Phpsy/2014-11-0400/3.3.2015/MPS
Review
Recent Developments in Pharmacotherapy of Alcoholism
Authors
M. Soyka1, 2, M. Lieb2
Affiliations
1
Key words ▶ alcohol ● ▶ alcoholism ● ▶ baclofen ● ▶ gabapentin ● ▶ nalmefene ● ▶ opioid antagonists ● ▶ topiramate ● ▶ varenicline ●
Abstract
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany Privatklinik Meiringen, Meiringen, Switzerland
▼
Introduction: Alcohol use disorders are common, but only a small minority of patients receive adequate treatment. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions are established treatments, but few pharmacotherapies are available. Areas Covered: This narrative focuses on the neurobiological basis of alcohol use disorders and on emerging drugs that either have recently been approved or look likely to find their way into clinical practice. To date, acamprosate and the opioid antagonist naltrexone have been approved for treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial
Background
▼
received 10.11.2014 revised 05.02.2015 accepted 10.02.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1547237 Published online: 2015 Pharmacopsychiatry © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence M. Soyka, MD Privatklinik Meiringen Postfach 612 CH-3860 Meiringen Switzerland [email protected]
The leading psychiatric classification systems ICD-10 and DSM-IV follow a categorical approach and classify alcohol use disorders as alcohol abuse (harmful use) or dependence. Alcohol abuse (or harmful use) is characterised by somatic or psychiatric problems (and, in DSM only, social problems) induced by alcohol intake. Alcohol dependence is defined by a cluster of somatic, psychological and behavioural symptoms [1, 2]. The recently published DSM-5 has abandoned the categorical distinction between abuse and dependence and follows a dimensional approach. It specifies 11 symptoms for substance use disorders; 6 or more positive symptoms constitute a severe substance use disorder, 4 or 5 a moderate 1, 2–3 a mild one. Numerous studies indicate that alcohol use disorders are common; prevalence is estimated to be 7–10 % among adults in European countries and the USA [3–6]. Global prevalence rates among adults are estimated to range from 0 % to 16 % [7]. Recent data from primary care studies indicate that alcohol use disorders are dramatically underreported [8].
kappa agonist nalmefene was approved by the European Medicines Agency for reduction of alcohol consumption. Novel clinical approaches include drugs established for other indications such as the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. Developments in pharmacogenetics are discussed. Conclusions: The development of pharmaceutical agents to treat alcohol use disorders has lagged behind that of depression and schizophrenic psychosis and is hampered by an incomplete understanding of the neurobiological background. Pharmacogenetics may improve treatment in the future.
The authors prepared this narrative as an extension of and on the basis of previous work, in particular the Cochrane analyses on acamprosate and opioid antagonists in alcohol dependence by this group [9, 10]. It is also preparatory work for the upcoming first revision, in 2015/2016, of the WFSBP guidelines for biological treatment of alcohol dependence, which were originally published in 2011 [11]. The objectives of this narrative are to identify and evaluate recent studies and meta-analyses on pharmaceuticals used in the treatment of alcohol dependence. Medline/ PubMed was screened to identify related publications. The search focused on approved medications or those in phase 3 that look promising for this indication. Subjective expert judgement was used to select and evaluate papers.
Medical Need
▼
Only a small minority of patients with alcohol use disorders receive adequate help [12]; in Europe treatment rates are in the range of 10 % [13]. The medical consequences are significant:
Soyka M, Lieb M. Recent Developments in Pharmacotherapy … Pharmacopsychiatry
Downloaded by: University of Connecticut. Copyrighted material.
2
in Europe, almost 23 million people are affected [14] and 137 000 deaths per year are related to alcohol consumption, including 39 000 cases of liver cirrhosis, 13 000 cases of psychiatric and neurological disorders, 11 000 cases of cardiovascular disorders, 26 000 cases of malignant disorders and 18 000 suicides [1]. The net burden caused by alcohol consumption in EU countries is 1 in 7 deaths in men and 1 in 13 deaths in women [13]. The economic costs due to alcoholism are enormous [15]. Reduction of alcohol drinking is associated with fewer accidents and less suicide, aggression and cardiac arrest [16] and lower mortality rates [17].
Existing Treatment
▼
Numerous psychosocial and psychotherapeutic approaches are used to treat substance use disorders. Several meta-analyses have proven the efficacy of alcohol treatment in general, with modest effect sizes [18–20]. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions in particular are established and frequently used therapies with low to moderate effect sizes [21, 22]; other therapies include contingency management, 12-step therapies, relapse prevention, family therapy and case management [18, 20, 23–25]. Psychotherapy is also effective in patients treated with so-called anticraving drugs [26]. However, relapse to heavy drinking is very common after conventional alcohol therapies and abstinence rates rarely exceed 40 % [1]. A number of meta-analyses have proven the efficacy of alcohol treatment in general [23, 27], but empirical research suggests that allocation of patients to different treatments according to individual patient profiles is very difficult [28].
Scientific Rationale and Current Research Goals
▼
The neurobiological basis of alcoholism is complex and involves many factors (for review, see [29]). The neural substrates and neurocircuitry of alcohol dependence have been extensively studied. The limbic system, including the ventral tegmentum and nucleus accumbens, and the orbito- and prefrontal cortices have been identified as key structures in the neural circuit underlying addictive behaviour. Dopamine release in the nucleus accumbens is essential in processing reward for the reinforcing, “pleasant” effects of drugs of abuse such as alcohol. Limbic structures mediate reward processing, while the prefrontal cortex is crucial for cognitive control and the orbitofrontal cortex for motivation [30]. The molecular basis of alcohol dependence is more complex. Alcohol appears to have a low affinity to many neuroreceptors and no specific target. The numerous neurotransmitters it affects include inhibitory gamma-aminobutyric acid (GABA), the opioid endorphin system, glutamate, the endocannabinoid system, noradrenaline, dopamine and serotonin [31–33] as well as neuroendocrine systems [34]. Other variables mediating the vulnerability for alcohol dependence are stress and function of the hypothalamic-pituitary-adrenal (HPA) axis, among others. The opioidergic system may be viewed as a “hedonic” system and much treatment-relevant research has targeted the opioidendorphin system. Multiple lines of evidence suggest that opioid receptors are implicated in the development of alcohol use and alcoholism [8] and that the opioid system mediates the reinforcSoyka M, Lieb M. Recent Developments in Pharmacotherapy … Pharmacopsychiatry
ing effects of alcohol [35–37]. 3 major classes of opioid receptors have been identified, mu (µ), kappa (κ) and delta (δ) [35]. Alcohol stimulates the release of the endogenous opioid receptor ligands beta-endorphin, enkephalins and dynorphin [38–42]. Mu receptors mediate the analgesic and rewarding effects of opioids [43], and altered activity of mu-opioid receptor-mediated neurotransmission has been suggested as one of the key mechanisms underlying the reinforcement of alcohol consumption [35, 44]. Blockade of opioid receptors has been shown to decrease alcohol intake [36, 44, 45]. Opioid receptors in GABAergic neurons interact with dopaminergic neurons and thus mediate dopamine release [31], and midbrain dopamine neurons in the ventral tegmental area and their projections to the nucleus accumbens in the ventral striatum support reward anticipation and reinforcement [46]. For an excellent review on the role of the opioid system in alcohol dependence, see Nutt [47]. Functional neuroimaging studies indicate a substantial plasticity of opioid receptors and adaptations in the opioid system in chronic alcohol use. Positron emission tomography (PET) studies suggest a negative correlation between mu-opioid receptor binding and alcohol craving [48, 49].
Established Medications
▼
Few pharmacotherapies have become established as anti-craving drugs to reduce relapse risk or alcohol intake in alcoholism [11, 50–52]. Apart from the acetaldehyde dehydrogenase inhibitor disulfiram, which produces aversive effects when taken together with alcohol, empirical evidence is available for the efficacy of the putative N-methyl-D-aspartic acid (NMDA) modulator acamprosate and the opioid antagonist naltrexone in alcohol treatment [9, 53]. Acamprosate is used for relapse prevention of alcoholism. Its precise mechanism of action is not fully understood, but many data suggest that one of its primary mechanisms of action is modulation of the glutamatergic NMDA receptor [54]. Recent and very controversial data question the mechanism of action of acamprosate and indicate that the calcium part of the molecule is the only active compound [55]. Acamprosate is safe and usually well tolerated. A Cochrane analysis suggests that the only side effect is diarrhoea [9]. Acamprosate is administered as three 333 mg tablets 3 times a day in patients with a bodyweight ≥ 60 kg and 2 tablets twice a day in patients weighing ≤ 60 kg. Naltrexone is orally active and administered as 50 mg tablets once a day. In the USA, naltrexone is also available in a depot formulation. Naltrexone appears to reduce the rewarding effects of alcohol and has been tested in numerous controlled clinical trials [10], especially in combination with psychotherapy [56]. Although some recent clinical studies have shown negative results for acamprosate [57], meta-analyses indicate that acamprosate and naltrexone reduce relapse to heavy drinking or increase the abstinence rates in alcohol-dependent people [9, 53]. Correspondingly, the most recent systematic review for pharmacotherapy in alcohol use disorders concludes that both acamprosate and oral naltrexone are associated with a reduction in return to drinking [58]. However, Zindel and Kranzler [59] concluded that the beneficial effects of these approved medications are “only modestly greater than those of placebo, and their use is limited”. Consequently, they have limited use and public health impact [60].
Downloaded by: University of Connecticut. Copyrighted material.
Phpsy/2014-11-0400/3.3.2015/MPS
Review
New Developments
▼
Numerous agents have been tested or are currently under investigation for treatment of alcoholism (for reviews, see [33, 59, 61– 64]), but few drugs have emerged from preclinical findings and been evaluated in clinical studies. As Litten et al. [63] state, this process is “notoriously complex and challenging”. The European Medicines Agency’s guideline on the development of medicinal products for the treatment of alcohol dependence [65] states that efficacy should also be evaluated in terms of the difference in the percentage of treatment responders. This narrative focuses on emerging drugs that either have recently been approved or look likely to find their way into clinical practice.
Nalmefene
▼
Nalmefene, which was initially approved in the USA in the 1990s for the treatment of opioid overdoses, has a similar chemical structure to naltrexone [66], but may offer some advantages [67], including a more effective binding to central opioid receptors [68, 69], a higher bioavailability [70–72] and the absence of a dose-dependent association with liver toxicity [67]. Nalmefene is an antagonist at the mu- and delta-opioid receptor [68, 73] and a partial agonist at the kappa receptor [74]. The kappa receptor may be of relevance for motivational aspects of alcoholism [75–77]. Nalmefene does not act via any other receptor type (for a review, see [78]). Preclinical data suggest that kappa-opioid receptor antagonism decreases dependence-induced alcohol self-administration [75]. The relatively higher affinity of nalmefene at the kappa receptor may be responsible for the increased activation of the HPA axis via increased release of adrenocorticotropic hormone [79]. In alcoholism the opioid system interacts closely with the stress system; naltrexone and nalmefene may have different effects on the stress system. Elevated levels of stress hormones and glucocorticoids have been described in alcohol withdrawal and binge drinking and the HPA axis is activated by alcohol intake (for a review, see [80]). The oral bioavailability of nalmefene is 40 %, which is slightly higher than that of naltrexone [69, 81]. There is no evidence for liver toxicity [67]. Neuroimaging studies on the pharmacokinetics and pharmacodynamics of nalmefene suggest a slow dissociation of the drug from the mu-opioid receptor [69, 70]. PET study data with the opioid receptor ligand (11c) carfentanil indicate that nalmefene is rapidly absorbed: the mean half-life was 13.4 h after single and repeated dosing [69]. Single doses of 20–300 mg daily or 10–40 mg twice daily are usually well tolerated [69, 70, 82].
Preclinical findings
Few animal data are available for nalmefene [39, 83], but it was found to be significantly more effective than naltrexone in suppressing ethanol intake in ethanol-dependent rats [75, 77]. Like naltrexone, nalmefene reduces the subjective “high” feeling after alcohol consumption [84, 85].
Clinical findings
6 randomised controlled trials have been published on nalmefene [67, 82, 86–89], a lot fewer than on naltrexone [10]. Subsequent to pilot studies with limited statistical power [67, 82, 86], Anton et al. [86] evaluated 3 doses of nalmefene (5, 20 and 40 mg) in a double-blind comparison with placebo over a
Review 12-week treatment period (N = 270). Both the nalmefene and placebo groups showed a reduction in heavy drinking days, craving, gamma-glutamyl transferase (GGT) and carbohydratedeficient transferrin concentrations and no differences were found between the groups on these measures. A multicentre, randomised, placebo-controlled study by Karhuvaara et al. [88] in a sample of heavy drinkers (N = 403) found significant effects of nalmefene compared to placebo on the mean number of heavy drinking days (mean 8.6–9.3 in the nalmefene group, 10.6–12.0 in the placebo group; p = 0.0065). Furthermore, serum alanine aminotransferase and GGT levels decreased in the nalmefene group compared with the placebo group (p = 0.0088 and 0.0023, respectively). The most common adverse events associated with nalmefene were nausea, insomnia, fatigue, dizziness and alcoholic hangover. 2 large and adequately powered randomised placebo-controlled studies that explicitly focused on the efficacy of nalmefene in reducing alcohol use were conducted in Europe [87, 89]. Both used an “as needed” approach to compare 18 mg nalmefene with placebo and defined the primary goal as reduction of heavy drinking days. Neither study provides data on abstinence rates. One of the studies, Mann et al. [89], evaluated the as-needed use of nalmefene vs. placebo over 6 months in 579 patients with alcohol dependence. During the main treatment period, the mean percentage of days with study medication intake was 48.0 % in the nalmefene and 63.9 % in the placebo group. The study found a significant reduction of total daily alcohol consumption ( − 11.0 g/day [95 % confidence interval, CI − 16.8 to − 5.1]; p = 0.0003) and heavy drinking days ( − 2.3 days [95 % CI − 3.8 to − 0.8]; p = 0.0021) in the nalmefene group. In line with these findings, liver values decreased significantly more in the nalmefene group than in the placebo group. The number of patients who discontinued treatment was significantly higher in the nalmefene group, mostly because of adverse events. Treatment-emergent adverse events occurred in 81.5 % of the nalmefene group and 66.9 % of the placebo group. The main treatment-emergent adverse events relevant for discontinuation were nausea, dizziness, fatigue and headache. The other study, by Gual et al. [87], evaluated as-needed use in 718 patients. In this study, a total of 218 patients reduced their drinking days to 6 or fewer heavy drinking days/month or their average alcohol consumption to below the WHO medium drinking risk level already between screening and randomisation. During the main treatment period, the mean percentage of days with study medication intake was 57.0 % in the nalmefene and 65.2 % in the placebo group. The co-primary efficacy analyses showed a significant reduction in heavy drinking days in the nalmefene group compared to the placebo group from baseline to month 6 (group difference: − 1.7 days/month [95 % CI − 3.1; − 0.4]; p = 0.012). Reductions in liver enzymes were greater in the nalmefene group. In contrast to the Mann et al. [89] study, the incidence of adverse events leading to dropout was similar in both groups. Treatment-emergent adverse events occurred in 68.0 % of the nalmefene group and 59.1 % of the placebo group. Of interest in this context is a safety study by van den Brink et al. [90], which also found a higher rate of adverse events in the nalmefene than in the placebo group. Van den Brink et al. [91] performed an interesting subanalysis of the Mann et al. [89] and Gual et al. [87] studies. Since some patients had already reduced their alcohol drinking before study entry, the authors looked at patients who did not reduce their consumption after the initial assessment. The pooled analysis Soyka M, Lieb M. Recent Developments in Pharmacotherapy … Pharmacopsychiatry
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Phpsy/2014-11-0400/3.3.2015/MPS
consisted of 667 patients (332 placebo, 335 nalmefene). The authors found that nalmefene was significantly more effective than placebo in reducing the number of heavy drinking days [treatment difference: − 3.2 days (95 % CI: − 4.8; − 1.6); p
Review
Recent Developments in Pharmacotherapy of Alcoholism
Authors
M. Soyka1, 2, M. Lieb2
Affiliations
1
Key words ▶ alcohol ● ▶ alcoholism ● ▶ baclofen ● ▶ gabapentin ● ▶ nalmefene ● ▶ opioid antagonists ● ▶ topiramate ● ▶ varenicline ●
Abstract
Department of Psychiatry and Psychotherapy, Ludwig Maximilian University, Munich, Germany Privatklinik Meiringen, Meiringen, Switzerland
▼
Introduction: Alcohol use disorders are common, but only a small minority of patients receive adequate treatment. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions are established treatments, but few pharmacotherapies are available. Areas Covered: This narrative focuses on the neurobiological basis of alcohol use disorders and on emerging drugs that either have recently been approved or look likely to find their way into clinical practice. To date, acamprosate and the opioid antagonist naltrexone have been approved for treatment of alcohol dependence. Recently, the mu-opioid antagonist and partial
Background
▼
received 10.11.2014 revised 05.02.2015 accepted 10.02.2015 Bibliography DOI http://dx.doi.org/ 10.1055/s-0035-1547237 Published online: 2015 Pharmacopsychiatry © Georg Thieme Verlag KG Stuttgart · New York ISSN 0176-3679 Correspondence M. Soyka, MD Privatklinik Meiringen Postfach 612 CH-3860 Meiringen Switzerland [email protected]
The leading psychiatric classification systems ICD-10 and DSM-IV follow a categorical approach and classify alcohol use disorders as alcohol abuse (harmful use) or dependence. Alcohol abuse (or harmful use) is characterised by somatic or psychiatric problems (and, in DSM only, social problems) induced by alcohol intake. Alcohol dependence is defined by a cluster of somatic, psychological and behavioural symptoms [1, 2]. The recently published DSM-5 has abandoned the categorical distinction between abuse and dependence and follows a dimensional approach. It specifies 11 symptoms for substance use disorders; 6 or more positive symptoms constitute a severe substance use disorder, 4 or 5 a moderate 1, 2–3 a mild one. Numerous studies indicate that alcohol use disorders are common; prevalence is estimated to be 7–10 % among adults in European countries and the USA [3–6]. Global prevalence rates among adults are estimated to range from 0 % to 16 % [7]. Recent data from primary care studies indicate that alcohol use disorders are dramatically underreported [8].
kappa agonist nalmefene was approved by the European Medicines Agency for reduction of alcohol consumption. Novel clinical approaches include drugs established for other indications such as the GABA-B receptor agonist baclofen, anticonvulsants such as topiramate and gabapentin, the partial nicotine receptor agonist varenicline, and other drugs. Developments in pharmacogenetics are discussed. Conclusions: The development of pharmaceutical agents to treat alcohol use disorders has lagged behind that of depression and schizophrenic psychosis and is hampered by an incomplete understanding of the neurobiological background. Pharmacogenetics may improve treatment in the future.
The authors prepared this narrative as an extension of and on the basis of previous work, in particular the Cochrane analyses on acamprosate and opioid antagonists in alcohol dependence by this group [9, 10]. It is also preparatory work for the upcoming first revision, in 2015/2016, of the WFSBP guidelines for biological treatment of alcohol dependence, which were originally published in 2011 [11]. The objectives of this narrative are to identify and evaluate recent studies and meta-analyses on pharmaceuticals used in the treatment of alcohol dependence. Medline/ PubMed was screened to identify related publications. The search focused on approved medications or those in phase 3 that look promising for this indication. Subjective expert judgement was used to select and evaluate papers.
Medical Need
▼
Only a small minority of patients with alcohol use disorders receive adequate help [12]; in Europe treatment rates are in the range of 10 % [13]. The medical consequences are significant:
Soyka M, Lieb M. Recent Developments in Pharmacotherapy … Pharmacopsychiatry
Downloaded by: University of Connecticut. Copyrighted material.
2
in Europe, almost 23 million people are affected [14] and 137 000 deaths per year are related to alcohol consumption, including 39 000 cases of liver cirrhosis, 13 000 cases of psychiatric and neurological disorders, 11 000 cases of cardiovascular disorders, 26 000 cases of malignant disorders and 18 000 suicides [1]. The net burden caused by alcohol consumption in EU countries is 1 in 7 deaths in men and 1 in 13 deaths in women [13]. The economic costs due to alcoholism are enormous [15]. Reduction of alcohol drinking is associated with fewer accidents and less suicide, aggression and cardiac arrest [16] and lower mortality rates [17].
Existing Treatment
▼
Numerous psychosocial and psychotherapeutic approaches are used to treat substance use disorders. Several meta-analyses have proven the efficacy of alcohol treatment in general, with modest effect sizes [18–20]. Cognitive-behavioural therapies, motivational enhancement interviewing and brief interventions in particular are established and frequently used therapies with low to moderate effect sizes [21, 22]; other therapies include contingency management, 12-step therapies, relapse prevention, family therapy and case management [18, 20, 23–25]. Psychotherapy is also effective in patients treated with so-called anticraving drugs [26]. However, relapse to heavy drinking is very common after conventional alcohol therapies and abstinence rates rarely exceed 40 % [1]. A number of meta-analyses have proven the efficacy of alcohol treatment in general [23, 27], but empirical research suggests that allocation of patients to different treatments according to individual patient profiles is very difficult [28].
Scientific Rationale and Current Research Goals
▼
The neurobiological basis of alcoholism is complex and involves many factors (for review, see [29]). The neural substrates and neurocircuitry of alcohol dependence have been extensively studied. The limbic system, including the ventral tegmentum and nucleus accumbens, and the orbito- and prefrontal cortices have been identified as key structures in the neural circuit underlying addictive behaviour. Dopamine release in the nucleus accumbens is essential in processing reward for the reinforcing, “pleasant” effects of drugs of abuse such as alcohol. Limbic structures mediate reward processing, while the prefrontal cortex is crucial for cognitive control and the orbitofrontal cortex for motivation [30]. The molecular basis of alcohol dependence is more complex. Alcohol appears to have a low affinity to many neuroreceptors and no specific target. The numerous neurotransmitters it affects include inhibitory gamma-aminobutyric acid (GABA), the opioid endorphin system, glutamate, the endocannabinoid system, noradrenaline, dopamine and serotonin [31–33] as well as neuroendocrine systems [34]. Other variables mediating the vulnerability for alcohol dependence are stress and function of the hypothalamic-pituitary-adrenal (HPA) axis, among others. The opioidergic system may be viewed as a “hedonic” system and much treatment-relevant research has targeted the opioidendorphin system. Multiple lines of evidence suggest that opioid receptors are implicated in the development of alcohol use and alcoholism [8] and that the opioid system mediates the reinforcSoyka M, Lieb M. Recent Developments in Pharmacotherapy … Pharmacopsychiatry
ing effects of alcohol [35–37]. 3 major classes of opioid receptors have been identified, mu (µ), kappa (κ) and delta (δ) [35]. Alcohol stimulates the release of the endogenous opioid receptor ligands beta-endorphin, enkephalins and dynorphin [38–42]. Mu receptors mediate the analgesic and rewarding effects of opioids [43], and altered activity of mu-opioid receptor-mediated neurotransmission has been suggested as one of the key mechanisms underlying the reinforcement of alcohol consumption [35, 44]. Blockade of opioid receptors has been shown to decrease alcohol intake [36, 44, 45]. Opioid receptors in GABAergic neurons interact with dopaminergic neurons and thus mediate dopamine release [31], and midbrain dopamine neurons in the ventral tegmental area and their projections to the nucleus accumbens in the ventral striatum support reward anticipation and reinforcement [46]. For an excellent review on the role of the opioid system in alcohol dependence, see Nutt [47]. Functional neuroimaging studies indicate a substantial plasticity of opioid receptors and adaptations in the opioid system in chronic alcohol use. Positron emission tomography (PET) studies suggest a negative correlation between mu-opioid receptor binding and alcohol craving [48, 49].
Established Medications
▼
Few pharmacotherapies have become established as anti-craving drugs to reduce relapse risk or alcohol intake in alcoholism [11, 50–52]. Apart from the acetaldehyde dehydrogenase inhibitor disulfiram, which produces aversive effects when taken together with alcohol, empirical evidence is available for the efficacy of the putative N-methyl-D-aspartic acid (NMDA) modulator acamprosate and the opioid antagonist naltrexone in alcohol treatment [9, 53]. Acamprosate is used for relapse prevention of alcoholism. Its precise mechanism of action is not fully understood, but many data suggest that one of its primary mechanisms of action is modulation of the glutamatergic NMDA receptor [54]. Recent and very controversial data question the mechanism of action of acamprosate and indicate that the calcium part of the molecule is the only active compound [55]. Acamprosate is safe and usually well tolerated. A Cochrane analysis suggests that the only side effect is diarrhoea [9]. Acamprosate is administered as three 333 mg tablets 3 times a day in patients with a bodyweight ≥ 60 kg and 2 tablets twice a day in patients weighing ≤ 60 kg. Naltrexone is orally active and administered as 50 mg tablets once a day. In the USA, naltrexone is also available in a depot formulation. Naltrexone appears to reduce the rewarding effects of alcohol and has been tested in numerous controlled clinical trials [10], especially in combination with psychotherapy [56]. Although some recent clinical studies have shown negative results for acamprosate [57], meta-analyses indicate that acamprosate and naltrexone reduce relapse to heavy drinking or increase the abstinence rates in alcohol-dependent people [9, 53]. Correspondingly, the most recent systematic review for pharmacotherapy in alcohol use disorders concludes that both acamprosate and oral naltrexone are associated with a reduction in return to drinking [58]. However, Zindel and Kranzler [59] concluded that the beneficial effects of these approved medications are “only modestly greater than those of placebo, and their use is limited”. Consequently, they have limited use and public health impact [60].
Downloaded by: University of Connecticut. Copyrighted material.
Phpsy/2014-11-0400/3.3.2015/MPS
Review
New Developments
▼
Numerous agents have been tested or are currently under investigation for treatment of alcoholism (for reviews, see [33, 59, 61– 64]), but few drugs have emerged from preclinical findings and been evaluated in clinical studies. As Litten et al. [63] state, this process is “notoriously complex and challenging”. The European Medicines Agency’s guideline on the development of medicinal products for the treatment of alcohol dependence [65] states that efficacy should also be evaluated in terms of the difference in the percentage of treatment responders. This narrative focuses on emerging drugs that either have recently been approved or look likely to find their way into clinical practice.
Nalmefene
▼
Nalmefene, which was initially approved in the USA in the 1990s for the treatment of opioid overdoses, has a similar chemical structure to naltrexone [66], but may offer some advantages [67], including a more effective binding to central opioid receptors [68, 69], a higher bioavailability [70–72] and the absence of a dose-dependent association with liver toxicity [67]. Nalmefene is an antagonist at the mu- and delta-opioid receptor [68, 73] and a partial agonist at the kappa receptor [74]. The kappa receptor may be of relevance for motivational aspects of alcoholism [75–77]. Nalmefene does not act via any other receptor type (for a review, see [78]). Preclinical data suggest that kappa-opioid receptor antagonism decreases dependence-induced alcohol self-administration [75]. The relatively higher affinity of nalmefene at the kappa receptor may be responsible for the increased activation of the HPA axis via increased release of adrenocorticotropic hormone [79]. In alcoholism the opioid system interacts closely with the stress system; naltrexone and nalmefene may have different effects on the stress system. Elevated levels of stress hormones and glucocorticoids have been described in alcohol withdrawal and binge drinking and the HPA axis is activated by alcohol intake (for a review, see [80]). The oral bioavailability of nalmefene is 40 %, which is slightly higher than that of naltrexone [69, 81]. There is no evidence for liver toxicity [67]. Neuroimaging studies on the pharmacokinetics and pharmacodynamics of nalmefene suggest a slow dissociation of the drug from the mu-opioid receptor [69, 70]. PET study data with the opioid receptor ligand (11c) carfentanil indicate that nalmefene is rapidly absorbed: the mean half-life was 13.4 h after single and repeated dosing [69]. Single doses of 20–300 mg daily or 10–40 mg twice daily are usually well tolerated [69, 70, 82].
Preclinical findings
Few animal data are available for nalmefene [39, 83], but it was found to be significantly more effective than naltrexone in suppressing ethanol intake in ethanol-dependent rats [75, 77]. Like naltrexone, nalmefene reduces the subjective “high” feeling after alcohol consumption [84, 85].
Clinical findings
6 randomised controlled trials have been published on nalmefene [67, 82, 86–89], a lot fewer than on naltrexone [10]. Subsequent to pilot studies with limited statistical power [67, 82, 86], Anton et al. [86] evaluated 3 doses of nalmefene (5, 20 and 40 mg) in a double-blind comparison with placebo over a
Review 12-week treatment period (N = 270). Both the nalmefene and placebo groups showed a reduction in heavy drinking days, craving, gamma-glutamyl transferase (GGT) and carbohydratedeficient transferrin concentrations and no differences were found between the groups on these measures. A multicentre, randomised, placebo-controlled study by Karhuvaara et al. [88] in a sample of heavy drinkers (N = 403) found significant effects of nalmefene compared to placebo on the mean number of heavy drinking days (mean 8.6–9.3 in the nalmefene group, 10.6–12.0 in the placebo group; p = 0.0065). Furthermore, serum alanine aminotransferase and GGT levels decreased in the nalmefene group compared with the placebo group (p = 0.0088 and 0.0023, respectively). The most common adverse events associated with nalmefene were nausea, insomnia, fatigue, dizziness and alcoholic hangover. 2 large and adequately powered randomised placebo-controlled studies that explicitly focused on the efficacy of nalmefene in reducing alcohol use were conducted in Europe [87, 89]. Both used an “as needed” approach to compare 18 mg nalmefene with placebo and defined the primary goal as reduction of heavy drinking days. Neither study provides data on abstinence rates. One of the studies, Mann et al. [89], evaluated the as-needed use of nalmefene vs. placebo over 6 months in 579 patients with alcohol dependence. During the main treatment period, the mean percentage of days with study medication intake was 48.0 % in the nalmefene and 63.9 % in the placebo group. The study found a significant reduction of total daily alcohol consumption ( − 11.0 g/day [95 % confidence interval, CI − 16.8 to − 5.1]; p = 0.0003) and heavy drinking days ( − 2.3 days [95 % CI − 3.8 to − 0.8]; p = 0.0021) in the nalmefene group. In line with these findings, liver values decreased significantly more in the nalmefene group than in the placebo group. The number of patients who discontinued treatment was significantly higher in the nalmefene group, mostly because of adverse events. Treatment-emergent adverse events occurred in 81.5 % of the nalmefene group and 66.9 % of the placebo group. The main treatment-emergent adverse events relevant for discontinuation were nausea, dizziness, fatigue and headache. The other study, by Gual et al. [87], evaluated as-needed use in 718 patients. In this study, a total of 218 patients reduced their drinking days to 6 or fewer heavy drinking days/month or their average alcohol consumption to below the WHO medium drinking risk level already between screening and randomisation. During the main treatment period, the mean percentage of days with study medication intake was 57.0 % in the nalmefene and 65.2 % in the placebo group. The co-primary efficacy analyses showed a significant reduction in heavy drinking days in the nalmefene group compared to the placebo group from baseline to month 6 (group difference: − 1.7 days/month [95 % CI − 3.1; − 0.4]; p = 0.012). Reductions in liver enzymes were greater in the nalmefene group. In contrast to the Mann et al. [89] study, the incidence of adverse events leading to dropout was similar in both groups. Treatment-emergent adverse events occurred in 68.0 % of the nalmefene group and 59.1 % of the placebo group. Of interest in this context is a safety study by van den Brink et al. [90], which also found a higher rate of adverse events in the nalmefene than in the placebo group. Van den Brink et al. [91] performed an interesting subanalysis of the Mann et al. [89] and Gual et al. [87] studies. Since some patients had already reduced their alcohol drinking before study entry, the authors looked at patients who did not reduce their consumption after the initial assessment. The pooled analysis Soyka M, Lieb M. Recent Developments in Pharmacotherapy … Pharmacopsychiatry
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consisted of 667 patients (332 placebo, 335 nalmefene). The authors found that nalmefene was significantly more effective than placebo in reducing the number of heavy drinking days [treatment difference: − 3.2 days (95 % CI: − 4.8; − 1.6); p
