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Evidence-Based Treatments of Addiction Author(s): Charles P. O'Brien Source: Philosophical Transactions: Biological Sciences, Vol. 363, No. 1507, The Neurobiology of Addiction: New Vistas (Oct. 12, 2008), pp. 3277-3286 Published by: The Royal Society Stable URL: http://www.jstor.org/stable/20208741 . Accessed: 05/12/2014 15:41

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PHILOSOPHICAL TRANSACTIONS

_of-?TT^ PhiL Trans' R' Soc' B (2008) 363' 3277~3286

THE ROYAL 4\ doi:10.1098/rstb.2008.0105 SOCIETY JAJJ Published online 18 July 2008

Review

Evidence-based treatments of addiction Charles P. O'Brien*

Department of Psychiatry, University of Pennsylvania, 3900 Chestnut Street, Philadelphia, PA 19104-6178, USA

Both pharmacotherapy and behavioural treatment are required to relieve the symptoms of addictive disorders. This paper reviews the evidence for the benefits of pharmacotherapy and discusses mechanisms where possible. Animal models of addiction have led to some medications that are effective in reducing symptoms and improving function but they do not produce a cure. Addiction is a chronic disease that tends to recur when treatment is stopped; thus, long-term treatment is recommended.

Keywords: addiction; relapse; withdrawal; endophenotype

1. INTRODUCTION Most theories of drug-addiction mechanisms have been based on animal models and, until recently, these theories have made the assumption that all subjects are alike in their responses to drugs (Deroche-Gamonet et ah 2004). In reality, human subjects are quite variable in how they respond to drugs. Moreover, data from the studies of non-human primates indicate that genetic variation is also important in other higher species. Drugs that demonstrate rewarding properties in animals also tend to be abused by humans, but only by a relatively small percentage of those humans

exposed (table 1). The most obvious effects of chronic

drug use are tolerance and physiological dependence and these phenomena translate well from animals to humans. However, tolerance and its complement,

physiological dependence, are normal reactions and do not imply addiction.

At the clinical level, the theoretical model of addiction is similar to that of an infectious disease such as tuberculosis. The development of addiction depends on

the interaction of agent, host and environment (figure 1). The progression from use to abuse to addiction is determined by this interaction. An understanding of addiction requires addressing all three of these classes of variables. Treatment and prevention efforts that fail to consider all three have not been successful. Therefore, it follows that pharmacological treatments must be imbedded in a comprehensive rehabilitation programme that addresses these variables to the extent possible.

While first use is under cognitive control, albeit usually influenced by social pressures, the user with genetic vulnerability will progress to a stage of compulsive use. At this point, volitional control is greatly diminished. As an

example, the reader need only think of friends and relatives who repeatedly relapse to compulsive cigarette smoking despite the knowledge of the hazards to their

*[email protected]

One contribution of 17 to a Discussion Meeting Issue 'The

neurobiology of addiction: new vistas'.

health and despite having expressed a conscious desire to abstain from smoking. At the neuronal level, this compulsive relapse suggests plasticity, a memory trace. No treatment has even been theorized, however, that could selectively 'erase' addiction memories

while not impairing adaptive memories and new

memory formation.

The mechanisms involved in the production of

euphoria vary according to the pharmacological category of the drug and have been discussed in earlier

papers of this issue. All have in common the activation of brain reward pathways that have evolved to ensure

survival, which largely explains the compelling nature of

drug reward. The activation of the reward system produces reinforcement of drug acquisition behaviours and associations between environmental cues that signal the arrival of drug effects or drug withdrawal symptoms as drugs disappear from the body through metabolism. The environmental stimuli that become neurologically associated with drug effects are variable and may include

persons, places and situations. Treatment approaches, therefore, have attempted to diminish the strength of these conditioned reflexes that lead to relapse and facilitate the development of new memories that

produce natural rewards. In this paper, pharmacological approaches that reduce aversive effects of drug cessation, reduce drug reward or reduce drug desire or craving will be discussed. Behavioural approaches are also necessary in combination with medication, but will not be discussed here.

The modern definition of addiction emphasizes uncontrolled drug use rather than tolerance and

physiological dependence as essential features of the disorder. It is generally recognized that addiction has

strong hereditary influences and once established, it behaves as a chronic brain disorder with relapses and remissions over the long term (McLellan et ah 2000). The diagnostic criteria, which are signs of compulsive drug seeking, are the same for all drug categories (ethanol, opioids, stimulants, sedatives, nicotine and

cannabinoids), even though the mechanisms for

activating the reward system are quite different.

3277 This journal is ? 2008 The Royal Society

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3278 C. P. O'Brien Review. Evidence-based treatments of addiction

Table 1. In a relatively small percentage of those humans

exposed, the risk of becoming addicted to nicotine was

approximately double the risk of cocaine. (By other

measures, cocaine has more powerful pharmacological effects than nicotine and this implies a role for host

(genetics) and environmental factors. Source: Anthony etal. (1994).)

risk of addiction

ever used (%) dependence (%) risk (%)

tobacco 75.6 24.1 31.9

cocaine 16.2 2.7 16.7

heroin 1.5 0.4 23.1

alcohol 91.5 14.1 15.4 cannabis 46.3 4.2 9.1

With active drug use, euphoria alternates with

craving to establish a cycle of addiction that becomes

increasingly entrenched and uncontrollable, despite medical and psychosocial hazards. Craving (a strong desire for a drug) can be precipitated by environmental

cues, stress or exposure to a small dose of the addictive

agent (priming). Cue-induced craving has been associ ated with limbic system activation in a large number of human neuroimaging studies using positron emission

tomography and functional magnetic resonance

imaging (Childress et al. 1999), and this pernicious and persistent phenomenon might be reversed by agents that dampen limbic activation. Human neuroimaging studies also demonstrate reductions in frontal lobe

metabolism with stimulant, opioid and alcohol depen dence, thus providing a possible explanation for deficiencies in behavioural inhibition among addicts

(Franklin et al. 2002). Numerous animal studies indicate that chronic exposure to addictive agents disturbs reward function (Koob et al. 2004). These

findings support a biological basis for addiction and are

guiding neuronal strategies that target specific clinical

components of addiction. The clinical data fit best when addiction is

considered to be a syndrome characterized by compul sive drug-seeking behaviour that impairs psychosocial functioning or health. Even after detoxification and

long periods of abstinence, relapse frequently occurs

despite sincere efforts to avoid further drug use. People or situations previously associated with drug use

elicit involuntary reactions and may provoke relapse (Wikler 1973; O'Brien et al. 1975). The biological

mechanisms for these reflex patterns are suggested by the data from animal models at the neurochemical and

molecular levels, as discussed in this issue. At the clinical level, conditioned cues produce intense craving through involuntary limbic activation, leading to self destructive drug use even after long periods of abstinence. In cocaine addicts, even a brief exposure (33 ms) to drug cues evokes limbic system activation

(Childress et al. 2008). A key point for the clinician to

realize is that the proneness to relapse is based on

changes in brain function, which continue for months or years after the last use of the drug. Of course, these

changes in brain function interact with environmental factors such as social stress and situational triggers.

,, + outcomes: agent (drug) ~

no use

?>

host ?r> S use

abuse environment

_^

' addiction

Figure 1. Addiction: resultant of interacting variables. Each

class of variables can increase or decrease the risk of

addiction. For example, high drug availability and low price (agent) would increase the risk, but genetic factors (host) or

opportunities for other pleasures in life (environment) could

offset the increased risk. Treatment approaches must also

address all of these variables.

If tolerance and withdrawal symptoms were the

only elements of addictive illness, treatment would

simply consist of detoxification, a process that allows the body to cleanse itself while receiving descending doses of a medication that reduces withdrawal

symptoms (O'Brien 2006). If drug taking does not

resume, homeostatic mechanisms will gradually readapt to the absence of the drug (LeBlanc et ah

1969) and tolerance will be diminished or lost. We now know that detoxification is, at best, a first step in treatment and that simply achieving a drug-free state is not the most significant accomplishment.

The more difficult aspect is the prevention of relapse to drug-taking behaviour.

2. DETOXIFICATION It is unfortunate that the majority of drug-dependent persons are merely treated with detoxification and little or no long-term follow-up care. This is not logical, but it is a fact of the current health-care system in the USA

(McLellan et ah 2005). Detoxification is actually performed by the patient's own metabolic processes. Thus, it can be accomplished voluntarily (although not

necessarily safely) through sheer will power by ceasing drug use or accomplished involuntarily when an addict is incarcerated or placed in a treatment programme

where access to drugs is denied. The withdrawal

syndrome from opiate addiction can be very uncom

fortable, but it is not life-threatening unless the patient has pre-existing medical problems. The symptoms consist of sweating, muscle aches, cramps, nausea,

diarrhoea, vomiting, lachrymation, rhinorrhoea, tre

mors, tachycardia and other signs of autonomie nervous system hyperactivity. The discomfort has been compared to a bad case of the flu. Several sorts of treatment of these symptoms are available. With drawal from sedatives, alcohol and stimulants will be considered below.

Replacing the drug of dependence or using another

drug in the same pharmacological category in gradually decreasing doses is a direct way to block withdrawal

symptoms. As in all forms of detoxification, transfer from a short-acting drug such as heroin to a longer acting drug such as methadone provides a smooth transition to the drug-free state. By appropriate dosing, detoxification can be achieved with minimal discom fort. A recent innovation for opiate dependence involves using the partial agonist buprenorphine as a

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Review. Evidence-based treatments of addiction C. P. O'Brien 3279

transition to the drug-free state. The patient can be switched from dependence on heroin or methadone to

buprenorphine, which is then stopped with few or no

withdrawal symptoms. The same principles apply in the detoxification from

nicotine dependence using nicotine replacement and from sedative (ethanol) dependence using another sedative such as a benzodiazepine. Stimulant (cocaine and amphetamine) withdrawal does not usually require medication, but rapid return to drug use is

frequent. A medication that reduces stimulant with drawal symptoms such as modafinil (see ?3d) may reduce relapse.

In the treatment of patients dependent on alcohol or other sedatives, appropriate detoxification is critical because the sedative withdrawal syndrome is potentially life-threatening. Whereas the acute administration of alcohol and sedatives increases y-aminobutyric acid

(GABA) and decreases glutamate activation, the reverse occurs with chronic exposure, producing a GABA

deficiency state and glutamate hyperactivity that increases the risk of seizures during withdrawal (Dackis & O'Brien

2003). There is evidence that sensitization to alcohol withdrawal symptoms occurs, so repeated withdrawals become progressively more severe. The treatment of withdrawal symptoms with benzodiazepines may retard the sensitization process (Brown et al. 1988). Benzo

diazepines effectively suppress the sedative withdrawal

syndrome, and with proper attention to electrolytes and

vitamins, the vast majority of patients can be safely eased into the alcohol-abstinent state in preparation for a long term rehabilitation programme.

Symptoms of nicotine withdrawal can be diminished

by nicotine replacement therapy through chewing gum, patch or nasal spray. Nicotine gum and nicotine patch do not achieve the peak plasma levels seen with

cigarettes, and thus they do not produce the same

magnitude of nicotine's pleasant effects. Comparisons with placebo treatment show large benefits for nicotine

replacement at six weeks, but the advantage diminishes with time.

The withdrawal syndrome from stimulants such as cocaine and amphetamine consists of hypersomnia, hyperphagia, bradycardia and a number of depressive symptoms that usually resolve over several days.

Interestingly, cocaine withdrawal symptoms appear to be predictive of treatment outcome. Kampman et al.

(2001) measured cocaine withdrawal symptoms in several trials using the Cocaine Selective Severity

Assessment. They found that more withdrawal symp toms in subjects at the start of treatment accurately predicted poorer outcome following treatment. Given these findings, the pharmacological reversal of cocaine withdrawal symptoms with agents such as modafinil

may improve clinical outcome (Dackis et al. 2005). Heavy marijuana users also develop a physical

dependence and may present for treatment when they are unable to stop daily use on their own (Haney et al.

2004). The symptoms consist of irritability, anxiety, marijuana craving, decreased quality and quantity of

sleep and decreased food intake. Various medications have been used to alleviate these symptoms and some clinicians have reported success with dronabinol, the

oral form of delta-9-tetrahydrocannabinol, but con trolled clinical trials are lacking.

(a) Detoxification by the suppression of autonomie hyperactivity For opiate detoxification, methadone is not always available due to legal limitations and buprenorphine

may be undesirable because it is a partial opiate agonist. Clonidine, an a2-agonist, reverses opiate withdrawal by acting on autoreceptors producing presynaptic inhibition of locus coeruleus activity. This

effectively reduces the large adrenergic component of

opioid withdrawal (Gerra et ah 2001). Lofexidine, a similar medication, has been successfully used in the

UK as an aid to opiate detoxification and is in clinical trials in the USA. Thus, clonidine and lofexidine have found a place in the clinic for treating the

symptoms of opioid withdrawal. Very rapid detoxifica tion under general anaesthesia has also been used, but there are no data to support an advantage over standard treatment.

3. PRINCIPLES OF RELAPSE PREVENTION As a chronic disorder, addiction requires long-term treatment that should be measured in months and

years. The strategies for preventing relapse have

traditionally involved counselling or psychotherapy and, more recently, include pharmacotherapies that

target clinical components of addictive illness. When

psychiatric disorders co-occur with addiction, these disorders must be treated concomitantly and preferably by the same treatment team. This paper focuses on the medication for the primary addictive disorder, but

counselling and medication of co-occurring disorders are equally important.

The treatment of addicted patients must always be individualized. This requires a complete evaluation so that coexisting medical, psychiatric and social pro blems can be addressed as needed. There are, however, common elements to treatment programmes. Treat

ments for addictive disorders may begin with detox

ification, but the key to successful treatment is the

long-term prevention of relapse by behavioural and

pharmacological means. Usually, these approaches should be combined; insistence on behavioural treat

ment alone and without medication remains one of the chief weaknesses in many treatment programmes. The

types of medication that have shown efficacy in combination with behavioural therapy in the preven tion of relapse can be classified as agonists (including partial agonists), antagonists and anti-craving medi

cations that work through a variety of mechanisms. Vaccines are an experimental approach that is currently being evaluated in clinical trials (Martell et ah 2005; Sofuoglu & Kosten 2006).

(a) Agonists and partial agonists The first use of an agonist for the treatment of addiction was reported in the 1960s by Vincent Dole and colleagues who demonstrated that daily metha done could transform the behaviour of opiate addicts, reducing craving and permitting the addict to engage in productive activities (Dole & Nyswander 1965).

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3280 C. P. O'Brien Review. Evidence-based treatments of addiction

Opiates (which are d?riv?tes of the opium poppy) and

opioids (which may be peptides or synthetic compounds) activate opiate receptors that are located

throughout the nervous system, as well as in the

endocrine, cardiovascular, gastrointestinal and other

systems of the body. The behavioural effects of opiates include intense euphoria and calming. The user becomes satisfied and relaxed, a state quite different from the euphoric excitement produced by stimulants. In the presence of pain, opiates and opioids produce analgesia, so there is both relaxation and relief of severe pain.

While opioids produce prompt physiological depen dence with repeated use, addiction seldom occurs in

patients receiving opioids for the relief of severe pain (Adams et al. 2006). Of course, prescription opiates and opioids can be abused and it is the responsibility of the physician to provide humane pain relief to patients in need while exercising caution to reduce the likelihood that the prescribed medication will be obtained by deliberate abusers. The use of heroin or other opiates purchased on the street for the

purpose of obtaining a 'high' has a significant risk of

producing addiction. Detoxification is not applicable to those opioid

dependent patients who prefer transition to mainten ance using methadone or buprenorphine. Methadone has a slow onset by the oral route. It is a long-acting jLi-opiate receptor agonist that largely prevents reward

or euphoria if the patient 'slips' and takes a dose of an

opiate. The mechanism for preventing euphoria is based on cross-tolerance in which tolerance (insensi tivity) acquired by the use of one drug in a category conveys tolerance to all drugs in that category. Of

course, the maintenance dose of methadone must be

adjusted to the purity of heroin on the street. A dose of heroin significantly higher in opioid equivalents than the maintenance dose of methadone would override the cross-tolerance effect. Patients can be maintained for many years on a properly adjusted dose of methadone. Craving for opioids is diminished or absent, and patients are able to engage in constructive activities. Cognition and alertness are not impaired, and complex tasks including higher education can be accomplished (Kreek 1992). Currently, approximately 200 000 former opiate addicts are being maintained on methadone in the

USA. Those with significant psychosocial problems require counselling or psychotherapy in addition to the medication.

As a partial agonist, buprenorphine produces limited opiate effects, and thus overdose is rare except

when combined with benzodiazepines. Owing to its

high affinity for the p-receptor, buprenorphine effec

tively prevents access to the receptor by other opiates and opioids, thus reducing the likelihood that other

opioids will be used. Patients treated with buprenor phine become physiologically dependent on it, as is the case with methadone, but if buprenorphine is stopped, withdrawal symptoms are quite mild. A limitation of

buprenorphine is the ceiling on opiate agonist effects

giving a maximal efficacy equivalent to approximately 40-50 mg of methadone. Addicts using large doses of

street heroin may find that buprenorphine is not

sufficiently potent to block withdrawal or drug craving. Nicotine replacement has been listed in ?2 as a

treatment of nicotine withdrawal. The administration of nicotine as a patch, gum or nasal spray can also be used as a maintenance treatment for extended periods as is the case with methadone. The levels obtained via a nicotine patch usually do not produce the pleasant responses achieved through smoking and there are

usually no withdrawal symptoms on stopping the

patch. Theoretically, smokers should be able to switch their nicotine dependence from administration via

smoking to nicotine delivered by patch, chewing gum or nasal spray. Although some smokers continue to chew nicotine gum for many months after giving up cigarettes, most discontinue nicotine replacement after a few weeks. The tendency to relapse may be strong, and thus it is important to teach patients behavioural

techniques to resist the urge to smoke. An interesting approach that showed some efficacy in clinical trials is the combination of nicotine and mecamylamine, a nicotinic receptor antagonist, to prevent relapse to

smoking. It was hypothesized that stimulation of

receptors by both an agonist and an antagonist would be more effective, and the side effects of the two drugs would tend to cancel each other (Rose et ah 2001). The clinical data on this combination have been mixed, and

more studies are needed.

Clinical serendipity played a role in the discovery of

bupropion as an effective treatment of nicotine

dependence (Ferry 1994). Originally used as an anti

depressant, bupropion was found to significantly improve abstinence rates in smokers whether or not

they were depressed (Swan et ah 2003). The mechanism is unclear, but one effect of bupropion is the relief of negative affect in recently abstinent smokers (Lerman et ah 2002).

A very recent medication that applies the partial agonist principle in the treatment of tobacco use disorder is varenicline (Foulds 2006). This is an a4

?2 nicotinic receptor partial agonist that has been

reported to relieve cigarette craving and to result in

a significantly higher rate of abstinence at 52 weeks (23%) than placebo (10.3%) or bupropion (14.6%) in company-sponsored double-blind trials

(Jorenby et ah 2006). Although agonist treatment is effective in opioid and

nicotine addiction, agonists have not been found effective in patients addicted to stimulants. Experi

ments using methylphenidate or dextroamphetamine as agonists for cocaine and methamphetamine addic tion have not been successful (Gorelick et ah 2004). Similarly, benzodiazepine treatment for alcohol or sedative dependence is ineffective. It is unclear why agonist treatment does not work in patients addicted to these substances.

(b) Antagonist treatment Advances in understanding how opioids interact with

opiate receptors to produce their pharmacological effects led to the development of specific antagonists that have high affinity for these receptors, but do not activate the chain of cellular events producing opioid drug effects. Naltrexone is an antagonist that has great

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Review. Evidence-based treatments of addiction C. P. O'Brien 3281

affinity for p-opiate receptors and significant but less affinity for ?- and K-opiate receptors. Unlike

methadone, it has no agonist effects, so there are no

opioid calming or other subjective effects. When first

introduced, naltrexone was thought to be an ideal medication for heroin addiction because it occupied opiate receptors and blocked the effects of subsequent heroin injections. Experience has shown that most heroin addicts prefer methadone because it provides mild opioid-reinforcing effects that are absent in naltrexone. Thus, naltrexone has been used very little

except for white-collar opiate addicts such as

physicians, nurses and former addicts released from

prison on probation (Cornish et al. 1997). The effects of blocking opiate receptors probably depend on the

degree of tonic activation of the endogenous opioid system. Some normal volunteers given naltrexone

experience nausea and dysphoria, while others experi ence no reaction. Although long-term blockade of

opiate receptors might be expected to produce impairment of neuroendocrine function, remarkably few effects have been noted even in patients who have taken naltrexone daily for several years.

In 2006, a slow-release (depot) injectable prep aration of naltrexone was given FDA approval and

made available for prescription. Paradoxically, it was

approved only for alcoholism because it was discovered in animal models that alcohol activated endogenous opioids (Altshuler et al. 1980). Subsequent work has

clearly shown that endogenous opioids are involved in alcohol reinforcement. This was a discovery in an animal model that led directly to a completely novel treatment for alcoholism in humans. Such translational

examples give hope that knowledge gained from basic research will eventually lead to new and better treatments. In 1983, clinical trials began and it was found that blocking opiate receptors with naltrexone

significantly reduced relapse to clinically significant drinking (Volpicelli etal. 1990, 1992).

Of course, the depot form of naltrexone is also effective for the treatment of opioid addiction (Comer et al. 2006), and clinical trials are underway that will

eventually lead to FDA approval for that indication in addition to alcoholism. Thus, opiate receptor antagon ists have been found to be effective in the treatment of both opiate addiction (blocking external opiates) and alcoholism (blocking endogenous opioids). The

availability of a depot form is expected to signifi cantly improve the adherence to medication for this treatment method.

(c) Genomic subcategories The evidence for genetic influence on vulnerability to addiction is strong, but as with other complex psychiatric disorders, gene association studies based on diagnosis have not identified consistent suscep tibility genes. Diagnosis in psychiatry still depends on behaviour rather than biomarkers. Recently, a sub

category of alcoholism based on a functional al?ele of the gene for the p-opiate receptor has been studied as a candidate gene for an alcoholism endophenotype. The critical functional observation is an increased stimulation effect from alcohol in carriers of this gene. Recent reports of significantly improved treatment

results in alcoholic patients selected on the basis of this genetic variant have raised the exciting prospect of alcoholism treatment guided by genomic testing (O'Brien 2008).

The variant is an A to G substitution at position 118 of exon 1 of the ji-opioid receptor gene and results in a

receptor that has been reported to have greater affinity for ?-endorphin (Bond et ah 1998). Individuals with this al?ele have been found to perceive greater stimulation from a given dose of alcohol (Ray &

Hutchison 2004) and the stimulation was found to be blocked by naltrexone pretreatment (Ray & Hutchison

2007). Reduced euphoria from alcohol was also

reported in clinical trials of alcoholics randomized to naltrexone and in heavy-drinking volunteers with a

family history of alcoholism given alcohol in the

laboratory. A retrospective analysis of alcoholic patients in a naltrexone clinical trial found that those with the

G al?ele did poorly when randomized to placebo, but had a significantly better outcome when random ized to naltrexone (Oslin et ah 2003). This finding

was replicated in another clinical trial (Anton et ah

2008), but not in a small sample of us Veterans Affairs alcoholics (Gelernter et al. 2007).

Taken together, the various lines of evidence suggest that alcohol activates the endogenous opioid system and this activation is exaggerated in carriers of this

genetic variant. The proposed circuitry involves

?-endorphin neurons that modulate ventral tegmental GAB A neurons inhibiting dopamine (DA) neurons. Alcohol causes a release of ?-endorphin that inhibits GABA neurons, thus releasing DA neurons from inhibition and allowing dopaminergic stimulation.

This mechanism is supported by microdialysis studies

showing that the alcohol-induced DA increase is blocked by naltrexone (Gonzales & Weiss 1998).

(d) Blockade of euphoria There are different mechanisms whereby medications can block or diminish the euphoria produced by drugs of abuse. Antagonist treatment prevents the addictive

agent from effective binding to brain receptors that mediate the euphoric response. This is best illustrated

by naltrexone treatment in opiate dependence, since the mechanism of opiate euphoria results from the stimulation of |i-opiate receptors. The mechanism of stimulant euphoria is not well understood, so it has been more difficult to develop medications to block this essential clinical phenomenon. Nicotine replacement therapy for smokers can reduce the pleasure of smoking by a cross-tolerance mechanism similar to that of

methadone for heroin euphoria. Modafinil, a medication that retards sleep onset, has

been shown to block cocaine-induced euphoria in three human laboratory studies of predominantly male

subjects (Dackis et ah 2003; Malcolm et ah 2006; Hart et ah 2007). The mechanism of this blockade is unknown. Other medications block cocaine reward in animal studies (but not yet reliably demonstrated in humans) by increasing GABA-inhibitory effects on reward pathways such as ventral tegmental-ventral striatal DA pathways. These include medications such as topiramate (Kampman et ah 2004), vigabatrin (Brodie et ah 2005) and baclofen (Weerts et ah 2007).

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3282 C. P. O'Brien Review. Evidence-based treatments of addiction

Animal models suggest that this GABA-enhancing mechanism may block the rewarding effects of alcohol as well as cocaine.

(e) Medications that produce an aversive response

Until 1995, disulfiram was the only medication available to prevent relapse to uncontrolled drinking in detoxified alcoholics. This medication blocks the metabolism of

alcohol, causing the accumulation of acetaldehyde, a noxious by-product. The resulting acetaldehyde reaction is so unpleasant that it effectively prevents patients from consuming any alcohol. Disulfiram has a

place in the pharmacopoeia of medications for alcohol ism but its usefulness is limited. Despite treatment contracts and even legal coercion, most alcoholics will not take disulfiram regularly and randomized clinical trials have not shown disulfiram to be efficacious (Fuller et al. 1986). Aversive conditioning has also been tried

by timing an injection of emetine to produce vomiting while presenting the smell and taste of alcohol (Childress et al. 1985). A short-term success has been reported, but the technique has never become widespread.

(f ) Anti-craving medications The pharmacological reversal of clinically significant neuroadaptations has long been employed with detox ification regimens, and the normalization of more

persistent neuroadaptations might identify agents with anti-craving action (O'Brien 2005). In addition to chronic neuroadaptations in reward-related

pathways, prefrontal cortical dysregulation has been demonstrated in stimulant, opioid and alcohol depen dence (Dackis & O'Brien 2005), and is now viewed as a core component of addiction that contributes to poor impulse control, reduced motivation and denial in addicted individuals. Consequently, agents that enhance prefrontal cortical metabolism hold promise in the treatment of addiction.

Acamprosate, a medication that appears to decrease the desire for alcohol, was developed in Europe and has been available in the USA since 2004. Acamprosate appears to reduce the long-lasting neuronal hyperexcit

ability that follows chronic alcohol use (Kranzler &

Gage 2008). The mechanisms are unclear but may include alterations in glutamate receptor gene

expression. This medication suppresses the intake of alcohol in rats and, as with naltrexone, activity in the animal model predicts clinical efficacy. In double-blind

studies, acamprosate has been shown to increase the likelihood of continuous abstinence in alcoholics and to shorten the period of drinking if the patient slips and consumes some alcohol.

The opiate receptor antagonist naltrexone has been

reported in several clinical trials to reduce alcohol

craving (O'Brien 2005) as well as alcohol reward. Human laboratory studies of alcohol priming in non

treatment-seeking alcoholics demonstrated a reduction

in alcohol craving and alcohol drinking in spite of the alcohol priming drink in participants who were not

seeking treatment (O'Malley et al. 2002). Preclinical data have also shown an effect of alcohol

on serotonergic systems. This has motivated trials

using medications affecting that system. Ritanserin, a

5-hydroxytryptamine-2 (5-HT2) receptor antagonist, was found to be no more effective than placebo in the treatment of alcoholism (Johnson et al. 1996). Ondansetron, a 5-HT3 antagonist, was found to reduce

drinking in early-onset alcoholics both alone (Johnson et ah 2000) and in combination with naltrexone

(Ait-Daoud et ah 2001). Specific craving studies have not been addressed with the serotonergic medications.

4. STIMULANT ADDICTION (a) Cocaine sensitization Sensitization is a progressive increase in the beha vioural effects of a drug when a steady dose is

repeatedly administered. This is a consistent finding in rodent studies, but it has not been clearly demonstrated in human cocaine addicts. Sensitization is typically measured by increased behavioural hyper activity when the same dose is given daily to an animal. In human cocaine users, sensitization for euphoric effects of cocaine is not typically seen. On the contrary, some experienced users report that they require more

cocaine over time to obtain euphoria, that is, drug tolerance. In the laboratory, tachyphylaxis (rapid tolerance) has been observed with reduced effects when the same dose was given repeatedly in one session. Since not all animals show behavioural sensitization to cocaine, and not all human cocaine users become addicted, it is possible that cocaine addicts whom we can observe in treatment are the

minority of users who failed to sensitize. Another possible explanation is that evidence of

sensitization in human cocaine users may manifest as

paranoid or psychotic symptoms. This idea is based on the fact that binge-limited paranoia begins after long term cocaine use (mean interval 35 months) in vulnerable users (Satel & Edell 1991). Thus, a long term exposure may be required to sensitize the patient to experience paranoia. The phenomenon of kindling has also been invoked to explain cocaine sensitization. Sub-convulsive doses of cocaine given repeatedly will

eventually produce seizures in rats (Post et ah 1987). This observation has been compared to electrical

kindling of seizures and may underlie the gradual development of paranoia.

Cocaine users experience intense craving when

exposed to cocaine-related cues, which typically include the neighbourhood where they have used

cocaine, the sight of cocaine, cocaine paraphernalia and cash (used to purchase cocaine). This response has been measured in the laboratory when abstinent cocaine users are shown video scenes associated with cocaine use (Ehrman et ah 1992). The conditioned

response consists of physiological arousal and increased

drug craving. Cue-induced craving leads directly to

relapse in addicted patients, even after long periods of abstinence. Medications that block limbic activation in

response to cocaine cues may prove effective against this relapse mechanism.

Numerous studies have been conducted on medi cations that might aid in the rehabilitation of cocaine addicts. A detailed review would not be useful since

most are no longer used. Among those medications still under study in clinical trials as a treatment for

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Review. Evidence-based treatments of addiction C. P. O'Brien 3283

stimulant addiction are modafinil (Dackis et al. 2005), disulfiram (Carroll et al. 2004) and topiramate (Kampman et al. 2006).

Buprenorphine, a partial opioid agonist, has been found to reduce cocaine self-administration in monkeys (Mello & Negus 2007), but studies in cocaine-dependent patients have yielded mixed results. A recent controlled

study of buprenorphine in a population of combined

opiate- and cocaine-dependent patients has shown a

positive effect in reducing the use of both cocaine and opiates (Montoya et al. 2004). The results were consistent with the hypothesis that buprenorphine is effective for cocaine only in higher doses, 16 mg or greater.

Studies in animals have consistently shown that the enhancement of GABA activity reduces cocaine self administration (Roberts et al. 1996). Preliminary results from clinical trials using baclofen, a GABAB agonist, and topiramate, which activates GABAA receptors, suggest that this approach may reduce cocaine use in human subjects as well (Shoptaw et al.

2003). Controlled clinical trials of treatment of cocaine and methamphetamine addicts using vigabatrin, an inhibitor of GABA transaminase, are just beginning (Brodiez al. 2005).

Another recent novel approach involves modafinil, a drug that produces alerting via a complex mechanism

involving enhanced glutamate activity. As mentioned in

?3d, modafinil partially blocks cocaine-induced euphoria in the laboratory. In a randomized clinical trial, Dackis

reported that modafinil-treated subjects significantly reduced their use of cocaine when compared with

placebo-treated subjects (Dackis et al. 2005). Modafinil is currently under intense investigation as a potential first-line treatment for cocaine dependence.

(b) Other stimulants

Amphetamine, dextroamphetamine, methamphet amine, phenmetrazine, methylphenidate and diethyl propion all produce behavioural activation similar to that of cocaine. Amphetamines increase synaptic DA levels primarily by stimulating presynaptic DA release rather than by blockade of reuptake at the DA

transporter, as is the case with cocaine. Intravenous or smoked methamphetamine is an important drug of abuse in the western half of the USA, and it produces an abuse/dependence syndrome similar to that of cocaine. Paranoid psychosis is more common with

amphetamine abuse. In some geographical areas,

methamphetamine abuse has reached epidemic pro portions and there are intensive efforts to develop behavioural and medication treatments for this serious addiction (Rawson et al. 2000).

A different picture arises when oral stimulants are

prescribed in a weight-reduction programme. These

drugs do reduce appetite and weight on a short-term

basis, but the effects diminish over time as tolerance

develops. In rodents, there is a rebound of appetite and

weight gain when amphetamine use is stopped. In obese humans, weight loss after amphetamine treat ment is usually temporary. Anorectic medications, therefore, are not considered to be a treatment for

obesity by themselves, but rather a short-term adjunct to behavioural treatment programmes. It is noteworthy

that drug abuse manifested by drug-seeking behaviour occurs in only a small proportion of patients given stimulants to facilitate weight reduction.

(c) Cannabinoids (marijuana) Cannabinoids are the most widely abused illegal drugs. The frequency of addiction among marijuana users in the USA is approximately 9%. Tolerance to the effects of marijuana has been demonstrated in both humans and animals (Jones et ah 1981). Withdrawal symptoms and signs are not typically seen in clinical populations, but some patients report compulsive frequent mar

ijuana use. In 2002, over 280 000 people entered treatment for cannabis dependence (NIDA 2007).

There is no specific treatment for marijuana depen dence at this time, but cannabinoid receptor antagon ists are logical candidates for investigation. The

withdrawal syndrome does not require medication unless persistent signs of depression are present. Prevention of relapse is accomplished by behavioural treatments such as those used in the treatment of alcoholism or cocaine addiction (Stephens et ah 2002).

Medication such as the cannabinoid agonist dronabinol has been used clinically to treat withdrawal, but randomized trials are lacking. Cannabinoid receptor antagonists are available, but have not yet been tested in clinical trials for marijuana addiction.

(d) Hallucinogenic drugs Addiction in the usual sense does not occur with this

category of drugs, so they will not be discussed in this

paper. Their use carries significant risks and counsel

ling is the only effective approach.

5. THERAPEUTICS UNDER DEVELOPMENT (a) The vaccine approach Immunization against the effects of an abused drug was first tested using morphine. Monkeys were immunized with morphine-6-hemisuccinate-bovine serum albu

min, and the resultant morphine antibodies were found to reduce self-administration of heroin but not cocaine

(Killian et ah 1978). Recently, active immunization with a new, stable cocaine conjugate has been found to

suppress cocaine, but not amphetamine-induced loco

motor activity and stereotyped behaviour in rats (Rocio et ah 1995). Brain levels of cocaine were also lowered by the antibodies, and rats and mice were found to reduce intravenous cocaine self-administration after the pas

sive transfer of cocaine antibodies (Kantak et ah 2000). A clinical trial involving 34 subjects showed that the vaccine caused few side effects and produced dose related levels of antibodies (Martell et ah 2005). Recent studies have shown further improvement in the

vaccine, but additional studies involving dose-response relationships to clinical response are necessary. In

spite of cocaine antibodies, relapse may still be

possible by using a high dose of the drug or by taking a different stimulant.

(b) Current status of pharmacotherapy Medications that target addiction phenomena, such as

euphoria, withdrawal and craving, are being developed as adjunctive treatments that may significantly improve

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3284 C. P. O'Brien Review. Evidence-based treatments of addiction

clinical outcome. In the case of alcoholism, a

completely novel treatment that probably would not have been discovered in the clinic was developed from animal models. The development of new agents has been greatly facilitated by research, revealing the

underlying neuronal mechanisms of these phenomena. Although the many types of drug use disorders have common aspects, there are also many differences that

must be specifically addressed with different pharma cological strategies. In addition, all patients require a full evaluation and tailored treatment plans that take their unique set of problems into account. It is especially important to identify and stabilize

co-occurring medical and psychiatric disorders in the addicted population. Currently, effective medications are available for some addictive disorders, and others will certainly be developed through continued research. When viewed in comparison with other chronic

diseases, the current treatments for addiction are

reasonably successful (O'Brien & McLellan 1996; McLellan et al. 2000). Long-term treatment is

accompanied by improvements in physical status, as well as in mental, social and occupational functions. Treatment is usually not curative. As is the case with other chronic diseases, when the treatment is ended, relapse eventually occurs in most cases.

REFERENCES Adams, E. H., Breiner, S., Cicero, T. J., Geller, A., Inciardi,

J. A., Schnoll, S. H., Senay, E. C. & Woody, G. E. 2006 A

comparison of the abuse liability of tramadol, NSAIDs, and hydrocodone in patients with chronic pain. J. Pain

Symptom Manage. 31, 465-476. (doi:10.1016/j.jpainsym

man.2005.10.006)

Ait-Daoud, N., Johnson, B. A., Javors, M., Roache, J. D. &

Zanca, N. A. 2001 Combining ondansetron and naltrexone

treats biological alcoholics: corroboration of self-reported

drinking by serum carbohydrate deficient transferrin, a

biomarker. Alcohol. Clin. Exp. Res. 25, 847-849. (doi: 10.

1111/j.l 530-0277.2001.tb02289.x) Altshuler, H. L., Phillips, P. A. & Feinhandler, D. A. 1980

Alteration of ethanol self-administration by naltrexone. Life Sei. 26, 679-688. (doi:10.1016/0024-3205(80)90257-X)

Anthony, J. C, Warner, L. A. & Kessler, R C. 1994

Comparative epidemiology of dependence on tobacco,

alcohol, controlled substances, and inhalants: basic

findings from the National Comorbidity Survey. Exp. Clin. Psychopharmacol. 2, 244-268. (doi: 10.1037/1064

1297.2.3.244)

Anton, R. F., Oroszi, G, O'Malley, S., Couper, D., Swift, R,

Pettinati, H. & Goldman, D. 2008 An evaluation of

u-opioid receptor (OPRM1) as a predictor of naltrexone

response in the treatment of alcohol dependence: results

from the combined pharmacotherapies and behavioral

interventions for alcohol dependence (COMBINE) study. Arch. Gen. Psychiatry 65, 135-144. (doi:10.1001/arch

psyc.65.2.135)

Bond, C. et ah 1998 Single-nucleotide polymorphism in the human mu opioid receptor gene alters ?-endorphin

binding and activity: possible implications for opiate addiction. Proc. Nati Acad. Sei. 95, 9608-9613. (doi:10.

1073/pnas.95.16.9608) Brodie, J. D, Figueroa, E., Laska, E. M. & Dewey, S. L. 2005

Safety and efficacy of y-vinyl GABA (GVG) for the treatment of methamphetamine and/or cocaine addiction.

Synapse 55, 122-125. (doi:10.1002/syn.20097)

Brown, M. E., Anton, R. F., Malcolm, R. & Ballenger, J. C.

1988 Alcohol detoxification and withdrawal seizures:

clinical support for a kindling hypothesis. Biol. Psychiatry 23, 507-514. (doi:10.1016/0006-3223(88)90023-6)

Carroll, K. M., Fenton, L. R., Ball, S. A., Nich, C,

Frankfurter, T. L., Shi, J. & Rounsaville, B. J. 2004

Efficacy of disulfiram and cognitive behavior therapy in

cocaine-dependent outpatients: a randomized placebo controlled trial. Arch. Gen. Psychiatry 61, 264-272.

(doi: 10.1001/archpsyc.61.3.264) Childress, A. R, McLellan, A. T. & O'Brien, C. P. 1985

Behavioral therapies for substance abuse. Int. J. Addict. 20, 947-969.

Childress, A. R, Mozley, P. D., McElgin, W., Fitzgerald, J.,

Reivich, M. & O'Brien, C. P. 1999 Limbic activation

during cue-induced cocaine craving. Am. J. Psychiatry

156, 11-18.

Childress, A. R. et al 2008 Prelude to passion: limbic activation by "unseen" drug and sexual cues. PLoS ONE

3, el506. (doi: 10.137l/journal.pone.0001506) Comer, S. D., Sullivan, M. A., Yu, E., Rothenberg, J. L.,

Kleber, H. D., Kampman, K., Dackis, C. & O'Brien, C. P.

2006 Injectable, sustained-release naltrexone for the

treatment of opioid dependence: a randomized, placebo controlled trial. Arch. Gen. Psychiatry 63, 210-218.

(doi:10.1001/archpsyc.63.2.210) Cornish, J. W., Metzger, D., Woody, G. E., Wilson, D.,

McLellan, A. T., Vandergrift, B. & O'Brien, C. P. 1997

Naltrexone pharmacotherapy for opioid dependent federal

probationers. J. Subst. Abuse Treat. 14, 529-534. (doi: 10.

1016/S0740-5472(97)00020-2) Dackis, C. A. & O'Brien, C. 2003 The neurobiology of

alcoholism. In Handbook of psychiatric disorders (eds S. Gershon & R Soires), pp. 563-580. New York, NY: Marcel Dekker.

Dackis, C. A. & O'Brien, C. 2005 Neurobiology of addiction:

treatment and public policy ramifications (commentary). Nat. Neurosci. 8, 1431-1436. (doi:10.1038/nnll05-1431)

Dackis, C. A. et al 2003 Modafinil and cocaine: a double

blind, placebo-controlled drug interaction study. Drug Alcohol Depend. 70, 29-37. (doi: 10.1016/S0376-8716(02) 00335-6)

Dackis, C. A., Kampman, K. M., Lynch, K. G., Pettinati, H. M. & O'Brien, C. P. 2005 A double-blind, placebo controlled trial of modafinil for cocaine dependence.

Neuropsychopharmacology 30, 205-211. (doi: 10.1038/

sj.npp. 1300600) Deroche-Gamonet, V., Belin, D. & Piazza, P. V. 2004

Evidence for addiction-like behavior in the rat. Science

305, 1014-1017. (doi: 10.1126/science. 1099020) Dole, V. P. & Nyswander, M. 1965 A medical treatment for

diacetylmorphine (heroin) addiction: a clinical trial with methadone hydrochloride. J. Am. Med. Assoc. 193, 80-84.

Ehrman, R, Robbins, S., Childress, A. R & O'Brien, C. P.

1992 Conditioned responses to cocaine-related stimuli in

cocaine abuse patients. Psychopharmacology 107, 523-529.

(doi: 10.1007/BF02245266) Ferry, L. 1994 Bupropion versus placebo for nicotine

dependence. American Psychiatric Association, Annual

Meeting Abstracts, New Research no. 544. Washington, DC: APA Press.

Foulds, J. 2006 The neurobiological basis for partial agonist treatment of nicotine dependence: varenicline. Int.

J. Clin. Pract. 60, 571-576. (doi:l0.1111/j.l368-5031.

2006.00955.x) Franklin, T. R, Acton, P. D., Maldjian, J. A., Gray, J. D.,

Croft, J. R, Dackis, C. A., O'Brien, C. P. & Childress, A. R 2002 Decreased gray matter concentration in the

Phil Trans. R. Soc. B (2008)

This content downloaded from 206.224.223.240 on Fri, 5 Dec 2014 15:41:30 PM All use subject to JSTOR Terms and Conditions

Review. Evidence-based treatments of addiction C. P. O'Brien 3285

insular, orbitofrontal, cingulate, and temporal cortices of

cocaine patients. Biol. Psychiatry 51, 134-142. (doi: 10.

1016/S0006-3223(01)01269-0) Fuller, R. K. et ah 1986 Disulfiram treatment of alcoholism.

A Veterans Administration cooperative study. J. Am. Med.

Assoc. 256, 1449-1455. (doi: 10.1001/jama.256.11.1449) Gelernter, J., Gueorguieva, R, Kranzler, H. R, Zhang, H.,

Cramer, J., Rosenheck, R. & Krystal, J. H. 2007 Opioid receptor gene (OPRM1, OPRK1, and OPRD1) variants and response to naltrexone treatment for alcohol depen dence: results from the VA Cooperative Study. Alcohol Clin. Exp. Res. 31, 555-563.

Gerra, G, Zaimovic, A., Giusti, F., Di Gennaro, C,

Zambelli, U, Gardini, S. & Delsignore, R. 2001 Lofexidine versus clonidine in rapid opiate detoxification.

J. Subst. Abuse Treat. 21, 11-17. (doi:10.1016/S0740

5472(01)00178-7) Gonzales, R A. & Weiss, F. 1998 Suppression of ethanol

reinforced behavior by naltrexone is associated with

attenuation of the ethanol-induced increase in dialysate

dopamine levels in the nucleus accumbens. J. Neurosci. 18, 10 663-10 671.

Gorelick, D. A., Gardner, E. L. & Xi, Z. X. 2004 Agents in development for the management of cocaine abuse.

Drugs 64, 1547-1573. (doi: 10.2165/00003495-200464 140-00004)

Haney, M., Hart, C. L., Vosburg, S. K, Nasser, J., Bennett,

A., Zubaran, C. & Foltin, R. W. 2004 Marijuana withdrawal in humans: effects of oral THC or divalproex.

Neuropsychopharmacology 29, 158-170. (doi: 10.1038/

sj.npp.1300310) Hart, C. L., Haney, M., Vosburg, S. K, Rubin, E. & Foltin,

R W. 2007 Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 33, 761-768. (doi: 10.1038/sj.npp. 1301472)

Johnson, B. A. et ah 1996 Ritanserin in the treatment

of alcohol dependence?a multi-center clinical trial.

Psychopharmacology 128, 206-215. (doi:10.1007/s002130 050126)

Johnson, B. A., Roache, J. D., Javors, M. A., DiClemente, C. C, Cloninger, C. R, Prihoda, T. J., Bordnick, P. S.,

Ait-Daoud, N. & Hensler, J. 2000 Ondansetron for

reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial [see

comments]. J. Am. Med. Assoc. 284, 963-971. (doi: 10.

1001/jama.284.8.963) Jones, R T., Benowitz, N. L. & Herning, R. I. 1981 Clinical

review of cannabis tolerance and dependence. J. Clin.

Pharmacol. 21, 143S-152S. (doi:10.1007/BF00637515) Jorenby, D. E., Hays, J. T., Rigotti, N. A., Azoulay, S.,

Watsky, E. J., Williams, K. E., Billing, C. B., Gong, J. &

Reeves, K. R. 2006 Efficacy of varenicline, an oc4?2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a

randomized controlled trial. J. Am. Med. Assoc. 296, 56-63. (doi:10.1001/jama.296.1.56)

Kampman, K. M. et ah 2001 Cocaine withdrawal symptoms and initial urine toxicology results predict treatment

attrition in outpatient cocaine dependence treatment.

Psychol. Addict. Behav. 15, 52-59. (doi: 10.1037/0893 164X.15.1.52)

Kampman, K. M., Pettinati, H., Lynch, K. G., Dackis, C,

Sparkman, T., Weigley, C. & O'Brien, C. P. 2004 A pilot trial of topiramate for the treatment of cocaine depen dence. Drug Alcohol Depend. IS, 233-240. (doi: 10.1016/ j.drugalcdep.2004.03.008)

Kampman, K. M., Dackis, C, Lynch, K. G, Pettinati, H.,

Tirado, C, Gariti, P., Sparkman, T., Atzram, M. & O'Brien, C. P. 2006 A double-blind, placebo-controlled trial of amantadine, propranolol, and their combination for the

treatment of cocaine dependence in patients with severe

cocaine withdrawal symptoms. Drug Alcohol Depend. 85, 129-137. (doi:10.1016/j.drugalcdep.2006.04.002)

Kantak, K. M., Collins, S. L., lipman, E. G., Bond, J.,

Giovanoni, K. & Fox, B. S. 2000 Evaluation of anti

cocaine antibodies and a cocaine vaccine in a rat self

administration model. Psychopharmacology 148, 251-262.

(doi: 10.1007/s002130050049) Killian, A., Bonese, K, Rothberg, R, Wainer, B. & Schuster,

C. 1978 Effects of passive immunization against morphine on heroin self-administration. Pharmacol. Biochem. Behav.

9, 347-352. (doi:10.1016/0091-3057(78)90295-2) Koob, G. R, Ahmed, S. H, Boutrel, B., Chen, S. A., Kenny,

P. J., Markou, A., O'Dell, L. E., Parsons, L. H. & Sanna, P. P. 2004 Neurobiological mechanisms in the transition

from drug use to drug dependence. Neurosci. Biobehav.

Rev. 27, 739-749. (doi:10.1016/j.neubiorev.2003.11.007) Kranzler, H. R. & Gage, A. 2008 Acamprosate efficacy in

alcohol-dependent patients: summary of results from

three pivotal trials. Am. J. Addict. 17, 70-76. (doi: 10.

1080/10550490701756120) Kreek M. J. 1992 Rationale for maintenance pharmacother

apy of opiate dependence. In Addictive states (eds C. P.

O'Brien & J. Jaffe), ch.13, pp. 205-230. New York, NY:

Raven Press.

LeBlanc, A., Kalant, H, Gibbins, R. & Berman, N. 1969

Acquisition and loss of tolerance to ethanol by the rat.

J. Pharmacol. Exp. Ther. 168, 244-250.

Lerman, C, Roth, D., Kaufman, V., Audrain, J., Hawk, L.,

Liu, A., Niaura, R & Epstein, L. 2002 Mediating mechanisms for the impact of bupropion in smoking cessation treatment. Drug Alcohol Depend. 67, 219-223.

(doi: 10.1016/S0376-8716(02)00067-4) Malcolm, R et al 2006 Modafinil and cocaine interactions.

Am. J. Drug Alcohol Abuse 32, 577-587. (doi:10.1080/ 00952990600920425)

Martell, B. A., Mitchell, E., Poling, J., Gonsai, K. & Kosten, T. R. 2005 Vaccine pharmacotherapy for the treatment of

cocaine dependence. Biol. Psychiatry 58, 158-164.

(doi:10.1016/j.biopsych.2005.04.032) McLellan, A. T., Lewis, D. C, O'Brien, C. P. & Kleber, H. D.

2000 Drug dependence, a chronic medical illness:

implications for treatment, insurance, and outcomes

evaluation. J. Am. Med. Assoc. 284, 1689-1695. (doi:10.

1001/jama.284.13.1689) McLellan, A. T., Weinstein, R. L., Shen, Q., Kendig, C. &

Levine, M. 2005 Improving continuity of care in a public addiction treatment system with clinical case manage

ment. Am. J. Addict. 14, 426-440. (doi: 10.1080/105504

90500247099) Mello, N. K. & Negus, S. S. 2007 Effects of d-amphetamine

and buprenorphine combinations on speedball (cocaine +

heroin) self-administration by rhesus monkeys. Neuropsy

chopharmacology 32, 1985-1994. (doi: 10.1038/sj.npp.

1301319) Montoya, I. D. et al 2004 Randomized trial of buprenorphine

for treatment of concurrent opiate and cocaine depen dence. Clin. Pharmacol. Ther. IS, 34-48. (doi:10.1016/

j.clpt.2003.09.004) NIDA 2007 Marijuana facts. NIDA. See http://www.nida.

nih.gov/MarijBroch/parentpg 17-18N.html#Addicted. O'Brien, C. P. 2005 Anticraving medications for relapse

prevention: a possible new class of psychoactive medi

cations. Am. J. Psychiatry 162, 1423-1431. (doi:10.1176/ appi.ajp.162.8.1423)

O'Brien, C. P. 2006 Drug addiction and drug abuse. In

Goodman & Gilman's the pharmacological basis of thera

peutics (eds L. Brunton, J. Lazo & K. Parker), pp. 607-627, 11th edn. New York, NY: McGraw-Hill.

Phil. Trans. R. Soc. B (2008)

This content downloaded from 206.224.223.240 on Fri, 5 Dec 2014 15:41:30 PM All use subject to JSTOR Terms and Conditions

3286 C. P. O'Brien Review. Evidence-based treatments of addiction

O'Brien, C. P. 2008 Prospects for a genomic approach to the

treatment of alcoholism. Arch. Gen. Psychiatry 65, 132-133. (doi:10.1001/archgenpsychiatry.2007.32)

O'Brien, C. P. & McLellan, A. T. 1996 Myths about the

treatment of addiction. Lancet 347, 237-240. (doi: 10.

1016/S0140-6736(96)90409-2) O'Brien, C. P., O'Brien, T. J., Mintz, J. & Brady, J. P. 1975

Conditioning of narcotic abstinence symptoms in human

subjects. Drug Alcohol Depend. 1, 115-123. (doi: 10.1016/ 0376-8716(75)90013-7)

O'Malley, S. S., Krishnan-Sarin, S., Farren, C, Sinha, R. &

Kreek, J. 2002 Naltrexone decreases craving and alcohol

self-administration in alcohol-dependent subjects and

activates the hypothalamo-pituitary-adrenocortical axis.

Psychopharmacology (Berl.) 160, 19-29. (doi: 10.1007/ S002130100919)

Oslin, D. W, Berrettini, W, Kranzler, H. R., Pettinati, H.,

Gelernter, J., Volpicelli, J. R. & O'Brien, C. P. 2003 A functional polymorphism of the mu-opioid receptor gene is associated with naltrexone response in alcohol-depen dent patients. Neuropsychopharmacology 28, 1546-1552.

(doi:10.1038/sj.npp.l300219) Post, R M., Weiss, S. R B., Pert, A. & Uhde, T. W 1987

Chronic cocaine administration: sensitization and kindling effects. In Cocaine: clinical and biobehavioral aspects,

pp. 109-173. New York, NY: Oxford University Press.

Rawson, R., Huber, A., Brethen, P., Obert, J., Gulati, V,

Shoptaw, S. & Ling, W 2000 Methamphetamine and cocaine users: differences in characteristics and treatment

retention. J. Psychoactive Drugs 32, 233-238.

Ray, L. A. & Hutchison, K. E. 2004 A polymorphism of the mu-opioid receptor gene (OPRM1) and sensitivity to the effects of alcohol in humans. Alcohol Clin. Exp. Res. 28, 1789-1795. (doi:10.1097/01.ALC0000148114. 34000.B9)

Ray, L. A. & Hutchison, K. E. 2007 Effects of naltrexone on

alcohol sensitivity and genetic moderators of medication

response: a double-blind placebo-controlled study. Arch.

Gen. Psychiatry 64, 1069-1077. (doi:10.1001/archpsyc.

64.9.1069) Roberts, D. C, Andrews, M. M. & Vickers, G. J. 1996

Baclofen attenuates the reinforcing effects of cocaine in

rats. Neuropsychopharmacology 15, 417-423. (doi: 10.1016/

0893-133X(96)00002-4) Rocio, M., Carrera, A., Ashley, J. A., Parsons, L. H.,

Wirsching, P., Koob, G. F. & Janda, K. D. 1995

Suppression of psychoactive effects of cocaine by active

immunization. Nature 378, 727-730. (doi: 10.1038/

378727a0) Rose, J. E., Behm, F M. & Westman, E. C. 2001 Acute effects

of nicotine and mecamylamine on tobacco withdrawal

symptoms, cigarette reward and ad lib smoking. Pharmacol

Biochem. Behav. 68, 187-197. (doi:10.1016/S0091-3057 (00)00465-2)

Satel, S. L. & Edell, W. S. 1991 Cocaine-induced paranoia and psychosis proneness. Am. J. Psychiatry 148, 1708-1711.

Shoptaw, S., Yang, X., Rotheram-Fuller, E. J., Hsieh, Y. C,

Kintaudi, P. C, Charuvastra, V. C. & Ling, W. 2003

Randomized placebo-controlled trial of baclofen for

cocaine dependence: preliminary effects for individuals

with chronic patterns of cocaine use. J. Clin. Psychiatry 64, 1440-1448.

Sofuoglu, M. & Kosten, T. R. 2006 Emerging pharma

cological strategies in the fight against cocaine addiction.

Expert Opin. Emerg. Drugs 11, 91-98. (doi: 10.1517/

14728214.11.1.91) Stephens, R. S., Babor, T. F, Kadden, R. & Miller, M. 2002

The Marijuana Treatment Project: rationale, design and participant characteristics. Addiction 97(Suppl. 1), 109-124. (doi:10.1046/j.l360-0443.97.s01.6.x)

Swan, G. E., McAfee, T. & Curry, S. J. 2003 Effectiveness of

bupropion sustained release for smoking cessation in a

health care setting: a randomized trial. Arch. Intern. Med.

163, 2337-2444. (doi: 10.1001/archinte. 163.19.2337) Volpicelli, J. R., O'Brien, C. P., Alterman, A. I. & Hayashida,

M. 1990 Naltrexone and the treatment of alcohol

dependence: initial observations. In Opioids, bulimia, alcohol

abuse and alcoholism (?d. L. B. Reid), pp. 195-214. New

York, NY: Springer-Verlag.

Volpicelli, J. R, Alterman, A. I., Hayashida, M. & O'Brien, C. P. 1992 Naltrexone in the treatment of alcohol

dependence. Arch. Gen. Psychiatry 49, 876-880.

Weerts, E. M., Froestl, W, Kaminski, B. J. & Griffiths, R R.

2007 Attenuation of cocaine-seeking by GABA B receptor agonists baclofen and CGP44532 but not the

GABA reuptake inhibitor tiagabine in baboons. Drug Alcohol Depend. 89, 206-213. (doi:10.1016/j.drugalcdep. 2006.12.023)

Wikler, A. 1973 Dynamics of drug dependence: implications of a conditioning theory for research and treatment. Arch.

Gen. Psychiatry 28, 611-616.

Phil. Trans. R. Soc. B (2008)

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