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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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3.1. Opioid dependence

Opioid dependence is characterized by a cluster of cognitive, behavioural and physiological features. The International Classification of Diseases, 10th edition (ICD-10) [14] identifies six such features:

  • a strong desire or sense of compulsion to take opioids
  • difficulties in controlling opioid use
  • a physiological withdrawal state
  • progressive neglect of alternative pleasures or interests because of opioid use
  • persisting with opioid use despite clear evidence of overtly harmful consequences.

ICD-10 defines opioid dependence as the “presence of three of more [of these features] 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.

3.2. 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 [15].

Recent decades have seen a substantial increase in our understanding of the neurobiological aspects of substance dependence [9]. 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 [16].

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 [17, 18]. 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 [19].

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 [20, 21, 22]. They also induce dopamine release directly, by interacting with opioid receptors in the nucleus accumbens [23, 24].

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 [25], 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 [26].

3.3. 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 [2]. 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 [2].

3.4. 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 [5]. 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 [2]. Despite this situation, measures that prevent the spread of HIV in IDU, including opioid agonist maintenance treatment, have less than 5% coverage worldwide [27].

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 [28]. 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, opioid-dependent individuals have been found to have an annual mortality of 2–4% per annum, or 13 times that of their peers [29]. This increased mortality is primarily due to overdoses, violence, suicide, and smoking and alcohol-related causes [30, 31, 32]. In countries with high HIV prevalence, acquired immunodeficiency syndrome (AIDS) also makes a significant contribution to mortality [33].

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 [34]. 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 [35].

3.5. 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) [36, 37, 38].

3.6. 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 [39, 40, 41, 42]. Contact with treatment is one factor associated with recovery from opioid dependence; other factors include personal motivation, religion, spirituality, family and employment [41].

3.7. 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 [9].

3.8. 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.


Pharmacological management of opioid withdrawal is usually by one of the following:

  • gradual cessation of an opioid agonist (i.e. methadone)
  • 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 [43, 44]; the implication being that a single detoxification episode should not be promoted as effective 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 [43, 45]. However, relapse to heroin use following the cessation of agonist maintenance treatment is common [46, 47, 48]and research is lacking on when, who and how to withdraw from opioid agonist maintenance treatment.


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.

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: NBK143178


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