Pharmacological treatments for heroin and cocaine addiction
Introduction
The use of opioids continues to increase and it is estimated that a total of 8 million people worldwide abuse opioids. The regions with the highest annual prevalence (2%) are South East and South West Asia (van der Burgh, 1999). In the US, the annual prevalence is about 0.4%, and the estimated number of heroin-dependent people amounts to 800,000. Of these, only 180,000 (22%) receive the currently most effective treatment, i.e. opioid-agonist maintenance therapy (National Institute of Health, 1999). At the same time, the US has about 1 million cocaine addicts (Substance Abuse and Mental Health Services Administration, 1999). In Europe, the annual prevalence of problematic illicit drug use (mainly opioid and cocaine dependence) ranges from a low of 0.3% in The Netherlands to a high of 0.9% in Luxembourg and Portugal. Participation in opioid-agonist treatment ranges from an estimated 6–22% in the United Kingdom to 41–86% in Spain (European Monitoring Centre for Drug and Drug Abuse, 2001).
Since the introduction of methadone in the 1960s, a large number of new effective pharmacological and psychosocial treatments have become available for the treatment of opioid dependence. These treatments aim at improving the clinical outcome of drug-dependent patients and at reducing drug-related criminality and public nuisance. Effectiveness of these interventions is currently well documented in literature reviews by established researchers and clinicians (e.g. Kreek et al., 2002, Gonzalez et al., 2002, Kosten and George, 2002) and in formal systematic reviews of the Cochrane collaboration. At the same time, a great number of different compounds have been tested for the treatment of cocaine dependence. However, in general, the results of these attempts have been less successful. Most of the studies have been reviewed by clinicians and researchers, and recently, a formal systematic review has been published about a selection of the tested compounds (Silva de Lima et al., 2002).
In this overview, we briefly summarize the findings of these reviews. In addition, we briefly describe some of the more promising recent developments that aim to improve the outcome of patients currently not benefiting from the existing treatments.
Addiction is currently considered a chronic relapsing disease that is due to a combination of genetic, drug-induced and environmental factors Leshner, 1997, McLellan, 2002, Hser et al., 2001. Hence, this review is organized according to the different treatment stages generally distinguished for this kind of diseases (Health Council of the Netherlands, 2002): crisis intervention directed for immediate survival; cure or recovery directed towards stable abstinence from all drugs; care or partial remission directed towards reduction or stabilization of illicit drug use, improvement of medical and social functioning and prevention of addiction-related harms; and palliation for those patients with a limited life time expectancy.
Although drug abuse has different initial targets and actions, the resultant actions share several key features owing to common effects on crucial neural circuits. In both animal and human models of addiction, different stages in the addiction process have been identified often indicated with the terms initiation, continuation, withdrawal and relapse. Different neurotransmitters and different brain structures and neural circuits are involved in each of these phases Kreek et al., 2002, van Ree, 2002, de Vries and de Schippenberg, 2002, Kosten and George, 2002. In the first phase of initiation, μ-opioid receptors (endorphins) and dopamine (DA) seem to play an important role in the acute reinforcing effects of drug abuse (including alcohol) with the ventral tegmental area (VTA) and the nucleus accumbens (NcA) as the primary areas of interest. In the second phase of continued drug use and drug craving, a large variety of neurotransmitters is involved, including DA in the NcA, corticotropin-releasing hormone (CRH) in the amygdala and glutamate in the frontal-cingulate circuit. In the third phase of detoxification and withdrawal, glutamate and norepinephrine are crucial and the locus coeruleus seems to be the most important brain region. In the fourth phase of relapse into drug use after sustained abstinence, the orbitofrontal cortex, anterior cingulate gyrus and the amygdala are important brain regions, with the neurotransmitters norepinephrine and CRH as important representatives of the brain stress system (stress-induced relapse), and γ-amino butyric acid (GABA) and glutamate as important representatives of the compulsive and habit system (cue-induced relapse).
This brief review of neurotransmitter and neural circuits that are assumed to be involved in the development and continuation of addictive behaviours clearly shows that there are many different ways to pharmacologically intervene in the addictive process in an attempt to block rewarding effects, to replace illicit drugs by other less addictive or less harmful compounds, to restore the balance between the different neural systems or to prevent hyper-reactivity of the stress axis. In the following review of currently available treatments for heroin and cocaine addiction, many of these neurotransmitter systems and neural circuits are used to obtain beneficial effects for these patients.
Section snippets
Heroin addiction
The primary action of opioids seems to be the inhibition of γ-amino butyric acid (GABA)ergic neurons that normally tonically inhibit the dopaminergic neurons in the ventral tegmental area (VTA), which leads to a surge of dopamine in the nucleus accumbens (NcA) and other mesolimbic–mesocortical brain regions (Kreek et al., 2002).
Cocaine addiction
The primary action of cocaine concerns not only blocking of the presynaptic transporter for dopamine (DAT), but also the presynaptic transporters for serotonin (5-HTT) and norepinephrine (NET), thereby flooding the synapse with dopamine, serotonin and norepinephrine not only in the nucleus accumbens, but also in related regions of the mesolimbic–mesocortical dopamine system (Kreek et al., 2002).
Some new developments
Two important new developments will be reviewed here: the potential role of cannabinoid receptor antagonists in opioid and cocaine relapse prevention, and the possibility that pharmacological attenuation of the stress response in opioid- and cocaine-dependent patients could reduce opioid consumption and relapse in former opioid-dependent patients.
Animal reinstatement models have shown that drug seeking behaviour can be triggered by re-exposure to the drug, by re-exposure to stimuli previously
Conclusion
A broad range of proven effective pharmacological and psychosocial interventions for the treatment of opioid dependence is now available, and some promising new interventions are waiting to be tested in clinical trials (e.g. Fiellin and O'Connor, 2002). A different picture emerges from studies in cocaine-dependent patients: no effective treatments are currently available for unselected cocaine addicts (e.g. Kreek et al., 2002). However, recent research indicates that some treatments might be
References (137)
- et al.
Low (40 mg) versus high (80 mg) dose methadone in a 180-day heroin detoxification program
J. Subst. Abuse Treat.
(1994) - et al.
Auricular acupuncture in the treatment of cocaine abuse. A study of efficacy and dosing
Subst. Abuse Treat.
(1999) - et al.
Bystander resuscitation attempts at heroin overdose: does it improve outcomes?
Drug Alcohol Depend.
(2002) - et al.
Retention rate and illicit opioid use during methadone maintenance interventions: a meta-analysis
Drug Alcohol Depend.
(2002) - et al.
Disulfiram versus placebo for cocaine dependence in buprenorphine maintained subjects: a preliminary trial
Biol. Psychiatry
(2000) - et al.
Prison based detoxification for opioid dependence: a randomised double blind controlled trial of lofexidine and methadone
Drug Alcohol Depend.
(2002) - et al.
Effectiveness of propanolol for cocaine dependence treatment may depend on cocaine withdrawal symptom severity
Drug Alcohol Depend.
(2001) - et al.
A pilot trial of piracetam and ginkgo bilboa for the treatment of cocaine
Addict. Behav.
(2003) - et al.
A pilot trial of olanzapine for the treatment of cocaine dependence
Drug Alcohol Depend.
(2003) - et al.
A novel opioid maintenance program for prisoners: preliminary findings
J. Subst. Abuse Treat.
(2002)