Pharmacological treatments for heroin and cocaine addiction

Wim van den Brink

*, Jan M. van Ree

Department of Psychiatry, Academic Medical Center, University of Amsterdam, Tafelbergweg 25, 1105 BC Amsterdam, The Netherlands

Department of Pharmacology and Anatomy, Rudolf Magnus Institute of Neuroscience, Utrecht University, The Netherlands

Abstract

Aims

: To provide an overview of the pharmacological options for the treatment of heroin- and cocaine-dependent patients based on known biochemical pathways to addiction and the chronic disease model as a starting point for treatment planning.

Results

: Recent pre-clinical andclinical studies indicate that different brain structures and different neurotransmitters are involved in different stages of the addiction process.In addition, clinical experience shows that heroin and cocaine addiction can best be conceptualised and treated as a chronic, relapsingdisorder with the following treatment goals: crisis intervention, cure or recovery (detoxification, relapse prevention) and care or partialremission (stabilization and harm reduction). The various high-quality studies, systematic literature reviews and formal meta-analyses clearlydemonstrate that today many proven effective interventions are available for crisis intervention, detoxification, stabilization and harmreduction for heroin-dependent patients. Interventions directed at relapse prevention are still problematic and only effective in a minority of motivated patients in stable living conditions and adequate social support. In contrast, no proven effective pharmacological interventions areavailable for the treatment of cocaine-dependent patients, maybe with the exception of some patient groups that seem to benefit fromtreatment with disulfiram or amantadine. Treatment innovations are primarily based on experimental animal studies. Newly developedcannabinoid receptor antagonists and cortisol synthesis inhibitors show great promise.

Conclusion

: Heroin addiction is a chronic relapsingdisease that is difficult to cure, but stabilization and harm reduction can greatly increase the life time expectancy and the quality of life of the patient, his direct environment and society as a whole. Currently, no proven effective pharmacological interventions are available for cocaineaddiction, and treatment has to rely on existing cognitive behaviour therapies combined with contingency management strategies.

Keywords:

Pharmacological treatment; Heroin; Cocaine

1. Introduction

The use of opioids continues to increase and it isestimated that a total of 8 million people worldwide abuseopioids. 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%, andthe estimated number of heroin-dependent people amountsto 800,000. Of these, only 180,000 (22%) receive thecurrently most effective treatment, i.e. opioid-agonist main-tenance therapy(National Institute of Health, 1999).At the same time, the US has about 1 million cocaine addicts(Substance Abuse and Mental Health Services Administra-tion, 1999). In Europe, the annual prevalence of problematicillicit 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 theUnited Kingdom to 41–86% in Spain(European Monitor-ing Centre for Drug and Drug Abuse, 2001).Since the introduction of methadone in the 1960s, a largenumber of new effective pharmacological and psychosocialtreatments have become available for the treatment of opioiddependence. These treatments aim at improving the clinicaloutcome of drug-dependent patients and at reducing drug-related criminality and public nuisance. Effectiveness of these interventions is currently well documented in literaturereviews 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 Cochranecollaboration. At the same time, a great number of different compounds have been tested for the treatment of cocainedependence. However, in general, the results of theseattempts have been less successful. Most of the studies have been reviewed by clinicians and researchers, and recently, a

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formal systematic review hasbeen published about a selec-tion 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 themore promising recent developments that aim to improvethe outcome of patients currently not benefiting from theexisting treatments.Addiction is currently considered a chronic relapsingdisease that is due to a com bination of genetic, drug-inducedand environmental factors(Leshner, 1997; McLellan, 2002;Hser et al., 2001). Hence, this review is organized accordingto 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 alldrugs; care or partial remission directed towards reductionor stabilization of illicit drug use, improvement of medicaland social functioning and prevention of addiction-relatedharms; and palliation for those patients with a limited lifetime expectancy.Although drug abuse has different initial targets andactions, the resultant actionsshare severalkey featuresowingto common effects on crucial neural circuits. In both animaland human models of addiction, different stages in theaddiction process have been identified often indicated withthe terms initiation, continuation, withdrawal and relapse.Different neurotransmitters and different brain structures andneural 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,

-opioid receptors (endorphins) and dopamine(DA) seem to play an important role in the acute reinforcingeffects of drug abuse (including alcohol) with the ventraltegmental area (VTA) and the nucleus accumbens (NcA) astheprimaryareasofinterest.Inthesecondphaseofcontinueddrug use and drug craving, a large variety of neurotransmit-ters is involved, including DA in the NcA, corticotropin-releasing hormone (CRH) in the amygdala and glutamate inthe frontal-cingulate circuit. In the third phase of detoxifica-tion and withdrawal, glutamate and norepinephrine are cru-cial 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 cingu-late gyrus and the amygdala are important brain regions, withthe neurotransmitters norepinephrine and CRH as important representatives of the brain stress system (stress-inducedrelapse), and

-amino butyric acid (GABA) and glutamateas important representatives of the compulsive and habit system (cue-induced relapse).This brief review of neurotransmitter and neural circuitsthat are assumed to be involved in the development andcontinuation of addictive behaviours clearly shows that there are many different ways to pharmacologically inter-vene in the addictive process in an attempt to block rewarding effects, to replace illicit drugs by other lessaddictive 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 addic-tion, many of these neurotransmitter systems and neuralcircuits are used to obtain beneficial effects for these patients.

2. Heroin addiction

The primary action of opioids seems to be the inhibitionof

-amino butyric acid (GABA)ergic neurons that normallytonically inhibit the dopaminergic neurons in the ventraltegmental area (VTA), which leads to a surge of dopaminein the nucleus accumbens(NcA) and other mesolimbic– mesocortical brain regions(Kreek et al., 2002).

2.1. Crisis intervention

It is well established that non-fatal overdose is highly prevalent among opioid addicts(Warner-Smith et al., 2001), and that the short-acting opioid-antagonist naloxone iseffective in treating respiratory depression and coma in patients with an opioid overdose. In a review of existingstudies, there was no evidence to suggest that subcutaneousor intramuscular routes of administration are inferior tointravenous administration of naloxone(Clarke, 2001).This is an important conclusion for countries that consider thedistribution of naloxone to heroin addicts for peer adminis-tration in order to prevent fatal overdose(Lenton andHargreaves, 2000). In a retrospective cohort study, it wasfound that bystander cardiopulmonary resuscitation is rela-tively rare, but rather effective if applied in an adequate wayleading to less hospitalisations and a small but important improvement in clinical outcome(Dietze et al., 2002). Together, these interventions may provide important possi- bilities to save lives and prevent unnecessary damage. The best prevention of (fatal) overdoses is, however, participa-tion in opioid-assisted treatments such as methadone or buprenorphine maintenance.

2.2. Cure: detoxification and relapse prevention

Although opioid addiction is generally regarded as achronic relapsing disease, the primary interest is still the cureof this disease, i.e. long-term stable abstinence from allopioids. Stable abstinence is achieved in two phases: adetoxification phase in which the patient has to reduce andfinally stop the consumption of all opioids, and a phase of relapse prevention in which abstinence has to be maintained.

2.2.1. Detoxification

The various Cochrane reviews on detoxification indicatethat the most extensively tested and most effective strategyfor the detoxification of heroin-dependent patients is replacement by and subsequent tapering of the long-acting

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opioid-agonist methadone. The best results can be obtainedthroughinpatient methadonetapering lasting no more than 3weeks(Amato et al., 2002).The process and outcome of long-acting opioid-agonist tapering may be improvedthrough additional pr escription of a calcium channel blocker such as nimodipine(Jimenez-Lerma et al., 2002),whereas additional prescription of amantadine does not seem toimprove the effectiveness of methadone tapering in hero-in-dependent patients with or without co-morbid cocainedependency(Perez de los Cobos et al., 2001).Other effective strategies include replacement of heroin by the partial opioid-agonist buprenorphine which is subse-quently tapered off or by discontinuation of heroin withtreatment of withdrawal symptoms using an

-adrenergicagonist (Gowing et al., 2002a,b).In a recent review,Kosten and O’Connor (2003)seem to prefer buprenorphine over methadone as their first choice detoxification strategy. Oneof the latest proposals is to detoxify heroin addicts with asingle high dose of buprenorphine (32 mg), because thecombination of a high dose, the relative long plasma half-life and the slow dissociation kinetics of the drug from theopioid receptors seems to create a slow tapering process(Kutz and Reznik, 2002).Detoxification can also be supported by

-adrenergicagonists such as clonidine or lofexidine. It has now beenshown that lofexidine is preferred over clonidine, becausehypotension is less likely to occur with lofexidine(Gowingat al., 2002b). This makes lofexidine particularly suitable in prison contexts when methadone prescription is not possible(Howells et al., 2002).In an attempt to shorten the detoxification phase, toincrease detoxification completion rates and to enhanceinitiation of pharmacologically supported relapse preven-tion, naltrexone-assisted detoxification procedures withand without heavy sedation or full anaesthesia wereintroduced. According to the Cochrane review, the useof an opioid-antagonist (naltrexone, naloxone or both)together with an

-adrenergic agonist to amelioratewithdrawal symptoms is a feasible detoxification strategy, particularly as a means of facilitating entry into mainte-nance with an opioid-antagonist (Gowing et al., 2002c).The withdrawal syndrome associated with this strategy islikely to be somewhat more severe than in withdrawalmanagement with an

-adrenergic agonist alone, but signs and symptoms are likely to resolve more quickly,resulting in the overall withdrawal episode being per-ceived as somewhat less severe than with clonidine or lofexidine alone. However, patients should be warned of the possibility of delirium in the first day of naltrexoneadministration(Gowing et al., 2002c).In a recent rando- mised clinical trial, clonidine, clonidine plus naltrexone,and clonidine and naltrexone in combination with bupre-norphine were compared. After stabilization for as little as3 days, patients taking buprenorphine had less withdrawalsymptoms than patients in the other two groups(O’Con-nor et al., 1997). With regard to naltrexone-assisteddetoxification under heavy sedation or full anaesthesia,the Cochrane reviewers cautiously conclude that ‘‘thisapproach must be regarded as experimental with bothrisks and benefits remaining uncertain’’(Gowing et al.,2002d). Despite earlier reports, most patients still experi-ence moderate withdrawal symptoms lasting at least a fewdays following anaesthetic procedure. In addition, severalserious adverse medical events related to the anaesthetic procedure were reported. In a report on the first rando-mised controlled trial directly comparing naltrexone-assis-ted detoxification with and without full anaesthesia, theauthors clearly state that heavy sedation or full anaesthe-sia has no place in naltrexoneassisted rapid detoxification(de Jong and Krabbe, 2002).Although methadone or buprenorphine maintenance isthepreferred treatment of pregnant heroin-dependent wom-en(Rohrmeister et al., 2002; Lejeune et al., 2001; Fischer et al., 2000), naltrexone-assisted detoxification might be agood option to assist those women who are unable tostabilize on methadone or buprenorphine and continue touse street drugs. In a series of 18 cases with detoxificationsin all three trimesters, no neonatal, maternal or obstetriccomplications were observed following naltrexone detoxifi-cation(Hulse et al., 2001).

2.2.2. Relapse prevention

Traditional relapse prevention programs were limited tolong-term inpatient treatments intended to last at least 9months and often using the therapeutic community format.In many countries, this model has been replaced by shorter inpatient treatments generally lasting less than 6 weeks. The positive effects of both long-term and short-term programsare, however, rather limited. In a 3-month follow-up of 242opioid-dependent patients in residential treatment in the National Treatment Outcome Research Study (NTORS),34% of the patients relapsed to heroin use within 3 days,45% within 7 days, 50% within 14 days and 60% within 90days. According to the authors, the results of this studyhighlight the need to provide aftercare services to help patients maintain the gains achieved during treatment andto avoid the high risk of relapse at this time(Gossop et al.,2002).One possibility to reduce the risk of relapse to illegalopioid use is long-term prescription of an opioid antagonistssuch as naltrexone. The first obstacle involved in thisstrategy is the high drop-out rate during detoxificationresulting in highly selective patient samples in most of thenaltrexone maintenance studies(Schufman et al., 1994).Once in naltrexone maintenance treatment, the results arenot very promising either. Based on a systematic review of available evidence, the Cochrane reviewers conclude that ‘‘at present, there is no sufficient evidence of efficacy of naltrexone to justify its use in the maintenance treatment of opioid dependence’’(Kirchmayer et al., 2002).This conclusion is corroborated by the findings of the NationalEvaluation of Pharmacotherapies for Opioid Dependence

W. van den Brink, J.M. van Ree / European Neuropsychopharmacology 13 (2003) 476–487