Drugs 2004; 64 (14): 1547-1573

. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1547 1. Scope of the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1548 2. Approaches to the Problem . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1549 2.1 Pharmacological Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1549 2.2 Animal Models . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1550 3. Drug Development Strategies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1550 3.1 Direct Action on the Dopamine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551 3.1.1 Compounds Targeting the Dopamine Transporter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1551 3.1.2 Compounds Targeting Dopamine Receptor Subtypes . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1552 3.2 Indirect Modulation of the Dopamine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553 3.2.1 Compounds Targeting the Serotonin System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553 3.2.2 Compounds Targeting the Opioid System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1553 3.2.3 Compounds Targeting the GABAergic System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1554 3.2.4 Compounds Targeting the Glutamate System. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1554 3.2.5 Compounds Targeting the Endocannabinoid System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1555 3.2.6 Compounds Targeting Neuropeptides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1556 4. Marketed Medications Undergoing Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558 4.1 US National Institute on Drug Abuse Clinical Research Efficacy Screening Trial Programme 1558 4.2 Dopaminergic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1558 4.3 GABAergic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1560 4.4 Serotonergic Agents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561 4.5 NMDA Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561 4.6 Calcium Channel Antagonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1561 4.7 Stimulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562 4.8 Other Medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1562 5. Unmarketed Medications Undergoing Clinical Evaluation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1563 6. Pharmacokinetic Treatment Approach. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1565 7. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1566 Cocaine abuse is a serious health problem in many areas of the world, yet there Abstract are no proven effective medications for the treatment of cocaine dependence. Preclinical studies suggest that the reinforcing effect of cocaine that promotes its abuse is mediated by blockade of the presynaptic dopamine transporter. This results in increased dopamine activity in the mesolimbic or meso-accumbens dopamine reward system of brain. Development of new medications to treat cocaine dependence has focused on manipulation of this dopamine system, either 1548 Gorelick et al. by direct action on dopamine binding sites (transporter or receptors) or indirectly by affecting other neurotransmitter systems that modulate the dopamine system. In principle, a medication could act via one of three mechanisms: (i) as a substitute for cocaine by producing similar dopamine effects; (ii) as a cocaine antagonist by blocking the binding of cocaine to the dopamine transporter; or (iii) as a modulator of cocaine effects by acting at other than the cocaine binding site. The US National Institute on Drug Abuse has a Clinical Research Efficacy Screening Trial (CREST) programme to rapidly screen existing medications. CREST identified four medications warranting phase II controlled clinical trials: cabergoline, reserpine, sertraline and tiagabine. In addition, disulfiram and selegiline (deprenyl) have been effective and well tolerated in phase II trials. However, selegiline was found ineffective in a recent phase III trial. Promising existing medications probably act via the first or third aforementioned mechanisms. Sustained-release formulations of stimulants such as methylphenidate and amfetamine (amphetamine) have shown promise in a stimulant substitution approach. Disulfiram and selegiline increase brain dopamine concentrations by inhibition of dopamine-catabolising enzymes (dopamine-β-hydroxylase and monoamine oxidase B, respectively). Cabergoline is a direct dopamine receptor agonist, while reserpine depletes presynaptic stores of dopamine (as well as norepinephrine and serotonin). Sertraline, baclofen and vigabatrin indirectly reduce dopamine activity by increasing activity of neurotransmitters (serotonin and GABA) that inhibit dopamine activity. Promising new medications act via the second or third aforementioned mechanisms. Vanoxerine is a long-acting inhibitor of the dopamine transporter which blocks cocaine binding and reduces cocaine self-administration in animals. Two dopamine receptor ligands that reduce cocaine self-administration in animals are also undergoing phase I human safety trials. Adrogolide is a selective dopamine D1 receptor agonist; BP 897 is a D3 receptor partial agonist. A pharmacokinetic approach to treatment would block the entry of cocaine into the brain or enhance its catabolism so that less cocaine reached its site of action. This is being explored in animals using the natural cocaine-metabolising enzyme butyrylcholinesterase (or recombinant versions with enhanced capabilities), catalytic antibodies, and passive or active immunisation to produce anti-cocaine binding antibodies. A recent phase I trial of a ‘cocaine vaccine’ found it to be well tolerated and producing detectable levels of anti-cocaine antibodies for up to 9 months after immunisation. 1. Scope of the Problem spread evenly around the world. Two-thirds (67.9%) of cocaine users live in the Americas (47% in North Cocaine use and misuse represent a significant America) and another fifth (20.9%) in Western Euglobal public health problem. The United Nations rope. In contrast, only 3% live in Asia and Oceania. Drug Control Program (UNDCP) estimates that coEspecially detailed information about the extent caine use affects about 13.4 million people (0.3% of of cocaine use and its consequences is available the global population above age 14 years), making it from the US. The National Household Survey on the second most common illegal drug of abuse in terms of treatment demand.[1] This problem is not Drug Abuse[2] estimated in 2001 that 27 788 000  2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (14) Management of Cocaine Abuse 1549 Americans had used cocaine at least once in their ance coverage and price resistance by government funders. lifetime, 4 186 000 had used it in the past year, 1 676 000 had used it in the past month and 756 000 This article describes the potential leads to effective medication provided by the increasing knowwere dependent on cocaine (by US psychiatric criteledge of the neuropharmacology of cocaine, and ria[3]). These estimates are based on interviews with then briefly reviews those medications currently a stratified random sample of 68 929 non-instituundergoing clinical evaluation. tionalised individuals 12 years or older designed to be representative of the US population. That same 2. Approaches to the Problem year a survey of over 500 acute care hospitals estimated that 193 034 cocaine-using patients visited hospital emergency departments in 2001, a rate of 2.1 Pharmacological Strategies 76 visits per 100 000 population.[4] A 1999 survey of In principle, at least four pharmacological appublically funded substance abuse treatment proproaches might be useful in the treatment of cocaine grammes in the US found almost a quarter of a dependence.[6,7] First, substitution treatment with a million (218 311) patients seeking treatment for cocross-tolerant stimulant might suppress withdrawal caine abuse.[5] In addition to the direct effects of symptoms and cocaine craving and/or make patients cocaine, cocaine use contributes to other health tolerant to acute reinforcing effects of cocaine. This problems, such as the spread of infectious diseases is analogous to methadone maintenance treatment (e.g. HIV, hepatitis C and tuberculosis). for heroin dependence or nicotine replacement therThese epidemiological data illustrate the continuapy for tobacco dependence. Compounds that mimic ing need for effective treatment for cocaine dependthe effects of cocaine should have a slow onset of ence. More than two dozen medications developed action (and slow binding to site of action) to miniand marketed for other indications have been evalumise substance abuse liability.[10] Secondly, an anated as treatment for cocaine dependence (for retagonist medication that blocks the binding of coviews, see Gorelick[6,7] and de Lima et al.[8]). Yet, caine to its site of action might lead to extinction of after almost two decades of research, there is still no cocaine-taking behaviour because cocaine would no well established, effective medication for the treatlonger be rewarding. This is analogous to naltrexone ment of cocaine dependence, nor is any medication treatment for heroin dependence (naltrexone being a approved for this indication by any national medicalong-acting antagonist at the opioid μ receptor at tions regulatory authority (such as the US FDA). which heroin acts). Thirdly, a medication might act One factor contributing to this lack is the relatively at other sites to functionally antagonise the effects of small amount of drug development activity for this cocaine, leading to a reduction of reinforcing effects indication by pharmaceutical companies, especially of or craving for cocaine. Because cocaine is considlarge multinational companies. In addition to perered to exert its reinforcing effect primarily by inceived inadequacy of the science base, several marcreasing dopamine activity in the brain mesocorket barriers have been identified as contributing to ticolimbic ‘reward’ circuit, this approach might be the dearth of activity by pharmaceutical compaimplemented by influencing brain dopamine acnies:[9] (i) the small and uncertain market for cocaine tivity, either by direct action on dopamine binding dependence pharmacotherapy, because of uncertain sites (see section 3.1) or by affecting other neuromarket penetration and poor patient compliance; (ii) transmitters that modulate dopamine activity (see a substance abuse treatment system that limits acsection 3.2).[11,12] This is analogous to naltrexone cess to the market because of limited physician treatment for alcoholism (alcohol does not act diinvolvement and anti-medication attitudes among rectly on the opioid μ receptors blocked by naltrexnon-physician clinicians; and (iii) limited and uncerone, but its effects are influenced by endogenous tain payment for medication because of poor insuropioid activity). Fourthly, cocaine pharmacokinetics  2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (14) 1550 Gorelick et al. could be altered so that less drug reached the brain taking. These are triggers that can provoke relapse to or remained at its site(s) of action in the brain (see drug taking in humans. section 6). 3. The conditioned place preference model uses Preclinical research has focused on several apPavlovian conditioning to model drug craving (for proaches to these goals: (i) development of more review, see Tzschentke[16]). Animals are tested selective ligands for the presynaptic dopamine (when free of drug) to determine whether they prefer transporter, the presumed major site of action for an environment in which they previously expericocaine in producing dependence, and for the severenced drug as compared with another environment. al subtypes of dopamine receptors; (ii) manipulation 4. The drug discrimination model assesses the deof other neurotransmitter systems that influence the gree to which the subjective effects of one drug dopaminergic reward system; (iii) prevention or resemble the subjective effects of another drug (for amelioration of consequences of actions of cocaine; review, see Colpaert[17]). The animal is trained to and (iv) alteration of cocaine pharmacokinetics to make one response when drugged (e.g. with coreduce brain concentrations. caine) and another when given inactive vehicle. It is used in anti-addiction drug development to evaluate 2.2 Animal Models whether a putative therapeutic agent enhances or diminishes the overall subjective state induced by Preclinical animal models of cocaine dependence the addictive drug (e.g. cocaine). and relapse are used to screen for potential clinically 5. The electrical brain stimulation reward model effective anti-addiction medications. The true preassesses the degree of drug-induced enhancement of dictive validity of any animal model is unknown brain reward in animals trained to respond for elecuntil an effective treatment medication is available trical stimulation of specific brain-reward loci, such as a ‘gold standard’. as the ventral tegmental area, medial forebrain bunThe following six behavioural models are comdle, and nucleus accumbens.[18] This model is useful monly used in preclinical research to develop new both to screen compounds for potential anti-addicmedications for the treatment of cocaine (and other tive therapeutic properties and, conversely, to screen drug) dependence.[13] compounds for potential reward-enhancing proper1. Drug self-administration is the model with the ties, which might be predictive of addictive potenmost face validity for human drug taking.[14] Laboratial. tory animals will work to self-administer addictive 6. The behavioural sensitisation (sometimes termed drugs such as cocaine by a variety of routes of reverse tolerance) model refers to the progressive administration. In a variant of this model, animals increase of behavioural responses to psychostimuwill work to receive a sensory stimulus previously lants that develops during their repeated administraassociated with drug administration (so-called tion, an effect that persists long after drug withdrawsecond-order reinforcement model). This has been al.[19,20] Locomotor sensitisation in rodents has been considered an animal model of drug seeking. used as an animal model of the progressive intensifi2. The reinstatement model is considered a model of cation of drug-induced reward and/or incentive morelapse to drug use after abstinence (for review, see tivation,[21] the latter perhaps relating to drug cravShaham et al.[15]). Animals are trained to stable drug ing and relapse. self-administration behaviour, and then the drugtaking behaviour is completely extinguished. Re3. Drug Development Strategies lapse to drug-taking behaviour is then provoked by exposure to external stimuli. Three types of external A wide variety of compounds have been evalustimuli reliably trigger relapse in this model – a ated for therapeutic potential, based upon current single ‘free’ administration of drug, stress, or enviknowledge (or belief) about the brain mechanisms, ronmental stimuli previously associated with drug loci and neurotransmitter systems underlying drug  2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (14) Management of Cocaine Abuse 1551 taking, drug seeking and/or relapse. A promising animals self-administering intravenous cocaine apcompound is considered one that reduces effects of pear to do so in order to maintain nucleus accumcocaine in animal models (e.g. self-administration, bens dopamine levels within a set range, with deconditioned place preference, reinstatement of drug creased nucleus accumbens dopamine triggering votaking) at doses that do not disrupt other behaviours. litional self-administrations and increased nucleus A promising compound should preferably not itself accumbens dopamine correlating with behavioural be self-administered, suggesting that it has low indices of receipt of drug reward. Therefore, much abuse liability. preclinical research has been devoted to pharmacotherapeutic strategies targeted on this dopamine system. 3.1 Direct Action on the Dopamine System The addictive qualities of cocaine are believed to 3.1.1 Compounds Targeting the Dopamine Transporter be mediated primarily by its enhancement of activity in the meso-accumbens dopamine system of the Primate, including human, studies show a posibrain. This enhancement occurs by cocaine binding tive correlation between dopamine transporter occuto presynaptic dopamine transporters and blocking pancy by cocaine and the positive reinforcing effects the reuptake of dopamine, resulting in more dopof cocaine, with at least 50% occupancy needed to amine remaining in the synapse (for review, see produce an effect.[23,24] Reduction of cocaine selfGardner,[14] Wise and Gardner[22]). Evidence that administration in animals by dopamine transporter this action mediates rewarding and reinforcing efblockers is also associated with their degree of transfects of cocaine includes the facts that: (i) brainporter occupancy, with at least 50% occupancy restimulation reward is elicited specifically from quired to show an effect.[23] dopaminergic loci within the meso-accumbens dopThese findings suggest the potential of dopamine amine system; (ii) dopamine antagonists selectively transporter blockers[25] with slow onset and long inhibit brain-stimulation reward at doses that have duration of action to minimise abuse liability. no effect on motor performance; (iii) cocaine potenSelectivity in blocking the cocaine binding site withtiates the rewarding effects of brain-stimulation reout affecting the dopamine site (thereby leaving ward; (iv) the potencies of cocaine and cocaine-like normal dopamine reuptake) is also desirable in drugs in animal self-administration studies correlate minimising abuse liability.[26] A wide variety of highly with their potencies to bind to the dopamine chemical structures have been used as templates in transporter but not to other presynaptic and postdeveloping such a compound. These include cosynaptic binding sites; (v) cocaine is preferentially caine analogues,[27] methylphenidate analogues,[26] self-administered by animals into dopaminergic tropanes,[28] benzatropine (benztropine) anabrain loci as opposed to other brain loci; (vi) doplogues,[29] substituted piperazines[30] and inamine-selective lesions of the nucleus accumbens danamines.[31] attenuate the rewarding effects of intravenous coDrugs that rapidly enter the brain and quickly caine; (vii) dopaminergically selective pharmacoelevate nucleus accumbens dopamine levels appear logical blockade enhances intravenous cocaine selfto have high addictive potential.[32] Thus, the best administration at low doses (a compensatory effect, candidates are compounds with slow onset and/or similar to the effect of decreasing the amount of prolonged duration of action, which appear to confer cocaine per infusion) and completely blocks it at lower addictive potential. Table I lists promising higher doses; (viii) addictive drugs, including cocompounds in this class and their effects in various caine, preferentially increase dopamine levels in the animal models. One compound from this class, nucleus accumbens as opposed to other brain loci; vanoxerine (GBR 12909), is currently undergoing (ix) self-administered cocaine preferentially eleclinical evaluation (see section 5). vates nucleus accumbens dopamine levels; and (x)  2004 Adis Data Information BV. All rights reserved. Drugs 2004; 64 (14) 1552 Gorelick et al. Table I. Potential anti-cocaine addiction compounds with direct action on the dopamine system Compound Mechanism of action Effects SelfReferences on cocaine action other administered?