Basic Science and Human Laboratory Studies

The endogenous opioid system, particularly through its interactions with the cortico-mesolimbic dopamine system, is involved in the expression of alcohol’s reinforcing effects ^a

a References .

Schematic representation of opioid interactions with the cortico-mesolimbic dopamine reward pathway. Functional activity of beta-endorphin pathways primarily originating from the nucleus arcuatus can lead to increased dopamine release in the nucleus accumbens via two mechanisms. First, beta-endorphins can disinhibit the tonic inhibition of γ-aminobutyric acid ( GABA ) neurons on dopamine cells in the ventral tegmental area. Second, beta-endorphins can stimulate dopamine cells in the nucleus accumbens directly. Both mechanisms may be important for alcohol reward. Alcohol stimulates beta-endorphin release in both the nucleus accumbens and ventral tegmental area. Mu receptor antagonists such as naloxone and naltrexone block these central effects of beta-endorphins. Embellished from Gianoulakis.

Reprinted from Johnson and Ait-Daoud, with kind permission from Springer Science+Business Media.

Although naltrexone has some affinity for the kappa-opioid receptor, its principal pharmacological effect on alcohol consumption is through blockade of the mu-opioid receptor, as mice that lack the mu-opioid receptor do not self-administer alcohol. Furthermore, alcohol intake increases beta-endorphin release in brain regions such as the nucleus accumbens, an effect that is blocked by naltrexone. Mu receptor antagonists such as naltrexone and naloxone also suppress ethanol intake across a wide range of animal paradigms ^b

b References .

Ethanol has complex neurobiological interactions that affect the production, secretion, and binding of opioids to their receptors, thereby hinting at a fundamental mechanistic process linking the two. This relationship does, however, remain imperfectly understood. For example, animals bred for high ethanol preference exhibit an exaggerated reactive rise in beta-endorphin level following ethanol intake. Yet, naltrexone’s ability to suppress ethanol-associated increases in beta-endorphin level appears greater in animals bred for low rather than high preference for alcohol. Indeed, from a group of animals in the beta-endorphin–deficient mutant mouse line—C57BL/6-Pomc1(tm1Low)—the highest ethanol consumption occurred in the heterozygotes (50% beta-endorphin deficient) and not the homozygotes (no beta-endorphin) or control group of sibling wild-type mice from the same strain. These findings do suggest, however, that molecular genetic differences that alter beta-endorphin expression, not simply its plasma levels, modulate the level of response to naltrexone. Nevertheless, there is growing evidence in humans that differences in the OPRM1 mu-opioid receptor gene are associated with differential therapeutic response to naltrexone—a theme that is explored in detail later in this review.

Human laboratory studies that have evaluated naltrexone’s effects on alcohol-induced positive subjective mood and craving have yielded mixed results. Although it has been shown that naltrexone can reduce alcohol-induced positive subjective mood, albeit with increased sedation, and increase the latency to consume alcohol among social drinkers, others have reported no effect. It does appear, however, that a positive familial loading for alcoholism might predict the potential anti-drinking and anti-craving effects of naltrexone in human laboratory studies. For example, King et al. showed that social drinkers with a familial loading for alcoholism were more likely than those without it to exhibit a decrease in the stimulant effects of alcohol following naltrexone treatment. Nevertheless, they also reported concomitant negative mood exemplified by increased tension, fatigue, and confusion and decreased vigor, as well as notable adverse events such as nausea and vomiting following naltrexone. More recently, Krishnan-Sarin et al. have shown that individuals with a family history of alcoholism, compared with their family history–negative counterparts, consumed less alcohol in a laboratory paradigm. Obviously, these results would lead to the speculation that there could be a genetic explanation for differential response to naltrexone’s effects on craving and alcohol consumption among individuals with alcohol use disorder, which can be studied in the human laboratory. Nevertheless, even here, what has been demonstrated is that naltrexone increases the urge to drink among alcohol-dependent individuals who are aspartate (Asp) carriers of the OPRM1 gene but has no effect on their homozygote, that is, asparagine-carrying, counterparts in a cue-reactivity laboratory paradigm. Despite the dissimilarities between studies, including the subject’s motivation toward seeking treatment, experimental set, setting, expectations, and paradigm, these results do appear to be in contrast with the report that naltrexone preferentially protected against relapse in Asp-carrying alcohol-dependent individuals. The implications of these findings are discussed in the clinical subsection below.

In sum, basic science studies support the finding that naltrexone can reduce ethanol drinking and related behaviors in animals. Naltrexone appears most effective in suppressing the expected ethanol-induced increase in beta-endorphin level among animals that exhibit an exaggerated beta-endorphin response. The pharmacogenetic construct for understanding preferential response to naltrexone is not well understood and is even contrary to expectations. Generally, human laboratory studies provide some support for naltrexone as a medication that can reduce craving for alcohol as well as its consumption; however, these effects appear to be more readily demonstrable among individuals with high familial loading for alcoholism. An initial pharmacogenetic exploration did not demonstrate that naltrexone’s anti-drinking effect is greatest among non–treatment-seeking, alcohol-dependent individuals who carry the Asp variant of the OPRM1 gene.

Clinical Studies With Oral Naltrexone

In 1994, the US Food and Drug Administration (FDA) approved naltrexone for the treatment of alcohol dependence based on data from two relatively small (total N = 167) studies. In those studies, recently abstinent, alcohol-dependent individuals who received naltrexone (50 mg/day), compared with their counterparts who got placebo, were less likely to relapse during the treatment period of 12 weeks. Nevertheless, 5 months after treatment, the relapse rates for the naltrexone and placebo groups were similar. The anti-alcohol-craving effects that were ascribed to naltrexone were based on three findings. First, individuals with the highest level of baseline craving appeared to benefit the most from naltrexone. Second, abstinent individuals who had received naltrexone had less of an impulse to initiate drinking. Third, even among those who sampled alcohol, less pleasure was derived from the beverage. These earlier studies were limited by the fact that only male veterans were tested in one of the studies, and either there was no biomarker used to corroborate the self-reported data or when the liver enzyme γ-glutamyl transferase was used as a biomarker the results were not contributory —presumably due to the relative insensitivity of this measure to capture transient drinking patterns.

Notably, in two large meta-analyses, naltrexone has been demonstrated to be efficacious at reducing the risk of relapse among recently abstinent, alcohol-dependent individuals. What has emerged from an examination of these studies was that naltrexone’s effect size was small, with a corresponding number needed to treat (i.e., the number of individuals who need to be treated to prevent relapse in a single individual) of seven. An important threat to demonstrating efficacy for naltrexone is not having quite high enough levels of medication compliance. Indeed, in a 3-month follow-up and systematic replication of their study, Volpicelli et al. found only a significant effect of naltrexone treatment compared with placebo recipients if the pill-taking rate exceeded 90%; even here, the difference in the percentage of drinking days between the naltrexone and placebo groups was small—3% and 11%, respectively.

Perhaps because of this small effect size, some studies have failed to demonstrate naltrexone’s efficacy in treating alcohol dependence. For instance, in the United Kingdom collaborative trial led by Chick et al., no overall difference was found between the naltrexone 50 mg/day and placebo groups on any of the endpoint measures; however, when individuals with less than 80% pill-taking compliance were excluded from the analysis, naltrexone was associated with a lower percentage of days drinking compared with placebo—12% versus 20%, respectively. With naltrexone treatment, reduced pill-taking compliance is typically the result of adverse events such as nausea that can be reported as significant in up to 15% of trial participants. Therefore, new technologies that aim to improve compliance by delivering naltrexone in depot form might possess a therapeutic advantage to the oral formulation. These technologies are discussed later in this section.

It is important to note that the landmark COMBINE study ( N = 1383) has served to underscore that naltrexone (100 mg/day) plus medication management to enhance compliance compared with placebo reduced the risk of a heavy drinking day (hazard ratio [HR] 0.72, 97.5% CI 0.53–0.98; P = 0.02). Uniquely, this study used a higher naltrexone dose (i.e., 100 mg/day vs. 50 mg/day), and the high compliance rate of pill taking—85.4%—improved clinical outcome.

Recently, it has been proposed that individuals with the Asp variant of the OPRM1 gene exhibited preferentially higher relapse prevention rates when receiving naltrexone treatment. As described previously, a similar response to naltrexone treatment on cue-elicited craving was not observed among non–treatment-seeking, alcohol-dependent individuals in a human laboratory study. Furthermore, a recent clinical trial did not find a preferential effect of naltrexone treatment on any of the variants of the OPRM1 gene. Notably, the functional importance of variation in the OPRMI gene is still being elucidated. Although earlier studies in transfected cells suggested that the OPRM1-Asp variant had a threefold higher affinity for beta-endorphin than OPRM1-Asn, which would suggest enhanced function, this has not been corroborated by others. In humans, a commonly investigated single-nucleotide polymorphism (or SNP), rs1799971, which encodes an Asn40Asp amino acid substitution, occurs in exon 1 of the OPRM1, in which an adenine to guanine substitution (A118G) exchanges an asparagine for an aspartic acid at a putative N -glycosylation site (N40D). Recent in vitro transfection studies have, however, have suggested that the minor G118 allele might be associated with lower OPRM1 protein expression than the A118 allele. In humans, A118G was found in one study to predict the efficacy of naltrexone in reducing the likelihood of heavy drinking in alcohol-dependent participants. In contrast, not all studies have shown these effects. For example, a study in male veterans reported no moderating effect of the A118G SNP and the SNP did not improve drinking outcome among African Americans. A further complication to estimating the general clinical significance of the effects of the Asp allele on pharmacotherapeutic response to naltrexone is that its frequency can vary considerably between populations—from as low as 0.047 in African Americans to 0.154 in European Americans, and as high as 0.485 among those of Asian descent. More genetic studies are, therefore, needed to elucidate fully the mechanistic effects of the Asp allele, and to establish whether or not naltrexone response varies by variation at the OPRM1 gene.

Certain clinical characteristics have been associated, however, with good clinical response to naltrexone, and these include a family history of alcohol dependence or strong cravings or urges for alcohol.

Naltrexone’s utility compared with placebo as an add-on treatment in individuals with alcohol use disorder and comorbid bipolar I or II disorder was investigated recently. All individuals received their concomitant medications prescribed for bipolar disorder prior to study entry, along with standardized cognitive behavioral therapy designed for the treatment of bipolar disorder and substance use at scheduled intervals during treatment. Naltrexone showed trends ( P < 0.10) toward a greater decrease in drinking days and alcohol craving but did not differ statistically from placebo on any outcome measure of drinking.

Naltrexone’s utility compared with placebo as a treatment for alcohol dependence and smoking cessation also has been studied recently. In that placebo-controlled study, there was no overall effect of naltrexone on either the consumption of alcohol or smoking. In a subsequent subset analysis confined to heavy drinkers (defined as those with at least one heavy drinking episode during the 2-week pre-enrollment baseline period), there was an effect of naltrexone to reduce heavy drinking; however, again there was no effect on smoking. Of interest, there was a significant negative association between quitting smoking and decreasing alcohol consumption, whereby greater success in stopping smoking was correlated with increased amounts of heavy drinking. These results do not provide strong support for the use of naltrexone as a medication for the simultaneous reduction or cessation of alcohol consumption and smoking among individuals comorbid for these conditions.

Although the use of naltrexone in the treatment of alcohol use disorder is supported by the scientific evidence and accepted by many regulatory agencies, most studies have looked at the target variable of naltrexone’s propensity to prevent relapse. It is, therefore, not surprising that most studies have found that opioid antagonists reduce relapse to heavy drinking. It is notable that there also is some evidence that naltrexone may be more efficacious when prescribed to individuals who are actively drinking. This appears consistent with naltrexone’s known effect on the endogenous opioid system, particularly through its interactions with the cortico-mesolimbic dopamine system. Alcohol stimulates beta-endorphin release in both the nucleus accumbens and ventral tegmental area, and opioid antagonists such as naltrexone block these central effects of beta-endorphins with the overall gain of a reduction in the reinforcing effect of alcohol. If there is no alcohol, then there is no alcohol-induced release of endogenous opioids for an opioid antagonist to block. In most clinical trials, no significant benefit from naltrexone was found while participants were abstinent, the primary effect of naltrexone was seen in participants who drank any alcohol while being enrolled in the trial. This work has been promoted by David Sinclair and his team in Finland. They provided evidence that opioid antagonists such as naloxone, nalmefene, or naltrexone had to be given in conjunction with alcohol drinking to produce positive results in animals. Furthermore, their results indicated that giving naltrexone, naloxone, or nalmefene during abstinence was not useful, as the major benefit from an opioid antagonist is produced by the mechanism of extinction. Clinical trials from David Sinclair and his group showed that alcohol craving and drinking slowly diminished over many weeks in the form of an extinction curve. ^c

c References .

Prescribing naltrexone to abstinent detoxified alcoholics is hypothesized to affect conditioned cue craving as the release of endorphins become conditioned to cues present around alcohol drinking. Naltrexone during abstinence could extinguish the ability of these cues to cause craving; however, it is possible that without the interaction of alcohol to allow for extinction of the behavior, the overall effect may be limited.

In sum, the majority of the data confirm that naltrexone is an efficacious medication for treating alcohol dependence. The therapeutic treatment effect size is, however, small, and poor pill-taking compliance can be associated with poor clinical outcome. Naltrexone can be used safely in individuals with alcohol use disorder without prior detoxification and could be effective even if it is taken only when drinking is expected, although more research evaluating the targeted approach to naltrexone treatment is needed. As a caution, it must be remembered that the FDA does have a black box warning that naltrexone administration could complicate or exacerbate liver damage among individuals with alcohol use disorder. There remains a dearth of published studies on the effects of different doses of naltrexone on drinking outcome. Further research is needed to establish whether naltrexone’s therapeutic efficacy in treating alcohol use disorder differs among individuals who have variants of the OPRM1 gene. Individuals with alcohol use disorder that have a positive family history or strong cravings for alcohol might benefit the most from naltrexone treatment. Naltrexone does not appear to be a promising medication for the contemporaneous reduction or cessation of alcohol consumption and smoking.

Clinical Studies With Depot Naltrexone

Three extended-release formulations of naltrexone for deep intramuscular injection have been developed—Vivitrol (Alkermes, Inc., Cambridge, MA, USA), Naltrel (Drug Abuse Sciences, Inc., Paris, France), and Depotrex (Biotek, Inc., Woburn, MA, USA). The premise for developing these depot formulations of naltrexone is threefold. First, a well-formulated depot preparation can maintain relatively constant plasma levels by producing a slow but regular release of naltrexone. Individuals who take oral naltrexone and have notable adverse events such as nausea that can lead to study discontinuation probably experience this phenomenon due to the rapid rise in plasma levels following initial doses of oral naltrexone. Hence, a depot formulation might be expected to decrease these initial adverse events if it provided a more gradual rise in naltrexone plasma levels. Second, by providing a monthly depot preparation, compliance with receiving the medication is optimized and should be greater than reliance on remembering to take tablets. Third, because plasma levels should remain relatively constant throughout the month following the administration of a depot preparation, there should be relatively greater exposure to the therapeutic dose, thereby facilitating good clinical outcome. Information pertaining to the three depot preparations of naltrexone that are being tested is provided below.

Vivitrex or Vivitrol

Vivitrex, or Vivitrol as it is known now, is naltrexone formulated into poly-(lactide-co-glycolide), small-diameter (<100 μm), injectable microspheres that contain other proprietary active moieties, which lead to its extended-release properties lasting for several weeks. In 2004, Johnson et al. published the initial safety, tolerability, and efficacy trial of Vivitrex for treating alcohol dependence. The design of the study was a 16-week randomized, placebo-controlled, double-blind clinical trial. Of the 25 alcohol-dependent individuals who participated in the trial, five received placebo and the remainder ( N = 20) received 400 mg of Vivitrex. Results of that trial showed the safety of Vivitrex, with the most common adverse events being nonspecific abdominal pain, nausea, pain at the injection site, and headaches. None of the placebo recipients dropped out due to adverse events; in contrast, two of those who got Vivitrex discontinued for that reason. Due to the unbalanced design and small subject numbers, any inferences regarding efficacy had to be viewed quite cautiously. Nevertheless, there was a trend for those on Vivitrex, compared with placebo, to have a lower percentage of heavy drinking days—11.7% vs. 25.3%. Later, in a large placebo-controlled, double-blind, randomized, multisite, 24-week clinical trial, Garbutt et al. showed that high-dose Vivitrex (380 mg) recipients had a significantly lower percentage of heavy drinking days than those who got placebo (HR 0.75, 95% CI 0.60–0.94; P = 0.02). Recipients of low-dose Vivitrex (190 mg) had outcomes similar to those who got placebo. The treatment response signal in the high-dose Vivitrex recipients came from the male participants, as the effect of both Vivitrex doses was no different from that in women who took placebo (HR 1.23, 95% CI 0.85–1.78; P = 0.28). The lack of efficacy for Vivitrol in women has been ascribed to greater subclinical affective symptoms, less of a family history of alcoholism (which is meant to be associated with good clinical outcomes to naltrexone), more responsiveness to placebo, and more clinical heterogeneity in the sample. In contrast with the premise for developing depot preparations, the dropout rate of 14.1% in the high-dose Vivitrex group was similar to that reported in studies with oral naltrexone. The chosen objective biomarker to corroborate the self-reported data—γ-glutamyl transferase—did not show a difference between any of the Vivitrex doses and the placebo group. The common reasons for study discontinuation were injection site reactions, headaches, and nausea. Serious adverse events were reported in two participants taking active medication that resulted in an interstitial pneumonia and an allergic-type eosinophilic pneumonia, both of which resolved after medical treatment. Thus the evidence remains that Vivitrol appears to be efficacious in preventing heavy drinking in men; however, it was approved by the FDA for treatment of both men and women based on the extant literature on naltrexone as a treatment for alcohol dependence. The expected advantage of Vivitrol for increasing compliance did not materialize quickly, although this might become more manifest in generic treatment settings rather than in a closely monitored clinical trial. The potential for hypersensitivity reactions to Vivitrol, although small, does require postmarketing evaluation by the FDA.

Naltrel

Naltrel consists of naltrexone incorporated into microspheres of poly-( dl -lactide) polymer. These microspheres, stored in single-dose vials, are suspended in a diluent that contains carboxymethylcellulose, mannitol, polysorbate 80, and water for injection. The polylactide polymer is metabolized to water and carbon dioxide. Then, as the microspheres degrade, naltrexone is released. In 2004, Kranzler et al. studied the safety and efficacy of Naltrel in treating male and female alcohol-dependent individuals receiving monthly motivation enhancement-based therapy in a double-blind, placebo-controlled, 3-month randomized controlled trial ( N = 157). The initial dose of Naltrel (150 mg) was delivered as a deep intramuscular injection into each buttock, and subsequent monthly doses were just 150 mg. Placebo injections were provided at the same frequency and constitution but lacked the active compound. Adverse events reported significantly more frequently in those who received Naltrel compared with those how received placebo included injection site reactions, chest pain, and upper abdominal pain. Placebo recipients were, however, more likely to report irritability than those who got Naltrel. Although 6 (3.8%) of the placebo recipients dropped out, 13 (8.2%) who got Naltrel discontinued treatment. Naltrel® was superior to placebo at increasing the mean number of cumulative abstinent days (52.8 days, 95% CI 48.5–57.2 days, vs. 45.6 days, 95% CI 41.1–50.0 days, respectively; P = 0.018) and having a longer median time to first drink (5 days, 95% CI 3–9 days, vs. 3 days, 95% CI 2–4 days, respectively; P = 0.003). The effects of gender on treatment outcome were not examined.

Somewhat in contrast, a single-site, 6-week trial of 16 alcohol-dependent individuals who received one intramuscular dose of Naltrel (300 mg) suggested low tolerability, with 198 adverse events being reported. Of these, 17 were considered to be severe and included fatigue, gastrointestinal pain, irritability, nausea, somnolence (two reports), headache (four reports from three subjects), injection site pain, injection site mass, lethargy, depression, increased level of γ-glutamyl transferase (an index of heavy drinking ), back pain, and flatulence. No serious adverse events were reported. Drinking outcomes showed an improving trend over the duration of the trial.

Nevertheless, further studies on the safety and efficacy of the Naltrel formulation are warranted. Additional data are needed to determine whether, as with Vivitrol, there is a differential response on drinking outcomes between men and women who receive Naltrel.

Depotrex

Rather little public information is available on the Depotrex depot formulation. Like the other depot formulations, Depotrex appears to provide steady increases in plasma naltrexone levels and is an effective mu-opioid receptor antagonist. Pharmacokinetic data from 12 heroin-dependent individuals who received low and high doses of Depotrex—192 mg and 384 mg, respectively—showed that both doses maintained plasma naltrexone levels above 1 ng/mL for up to 4 weeks. Average peak levels for the low and high doses of Depotrex were 3.8 ng/mL and 8.9 ng/mL, respectively. Plasma beta-naltrexol, the major metabolite of naltrexone, was greater proportionately but could not be detected 5 weeks following Depotrex administration. Both doses of Depotrex antagonized the positive subjective effects of heroin. Reported adverse events were minimal and included mild discomfort at the injection site, with no irritation or erythema. The promising earlier study by Kranzler et al. of Depotrex (206 mg) in the treatment of alcohol dependence needs to be followed up.

In sum, depot formulations of naltrexone may offer some advantages such as increased compliance over the oral formulations. This advantage has, however, been difficult to demonstrate in randomized controlled trials but might become more apparent when these depot formulations are used in generic practices. Depot formulations do not appear to be more efficacious than the oral formulations, and with one of these—Vivitrol—no therapeutic effect in women has been demonstrated. The adverse event profiles of depot formulations of naltrexone that have been reported in randomized controlled trials appear similar in frequency and intensity to those observed for the oral formulation. The different depot formulations do appear to be similar in characteristics and profile, and more clinical information about which one to select to treat a particular alcohol-dependent individual, if all are approved by the FDA, shall be needed.

Nalmefene

Nalmefene is an opioid antagonist with the reported advantage over naltrexone being a longer half-life, greater oral bioavailability, and no evidence of liver toxicity. Also unlike naltrexone, which is principally an antagonist at mu and delta opioid receptors, nalmefene is a partial agonist at the kappa receptor. Of interest, it has been speculated that this effect of nalmefene on the kappa receptor would render it likely to be more effective than naltrexone. Specifically, notwithstanding its effects to modulate endogenous dopamine function by antagonism at the mu opioid receptor, it also has been hypothesized that nalmefene may modulate the hypothesized overactivity of the dynorphin/kappa receptor by acting as a functional antagonist to decrease alcohol self-administration more markedly in alcohol-dependent compared with nondependent rats. Nevertheless, even though it would be tempting to extend this hypothesis to humans, the relationship between dynorphin/kappa receptor and alcohol consumption remains complex and not well understood.

In a small placebo-control, double-blind, randomized study of 21 individuals with alcohol-dependence, nalmefene 10 mg/day appeared to decrease significantly the number of drinks/drinking day but not any other measure of alcohol consumption. In a second study by the same, 105 alcohol-dependent individuals were given a dosage of nalmefene 20 mg/day and 80 mg/day, and there was no significant difference among them, although more individuals relapsed to placebo (OR 2.4, 95% CI 1.05–5.59). Nevertheless in a much larger controlled study of 270 alcohol-dependent individuals taking nalmefene at a dose of 5 mg/day, 20 mg/day, or 40 mg/day, there was no significant effect compared with placebo for any of the nalmefene doses.

Nalmefene was, however, approved for the treatment of alcohol use disorder in Europe based on the results of three large-scale studies. In the first 24-week, controlled study ( n = 604), nalmefene 18 mg/day compared with placebo was associated with a significantly greater reduction in the number of heavy drinking days per month (−2.3 days, 95% CI −3.8 to −0.8). In addition, when the subjects consumed alcohol, they drank less significantly while on nalmefene compared with placebo (−11 g/day, 95% CI −16.8 to −5.1). In the second study (ESENSE 2; n = 718), which was 24 weeks in length, nalmefene (18 mg/day) also was given on an as-needed basis compared with placebo. Nalmefene compared with placebo was associated with a significantly greater reduction in the number of heavy drinking days per month (−1.7 days per month, 95% CI −3.1 to −0.4; P = 0.012) but not total alcohol consumption (−4.9 g/day; 95% CI −10.6 to 0.7; P = 0.088). Subpopulation analysis from ESENSE 1 and 2 appeared to strengthen the data, whereby for the 667 individuals who met World Health Organization high-risk drinking level criteria (>60 g/day and >40 g/day, for men and women, respectively), the effect of nalmefene compared with placebo appeared to be more striking than that of the combined study population (n = 1.322) (−3.2 heavy drinking days, 95% CI −4.8 to −1.6; P < 0.0001 versus −2.0 heavy drinking days, 95% CI −3.0 to −1.0; P < 0.0001, respectively), and in alcohol consumption (−14.3 g/day, 95% CI −20.8 to −7.8; P < 0.0001 versus −7.6 g/day, 95% CI −11.6 to −3.5; P <0.0003, respectively). For all the studies, the adverse event profile was mild to moderate, with the most common reactions being nausea, dizziness, insomnia, and headache. Confusion, and rarely, hallucinations and dissociations were reported. Adverse events typically occurred early in treatment and were of relatively short duration.

In sum, nalmefene under the brand name Selincro was approved in Europe in February 2013 for the treatment of alcohol use disorder, with the effect of reducing heavy drinking among those deemed not to be in need of detoxification. Nalmefene appears to be well tolerated, although it remains unproven that it is any more efficacious than naltrexone despite the pharmacological expectations.

Metabotropic Glutamate Receptor-5 Modulator and N -Methyl- d -Aspartate Antagonist—Acamprosate

Acamprosate’s principal neurochemical effects have been attributed to antagonism of N -methyl- d -aspartate glutamate receptors, which restore the balance between excitatory and inhibitory neurotransmission that is dysregulated following chronic alcohol consumption. Recently, however, it also has been proposed that acamprosate modulates glutamate neurotransmission at metabotropic-5 glutamate receptors. Evidence that acamprosate modulates a novel site of action at metabotropic-5 glutamate receptors comes from the finding that it inhibits the binding and neurotoxic effects of (±)-1-aminocyclopentane- trans -1,3-dicarboxylic acid. Acamprosate has been shown to decrease: (1) ethanol consumption in rodents, but this effect may not be specific in food-deprived C57BL/6 J mice as both ethanol and water were reduced in a schedule-induced polydipsia task ; (2) dopamine hyperexcitability in the nucleus accumbens during alcohol withdrawal ; (3) general neuronal hyperexcitability ; (4) glutamatergic neurotransmission in alcohol-dependent rats ; (5) voltage-gated calcium channel activity, and (6) the expression of brain c-fos , an immediate early gene associated with alcohol withdrawal. Nevertheless, it is acamprosate’s ability to suppress alcohol-induced glutamate receptor sensitivity, as well as conditioned cue responses to ethanol in previously dependent animals even after prolonged abstinence, that has been linked with its therapeutic effect in humans—dampening negative affect and craving postabstinence ( Fig. 51.2 ).

Schematic representation of acamprosate’s effects. Acamprosate has four principal effects: A, reducing postsynaptic excitatory amino acid neurotransmission at N -methyl- d -aspartate ( NMDA ); B, diminishing Ca ²⁺ influx into the cell, which interferes with expression of the immediate early gene c-fos ; C, decreasing the sensitivity of voltage-gated calcium channels; and D, modulating metabotropic-5 glutamate receptors ( mGluR5s ). mGluR5s are postsynaptic and are coupled to their associated ion channels by a second messenger cascade system (not shown). Also shown in this representation is synthesis of c-fos and c-jun in the endoplasmic reticulum, which can bind with DNA to alter the transcription of late effector genes. Late effector genes regulate long-term changes in cellular activity such as the function of receptors, enzymes, growth factors, and the production of neurotransmitters.

Adapted from Johnson and Ait-Daoud, with kind permission from Springer Science+Business Media—adapted version reprinted from Johnson, with permission from Elsevier—and from Spanagel and Zieglgansberger.

Of interest, there has been a paucity of human laboratory studies that have examined the potential effects of acamprosate on alcohol-related behaviors associated with its abuse liability. Evidence from a human magnetic resonance imaging (MRI) study does, however, support acamprosate’s ability to modulate glutamate neurotransmission as it decreases activity in brain regions rich in N -acetylaspartate and glutamate. Human laboratory studies in both volunteers and alcohol-dependent individuals also have shown that acamprosate—that is, calcium acetyl homotaurinate—is relatively safe, with the most important adverse events being diarrhea, nervousness, and fatigue, especially at a relatively high dose (3 g/day). Because acamprosate is excreted unchanged in the kidneys, there is no risk of hepatotoxicity, but it should be used with caution in those with renal impairment. Acamprosate has no significant clinical interaction with alcohol. Recently, it was shown that acamprosate can reduce heart rate response but not the increase in cortisol or subjective craving following the presentation of alcohol cues—a finding that suggests utility for acamprosate in managing autonomic dysregulation in abstinent alcoholics exposed to a high risk for relapse situations.

Most of the clinical evidence for the efficacy of acamprosate in the treatment of alcohol dependence comes from a series of European studies. In 2004, Mann et al. wrote a meta-analysis of 17 published studies that included 4087 alcohol-dependent individuals. In that report, continuous abstinence rates at 6 months were greater than for those who got placebo (acamprosate, 36.1%; placebo, 23.4%; relative benefit, 1.47; 95% CI 1.29–1.69; P < 0.001). The overall pooled difference in success rates between acamprosate and placebo was 13.3% (95% CI 7.8%–18.7%), and the number needed to treat was 7.5. Similar results were obtained from another meta-analysis conducted at about the same time. Generally, the effect size of acamprosate is small—0.14 for increasing the percentage of nonheavy drinking days and 0.23 for reducing the relapse to heavy drinking. Early studies also had some methodological problems, including nonstandardization of diagnostic criteria and the psychosocial adjunct to the medication, which were resolved in later trials.

Despite approval by the FDA on July 29, 2004, for the use of acamprosate in the treatment of alcohol dependence, largely based on the data from European studies, the results of studies in the United States have been disappointing. In the United States multisite trial by Lipha Pharmaceuticals, Inc., there was no overall clinical evidence that acamprosate was superior to placebo among a heterogeneous cohort of alcohol-dependent individuals; however, post hoc analysis suggested that a subgroup of alcoholics with a treatment goal of abstinence might derive benefit. Furthermore, in 2006, the multi-site COMBINE study also failed to find any therapeutic benefit of acamprosate compared with placebo on any drinking outcome measures. Obviously, the findings of these US studies have reduced the enthusiasm for using it by addiction specialists in the United States. From a scientific perspective, these findings do raise the question as to what type of alcohol-dependent individual benefits the most from acamprosate and why there is an important discrepancy between the results of US and European studies.

From the European studies, acamprosate appears to benefit alcohol-dependent individuals with increased levels of anxiety, physiological dependence, negative family history, late age at onset, and female gender.

There are at least four possible explanations for the discrepancy between US and European studies. First, the populations sampled differ, with European, compared with US, studies having alcohol-dependent individuals with more prolonged drinking histories and alcohol-related neurological and psychosocial impairments. Thus it is tempting to speculate that European studies might have included individuals with greater neuroplasticity and, therefore, higher response to the ameliorating effects of anti-glutamatergic agents such as acamprosate. Second, US, compared with European, studies have tended to have higher levels of standardized psychosocial intervention as an adjunct to acamprosate, thereby masking the effect of the medication. Third, the therapeutic effect of acamprosate is small; hence, by chance, some trials can be expected to fail, especially those conducted in a multisite rather than a single-site environment due to the greater heterogeneity and variability of the cohort and research settings. Fourth, it is possible that future research might uncover other important differences between US and European cohorts to explain the discrepant findings such as potential differences in participants’ subtype, stage of the alcoholism disease, or biomolecular constitution.

In sum, European studies have clearly demonstrated efficacy for acamprosate as a treatment for alcohol dependence. Acamprosate was FDA approved in the United States largely based on the results of the European studies. Acamprosate’s therapeutic effect is small, but it is well tolerated, with the most prominent adverse events being diarrhea, nervousness, and fatigue, especially at a relatively high dose (3 g/day). In contrast, studies in the United States have, to date, been unable to find efficacy for acamprosate among a heterogeneous group of alcohol-dependent individuals. The reason for this discrepancy between the results of US and European studies has not been established. Perhaps, however, this discrepant finding might be due to differences in participants’ selection, subtype, stage of the alcoholism disease, or biomolecular constitution that are yet to be determined. Intriguingly, preliminary results presented for the recently completed multisite collaborative European Study—Project Predict—also did not find an effect for acamprosate in the treatment of alcohol dependence. Future studies are needed to delineate more clearly what type of alcohol-dependent individual can benefit from acamprosate treatment.

Other N -Methyl- d -Aspartate Receptor Antagonists

Other N -methyl- d -aspartate receptor antagonists such as memantine and neramexane are being studied for the treatment of alcohol dependence. Both compounds have been shown in animal models to suppress ethanol-induced N -methyl- d -aspartate receptor upregulation, thereby reducing ethanol sensitization and the propensity for subsequent drug use (for a review, see Nagy and Kotlinska et al. ). In a human laboratory study, memantine reduced alcohol craving prior to but not after the experimental administration of alcohol. This would suggest that memantine might have the effect of reducing postcessation craving for alcohol. This finding is supported by a later report that memantine might have effects comparable to diazepam at ameliorating alcohol withdrawal symptoms. Nevertheless, despite the early preliminary findings, a recent pilot clinical trial comparing memantine with placebo for the treatment of alcohol dependence reported that the greater therapeutic effect at reducing the percentage of heavy drinking days and increasing the percentage of days abstinent occurred among the placebo group. Although this pilot study did not provide support for memantine as an efficacious treatment for alcohol dependence, further studies are needed to make a final determination of memantine’s therapeutic potential for this indication. Recently, it was reported that memantine was as effective as escitalopram (the S-enantiomer of citalopram, a selective serotonin reuptake inhibitor) for the treatment of alcohol dependence in individuals with comorbid major depressive disorder. That study, however, lacked a placebo treatment arm; therefore, it has not been established that memantine is an efficacious treatment for alcohol dependence with comorbid major depression. No human study on the therapeutic effects of neramexane in treating alcohol dependence has been published.

Alpha-Amino-3-Hydroxy-5-Methylisoxazole-4-Propionic Acid and Kainate Glutamate Receptor Antagonist—Topiramate

Topiramate, a sulfamate-substituted fructopyranose derivative, has six important mechanisms of action. In addition to its ability to antagonize alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors and kainate glutamate receptors, topiramate facilitates inhibitory GABA _A -mediated currents at nonbenzodiazepine sites on the GABA _A receptor, inhibits L-type calcium channels and limits calcium-dependent second messenger systems, reduces activity-dependent depolarization and excitability of voltage-dependent sodium channels, activates potassium conductance, and is a weak inhibitor of carbonic anhydrase isoenzymes, CA-II and CA-IV, which are found in both neuronal and peripheral tissues. In renal tubules, carbonic anhydrase isoenzyme inhibition reduces hydrogen ion secretion and increases secretion of Na ⁺ , K ⁺ , HCO ₃ ⁻ , and water, thereby enhancing the likelihood of acidosis and renal stone formation.

Johnson has proposed a neuropharmacological model by which topiramate can decrease alcohol reinforcement and the propensity to drink ( Fig. 51.3 ). Nevertheless, few studies on the effects of topiramate on ethanol consumption in animals have been published. An initial animal study had shown complex effects of topiramate on ethanol drinking in C57BL/6 mice. In that study, high-dose (50 mg/kg) but not low-dose (1, 5, and 10 mg/kg) topiramate suppressed ethanol intake 2 hours after it was injected into the animal. Topiramate also decreased saccharin preference, but its ability to suppress ethanol preference was associated with some increase in water intake. Notably, in an elegant, recent animal study, Nguyen et al. demonstrated that topiramate can suppress ethanol drinking in C57BL/6 mice; in addition, in contrast with the effects of naltrexone and tiagabine in the same animals, the mice treated with topiramate did not develop any tolerance to its anti-drinking effects. Furthermore, topiramate has been shown to suppress ethanol drinking persistently in alcohol-preferring (P) but not Wistar rats. In addition to its ethanol-suppressing effects, there is evidence that topiramate can reduce alcohol- withdrawal symptoms in a model of handling-induced convulsions. Hence, the preponderance of the animal literature does support topiramate as a promising medication for the treatment of alcohol dependence. Nevertheless, the effect of topiramate on ethanol drinking in animals appears to be less striking than that on drinking outcomes in humans, which are presented below. This challenges the notion that animal models can directly predict treatment response in humans, especially when a variety of models have not been used or been available to characterize or “fingerprint” response. The results of additional animal experiments examining topiramate’s mechanistic effects on ethanol consumption or related behaviors in animals are, therefore, awaited eagerly.

Schematic illustration of the hypothesized effects of acute and chronic alcohol, both with and without topiramate, on the cortico-mesolimbic dopamine ( DA ) reward circuit. ( Upper left ) Acute alcohol suppresses the firing rate of ventral tegmental area ( VTA ) γ-aminobutyric acid ( GABA ) neurons, which leads to less suppression of VTA DA neuronal activity. This disinhibition leads to VTA DA neuronal firing and DA release in the nucleus accumbens ( N Acc ). ( Lower left ) With chronic drinking, VTA GABA neurons are hyperexcitable, mainly because of increased glutamatergic input, less GABA tone from the N Acc, and rebound firing of GABA neurons because of their long-term suppression from repeated alcohol ingestion. This leads to VTA DA hypofunction and decreased release (compared with the acute condition) of DA in the N Acc. ( Upper right ) During acute drinking, the GABAergic influence of topiramate probably predominates, particularly in the N Acc. This leads to greater inhibition of N Acc DA neurons, and greater GABA tone from the N Acc to the VTA suppresses VTA DA cell firing. Topiramate concomitantly inhibits the excitatory effects of glutamatergic neurons on DA neurons in the VTA and N Acc. These combined actions of topiramate should lead to profound suppression of DA neuronal activity and DA release in the N Acc. Hence, topiramate reduces the DA-mediated reinforcing effects of acute alcohol. ( Lower right ) During chronic drinking, the predominant neuronal activity resides with the hyperexcitable state of VTA GABA neurons. Because of GABA-mediated inhibition and glutamatergic blockade of these neurons, topiramate “normalizes” VTA GABA neuronal activity. Although this would, at first, suggest that DA release in the N Acc would be enhanced, this does not occur, and DA release in the N Acc is most likely reduced because these N Acc terminals are contemporaneously inhibited by GABA inhibition and blockade of glutamate ( GLU ). In the chronic drinker, the anti-glutamatergic and L-type calcium channel effects of topiramate to block sensitization might predominate. Hence, topiramate would make it easier for a chronic alcoholic to withdraw from alcohol because rebound DA release would not occur (if drinking were ceased abruptly), and topiramate would aid in relapse prevention because alcohol’s reinforcing effects would be decreased. Line weights represent relative strengths of neuronal activity (heavy, medium, and light). The broken line represents decreased tone. VP, Ventral pallidum.

Reprinted from Johnson, courtesy of Blackwell Publishing, Inc.

Recently, Johnson et al. and Ma et al. showed in a double-blind, randomized clinical trial that topiramate (up to 300 mg/day), compared with placebo, improved all drinking outcomes, decreased craving, and improved the quality of life of alcohol-dependent individuals who received 12 weeks of weekly brief behavioral compliance enhancement treatment. The improvements in self-reported drinking outcomes were confirmed by plasma γ-glutamyl transferase, an objective biochemical measure of alcohol consumption. The therapeutic effect size for the primary efficacy variable—percentage of heavy drinking days—was 0.63.

In a 6-week experimental study of 76 heavy drinkers who were not seeking treatment, Miranda et al. showed that low-and high-dose topiramate—200 mg/day and 300 mg/day, respectively—were significantly better than placebo at decreasing the percentage of heavy drinking days.

Furthermore, in a subsequent 17-site ( N = 371) US trial, topiramate (up to 300 mg/day) was again superior to placebo at improving all self-reported drinking outcomes, γ-glutamyl transferase level, and some measures of quality of life among alcohol-dependent individuals who received 14 weeks of weekly brief behavioral compliance enhancement treatment. Topiramate’s therapeutic effect size for the reduction in percentage of heavy drinking days was 0.52, and the number needed to treat was 3.4.

Topiramate’s effects on glutamate receptors appear to be more potent and selective for those containing the GluK1 and GluK2 subunits encoded by GRIK1 and GRIK2, respectively. One SNP, rs2832407, a C-to-A noncoding substitution, has been found to be associated with alcohol use disorder, with the C allele being more common in subjects with the disorder. The same allele was found to be related to significantly fewer adverse medications when participants were treated with topiramate.

In a 12-week randomized placebo-controlled clinical trial of 138 individuals with alcohol use disorder, treatment with 200 mg of topiramate significantly reduced heavy drinking days and increased abstinent days as compared to placebo. In a subset of the population, mainly the European American subsample (N = 122), topiramate’s effect on heavy drinking days was significantly influenced by the rs2832407 C-allele, with homozygotes having a more favorable response.

Taken together, these clinical studies provide strong evidence that topiramate is a promising medication for the treatment of alcohol use disorder. Encouragingly, topiramate’s therapeutic effect size is in the moderate range, and the clinical effects appear to increase with greater length of time on the medication.

Generally, topiramate has a favorable adverse event profile, with most reported symptoms being classified as mild to moderate. The most common adverse events are paresthesia, anorexia, difficulty with memory or concentration, and taste perversion. Slow titration to the ceiling dose (up to 300 mg/day) for 8 weeks is critical to minimizing adverse events and improving tolerability ( Table 51.1 ); however, about 10% of individuals taking topiramate may experience some cognitive difficulty, irrespective of the dose titration schedule. Topiramate use has been linked with acute but rare visual adverse events. As of January 2005, there had been 371 spontaneous reports of myopia, angle-closure glaucoma, or increased intraocular pressure, for a rate of 12.7 reports per 100,000 patient-years exposure. Usually, the syndrome of acute bilateral myopia associated with secondary angle-closure glaucoma presents as the acute onset of visual blurring, ocular pain, or both. Associated bilateral ophthalmologic findings can include myopia, shallowing of the anterior chamber, conjunctival hyperemia, and raised intraocular pressure. This syndrome resolves within a few days of discontinuing topiramate administration.

Although topiramate has not shown efficacy in the treatment of bipolar disorder, there is an ongoing National Institutes of Health–funded study of its efficacy in the treatment of individuals with comorbid alcohol use disorder and bipolar disorder. It is presumed that among individuals whose bipolar disorder is stabilized by concurrent medication prior to the trial, topiramate would have an added effect to improve drinking outcomes. Results of this study are awaited eagerly. Another anticonvulsant, valproic acid, is promising, as it has been shown to decrease heavy drinking in alcohol-dependent individuals with bipolar disorder.

As a subgroup analysis of a 12-week double-blind, randomized, controlled trial, the effect of topiramate versus placebo among alcohol-dependent smokers was evaluated. Topiramate recipients were significantly more likely than placebo recipients to become abstinent from smoking (OR 4.46, 95% CI 1.08–18.39; P = 0.04). Using a serum cotinine level of ≤28 ng/mL to segregate nonsmokers from smokers, the topiramate group had 4.97 times the odds of being nonsmokers (95% CI 1.1–23.4; P = 0.04). The strength of these results showing topiramate’s treatment efficacy is bolstered by the fact that smoking cessation was not a goal of the study, and no specific measures, advice or counseling, or therapeutic targets were provided to help the participants quit smoking; thus the improvements in smoking rate represent a naturalistic change in behavior. Of interest, cigarette consumption and serum cotinine levels lessened as individuals became more abstinent in the topiramate group. In contrast, increasing abstinence from alcohol was associated with greater consumption of cigarettes and higher serum cotinine levels for the placebo group. These findings provide initial support for the proposal that topiramate may be an efficacious medicine for the simultaneous treatment of alcohol use disorder and smoking.

In sum, predicated upon a neuropharmacological conceptual model, there now is strong clinical support for topiramate as a promising medication for the treatment of alcohol use disorder. Topiramate’s therapeutic effects appear to be robust, with a medium effect size, thereby potentially ushering in a new era of a reliably efficacious medicine for the treatment of alcohol use disorder with or without smoking. The moderator effect of rs2832407, if validated, would facilitate the identification of heavy drinkers who are likely to respond well to topiramate treatment with the best safety profile and provide an important personalized treatment option. Intriguingly, although the animal data also provide neuropharmacological support for topiramate’s anti-drinking effects, more research is needed to characterize fully or fingerprint the pattern of response. Such preclinical studies should enable us to elucidate more clearly the basic mechanistic processes that underlie topiramate’s efficacy as a treatment for alcohol use disorder. Although it is not yet known whether topiramate will be useful in treating alcohol-dependent individuals with bipolar disorder, another anticonvulsant (i.e., valproic acid) has shown some promise.

Selective Serotonin Reuptake Inhibitors

For decades, it has been known that pharmacological manipulations that deplete the brain of serotonin decrease the preference for ethanol. Using preference paradigms, pharmacological agents that inhibit serotonin reuptake from the synapse reduce the voluntary consumption of ethanol solutions using the preference paradigm. ^d

d References .

Although these preclinical studies have shown that selective serotonin reuptake inhibitors can reduce ethanol consumption, the selectivity of this effect on reinforcement as opposed to general consummatory behaviors has been questioned.

The inhibition of serotonin reuptake function has complicated the effects on food intake and fluid consumption. Selective serotonin reuptake inhibitors do suppress food intake and fluid consumption and decrease palatability. Yet, motivational factors exert some control on the expression of these behaviors. For instance, selective serotonin reuptake inhibitors enhance satiety but selectively reduce preference for certain macronutrients (i.e., sweet items and carbohydrates) (cf. Heisler et al. and Heisler et al. ) that increase the palatability and rewarding effects of food. Hence, selective serotonin reuptake inhibitors might decrease ethanol consumption via the suppression of nonspecific general consummatory behaviors and specific anti-reinforcing effects.

Studies conducted using operant techniques have also supported a role for selective serotonin reuptake inhibitors in the suppression of ethanol consumption. Haraguchi et al. showed that same-day pretreatments with fluoxetine dose-dependently reduced ethanol responding. Nevertheless, whereas the chronic administration of selective serotonin reuptake inhibitors to C57BL/6 J male mice produced an initial suppression of lever pressing for ethanol, there was a later rebound to baseline levels of responding for ethanol and ethanol consumption. These results are somewhat similar to those of Murphy et al., who observed that fluoxetine administered to rats in a single daily infusion produced a significant reduction in ethanol-reinforced responding that started on the first day of treatment and increased on subsequent days of the 7-day treatment regimen. Responding for ethanol returned to pretreatment levels following cessation of fluoxetine treatment. Food intake, although somewhat suppressed initially, appeared to return to baseline levels on subsequent treatment days. Again, these results demonstrate that the suppression of ethanol intake by selective serotonin reuptake inhibitors follows a pattern of initial suppression of consummatory behavior followed by a reduction in reinforcement; thus when the selective serotonin reuptake inhibitors are discontinued, there is an extinction-like pattern of a return to the baseline behavior.

Despite the promise of these preclinical results, there is, at present, little support for the proposal that selective serotonin reuptake inhibitors are an efficacious treatment for a heterogeneous group of alcohol-dependent individuals. Initial studies of small sample size reported that selective serotonin reuptake inhibitors can produce short-term (1–4 week) decreases in alcohol consumption among problem drinkers. Nevertheless, these studies were limited by at least three factors. First, most of the studies were conducted in men, thereby limiting the generalizability of the results to the general population. Second, the adjunctive psychosocial treatment, which can decrease the apparent efficacy of the putative therapeutic medication because this too can have an important effect on drinking outcomes, was not standardized. Third, the treatment periods were short; thus it was not possible to determine whether these initial effects, which could be due to nonspecific factors, would be sustained. Indeed, the problem with studies of short duration that focus on a chronic relapsing disorder such as alcohol use disorder was highlighted in a later study by Gorelick and Paredes, who found that there also was an effect for fluoxetine, compared with placebo, to decrease alcohol consumption by about 15% in the first 4 weeks of the trial but not over the entire length of the trial. In addition, Naranjo et al. did not demonstrate that citalopram (40 mg/day) was superior to placebo in a 12-week treatment trial. Further, neither Kabel and Petty nor Kranzler et al. in two separate 12-week studies found fluoxetine (60 mg/day) to be superior to placebo for the treatment of alcohol use disorder.

There has been renewed understanding about how the administration of functionally different serotonergic agents can lead to different drinking outcomes among various subtypes of alcoholic (for a review, see Johnson ). Adapted from Cloninger’s classification scheme , two methods for subtyping alcoholics have been used in these pharmacotherapy studies. Basically, a particular type of alcoholic (i.e., Type A-like or late onset) characterized by a later age of onset of problem drinking (typically over the age of 25 years), a preponderance of psychosocial morbidity, and low familial loading can experience improved drinking outcomes after selective serotonin reuptake inhibitor treatment.

Although early human laboratory studies showed that Type B-like or early onset alcoholics, characterized by an early age of problem drinking onset (i.e., before the age of 25 years), high familial loading for alcohol use disorder, and a range of impulsive or antisocial traits, might be centrally deficient in the major metabolite of serotonin, 5-hydroxyindoleacetic acid, the implications of this finding were, perhaps, oversimplified. At a cursory glance, it would appear that a selective serotonin reuptake inhibitor, by increasing serotonin turnover, would compensate for this dysfunction; thus these Type B-like or early onset alcoholics would then be expected to experience improved drinking outcomes following selective serotonin reuptake inhibitor treatment. Remarkably, the literature has demonstrated quite the opposite. For instance, Kranzler et al. observed that fluoxetine treatment appeared to worsen the clinical benefit of the adjunctive cognitive behavioral treatment and that there was no difference from placebo. Actually, Type A-like or late-onset alcoholics, with presumably more normative serotonin function, have been observed to experience improved drinking outcomes from sertraline both during active treatment and at 6-month follow-up. In addition, Chick et al. have shown that early onset or Type B-like alcoholics were more likely to relapse than their late-onset or Type A-like counterparts following fluvoxamine treatment.

Obviously, the relationship between serotonergic dysfunction and Type B-like or early onset alcoholism is not the simple result of a deficiency state. Indeed, Johnson has hypothesized that an explanation for this effect might be allelic variation at the serotonin transporter, which leads to the differential expression of serotonin function. Of course, other biomolecular explanations are possible, and further research is needed to elucidate this important area of research.

Fluoxetine has been reported to be beneficial for the treatment of alcohol-dependent individuals with suicidal tendencies and severe comorbid depression. A recent study did not find that sertraline treatment was more beneficial than placebo in treating depressed men and women with alcohol use disorder irrespective of the severity of the depression. In another trial, sertraline was again found not to be beneficial in both men and women for the treatment of comorbid alcohol use disorder and depression, although women did have a very slight but not clinically meaningful improvement in depressive symptoms. Notably, it has not been shown that the reduction in dysphoria in depressed alcoholics is associated with concomitant decreases in alcohol consumption. Hence, the only conclusion that can be drawn at present is that except for a subtype of depressed alcoholic with suicidal tendencies or, perhaps, in women, there is not much evidence to recommend selective serotonin reuptake inhibitors over placebo for the treatment of depressed alcoholics.

Sertraline might have some utility in the treatment of alcohol-dependent individuals whose comorbid posttraumatic stress disorder is associated with early trauma, thereby suggesting that different subtypes might vary in treatment response. In addition, there is promise that paroxetine might prove useful in treating alcohol-dependent individuals with social phobia. There is no specific treatment, apart from symptomatic management, for the treatment of alcohol-dependent individuals with comorbid generalized anxiety disorder.

In sum, despite strong animal data that would support the use of selective serotonin reuptake inhibitors as a promising treatment for alcohol use disorder, there is no evidence that they are of therapeutic benefit to a heterogeneous group of alcohol-dependent individuals. Notably, however, there is growing confirmation that selective serotonin reuptake inhibitors can improve the drinking outcomes of Type A-like or late-onset alcoholics. Rather than being a cause for discouragement, this finding might (a) open up the possibility of identifying important biogenetic or pharmacological mechanisms that underlie the alcoholism disease and (b) improve understanding about which type of alcohol-dependent individual can benefit the most from specific serotonergic treatment. Furthermore, there is no current evidence that providing a selective serotonin reuptake inhibitor to a depressed alcoholic without severe depressive symptoms and suicidal tendencies is of therapeutic benefit. Hence, what is clear is that clinicians should be cautious in prescribing selective serotonin reuptake inhibitors to alcohol-dependent individuals for the treatment of minor depressive or affective symptoms. Not only is this strategy unlikely to be a therapeutic benefit over placebo, and perhaps appropriate psychosocial management, but drinking outcomes can actually be worsened, especially if the alcohol-dependent individual is Type A-like or of late onset. There is some evidence that selective serotonin reuptake inhibitors might be useful in treating a cohort of alcohol-dependent individuals whose posttraumatic stress disorder is associated with early trauma, and in treating alcoholics with social phobia.

Serotonin-1 Partial Receptor Agonist

Preclinical studies have suggested that the serotonin-1A partial agonist, buspirone, may be effective at reducing ethanol consumption. Buspirone decreased volitional alcohol consumption from 60% to 30% in macaque monkeys, but there was considerable interindividual variation. In Sprague-Dawley rats, buspirone significantly reduced ethanol intake in animals induced to drink by repeated brainstem injection of tetrahydropapaveroline. In a group of medium alcohol-preferring rats, buspirone (0.0025–0.63 mg/kg) reduced, while buspirone (>2.5 mg/kg) increased, alcohol consumption without affecting water consumption. Although buspirone is a partial serotonin-1A agonist, the net effect of its repeated administration is to enhance serotonin function via facilitation of the postsynaptic receptor, which is more sensitive than the autoreceptor, and downregulation of autoreceptor function. Nevertheless, this preclinical evidence would have been strengthened by operant studies examining the dose-response characteristics of buspirone as a function of ethanol concentration.

Buspirone has not been demonstrated to be an efficacious medication for the treatment of alcohol-dependent individuals without comorbidity. In a review of five published trials, buspirone was without a convincing effect in noncomorbid alcoholics; however, alcoholics with comorbid anxiety experienced some benefit. Hence, buspirone’s anxiolytic effects might translate to those who also are dependent on alcohol.

In summation, there is no current evidence that would suggest a role for buspirone in the treatment of alcohol use disorder without comorbid anxiety disorder.

Serotonin-2 Receptor Antagonist

Preclinical studies have suggested that the serotonin-2 receptor antagonist, ritanserin, can reduce ethanol consumption in animals (cf. Svensson et al. ). In addition, the serotonin-2 antagonists, amperozide and FG5974, ^187,274 significantly suppress ethanol intake without affecting water consumption. The exact mechanism by which serotonin-2 receptor antagonists might reduce ethanol consumption is unknown. It has been suggested, however, that they might exert their effects by acutely substituting for alcohol’s pharmacobehavioral effects by facilitating burst firing in cortico-mesolimbic dopamine neurons, or by the suppression of dopamine neurotransmission following their chronic administration.

In the clinical setting, ritanserin is not an efficacious treatment for alcohol use disorder. In a rigorously conducted, 12-week, multicenter clinical trial ( N = 423) of ritanserin (2.5 or 5 mg/day) versus placebo as an adjunct to weekly cognitive behavioral therapy, none of the ritanserin doses was superior to placebo. In a later study using similar methodology, ritanserin (2.5, 5.0, or 10.0 mg/day) was not superior to placebo at improving drinking outcomes. Although higher doses of ritanserin might be of therapeutic benefit, testing these doses is precluded by ritanserin’s potential to cause dose-dependent prolongation of the QTc interval on electrocardiography, thereby increasing the potential for life-threatening cardiac arrhythmias.

In summation, there is no clinical evidence that would support the use of ritanserin as a treatment for alcohol use disorder.

Serotonin-3 Receptor Antagonists

Preclinical studies provide strong support for the role of the serotonin-3 receptor in mediating alcohol’s important neurochemical effects, and for serotonin-3 receptor antagonists to be promising treatment for alcohol use disorder.

In neurophysiological experiments, ethanol potentiates serotonin-3 receptor-mediated ion currents in NCB-20 neuroblastoma cells and in human embryonic kidney 293 cells (or HEK 239, a specific cell line originally derived from human embryonic kidney cells) transfected with serotonin-3 receptor antagonist complementary DNA. Serotonin-3 receptor antagonists block these effects. Thus the serotonin-3 receptor is a site of action for ethanol in the brain.

Pharmacobehavioral studies show that many of alcohol’s reinforcing effects are mediated by serotonin-3 and dopamine interactions in the cortico-mesolimbic system.

Serotonin-3 receptor antagonists have three principal effects that demonstrate their ability to modulate ethanol consumption and related behaviors. First, serotonin-3 receptor antagonists suppress hyperlocomotion in the rat induced by dopamine or ethanol injection into the nucleus accumbens . Second, serotonin-3 receptor antagonists inhibit DiMe-C7 (a neurokinin)-induced hyperlocomotion, which also is reduced by the dopamine antagonist, fluphenazine. Third, serotonin-3 receptor antagonists reduce ethanol consumption in several animal models and across different species ^e

e References .

Human laboratory studies have generally supported a role for the serotonin-3 antagonist ondansetron in reducing preference and craving for alcohol. In two distinct experiments, Johnson and Cowen and Johnson et al. showed that ondansetron pretreatment attenuated low-dose alcohol-induced positive subjective effects (including the desire to drink). Swift et al., using much higher alcohol and ondansetron doses, also discovered that ondansetron compared with placebo pretreatment reduced alcohol preference; however, a mixture of both stimulant and sedative interactions between ondansetron and alcohol also was observed. Whereas Doty et al. did not find an effect of ondansetron on alcohol-induced mood, their experimental model of using a group rather than individual experimental setting could have decreased the sensitivity of their assessments.

Three clinical studies have provided evidence that ondansetron is a promising treatment for alcohol-dependent individuals, particularly those with an early onset or Type B-like subtype.

First, in a 6-week, double-blind, placebo-controlled study of 71 nonseverely alcohol-dependent males, Sellers et al. observed that the 0.5-mg dose but not the 4-mg dose of ondansetron was associated with a nonsignificant trend ( P = 0.06) toward a reduction in alcohol consumption. Post hoc analysis that eliminated 11 subjects who consumed less than 10 drinks/drinking day rendered the difference in drinking outcomes between the ondansetron 0.5 mg and placebo groups to be significant statistically ( P = 0.001). Despite the limitations of this initial trial, which included a relatively short treatment period, the inclusion of just males, and the small number of subjects, the results of this study provided general support for ondansetron’s promise in treating alcohol use disorder. In addition, these results showed that ondansetron may exhibit a nonlinear dose-response effect in the treatment of alcohol use disorder.

Second, in a large-scale ( N = 321), 12-week, randomized, double-blind clinical trial in which alcohol-dependent individuals received weekly cognitive behavioral therapy, Johnson et al. showed that ondansetron (1, 4, and 16 μg/kg, b.i.d.) was superior to placebo at improving drinking outcomes of those of the early onset or Type B-like subtype but not the late onset or Type A-like subtype. The self-reported decreases in alcohol consumption were corroborated by the concomitant reduction in carbohydrate-deficient transferrin level—a biomarker of transient alcohol consumption.

Third, Kranzler et al. provided replication of the results by Johnson et al. by showing that early onset (Type B-like) alcoholics had a significantly greater improvement in drinking outcomes compared with their late-onset (Type A-like) counterparts following 8 weeks of ondansetron (4 μg/kg, b.i.d.) treatment.

Intriguingly, these results demonstrate a differential effect of ondansetron treatment by subtype of alcohol-dependent individual. Indeed, the contrast is striking when compared with the effects of selective serotonin reuptake inhibitors on different subtypes of alcohol-dependent individuals as described earlier. Basically, early onset or Type B-like alcoholics with apparent serotonergic deficiency respond best to a medication that blocks the serotonin-3 receptor, whereas late-onset or Type A-like alcoholics with apparently normal serotonergic function derive the most benefit from a medication that can increase serotonin turnover and function. One potential disadvantage of subtyping by psychosocial variables is that they might not be stable across all populations (i.e., differences by ethnicity and regions could occur due to different exposure levels to alcohol), and the more complex algorithms for subtyping (e.g., into Type A or B) cannot be carried out prospectively or applied directly to a single individual. Arguably, more stable and generalizable dichotomization of different populations of alcoholics responsive to ondansetron might be achievable using pertinent and specific biomolecular variables.

As mentioned earlier, Johnson has proposed a biomolecular explanation for these effects; however, other plausible possibilities might exist. A detailed elaboration of this concept is beyond the scope of this review. Nevertheless, the key feature is that polymorphic variation(s) at the serotonin transporter gene might result in a relative intrasynaptic hyposerotonergic state with consequent upregulation of postsynaptic serotonin receptors. Alcohol-dependent individuals with these polymorphic types may be prone to a heavier and more chronic pattern of drinking, perhaps through a counterregulatory mechanism to increase serotonin turnover. Because this attempted counterregulation through increased alcohol consumption can only be partially effective, as further drinking reduces the expression of the serotonin transporter gene further, a vicious cycle is set up. Johnson has proposed that ondansetron treatment may ameliorate heavy or severe drinking in such alcohol-dependent individuals, presumably by blockade of upregulated postsynaptic serotonin receptors. Indeed, preliminary statistical analysis of a recent clinical trial does suggest that ondansetron may have an effect to decrease severe drinking among individuals with specific polymorphisms of the serotonin transporter gene.

In a landmark controlled trial (n = 283), Johnson et al. showed that individuals with the LL genotype who received ondansetron had a lower mean number of drinks per drinking day (−1.62) and a higher percentage of days abstinent (11.27%) than those who received placebo. Among ondansetron recipients, the number of drinks per drinking day was lower (−1.53) and the percentage of days abstinent higher (9.73%) in LL compared with LS/SS individuals. LL individuals in the ondansetron group also had a lower number of drinks per drinking day (−1.45) and a higher percentage of days abstinent (9.65%) than all other genotype and treatment groups combined. For both number of drinks per drinking day and percentage of days abstinent, 5’-HTTLPR and rs1042173 variants interacted significantly. LL/TT individuals in the ondansetron group had a lower number of drinks per drinking day (−2.63) and a higher percentage of days abstinent (16.99%) than all other genotype and treatment groups combined. These results provided the proof of concept to show the efficacy of pharmacogenetic treatment of alcohol use disorder using ondansetron. In an extended evaluation of that study, Johnson et al. also showed that individuals carrying one or more of genotypes rs1150226-AG and rs1176713-GG in HTR3A and rs17614942-AC in HTR3B showed a significant overall mean difference between ondansetron and placebo in drinks per drinking day (22.50; effect size = 0.867), percentage of heavy drinking days (220.58%; effect size = 0.780), and percentage of days abstinent (18.18%; effect size = 0.683). Combining these HTR3A/HTR3B and SLC6A4-LL/TT genotypes increased the target cohort from approaching 20% (identified in the previous study) to 34%. These added results present compelling evidence that a combined five-marker genotype panel can be used to predict the outcome of treatment of alcohol dependence with ondansetron. Thus certain subtypes of individuals with alcohol use disorder exist, whereby pharmacogenetic treatment using ondansetron can be targeted effectively toward a specific genetically defined cohort. Furthermore, these results open up the possibility of developing associated messenger RNA (mRNA) biomarkers to track treatment response with ondansetron. It is intriguing that ondansetron also has shown efficacy in treating alcohol-dependent individuals with social phobia, presumably because of its anxiolytic effects. The results of this study do, however, need to be validated by a larger clinical trial.