevented. 

# Domestic manufacture
Some or all of the buprenorphine needed by a country may be manufactured by domestic enterprises, under the regulation of the government. Regulation of manufacture of psychotropic substances includes licensing, requirements for record keeping and reporting. Provisions relating to manufacture of pharmaceutical products in general, such as secure storage, and quality control, also apply.

# Regulation of health-care workers
The convention recognizes that individual governments must decide the level of regulation of the individuals directly involved in dispensing psychotropic substances (i.e. pharmacists, physicians and nurses). However, it expresses several principles that should be observed: individuals must be adequately qualified, and authorized to dispense - psychotropic substances by their professional licence to practice, or be specially licensed to do so movement may occur only between duly authorized parties - a medical prescription is required before psychotropic substances may be - dispensed to a patient, except when individuals may lawfully obtain, use, dispense or administer such substances in the duly authorized exercise of therapeutic or scientific functions prescriptions need to be issued in accordance with sound medical practice - and subject to regulation to protect public health and welfare, particularly the number of times such prescriptions may be refilled and the duration of their validity.

# Drug abuse versus patient need
The convention recognizes that governments have the right to impose further restrictions if they consider such restrictions necessary to prevent diversion and misuse of psychotropic substances. However, this right must be continually balanced against the responsibility to ensure the availability of psychotropic substances for medical purposes.

# Obtaining a supply of buprenorphine
Reliable supply of buprenorphine is vital because interruptions to the supply are distressing for patients and place them at high risk of relapse to illicit opioid use. Although not required by the convention, most exporting countries will adhere to the additional voluntary control measures recommended by ECOSOC (see below). In practice, all importing countries should remember that they might encounter difficulties obtaining buprenorphine if they do not have an assessment (a simplified estimate of the annual requirements for a psychotropic substance, see below) covering the amount to be imported and an import authorization or 'no objection' certificate for each separate import.

# Assessment of medical needs for buprenorphine in accordance with ECOSOC resolution 1993/38
National drug regulatory authorities should prepare an assessment of the annual requirements for buprenorphine of their country. INCB recommends that this assessment should be revised at least every three years. The assessment or its revision can be submitted at any time. The responsibility for determining the amounts of buprenorphine necessary to meet the medical and scientific need in a country rests entirely with the national governments. INCB publishes changes in the assessments received from governments on a monthly basis, as a guide to exporting countries.

# The import-export system
A specific sequence of steps is specified in the convention for the import and export of psychotropic substances. Additional requirements have been recommended by ECOSOC, and they are adhered to by most governments.

# Mandatory controls foreseen by the convention
The convention foresees mandatory import-export authorizations only for substances included in Schedules I and II.
When exporting Schedule III substances, such as buprenorphine, exporters have to submit two copies of an export declaration to the competent authorities of the exporting country, and the third copy of the export declaration has to accompany the consignment. The government of the exporting country must forward the export declaration to the competent authorities of the importing country as soon as possible, but not later than 90 days after the date of the dispatch. Countries may require the importer to transmit the copy accompanying the consignment, duly endorsed stating the quantities received and the date of receipt, to the competent authorities of the importing country.
The export declaration must include: the international non-proprietary name (INN) of the substance, or failing - such a name, the designation of the substance in the Schedule the quantity and pharmaceutical form in which the substance is exported, - and, if in the form of a preparation, the name of the preparation the name and address of the importer - the name and address of the exporter - the date of the dispatch. 

# Voluntary controls foreseen by ECOSOC resolutions
In accordance with ECOSOC resolution 1996/30, most governments have extended the import-export authorization system to Schedule III and IV substances, including buprenorphine. An import can only take place with the approval of the national drug regulatory authorities of the importing country and should remain within the assessment for buprenorphine established by the importing country. Approved export authorizations must accompany each consignment. The steps involved in the import-export process, in accordance with the recommendations of the ECOSOC resolutions
The entity wishing to import buprenorphine applies to its regulatory - authority for an import authorization.
The regulatory authority considers whether the entity is properly licensed - and whether the substance and amount are within the assessment; if approved, an original import authorization or 'no objection' certificate and the appropriate number of copies are issued. (One copy should be sent to the competent authorities of the exporting country. The original and one copy should go to the importer who will send the original to the exporter and will keep one copy for the Customs declaration. One copy should go to the Customs authorities of the importing country and an additional copy should be kept in the records of the importing country's competent authority.)
The importer sends the original of the import authorization or certificate - to the company responsible for the export of the substance. The exporter applies to its drug regulatory authority for an export - authorization.
The regulatory authority of the exporting country checks that an import - authorization has been issued and that the exporter is properly licensed, and that the assessment of the importing country is sufficient; if the application is approved, an export authorization is issued. The regulatory authority of the exporting country sends a copy of the - export authorization to the regulatory authority of the importing country. Two copies should go to the exporter, one of which must accompany the consignment. One copy should go to the Customs authorities of the exporting country and an additional copy should be kept in the records of the exporting country's competent authority.
The exporter ships the drugs to the importer, along with the copy of the - export authorization.
The consignment must pass a customs inspection.
The importer sends the export authorization to its regulatory authority.
After receiving the consignment, the importing authority shall return the accompanying export authorization to the regulatory authority of the exporting country with an endorsement certifying the amount actually imported.

# A7.3 Guidelines for regulation of health professionals
It is understood that regulatory requirements for physicians, nurses and pharmacists to dispense opioids to patients will differ from country to country. However, the following are general criteria that can be used to develop Patient access. Opioids should be available in locations that will be 6.
accessible to as many opioid-dependent patients as possible. Medical decisions. Decisions concerning the type of drug to be used, the 7.
amount of the prescription and the duration of therapy are best made by medical professionals on the basis of the individual needs of each patient.
This annex describes weaknesses and gaps revealed by a review of the evidence to support treatment, conducted during the preparation of these guidelines.

# A8.1 Gaps in the evidence

# Comparisons between opioid agonist maintenance, detoxification and opioid antagonist approaches
Few studies comparing naltrexone treatments with opioid agonist maintenance treatments were found. The only randomized trial to compare methadone or buprenorphine with naltrexone was conducted in intravenous buprenorphine users . There were no studies comparing long-acting naltrexone formulations to opioid agonist treatment approaches.
No studies assessed the potential benefit to populations of having more than one treatment available (e.g. buprenorphine and methadone, or opioid antagonists and opioid agonists).
No randomized trials were conducted in specific populations (e.g. young people, people with short histories of dependence, people who do not inject and pregnant women) to compare approaches based on opioid detoxification with approaches based on opioid agonist maintenance treatment. Although evidence strongly favours opioid agonist approaches, opioid detoxification remains the most requested treatment in many settings.

# Impact of treatment on HIV transmission
Well-conducted observational studies to evaluate the impact of pharmacological treatment on HIV transmission would be useful, because most randomized trials did not collect data on HIV risk practices and HIV transmission. In particular, more data on the impact of buprenorphine treatment on HIV transmission is needed, because this treatment is unsupervised in many settings.

# Optimal doses
Although there are sufficient studies on the optimal doses of methadone to make recommendations, the same is not true for buprenorphine. Research is also needed on the optimal doses of methadone and buprenorphine in noninjecting drug users (e.g. opium smokers).

# Supervised dosing in agonist maintenance treatment
For both methadone and buprenorphine, surprisingly little research has been conducted on the impact of dosing supervision on treatment outcome. This is a particularly important question given the widespread use of unsupervised buprenorphine treatment in several countries.

# Antagonist treatment in different settings
There is a discrepancy between the modest benefits of oral naltrexone treatment in developed countries and reports from clinicians of the usefulness of naltrexone in developing countries. Further research on opioid antagonists in developing countries is needed.

# Prescription opioid dependence
In many countries, the number of people with prescription opioid dependence now exceeds the number of people with illicit opioid dependence. More research is required on the use of opioid detoxification and agonist maintenance in this population, including the required degree of supervision.
The relative lack of research in young people and people with brief histories of opioid dependence is concerning, because this population may have the greatest capacity for change. More research is needed on psychosocial assistance, including family-based approaches, and on the relative merits of opioid agonist treatment and withdrawal, and antagonist treatment.

# Pregnancy and breastfeeding
More research is required to establish the safety of buprenorphine and naltrexone for pregnant and breastfeeding women.

# Outcomes of planned cessation of agonist maintenance treatment
More research is needed on when opioid agonist treatment can be stopped without leading to high rates of relapse. Studies comparing methods of cessation of agonist maintenance treatment are also required.

# Psychosocial support
More research is needed on various psychosocial approaches to treatment, particularly the more social approaches, such as employment and residential programmes.

# A8.2 Methodological issues in research

# Study size
Many studies are too small to adequately address the questions being asked. This may reflect the difficulties in funding clinical trials in this population, and the relatively small sizes of many treatment centres. Larger studies are required on most topics. In addition, many studies replicate earlier trials despite there remaining gaps in the evidence. Treatment networks at international levels may be needed to coordinate large trials to answer simple questions, a method that has been used in many fields of medicine in recent decades.

# Study duration
The follow-up period of most studies is too short, given that opioid dependence is a chronic condition.

# Study design
Most randomized trials considered in this review did not use intention-to-treat analyses, and many did not document allocation concealment. Although it is difficult to blind study participants in studies of psychoactive medication, greater consideration should be given to the use of blinding in outcome assessment and in the statistical analysis.

# Outcome measures
Intention-to-treat analysis includes both "in treatment" and "out of treatment" patients. Most calculations assume that all people who drop out of treatment return to baseline levels of drug use. In reality, some people will start another form of treatment and other people will no longer require treatment. Although treatment retention is an important proxy measure in the absence of other relevant outcomes, continuous retention in treatment and treatment status at follow-up should be regarded as a measure of exposure to the intervention, rather than as a health outcome. Given that developments are taking place in pharmacogenetics research, consideration should be given to the storage of blood samples for such analysis from clinical trial participants, with their consent.
The impact of drug use beyond the individual (e.g. family, carers and society) should also be considered. Data for social cost estimates (e.g. criminal activity, health-care use, income and receipt of government benefits) are lacking for many settings. Cost-effectiveness and cost-benefit analyses are also possible if the cost of treatment is measured.

# A8.3 Programmatic and systems research
Most research on treatments for opioid dependence has used the individual patient as the unit of analysis. There is significant variability in the conduct of treatment for opioid dependence worldwide. Greater emphasis on the treatment programme and the treatment system may improve the capacity of treatment systems to become more efficient and effective. Suggested research topics include the choice of treatment settings (e.g. primary care), dosing mechanisms and integration with other treatment systems (e.g. HIV treatment programmes).
From a public health perspective, the highest priority is to reduce the gap between the number of people with opioid dependence and the number with access to effective treatments.

# Objective Opiate Withdrawal Scale (OOWS)
Observe the patient during a 5 minute observation period then indicate a score for each of the opioid withdrawal signs listed below (items 1-13). Add the scores for each item to obtain the total score

# TOTAL SCORE
Source: Handelsman et al 1987  Annex 10 Opioid withdrawal scales   Annex 11 Summary of characteristics of selected psychoactive substances Specific cautions regarding the use of methadone and buprenorphine

# Intoxicated or sedated patients
Methadone and buprenorphine should not be given to patients showing signs of intoxication or sedation, due to the risk of sedative overdose. The risks of methadone and buprenorphine use in opioid-dependent patients who are frequently intoxicated with sedatives such as alcohol and benzodiazepines, needs to be balanced against the benefits of treatment.

# Severe hepatic/renal dysfunctions
The metabolism and elimination of methadone and buprenorphine may be affected by either hepatic or renal dysfunction in which case the dose or dosing frequency should be adjusted accordingly.

# Respiratory insufficiency
In patients with respiratory insufficiency, methadone and buprenorphine may reduce the respiratory drive.
In patients with active psychosis the risks and benefits of methadone and buprenorphine need to be carefully considered.

# Methadone maintenance treatment
The initial daily dose of methadone should depend on the level of neuroadaptation to opioids. It should generally not be more than 20 mg, except in cases of higher tolerance to opioids, and even then should not be more than 30 mg. For people with low or uncertain levels of tolerance to opioids, the initial daily dose should be 10-15 mg. Caution should be exercised with initial methadone doses more than 20 mg daily. Observing patients 2-3 hours after their dose enables the best assessment of the degree of tolerance to opioids. If patients have significant opioid withdrawal symptoms 2-3 hours after their dose of methadone, then they should be given an additional 5-10 mg methadone and a corresponding increase in their next daily dose. If patients are sedated after their dose of methadone, then the next daily dose should be reduced (and the patient monitored until they are no longer sedated, or treated for overdose, if necessary).
Patients should be observed each day prior to dosing. Patients who are sedated or intoxicated should not be given further doses methadone until the sedation has abated.
Precautions for commencing methadone include: high-risk polydrug use, mental illness, low levels of neuroadaptation to opioids (i.e. recent incarceration), and significant concomitant medical problems.
Once patients are taking opioid agonist maintenance treatment without intoxication or significant withdrawal symptoms, the aim is to titrate the methadone dose to its most effective level. The daily dose of methadone should then be increased by 5-10 mg every few days, as needed, to reduce cravings for opioids, and illicit opioid use. The dose should not be increased by more than 20 mg per week.
Patients should be reviewed prior to each dose increase.
The average effective dose of methadone is 60-120 mg.

# Switching from buprenorphine to methadone
Commence methadone 24 hours after the last dose of buprenorphine. From buprenorphine doses of 8 mg daily and above, commence with 30 mg methadone daily. From buprenorphine doses of 4-8 mg daily, commence with 20-30 mg methadone daily. With buprenorphine doses below 4 mg daily, commence with less than 20 mg methadone daily.

# Missed methadone doses
If one of two doses are missed the patient can be maintained on the same methadone dose.
If three doses are missed the next methadone dose should be reduced by 25% to adjust for the possible reduction in tolerance. If it is well tolerated, doses can return to previous dose levels. If four doses are missed the next dose should be reduced by 50% to adjust for the potential reduction in tolerance. If the dose is well tolerated doses can be increased over several days to previous levels.
If more than four doses are missed, patients should resume induction from baseline.

# Frequency of doses
Methadone can be administered daily for most patients. In approximately 30% of patients, methadone does not produce effects that are evenly sustained over 24 hours. This can also occur in pregnancy and when methadone is used in combination with medications that increase its metabolism. In such cases methadone can be administered twice a day, dividing the dose in two. When it is too difficult to pick up the medication twice a day, or when take-home doses are not suitable, then buprenorphine should be considered. Increasing the dose of methadone will increase the duration of action to some extent, but the main determinant is the rate of metabolism of methadone.

# Reducing dosage and stopping treatment.
The decision to discontinue therapy with methadone should be made as part of a comprehensive treatment plan. Evidence suggests that it is associated with a risk of relapse to illicit opioid use and patients should be informed of these risks. Research is lacking on factors predicting successful withdrawal from agonist maintenance, however these may include a brief drug-use history prior to opioid agonist maintenance, no previous treatments prior to opioid agonist treatment, current employment, stable accommodation, cessation of illicit opioid use, cessation of other drug use (including cannabis), and a positive change of social and physical environment since starting treatment.
The daily dose can be generally reduced by up to 2.5 to 5 mg per week without severe opioid withdrawal symptoms. Patients should be reviewed frequently during dose reductions and adjustments to the dose made in accordance with clinical need.

# Methadone for opioid detoxification
Commence with 10-20 mg methadone daily, according to the severity of dependence and degree of tolerance to opioids. Reduce the daily methadone dose by 1-2 mg per day. Patients will continue to experience mild opioid withdrawal symptoms in the week after methadone is ceased.

# Annex 12 Prescribing guidelines

# Buprenorphine maintenance treatment
An adequate maintenance dose, titrated to clinical effectiveness, should be achieved as rapidly as possible to prevent undue opioid withdrawal symptoms due to inadequate dosage.
Prior to induction, consideration should be given to the nature of opioids being used (i.e. long or short-acting), the time since last opioid use, and the degree or level of opioid dependence (i.e. opioid tolerance).
Patients taking street heroin (or other short-acting opioids). When treatment starts, the dose of buprenorphine should be taken at least six hours after the patient last used opioids, or when the early signs of withdrawal appear. The recommended starting dose is 4 mg buprenorphine on day 1, with a possible additional 4 mg depending on the individual patient's requirement.
Patients on methadone. Before starting treatment with buprenorphine, the maintenance dose of methadone should be reduced to 30 mg/day. The first dose of buprenorphine should be taken at least 24 hours after the patient last used methadone. The initial 4 mg buprenorphine induction dose should ideally be administered when withdrawal signs are evident.
Precautions for commencing buprenorphine include: high-risk polydrug use, mental illness, low levels of neuroadaptation to opioids (i.e. recent incarceration), and significant concomitant medical problems.
The dose of buprenorphine should be increased progressively according to the clinical effect in the individual patient. It is recommended to use 8-24 mg daily, the daily dose should not exceed 32 mg. The dosage is adjusted according to reassessments of the clinical and psychological status of the patient.

# Less than daily dosing with buprenorphine
After a satisfactory period of stabilization has been achieved the frequency of dosing may be decreased to dosing every other day at twice the individually titrated daily dose. For example, a patient stabilized to receive a daily dose of 8 mg may be given 16 mg on alternate days, with no medication on the intervening days. However, the dose given on any one day should not exceed 32 mg.
In some patients, after a satisfactory period of stabilization has been achieved, the frequency of dosing may be decreased to three times a week (for example on Monday, Wednesday and Friday). The dose on Monday and Wednesday should be twice the individually titrated daily dose, and the dose on Friday should be three times the individually titrated daily dose, with no medication on the intervening days. However, the dose given on any one day should not exceed 32 mg.

# Transfer to methadone
Commence methadone 24 hours after the last dose of buprenorphine. From buprenorphine doses of 8 mg daily and above, commence with 30 mg methadone daily. From buprenorphine doses of 4-8 mg daily, commence with 20-30 mg methadone daily. With buprenorphine doses below 4 mg daily, commence with less than 20mg methadone daily.

# Reducing dosage and stopping treatment
The decision to discontinue therapy with buprenorphine should be made as part of a comprehensive treatment plan. Studies suggest that it is associated with a risk of relapse to illicit opioid use and patients should be informed of these risks. Research is lacking on factors predicting successful withdrawal from opioid agonist maintenance; however, these factors may include a brief drug-use history before opioid agonist maintenance, no previous treatments before opioid agonist treatment, current employment, stable accommodation, cessation of illicit opioid use, cessation of other drug use (including cannabis), and a positive change of social and physical environment since starting treatment.
The daily dose of buprenorphine can generally be reduced by up to 4-8 mg per week without severe opioid withdrawal symptoms. Patients should be reviewed frequently during dose reductions and adjustments to the dose made in accordance with clinical need.

# Buprenorphine for opioid detoxification
Different dose schedules have been used for detoxification from opioids using buprenorphine. One suggested schedule is:

# Alpha 2 adrenergic agonists for opioid detoxification
Alpha adrenergic agonists can cause significant hypotension and bradycardia and should not be the treatment of choice for the management of opioid withdrawal in elderly patients and patients with coronary insufficiency, ischaemic heart disease, bradycardia, cerebrovascular disease, pregnancy and breastfeeding. It is recommended to monitor the pulse and blood pressure when using clonidine, and to withhold or reduce the dose if the patient experiences symptoms of reduced circulation (e.g. dizziness on standing) or if the pulse or the blood pressure become too low (e.g. pulse less than 50 bpm, blood pressure less than 90/60 mmHg).
In the management of opioid withdrawal, clonidine is generally administered in doses of up to 100-300 mcg, three or four times daily, up to a maximum of 10-17 mcg/kg/day, reducing after the first two days and finishing by day 4 or 5. In an inpatient or residential setting, the initial dose should be in the range of 1-2 mcg/kg, with subsequent doses adjusted accordingly.
In outpatient settings, where blood pressure is not being monitored, lower doses should be used, with maximum daily doses of 450-900 mcg, according to the patient's weight and severity of opioid withdrawal.
Initially the dose is 0.4-0.6 mg twice daily, increasing as necessary and tolerated to a maximum of 2.4 mg daily, in 2-4 divided doses. Treatment should be for 7-10 days, followed by a gradual withdrawal of 2-4 days.
Initially the dose should be 0.25 to 0.5 mg per day, increased as necessary and tolerated to 1-2 mg daily (in 1-4 divided doses) for 3-5 days then tapering over 2-3 days.
Refraining from drug use. A person taking prescribed methadone but no illicit opioids would still be described as abstinent. The term "abstinence" should not be confused with the term "abstinence syndrome", which refers to withdrawal syndrome.

# Agonist maintenance therapy, opioid
Treatment of drug dependence by prescribing a substitute drug to which the patient is cross-dependent and cross-tolerant. Examples of agonist maintenance therapies are methadone and buprenorphine to treat heroin dependence, and nicotine gum to replace tobacco smoking. The goals of agonist maintenance therapy are to eliminate or reduce use of a particular substance (especially if it is illegal), reduce the harm and health risks of a particular method of substance administration (e.g. risk of disease from needle-sharing) and reduce the social consequences of drug dependence. Agonist maintenance therapy can last from several months to more than 20 years, and is often accompanied by other treatment (e.g. psychosocial treatment). It is sometimes distinguished from tapering-off therapy. (See opioid withdrawal syndrome.)

# Bloodborne diseases
Diseases such as HIV and hepatitis B and C, which are spread by blood-to-blood contact (e.g. needle sharing).

# Convention on Psychotropic Substances, 1971
The Convention on Psychotropic Substances, 1971 is the second of the international drug control treaties, supplementing the Single Convention on Narcotic Drugs, 1961. It aims to control psychotropic substances, as defined under this convention, and to prevent their abuse. The Convention outlines a number of responsibilities for parties. The International Narcotics Control Board (INCB), which submits its reports to the Economic and Social Council (ECOSOC) through the Commission on Narcotics Drugs (CND) is responsible for monitoring the compliance by governments with the 1971 Convention, ensuring on the one hand that psychotropic substances are available for medical and scientific use, and on the other hand that diversion from licit sources to illicit traffic does not occur. Buprenorphine is listed in the Convention on Psychotropic Substances.
As a general term, the state of needing or depending on something or someone for support or to function or survive. As applied to opioids, implies the need for repeated doses of a drug to feel good or to avoid feeling bad.
In 1964, a World Health Organization (WHO) Expert Committee introduced the term "dependence" to replace addiction and habituation. The term can generally be used with reference to dependence on any psychoactive drugs (e.g. drug dependence, chemical dependence, substance dependence), or with specific reference to a particular drug or class of drugs (e.g. opioid dependence). Although ICD-10 has a specific definition for dependence, described in terms applicable across drug classes, the symptoms of dependence will vary for each specific drug.
Dependence often refers to both the physical and psychological elements of drug dependence. More specifically, psychological or psychic dependence refers to the experience of impaired control over drug use (including cravings and compulsions to use drugs) while physiological or physical dependence refers to tolerance and withdrawal symptoms (see neuroadaptation). However, in biologically oriented discussion, dependence is often used to refer only to physical dependence.
Dependence or physical dependence is also used in a narrower sense in the psychopharmacological context, to refer solely to the development of withdrawal symptoms on cessation of drug use.
The process of an individual being withdrawn from the effects of a psychoactive substance. When referring to a clinical procedure, detoxification refers to a withdrawal process that is carried out in a safe and effective manner, minimizing the withdrawal symptoms. The facility where this takes place may be called a detoxification or "detox" centre.

# Harm reduction
In the context of alcohol or other drugs, harm reduction (or harm minimization) describes policies or programmes that focus directly on reducing the harm resulting from the use of alcohol or drugs. The term is used particularly to refer to policies or programmes that aim to reduce the harm without necessarily changing the underlying drug use; examples include needle and syringe exchanges to counteract needle sharing among heroin users, and self-inflating airbags in automobiles to reduce injury in accidents, particularly as a result of drink-driving. Harm-reduction strategies cover a wider range of activities than simple reduction of supply and demand.

# Harmful use of opioids
A pattern of psychoactive substance use that is causing damage to health (ICD-10, code F11.1). The damage may be physical (e.g. in the cases of hepatitis from the self-administration of injected psychoactive substances) or mental. Harmful use often, but not always, has adverse social consequences; social consequences alone, however, are not sufficient to justify a diagnosis of harmful use.
The term was introduced in ICD-10 and replaced "non-dependent use" as a diagnostic term.

# Narcotic drug
Narcotic drugs are the substances included in Schedules I and II of the Single Convention on Narcotic Drugs, 1961, (see below), whether natural or synthetic. Methadone is a narcotic drug.
The changes in neurones associated with both tolerance and the appearance of withdrawal syndrome. Individuals can exhibit neuroadaptation without showing the cognitive or behavioural manifestation of dependence. For example, surgical patients given opioid substances to relieve pain may sometimes experience withdrawal symptoms but may not recognize these symptoms or have any desire to continue taking drugs.
One of a group of alkaloids derived from the opium poppy (Papaver somniferum), with the ability to induce analgesia, euphoria, and, in higher doses, stupor, coma, and respiratory depression. The term excludes synthetic opioids.
The generic term applied to alkaloids from the opium poppy (Papaver somniferum), their synthetic analogues, and compounds synthesized in the body. All of these substances interact with the same specific receptors in the brain, have the capacity to relieve pain and produce a sense of well-being Annex 13 Glossary (euphoria). The opium alkaloids and their synthetic analogues also cause stupor, coma and respiratory depression in high doses.
Opium alkaloids and their semisynthetic derivatives include morphine, diacetylmorphine (diamorphine, heroin), hydromorphine, codeine and oxycodone. Synthetic opioids include levorphanol, propoxyphene, fentanyl, methadone, pethidine (meperidine) and the agonist-antagonist pentazocine. Endogenously occurring compounds with opioid actions include the endorphins and enkephalins.
The most commonly used opioids (such as morphine, heroin, hydromorphine, methadone and pethidine) bind preferentially to the -receptors; they produce analgesia, mood changes (e.g. euphoria, which may change to apathy or dysphoria), respiratory depression, drowsiness, psychomotor retardation, slurred speech and impaired concentration, memory and judgement.
Physical consequences of opioid use (mostly resulting from intravenous administration) include hepatitis B, hepatitis C, HIV, septicaemia, endocarditis (inflammation of the inner layer of the heart), pneumonia and lung abscess, thrombophlebitis (blood clots causing vein inflammation) and rhabdomyolysis (breakdown of muscle fibres). Psychological and social impairment is common, reflecting the illicit nature of non-medical opioid use.

# Opioid, endogenous
Any of the naturally occurring brain neuropeptides, which include at least two major groups-the enkephalins and the endorphins. Both can interact with opiate-binding sites (receptors) and thus may modulate the perception of pain. Endorphins also appear to modulate mood and responses to stressful stimuli (see opioid).

# Opioid intoxication
A condition that follows the administration of opioids, resulting in disturbances in the level of consciousness, cognition, perception, judgement, affect, behaviour or other psychophysiological functions and responses. These disturbances are related to the acute pharmacological effects of, and learned responses to, opioids. With time, these disturbances resolve, resulting in complete recovery, except where tissue damage or other complications have arisen.
Intoxication depends on the type and dose of opioid, and is influenced by factors such as an individual's level of tolerance. Individuals often take drugs in the quantity required to achieve a desired degree of intoxication. Behaviour resulting from a given level of intoxication is strongly influenced by cultural and personal expectations about the effects of the drug.
Acute intoxication is the ICD-10 term for intoxication of clinical significance (F11.0). Complications may include trauma, inhalation of vomitus, delirium, coma and convulsions, depending on the substance and method of administration.

# Opioid overdose
The use of opioids in amounts that produce acute adverse physical or mental effects. Deliberate overdose is a common method of suicide. In absolute numbers, overdoses of licit opioids tend to be more common than those of illicit opioids. Overdose may produce transient or lasting effects, or death; the lethal dose of a particular opioid varies with the individual and with circumstances.

# Opioid-use disorders
A group of conditions associated with the use of opioids. In ICD-I0, section F11.0-9 ("Mental and behavioural disorders due to psychoactive substance use (opioids)") contains a wide variety of disorders of different severity and clinical form, all having in common the use of opioids, which may or may not have been medically prescribed. The clinical states that may occur include acute intoxication, harmful use, dependence syndrome, withdrawal syndrome (or withdrawal state), withdrawal state with delirium, psychotic disorder, late-onset psychotic disorder and amnesic syndrome.

# Opioid withdrawal syndrome
Over time, morphine and its analogues induce tolerance and neuroadaptive changes that are responsible for rebound hyperexcitability when the drug is withdrawn. The withdrawal syndrome includes craving, anxiety, dysphoria, yawning, sweating, piloerection (gooseflesh), lacrimation (excessive tear formation), rhinorrhoea (running nose), insomnia, nausea or vomiting, diarrhoea, cramps, muscle aches and fever. With short-acting drugs, such as morphine or heroin, withdrawal symptoms may appear within 8-12 hours of the last dose of the drug, reach a peak at 48-72 hours, and clear after 7-10 days. With longer acting drugs, such as methadone, onset of withdrawal symptoms may not occur until 1-3 days after the last dose; symptoms peak between the third and eighth day and may persist for several weeks, but are generally milder than those that follow morphine or heroin withdrawal after equivalent doses.

# Psychosocial intervention
Any non-pharmacological intervention carried out in a therapeutic context at an individual, family or group level. Psychosocial interventions may include structured, professionally administered interventions (e.g. cognitive behaviour therapy or insight oriented psychotherapy) or non-professional interventions (e.g. self-help groups and non-pharmacological interventions from traditional healers).

# Psychotropic substance
Psychotropic substances are the substances, natural or synthetic, or any natural material in Schedules I, II, III or IV of the Convention on Psychotropic Substances, 1971, (see above). Among others, buprenorphine and benzodiazepines are psychotropic substances.

# Single Convention on Narcotic Drugs, 1961
The Single Convention on Narcotic Drugs, 1961 (as amended by the 1972 Protocol) is the main international drug control treaty. Replacing a number of previous conventions, it aims to limit the cultivation, production, manufacture and use of narcotic drugs to medical and scientific purposes, while ensuring their availability for such purposes. The convention lists a number of narcotic drugs, and outlines the responsibilities of parties with regard to the production, manufacture, distribution and use of these drugs in their countries. The INCB, which submits its reports to ECOSOC through the CND, is responsible for monitoring the compliance of governments with the provisions of this treaty. Methadone is listed in the Single Convention on Narcotic Drugs, 1961.
A decrease in response to a drug dose that occurs with continued use. If an individual is tolerant to a drug, increased doses are required to achieve the effects originally produced by lower doses. Both physiological and psychosocial factors may contribute to the development of tolerance. Physiological factors include metabolic and functional tolerance. In metabolic tolerance, the body can eliminate the substance more readily, because the substance is metabolized at an increased rate. In functional tolerance, the central nervous system is less sensitive to the substance. An example of a psychosocial factor contributing to tolerance is behavioural tolerance, where learning or altered environmental constraints change the effect of the drug. Acute tolerance refers to rapid, temporary accommodation to the effect of a substance following a single dose. Reverse tolerance, also known as sensitization, refers to a condition where the response to a substance increases with repeated use. Tolerance is one of the criteria of the dependence syndrome.

# Withdrawal syndrome (abstinence syndrome, withdrawal reaction, withdrawal state)
A group of symptoms of variable clustering and degree of severity that occur on cessation or reduction of use of a psychoactive substance that has been taken repeatedly, usually for a prolonged period or in high doses (ICD-10 code F1x.3). Withdrawal syndrome may be accompanied by signs of physiological disturbance. It is one of the indicators of dependence syndrome, and is the defining characteristic of the psychopharmacological definition of dependence.
The onset and course of withdrawal syndrome are time limited and relate to the type of substance and dose being taken immediately before cessation or reduction of use. Typically, the features of withdrawal syndrome are the opposite of acute intoxication.
Opioid withdrawal is accompanied by rhinorrhoea (running nose), lacrimation (excessive tear formation), aching muscles, chills, piloerection (gooseflesh) and, after 24-48 hours, muscle and abdominal cramps. Drug-seeking behaviour is prominent and continues after the physical symptoms have abated.