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Rational Development of AddictionPharmacotherapies: Successes, Failures,and Prospects R. Christopher Pierce1, Charles P. O’Brien2, Paul J. Kenny3, and Louk J. M. J. Vanderschuren4,5 1Center for Neurobiology and Behavior, Department of Psychiatry, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104 2Treatment Research Center Department of Psychiatry, University of Pennsylvania School of Medicine, 3Department of Molecular Therapeutics, The Scripps Research Institute—Florida, Jupiter, 4Rudolf Magnus Institute of Neuroscience, Department of Neuroscience and Pharmacology, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands 5Department of Animals in Science and Society, Division of Behavioural Neuroscience, Faculty of Veterinary Medicine, Utrecht University, Yalelaan 2, 3584 CM Utrecht,The Netherlands Correspondence: [email protected] There are currently effective, U.S. Food and Drug Administration (FDA)-approved therapiesfor alcohol, nicotine, and opioid addiction. In some cases these therapeutics were rationallydesigned and tested using a combination of various animal models of addiction. In manycases, however, effective drug therapies for addiction were derived from the testing of com-pounds developed for other CNS disorders (e.g., analgesics and antidepressants), which weretested clinically in the absence of prior animal research using addiction models. This articlewill review the development of eight compounds that are currently most effective in thetreatment of alcohol, opioid, and nicotine addiction with an emphasis on pharmacologicalmechanisms as well as the utility of animal models of addiction in the development of thesetherapeutics. In contrast to these successes, animal research has identified a number ofpromising medications for the treatment of psychostimulant addiction, none of whichhave proven to be effective clinically. This raises questions about the validity of currentanimal models of psychostimulant addiction. A specific example of an apparently promisingpharmacotherapeutic for cocaine addiction (the D1 dopamine receptor antagonist ecopi-pam) that failed clinically will be examined to determine if this truly represents a challenge tothe predictive validity of current models of cocaine addiction. In addition, the developmentof promising cocaine addiction therapeutics derived from animal research will be reviewed.
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The earliest references to animal models of thedevelopmentofmorerecentaddictionphar- addiction in the literature all referred to macotherapies, the first successes came from work on opioids, mainly morphine. Research drugs that were developed for other purposes.
using animal models prior to 1960 used the Forexample, methadone, the first trulysuccessful term addiction loosely given that the drug of addiction therapeutic, was originally developed abuse was experimenter delivered. For example, at Hoechst in the 1930s as an analgesic. Metha- Plant and Pierce (1928) administered very done was tested for analgesic efficacy by scientists high doses of morphine to dogs daily for 2 –3 at Lilly and Wellcome in the 1940s (Scott et al.
months. Indeed, the doses chosen were toxic 1947; Thorp et al. 1947). In early papers, metha- in some cases as the investigtors reported that done was sometimes spelled methadon and also “two of our animals died in convulsions on dos- was called dolophine. As an aside, it has been es of 190 and 220 mg. per kilogram.” At that erroneously reported that methadone, which time, the severity of the withdrawal syndrome was developed in Germany, was originally named was thought to be the primary factor contribut- after Hitler (i.e., adolophine). Then as now, a ma- ing to relapse among opioid-dependent hu- jor goal of opioid research was to identify effec- mans. Therefore, Plant and Pierce sought to ex- tive analgesics that lacked an addiction liability.
amine and characterize opioid withdrawal in Therefore, methadone was tested by a group of animals. Following cessation of morphine treat- prominent behavioral pharmacologists whose ment, they noted that “five of our dogs showed findings were summed up as follows: “we believe that unlessthe manufacture and use of methadon first week of withdrawal, in that they became are controlled addiction to it will become a seri- very cross” and “one animal died in convulsions ous public health problem” (Isbell et al. 1947).
on the third day of withdrawal” (Plant and This conclusion was based in part on reports Pierce 1928). These authors summed up their from their patients (recovering addicts) such as: observations as follows: “The period of addic- “That is great stuff. I wouldn’t have believed it tion in dogs has given a picture that follows possible for a synthetic drug to be so like mor- closely the description of addiction in man [in- phine. Can you get it outside? Will it be put cluding vomiting, constipation, hypersensitive- under the narcotic laws? I wish I could get it to ness, scratching, irritability, and decrease in nar- kick my next habit.” The investigators also noted cotic action of the drug].” Note that Pierce and that “methadon prevented the appearance of Plant defined addiction as opioid withdrawal signs of physical dependence in 12 men who and tolerance (Plant and Pierce 1928).
had been proved to be addicted to morphine” The first valid animal model of addiction (Isbell et al. 1947). These observations suggested was developed in the early 1960s. As a first step that methadone might be used to treat opioid toward developing a model in which animals addiction. This idea was not tested until the self-administer drugs of abuse, two water-de- 1960s, with the publication of the landmark prived rhesus monkeys were trained to press a study by Dole and Nyswander (1965), which lever to receive intravenous infusions of saline showed that methadone relieved “narcotic hun- (Clark et al. 1961). The investigators also showed ger” and produced tolerance such that the eu- that saline self-administration could be extin- phoric effect of heroin was substantially blunted.
guished and brought under stimulus control (i.e., the monkeys would lever press for light both full m opioid receptor agonists with sub- cues previously paired with the saline infusions) stantial addiction liabilities, methadone is a (Clark et al. 1961). Subsequently, it was shown preferable addiction therapeutic because of a that rats (Weeks 1962) and monkeys (Thomp- substantially longer half-life and higher oral son and Schuster 1964) would self-administer bioavailability. Methadone distribution is re- stricted to clinics to ensure that the drug is Although results from the self-administra- taken orally, which obviates withdrawal and tion paradigm have contributed significantly to maintains tolerance in the absence of euphoria.
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Development of Addiction Pharmacotherapies Methadone is not prescribed for home use be- agonist, perhaps homotaurine derivatives might cause of the legitimate fear that, in the absence serve as alcohol replacement therapies (Bois- of monitoring, the drug will be solubilized and mare et al. 1984). Indeed, calcium bis acetylho- administered intravenously, thereby producing motaurine (acamprosate) significantly reduced a high roughly equivalent to morphine or her- the voluntary intake of alcohol by rats (Boismare oin administered by the same route. In the case et al. 1984). Based on this result, acamprosate of methadone, the clinical trial came before an- was tested in a double-blind placebo-controlled imal studies. Over the years, a number of animal clinical trial with the success criterion defined as studies have confirmed that methadone pre- alcohol abstinence following three months of vents opioid withdrawal and blunts relapse in outpatient treatment. Results indicated that 20 animal models of craving (Goode 1971; Jones of 33 patients receiving acamprosate remained alcohol-free compared to 12 of 37 subjects re- Although there is no question that metha- ceiving placebo (Lhuintre et al. 1985). The effi- done has proven to be effective in the treatment cacy of acamprosate as an effective alcoholism of opioid addiction, there are several problems therapeutic has been repeatedly replicated (Ma- with the methadone clinic model. Primarily, the son and Heyser 2010). Acamprosate has been distance to the closest clinic may render daily used for the treatment of alcoholism in Europe clinic visits unfeasible. For some patients living since 1989. Surprisingly, the precise mechanism in close proximity to a clinic, the stigma as- of action of acamprosate remains unclear. Be- sociated with daily visits to a methadone clinic cause of the ambiguity of the drug’s mecha- reduces compliance. A clever pharmacological nism of action, the U.S. FDA delayed approval strategy was recently developed to produce an of acamprosate (marketed as Campral) until opioid addiction therapeutic that could be taken 2004. In the U.S., acamprosate is currently the at the convenience of the patient. It was noted that first-line pharmacotherapy for alcoholism.
opioid agonists have good oral bioavailability, Although acamprosate was targeted for the whereas the opioid receptor antagonist naloxone treatment of alcoholism because of presumed does not. Thus, if a pill contains both compounds effects on GABA and taurine transmission, the and is taken orally, the opioid receptor agonist therapeutic effects of this drug appear to be due effect predominates. In contrast, if the therapeu- primarily to effects on glutamate systems. Al- tic is administered intravenously the antagonist though initial reports suggested that acampro- would block the agonist effect. This strategy led to sate is an NMDA receptor antagonist, subse- the development of Suboxone, which is a combi- quent work indicated that acamprosate acts as nation of buprenorphine and naloxone. Bupre- a partial agonist at spermidine sites on NMDA norphine, which was developed by Reckitt and receptors (Dahchour and De Witte 2000). More Colman in the 1970s as an analgesic, was chosen recent evidence revealed that acamprosate also over methadone because it is a partial m opioid is an mGluR5 receptor antagonist (De Witte et receptor agonist which, in contrast to methadone, al. 2005). Alcohol withdrawal is associated with has a low instance of death associated with over- a number of changes in neurotransmission in- dose (Mendelson and Jones 2003). Suboxone was cluding, notably, increased glutamate transmis- approved by the FDA for the treatment of opioid sion in regions of the CNS (Mason and Heyser addiction in 2002 and rapidly became the first- 2010). A growing body of evidence is consistent line treatment for opioid addiction.
with the notion that acamprosate blunts alcoholcraving and withdrawal by normalizing gluta-mate transmission (Heilig and Egli 2006).
Acamprosate, a homotaurine derivative, was developed in France in the 1980s. The rationalewas that because alcohol activates GABAA re- In the early 1970s, receptor binding assays were ceptors and homotaurine is a GABA receptor used to show that “narcotic antagonists” such as Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a012880 2012 by Cold Spring Harbor Laboratory Press
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naloxone bind to specific receptors in the brain.
acts as a punishing agent in the event of relapse Opioid receptor antagonists including naltrex- rather than a therapeutic. Although disulfiram one and naloxone were subsequently tested as continues to be used in the treatment of alco- pharmacotherapies for opioid addiction (Mar- holism, there are concerns related both to the tin et al. 1973). The discovery of endogenous safety and effectiveness of this compound (Hei- opioids and their receptors prompted research into the potential role of opioid peptides in theeffects of many drugs including alcohol. Initial reports suggested that naltrexone and naloxone reduced alcohol preference in hamsters and rats(Ross et al. 1976) and attenuated alcohol rein- The history of nicotine replacement therapies forcement in rhesus monkeys (Altshuler et al.
dates to a letter Dr. Claes Lundgren, a physiol- 1980). Based on these and similar findings, a ogy professor at Lund University, sent to his placebo-controlled, double blind clinical trial friend Ove Ferno¨ at Aktiebolaget Leo pharma- examining the effect of naltrexone on alcohol ceutical company in 1967. Lundgren and his relapse was performed. Results indicated that colleague, Stephan Lichtneckert, suggested oral naloxone cut the relapse rate approximately in nicotine as a substitute for tobacco based on half compared to controls (Volpicelli et al. 1992).
the observation that sailors sometimes switched These results were rapidly replicated, with the from smoking to chewing tobacco without dif- highest rates of abstinence observed in patients ficultly when assigned to submarine duty. Ferno¨ who received both naltrexone and supportive immediately recognized the promise and com- therapy (O’Malley et al. 1992). Numerous trials mercial potential of nicotine replacement and subsequently showed that naltrexone is effective embarked on a research program to design a means to orally administer nicotine with delayed A single nucleotide polymorphism at A118G absorption. The result was nicotine gum. Years (Asn40Asp) in exon I of the m opioid receptor later Ferno¨ reflected on his work as follows: “Put- was identified and shown to triple the potency ting nicotine into chewing gum is not an inven- of b-endorphin at these receptors (Bond et al.
tion. Fixing the nicotine to an ion exchange resin 1998). This polymorphism was shown to be as- and putting that into a chewing gum to enable sociated with alcohol addiction (Bart et al. 2005) the chewer to control the rate of release—that is and individuals with one or two copies of the an invention” (Ferno 1994). Initial clinical trials Asp40 allele treated with naltrexone had signifi- performed in Sweden (Ferno 1973) and London cantly lower rates of relapse than patients homo- (Russell et al. 1976) in the 1970s indicated that zygous for the Asn40 allele (Oslin et al. 2006).
nicotine gum was effective in reducing nicotine Thus, naltrexone treatment of alcoholism is one withdrawal and maintaining smoking absti- of the few examples of a pharmacogenomic ther- nence. A landmark randomized double blind apeutic. Naltrexone, which is marketed as Revia placebo controlled clinical trial published in and Depade, has been used in the treatment of 1982 indicated that smoking abstinence was alcoholism since 1995. In 2006, an extended-re- 47% in the nicotine gum group compared to a lease naltrexone formulation (Vivitrol) was ap- 21% success rate among controls (Jarvis et al.
proved by the U.S. FDA for the treatment of al- 1982). These results led to the approval of nico- tine gum, which Aktiebolaget Leo (now McNeil Disulfiram also is used in the treatment of SB) named Nicorette, by the U.S. FDA in 1984.
alcoholism. However, this drug does not specif- Although nicotine gum remains the most pop- ically target aspects of addiction or withdrawal.
ular form of nicotine replacement therapy, nic- Rather, disulfiram blocks aldehyde dehydroge- otine lozenges, patches, nasal sprays, and inhal- nase resulting in the accumulation of acetalade- ers (including so-called electronic cigarettes) hyde after alcohol ingestion, which produces also are effective in maintaining abstinence an array of aversive symptoms. Thus, disulfiram from tobacco use (Polosa and Benowitz 2011).
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Development of Addiction Pharmacotherapies arette smokers have higher rates of depression history of Nicorette. More recently, a rational that may be exacerbated by nicotine withdrawal strategy led to the development of the partial (Glassman et al. 1990). Double blind placebo nicotinic receptor agonist varenicline for smok- controlled clinical trials revealed that a sus- ing cessation. Nicotinic acetylcholine receptors tained-release formulation of bupropion signif- (nAChRs) are pentameric ligand-gated ions icantly increased the rate of smoking cessation channels composed of combinations of at least (Hurt et al. 1997). Bupropion was approved for seventeen different subunits (Pierce and Ku- the treatment of nicotine addiction in 1997 and maresan 2006). A number of studies indicate is marketed as Zyban. Similar to some other that a4b2 nAChRs, which are the most widely antidepressants, bupropion is a dopamine and expressed subtypes in the brain, play a critical norepinephrine reuptake inhibitor. Interesting- role in nicotine-induced dopamine release and ly, bupropion also is a nAChR antagonist at var- reinforcement (Mineur and Picciotto 2008).
ious subtypes including a4b2 (Slemmer et al.
The a4b2 nAChR partial agonist varenicline 2000), which may account for the effectiveness was developed by Pfizer for smoking cessation.
of bupropion as a smoking cessation agent rel- The rationale being that varenicline might serve the dual purpose of moderately increasing mes-olimbic dopamine levels, which are reduced during nicotine withdrawal, and also blunt nic-otine-induced dopamine release in the event Despite decades of focused research effort, there of relapse (Coe et al. 2005). Animal studies re- are no effective pharmacotherapies for psycho- vealed that varenicline reduced nicotine-in- stimulant addiction. Indeed, a broad range of duced dopamine release in the nucleus accum- drugs targeting multiple CNS transmitter sys- bens (Coe et al. 2005) and inhibited nicotine tems have been tested as treatments for psychosti- self-administration as well as the reinstatement mulant dependence without success (Kampman of nicotine seeking (O’Connor et al. 2010). A et al. 2005). Drugs that modulate dopaminer- randomized double blind clinical trial showed gic transmission were among the first assessed that the smoking abstinence rate with vareni- for the treatment of psychostimulant addic- cline was 44% compared with nearly 18% for tion both in animal studies and clinical trials.
placebo (Gonzales et al. 2006; Jorenby et al.
Dopamine receptors are classified as either D1- 2006). Notably, measures of nicotine withdraw- like or D2-like. There was substantial interest in al and craving also were reduced by varenicline D1-like dopamine receptor antagonists as psy- (Gonzales et al. 2006). Based on these results, chostimulant addiction therapeutics because the U.S. FDA fast tracked approval for vareni- they lack the sometimes serious extrapyrami- cline (Chantix) as a smoking cessation drug, dal side-effects associated with D2-like dopa- mine receptor antagonists (Haney and Speal- The initial varenicline smoking cessation clinical trials used bupropion as a positive con- studies revealed that acute administration of trol. The abstinence rate for bupropion was D1-like dopamine receptor antagonists attenu- nearly 30%, significantly greater than placebo ated the reinforcing effects of cocaine (Romach but substantially lower than varenicline (Gonza- et al. 1999; Platt et al. 2002). However, clinical les et al. 2006; Jorenby et al. 2006). Bupropion, use of a D1-like dopamine receptor antagonist which was developed by Burroughs Wellcome requires repeated administrations. Unfortunate- (now GlaxoSmithKline), was approved for the ly, when humans were maintained on the D1- treatment of depression by the U.S. FDA in 1985.
like dopamine receptor antagonist, ecopipam, A sustained release formulation of bupropion, cocaine self-administration actually increased marketed as Wellbutrin SR, remains a highly (Haney et al. 2001). This finding is consistent successful antidepressant. Antidepressants were with results from rhesus monkeys utilizing tested as smoking cessation agents because cig- continuous drug administration (Kleven and Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a012880 2012 by Cold Spring Harbor Laboratory Press
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Woolverton 1990) and is likely caused by antag- are partial agonists. Clearly, the most successful onist-induced increases in D1 dopamine recep- treatments for addiction involve receptor stim- tor density in the brain (Haney and Spealman ulation, with the primary goal of obviating drug 2008). It is important to emphasize that in the withdrawal. Agonist therapeutics also repro- case of ecopipam the animal and human data duce some of the positive aspects of the drug paralleled one another both when the drug was of abuse (e.g., mood elevation), which enhances administered acutely and repeatedly.
compliance. Partial agonists are particularly ap- pealing because they blunt the psychoactive ef- rationally developed therapeutics for psycho- fects of the drug of abuse in the event of relapse.
stimulant addiction that appear promising. N- Moreover, the risk of overdose is substantially acetylcysteine (NAC), which is used to treat diminished with partial relative to full agonists.
acetaminophen overdose, has been shown to The fact that partial agonists are particularly normalize decreased nucleus accumbens gluta- effective addiction therapeutics raises the ques- mate levels following cocaine self-administra- tion of partial dopamine agonist treatments for tion as well as the reinstatement of cocaine- psychostimulant addiction (Platt et al. 2002).
seeking behavior in rats (Baker et al. 2002, Surprisingly, there is very little research in this 2003). Recent clinical trials show that NAC at- area. Indeed, the only compound tested is the tenuated cocaine use and decreased desire to use D2-like dopamine receptor partial agonist ari- cocaine (LaRowe et al. 2007; Mardikian et al.
piprazole, which is approved for the treatment 2007). Another interesting strategy is the devel- of schizophrenia, depression, and bipolar disor- opment of cocaine vaccines. Active immuniza- der. Aripirazole reduced cocaine reinstatement tion with a cocaine vaccine attenuated cocaine in rats (Feltenstein et al. 2007) and decreased the self-administration as well as the reinstatement discriminative stimulus properties of amphet- of cocaine seeking in rats (Kantak et al. 2000).
amine in a human laboratory study (Lile et al.
Clinical data indicate that the cocaine vaccine, 2005). Initial clinical trial results have been TA-CD, produced selective anticocaine antibod- mixed with one study reporting that aripipra- ies, which blunted the intoxicating effects of zole reduced cocaine craving and use (Meini cocaine (Haney et al. 2010). In these studies in- et al. 2011). In contrast, another clinical trial sufficient immune responses to vaccines is a per- showed that aripiprazole increased the self-ad- sistent issue, which has led to the development ministration of smoked cocaine, apparently to of novel vaccines designed to generate consis- compensate for decreased subjective effects of tently high antibody titers (Wee et al. 2011).
cocaine (Haney et al. 2011). These experiments In terms of the validity of animal models highlight both the promise of partial agonists in of psychostimulant addiction, we note that the the treatment of psychostimulant addiction and preclinical and clinical data are consistent when the persistent frustration in developing clearly the animal model is drug self-administration(Haney and Spealman 2008). Moreover, twoof the more promising cocaine addiction ther- Table 1. Therapeutics used in the treatment of addic- apeutics (NAC and cocaine vaccines) were test- ed primarily with self-administration models of We have reviewed the development of the eight main compounds currently used in the treat- ment of addictions. As outlined in Table 1, two of these drugs are antagonists, one is a trans- porter inhibitor, two are full agonists, and three Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a012880 2012 by Cold Spring Harbor Laboratory Press
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system: The final common pathway for the reinforcing Cite this article as Cold Spring Harb Perspect Med doi: 10.1101/cshperspect.a012880 2012 by Cold Spring Harbor Laboratory Press

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