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Pharmacotherapy for Alcoholism and Some Related Psychiatric and Addictive Disorders: Scientific Basis and Clinical Findings
Acknowledgments
We are grateful to Elsevier for permission to reproduce some text from a recent review article. We also thank the National Institute on Alcohol Abuse and Alcoholism for its support through grants 5 R01 AA010522–14, 5 R01 AA012964–06, 5 R01 AA014628–04, and 5 R01 AA013964–05; the National Institutes of Health for its support through University of Virginia General Clinical Research Center Grant M01 RR00847, and Robert H. Cormier, Jr., Ann Richards, and Dr. Chamindi Seneviratne for their assistance with manuscript preparation.
Introduction
In May 2013, the American Psychiatric Association issued the Fifth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) integrating the two DSM-IV disorders, alcohol abuse and alcohol dependence, into one single disorder called alcohol use disorder, with three levels of severity—mild, moderate, and severe. One of the goals in revising the DSM-IV-TR was to improve the scientific basis for psychiatric diagnosis and classification. Craving was introduced as a criterion for the diagnosis of alcohol use disorder given that some data that suggested a positive correlation with drinking severity and is the eighth most frequently reported symptom of the 12 symptoms that define the diagnosis of alcohol use disorder.
Globally and in the United States, alcohol dependence is analogous to alcohol use disorder of moderate to severe rank, and rates as fifth and third, respectively, on the list of preventable causes of morbidity and mortality. From 2006 to 2010 in the United States, an average of 87,798 (27.9/100,000 population) deaths per year were attributed to alcohol, with 2.5 million (831.6/100,000) years of potential life lost to alcohol) and an overall estimated cost to the nation of about $249 billion. Results from the National Epidemiologic Survey on Alcohol and Related Conditions III collecting data on the new DSM-5 classification reported that the 12-month and lifetime prevalences of were 13.9% and 29.1%, respectively, with a prevalence that was highest for men (17.6% and 36.0%, respectively), whites (14.0% and 32.6%, respectively), and Native Americans (19.2% and 43.4%, respectively). Significant associations were found between 12-month and lifetime alcohol use disorder and other substance use disorders, major depressive, bipolar I disorders, and personality disorders across all levels of severity, with odds ratios (ORs) ranging from 1.2 (95% confidence interval [CI] 1.08–1.36) to 6.4 (95% CI 5.76–7.22). Associations between alcohol use disorder and panic disorder, specific phobia, and generalized anxiety disorder were modest; ORs ranged from 1.2 (95% CI 1.01–1.43) to 1.4 (95% CI 1.13–1.67) across most levels of severity. Alcohol use disorder increases the risk of depression up to fourfold. Depression in individuals with alcohol use disorder increases the degree of morbidity and risk for suicide. Individuals with bipolar disorder have a high prevalence of 46% to develop an alcohol-related disorder; indeed, the odds of a bipolar disorder if a person has an alcohol-related disorder are 5.1 times greater than in an individual without an alcohol-related disorder. Individuals with comorbid bipolar and alcohol use disorder are at increased risk of violent behavior, treatment nonadherence, high rates of hospitalization, and mortality. Anxiety-related disorders also occur frequently among alcohol-dependent individuals (with a prevalence rate of 19.4%), especially general anxiety disorder, social phobia, and posttraumatic stress disorder. Up to 90% of individuals with alcohol use disorders are smokers, and the heaviest drinkers tend to smoke the most. In a sample size ranging from 80 to 1142, surveys of individuals with a diagnosis of moderate to severe alcohol use disorder from inpatient and outpatient treatment facilities showed an 86%–97% smoking rate among males and an 82%–90% rate among females. Smoking increases the health risks and associated morbidity and mortality of alcohol use disorder greatly, and vice versa. Comorbid psychiatric disorder or smoking complicates the treatment of alcohol use disorder and increases the level of public health concern.
Alcohol use disorder is a chronic relapsing medical disorder. Notwithstanding its psychological and social ramifications, once established, alcohol use disorder is essentially a brain disorder that bears many of the characteristics of other medical relapsing disorders such as diabetes and hypertension. Indeed, without a pharmacological adjunct to psychosocial therapy, the clinical outcome is poor, with up to 70% of clients resuming drinking within 1 year. Comorbid psychiatric or smoking-related behavior with alcohol dependence would be expected to increase these rates of relapse.
Alcohol use disorder is a treatable disorder when efficacious medications are added to enhance the effects of psychosocial treatment. Advances in the neurosciences have facilitated the development of medications that target neurotransmitter systems, which modulate activity in the cortico-mesolimbic dopamine pathway, the primary circuit by which alcohol’s reinforcing effects associated with its abuse liability are expressed. In addition, neuronal circuits in the extended amygdala modulate the expression of alcohol reinforcement in the cortico-mesolimbic dopamine pathway and increase the propensity for conditioned behaviors to trigger relapse. It is now well accepted that some individuals with alcohol use disorder may possess a biological predisposition to the disease. These biologically vulnerable individuals with alcohol use disorder can be expected to benefit from specific adjunctive medications targeted toward correcting or ameliorating their underlying neurobiological abnormalities. Furthermore, we are now better at controlling the “dose” of adjunctive psychosocial treatments, thereby optimizing the therapeutic response of the candidate medicines. Targeting medicinal treatments toward psychiatric or smoking-related disorders that are comorbid with alcohol use disorder is complex because the neuronal targets are broadened, and the implications of altering their function are less well understood.
Recently, the treatment of alcohol use disorder has been advanced by development of new models as well as broader therapeutic objectives. An important model is that with appropriate pharmacotherapy it is possible to initiate treatment while the individual is still drinking heavily and at the point of maximum crisis and help-seeking behavior. To broaden access to treatment, effective but brief and standardized behavioral treatment has been developed to accompany medication delivery; thus these medications can now be provided more readily in the general practice setting. Finally, it is now better recognized that although abstinence might be the ultimate goal in treating individuals with alcohol use disorder; reducing the frequency of heavy drinking has the major impact of decreasing alcohol-related consequences and improving quality of life.
In this review, we focus on the development of those medications for which there is clinical information and that have been designed to reduce the desire to drink, to promote abstinence, or both. Basically, of the numerous neurotransmitter systems that have been identified for the development of new medicines, the most promising compounds appear to be those that modulate the function of opioids, glutamate with or without γ-aminobutyric acid (GABA), and serotonin. Other putative therapeutic medications including direct modulators of dopamine function, enzyme inhibitors, and neuroinflammatory pathways are also discussed. Each subsection of this chapter provides an overview of the basic science, clinical studies, and future directions for the development of specific promising medications from these neurobiological systems. Emphasis is made in places where the development of a particular medications has advanced the development of a new treatment model or broadened therapeutic objectives. As appropriate, subsections are expanded or added where there is the discussion of a medication that has been tested for the treatment of alcohol use disorder with a comorbid psychiatric disorder or smoking pertinent to this review. We conclude the chapter with remarks pertaining to current barriers to treatment and how they might be overcome.
Opioids: Mu Receptor Antagonist—Naltrexone
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 .
( Fig. 51.1 ). Obviously, opioid receptors also have interactions with other neurotransmitters, including those in the glutamate, GABA, serotonin, cannabinoid, and perhaps glycine systems, that contribute to its effects on ethanol intake.
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 .
(cf. Berman et al., Juarez and Eliana, and Ross et al. ). More recently, there also has been interest in elucidating the role of the hypothalamic-pituitary-adrenocortical axis in stress-induced ethanol consumption and sensitivity and how this might be influenced by naltrexone treatment.
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 .
Data from other clinical trials also showed that targeted prescription of naltrexone reduces heavy drinking when combined with some type of skill building intervention.
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.
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