Pharmacological Approaches to Reducing Craving in Patients with Alcohol Use Disorders

Abstract

Research on the concept of craving may lead to a better understanding of the biobehavioral circuitries that contribute to the complexity of Alcohol Use Disorders (AUD). The experiences described as craving or desire to drink, are often associated with physical responses such as increased salivation, heart rate and alteration of stress hormones as well as psychological responses such as anxiety and depression. Greater craving has been associated with the increased probability of alcohol relapse. Reversal of craving, understood as a symptom of protracted abstinence, offers the possibility of preventing relapses and treating alcoholism. Various medications have been studied to establish whether they are able to reduce craving; however, the results obtained from clinical studies have been inconsistent. Here we review the interdisciplinary models developed to evaluate craving, then the different approaches used to assess and measure craving, and finally, the medications utilized and tested to lessen craving in patients suffering from AUD.

1. Background

As a subjective experience, craving is a difficult phenomenon to define, but is used by patients, clinicians and researchers to describe a strong desire to drink alcohol. It was first recognized as a component of alcoholism in 1955 (1). The term, however, was acknowledged later in the scientific and clinical communities (2) and investigated for its association with alcohol withdrawal and relapse (3-5). The experience of craving has been identified as on a continuum, rather than an on-and-off symptom. Craving is also positively correlated with negative emotions (6, 7), stress and anxiety (8-10), and negatively correlated with length of alcohol abstinence (11).

Researchers have used different definitions for craving. For example, craving has been described by some as “desire and urge,” while others have suggested the definition of craving to be only the “desire” for experiencing the effects of a drug, while specifying the term “urge” to the behavioral intention to use it (4). Additionally, in clinical practice, it is a difficult symptom to assess because patients may deny experiencing it (2). Moreover they may be unable to recognize it because of the overwhelming emotional experience during abstinence and withdrawal (12), or simply because they do not remember having experienced craving before the relapse occurred (13). Proposing a uniform definition for craving has been challenging due to the lack of a valid method to measure psychological, behavioral and brain function of subjective experiences (14, 15). Furthermore, because of the lack of a standardized definition, operationalizing valid and reliable preclinical models that can be used as predictors of human craving is especially challenging. (16).

The understanding of craving has evolved considerably due to progress in many cross-interdisciplinary studies. For example, elucidating neurobiological circuitries (17, 18), developing preclinical models (19-21), and evolving cue-elicitation investigation in human studies (22) are several approaches that researchers have investigated to understand the role of craving in Alcohol Use Disorder (AUD). In addition, cognitive psychology (23), have advanced neuroimaging techniques (24-26), and pharmacological studies (27-29) have inferred that overlapping neurochemical systems contribute to alcohol craving.

While actively discussed as a symptom in addictive behavior disorders (30-33) craving is called “a strong desire or sense of compulsion to take the substance” in the International Statistical Classification of Diseases and Related Health Problems 10^th Revision (ICD-10). The inclusion of a “craving” criterion to the just released fifth revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) was predicted to bring an improvement in the application of the diagnostic criteria used to assess alcohol problems (35). In addition to the merger of the two diagnoses of Alcohol Abuse and Alcohol Dependence into a monothetic diagnosis of AUD, recent research evaluated the addition of the “craving” criterion proposed to the DSM-5 diagnosis of AUD (36, 37). Empirically, while the AUD coalesced criterion of the DSM-5 includes individuals less severely affected than those meeting only DSM-IV criteria , the consequences of adding the craving criterion could not be fully evaluated due to the lack of relevant comparative data regarding craving (36).

The hypothesis that an ideal pharmacotherapy to treat alcoholism should target a decrease in alcohol craving was first suggested in the 1990s (38). While many behavioral and pharmacotherapy approaches targeting craving are shown to reduce alcohol consumption in randomized controlled trials (RCTs) (12), craving has not consistently been associated with reduced alcohol relapse (4, 39-43). Moreover, pharmacological approches alone or combined with behavioral interventions that reduced drinking by attenuating craving did not always improve drinking outcomes (4, 44).

2. Alcohol Craving: Models and Neurobiology

Several clinical and preclinical models and approaches have been proposed to assess craving and relapse. One of the first approaches to establish a comprehensive definition for alcohol craving was derived from the hypothesis that numerous mechanisms were responsible for the urge to drink, and therefore a multidisciplinary approach was necessary to elucidate the basis of alcohol craving (45).

Psychological approaches to assess craving include: the study of the conditioning (alcohol-related cues; i.e. association of experience with alcohol ingestion, which become conditioned stimuli), and cognitive models (cognitive processes, which dictate response to alcohol and alcohol-related cues during abstinence). Further, alcohol cue-exposure techniques have been utilized to evaluate cognitive changes in alcoholics (46). According to the conditioning model, relapse situations originate from neutral stimuli that produce conditioned craving after repeated pairing of environmental stimuli and withdrawal. Many human studies targeting experimental approaches have used the cue-exposure paradigm to test pharmacotherapies for potential alcohol anti-craving properties (47). Cue-reactivity models developed in laboratory studies allow assessing the potential risk factors for alcohol relapse. In addition, cue-reactivity sessions provide a platform to evaluate potential medications for protracted abstinence, as an alternative to laboratory methods involving alcohol administration (48, 49). Because of the simplicity of the model adopted in original studies, craving has not always predicted alcohol relapses. The dynamics of craving (tonic, phasic, pulsatile, continuous, discontinuous) (50) and integration of neurochemical circuitry in the three-pathway psychobiological model (the reward, relief and obsessive craving) offered the opportunity to simultaneously evaluate multiple psychoneuro-networks in AUD (51). From the dual process model (23), craving was conceptualized as the result of an imbalance between reflective and reflexive systems. Alcohol may increase hyper-excitability in reflexive brain areas (prefrontal cortex) and reduce reflective circuitries (amygdala). Later experimental psychology approaches corroborated that drugs (as well as alcohol) have the ability to trigger specific inner mechanisms (from the locus of the emotions, such as the amygdala) that modulate, or even take over, individual cognitive resources that are needed for exercising willpower to resist drugs (52).

Reaching for alcohol, rather than trying to avoid it, is a more common behavior in heavy-drinking alcohol dependent individuals. This harmful behavior is hypothesized to be related to cue-induced craving (53). Attention bias has also been associated with subjective craving (54), however the “substance-seeking” is not always a conscious experience (55). Finally, lack of self-control, impulsivity and suppression of unwanted affects are also attributed to “resource depletion,” that may trigger urges and craving (56).

Preclinical models have generated many hypotheses to explain the neurobiological mechanisms associated with anticipatory states that have significant relevance for studies on the neurobiology of craving (57) and relapse (58). A dysregulation of the brain reward processing produced by alteration on mesolimbic dopamine (DA), glutamate, γ-aminobutyric acid (GABA), and stress circuitries, may be responsible for the compulsive drug use and a loss of control over drug taking (59). This neuroadaptive model for craving was based on the theory that hyper-sensitization to drugs (including alcohol) and drug-associated stimuli converts ordinary 'wanting' into craving, and prolonged abstinence may prompt reward memory, thereby inducing craving (55).

The effects of alcohol in the development of craving has been hypothesized to directly affect the mesolimbic DA pathway (60). The implication of the limbic system in the mediation of craving and loss of control is described as the incentive sensitization model. The acquisition and sensitization of craving for alcohol (and other addictive drugs) may develop by repeated exposure and release of DA in response to cues (55, 61, 62). Additionally, the dopamine receptor subtypes described as D₁-like (D₁ and D₅) and D₂-like (D_2-4) are expressed in brain structures such as the amygdala and hippocampus, both of which have been implicated in human and preclinical models of addiction (55, 63-65). The mesolimbic DA pathway projecting from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) has been recognized as a site for the reinforcing actions of ethanol and other addictive drugs in preclinical models (Figure 1, blue arrow) (66-68). In addition, glutamatergic neurotransmission projecting from the prefrontal cortex (PFC), amygdala and hippocampus to the NAcc and VTA are associated with relapse (Figure 1, red arrows) (69). Alcohol is shown to modulate mesolimbic pathways and induce the urge to drink and loss of control (55).

Figure 1. Involvement of the Limbic System in the Mediation of Craving.

Mesolimbic dopamine pathways that project from the ventral tegmental area (VTA) to the nucleus accumbens (NAcc) are recognized as sites for the reinforcing actions of ethanol and other addictive drugs, blue arrow; glutamatergic projections from the prefrontal cortex (PFC), amygdala and hippocampus to the NAcc and VTA are associated with relapse, red arrows (Image created using Brain Explore2, Allen Human Brain Atlas, available to download from http://human.brain-map.org/static/brainexplorer 9/12/2013).

The loss of control, with the manifestation of withdrawal symptoms (51), may be due to the alteration of the increased dopaminergic and glutamatergic action and a decrease of GABAergic neurotransmission (25, 70, 71). The modulation of serotonin (5-HT), or 5-hydroxytryptamine-mediated signal transmission has been linked to increased alcohol consumption (72, 73) and to the obsessive-compulsive behavior in alcohol craving (74, 75). Serotonergic neurons, located in the raphe nucleus, project to the amygdala, VTA, hippocampus and to the NAcc. Serotonin traverses the synaptic clefts, tightly regulated by transporters and bind to a discrete group of 5-HT-subtype receptors, which selectively can affect behaviors and mood states. Furthermore, the serotonergic system interacts with other neurotransmitters such as GABA in the hippocampal formation (influencing cognition and judgment) and with DA in the VTA (mediating rewarding effects).

Alcohol alters the serotonergic system in both acute and chronic exposure. Single alcohol ingestion may increase central 5-HT levels (72) and activate 5-HT₃ receptors (76), which are widely distributed in the brain. Chronic alcohol exposure may be responsible for the 5-HT₂ receptor adaptive changes resulting from the effort to compensate for the continuous alcohol-induced alterations (such as increasing receptor number) (77). Augmented activation of the 5-HT₃ receptors in the GABAergic neurons results in increased neuronal inhibition, and in the increase in the mesolimbic DA activity contributes to enhancement of alcohol rewarding effects. This dual mechanism has been described as the two-stage process of craving (55, 78, 79). Moreover, the deleterious neuroadaptations of the 5-HT₂ receptor in the effort to re-establish normal homeostasis functions, may be responsible for the individual’s anxiety (80) and withdrawal symptoms (81), mood dysregulation and obsessive alcohol-seeking behaviors (51) that may result in the development of craving. A deficiency of serotonergic function at any level of this highly structured system may contribute to craving and increase the vulnerability to develop AUD (78). The role of serotonergic neurotransmission in alcohol craving has been evaluated using several methodologies, which include interventions favoring serotonergic neurotransmission, stabilization of mood, and reduction of obsessional thinking (51).

Extensive preclinical data demonstrate an essential role for the endogenous opioid system in stimulation of DA release by ethanol in the NAcc (82). More recently, positron emission tomography (PET) studies show a correlation between alcohol craving and μ-opioid receptors in alcoholic individuals during abstinence (24, 83). Under physiological conditions, the action of the endogenous opioid system is very subtle. Acute alcohol exposure stimulates the release of brain β-endorphins, which may interact with brain regions that affect many neurobiological and behavioral effects of alcohol, either by opioid-receptor binding in the mesolimbic region, or by distant action such as activating the hypothalamic-pituitary axis (HPA). As we noted previously for other neurobiological systems affected by alcohol ingestion, chronic alcohol exposure induces adaptive changes to maintain normal homeostatic levels to overcome the effects of alcohol deprivation. Therefore, the decrease in β-endorphin activity during alcohol abstinence may favor alcohol consumption through the mechanisms of negative reinforcement, inducing craving and promoting relapses. Interventions on both direct and endocrine-like functions of the endogenous opioid system may alter mood and motivation, and may modify drinking behaviors, control alcohol craving, and prevent relapses in individuals suffering from AUD (84).

In summary, human and animal models have been developed to elucidate the underlying mechanism of craving both at psychological, neurobiological, behavioral, cellular and molecular levels. However the subjective, self-reported cognition of a state obtained in human laboratory studies is not feasible to measure in preclinical setting (16). Paradigms such as stress-induced techniques, conditioning, extinction and self-operant chambers are utilized to evaluate alcohol consumption and deprivation prior to drinking or during protracted abstinence (85). More recently, others have developed novel preclinical paradigms to test tolerance during intoxication following withdrawal periods (86).

Future craving research should incorporate a large array of interdisciplinary theories since little is known of craving in the naturalistic environment. Our current research is based mostly on assessing craving under detoxification (withdrawal craving) or undergoing laboratory sessions (cue-reactivity craving) (50). From a neurobiological perspective, addictive drugs produce incremental neuroadaptations, which may encompass many systems and consequent behavioral and psychological effects. To facilitate the translation of these findings into the clinical setting, neuroadaptive mechanisms entail an integration of basic neuroscience with psychology, including genetics. Neuroadaptations may be increased in subjects who have inherited a genetic predisposition (87-89) or because they have acquired susceptibility through repeated experience of intense stress (90, 91).

3. Measuring Craving

Because there is no uniformly accepted definition for craving (15), a measure that captures both the psychological and neurobiological aspects of urge and desire has been elusive (14). The different types of craving such as physical craving (with manifestation of withdrawal symptoms) or impulsive craving (excitability triggered by cues) (50) are not experienced by all alcohol-dependent individuals or may be experienced at different times during alcohol abstinence. Craving variability may be due to the individual salience of drinking, tolerance, intensity of withdrawal symptoms, and subjective awareness of a compulsion to drink alcohol (16). Measurement error in assessing craving has limited the selection and monitoring of pharmacotherapies that target the desire and urge to drink during abstinence.

The major problem with assessing and measuring craving is that it is a self-reported event and the validation of subjective craving is a major issue in measuring craving in alcoholic individuals. In clinical research studies, craving assessments have included both subjective approaches (questionnaires and drinking behaviors) and objective parameters (measures of autonomic responses such as heart rate changes and salivary output). Physical responses, however, do not assure that craving measurements are precise. Autonomic responses can be triggered by numerous homeostatic imbalances, (thermoregulation, circadian rhythm, baroreceptors), which are very common in patients during withdrawal or in those suffering from other comorbidities. The retrospective nature of the self-reported measurement of subjective experiences by patients is widely accepted both in research and clinical settings to assess alcohol urge and desire despite the lack of an absolute scale for craving (92). The measurement of craving should include a series of items that have common meaning for the participants and the researchers. Cravingis a continuous experience that cannot be exclusively restricted to a specific point during an episode of craving (93).

A commonly used measure of alcohol craving is the single-item measure which assesses craving in terms of frequency or intensity on a continuous scale (i.e. Likert or Visual Analogue Scales; VAS) (94). This approach is easy to implement, but focuses only on the current state and does not provide robust prediction over time (95, 96). A more robust measurement of alcohol craving is the multiple-item Penn Alcohol Craving Scale. It is comprised of five items that assess frequency, intensity, and duration of craving (97), and is widely used and accepted in RCTs (14). The Yale–Brown Obsessive Compulsive Scale—heavy drinkers was developed based on the theory that craving is similar to obsessive-compulsive disorder behaviors (74, 98). Its modified version, the Obsessive Compulsive Drinking Scale (OCDS) (2, 3, 99, 100) is regarded among the better performing multi-item measures for alcohol craving (14). The Questionnaire of Alcohol Urges, Alcohol Urge Questionnaire (101) and Alcohol Craving Questionnaire (ACQ), were derived from the 32-item Questionnaire for Smoking Urges (13). Desire to drink is also a fluctuating experience assessed during abstinence (102) and the Desires for Alcohol Questionnaire (103) attempts to capture this subjective experience as well. These questions seek to assess the desire, pleasure, reinforcement, and control over drinking. Currently, it is impossible to assess if one questionnaire is more suitable than another in assessing alcohol craving. Factors affecting self-reported measure of craving are extensive, and due to the individual differences in the severity of alcohol dependence, are conceptually complex and have challenged researchers to develop additional questionnaires such as the Jellinek Craving Questionnaire (96) and Alcohol Craving Experience Questionnaire (94, 103, 104).

Craving may also result from an affective state; therefore, analysis of facial expressions has been utilized to measure craving in clinical studies. Facial muscle activity, measured by facial electromyography (EMG), has been used to effectively assess global positive and negative facial expressions (105) and previously utilized in measuring craving in smoking studies (106). Measuring craving though imaging studies showing specific craving manipulation, has been widely used to determine the participation of isolated brain structures. For example, using PET (107) and functional Magnetic Resonance Imaging (fMRI) (108), it was possible to assess craving in real time (as measured on a visual analog scale) during alcohol cue-induced activation. Using these approaches, it was possible to visualize the involvement of specific neuroanatomical regions such as the amygdala (emotional locus), hippocampus (cognitive nucleus), and ventral striatum (with the NAcc being one of the primary neural substrates mediating addiction) specifically at the moment when patients were experiencing craving.

In summary, several tools and questionnaires are available to measure craving, but no single approach available today represents a state-of-the-art instrument to measure and capture craving from psychological and neurobiological perspectives (14).

4. Current Pharmacotherapy Treatments to Reduce Craving for Alcohol

Specifically targeting the psychological aspects associated with the three pathway psychological model of alcohol craving (51),experimental approaches to evaluate pharmacotherapies to reduce craving have been based on a theory of dysregulation of neurobiological mechanisms of craving associated with clinical symptoms in alcoholic individuals. First, targeting of the reward pathways, which involve the stimulating effects of alcohol, may result from DA and/or opioid dysregulation. Therefore, opioid receptor antagonists (e.g., naltrexone) and DA receptor antagonists (e.g. atypical antipsychotics) have been evaluated as anti-craving medications. Another possible approach targets obsessive mechanisms. The second pathway affects the dysregulation of the 5-HT system, resulting in intrusive thoughts about drinking with impaired social functioning. As such, 5-HT₃ antagonists (e.g. ondansetron) and serotonin specific re-uptake inhibitors (SSRIs; e.g. sertraline) have been tested extensively. Finally, the dysregulation of relief circuitry, resulting from GABAergic and glutamatergic activity, hypothesized to be responsible for several withdrawal symptoms (anxiety, tension, and arousal), was evaluated with pharmacological treatments (e.g. baclofen, gabapentin, topiramate). Please see Table 1. for the medications discussed in this section and their mechanisms of action.

Table 1.

Medications and their mechanisms of action

Medications	Receptor Selectivity and other Mechanisms of Action	System
naltrexone	μ, κ and δ competitive antagonist	opioid
nalmefene	μ, κ and δ competitive antagonist
haloperidol	D2-antagonist	dopamine
aripiprazole	D2 and 5-HT1A/2C partial agonist 5-HT2A antagonist
quetiapine	D1-2 antagonist 5-HT1A partial agonist 5-HT2A antagonist adrenergic α1-2 antagonist
olanzapine	D2,4 and 5-HT2 antagonist
ondansetron	5-HT3 antagonist	serotonin
fluoxetine	serotonin-specific reuptake inhibitor (SSRI)
topiramate	α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)/kainate glutamate antagonist gamma-amino butyric acid (GABA)a agonist carbonic anhydrase enzyme antagonist	inhibition
lamotrigine	sodium channel blocker
levetiracetam	not fully elucidated, but it has been found to target high-voltage, N-type calcium channels, the synaptic vesicle protein 2A (SV2A)
zonisamide	modulation of voltage-gated ion channels, enhancement of synaptic inhibition, and inhibition of synaptic excitation
baclofen	GABAB agonist
gamma- hydroxybutyrlc acid (GHB)	GABAA agonist GHB antagonist
memantlne	n-methyl d-aspartate (NMDA) antagonist	glutamate
acamprosate	NMDA antagonist metabotropic glutamate receptor-5 (mGluR5) antagonist
disulflram	acetaldehyde dehydrogenase inhibition	alcohol metabolism
varenlcllne	α4β2 partial agonist	adrenergic
prazosin	α1 antagonist

4.1 Pharmacological Interventions that Target the Reward Pathway

4.1.1 Opioid Receptors Antagonists

Naltrexone is an opioid-receptor antagonist that has Food and Drug Administration (FDA)-approved indication to treat alcoholism. In the last 20 years, many RCTs evaluating naltrexone for alcoholism, included craving as an outcome. Randomized clinical trials data show that naltrexone-treated patients drink less both in terms of quantity and frequency when compared with placebo-treated subjects (109) and craved less alcohol compared to acamprosate-treated subjects (15). Naltrexone, at a dose of 50 mg/day in combination with a behavioral therapy, decreases alcohol relapse and was also attributed to a reduction of craving (110). Later clinical studies showed that naltrexone was more effective in heavy drinking alcoholics (111) and in patients with a strong family history of alcoholism (112). Heavy drinking early-onset alcoholics, defined as Type B alcoholics, tend to crave alcohol more intensely than moderate drinking late-onset (or Type A) alcoholics (113). These data support the usefulness of using a craving measurement as a clinical guide in assessing relapse risk in heavy drinking alcoholics; however, the role of craving in treatment outcomes and as a predictor of drinking in moderate drinking alcoholics remains unclear.

The fact that naltrexone compared to placebo or acamprosate was effective in reducing overall alcohol consumption in heavy drinking alcoholics brought about the possibility of a feedback loop between craving and amount of drinking in the COMBINE trial (44). Interestingly, it was demonstrated that naltrexone was more successful in reducing relapse when patients experienced a high level of alcohol craving at study randomization (38, 114-116). This observation suggests that naltrexone may represent a pharmacotherapy to help patients at the initial state of recovery, when craving is at its most intense.

To establish whether opioid antagonists may be an effective anti-craving pharmacotherapy, clinical researchers have used different approaches. For example, a study was designed to administer naltrexone “as-needed” in anticipation of high-risk drinking, when triggers were expected, or when drinking was felt to be imminent (117). Compared to placebo, patients in the naltrexone intervention reported less craving and showed reduced drinking after 12 weeks. This approach targeted two important aspects: (1) craving intensity, which addresses the primary impact on relapse issues when the craving experience is acute (14); and (2) craving frequency and duration, which addresses the concept of time of maximum desire (50, 94). A subsequent trial corroborated the targeted naltrexone data showing that naltrexone (compared to placebo) taken only when craving occurs was effective in maintaining alcohol reduction by heavy drinking alcoholics (118). The efficacy of “as-needed” modification of the opioid system to reduce alcohol consumption in patients suffering from AUD has also been used with nalmefene, an opioid antagonist with a longer half-life, greater oral bioavailability, and no observed dose-dependent liver toxicity compared to naltrexone (119). Nalmefene was recently approved, “as needed” by European Medicine Agency as a treatment for alcoholism.

Researchers adopted the use of a combination of pharmaceutical and behavioral therapies and evaluated the results compared with monotherapies (44, 120-124). Investigators of the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study demonstrated that naltrexone alone, not in combination with Combined Behavioral Intervention (CBI), improved alcohol drinking outcomes (125). However, both naltrexone and CBI were shown to reduce craving; yet naltrexone’s anti-craving effects were only visible after four weeks of treatment, while CBI required 12 weeks of intervention before reducing craving episodes (44).

The anti-craving effect of naltrexone was also evaluated in longer studies. A 12-month-long open-label study in India compared the efficacy of naltrexone and disulfiram in preventing alcohol relapses in conditions similar to those in routine clinical practice (126). The study demonstrated that naltrexone was superior to disulfiram in reducing craving (126). This study supported the beneficial anti-craving effect of naltrexone in another long-term (12-month) randomized single-blind study comparing the effect of naltrexone to acamprosate (15). While the mean time to “first drink” was similar between the naltrexone (44 days) and acamprosate (39 days) groups, the time to “first relapse” (five or more drinks) was longer in the naltrexone (63 days) than acamprosate (42 days) group. At the end of treatment, participants in the naltrexone group experienced less craving than in the acamprosate group. Alternately, despite the positive results in reducing craving when compared to other medications, naltrexone failed to be effective in reducing relapse in chronic heavy-drinking alcoholics, in another study (127).

As a large result of genetic heritability, alcoholic individuals with a family history of alcoholism appear to have greater benefits with naltrexone therapy compared with those who do not (128).. The effect of naltrexone as an anti-craving medication may be moderated by variations in the μ-opioid receptor gene OPRM1 (89, 129, 130). The A118G single nucleotide polymorphism (SNP) of the OPRM1 (μ) gene was tested in a double-blind, placebo-controlled laboratory trial of naltrexone in heavy drinking alcoholics (88). Individuals with at least one copy of the G allele reported lower alcohol craving and higher alcohol-induced “high” than patients with the A homozygous allele. In other words naltrexone attenuated alcohol craving and an alcohol-induced “high” with a stronger effect among patients with the heterozygous G allele (88). The efficacy of naltrexone in reducing relapses however, was not confirmed by a study of polymorphic variants at each of the three opioid receptor genes, OPRM1, OPRK1 (κ) and OPRD1 (δ) (131). The study specifically focused on the OPRM1 Asn40Asp variant, that was previously identified as a predictor of response to naltrexone (51, 89, 129, 130). The moderating effects of Asn40Asp variant on the relation between craving, alcohol consumption and the attenuating effects of naltrexone was however, confirmed by a recent 12-week, RCT (132). In summary, naltrexone is one of the most evaluated medications in clinical research for reducing craving. It was superior to placebo in lessening craving, preventing relapse to heavy drinking, and in increasing the percentage of abstinent days. The results obtained from numerous studies are consistent with providing evidence that naltrexone may reduce craving when compared to other medications (acamprosate and disulfiram); however, it was not effective in reducing alcohol drinking as a long-term clinical outcome.

4.1.2 Dopamine Receptor Antagonists

The involvement of the dopaminergic limbic system (133) and the ‘incentive sensitization’ model of craving (55, 62) suggests that dopamine antagonists may counteract the DA moderated effects of alcohol intoxication (134). A RCT investigating the effect of the D₂-antagonist haloperidol in alcohol-dependent individuals showed that pre-treatment with haloperidol significantly reduced alcohol craving, amount of alcohol ingested, and reduced impulsivity (134). The detrimental consequences associated with the first generation of antipsychotics, such as the extrapyramidal effects involving motor control (akathisia) and involuntary movement disorder (tardive dyskinesia), have limited their use both in research and clinical applications in treating AUD (135-137). Subsequently, it was hypothesized that if the first generation of antipsychotics proved to block alcohol cue-elicitation and blunt craving experiences, newer atypical antipsychotics might reduce craving symptoms without the substantial adverse effect profile associated with first-generation antipsychotics (138). Ultimately, the use of atypical antipsychotics was shown to provide some benefit to patients suffering from AUD and those with concomitant psychiatric illness (139-143).

Aripiprazole is an atypical antipsychotic that acts as a partial agonist both at D₂ and at the 5-HT_1A receptors, and like the other atypical antipsychotics, also displays an antagonist profile at the 5-HT_2A receptor. Aripiprazole, first proposed in 2003 for use in alcoholism (144), also antagonizes the 5-HT₇ receptor and acts as a partial agonist at the 5-HT_2C receptor. Aripiprazole was subsequently tested in a multi-site RCT, but failed to meet its primary outcomes (145). Aripiprazole, in another double-blind, comparison trial was shown to reduce craving (146), but to a lesser extent than with naltrexone (147).

Quetiapine, which binds to D_1-2, 5-HT_1A-2A, and adrenergic α_1-2 receptors, has shown to improve abstinence possibly by addressing sleep disturbances in alcohol-dependent patients (148, 149). Furthermore, quetiapine was also shown to provide benefits in reducing craving in patients suffering from the more complicated type B alcoholism (139). In a case study of alcoholics with mood disorder comorbidity and persistent craving after withdrawal, eight of nine individuals who received quetiapine , remained abstinent during a two-to-seven-month period (150). In a later open-label study, quetiapine was used as the sole therapy for patients suffering from alcohol dependence with a comorbid diagnosis of bipolar disorder, schizophrenia, or other borderline personality disorder (151). In this study of alcoholic patients with a concurrent Axis I disorder, quetiapine not only reduced overall alcohol consumption and psychiatric symptom intensity , but also reduced craving (151). The extended release formulation of quetiapine was also evaluated in a larger multi-site trial, however was no better than placebo in reducing heavy drinking in alcoholic patients and also failed to improve craving (152).

Olanzapine, an atypical D_2,4 and 5-HT₂ antagonist, was investigated in a placebo-controlled RCT where participants were subsequently exposed to both the control and alcohol cues in each session (138). The results demonstrated that a single dose of olanzapine was capable of reducing alcohol urge to drink and loss of control without affecting the alcohol reward mechanism (138). Because olanzapine possesses a high affinity for the D₄ receptor, clinical researchers continue to investigate whether the DRD4 gene may influence the effect of a priming dose of alcohol on craving in alcohol-dependent patients. This pharmacogenomic approach targets the effect of craving in heavy drinking alcoholics with different variable numbers of tandem repeat (VNTR) polymorphisms of the D4 DA receptor gene (DRD4 VNTR). Olanzapine was capable of reducing craving exclusively in patients who possess a long sequence of DRD4 VNTR repeat alleles after exposure to alcohol cues (87). A follow-up 12-week study using olanzapine showed that individuals with the DRD4 7-repeat allele or greater reported reductions in cue-elicited alcohol craving and consumption, while olanzapine did not attenuate alcohol craving in subjects with less than the DRD4 7-repeat allele (153).

Researchers reporting the results of a recent study that evaluated the genetic influences of the dopaminergic pathways involving DA receptor genes (DRD_1-4), and the gene that encodes the DA transporter, (solute carrier family 6, member 3;SLC6A3), concluded that despite the large sample size (n = 3,976), it was not possible to identify a strong enough genetic influence by DA to moderate craving with the severity of alcohol dependence (154).

In summary, pharmacological interventions that target the antagonist effect at the limbic system by counteracting the dopaminergic effects of alcohol intoxication with the intent of mediating craving has not provided consistent results even though it had provided some benefit in patients suffering from AUD and those with concomitant psychiatric illness.

4.2 Pharmacological Interventions that Target the Obsessive Mechanisms

4.2.1 Serotonin System: 5-HT Receptors Antagonists and SSRIs

The role of the serotonergic system in alcohol craving has focused mainly on the participation of the impulse-control processes as meditators of addictive behaviors (78), targeting both antagonism at the widely expressed 5-HT₃ receptor and inhibitory action of SSRIs. Ondansetron is a 5-HT₃ receptor antagonist used as an antiemetic for postoperative nausea and has been shown to have beneficial effects in reducing drinking behavior in early onset drinkers (155, 156). An fMRI study that targeted the ventral striatum, an area of the brain identified as being cue-stimulated with release of alcohol-induced DA output (157), demonstrated that naltrexone and ondansetron, alone or in combination, decreased alcohol cue-induced activation (108).

The serotonergic system has also been identified as a critical component of the craving experience (78). In an early placebo-controlled trial, the SSRI fluoxetine, reduced craving for alcohol (158). However, in a subsequent trial, while it was reported that craving was reduced, there were no differences in alcohol drinking outcomes (159). Despite the intense research dedicated to understanding the effects of alcohol on the serotonergic system, RCTs utilizing SSRIs have reported conflicting results (160-162). The lack of clinical consensus regarding the beneficial outcomes using SSRIs may be due to the complexity of the serotonergic system, since distinct 5-HT receptor subtypes act on several neural mechanisms associated with alcohol consumption (163, 164). In addition, different genetic variations in the 5-HT system suggest that diverse populations previously discussed such as Type A and Type B alcoholics (113) may respond differentially to SSRI treatment (165-167) or even benefit from treatment using specific 5-HT₃-receptor antagonists (155, 168-170). The Type B group may benefit from a pharmacotherapy that offers more than blocking 5-HT reuptake (139).

Genetic influences may be responsible for some of the conflicting results in the study of the relationship between 5-HT and alcohol dependence. For example, the gene that encodes the 5-HT transporter, (solute carrier family 6, member 4;SLC6A4) contains a SNP (rs1042173) that may be a genetic marker for cue-induced alcohol craving among alcoholics (171). More specifically these data support the hypothesis that an underlying neurobiological mechanism associated with the rs1042173-TT genotype may trigger a disproportionate craving in response to alcohol consumption (171).

4.3 Pharmacological Interventions that Target a Relief Mechanism

4.3.1 Inhibition System

Topiramate is a FDA-approved antiepileptic drug with multiple mechanisms of action including antagonism of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA)/kainate glutamate receptors, potentiation of GABA, enhancement of GABA_A receptor function, and inhibition of the carbonic anhydrase enzyme. Topiramate, at 300mg/day (after titration), was evaluated as a possible treatment to reduce drinking days with positive outcomes compared to placebo in reducing the percentage of heavy drinking days from baseline and overall drinking days (172). It was also suggested that topiramate may attenuate drinking consumption by lessening alcohol craving (173). A laboratory study evaluated a lower dose of topiramate (200mg/day) in an alcohol-cue reactivity paradigm showing that topiramate reduced drinking during the titration period as compared to placebo, but did not alter craving (43). The results from this study suggested that topiramate might reduce drinking at lower doses than previously tested, and that the reduced drinking may not be linked to the reduction of craving. A pharmacogenetic investigation also reported that a SNP (rs2832407) of the glutamate receptor GluR5 gene (GRIK1) was associated with the serum level of topiramate, affecting the severity of topiramate-induced side effects based on genotype (174).

Lamotrigine, levetiracetam and zonisamide are other anti-epileptic medications with a broad combination of mechanisms of action (175-177) evaluated for treating alcohol craving or urge. Lamotrigine is a sodium channel blocker with many indeterminate mechanisms of action. Lamotrigine reduced craving both in preclinical models (178) and in human trials (142). In combination with clozapine, lamotrigine was shown to reduce craving among patients suffering from schizophrenia and comorbid alcohol dependence (142). Levetiracetam has been shown to reduce alcohol craving in open-label studies (179); however, in a double-blind, placebo-controlled RCT, levetiracetam did not show benefits in alcohol consumption in patients suffering from severe AUD (180). In an open-label study of alcohol-dependent patients, zonisamide reduced craving, weekly drinking and urge (181). Zonisamide also reduced heavy drinking, overall drinking and urge in a double-blind RCT compared to placebo (182).

Baclofen, a GABA_B receptor agonist approved by the FDA to control muscular spasticity, has been used with beneficial effect to treat AUD (183-185). Based on its limited liver metabolism, baclofen was hypothesized as a pharmacotherapy intervention suitable for alcoholic patients with cirrhosis (186), including those with Hepatitis C virus (HCV) infection (187), and effective in suppressing alcohol withdrawal (183, 185, 188). The positive outcomes, measured as lessening craving in alcoholics (189-192), were suggested by the effects of baclofen in reducing anxiety (190, 193), which is often comorbid in alcoholics (194). It was also demonstrated that despite the previous positive drinking outcomes and the reduction of anxiety, baclofen was not superior to placebo in the treatment of alcohol dependence (195). In addition to the difference in severity of alcohol dependence (196) and high placebo effect (197), a reason for these conflicting results might be the large variability of baclofen’s pharmacokinetics profile in alcoholics (198). Finally, a recent pilot laboratory study provided preliminary evidence that baclofen may not reduce cue-induced craving. By contrast, this study suggested that baclofen’s ability to reduce alcohol drinking might be secondary to its ability to alter alcohol-related biphasic effects (199).

Gamma-hydroxybutyric acid (GHB), approved in Italy and Austria as a treatment for alcohol dependence, has been investigated as an anti-craving medication for alcohol dependence (200). GHB is a naturally occurring substance that is approved for restricted use by the FDA to treat narcolepsy. GHB has also been used as a general anesthetic and to treat conditions such as insomnia, clinical depression and alcoholism in Europe. It is also used as an illegal intoxicant or as a date rape drug (200). The transient beneficial effect of GHB in reducing craving compared to placebo (201, 202) may be due to the short half-life of the drug (203). In one study, patients receiving the same dose of GHB (50 mg/kg) from three to six times per day reported less craving than at baseline (204). Despite the encouraging results from investigations of GHB in lessening craving, the clinical application of a drug that requires administration six times per day in patients suffering from AUD, often with other comorbidities, and is itself an addicting substance, is difficult to justify. Nonetheless, GHB is widely used in some European countries but its distribution is done under very strict medical monitoring (205).

4.3.2 Glutamate System: NMDA Receptor Antagonists

Glutamate, the major excitatory neurotransmitter in the brain, utilizes both inotropic and metabotropic receptors to transduce excitatory signals. The NMDA receptors are gated by membrane potentials and provide binding sites simultaneously for both glycine and glutamate. NMDA receptors represent one of the highest affinity ethanol targets in the central nervous system (CNS;206-209). Specifically, ethanol inhibits responses to n-methyl-d-aspartate (NMDA) in distinct regional variants in the NMDA receptor subunit composition. Preclinical glutamatergic studies have therefore dedicated intense research in exploring novel pharmacotherapies for alcoholism (210, 211). In clinical studies, NMDA antagonists have been used to produce a state of intoxication that resembles ethanol’s effects (212). Therefore, pharmacotherapies that could counteract this effect by acting on NMDA receptors have been investigated in alcohol-dependent patients (213). Moreover, the potential benefits of NMDA receptor antagonists as treatments for craving in alcohol-dependent patients have also been investigated in preclinical (214) and clinical trials (215).

Human studies using memantine, an NMDA receptor (NMDAR) antagonist, show that NMDAR neurotransmission may be involved in both alcohol craving and alcohol-induced subjective dissociative effects (215, 216). While a human laboratory study reported that pretreatment with memantine but not treatment of post-alcohol consumption, lessened craving (215), memantine had no effect on drinking in a placebo-controlled trial (217)

Though approved in Europe since 1989, acamprosate (N-acetyl homotaurine) was only approved in the United States (US) for treating alcohol dependence in 2004. In vitro studies show that acamprosate may attenuate excessive glutamatergic activity by blocking toxicity produced by abrupt ethanol withdrawal (218). The action of acamprosate on the metabotropic glutamate receptor 5 (mGluR5) has been shown both in preclinical models (219) and in clinical findings (220). The inclusion of acamprosate as an adjunct pharmacotherapy to psychotherapy was shown to be successful in reducing the incidence of relapse (221) and maintaining abstinence in alcohol-dependent patients (222, 223). A double-blind RCT that administered acamprosate for 21 days demonstrated that acamprosate-treated patients showed significantly reduced craving compared to placebo (224).

The effective acamprosate response in alcohol-dependent subjects may be influenced by genetically-controlled variation of NMDA receptors and mGLUR5 (219). Pharmacogenetically-relevant variants for alcohol-dependent patients were explored in a genome-wide association study that included a follow-up study with relapse behavior and pharmacological treatment response in patients suffering from AUD (225). This double-blind, placebo-controlled RCT with acamprosate or naltrexone, reported that the intronic SNP rs13273672, an SP encoded by the gene for the euthroid transcription factor GATA-binding protein 4 (GATA4), was associated with relapse in the acamprosate-treated arm only, and a potential predictor of response to acamprosate among alcoholic individuals. However, the genetically moderated response to acamprosate was not associated with craving.

4.4 Pharmacological Interventions that Target other Mechanisms

4.4.1 Alcohol Metabolism

Disulfiram was the first medication that received an FDA indication to treat alcoholism. It produces aversive effects by interfering with alcohol metabolism and increasing acetaldehyde concentration (226). In RCTs, disulfiram has demonstrated inconsistent results as a pharmacotherapy to increase abstinence in alcoholics by reducing craving. As an adjunct therapy, disulfiram has facilitated clinical benefits in reducing alcohol craving by providing additional psychological support (227). An eight-month study comparing disulfiram with acamprosate demonstrated that despite disulfiram showing more beneficial effects in preventing relapses in alcoholics, the acamprosate group reported lower craving (228).

Another study testing disulfiram in patients with a concurrent Axis I psychiatric disorder and alcohol dependence suggested that disulfiram might have some benefits in reducing alcohol craving (229). This effect may be attributed to disulfiram interfering with the metabolism of DA (230), and therefore potentially influencing the development of craving. Additionally, subjects with post-traumatic stress disorder (PTSD) had better alcohol outcomes with disulfiram when compared to naltrexone and placebo (231). Patients diagnosed with PTSD receiving disulfiram responded better than non-PTSD patients, possibly because of disulfiram inhibition of DA beta-hydroxylase in the CNS, potentially resulted in an excess of DA and decreased synthesis of norepinephrine (232). The beneficial effect of disulfiram is limited to trials where the drug is administered under supervision (233) and does not provide enough evidence to support its use to treat AUD or to reduce craving in the clinical setting (234).

4.4.2 Adrenergic System: Nicotinic Receptor Antagonists

Because both nicotine and ethanol increase DA release in the reward pathway, it has been hypothesized that they may play a synergistic role when administered simultaneously (235). In addition, some of the effects of ethanol in the brain seem mediated by the activation of neuronal nicotinic acetylcholine receptors (nAChRs) (236). Varenicline is an FDA-approved treatment for smoking cessation that targets the nAChRs and has been investigated both in preclinical (237-239) and clinical (240, 241) settings as a medication to reduce alcohol consumption. Varenicline has been shown to have beneficial effects in preclinical craving models in reducing cue-induced ethanol relapses, but not nicotine seeking in self-administration-reinstatement models (242). A double-blind, placebo-controlled study examined the effect of varenicline following a priming alcohol drink, and showed that varenicline attenuated alcohol craving and reduced subjective reinforcing alcohol effects (243). Furthermore, a randomized, double-blind, 16-week study in heavy-drinking smokers designed to determine the effects of varenicline on alcohol craving revealed that patients allocated to the varenicline-arm reported less craving than the placebo group (240). In a recent pilot study, the varenicline effects in term of drinking outcomes were not significantly more effective than placebo (244), however, a multi-site 13-week RCT that assessed varenicline in alcohol-dependent patients (both smokers and nonsmokers) showed that the varenicline group reported significantly lower alcohol craving than the placebo contol (245).

Prazosin, a FDA-approved α₁ receptor antagonist medication approved to treat blood pressure and benign prostatic hyperplasia, was demonstrated to be efficacious in stress-induced alcohol reinstatement in preclinical models (246-248). The rationale to utilize prazosin to treat AUD was based on the potential to antagonize postsynaptic α₁ activity involved in stress-induced reinstatement of alcohol seeking and modulate craving experiences. A preliminary clinical study peformed during early recovery from alcoholism reported a favorable outcome in reducing alcohol craving, anxiety, and negative emotion following stress exposure in patients taking prazosin(249). In a second study using 16mg/day of prazosin compared to placebo, among the 20 completers, the prazosin group reported fewer drinking days per week than the placebo group during the final 3 weeks of the study (250).

5. Conclusion

The challenges associated with the understanding of alcohol craving and its role in AUD has been a difficult task to operationalize in both in the research and clinical settings. Researchers have developed interdisciplinary craving models to reduce the knowledge gap attempt to explain betweenthe brain circuitry pathways and the central behavioral feature of addiction. Clinicians have assessed and measured craving to monitor the efficacy of pharmacotherapies in patients suffering from AUD. However, based on a relatively rudimentary understanding of the subjective nature of craving, accurate assessment of what experiencing craving is to both the patient and clinician at this time is impossible. Scientists though continue to strive to find medications that reduce drinking and craving, with the assumption that treating both will result in better outcomes. As a result, many drugs have been studied with mixed results.

Naltrexone, a medication evaluated extensively in clinical research was shown to be superior to placebo and other interventions (CBI, disulfiram and acamprosate) in lessening craving; however, it was not effective in reducing alcohol drinking as a long-term clinical outcome. Pharmacological interventions that target the antagonist effect at the limbic system (antipsychotics) have not provided consistent results even though they demonstrated benefit in patients with concomitant psychiatric illness. RCTs Randomized controlled trials utilizing SSRIs have reported inconclusive results on their therapeutic effect in preventing relapses and lessening craving for alcohol. Varenicline, which utilizes the similar craving aspects and the synergistic effects of smoking and alcohol, was shown to reduce craving and smoking both in smokers and in nonsmokers; however, craving is was not always associated with reducing alcohol drinkingconsumption. A better understanding of the neurobiology associated with AUD and more comprehensive methods to measure and assess craving may favor more effective pharmacological interventions that lead to beneficial clinical outcomes

The development of alternative approaches that aim to reduce craving has yielded interesting interventions that need further evaluation. For example, by easing stress-induced alcohol seeking, it may be possible to reduce craving experiences, diminish risk of relapses and facilitate the formation of memories with less deleterious behavioral consequences (251). There are no current medications that target stress-induced craving at the extrahypothalamic brain level in order to reduce compulsive alcohol seeking, although non-peptidic, blood-brain barrier penetrating corticotropin releasing factor (CRF)-receptor 1 antagonists have shown efficacy in animal models to treat alcoholism (252, 253). A pharmacological intervention that targets stress-induced alcohol craving may be more suitable for patients that suffer anxiety or are prone to stress-triggered situations such as cue-induced relapses (254). CRF-antagonists that target the effect of stress in alcohol consumption, despite evidence that stress increases risk of relapses and induces alcohol craving, demonstrated in clinical investigation that not all alcoholics during abstinence experience anxiety, therefore limiting CRF-antagonists for patients who are prone to stress-triggered situations such as cue-induced relapses. Craving is dictated by intertwined mechanisms that affect adjacent neuronal or distant physiologic systems. Current research on evaluating medications that target multi-systems may lead to new pharmacological approaches to treat AUDs.

Key points.

1. Now recognized by the DSM-5 as an important diagnostic assessment for alcoholism, craving is a superfluous subjective concept difficult to express and accurately assess across the heterogeneous population of alcoholics.

2. Though related to alcohol relapse, a reduction in craving seen with pharmacotherapy has not consistently been associated with a reduction in drinking.

3. A better understanding of craving is needed to help advance the successful treatment of alcoholism.