Review European Addiction Research
Published online: August 29, 2015
Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
Efficacy of Medications Approved for the Treatment of Alcohol Dependence and Alcohol Withdrawal Syndrome in Female Patients: A Descriptive Review Roberta Agabio a Pier Paolo Pani b Antonio Preti c Gian Luigi Gessa a, d Flavia Franconi e
a
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Social-Health Services, Cagliari Health Public Trust (ASL Cagliari), c Unit of Psychosomatics and Clinical Psychiatry, University Hospital, University of Cagliari, d Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Cagliari, and e Department of Biomedical Sciences, University of Sassari, Sassari, Italy
b
Abstract The aim of this study was to evaluate whether the number of women recruited for studies to establish the efficacy of medications approved for treatment of alcohol dependence (AD) and of alcohol withdrawal syndrome (AWS) is sufficient to reveal possible gender differences in the response to these medications and in suggesting the use of different doses in female patients. Our results show that the rates of women recruited for studies evaluating the efficacy of disulfiram (1%), benzodiazepines (3%), and anticonvulsants (13%) were too low to establish possible gender differences. The rates of women recruited for studies evaluating the efficacy of acamprosate (22%), naltrexone (23%), and nalmefene (30%) were higher and allowed evaluation of data obtained for female patients. Women receive medications for treatment of AD and/or AWS for which efficacy has been demonstrated in studies in which men were more largely represented. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1022–6877/15/0221–0001$39.50/0 E-Mail [email protected] www.karger.com/ear
Introduction
Pharmacotherapy is emerging as a valuable tool for the treatment of alcohol dependence (AD), but only a few medications are available to date. Currently, medications approved in the United Kingdom and/or in the United States for AD treatment to help patients achieve abstinence, or at least to reduce alcohol consumption, comprise disulfiram, naltrexone, acamprosate, nalmefene and gamma-hydroxybutyrate (GHB) [1–3]. Briefly, disulfiram is the oldest medication for the treatment of AD, approved by the FDA since 1948 [3]. Its mechanism of action involves inhibition of aldehyde dehydrogenase (ALDH), the enzyme responsible for converting acetaldehyde to acetate during alcohol metabolism, which leads to the accumulation of acetaldehyde after alcohol intake [4]. Accumulation of acetaldehyde causes a consequent aversive reaction that deters further alcohol use [5]. Accordingly, disulfiram is indicated for the prevention of relapse in abstinent patients.
G.L.G. and F.F. contributed equally to this work.
Roberta Agabio, MD Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology University of Cagliari, Cittadella Universitaria S.S. 554, km. 4.500, IT–09042, Monserrato CA (Italy) E-Mail agabio @ unica.it
Downloaded by: University of Tennessee 198.143.47.33 - 1/27/2016 4:26:30 AM
Key Words Alcohol dependence · Alcohol withdrawal syndrome · Women · Pharmacotherapy · Gender differences
2
Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
tural factors involved in the response to medical treatments, and sex differences in response to medications have been described for several treatment methods [21– 25]. For instance, it has been observed that women eliminate the hypnotic medication zolpidem more slowly than men do, and lower doses of this medication have been recommended for women compared to men [26, 27]. Similarly, women could differ from men in the response to medications approved for treatment of AD and/or AWS. Women differ from men with regard to several AD aspects [28–34]. This mental disorder is twice as prevalent in men as in women [35], although women suffer serious negative consequences of alcohol consumption much early in life and to a greater degree than men. In addition, women also experience specific alcohol-related problems, such as the risk of foetal alcohol syndrome if alcohol is consumed during pregnancy [36, 37]. The higher vulnerability to the development of alcohol-related consequences in women is, at least in part, due to sex differences in alcohol pharmacokinetics. The risk of medical consequences is related to blood alcohol concentration, and after drinking equivalent amounts of alcohol, women achieve higher blood alcohol concentration than men of similar body weight [38–40]. This occurs because women have a smaller volume of distribution (due to a higher proportion of body fat and lower body water than men) and a lower first-pass metabolism of alcohol than men (because of lower levels of the gastric enzyme that metabolises alcohol: alcohol dehydrogenase) [38]. For these reasons, women are advised to consume lower amounts of alcohol than men do. Gender difference has also been described as an important factor in determining alcohol consumption, as well as the response to alcohol at comparable blood alcohol concentration. For instance, in humans and non-human adult primates, males consume higher amounts of alcohol than females [33, 41] do, while in rodents, females consume higher amounts of alcohol than males [42, 43]. Moreover, aggressive behaviour after alcohol consumption is less evident in women than in men [44], and female rats are more sensitive than males to alcohol-induced hypothermia [45]. Both animal and clinical studies have found that females tend to develop less severe AWS than males [31, 46]. Complex interactions between intrinsic sex differences in brain organization and the activational effects of circulating gonadal steroids, neuroactive steroids (steroids synthesised in the brain, adrenals, and gonads that affect neuronal excitability), and stress hormones have been proposed to explain these findings [47, 48]. For instance, as allopregnanolone, a metabolite of Agabio/Pani/Preti/Gessa/Franconi
Downloaded by: University of Tennessee 198.143.47.33 - 1/27/2016 4:26:30 AM
Naltrexone is a competitive antagonist of μ-opioid receptors, approved by the FDA in 1994 for the treatment of AD [2, 3]. Its mechanism of action is not fully understood [2]. As the rewarding effects of alcohol are partly mediated through the opioid receptors, blocking of these receptors could explain the reduction in reward effects induced by alcohol consumption and subsequently the reductions in intake and cravings for alcohol [6]. Concerns about low adherence for oral formulations led to the development of slow-release formulations of naltrexone [6]. Nalmefene is a μ-opioid antagonist, like naltrexone, but, compared to naltrexone, nalmefene has a longer plasma half-life, higher bioavailability, and lower liver toxicity [7]. This medication has been recently approved by the European Committee for Medicinal Products for Human Use for the treatment of AD [8]. In the United States, acamprosate is currently the most widely prescribed medication to prevent AD relapse [9, 10]. The mechanism of action of acamprosate is not completely known. It shares similarities with several amino acids, such as glutamate, gamma-aminobutyric acid, aspartate, glycine, and taurine [11]. Converging evidence indicates that acamprosate normalises a hyper-glutamatergic state caused by extensive alcohol exposure and repeated phases of alcohol withdrawal, restoring the balance between inhibitory and excitatory neurotransmitters, and attenuating alcohol craving [12]. GHB is an endogenous neurochemical currently marketed in some European countries for the treatment of AD [13]. The mechanism of action of GHB in the treatment of AD is substitutive [1]. While substitution therapy carriers a lower risk than the use of the substance of abuse, the substitute also has a potential for abuse, and cases of GHB intoxication have been reported [14, 15]. For this reason, in the United States, GHB has not been approved for the treatment of AD [13]. Finally, medications approved in the Europe and/or the United States for the treatment of alcohol withdrawal syndrome (AWS) comprise benzodiazepines (e.g. diazepam, chlordiazepoxide, and lorazepam), anticonvulsants (e.g. carbamazepine, valproic acid, and phenytoin), and GHB [16–18]. Unfortunately, AD medications are not effective in all patients, and the magnitude of the response to these medications is generally modest [3]. To improve the efficacy of AD medications, there is growing interest in investigating possible factors that mediate the response to pharmacotherapy, such as different patient characteristics and genetic factors [19, 20]. It is notable that women and men vary largely in terms of biological and psychosocial-cul-
Methods Search Methods for Identification of Reviews A systematic search was conducted on PubMed/Medline and the Cochrane database of Systematic Reviews to identify metaanalyses on the efficacy of medications approved for AD and AWS treatment. A first systematic search was conducted using the keywords ‘pharmacological treatment (mesh) AND alcohol dependence (mesh)’, and a second systematic search using the keywords ‘pharmacological treatment (mesh) AND alcohol withdrawal syndrome’. In both searches, the filters meta-analysis, Humans, and English language were activated. The search was performed in August 2014. When no meta-analysis was found for a medication, a manual search throughout the reading of the other selected metaanalyses was conducted. When more than one eligible meta-analysis was available for the same medication, the more recent one was selected.
Medications for AD Women
Criteria for Considering Reviews for Inclusion Only meta-analyses on the efficacy of medications already approved for AD and/or AWS treatment were included. Other inclusion criteria were (1) use of rigorous methods to minimise bias, (2) diagnosis of AD and/or AWS according to appropriate standard criteria (e.g. the criteria of Diagnostic and Statistical Manual of Mental Disorders), and (3) comparison between the results obtained by patients treated with the pharmacological intervention and those obtained by patients treated with placebo. Recent primary clinical trials not yet part of the selected meta-analyses were not included. In the first search, only meta-analyses on one of the following medications were included: (1) naltrexone, (2) acamprosate, (3) nalmefene, (4) disulfiram, and (5) GHB. In the second search, only meta-analyses on one of the following medications approved for AWS treatment were included: (1) benzodiazepines, (2) anticonvulsants, and (3) GHB. Assessment of the Methodological Quality of Included Reviews The quality of the included reviews was not evaluated, as it was assured by selecting meta-analyses. Data Extraction and Management From each selected meta-analysis, the following information was collected: (1) number of randomised controlled trials (RCTs) evaluated; (2) number of patients recruited by these RCTs; (3) number of RCTs in which only male patients were recruited; (4) number of RCTs in which the sex of patients was not indicated; (5) number of RCTs in which female and male patients were recruited; (6) number of RCTs in which only female patients were recruited; (7) medication doses administered (when this information was not specified by the meta-analysis, it was obtained from the original article on the RCT); and (8) levels of medication efficacy assigned by the meta-analysis, regardless of patient sex. From this information, the following data were calculated: (1) the rate of female patients among patients for whom sex was known; (2) the highest and lowest doses used in any RCTs. Sufficient Number of Female Patients Recruited for RCTs Considering that the lifetime prevalence of AD is twice as high in men as in women [35], female patients should constitute approximately one-third of the sample of patients recruited in studies evaluating the efficacy of medications for this disorder (33% of patients). Assessment of Efficacy For each medication (or class of medications), the efficacy, regardless of the sex of the patient, evaluated by the selected metaanalysis was expressed in levels (table 1) [52–54]. When a metaanalysis showed superiority of a medication to placebo, level A1 was assigned; when a meta-analysis did not show superiority of a medication to placebo, level C was assigned. The efficacy of each medication in female patients was assigned according to the criteria provided in table 1, considering the source of the evidence and possible negative results.
Results
The first search for meta-analyses of medications approved for AD treatment identified 79 articles. Among these, 75 were excluded (see online suppl. references; Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
3
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progesterone, has shown an anticonvulsant effect in some preclinical models, the current hypothesis is that females and males might have different sensitivity to AWS owing to the effects of neurosteroids [47, 49]. Some of the sex differences observed in alcohol consumption and/or in responses to alcohol have been attributed to differences in levels of oestrogens and androgens between women and men. Indeed, it has been observed that oestrogen and androgen levels modulate the mesocorticolimbic ‘reward’ dopaminergic system [50], and that women release less amounts of dopamine in the ventral striatum compared to men after acute alcohol consumption [51]. Human and preclinical studies have also shown that the pattern of alcohol consumption varies throughout the different phases of the menstrual cycle, and these differences have been attributed, at least in part, to different levels of oestrogens and progesterone [50]. In view of all these sex differences, it can be hypothesised that women and men might also differ in their response to medications approved for treatment of AD and/or AWS, and might require different doses of these medications. To test this hypothesis, we performed a descriptive review of studies on the efficacy of these medications to evaluate: (a) whether a sufficient number of women were recruited to evaluate possible sex differences in the response; (b) if the number of women was sufficient, whether sex differences in the response were observed; and (c) the doses administered in these studies. To this end, recent meta-analyses evaluating the efficacy of AD and/or AWS medications were selected. From these meta-analyses, data on female patients and medication doses administered were collected. When this information was not available in the selected meta-analyses, the primary clinical trials were examined.
Table 1. Levels of efficacy
Level
Source of the evidence
If negative RCTs do exist
A1
One meta-analysis shows superiority to placebo (with a narrow confidence interval in at least 3 RCTs, at least one of which was large)
They have already been evaluated by the meta-analysis
A2
At least 2 positive RCTs show superiority to placebo (with a narrow confidence interval in at least 1 large RCT)
They are outweighed by: (1) a meta-analysis on all available studies showing non-inferiority to an established comparator treatment, or (2) at least 2 more positive studies showing superiority to placebo
B
One or more RCTs shows superiority to placebo
They are outweighed by: (1) a meta-analysis of all available studies showing non-inferiority to an established comparator treatment, or (2) at least 1 more positive study showing superiority to placebo
C
Inconsistent evidence from any number of RCTs
They are not outweighed by positive RCTs
This table summarises how the level of efficacy was established, considering the source of the evidence and possible negative results. RCTs = Randomised, controlled trials based on a double-blind, parallel-group design. Large = Number of patients recruited ≥100 subjects.
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Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
a week, but it was not specified whether women received lower doses of disulfiram than men did [60]. The meta-analysis selected for acamprosate evaluated the results obtained by 24 RCTs and found that this medication significantly reduced the risk of any drinking after detoxification (14% lower risk), and increased the cumulative duration of abstinence (3 additional days a month) [56]. According to these results, the level A1 of efficacy for AD treatment was assigned to acamprosate, regardless of sex (table 2). The rates of women recruited in these 24 RCTs are shown by table 4. Globally, (a) 2 RCTs recruited only male patients (n = 85 men), whereas (b) the other 22 RCTs recruited both female and male patients (1,326 women in a sample of 6,062 patients (21.9%)). All the RCTs compared acamprosate to placebo. Among the total sample of patients (n = 6,147 patients), 1,326 were women (21.9%). The rate of women recruited for RCTs evaluating the efficacy of acamprosate was close to the real frequency of female patients with AD and allowed a gender analysis (tables 2 and 4; fig. 1). Specifically, the second meta-analysis selected found no sex differences in all the outcomes evaluated [57]. According to these results, the level A1 of efficacy for AD treatment was assigned to acamprosate for AD female patients (table 2). The daily dose of acamprosate ranged from 1,332 to 3,000 mg; in most studies, the dose was adjusted according to body weight (1,332 mg for body weight
Published online: August 29, 2015
Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
Efficacy of Medications Approved for the Treatment of Alcohol Dependence and Alcohol Withdrawal Syndrome in Female Patients: A Descriptive Review Roberta Agabio a Pier Paolo Pani b Antonio Preti c Gian Luigi Gessa a, d Flavia Franconi e
a
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Social-Health Services, Cagliari Health Public Trust (ASL Cagliari), c Unit of Psychosomatics and Clinical Psychiatry, University Hospital, University of Cagliari, d Neuroscience Institute, National Research Council of Italy, Section of Cagliari, Cagliari, and e Department of Biomedical Sciences, University of Sassari, Sassari, Italy
b
Abstract The aim of this study was to evaluate whether the number of women recruited for studies to establish the efficacy of medications approved for treatment of alcohol dependence (AD) and of alcohol withdrawal syndrome (AWS) is sufficient to reveal possible gender differences in the response to these medications and in suggesting the use of different doses in female patients. Our results show that the rates of women recruited for studies evaluating the efficacy of disulfiram (1%), benzodiazepines (3%), and anticonvulsants (13%) were too low to establish possible gender differences. The rates of women recruited for studies evaluating the efficacy of acamprosate (22%), naltrexone (23%), and nalmefene (30%) were higher and allowed evaluation of data obtained for female patients. Women receive medications for treatment of AD and/or AWS for which efficacy has been demonstrated in studies in which men were more largely represented. © 2015 S. Karger AG, Basel
© 2015 S. Karger AG, Basel 1022–6877/15/0221–0001$39.50/0 E-Mail [email protected] www.karger.com/ear
Introduction
Pharmacotherapy is emerging as a valuable tool for the treatment of alcohol dependence (AD), but only a few medications are available to date. Currently, medications approved in the United Kingdom and/or in the United States for AD treatment to help patients achieve abstinence, or at least to reduce alcohol consumption, comprise disulfiram, naltrexone, acamprosate, nalmefene and gamma-hydroxybutyrate (GHB) [1–3]. Briefly, disulfiram is the oldest medication for the treatment of AD, approved by the FDA since 1948 [3]. Its mechanism of action involves inhibition of aldehyde dehydrogenase (ALDH), the enzyme responsible for converting acetaldehyde to acetate during alcohol metabolism, which leads to the accumulation of acetaldehyde after alcohol intake [4]. Accumulation of acetaldehyde causes a consequent aversive reaction that deters further alcohol use [5]. Accordingly, disulfiram is indicated for the prevention of relapse in abstinent patients.
G.L.G. and F.F. contributed equally to this work.
Roberta Agabio, MD Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology University of Cagliari, Cittadella Universitaria S.S. 554, km. 4.500, IT–09042, Monserrato CA (Italy) E-Mail agabio @ unica.it
Downloaded by: University of Tennessee 198.143.47.33 - 1/27/2016 4:26:30 AM
Key Words Alcohol dependence · Alcohol withdrawal syndrome · Women · Pharmacotherapy · Gender differences
2
Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
tural factors involved in the response to medical treatments, and sex differences in response to medications have been described for several treatment methods [21– 25]. For instance, it has been observed that women eliminate the hypnotic medication zolpidem more slowly than men do, and lower doses of this medication have been recommended for women compared to men [26, 27]. Similarly, women could differ from men in the response to medications approved for treatment of AD and/or AWS. Women differ from men with regard to several AD aspects [28–34]. This mental disorder is twice as prevalent in men as in women [35], although women suffer serious negative consequences of alcohol consumption much early in life and to a greater degree than men. In addition, women also experience specific alcohol-related problems, such as the risk of foetal alcohol syndrome if alcohol is consumed during pregnancy [36, 37]. The higher vulnerability to the development of alcohol-related consequences in women is, at least in part, due to sex differences in alcohol pharmacokinetics. The risk of medical consequences is related to blood alcohol concentration, and after drinking equivalent amounts of alcohol, women achieve higher blood alcohol concentration than men of similar body weight [38–40]. This occurs because women have a smaller volume of distribution (due to a higher proportion of body fat and lower body water than men) and a lower first-pass metabolism of alcohol than men (because of lower levels of the gastric enzyme that metabolises alcohol: alcohol dehydrogenase) [38]. For these reasons, women are advised to consume lower amounts of alcohol than men do. Gender difference has also been described as an important factor in determining alcohol consumption, as well as the response to alcohol at comparable blood alcohol concentration. For instance, in humans and non-human adult primates, males consume higher amounts of alcohol than females [33, 41] do, while in rodents, females consume higher amounts of alcohol than males [42, 43]. Moreover, aggressive behaviour after alcohol consumption is less evident in women than in men [44], and female rats are more sensitive than males to alcohol-induced hypothermia [45]. Both animal and clinical studies have found that females tend to develop less severe AWS than males [31, 46]. Complex interactions between intrinsic sex differences in brain organization and the activational effects of circulating gonadal steroids, neuroactive steroids (steroids synthesised in the brain, adrenals, and gonads that affect neuronal excitability), and stress hormones have been proposed to explain these findings [47, 48]. For instance, as allopregnanolone, a metabolite of Agabio/Pani/Preti/Gessa/Franconi
Downloaded by: University of Tennessee 198.143.47.33 - 1/27/2016 4:26:30 AM
Naltrexone is a competitive antagonist of μ-opioid receptors, approved by the FDA in 1994 for the treatment of AD [2, 3]. Its mechanism of action is not fully understood [2]. As the rewarding effects of alcohol are partly mediated through the opioid receptors, blocking of these receptors could explain the reduction in reward effects induced by alcohol consumption and subsequently the reductions in intake and cravings for alcohol [6]. Concerns about low adherence for oral formulations led to the development of slow-release formulations of naltrexone [6]. Nalmefene is a μ-opioid antagonist, like naltrexone, but, compared to naltrexone, nalmefene has a longer plasma half-life, higher bioavailability, and lower liver toxicity [7]. This medication has been recently approved by the European Committee for Medicinal Products for Human Use for the treatment of AD [8]. In the United States, acamprosate is currently the most widely prescribed medication to prevent AD relapse [9, 10]. The mechanism of action of acamprosate is not completely known. It shares similarities with several amino acids, such as glutamate, gamma-aminobutyric acid, aspartate, glycine, and taurine [11]. Converging evidence indicates that acamprosate normalises a hyper-glutamatergic state caused by extensive alcohol exposure and repeated phases of alcohol withdrawal, restoring the balance between inhibitory and excitatory neurotransmitters, and attenuating alcohol craving [12]. GHB is an endogenous neurochemical currently marketed in some European countries for the treatment of AD [13]. The mechanism of action of GHB in the treatment of AD is substitutive [1]. While substitution therapy carriers a lower risk than the use of the substance of abuse, the substitute also has a potential for abuse, and cases of GHB intoxication have been reported [14, 15]. For this reason, in the United States, GHB has not been approved for the treatment of AD [13]. Finally, medications approved in the Europe and/or the United States for the treatment of alcohol withdrawal syndrome (AWS) comprise benzodiazepines (e.g. diazepam, chlordiazepoxide, and lorazepam), anticonvulsants (e.g. carbamazepine, valproic acid, and phenytoin), and GHB [16–18]. Unfortunately, AD medications are not effective in all patients, and the magnitude of the response to these medications is generally modest [3]. To improve the efficacy of AD medications, there is growing interest in investigating possible factors that mediate the response to pharmacotherapy, such as different patient characteristics and genetic factors [19, 20]. It is notable that women and men vary largely in terms of biological and psychosocial-cul-
Methods Search Methods for Identification of Reviews A systematic search was conducted on PubMed/Medline and the Cochrane database of Systematic Reviews to identify metaanalyses on the efficacy of medications approved for AD and AWS treatment. A first systematic search was conducted using the keywords ‘pharmacological treatment (mesh) AND alcohol dependence (mesh)’, and a second systematic search using the keywords ‘pharmacological treatment (mesh) AND alcohol withdrawal syndrome’. In both searches, the filters meta-analysis, Humans, and English language were activated. The search was performed in August 2014. When no meta-analysis was found for a medication, a manual search throughout the reading of the other selected metaanalyses was conducted. When more than one eligible meta-analysis was available for the same medication, the more recent one was selected.
Medications for AD Women
Criteria for Considering Reviews for Inclusion Only meta-analyses on the efficacy of medications already approved for AD and/or AWS treatment were included. Other inclusion criteria were (1) use of rigorous methods to minimise bias, (2) diagnosis of AD and/or AWS according to appropriate standard criteria (e.g. the criteria of Diagnostic and Statistical Manual of Mental Disorders), and (3) comparison between the results obtained by patients treated with the pharmacological intervention and those obtained by patients treated with placebo. Recent primary clinical trials not yet part of the selected meta-analyses were not included. In the first search, only meta-analyses on one of the following medications were included: (1) naltrexone, (2) acamprosate, (3) nalmefene, (4) disulfiram, and (5) GHB. In the second search, only meta-analyses on one of the following medications approved for AWS treatment were included: (1) benzodiazepines, (2) anticonvulsants, and (3) GHB. Assessment of the Methodological Quality of Included Reviews The quality of the included reviews was not evaluated, as it was assured by selecting meta-analyses. Data Extraction and Management From each selected meta-analysis, the following information was collected: (1) number of randomised controlled trials (RCTs) evaluated; (2) number of patients recruited by these RCTs; (3) number of RCTs in which only male patients were recruited; (4) number of RCTs in which the sex of patients was not indicated; (5) number of RCTs in which female and male patients were recruited; (6) number of RCTs in which only female patients were recruited; (7) medication doses administered (when this information was not specified by the meta-analysis, it was obtained from the original article on the RCT); and (8) levels of medication efficacy assigned by the meta-analysis, regardless of patient sex. From this information, the following data were calculated: (1) the rate of female patients among patients for whom sex was known; (2) the highest and lowest doses used in any RCTs. Sufficient Number of Female Patients Recruited for RCTs Considering that the lifetime prevalence of AD is twice as high in men as in women [35], female patients should constitute approximately one-third of the sample of patients recruited in studies evaluating the efficacy of medications for this disorder (33% of patients). Assessment of Efficacy For each medication (or class of medications), the efficacy, regardless of the sex of the patient, evaluated by the selected metaanalysis was expressed in levels (table 1) [52–54]. When a metaanalysis showed superiority of a medication to placebo, level A1 was assigned; when a meta-analysis did not show superiority of a medication to placebo, level C was assigned. The efficacy of each medication in female patients was assigned according to the criteria provided in table 1, considering the source of the evidence and possible negative results.
Results
The first search for meta-analyses of medications approved for AD treatment identified 79 articles. Among these, 75 were excluded (see online suppl. references; Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
3
Downloaded by: University of Tennessee 198.143.47.33 - 1/27/2016 4:26:30 AM
progesterone, has shown an anticonvulsant effect in some preclinical models, the current hypothesis is that females and males might have different sensitivity to AWS owing to the effects of neurosteroids [47, 49]. Some of the sex differences observed in alcohol consumption and/or in responses to alcohol have been attributed to differences in levels of oestrogens and androgens between women and men. Indeed, it has been observed that oestrogen and androgen levels modulate the mesocorticolimbic ‘reward’ dopaminergic system [50], and that women release less amounts of dopamine in the ventral striatum compared to men after acute alcohol consumption [51]. Human and preclinical studies have also shown that the pattern of alcohol consumption varies throughout the different phases of the menstrual cycle, and these differences have been attributed, at least in part, to different levels of oestrogens and progesterone [50]. In view of all these sex differences, it can be hypothesised that women and men might also differ in their response to medications approved for treatment of AD and/or AWS, and might require different doses of these medications. To test this hypothesis, we performed a descriptive review of studies on the efficacy of these medications to evaluate: (a) whether a sufficient number of women were recruited to evaluate possible sex differences in the response; (b) if the number of women was sufficient, whether sex differences in the response were observed; and (c) the doses administered in these studies. To this end, recent meta-analyses evaluating the efficacy of AD and/or AWS medications were selected. From these meta-analyses, data on female patients and medication doses administered were collected. When this information was not available in the selected meta-analyses, the primary clinical trials were examined.
Table 1. Levels of efficacy
Level
Source of the evidence
If negative RCTs do exist
A1
One meta-analysis shows superiority to placebo (with a narrow confidence interval in at least 3 RCTs, at least one of which was large)
They have already been evaluated by the meta-analysis
A2
At least 2 positive RCTs show superiority to placebo (with a narrow confidence interval in at least 1 large RCT)
They are outweighed by: (1) a meta-analysis on all available studies showing non-inferiority to an established comparator treatment, or (2) at least 2 more positive studies showing superiority to placebo
B
One or more RCTs shows superiority to placebo
They are outweighed by: (1) a meta-analysis of all available studies showing non-inferiority to an established comparator treatment, or (2) at least 1 more positive study showing superiority to placebo
C
Inconsistent evidence from any number of RCTs
They are not outweighed by positive RCTs
This table summarises how the level of efficacy was established, considering the source of the evidence and possible negative results. RCTs = Randomised, controlled trials based on a double-blind, parallel-group design. Large = Number of patients recruited ≥100 subjects.
4
Eur Addict Res 2016;22:1–16 DOI: 10.1159/000433579
a week, but it was not specified whether women received lower doses of disulfiram than men did [60]. The meta-analysis selected for acamprosate evaluated the results obtained by 24 RCTs and found that this medication significantly reduced the risk of any drinking after detoxification (14% lower risk), and increased the cumulative duration of abstinence (3 additional days a month) [56]. According to these results, the level A1 of efficacy for AD treatment was assigned to acamprosate, regardless of sex (table 2). The rates of women recruited in these 24 RCTs are shown by table 4. Globally, (a) 2 RCTs recruited only male patients (n = 85 men), whereas (b) the other 22 RCTs recruited both female and male patients (1,326 women in a sample of 6,062 patients (21.9%)). All the RCTs compared acamprosate to placebo. Among the total sample of patients (n = 6,147 patients), 1,326 were women (21.9%). The rate of women recruited for RCTs evaluating the efficacy of acamprosate was close to the real frequency of female patients with AD and allowed a gender analysis (tables 2 and 4; fig. 1). Specifically, the second meta-analysis selected found no sex differences in all the outcomes evaluated [57]. According to these results, the level A1 of efficacy for AD treatment was assigned to acamprosate for AD female patients (table 2). The daily dose of acamprosate ranged from 1,332 to 3,000 mg; in most studies, the dose was adjusted according to body weight (1,332 mg for body weight
