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Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence. Geneva: World Health Organization; 2009.

Cover of Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence

Guidelines for the Psychosocially Assisted Pharmacological Treatment of Opioid Dependence.

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5Programme level guidelines – for programme managers and clinical leaders

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.

5.1. 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.

5.2. 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 [75], people should be free to chose whether or not they participate in treatment.

The WHO Resource Book on Mental Health, Human Rights and Legislation [76] says that, to be valid, consent must satisfy the following criteria:

  • “The person/patient giving consent must be competent to do so, and competence is assumed unless there is evidence to the contrary.
  • Consent must be obtained freely, without threats or improper inducements.
  • There should be appropriate and adequate disclosure of information. Information must be provided on the purpose, method, likely duration and expected benefits of the proposed treatment; possible pain or discomfort and risks of the proposed treatment, and likely side-effects. This information should be adequately discussed with the patient.
  • Choices should be offered, if available, in accordance with good clinical practice; alternative modes of treatment, especially those that are less intrusive, should be discussed and offered to the patient.
  • Information should be provided in a language and form that is understandable to the patient.
  • The patient should have the right to refuse or stop treatment.
  • Consequences of refusing treatment, which may include discharge from the hospital, should be explained to the patient.
  • The consent should be documented in the patient's medical records.
  • The right to consent to treatment implies also the right to refuse treatment. If a patient is judged as 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.

5.3. 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.

5.3.1. 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.

5.3.2. 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.

5.3.3. 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.

5.4. 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.

5.5. 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.

5.6. Treatment provision

5.6.1. 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.

5.6.2. 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.

5.6.3. 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
  • measured responses for mild breaches of acceptable behaviour (e.g. warnings, fewer take-home dose privileges, more frequent medical visits, refusing or delaying doses if intoxicated)
  • final responses (e.g. treatment discharge and, if necessary, calling the police) for serious breaches of acceptable 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 non-confrontational 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 [77].

5.6.4. 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 follow-up. 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.

5.6.5. 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 [78, 79, 80]. 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.

5.6.6. 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.

5.6.7. 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 opioid-dependent patients, in association with pharmacological treatments of opioid dependence. At a minimum, this should include assessment of psychosocial needs, supportive counselling and links to existing family and community services.

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.

5.6.8. 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 [81].

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 [82]. Excellent results can be obtained for patients in opioid agonist maintenance treatment [83].

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, opioid-dependence 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 [84, 85, 86, 87].

A number of RCTs have demonstrated that substance-dependent patients are more likely to attend for medical care if the treatment is provided onsite; this can be arranged for minimal additional cost [88, 89, 90, 91, 92, 93]. An alternative approach – providing opioid agonist maintenance treatment at medical clinics [94] – 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.

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.

5.6.9. HEPATITIS B VACCINATION

Vaccination for hepatitis B is recommended for all opioid-dependent patients [95]. 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 [96, 97, 98]

On the other hand, it is useful to test levels of post-vaccination anti-hepatitis B antibodies, because significant numbers of people do not produce an adequate immune response [99, 100, 101]; in these cases, additional doses of vaccination should be given.

Many opioid-dependent patients will also benefit from vaccination against hepatitis A [102].

Recommendation (Best Practice)

Treatment services should offer hepatitis B vaccination to all opioid-dependent patients.

5.7. 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 [103].

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.

Copyright © 2009, World Health Organization.

All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: tni.ohw@sredrokoob). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: tni.ohw@snoissimrep).

Bookshelf ID: NBK143168

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