Opiate Agonist Therapy

Substitution therapy is defined as the administration under medical supervision of a prescribed psychoactive substancepharmacologically related to the one producing dependence – to people with substance dependence, for achieving defined treatment aims (usually improved health and well-being). Substitution therapy is widely used in the management of opioid dependence and is often referred to as “opioid substitution treatment,” “opioid replacement therapy”, or “opioid pharmacotherapy”.

 Agents suitable for substitution therapy of opioid dependence are those with some opioid properties, so that they have the capacity to prevent the emergence of withdrawal symptoms and reduce craving. At the same time they diminish the effects of heroin or other opioid drugs because they bind to opioid receptors in the brain. In general, it is desirable for opioid substitution drugs to have a longer duration of action than the drug they are replacing so as to delay the emergence of withdrawal and reduce the frequency of administration. As a result there is less disruption of normal life activities from the need to obtain and administer drugs, thereby facilitating rehabilitation efforts.

Whereas non-prescribed opioids are usually injected or inhaled by drug users, these prescribed medicines are usually administered orally in the form of a solution or a tablet. Agents used in substitution therapy can also be prescribed in decreasing doses over short periods of time (usually less than one month) for detoxification purposes. Opioid Agonist Pharmacotherapy is associated with prescription of relatively stable doses of opioid agonists (e.g. methadone and buprenorphine) over a long period of time (usually more than 6 months).

 The mechanisms of action of opioid substitution maintenance therapy include prevention of disruption of molecular, cellular and physiological events and, in fact, normalization of those functions already disrupted by chronic use of usually short-acting opiates such as heroin. The context of delivery of substitution therapy has important implications for the quality of the interventions, both to maintain adequate control and to ensure responsible prescribing.

 Since 1970, methadone maintenance treatment has grown substantially to become the dominant form of opioid substitution treatment globally.  Because the treatment was initially controversial, it has been  more rigorously evaluated than any other treatment  for opioid dependence.  The weight of evidence for benefits is substantial.

Source:  WHO, 1998; Kreek, 2000

Use of Buprenorphine in Treatment of Opioid Dependence

Buprenorphine is another prescribed drug for management of opioid dependence that has the potential of improving access to drug treatment by bringing more people into treatment in primary health care settings.

Whilst much of the work on substitutution therapy has focused on methadone, several new synthetic opioids such as slow release morphine and buprenorphine have been investigated as potential therapeutic agents in the treatment of opioid dependence.   

Buprenorphine inparticular has been underwent extensive clinical testing for treatment of opioid dependence and is becoming the medication used in the management of opioid dependence, not only in specialized clinics, but also in primary health care.

Its pharmacological properties and resultant clinical characteristics – especially its relatively long duration of action and high safety profile – appear certain to ensure buprenorphine an important place in the overall treatment of opioid dependence.

Pharmacologically, buprenorphine is a partial agonist at the mu receptor and a weak antagonist at the kappa receptor. Because it binds tightly to, and dissociates slowly from these receptors, buprenorphine exhibits an agonist ‘ceiling effect’, most noticeably in its respiratory depression effect, which accords the medication a high degree of clinical safety. Its tight binding with slow dissociation from receptors also provides a blockade for the effects of subsequently-administered agonists, precipitates withdrawal in patients maintained on a sufficient dose of full agonist, and provides prolonged duration of action with poor reversibility by naloxone. Furthermore, buprenorphine’s weak antagonist effect at the kappa receptor renders it devoid of psychotomimetic effects.

Further research has demonstrated buprenorphine’s limited levels of reinforcing efficacy in comparison to opioids, and established its ability to suppress heroin self-administration in opioid-dependent primates and humans.

The formulation containing both buprenorphine and the opioid antagonist naloxone has been  introduced for maintenance therapy of opioid dependence. Adding naloxone to buprenorphine aims at reducing a risk of diversion and injecting use of prescribed buprenorphine.

 Over the past decade a series of controlled clinical trials, using such outcome measures as illicit opiate use, retention in treatment, craving and global rating of improvement, have substantiated buprenorphine’s clinical safety and efficacy. When used in opioid substitution treatment for dependent pregnant women, it appears to be associated with a low incidence of neonatal withdrawal syndrome. Due to the above features, buprenorphine is a useful drug in the facilitation of withdrawal from opioids.

Sources: Barnett, Rodgers & Bloch, 2001; Fischer et al., 2000; Ling et al. 1998

Naloxone and naltrexone are medications that also block the effects of morphine, heroin and other opiates by acting as antagonists at the opioid receptors. They are especially useful in preventing relapse because they block all of the effects of opiates.

The effects are relatively long-lasting, ranging from 1-3 days.  This therapy begins after medically supervised detoxification, because naloxone and naltrexone do not protect against the effects of withdrawal, and can in fact precipitate  withdrawal symptoms in dependent people.Naltrexone itself has no subjective effects or potential for the development of dependence.

Patient noncompliance is a common problem.  Therefore, a favourable treatment outcome requires that there also be a positive therapeutic relationship, effective counseling or therapy, and careful monitoring of medication compliance.

Heroin-Assisted Treatment of Heroin Dependence

Heroin prescription for treatment of opioid dependence, practised on a limited scale in the United Kingdom for many years, gained increased international interest in the early 1990s, with feasibility studies in Australia and a first national study of heroin-assisted treatment in Switzerland that started in 1994.  This study led to the establishment of heroin-assisted treatment as one of the treatment options in Switzerland.  The findings  of the study showed that were significant reductions in illicit drug use, improvement in health status, and social integration (Uchtenhagen et al., 1999).  Follow-up results at 18 months documented stability of improvements also after discharge from the programme (Rehm, 2001).

A review by World Health Organization expert group  supported the main conclusions of the Swiss study, but also recommended further research in order to better identify the specific benefits of prescribed heroin (Ali et al.,1999). These recommendations  have been respected in  randomised  controlled trials;  one implemented in 1998-2001 in the Netherlands (van den Brink et al., 2002), one started in 2002 in Germany (Krausz, 2002).  Other similar research projects are in preparation (Fischer et al., 2002).  The shared objective of the trials is to test an additional therapeutic option for those heroin addicts for whom other treatments have failed and who are out of contact with the tretament system.

An international network of scientists, engaged in the projects mentioned above, has emerged  and organized three conferences for an exchange of methodological, therapeutic and practical problems and experience. The international debate on heroin-assisted treatemnt of opioid  dependence , initially mainly political and controversial, tends to become more scientific  and evidence-oriented (Bammer et al., 1999). 

Sources: Ali et al., 1999; Bammer et al., 1999; Uctenhagen et al., 1999; Rehm et al., 2001; van den Brink et al., 2002; Krausz, 2002; Fischer et al. (2002).

References: (1) (Neuroscience of Psychoactive Substance Use nd  Dependence, Chapter 4 Psychopharmacology Of  Opioids

Compiled & Edited: D. Shrira    Updated: 17 February 2007