Pharmacotherapy for alcohol dependence: A stratified approach A. Thompson, L. Owens, S.P. Pushpakom, M. Faizal, M. Pirmohamed PII: DOI: Reference:
S0163-7258(15)00101-1 doi: 10.1016/j.pharmthera.2015.05.010 JPT 6785
To appear in:
Pharmacology and Therapeutics
Please cite this article as: Thompson, A., Owens, L., Pushpakom, S.P., Faizal, M. & Pirmohamed, M., Pharmacotherapy for alcohol dependence: A stratified approach, Pharmacology and Therapeutics (2015), doi: 10.1016/j.pharmthera.2015.05.010
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ACCEPTED MANUSCRIPT P&T # 22749 PHARMACOTHERAPY FOR ALCOHOL DEPENDENCE:
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A STRATIFIED APPROACH
THOMPSON, A1. OWENS, L1&2. PUSHPAKOM, SP1. FAIZAL, M3. PIRMOHAMED, M1 Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of
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1
Liverpool, 1-5 Brownlow Street, Liverpool L69 3GL
Hepatology, Royal Liverpool University Hospital Trust, Ward 5z Link, Prescot Street. England
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Addiction Service, Mersey Care NHS Trust, 40 Upper Parliament Street, Liverpool,
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Merseyside L8 7LF
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UK
Address for correspondence: Munir Pirmohamed
Wolfson Centre for Personalised Medicine Institute of Translational Medicine Block A Waterhouse Building University of Liverpool Liverpool L69 3GL United Kingdom Telephone: +44 151 794 5549 Fax: +44 151 794 5059 1
ACCEPTED MANUSCRIPT Email: [email protected] Abstract
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Alcohol dependence is a common disorder in many societies worldwide, and remains
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difficult to identify and treat. It is also a risk factor for many secondary non-communicable
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diseases. Pharmacotherapy is one available treatment option, but appears to be underutilised in practice. Major barriers to use of medications in this area include lack of
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clinical guidance and questionable efficacy. However, for each medication there appears to be a subpopulation that responds positively, and understanding the moderating factors to
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treatment efficacy is an important research goal. Thus, this review provides a narrative regarding potential stratification techniques in pharmacological treatment of alcohol
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dependence, with a specific focus on typologies and pharmacogenetics. In addition, we
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discuss the basic background of stratified medicine and recent studies on genetic
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growing
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predisposition to alcohol dependence. repository
of
data
exists
for
both
approved
and
non-approved
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pharmacotherapies, but failure to replicate findings, inadequate sample sizes, and insufficient funding has resulted in a translational gap. Implementing evidence-based stratified/personalised therapy and identifying new therapeutic agents may lead to improved clinical outcomes and reduced financial burden. Despite some promising findings to date, much work is still required.
Keywords: Alcohol dependence; Pharmacogenetics; Typologies; Stratified medicine
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Abbreviations:
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5HT 5-hydroxytryptamine; ADH alcohol dehydrogenase; ALDH aldehyde dehydrogenase;
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ASN asparagine; ASP aspartate; DBH dopamine beta-hydroxylase; EOA early onset alcohol
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dependence; HTR7 5-hydroxytrytamine receptor 7; GABA γ-aminobutyric acid; LOA late onset alcohol dependence; NMDA N-methyl-D-aspartate; OPRM1 opioid receptor μ-1;
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OPRD1 opioid receptor delta-1; OPRK1 opioid receptor kappa-1; SLC6A4 solute carrier
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family 6 member 4
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1. Introduction
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2. Stratified approach to treating alcohol dependence
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Table of Contents
3. Naltrexone
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4. Acamprosate 5. Disulfiram
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6. Nalmefene 7. Baclofen
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8. Ondansetron
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9. Sertraline
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10. Topiramate
11. Relationship between genes involved in alcohol dependence and therapeutic response
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12. Conclusion
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1. Introduction
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Alcohol dependence is a major global public health concern, with the use and abuse of
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alcohol considered a leading risk factor for many non-communicable diseases (Jones et al.,
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2008). The mortality rate is high in this population, being nearly four times the age-adjusted rate for people without alcohol dependence (NICE, 2009). There are further social and
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economic costs linked to excessive alcohol drinking, with the annual global bill estimated at 760 billion Euros (Rehm et al., 2009). The aetiology of alcohol dependence is
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heterogeneous, and manifests from complex interactions between the environment and genes. This heterogeneity has been postulated as a confounder to treatment utilisation and
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efficacy, especially for pharmacotherapy (Litten et al., 2012). Empirical evidence is emerging
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however which suggests that a “stratified” approach to treatment may help optimise
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outcomes. Understanding the moderators that influence positive (or adverse) responses to a specific medication in a subgroup, or more desirably an individual, will assist healthcare
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practitioners in making more informed decisions when prescribing, and hopefully result in improved clinical outcomes. This review aims to provide a narrative of recent advances in the pharmacological treatment of alcohol dependence. There will be a focus on specific subgroups and underlying factors that may influence the efficacy of each medication, thus providing a rationale for a stratified approach to treatment. Specifically, attention will be given to stratification by typology and advances in pharmacogenetics. This review will start by providing a basic overview of stratified medicine. The main section of the article will cover the three medications approved for alcohol dependence treatment by The Medicines and Healthcare Products
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ACCEPTED MANUSCRIPT Regulatory Agency (UK) and Food and Drug Administration (USA): naltrexone, acamprosate and disulfiram. We will then discuss more contemporary drugs, including nalmefene, which
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was recently approved by The European Medicines Agency. This review will not cover the
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use of drugs during withdrawal from alcohol (detoxification); reviews on this topic are
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available elsewhere (for example, Amato et al., 2011; Amato et al., 2010; Minozzi et al., 2010). Furthermore, we also do not cover the utility of psychological interventions either
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when used alone or in combination with pharmacotherapy. We acknowledge this might be viewed as a limitation but we are unable to consider this variable in the scope of this review.
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Indeed, it is possible that more personalised approaches on the type and intensity of psychological intervention may also be of use in these patients.
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2. Stratified approach to treating alcohol dependence What is stratified medicine?
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Current medical practice is largely empirical, with treatment based on a “trial and error” paradigm targeting large populations of patients. Although this can be effective, many drugs
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have a significant number of non-responders or cause adverse reactions. Stratified medicine aims to identify these groups via shared biological or risk characteristics, and tailor subsequent treatment accordingly. One example of stratified medicine in practice is the improved efficacy of trastuzumab for the treatment of metastatic breast cancer in patients who overexpress the human epidermal growth factor-2 (HER2) gene (Slamon et al., 2001). Personalised medicine and precision medicine are related terms often used interchangeably in this area to describe treatment at individual patient-level rather than subgroup clustering. It has been suggested that personalised medicine is an additional step on the patient therapeutic continuum (Trusheim et al., 2007).
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ACCEPTED MANUSCRIPT Clinical stratification in alcohol dependence Identifying moderators of treatment efficacy is an important goal for any therapeutic aid.
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Those that are pertinent to alcohol dependence are presented in Table 1. Pharmacogenetics
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Pharmacogenetics is the study of genetic variation in drug response, with the aim of maximising clinical effectiveness and minimising toxicity by selecting the right drug for the
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right patient at the right dose. Such work is vital to ensure more precise prescribing which will benefit the patient and reduce costs. Rapid advances in sequencing technology coupled
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with international projects (e.g. International HapMap Project and Human Genome Project) have produced a wealth of data and repositories in this field. Several areas of medicine have
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already been influenced by pharmacogenetics, for example warfarin dosing (Pirmohamed et al., 2013), predicting responders to interferon-α in hepatitis C (Pirmohamed, 2011) and
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identification of individuals at risk of abacavir hypersensitivity reaction (Martin et al., 2012). The use of pharmacogenetics in drug treatment for alcohol dependence is in its infancy
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relative to the above examples. The most advanced empirical evidence exists for the μopioid receptor gene (OPRM1) polymorphism, Asn40Asp (rs1799971), which has been reported to predict naltrexone response (Chamorro et al., 2012). Pharmacogenetic studies relating to the treatment of alcohol dependence are summarised in Table 2 and discussed in the relevant sections of this review. Genetic predisposition to alcohol dependence Results from family studies indicate substantial heritability for alcohol dependence, approximately 40-60% (Kendler et al., 1992; Kendler et al., 1997; Milne et al., 2009; Prescott and Kendler, 1999). Despite advances in genetic testing and related analytical methods over 7
ACCEPTED MANUSCRIPT the last two decades, the genes and associated variants responsible for this predisposition remain somewhat enigmatic. However, the utilisation of larger samples alongside a shift in
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emphasis towards gene-gene interactions and more sophisticated models is showing
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promise in identifying novel alcohol dependent phenotypes and subsequent therapeutics.
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The identification of sub-phenotypes in alcohol dependence is important as this will reduce heterogeneity in participants recruited for research, fostering the identification of novel loci
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with larger effect sizes.
Comprehensive reviews of genetic studies relating to susceptibility to alcohol dependence
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have been published elsewhere (Enoch, 2013; Rietschel and Treutlein, 2013); here we provide a basic overview of significant new studies and those with potential implications for
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therapeutic development. The most robust findings to date have been for alcohol metabolising genes (Figure 1), aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase
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(ADH) (e.g. Gelernter et al., 2014; Park et al., 2013), which have been shown to influence alcohol tolerance.
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Two studies have investigated 5-hydroxytrytamine (serotonin) receptor 7 (HTR7) as a susceptibility factor for alcohol dependence. The first study was a genome-wide association study (GWAS) that reported a significant association between rs7916403 of HTR7 and alcohol dependence (Zlojutro et al., 2011). The second study was case-control study that was unable to replicate the aforementioned association, but implicated two different HTR7 polymorphisms in alcohol dependence, rs11596518 and rs7904560 (Kim et al., 2014). The first GWAS investigating genetic influence on age of onset in alcohol dependent families was published recently, and reported 38 SNPs showing genome-wide significance (Kapoor et al., 2014). The finding with greatest significance was intergenic SNP rs2168784 which was in 8
ACCEPTED MANUSCRIPT strong linkage disequilibrium with 33 other imputed/genotyped SNPs spanning a 60 kb region on chromosome 3. The SNP rs2168784 is flanked by the Sucrase Isomaltase (SI) gene,
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which is implicated in carbohydrate digestion and may impact the rate of alcohol
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metabolism. Replication of these results in other cohorts is required, alongside establishing
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evidence for underlying mechanistic plausibility. Understanding the predisposition that underlies this subphenotype is important as it may allow for earlier interventions that
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reduce the progression to dependence, or at least eventual severity. Two further GWAS have reported an association between the GATA4 polymorphism,
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r13273672, and alcohol dependence (Edenberg et al., 2010; Treutlein et al., 2009). A subsequent imaging study using Functional MRI has provided support for this association
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(Jorde et al., 2014). In 81 abstinent, alcohol-dependent patients, G allele carriers had significantly lower alcohol-cue-related activation in the bilateral amygdala compared with
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AA allele carriers. The increased response in A allele homozygotes predicted a lower risk for relapse to heavy drinking. GATA4 has also been shown to influence the efficacy of
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acamprosate (Kiefer et al., 2011), which is discussed below. Several studies have utilised a gene-set approach in an attempt to generate an integrated perspective of gene-gene and pathway interactions in alcohol dependence (Biernacka et al., 2013; Kendler et al., 2011; Reimers et al., 2011). In a recent study, enrichment gene-set analysis was used across 31 studies (Li et al., 2014). From pathways identified in the Kyoto Encyclopedia of Genes and Genomes, Li and Colleagues found the calcium signalling pathway had the most significant association with alcohol phenotypes. Despite calcium having numerous biological effects, the rationale for its association with alcohol dependence is unclear. The authors speculated possible links between the depressive
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ACCEPTED MANUSCRIPT effects of alcohol and altered calcium concentrations, but empirical validation is required. Han and Colleagues (2013) identified a gene subnetwork purported to underlie susceptibility
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to alcohol dependence in European and African Americans by integrating two GWAS and a
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human protein interaction network (HPIN). Following dense module searching within the
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HPIN, implementation of an arbitrary selection of the top 5% modules, and identification of overlapping modules between ethnicities, 39 nonredundant genes were included in the
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subnetwork. The subnetwork finding was successfully replicated in three independent samples with alcohol dependence and no association was found in bipolar disorder, major
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depression or type II diabetes samples. None of the genes in the subnetwork had SNPs that met genome-wide significance, meaning they would have been discarded under
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conventional GWAS analytical techniques, which highlights the advantage of a broader
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network-based approach in complex conditions. Genes that encode potassium channels or
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their interacting proteins were most common in the subnetwork. Potassium channels have been shown to be sensitive to alcohol and mediators of behavioural tolerance (Treistman
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and Martin, 2009), alongside being therapeutic targets in other conditions (e.g. cardiac arrhythmias), offering scope for future work. The findings outlined above are identifying potential new therapeutic opportunities, but clearly, the realisation of this will take time with further genomic and functional studies required. In the meantime, it is important to evaluate the current therapeutic strategies that are available, and determine whether we can make better use of them. 3. Naltrexone Mechanism of action: The mechanism of action of naltrexone in the treatment of alcohol dependence has not been fully elucidated; however interaction with the endogenous opioid
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ACCEPTED MANUSCRIPT system is suspected to play an important role. Naltrexone acts as a competitive antagonist at the opioid receptors in the central and peripheral nervous systems where it prevents
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binding of exogenous and endogenous ligands. This blockade decreases dopaminergic
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activity and thereby reduces the rewarding/pleasurable effects of alcohol (Ray et al., 2010).
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As such, naltrexone is considered to be an anti-craving medication that reduces the risk of relapse to heavy drinking (Bouza et al., 2004; Garbutt, 2010), rather than maintaining
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complete abstinence (Maisel et al., 2013).
Efficacy: The global efficacy of naltrexone is modest at best (Maisel et al., 2013;
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Srisurapanont and Jarusuraisin, 2005), which may account for its limited use in clinical practice (Mark et al., 2009). However, naltrexone efficacy has substantial variability with a
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subset of patients showing marked improvement in clinical outcomes. A recent systematic review of 28 studies reported that a positive family history of alcohol dependence or
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presence of the Asn40Asp polymorphism in the OPRM1 gene provided the strongest evidence as potential treatment moderators (Garbutt et al., 2014). A paucity of data
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however from well controlled, adequately powered, clinical trials has resulted in a gap in the translational pathway to clinical practice. Further meta-analytical findings have also suggested that abstinence prior to medication being administered is a strong predictor of naltrexone efficacy in both reducing heavy drinking (r = 0.52, P < 0.01) and prolonging abstinence (r = 0.60, P < 0.01) (Maisel et al., 2013). This evidence is consistent with current clinical guidelines (e.g., NICE, 2009). Kiefer et al. (2005) re-evaluated their results of a double-blind, placebo-controlled study comparing and combining acamprosate and naltrexone treatment by subgrouping 143 patients according to both Lesch (Lesch and Walter, 1996) and Cloninger (Cloninger et al.,
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ACCEPTED MANUSCRIPT 1981) typologies (see Table 3). For naltrexone alone, Lesch type III and IV patients (n=14) had significantly more days to both first drink and relapse to heavy drinking compared with
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placebo. Combined naltrexone and acamprosate treatment also mediated a greater time to
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first drink in type IV individuals (n=6), but this effect appears to be more dependent on the
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influence of naltrexone as acamprosate alone produced marginal differences compared with placebo. Cloninger type II patients (n=34) had significantly better outcomes in both
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measures across all three treatment groups compared with the eight patients assigned placebo. Further analysis of this study alongside other data (Rubio et al., 2005) supported
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these findings, with Cloninger type II patients having more positive responses to naltrexone (Kiefer et al., 2008). Conversely, when using Babor typology (Babor et al., 1992) it has been
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suggested that naltrexone is only significantly effective in type A patients (Bogenschutz et
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al., 2009), which have many features that are opposite to Cloninger type II. Of interest,
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these effects were only noted in the patients receiving medical management alone; in patients who received adjunct behavioural therapy, statistical significance was lost.
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Pharmacogenetics: The role of the OPRM1 Asn40Asp polymorphism as a potential determinant of naltrexone response has received the most interest from researchers as a pharmacogenetic target. This A→G polymorphism results in the substitution of asparagine to aspartate at position 40 (Asn40Asp; rs1799971) potentially causing structural variation in the receptor’s extracellular domain. A meta-analysis of six studies found that carriers of the G allele were less likely to relapse than those who were homozygous for the A allele when treated with naltrexone (Chamorro et al., 2012). The use of sensitivity analysis revealed that removal of any one of three studies (Anton et al., 2008; Kim et al., 2009; Oslin et al., 2003) from the meta-analysis resulted in a loss of statistical significance, probably due to the non-
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ACCEPTED MANUSCRIPT significant outcomes reported in other studies (Gelernter et al., 2007; O’Malley et al., 2008). Furthermore, research published after the meta-analysis inclusion date has also failed to
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reach a consensus on this polymorphism’s predictive value. For example, Kranzler et al.
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(2013) reported that G allele carriers were at greater risk of drinking more at a time of day
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when craving was high compared with A allele homozygotes in a sample of 158 problem drinkers, but this difference dissipated with naltrexone treatment. Conversely, despite 12
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weeks of treatment with naltrexone reducing subjective and objective drinking, OPRM1 Asn40Asp genotype was not considered a predictor of treatment response (Coller et al.,
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2011). Similar results were reported for 107 individuals with co-occurring alcohol dependence and other Axis I disorders (Arias et al., 2014). Another meta-analysis called for
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further research in this area to improve the confidence in estimates (Jonas et al., 2014). The
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same manuscript also noted that all eligible studies utilised retrospective associations
selection.
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between treatment response and genotype; none assessed genotype-guided medication
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A recent publication however utilised a prospective design to investigate the moderating effect of the Asn40Asp polymorphism on naltrexone treatment response (Oslin et al., 2015). Participants were stratified by genotype and subsequently randomised to either placebo or naltrexone (50 mg/day). There were no significant genotype x treatment interactions for any drinking outcomes. The authors reported negligible trends in the opposite direction than hypothesised for the primary outcome measure, relapse to heavy drinking. The study however was substantially underpowered (n=221 across 4 groups; 82 G allele carriers), with 80% power to detect an interaction odds ratio of 3.72, which may have resulted from the
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ACCEPTED MANUSCRIPT lower than expected allele frequency in screened patients. This study is an important contribution to the literature in this area, but further work is still required.
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The OPRM1 Asn40Asp polymorphism remains one of the most promising genetic candidates with biological plausibility to moderate treatment response in alcohol dependents.
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Furthermore, the Asn40Asp genotype has been implicated in other behaviours with high levels of craving, such as sugar and fat intake (Davis et al., 2011; Haghighi et al., 2014). The
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studies conducted to date in alcohol dependents lack large samples (n ≤307), present heterogeneity in outcome measures, and until recently (Oslin et al., 2015) have failed to
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allocate participants based on prospective genotyping. Additional high quality clinical trials
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are required to fully elucidate the OPRM1 Asn40Asp polymorphism hypothesis.
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The role of genetic differences in the dopamine transporter (DAT) variable number of
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tandem repeat (VNTR) sequences in moderating treatment response has been explored with some interesting initial findings (Anton et al., 2012; Schacht et al., 2013). Anton et al. (2012) reported no moderating effect of the OPRM1 variant alone in a sample of 83 non-
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treatment-seeking alcohol dependent patients taking naltrexone over 7 days, but those that carried at least one DAT solute carrier family 6 member 3 (SLC6A3) 9 VNTR and were A homozygous for rs1799971 (n=6) significantly reduced their drinks/day in a natural environment compared with placebo. However, this finding was not replicated in a laboratory setting (Ashenhurst et al., 2012). Such findings suggest that naltrexone’s pathophysiological mechanisms may not be limited to μ-opioid receptors. Understanding the affinity of naltrexone to each receptor will be an important step in defining the optimal stratification approach. 4. Acamprosate 14
ACCEPTED MANUSCRIPT Mechanism of action: The mechanisms underlying the anti-relapse effects of acamprosate are
unclear.
Originally,
it
was
assumed
that
acamprosate
(calcium-bis
[N-
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acetylhomotaurinate]) acted by inhibiting the activity of N-methyl-D-aspartate (NMDA)
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receptors and thereby decreasing glutamatergic excitation associated with chronic alcohol
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intake and subsequent withdrawal (Mann et al., 2008; Tsai and Coyle, 1998). However, a series of animal and human studies postulated that the effects of acamprosate could be
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attributed solely to the active calcium component of the drug (Spanagel et al., 2013). The results from this group require external replication alongside further investigations to
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confirm the hypothesis that N-acetylhomoturinate alone is biologically inactive and that calcium salts alone mimic the efficacy of acamprosate.
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Efficacy: As with naltrexone, acamprosate has small to modest effects and its efficacy appears to be limited (Rosner et al., 2010). From 24 RCTs with 6915 participants,
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acamprosate significantly reduced the risk of any drinking compared with placebo (RR 0.86; 95%CI 0.81 to 0.91) and the number needed to treat was 9. There was no difference in
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effects between industry-sponsored (RR 0.88; 95%CI 0.80 to 0.97) and non-profit trials (RR 0.88; 95% CI 0.81 to 0.96) when sensitivity analysis was performed. Further meta-analytical findings suggest that acamprosate efficacy does not differ between sexes (Mason and Lehert, 2012), is associated with longer abstinence when detoxification has occurred (r = 0.59) and is superior to naltrexone in maintaining abstinence (Maisel et al., 2013). However, two large multisite RCTs with similar designs, COMBINE (Anton et al., 2006) and PREDICT (Mann, Lemenager, et al., 2013), reported no beneficial effect of acamprosate compared with placebo, with samples of 1383 and 426, respectively.
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ACCEPTED MANUSCRIPT In 260 patients classified according to Lesch typology, type I and II patients have been shown to have a greater number of days sober taking acamprosate compared with placebo;
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no differences were observed for types III and IV (Lesch and Walter, 1996). These results
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were supported somewhat by Kiefer et al. (2005) who reported significantly increased days
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to first drink and relapse in Lesch type I patients. Conversely, data on a subgroup of 76 participants in the UK Multicentre Acamprosate Study found that there was no trend for
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Lesch type I and II individuals to have improved outcomes (Chick et al., 2000). Insufficient power and heterogeneous distribution of samples have been cited as a possible reason for
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these contradictory findings (Chick et al., 2000; Lesch et al., 2001). In the aforementioned Kiefer et al. (2005) study, those on acamprosate had significantly better outcomes than
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those allocated placebo. Taken together, these findings led to the hypothesis that Babor B
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and early onset alcohol dependent patients would also respond positively to treatment with
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acamprosate (Leggio et al., 2009), but these assumptions are yet to be tested. A pooled analysis of seven European studies explored the moderating effect of six clinical
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variables (physiological dependence at baseline, family history of alcoholism, age of onset, anxiety symptomatology at baseline, craving at baseline, and gender) on drinking outcomes (Verheul et al., 2005). Baseline measures of anxiety and craving were found to predict cumulative and continuous abstinence duration across the treatment groups. The efficacy of acamprosate alone was not associated with any of these variables. One of the primary strengths of this study was a large sample size (n=1010-1485) and associated statistical power (β ≥ 0.87). Such results further highlight the difficulty in identifying treatment responders in this population, although this did not preclude the authors concluding,
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ACCEPTED MANUSCRIPT “Acamprosate can be considered as a potentially effective pharmacotherapy for all patients with alcohol dependence”.
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Pharmacogenetics: Research attempting to establish the influence of genetic variation on the efficacy of acamprosate is in its infancy compared with naltrexone. Subgroup analysis
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from the PREDICT study reported that SNP rs13273672, which is located intronically in GATA4, was associated with relapse prevention during treatment with acamprosate (Kiefer
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et al., 2011) but not naltrexone. GATA4 regulates the transcription of atrial natriuretic peptide (McBride and Nemer, 2001), which has purported actions in the pathophysiology of
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withdrawal and relapse (Kiefer and Wiedemann, 2004). Atrial natriuretic peptide is believed to influence glutamatergic mechanisms (Kovacs, 2003), the hypothesised primary site of
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action for acamprosate, which led the authors to conclude that acamprosate’s efficacy may be moderated by allelic variation in rs13273672. However, the functional relevance of this
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association needs to be delineated as the SNP is intronic. Glutamate receptor subunit epsilon-2 (GRIN2B) SNP rs2058878 has shown significant
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association with length of abstinence in a sample of 225 alcohol dependents during 3 months of acamprosate treatment in a community-based programme (Karpyak et al., 2014). Carriers of the minor A allele had improved outcomes compared with non-carriers. In a replication sample of 110 patients from the PREDICT study (Mann et al., 2009) statistical significance was not reached (P = 0.068). However, significance was noted for GRIN2B SNP rs2300272 in the replication sample, with presence of the minor allele (frequency = 0.48) associated with shorter abstinence. These are novel findings in humans, and work is required to replicate results and further understand the biological mechanisms involved.
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ACCEPTED MANUSCRIPT Several plausible rationales were presented by the authors including increased GluN2Bcontaining NMDA subunit expression and changes in calcium influx.
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A 21-day study with 126 participants reported that compared with naltrexone, those on acamprosate who were homozygous for the C allele (T1519C) in gamma-aminobutyric acid
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receptor subunit alpha-6 (GABRA6) and homozygous for the A1 allele in the dopamine receptor D2 (DRD2) Taq1A (rs1800497) polymorphism had lower cue-induced craving
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(Ooteman et al., 2009). However, the Taq1A polymorphism is actually located 10 kb downstream of DRD2 in the last exon of ANKK1 (Neville et al., 2004). The interaction
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between genes in this chromosomal region and alcohol dependence remains unclear (Dick et al., 2007). It is hypothesised that the A1 allele of the Taq1A polymorphism may exert its
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effects via alterations in brain opiate receptor expression and it has been shown that naloxone, an opioid antagonist like naltrexone, has lower binding affinity in A1 allele carriers
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(Ritchie and Noble, 1996). The study by Ooteman and Colleagues (2009) also found that those who were homozygous for the T allele (C1412T) in the gamma-aminobutyric acid
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receptor subunit beta-2 (GABRB2) and allocated acamprosate had reduced physiological cue reactivity to alcohol, as indexed by heart rate. Of interest, naltrexone administration resulted in lower cue-induced craving in Taq1A A2 allele homozygotes and reduced physiological cue reactivity in OPRM1 rs1799971 G allele carriers. 5. Disulfiram Mechanism of action: Disulfiram is an aversive medication that blocks the enzyme aldehyde dehydrogenase. Thus, when alcohol is consumed there is an accumulation of acetaldehyde that cannot be metabolised (Figure 1), which results in an unpleasant reaction. Due to this potential reaction, disulfiram’s mechanism of action is considered primarily psychological
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ACCEPTED MANUSCRIPT (Fuller and Gordis, 2004; Skinner et al., 2010). Alternatively, plausible pharmacodynamic mechanisms of action have been proposed from cocaine addiction research. Blocking of
metabolite
3,4-dihydroxyphenylacetaldehyde
(DOPAL)
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dopamine
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ALDH2 by a specific inhibitor released by disulfiram, ALDH2i, prevents the conversion of the to
3,4-
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dihydroxyphenylacetic acid (DOPAC). Condensing of increased DOPAL and dopamine in the ventral tegmental area neurons produces tetrahydropapaveroline, which inhibits tyrosine
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hydroxylase and subsequent dopamine production (Weinshenker, 2010; Yao et al., 2010). A reduction in dopamine is known to blunt the reward/reinforcement pathway. The role this
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effect plays in the treatment of alcohol dependence is unknown. It should be noted that disulfiram has been associated with hepatotoxicity (Chick, 1999), and should therefore be
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used with caution in patients either with or at risk of liver disease. Efficacy: A recent meta-analysis of 22 studies found that disulfiram was more successful
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than comparator conditions at improving drinking status. Although when study design was considered, only open-label RCTs had significantly enhanced outcomes (Skinner et al., 2014).
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The most likely explanation for this observation is that placebo groups in double blind trials are exposed to the same message about potential alcohol-induced adverse reactions, which results in the same mode of action between groups. It is also easy for participants to unmask treatment allocation by consuming a small quantity of alcohol and observing the effect. Pharmacogenetics: Two recent original articles investigating disulfiram’s efficacy are of relevance to this review. The first used a four-group single-blind design and genotyped for ALDH2 in 109 Japanese alcohol dependent individuals (Yoshimura et al., 2014). Overall, there were no significant differences between any of the groups for abstinence or dropouts. 19
ACCEPTED MANUSCRIPT However, when genotyping was considered, all participants with the inactive form of ALDH2 who were allocated disulfiram (n=5) remained abstinent during the study period. The
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inactive ALDH2 allele is common in East Asians (~35%) (Eng et al., 2007; Higuchi et al., 1996)
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and leads to a ‘natural’ adverse reaction to alcohol, which is similar to that produced by
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disulfiram but of smaller magnitude. Further exploration in larger samples is required to delineate whether innate inactivation of ALDH2 augments the aforementioned
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psychological and/or physiological responses to disulfiram to produce a subgroup of ‘super responders’. The second study investigated the moderating effects of OPRM1 rs1799971
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(Asn40Asp) and dopamine beta-hydroxylase (DBH) rs1611115 (C-1021T) genotypes in alcohol dependent individuals of European ancestry (n=107). Participants who were
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allocated disulfiram and continued to drink alcohol were likely to consume less if they were
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homozygous C allele carriers for the rs1611115 genotype (Arias et al., 2014). The authors
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speculated that this might result from T allele carriers having a more pronounced addictionprone and reward seeking phenotype. However, this is preliminary data and replication is
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required. 6. Nalmefene
Mechanism of action: Nalmefene, like naltrexone, modulates activity in the opioid receptor system. It acts as an antagonist at the mu and delta receptor and as a partial agonist at the kappa receptor (Bart et al., 2005). Like naltrexone, nalmefene is reported to suppress both craving and pleasure associated with alcohol and, as such, can be considered an anti-craving mediation rather than relapse preventing (Drobes et al., 2004), although reductions in relapse rates have been reported (e.g., Mason et al., 1999). Nalmefene was originally approved for the treatment of opioid overdose but recently received approval for alcohol
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ACCEPTED MANUSCRIPT dependence by the European Medicines Agency. However, correspondents in The British Medical Journal have criticised this move, citing possible reasons for reassessing this
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decision, including a poorly defined primary outcome measure, use of surrogate markers
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and conflicts of interest in the trials submitted for evaluation (Braillon, 2014; McNulty and
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Williams, 2014; Spence, 2014).
Efficacy: To date, seven RCTs have been published on the efficacy of nalmefene for treating
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alcohol-related disorders, with all but one reporting reduced heavy drinking (Anton et al., 2004). The findings from six randomised controlled trials (Anton et al., 2004; Gual et al.,
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2013; Karhuvaara et al., 2007; Mann, Bladström, et al., 2013; Mason et al., 1994; Mason et al., 1999) have been extensively reviewed elsewhere (Soyka, 2014). The most recent
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publication, the third prospective study from the (E)SENSE project, evaluated the efficacy and tolerability of nalmefene ‘as-needed’ treatment over 12 months in 675 alcohol
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dependent patients (van den Brink et al., 2014). One-hundred and twelve patients in the placebo group and 310 in the nalmefene group completed the study. There were
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statistically significant reductions in the number of heavy drinking days (1.6 days/month) and total alcohol consumed (6.5 g/day) in the nalmefene group compared with placebo; although neither primary outcome variable reached statistical significance at 6 months. This later finding contradicts previous results (Gual et al., 2013; Mann, Bladström, et al., 2013). Both of these studies found that the nalmefene group significantly reduced their heavy drinking days after 6 months, and one (Gual et al., 2013) reported that total alcohol consumption was lower at this time point. However, when Van den Brink and colleagues considered higher risk drinkers only, indexed by Timeline Follow-back data from the month preceding the screening visit, total alcohol consumption was significantly reduced at 6
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ACCEPTED MANUSCRIPT months, whilst both primary measures were significantly improved at the end of the study in this subgroup. These findings are in agreement with similar subgroup analysis from the
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first two studies (van den Brink et al., 2013). Further prospective RCTs are required in different subgroups of the population to acquire
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knowledge about global efficacy. To date, all studies have recruited predominately white, middle-aged males and many have excluded those with comorbidities. One study (van den
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Brink et al., 2014) included patients with comorbid psychiatric disorders, although the number recruited with such conditions was substantially lower than population estimates
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(Kessler et al., 1996).
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Pharmacogenetics: Secondary analysis of the Karhuvaara study (Karhuvaara et al., 2007)
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investigated pharmacogenetic moderators of nalmefene’s efficacy in 166 patients. A total of
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five SNPs were genotyped; two each in OPRM1 (including rs1799971) and OPRD1 and one in opioid receptor kappa-1 (OPRK1). The authors reported no main or moderating effects of
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these genotypes (Arias et al., 2008). 7. Baclofen
Mechanism of action: Baclofen is a γ-aminobutyric acid (GABA) β-receptor agonist that is primarily marketed as an anti-spasticity agent. More recently, several groups have investigated baclofen as potential pharmacological aid for treatment of alcohol dependence. The stimulation of GABAB-receptors by baclofen is thought to inhibit the release of the excitatory amino acids, glutamate and aspartate, which reduce the rewarding/pleasurable effects of alcohol. The activation of GABAB-receptors may also reduce the anxiogenic effects of alcohol (Addolorato et al., 2009). Importantly, excretion of
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ACCEPTED MANUSCRIPT baclofen in mainly via the kidneys (Wuis et al., 1990), and is therefore not contraindicated in patients with liver disease.
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Efficacy: As mentioned previously, alcohol dependent patients with comorbidities are often excluded from research, despite high prevalence of conditions such as alcoholic liver disease
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in this population (Mann et al., 2003). In a pioneering RCT, 84 patients with alcohol dependence and comorbid liver cirrhosis were randomised to receive baclofen 30 mg/day or
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placebo (1:1) for 12 weeks (Addolorato et al., 2007). Those allocated baclofen had significantly higher rates of abstinence (OR 6.3 [95% CI: 2.4-16.1]; P = 0.0001) and a greater
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number of cumulative days without consuming alcohol (62.8 vs 30.8 days). There were also significant reductions in several markers of liver injury. The placebo group had more
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dropouts (31% vs 14%) but this was statistically similar between groups, likely attributable to lack of statistical power due to the small sample size. Although it is worth noting, as per
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intention to treat analysis, these dropouts were considered to have relapsed in the final analysis, which may have influenced the magnitude of the true results. Baclofen was well
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tolerated both during the intervention phase and subsequent four week withdrawal period. Although liver cirrhosis was not used as a moderator of baclofen’s efficacy, this study provides insight into possible treatment stratification as well as scope for future research in this population; a related study protocol was recently published (Morley et al., 2013), and the results should hopefully provide further insight. Separate findings from post-hoc analysis of patients with hepatitis C were consistent with the main study; baclofen resulted in more patients achieving and maintaining abstinence than those allocated placebo (83.3% vs 25.0%) (Leggio et al., 2012). In contrast, Garbutt et al. (2010) found no significant effect of baclofen in several drink-related outcome measures.
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ACCEPTED MANUSCRIPT Although the findings are not consistent across the aforementioned studies, some evidence suggests that a greater number of mean daily drinks on drinking days and higher anxiety are
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moderators of baclofen’s efficacy. Also, preliminary data from a small open label trial found
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that female alcohol dependent patients may respond more positively to baclofen treatment
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(Flannery et al., 2004), however, these findings were not confirmed in a larger RCT (Garbutt et al., 2010). A French-language meta-analysis concluded there is weak support for the
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efficacy of low dose baclofen in maintaining abstinence, but reported a significant increase of 179% in patients abstinent at the end of trails compared with placebo (Lesouef et al.,
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2014).
Two small RCTs have been published from an international project (The International
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Baclofen Intervention Study) that initially aimed to conduct a large, multisite, double-blind, RCT investigating the efficacy of baclofen for alcohol dependence, but the recruitment
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target was not achieved. The first publication reported that a 60 mg/day dose of baclofen was significantly more effective at reducing the number of drinks per day than both 30
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mg/day and placebo; 30 mg/day was superior to placebo (Addolorato et al., 2011). The subsequent study found no significant treatment differences in any primary efficacy outcomes (e.g., days to relapse, drinks per drinking day, heavy drinking days during previous week), but alcohol consumption did significantly decrease over the treatment period (Morley et al., 2014). Each study began with a sample size of 42, which was then reduced as patients were lost to follow-up, these small sample sizes likely explain a number of nonsignificant trends towards improved outcomes for participants allocated either dose of baclofen. The study from Morley and Colleagues noted that patients with comorbid anxiety who were allocated baclofen generally reported significantly increased time to first drink
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ACCEPTED MANUSCRIPT (lapse) and first heavy drinking day (relapse) compared with placebo; the only nonsignificant post hoc difference was found between 60 mg/day and placebo.
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Whether high dose baclofen is more effective in the treatment of alcohol dependence is currently unknown and concerns have been raised about its tolerability and safety
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(Enserink, 2011). An observational study of 100 alcohol dependent individuals found that baclofen treatment with no superior dose limit (average maximal dose was 147 mg/day)
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was effective at reducing the risk of heavy drinking (De Beaurepaire, 2012). Interestingly, a significant relationship was observed between the amount of alcohol taken before
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treatment and the maximal dose of baclofen required, those with higher alcohol consumption required increased baclofen. Some trials studying high dose baclofen are
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ongoing (e.g., ClinicalTrials.gov Identifier: NCT01266655; NCT01980706).
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Pharmacogenetics: To date there have been no relevant pharmacogenetic studies for baclofen in alcohol dependence treatment.
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8. Ondansetron
Mechanism of action: Ondansetron, a serotonin 5-HT3 receptor antagonist, is predominately indicated for use as an antiemetic drug. However, due to its pharmacological properties it has been proposed as a treatment for alcohol dependence. 5-HT3 receptors are densely distributed in the mesocorticolimbic neuronal terminals, which regulate dopamine release (Chen et al., 1991). Ondansetron antagonises these receptors and blocks the pleasurable stimulation from alcohol and thereby reduces the urge to drink (Johnson, 2004). Efficacy: Ondansetron has been shown to be effective in early onset alcohol dependent patients in several studies (Johnson et al., 2002; Johnson et al., 2000; Kranzler et al., 2003).
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ACCEPTED MANUSCRIPT For this patient subgroup, a dose of 4 µg/kg twice per day for 11 weeks in a sample of 271 was found to be most efficacious for reducing drinks per day and drinks per drinking day,
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alongside increasing the percentage of days abstinent and total days abstinent, compared
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with doses of 1 and 16 µg/kg twice per day (Johnson et al., 2000). Other results have
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complemented these inverted U-shaped findings (Johnson et al., 2002). Subsequent analysis of the same dataset revealed that Babor type B alcohol dependent patients responded
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significantly better to ondansetron (4 μg/kg) than type A; however, early- vs. late-onset classification was still a better predictor of outcomes overall (Roache et al., 2008).
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A more recent study with a total sample size of 280 showed no association between age at onset of alcohol problems and response to ondansetron (Johnson et al., 2011), which is
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paradoxical to the earlier findings by the same research group. This finding, combined with some of the results from sertraline research (see section 9), has prompted a call for further
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exploration into the biological mechanisms underpinning age of onset and how different phenotypes interact with serotonin transporters (Roache, 2012). Moreover, consensus
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needs to be reached on the limits that define the upper and lower bounds of this dichotomous variable. If age of onset is found to be a reliable moderator for any alcohol dependence medication it likely would be welcomed by prescribers as it represents a cheap and relatively easy to determine variable. A pilot RCT in Brazil assessed the efficacy and safety of full dose ondansetron (16 mg/day) in severely dependent male alcohol dependent patients (Correa Filho and Baltieri, 2013). Of the 102 participants recruited almost half dropped out of the study. Of those retained, no significant differences were observed in percentage of days abstinent or heavy drinking days between the treatment and placebo groups; it should be noted that both groups had good
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ACCEPTED MANUSCRIPT outcomes for each variable. Multiple-imputation analysis was used to include those not retained in the study. This resulted in a small (3.8%), but statistically significant, reduction in
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the percentage of heavy drinking days for those treated with ondansetron compared with
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placebo. The authors openly criticise this approach and recommend future studies should
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account for substantial attrition in their sample size. There were trends to suggest that early- vs late-onset typology may have influenced results but these findings were not fully
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explained. Only minor adverse effects were reported, with no difference between groups. Although not overtly referred to in alcohol research to date, there are some concerns
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regarding ondansetron inducing QT prolongation. This needs to be considered when treating patients at risk of cardiac arrhythmias or where inducing QT prolongation may
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impact clinical management of any comorbidity (e.g. patients at risk of seizures).
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Pharmacogenetics: Differences at gene level have been explored in an attempted to explain individual variation in ondansetron response. In an 11 week two-site RCT, Johnson et al. (2011) initially stratified 283 patients based on their 5’-serotonin-transporter-linked
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polymorphic region (5’-HTTLPR) (LL/LS/SS), with additional genotyping for rs1042173 (T/G); both are found in the serotonin transporter gene, SLC6A4. When 5’-HTTLPR is considered alone, carriers of the LL genotype on ondansetron had a lower number of drinks per drinking day (−1.45) and a higher percentage of days abstinent (9.65%) than all other genotypes and treatment groups combined. When considered together, LL/TT carriers showed the biggest improvement in outcome measures with 2.63 less drinks per drinking day and a 16.99% increase in days abstinent. The ondansetron group reported significantly more fatigue.
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ACCEPTED MANUSCRIPT Secondary analysis of the aforementioned study by Johnson and colleagues (2011) explored the role of two further genes in predicting ondansetron’s efficacy, hydroxytryptamine
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receptor 3A (HTR3A) and hydroxytryptamine receptor 3B (HTR3B) (Johnson et al., 2013).
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Three genotypes (HTR3A-rs1150226-AG, HTR3A-rs1176713-GG, and HTR3B-rs17614942-AC)
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were found to be associated with positive outcomes (as above, plus percentage of days abstinent) when taking ondansetron. Approximately 34% of the study cohort carried one or
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a combination of the SLC6A4-LL/T and HTR3 genotypes that were associated with the largest ondansetron-induced reductions in drinking. Of the defined combinations presented in the
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study, one was considered a group of potential “super-responders” (possessing any one, two, or all three of the identified HTR3 genotypes; n=29/133) with a fivefold increase in
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percentage of subjects with no heavy drinking days when treatment groups were compared. 9. Sertraline
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Mechanism of action: Sertraline is a selective serotonin reuptake inhibitor (SSRI). As such, it acts as a 5-hydroxytryptamine (5-HT) agonist and may reduce the urge to drink and the
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pleasurable effects associated with alcohol. However, the routine use of SSRIs in clinical practice for alcohol dependence treatment is not recommended in certain countries, for example the UK (NICE, 2009). Nevertheless, several groups have conducted clinical research into sertraline’s efficacy for the treatment of alcohol dependence. Efficacy: In the first such study, 100 patients were randomised either to sertraline (maximum dose 200 mg/day) or placebo for 14 weeks and stratified according to lower risk/severity (type A) and higher risk/severity (type B) (Pettinati et al., 2000). Sertraline treatment in type A alcohol dependent patients (n=30) was associated with fewer drinking days (0.0% vs 22.4%) and increased likelihood of continuous abstinence (53.3% vs 16.0%)
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ACCEPTED MANUSCRIPT compared with placebo (n=25). There was also a trend to suggest that the same subgroup had a greater number of weeks to relapse. These findings were later reported to only be
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evident in type A men (Pettinati et al., 2004). Conversely, those defined as type B alcohol
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dependent patients and treated with sertraline (n=20) deteriorated compared with placebo
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(n=25), with more drinking days (8.2% vs 4.1%) and reduced likelihood of maintaining abstinence (10.0% vs 24.0%) (Pettinati et al., 2000). These effects persisted during the 6-
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month follow-up period (Dundon et al., 2004). Further exploration of the original data found that sertraline was not effective in alcohol dependent patients with current or lifelong
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comorbid depression (n=53) compared with those without depression (n=47) (Pettinati et al., 2001).
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Pharmacogenetics: In another series of studies utilising a single data set, Kranzler et al (2011) explored the moderating effect of age of onset and the 5’-HTTLPR polymorphism on
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sertraline response. The 5’-HTTLPR polymorphism has long-(L) and short-repeat (S) alleles. The long-repeat can be further divided according to the A→G SNP at rs25531, which alters
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the function of the allele. The function of LG is similar to that of S, and for the purposes of this study were grouped as S’; The LA allele was labelled L’. One-hundred and thirty four participants were randomised to either placebo (n=71) or sertraline (n=63), which was titrated from 50 mg/day to a maximum dose of 200 mg/day depending on tolerability. Completion rate for the study was 61.9%, although those who were early onset alcohol dependent patients with L’ and treated with sertraline had a high attrition rate, only 14.3% completed. Three participants receiving sertraline experienced serious adverse reactions that resulted in hospitalisation. At the end of the treatment period, late onset alcohol dependent patients who were L’ allele homozygous and treated with sertraline significantly
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ACCEPTED MANUSCRIPT reduced their number of drinking days compared with placebo (Cohen’s d = 0.48). Conversely, early onset alcohol dependent patients who carried the same allele make-up
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and treated with sertraline significantly increased their number of drinking days compared
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with placebo (Cohen’s d = 0.98). Similar trends were observed for the number of heavy
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drinking days but this variable did not reach statistical significance for late onset alcohol dependent patients. There were no observed effects for S’ allele carriers (Kranzler et al.,
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2011). Subsequent analysis used other typologies to stratify participants (Kranzler et al., 2012). Again, carriers of the S’ allele demonstrated no significant effect for either drinking
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outcome measure (drinking days and heavy drinking days). When L’ allele homozygotes were stratified according to Babor and two age of onset typologies, type A and late onset
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alcohol dependent patients on sertraline had significantly improved drinking behaviour
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compared with placebo. Conversely, type B and early onset alcohol dependent patients
10. Topiramate
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significantly deteriorated on sertraline compared with placebo.
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Mechanism of action: Topiramate is a broad-spectrum antiepileptic drug. It is hypothesised that the positive effects of topiramate on alcohol consumption manifest through neuronal stabilisation (Johnson and Ait-Daoud, 2010), which may result from inhibition of AMPA and kainate subtypes of glutamate receptors alongside up-regulation of GABAA receptor function (Shank and Maryanoff, 2008; White et al., 2000).Efficacy: Data from early clinical trials has been encouraging, with improvements in alcohol consumption outcomes and quality of life, and no serious adverse reactions (Olmsted and Kockler, 2008). A seven study meta-analysis (Blodgett et al., 2014) found that topiramate had superior effects on abstinence, heavy drinking, GGT and craving outcomes compared with results for both naltrexone and
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ACCEPTED MANUSCRIPT acamprosate, published elsewhere (Maisel et al., 2013). However, the total sample size of 1225 in the topiramate meta-analysis was too small to conduct any formal moderator tests.
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A drug utilisation study suggests that the use of topiramate to treat alcohol use disorders in
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USA Veterans has almost doubled between fiscal years 2009 and 2012 (Del Re et al., 2013),
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although total use is still under 2%.
In a 12 week double-blind trial, 150 treatment seeking alcohol dependent individuals were
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randomised to either topiramate (titrated from 25 to 300 mg/day) or placebo (1:1) (Johnson et al., 2003). Both groups demonstrated improvements in study outcomes from baseline but
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those reported in the topiramate group were statistically superior to placebo. Those receiving topiramate had 2.88 fewer drinks per day, 3.10 fewer drinks per drinking day,
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27.6% fewer heavy drinking days, 26.2% more days abstinent, and a -0.07 lower log plasma gamma-glutamyl transferase ratio, compared with placebo. Abstinence prior to study entry
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was not required, although the biggest reduction in drinking was seen between screening and enrolment. This pre-treatment decline in drinking is sometimes a caveat to finding
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statistically significant results, and is often cited as a limitation, however, within this study (Johnson et al., 2003), it demonstrates how topiramate could be used as an effective adjunct for individuals who are self-motivated to decrease alcohol consumption. There is also evidence from a laboratory-based study to suggest that topiramate (titrated to 200 and 300 mg/day) reduced heavy drinking in 61 non-treatment seeking drinkers (Miranda et al., 2008). There were no severe adverse reactions to topiramate but a substantial number of mild-moderate reactions were reported. In addition, several studies have been published using the same data set of 150 alcohol dependent patients. Compared with placebo, topiramate increased quality of life and
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ACCEPTED MANUSCRIPT overall well-being alongside reducing the level of dependence and harmful consequences of drinking (Johnson et al., 2004). Utilisation of a holistic (subjective and objective drinking to
analysing the
effects of
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measures and psychological outcomes) approach
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pharmacotherapy in this population is rare, but doing so adds strength to potential clinical
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effectiveness and should be encouraged.
Similar results were reported in a larger multi-site study (n=371) by the same group
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(Johnson et al., 2008; Johnson et al., 2007). Again there were significant improvements in all subjective and objective measures (same outcomes as Johnson et al., 2004), using both pre-
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specified and imputed models to account for dropout. Furthermore, improvements in physical and mental well-being were noted (Johnson et al., 2008). Unlike the previous study,
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this cohort had low representation from non-Caucasian groups (85% Caucasian). Participants on topiramate reported a large number of adverse reactions, many of which
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occurred significantly less in the comparator condition. Pharmacogenetics: In a pharmacogenetic study, 138 treatment seeking heavy drinkers
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(>90% met the DSM-IV criteria of current alcohol dependence) were allocated either topiramate (max dose 200 mg/day) or placebo (Kranzler, Covault, et al., 2014). The moderating effects of a noncoding intronic SNP in glutamate receptor ionotropic kainate-1 (GRIK1), rs2832407, were investigated in self-identified European American patients (n=122) only because of differences in allele frequency between ethnicities. In the entire cohort, the topiramate group had significantly better outcomes for the number of heavy drinking days (no heavy drinking days in last 4 weeks: OR = 2.75, 95% CI = 1.24 to 6.10) and days abstinent (abstaining from alcohol during the final week of treatment: OR = 2.57, 1.13-5.84). In the genotyped cohort, C allele homozygotes had a significant reduction in heavy drinking and
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ACCEPTED MANUSCRIPT there was trend to suggest an increase in number of days abstinent compared with placebo, whereas those carrying the A allele showed negligible differences. These positive results
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were confirmed through the analysis of daily interactive voice response surveys in the same
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cohort (Kranzler, Armeli, et al., 2014). There was a trend to suggest that topiramate
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mediated a significant reduction in drinks/day (β = -0.547, 95%CI: -1.153 to 0.059, P = 0.076), however a significant interaction was observed for medication group x genotype (β =
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topiramate reporting the best outcomes.
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-1.506, 95%CI: -2.719 to -0.293, P = 0.015), with those homozygous for the C allele on
11. Relationship between genes: A network pathway analysis
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It is clear that the relationship between genes and therapeutic response is complex. We
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attempted elucidation of relationship between various genes involved in treatment
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response to alcohol dependence by undertaking a network pathway analysis (Figure 2). We used Ingenuity Pathway Analysis software (http://www.ingenuity.com/products/ipa) and
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only included genes implicated in therapeutic response as outlined in this review. The pathway is based on both experimental data and prediction (high threshold only), and it draws information from a large number of databases and literature contained in the Ingenuity Knowledge Database. The information utilised includes published experimental data in human, rat and mouse models, and in vitro studies that include, but are not limited to, cells related to the brain and central nervous system. The aim of this analysis is to highlight various genes or pathways that may act alone or together to influence therapeutic response.
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ACCEPTED MANUSCRIPT Interestingly, the network analysis not only identified connections between treatment response pathways but also highlighted how these pathways are closely interlinked with
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genes that are important in susceptibility to alcohol dependence. Figure 2 shows the
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crosstalk between various receptors, transporters, cytoplasmic mediators and nuclear
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transcription factors involved in treatment response and alcohol dependence. Some key common regulators such as GATA4 and NFATc2, a calcium dependent factor, correlate with
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the calcium signalling pathway reported to be associated with alcohol phenotypes by Li and Colleagues (2014); and FOS interacts with multiple receptors that are important in alcohol
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dependence or therapeutic response. Various secreted mediators such as BDNF and IL4 are also shown here. Another important observation is the potential relevance of CYP enzymes
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such as CYP19A1 (aromatase), of which genetic variants are associated with craving for
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alcohol (Lenz et al., 2011). We acknowledge that this analysis may not be complete and we
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are limited by the curated information present in the Ingenuity database. We also acknowledge that some of the network connections are generated based on predictions and
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therefore require experimental validation. Nevertheless, it is sensible to speculate that mediators which are involved in the susceptibility to alcohol dependence may also play a significantly important role in modulating response to various drugs utilised in the treatment of this disorder.
12. Conclusion A growing collection of evidence is now available for pharmacotherapy-based treatment of alcohol dependence, which has contributed to positive clinical progress. However, barriers to utilisation in practice remain. Pragmatic approaches are required to ensure that evidence
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ACCEPTED MANUSCRIPT gathering is patient-centric and that healthcare practitioners willingly engage with treatment pathways as prescribing for alcohol dependence treatment remains low.
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Research in this discipline is buoyed by emerging therapeutic targets/agents alongside the possibility of stratified/personalised approaches to treatment which translate to positive
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real-world outcomes. To date, GWAS and associated meta-analyses have reported a number of risk alleles for alcohol dependence, but replication of these results has been limited.
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Network-based analysis has produced some promising initial findings, and combined with a multi -omics approach could provide the next frontier in the identification of risk factors and
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therapeutic candidates. This strategy has proven successful in other complex conditions, such as cancer. Furthermore, links with industry, advances in technology and novel
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analytical methods, such as the recently proposed Bayesian mixed treatment comparison meta-analysis in alcohol dependence (DeSantis and Zhu, 2014), are providing new direction
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in this and other research areas.
Treatment stratification aims to reduce adverse reactions and augment effectiveness. The
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modest global efficacy for acamprosate and naltrexone alongside the exploration of more contemporary drugs have benefited from this approach. However, many areas lack strong empirical evidence and current literature is often hampered by methodological limitations, including patient phenotype heterogeneity, inadequate sample sizes and serial use of cohorts. It would be unwise to suggest that RCTs are the only method that we can use to validate findings, as other designs have shown clinical utility (e.g. enrichment studies) and need to be evaluated in an integrative and intelligent manner. Prior to any future (clinical) trials the following would be useful to consider: i) the use of prospective stratification and justification for any subsequent subgroup analysis at the design stage; ii) the challenges
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ACCEPTED MANUSCRIPT associated with analytical methods, including the issue of assessment reactivity; iii) techniques to ensure adequate recruitment to the “minor” group(s); and iv) how
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stratification technique(s) could be implemented into clinical practice. Although there are many opportunities, there are also many challenges to the treatment of
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alcohol dependence. Barriers to treatment in this patient group include: low numbers attending services, stigmatisation, uncertainty surrounding the efficacy of all treatments,
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and lack of specialist knowledge. Furthermore, the gap between onset of dependence and treatment needs to be reduced to help optimise treatment success. Current
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identification/screening techniques are inadequate and represent a missed opportunity to
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provide early intervention.
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In summary, pharmacotherapy represents an important treatment modality in this
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population. Development of new therapeutic agents alongside ongoing empirical investigations into stratification of existing drugs should be an important research goal. Such work will hopefully lead to improved clinical outcomes, increased treatment utilisation and
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reduced costs.
Conflict of Interest The authors declare that there are no conflicts of interest References Addolorato, G., Leggio, L., Cardone, S., Ferrulli, A., & Gasbarrini, G. (2009). Role of the GABA(B) receptor system in alcoholism and stress: focus on clinical studies and treatment perspectives. Alcohol, 43, 559-563. Addolorato, G., Leggio, L., Ferrulli, A., Cardone, S., Bedogni, G., Caputo, F., et al. (2011). Dose– response effect of baclofen in reducing daily alcohol intake in alcohol dependence: 36
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Figure Legends
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Verheul, R., Lehert, P., Geerlings, P. J., Koeter, M. W., & van den Brink, W. (2005). Predictors of acamprosate efficacy: results from a pooled analysis of seven European trials including 1485 alcohol-dependent patients. Psychopharmacology, 178, 167-173. Weinshenker, D. (2010). Cocaine sobers up. Nature Medicine, 16, 969-970. White, H. S., Brown, S. D., Woodhead, J., Skeen, G. A., & Wolf, H. H. (2000). Topiramate Modulates GABA‐Evoked Currents in Murine Cortical Neurons by a Nonbenzodiazepine Mechanism. Epilepsia, 41, 17-20. Wuis, E., Dirks, M., Vree, T., & Van der Kleijn, E. (1990). Pharmacokinetics of baclofen in spastic patients receiving multiple oral doses. Pharmaceutisch Weekblad, 12, 71-74. Yao, L., Fan, P., Arolfo, M., Jiang, Z., Olive, M. F., Zablocki, J., et al. (2010). Inhibition of aldehyde dehydrogenase-2 suppresses cocaine seeking by generating THP, a cocaine use-dependent inhibitor of dopamine synthesis. Nature Medicine, 16, 1024-1028. Yoshimura, A., Kimura, M., Nakayama, H., Matsui, T., Okudaira, F., Akazawa, S., et al. (2014). Efficacy of disulfiram for the treatment of alcohol dependence assessed with a multicenter randomized controlled trial. Alcoholism: Clinical and Experimental Research, 38, 572-578. Zlojutro, M., Manz, N., Rangaswamy, M., Xuei, X., Flury‐Wetherill, L., Koller, D., et al. (2011). Genome‐wide association study of theta band event‐related oscillations identifies serotonin receptor gene HTR7 influencing risk of alcohol dependence. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, 156, 44-58.
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Figure 1. Alcohol metabolism pathway. Alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and catalase oxidise ethanol to acetaldehyde. Acetaldehyde is toxic and along with the byproducts produced during ethanol oxidation induces much of damage associated with alcohol consumption. Acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH).
Figure 2. Crosstalk between genes that are involved in alcohol dependence (given in green) and those that modulate the drug response (in blue). The pink lines show relationships which are important in alcohol dependence (continuous lines show direct relationship; broken lines show 45
ACCEPTED MANUSCRIPT indirect relationship). Receptors or transporters: OPRM1: opioid receptor, mu 1; OPRK1: opioid receptor, kappa 1; SLC6A3: solute carrier family 6 (also called DAT – dopamine transporter); DRD2: Dopamine receptor,D2; GABRB2: gammaaminobutyric acid (GABA) A receptor, beta 2; GRIN2B: glutamate receptor, ionotropic, N-methyl D-aspartate 2B; HTR7: 5-
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hydroxytryptamine (serotonin) receptor 7; GRIK1: glutamate receptor, ionotropic, kainate 1; Cytoplasmic proteins: CRH:
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corticotropin releasing hormone; IL4: interleukin 4; BDNF: brain-derived neurotrophic factor; CYP11A1: cytochrome P450,
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family 11, subfamily A, polypeptide 1; CYP19A1: cytochrome P450, family 19, subfamily A, polypeptide 1; TNF: tumor necrosis factor; PLAT: plasminogen activator, tissue; NPPA: natriuretic peptide A; Transcription factors: GATA4: GATA binding protein 4; NFATc2: nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2; ATM: ATM
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serine/threonine kinase; SP1: Sp1 transcription factor; FOS: FBJ murine osteosarcoma viral oncogene homolog.
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Table 1. Common variables used in the stratification of alcohol dependence
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Age
Comment The majority of research in this field is conducted in males. Alcohol dependence is more prevalent in males but alcohol generally affects females more severely. The majority of alcohol abusers are in their teens or twenty’s, with the highest prevalence of those undertaking treatment for AD being in their 40’s. The majority of sample populations have mean ages in their 40’s.
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Variable Gender
The availability of alcohol varies depending on societal, cultural and religious views. The majority of research has been conducted in those of European descent. Non-Caucasian populations are underrepresented in alcohol research, making universal application of results difficult. A subgroup of East Asians experience an adverse reaction to alcohol associated with a mutation in ALDH2 which has been hypothesised to be protective against alcohol misuse.
Family History
Alcohol dependence has a substantial hereditary component, 40-60%. However, a consensus is yet to be reached on the optimal description of positive family in this area of research. This lack of uniformity and the small number of studies negatively impacts on the overall strength of the evidence. In typology research, attempts are made to group individuals depending on the characteristics of their alcohol dependence, with the aim to guide diagnosis, predict prognosis and provide targeted treatments. The typologies discussed within this review are presented in table 3 (for a dedicated review see Leggio, Kenna et al. 2009). Excessive alcohol consumption is a risk factor for ~60 diseases/conditions. Also, those with alcohol use disorders can have underlying mental-health disorders that are caused by or are responsible for their alcohol misuse. Individuals with comorbidities are often excluded from research for reasons relating to safety, inherent complexity and maintaining sample homogeneity. The majority of medications utilised in alcohol dependence are metabolised in liver which is often compromised with excessive alcohol consumption (e.g., alcoholic liver disease). Baclofen has received some interest an alternative treatment for alcohol dependence as it is predominantly excreted by the kidneys. Please see pharmacogenetics sections and table 2.
Genetics
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Ethnicity
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Table 2. Primary findings from pharmacogenetic studies on the treatment of alcohol dependence that were longer than 10 weeks in duration
Kim et al, 2009
Rubio et al, 2002 Coller et al, 2011 Arias et al, 2014
Oslin et al, 2015 Kiefer et al, 2011
Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Acamprosate 1998 mg/day 12 weeks
149 European American and African American 32 Asian
OPRM1 (rs1799971) OPRM1 (rs648893) OPRK1 (rs963549) OPRD1 (rs2234918) OPRD1 (rs678849) OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) DBH (rs1611115) CC CT:TT OPRM1 (rs1799971) AA AG:GG GATA4 (rs13273672) AA AG:GG
45 Spanish
100 Australian Caucasian c 107 Caucasian
221 (98.2% White) 147
Relapse to heavy drinking
48 23 115 31
Good clinical outcome (abstinent or moderate drinker with no problems Rate of relapse to heavy drinking
Time to first relapse to heavy drinking
16 16
Relapse
29 16 Time to first relapse to heavy drinking
65 35
Abstinence from heavy drinking 15 17 Relapse to heavy drinking Relapse to heavy drinking
60 87
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Finding
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OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) AA AG:GG
Outcome measure
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71 European American 146 European American
N per b genotype
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Genetic variation
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Gelernter et al, 2007
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Anton et al, 2008
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Medication/dose/ Treatment duration Naltrexone 50-100 mg/day 11-24 weeks Naltrexone Titrated up to 100 mg/day 16 weeks Naltrexone 50 mg/day 13 weeks
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OR = 3.52 (CI = 1.03-11.96) 47.9% for AA 26.1% for AG:GG OR = 5.75 (CI = 1.88-17.54) 48.6% for AA 87.1% for AG:GG NS NS NS NS NS HR = 13.65 (CI: 1.68 – 110.20) 59.9 days for AA 73.3 days for AG:GG OR = 1.19 31% for AA 25% for AG:GG NS 11 days 10 days NS for rs1799971 T allele carriers reported greater abstinence from heavy drinking the “CC” genotype
NS NS A allele carriers were less likely to relapse compared with placebo OR = 2.26 (1.36-3.67; P = 0.0013)
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Johnson et al, 2013
Ondansetron 8 µg/kg of body weight/day 11 weeks
140 Caucasian and Hispanic
Kranzler et al, 2011
Sertraline Titrated to 200 mg/day 12 weeks
63 (21 EOA, 42 LOA)
Kranzler et al, 2014
Topiramate Titrated to 200 mg/day 12 weeks
56 European American
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Drinks per drinking day 7 3
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140 Caucasian and Hispanic
Abstinence
Heavy drinking days per week, abstinent days per week
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Ondansetron 8 µg/kg of body weight/day 11 weeks
166 Finnish
DBH (rs1611115) CC CT:TT OPRM1 (rs1799971) OPRM1 (rs648893) OPRK1 (rs963549) OPRD1 (rs2234918) OPRD1 (rs678849) SLC6A4 L’L’ L’S’:S’S’ SLC6A4 (rs1042173) TT TG:GG HTR3A (rs1150226) AG HTR3A (rs1176713) GG HTR3B (rs17614942) AC
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Johnson et al, 2011
c
107 Caucasian
Inactive ALDH2
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SLC6A4 L’L’ (EOA) L’S’:S’S’ (EOA) L’L’ (LOA) L’S’:S’S’ (LOA) GRIK1 (rs2832407) CC CA:AA
Drinks/drinking day Percentage of days abstinent
42 95
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Arias et al, 2008
54 East Asian
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Arias et al, 2014
Disulfiram 200 mg/day 26 weeks Disulfiram 250 mg/day 12 weeks Nalmefene Titrated to max dose of 40 mg/day 28 weeks
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Yoshimura et al, 2014
Drinks/drinking day
20 Percentage of days abstinent
6 17
Percentage of heavy drinking days Number of drinking days
7 14 12 30 Heavy drinking days
All 5 patients on disulfiram with inactive ALDH2 remained abstinent. Significant interaction between DBH rs1611115 and disulfiram, C allele homozygotes likely to consume less alcohol on drinking days NS NS NS NS NS Significantly lower drinks/drinking day in LL than S carriers -1.53 (CI: -2.59 to 0.47; effect size = 0.47). Significantly greater days abstinent 9.73% (CI: 0.95 to 18.50%; effect size = 0.29). Those with LL/TT had superior outcomes compared with other genotypes. Significant associations with improved outcomes in rs1150226 (AG) and rs17614942 (AC) genotypes. Significant association for drinks/drinking day in rs1176713 (GG).
Drinking days reduced for L allele homozygous (LOAs) treated with sertraline compared with placebo (d = 0.48). L allele homozygous (EOA) increased for the same measure (d = 0.98
Those with CC had significantly less heavy drinking days compared with placebo. There was a trend to Days abstinent suggest a similar outcome in days abstinent but this didn’t reach significance. Negligible differences were seen in A allele carriers. a Number of participants genotyped in the medication group; b Number of participants not presented for NS results; c Unable to extract the number of participants in each group from the original manuscript; EOA = Early Onset Alcohol Dependent Patients; LOA = Late Onset Alcohol Dependent Patients. 21 35
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Cloninger
Type I Later onset of dependence Men and women affected equally Likely binge drinkers: have periods of abstinence Rapid progression from mild to severe alc abuse High harm avoidance Type I Occasional/social drinking progresses into habitual drinking Increased alc craving and loss of control Alc consumed to counteract withdrawal symptoms “Normal” childhood and interpersonal relationships Positive FH Frequent outpatient treatment, eventually admitted for detoxification Alc consumption has minimal impact on social behaviour
Type B Cont. Poly drug use History of frequent treatment for substance misuse High life stress
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Lesch
Late-Onset Age of onset >25 years Type B Early onset of dependence Significant number of childhood risk factors Greater severe dependence Positive FH Greater psychopathological dysfunction Type I Cont. Low novelty seekers High award dependence Often accompanied by the development of ALD Respond better to treatment Experience losses of control and often feel guilty about drinking Type II Alc consumed for sedative effect (i.e. ‘self-medicating’) Pattern of consumption changes depending on environment Behavioural changes when intoxicated Decreased activity during leisure time Impaired interpersonal relationships Exhibits self-destructive tendencies when intoxicated Use of sedative drugs No severe somatic disorders No severe withdrawal symptoms
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Early-Onset Age of onset ≤25 years Type A Later onset of dependence Fewer childhood risk factors Less severe dependence Fewer alc-related problems Less psychopathological dysfunction
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Early vs. Late Onset Alcoholism Babor
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Table 3. Alcohol misuse typologies and their characteristics that are relevant to the present review
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Type II Early onset of dependence Primarily affects males Strong inheritable influences, often from father Unable to abstain, even though may desire to do so Are often impulsive and take risks Type III Alc Consumption to ‘self-mediate’ psychiatric disorders Alc free periods: patient drinks when psychiatric disorders are active Positive FH for psychiatric disorders Significantly impaired interpersonal relationships Aggressive behaviour whether intoxicated or sober Self-destructive whether intoxicated or sober Mild to moderate somatic symptoms of withdrawal
Type II Cont. Low harm avoidance High novelty seeking Low reward dependence Often manifest antisocial behaviour Often non-responders to treatment Type IV Severe intoxication following low alc consumption Brain damage
S0163-7258(15)00101-1 doi: 10.1016/j.pharmthera.2015.05.010 JPT 6785
To appear in:
Pharmacology and Therapeutics
Please cite this article as: Thompson, A., Owens, L., Pushpakom, S.P., Faizal, M. & Pirmohamed, M., Pharmacotherapy for alcohol dependence: A stratified approach, Pharmacology and Therapeutics (2015), doi: 10.1016/j.pharmthera.2015.05.010
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ACCEPTED MANUSCRIPT P&T # 22749 PHARMACOTHERAPY FOR ALCOHOL DEPENDENCE:
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A STRATIFIED APPROACH
THOMPSON, A1. OWENS, L1&2. PUSHPAKOM, SP1. FAIZAL, M3. PIRMOHAMED, M1 Wolfson Centre for Personalised Medicine, Institute of Translational Medicine, University of
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Liverpool, 1-5 Brownlow Street, Liverpool L69 3GL
Hepatology, Royal Liverpool University Hospital Trust, Ward 5z Link, Prescot Street. England
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Addiction Service, Mersey Care NHS Trust, 40 Upper Parliament Street, Liverpool,
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Merseyside L8 7LF
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UK
Address for correspondence: Munir Pirmohamed
Wolfson Centre for Personalised Medicine Institute of Translational Medicine Block A Waterhouse Building University of Liverpool Liverpool L69 3GL United Kingdom Telephone: +44 151 794 5549 Fax: +44 151 794 5059 1
ACCEPTED MANUSCRIPT Email: [email protected] Abstract
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Alcohol dependence is a common disorder in many societies worldwide, and remains
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difficult to identify and treat. It is also a risk factor for many secondary non-communicable
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diseases. Pharmacotherapy is one available treatment option, but appears to be underutilised in practice. Major barriers to use of medications in this area include lack of
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clinical guidance and questionable efficacy. However, for each medication there appears to be a subpopulation that responds positively, and understanding the moderating factors to
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treatment efficacy is an important research goal. Thus, this review provides a narrative regarding potential stratification techniques in pharmacological treatment of alcohol
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dependence, with a specific focus on typologies and pharmacogenetics. In addition, we
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discuss the basic background of stratified medicine and recent studies on genetic
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growing
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predisposition to alcohol dependence. repository
of
data
exists
for
both
approved
and
non-approved
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pharmacotherapies, but failure to replicate findings, inadequate sample sizes, and insufficient funding has resulted in a translational gap. Implementing evidence-based stratified/personalised therapy and identifying new therapeutic agents may lead to improved clinical outcomes and reduced financial burden. Despite some promising findings to date, much work is still required.
Keywords: Alcohol dependence; Pharmacogenetics; Typologies; Stratified medicine
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Abbreviations:
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5HT 5-hydroxytryptamine; ADH alcohol dehydrogenase; ALDH aldehyde dehydrogenase;
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ASN asparagine; ASP aspartate; DBH dopamine beta-hydroxylase; EOA early onset alcohol
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dependence; HTR7 5-hydroxytrytamine receptor 7; GABA γ-aminobutyric acid; LOA late onset alcohol dependence; NMDA N-methyl-D-aspartate; OPRM1 opioid receptor μ-1;
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OPRD1 opioid receptor delta-1; OPRK1 opioid receptor kappa-1; SLC6A4 solute carrier
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family 6 member 4
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1. Introduction
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2. Stratified approach to treating alcohol dependence
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Table of Contents
3. Naltrexone
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4. Acamprosate 5. Disulfiram
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6. Nalmefene 7. Baclofen
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8. Ondansetron
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9. Sertraline
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10. Topiramate
11. Relationship between genes involved in alcohol dependence and therapeutic response
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12. Conclusion
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1. Introduction
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Alcohol dependence is a major global public health concern, with the use and abuse of
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alcohol considered a leading risk factor for many non-communicable diseases (Jones et al.,
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2008). The mortality rate is high in this population, being nearly four times the age-adjusted rate for people without alcohol dependence (NICE, 2009). There are further social and
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economic costs linked to excessive alcohol drinking, with the annual global bill estimated at 760 billion Euros (Rehm et al., 2009). The aetiology of alcohol dependence is
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heterogeneous, and manifests from complex interactions between the environment and genes. This heterogeneity has been postulated as a confounder to treatment utilisation and
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efficacy, especially for pharmacotherapy (Litten et al., 2012). Empirical evidence is emerging
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however which suggests that a “stratified” approach to treatment may help optimise
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outcomes. Understanding the moderators that influence positive (or adverse) responses to a specific medication in a subgroup, or more desirably an individual, will assist healthcare
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practitioners in making more informed decisions when prescribing, and hopefully result in improved clinical outcomes. This review aims to provide a narrative of recent advances in the pharmacological treatment of alcohol dependence. There will be a focus on specific subgroups and underlying factors that may influence the efficacy of each medication, thus providing a rationale for a stratified approach to treatment. Specifically, attention will be given to stratification by typology and advances in pharmacogenetics. This review will start by providing a basic overview of stratified medicine. The main section of the article will cover the three medications approved for alcohol dependence treatment by The Medicines and Healthcare Products
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ACCEPTED MANUSCRIPT Regulatory Agency (UK) and Food and Drug Administration (USA): naltrexone, acamprosate and disulfiram. We will then discuss more contemporary drugs, including nalmefene, which
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was recently approved by The European Medicines Agency. This review will not cover the
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use of drugs during withdrawal from alcohol (detoxification); reviews on this topic are
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available elsewhere (for example, Amato et al., 2011; Amato et al., 2010; Minozzi et al., 2010). Furthermore, we also do not cover the utility of psychological interventions either
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when used alone or in combination with pharmacotherapy. We acknowledge this might be viewed as a limitation but we are unable to consider this variable in the scope of this review.
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Indeed, it is possible that more personalised approaches on the type and intensity of psychological intervention may also be of use in these patients.
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2. Stratified approach to treating alcohol dependence What is stratified medicine?
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Current medical practice is largely empirical, with treatment based on a “trial and error” paradigm targeting large populations of patients. Although this can be effective, many drugs
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have a significant number of non-responders or cause adverse reactions. Stratified medicine aims to identify these groups via shared biological or risk characteristics, and tailor subsequent treatment accordingly. One example of stratified medicine in practice is the improved efficacy of trastuzumab for the treatment of metastatic breast cancer in patients who overexpress the human epidermal growth factor-2 (HER2) gene (Slamon et al., 2001). Personalised medicine and precision medicine are related terms often used interchangeably in this area to describe treatment at individual patient-level rather than subgroup clustering. It has been suggested that personalised medicine is an additional step on the patient therapeutic continuum (Trusheim et al., 2007).
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ACCEPTED MANUSCRIPT Clinical stratification in alcohol dependence Identifying moderators of treatment efficacy is an important goal for any therapeutic aid.
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Those that are pertinent to alcohol dependence are presented in Table 1. Pharmacogenetics
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Pharmacogenetics is the study of genetic variation in drug response, with the aim of maximising clinical effectiveness and minimising toxicity by selecting the right drug for the
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right patient at the right dose. Such work is vital to ensure more precise prescribing which will benefit the patient and reduce costs. Rapid advances in sequencing technology coupled
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with international projects (e.g. International HapMap Project and Human Genome Project) have produced a wealth of data and repositories in this field. Several areas of medicine have
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already been influenced by pharmacogenetics, for example warfarin dosing (Pirmohamed et al., 2013), predicting responders to interferon-α in hepatitis C (Pirmohamed, 2011) and
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identification of individuals at risk of abacavir hypersensitivity reaction (Martin et al., 2012). The use of pharmacogenetics in drug treatment for alcohol dependence is in its infancy
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relative to the above examples. The most advanced empirical evidence exists for the μopioid receptor gene (OPRM1) polymorphism, Asn40Asp (rs1799971), which has been reported to predict naltrexone response (Chamorro et al., 2012). Pharmacogenetic studies relating to the treatment of alcohol dependence are summarised in Table 2 and discussed in the relevant sections of this review. Genetic predisposition to alcohol dependence Results from family studies indicate substantial heritability for alcohol dependence, approximately 40-60% (Kendler et al., 1992; Kendler et al., 1997; Milne et al., 2009; Prescott and Kendler, 1999). Despite advances in genetic testing and related analytical methods over 7
ACCEPTED MANUSCRIPT the last two decades, the genes and associated variants responsible for this predisposition remain somewhat enigmatic. However, the utilisation of larger samples alongside a shift in
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emphasis towards gene-gene interactions and more sophisticated models is showing
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promise in identifying novel alcohol dependent phenotypes and subsequent therapeutics.
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The identification of sub-phenotypes in alcohol dependence is important as this will reduce heterogeneity in participants recruited for research, fostering the identification of novel loci
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with larger effect sizes.
Comprehensive reviews of genetic studies relating to susceptibility to alcohol dependence
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have been published elsewhere (Enoch, 2013; Rietschel and Treutlein, 2013); here we provide a basic overview of significant new studies and those with potential implications for
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therapeutic development. The most robust findings to date have been for alcohol metabolising genes (Figure 1), aldehyde dehydrogenase (ALDH) and alcohol dehydrogenase
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(ADH) (e.g. Gelernter et al., 2014; Park et al., 2013), which have been shown to influence alcohol tolerance.
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Two studies have investigated 5-hydroxytrytamine (serotonin) receptor 7 (HTR7) as a susceptibility factor for alcohol dependence. The first study was a genome-wide association study (GWAS) that reported a significant association between rs7916403 of HTR7 and alcohol dependence (Zlojutro et al., 2011). The second study was case-control study that was unable to replicate the aforementioned association, but implicated two different HTR7 polymorphisms in alcohol dependence, rs11596518 and rs7904560 (Kim et al., 2014). The first GWAS investigating genetic influence on age of onset in alcohol dependent families was published recently, and reported 38 SNPs showing genome-wide significance (Kapoor et al., 2014). The finding with greatest significance was intergenic SNP rs2168784 which was in 8
ACCEPTED MANUSCRIPT strong linkage disequilibrium with 33 other imputed/genotyped SNPs spanning a 60 kb region on chromosome 3. The SNP rs2168784 is flanked by the Sucrase Isomaltase (SI) gene,
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which is implicated in carbohydrate digestion and may impact the rate of alcohol
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metabolism. Replication of these results in other cohorts is required, alongside establishing
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evidence for underlying mechanistic plausibility. Understanding the predisposition that underlies this subphenotype is important as it may allow for earlier interventions that
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reduce the progression to dependence, or at least eventual severity. Two further GWAS have reported an association between the GATA4 polymorphism,
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r13273672, and alcohol dependence (Edenberg et al., 2010; Treutlein et al., 2009). A subsequent imaging study using Functional MRI has provided support for this association
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(Jorde et al., 2014). In 81 abstinent, alcohol-dependent patients, G allele carriers had significantly lower alcohol-cue-related activation in the bilateral amygdala compared with
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AA allele carriers. The increased response in A allele homozygotes predicted a lower risk for relapse to heavy drinking. GATA4 has also been shown to influence the efficacy of
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acamprosate (Kiefer et al., 2011), which is discussed below. Several studies have utilised a gene-set approach in an attempt to generate an integrated perspective of gene-gene and pathway interactions in alcohol dependence (Biernacka et al., 2013; Kendler et al., 2011; Reimers et al., 2011). In a recent study, enrichment gene-set analysis was used across 31 studies (Li et al., 2014). From pathways identified in the Kyoto Encyclopedia of Genes and Genomes, Li and Colleagues found the calcium signalling pathway had the most significant association with alcohol phenotypes. Despite calcium having numerous biological effects, the rationale for its association with alcohol dependence is unclear. The authors speculated possible links between the depressive
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ACCEPTED MANUSCRIPT effects of alcohol and altered calcium concentrations, but empirical validation is required. Han and Colleagues (2013) identified a gene subnetwork purported to underlie susceptibility
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to alcohol dependence in European and African Americans by integrating two GWAS and a
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human protein interaction network (HPIN). Following dense module searching within the
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HPIN, implementation of an arbitrary selection of the top 5% modules, and identification of overlapping modules between ethnicities, 39 nonredundant genes were included in the
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subnetwork. The subnetwork finding was successfully replicated in three independent samples with alcohol dependence and no association was found in bipolar disorder, major
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depression or type II diabetes samples. None of the genes in the subnetwork had SNPs that met genome-wide significance, meaning they would have been discarded under
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conventional GWAS analytical techniques, which highlights the advantage of a broader
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network-based approach in complex conditions. Genes that encode potassium channels or
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their interacting proteins were most common in the subnetwork. Potassium channels have been shown to be sensitive to alcohol and mediators of behavioural tolerance (Treistman
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and Martin, 2009), alongside being therapeutic targets in other conditions (e.g. cardiac arrhythmias), offering scope for future work. The findings outlined above are identifying potential new therapeutic opportunities, but clearly, the realisation of this will take time with further genomic and functional studies required. In the meantime, it is important to evaluate the current therapeutic strategies that are available, and determine whether we can make better use of them. 3. Naltrexone Mechanism of action: The mechanism of action of naltrexone in the treatment of alcohol dependence has not been fully elucidated; however interaction with the endogenous opioid
10
ACCEPTED MANUSCRIPT system is suspected to play an important role. Naltrexone acts as a competitive antagonist at the opioid receptors in the central and peripheral nervous systems where it prevents
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binding of exogenous and endogenous ligands. This blockade decreases dopaminergic
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activity and thereby reduces the rewarding/pleasurable effects of alcohol (Ray et al., 2010).
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As such, naltrexone is considered to be an anti-craving medication that reduces the risk of relapse to heavy drinking (Bouza et al., 2004; Garbutt, 2010), rather than maintaining
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complete abstinence (Maisel et al., 2013).
Efficacy: The global efficacy of naltrexone is modest at best (Maisel et al., 2013;
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Srisurapanont and Jarusuraisin, 2005), which may account for its limited use in clinical practice (Mark et al., 2009). However, naltrexone efficacy has substantial variability with a
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subset of patients showing marked improvement in clinical outcomes. A recent systematic review of 28 studies reported that a positive family history of alcohol dependence or
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presence of the Asn40Asp polymorphism in the OPRM1 gene provided the strongest evidence as potential treatment moderators (Garbutt et al., 2014). A paucity of data
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however from well controlled, adequately powered, clinical trials has resulted in a gap in the translational pathway to clinical practice. Further meta-analytical findings have also suggested that abstinence prior to medication being administered is a strong predictor of naltrexone efficacy in both reducing heavy drinking (r = 0.52, P < 0.01) and prolonging abstinence (r = 0.60, P < 0.01) (Maisel et al., 2013). This evidence is consistent with current clinical guidelines (e.g., NICE, 2009). Kiefer et al. (2005) re-evaluated their results of a double-blind, placebo-controlled study comparing and combining acamprosate and naltrexone treatment by subgrouping 143 patients according to both Lesch (Lesch and Walter, 1996) and Cloninger (Cloninger et al.,
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ACCEPTED MANUSCRIPT 1981) typologies (see Table 3). For naltrexone alone, Lesch type III and IV patients (n=14) had significantly more days to both first drink and relapse to heavy drinking compared with
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placebo. Combined naltrexone and acamprosate treatment also mediated a greater time to
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first drink in type IV individuals (n=6), but this effect appears to be more dependent on the
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influence of naltrexone as acamprosate alone produced marginal differences compared with placebo. Cloninger type II patients (n=34) had significantly better outcomes in both
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measures across all three treatment groups compared with the eight patients assigned placebo. Further analysis of this study alongside other data (Rubio et al., 2005) supported
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these findings, with Cloninger type II patients having more positive responses to naltrexone (Kiefer et al., 2008). Conversely, when using Babor typology (Babor et al., 1992) it has been
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suggested that naltrexone is only significantly effective in type A patients (Bogenschutz et
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al., 2009), which have many features that are opposite to Cloninger type II. Of interest,
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these effects were only noted in the patients receiving medical management alone; in patients who received adjunct behavioural therapy, statistical significance was lost.
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Pharmacogenetics: The role of the OPRM1 Asn40Asp polymorphism as a potential determinant of naltrexone response has received the most interest from researchers as a pharmacogenetic target. This A→G polymorphism results in the substitution of asparagine to aspartate at position 40 (Asn40Asp; rs1799971) potentially causing structural variation in the receptor’s extracellular domain. A meta-analysis of six studies found that carriers of the G allele were less likely to relapse than those who were homozygous for the A allele when treated with naltrexone (Chamorro et al., 2012). The use of sensitivity analysis revealed that removal of any one of three studies (Anton et al., 2008; Kim et al., 2009; Oslin et al., 2003) from the meta-analysis resulted in a loss of statistical significance, probably due to the non-
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ACCEPTED MANUSCRIPT significant outcomes reported in other studies (Gelernter et al., 2007; O’Malley et al., 2008). Furthermore, research published after the meta-analysis inclusion date has also failed to
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reach a consensus on this polymorphism’s predictive value. For example, Kranzler et al.
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(2013) reported that G allele carriers were at greater risk of drinking more at a time of day
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when craving was high compared with A allele homozygotes in a sample of 158 problem drinkers, but this difference dissipated with naltrexone treatment. Conversely, despite 12
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weeks of treatment with naltrexone reducing subjective and objective drinking, OPRM1 Asn40Asp genotype was not considered a predictor of treatment response (Coller et al.,
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2011). Similar results were reported for 107 individuals with co-occurring alcohol dependence and other Axis I disorders (Arias et al., 2014). Another meta-analysis called for
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further research in this area to improve the confidence in estimates (Jonas et al., 2014). The
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same manuscript also noted that all eligible studies utilised retrospective associations
selection.
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between treatment response and genotype; none assessed genotype-guided medication
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A recent publication however utilised a prospective design to investigate the moderating effect of the Asn40Asp polymorphism on naltrexone treatment response (Oslin et al., 2015). Participants were stratified by genotype and subsequently randomised to either placebo or naltrexone (50 mg/day). There were no significant genotype x treatment interactions for any drinking outcomes. The authors reported negligible trends in the opposite direction than hypothesised for the primary outcome measure, relapse to heavy drinking. The study however was substantially underpowered (n=221 across 4 groups; 82 G allele carriers), with 80% power to detect an interaction odds ratio of 3.72, which may have resulted from the
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ACCEPTED MANUSCRIPT lower than expected allele frequency in screened patients. This study is an important contribution to the literature in this area, but further work is still required.
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The OPRM1 Asn40Asp polymorphism remains one of the most promising genetic candidates with biological plausibility to moderate treatment response in alcohol dependents.
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Furthermore, the Asn40Asp genotype has been implicated in other behaviours with high levels of craving, such as sugar and fat intake (Davis et al., 2011; Haghighi et al., 2014). The
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studies conducted to date in alcohol dependents lack large samples (n ≤307), present heterogeneity in outcome measures, and until recently (Oslin et al., 2015) have failed to
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allocate participants based on prospective genotyping. Additional high quality clinical trials
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are required to fully elucidate the OPRM1 Asn40Asp polymorphism hypothesis.
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The role of genetic differences in the dopamine transporter (DAT) variable number of
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tandem repeat (VNTR) sequences in moderating treatment response has been explored with some interesting initial findings (Anton et al., 2012; Schacht et al., 2013). Anton et al. (2012) reported no moderating effect of the OPRM1 variant alone in a sample of 83 non-
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treatment-seeking alcohol dependent patients taking naltrexone over 7 days, but those that carried at least one DAT solute carrier family 6 member 3 (SLC6A3) 9 VNTR and were A homozygous for rs1799971 (n=6) significantly reduced their drinks/day in a natural environment compared with placebo. However, this finding was not replicated in a laboratory setting (Ashenhurst et al., 2012). Such findings suggest that naltrexone’s pathophysiological mechanisms may not be limited to μ-opioid receptors. Understanding the affinity of naltrexone to each receptor will be an important step in defining the optimal stratification approach. 4. Acamprosate 14
ACCEPTED MANUSCRIPT Mechanism of action: The mechanisms underlying the anti-relapse effects of acamprosate are
unclear.
Originally,
it
was
assumed
that
acamprosate
(calcium-bis
[N-
T
acetylhomotaurinate]) acted by inhibiting the activity of N-methyl-D-aspartate (NMDA)
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receptors and thereby decreasing glutamatergic excitation associated with chronic alcohol
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intake and subsequent withdrawal (Mann et al., 2008; Tsai and Coyle, 1998). However, a series of animal and human studies postulated that the effects of acamprosate could be
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attributed solely to the active calcium component of the drug (Spanagel et al., 2013). The results from this group require external replication alongside further investigations to
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confirm the hypothesis that N-acetylhomoturinate alone is biologically inactive and that calcium salts alone mimic the efficacy of acamprosate.
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Efficacy: As with naltrexone, acamprosate has small to modest effects and its efficacy appears to be limited (Rosner et al., 2010). From 24 RCTs with 6915 participants,
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acamprosate significantly reduced the risk of any drinking compared with placebo (RR 0.86; 95%CI 0.81 to 0.91) and the number needed to treat was 9. There was no difference in
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effects between industry-sponsored (RR 0.88; 95%CI 0.80 to 0.97) and non-profit trials (RR 0.88; 95% CI 0.81 to 0.96) when sensitivity analysis was performed. Further meta-analytical findings suggest that acamprosate efficacy does not differ between sexes (Mason and Lehert, 2012), is associated with longer abstinence when detoxification has occurred (r = 0.59) and is superior to naltrexone in maintaining abstinence (Maisel et al., 2013). However, two large multisite RCTs with similar designs, COMBINE (Anton et al., 2006) and PREDICT (Mann, Lemenager, et al., 2013), reported no beneficial effect of acamprosate compared with placebo, with samples of 1383 and 426, respectively.
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ACCEPTED MANUSCRIPT In 260 patients classified according to Lesch typology, type I and II patients have been shown to have a greater number of days sober taking acamprosate compared with placebo;
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no differences were observed for types III and IV (Lesch and Walter, 1996). These results
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were supported somewhat by Kiefer et al. (2005) who reported significantly increased days
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to first drink and relapse in Lesch type I patients. Conversely, data on a subgroup of 76 participants in the UK Multicentre Acamprosate Study found that there was no trend for
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Lesch type I and II individuals to have improved outcomes (Chick et al., 2000). Insufficient power and heterogeneous distribution of samples have been cited as a possible reason for
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these contradictory findings (Chick et al., 2000; Lesch et al., 2001). In the aforementioned Kiefer et al. (2005) study, those on acamprosate had significantly better outcomes than
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those allocated placebo. Taken together, these findings led to the hypothesis that Babor B
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and early onset alcohol dependent patients would also respond positively to treatment with
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acamprosate (Leggio et al., 2009), but these assumptions are yet to be tested. A pooled analysis of seven European studies explored the moderating effect of six clinical
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variables (physiological dependence at baseline, family history of alcoholism, age of onset, anxiety symptomatology at baseline, craving at baseline, and gender) on drinking outcomes (Verheul et al., 2005). Baseline measures of anxiety and craving were found to predict cumulative and continuous abstinence duration across the treatment groups. The efficacy of acamprosate alone was not associated with any of these variables. One of the primary strengths of this study was a large sample size (n=1010-1485) and associated statistical power (β ≥ 0.87). Such results further highlight the difficulty in identifying treatment responders in this population, although this did not preclude the authors concluding,
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ACCEPTED MANUSCRIPT “Acamprosate can be considered as a potentially effective pharmacotherapy for all patients with alcohol dependence”.
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Pharmacogenetics: Research attempting to establish the influence of genetic variation on the efficacy of acamprosate is in its infancy compared with naltrexone. Subgroup analysis
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from the PREDICT study reported that SNP rs13273672, which is located intronically in GATA4, was associated with relapse prevention during treatment with acamprosate (Kiefer
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et al., 2011) but not naltrexone. GATA4 regulates the transcription of atrial natriuretic peptide (McBride and Nemer, 2001), which has purported actions in the pathophysiology of
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withdrawal and relapse (Kiefer and Wiedemann, 2004). Atrial natriuretic peptide is believed to influence glutamatergic mechanisms (Kovacs, 2003), the hypothesised primary site of
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action for acamprosate, which led the authors to conclude that acamprosate’s efficacy may be moderated by allelic variation in rs13273672. However, the functional relevance of this
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association needs to be delineated as the SNP is intronic. Glutamate receptor subunit epsilon-2 (GRIN2B) SNP rs2058878 has shown significant
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association with length of abstinence in a sample of 225 alcohol dependents during 3 months of acamprosate treatment in a community-based programme (Karpyak et al., 2014). Carriers of the minor A allele had improved outcomes compared with non-carriers. In a replication sample of 110 patients from the PREDICT study (Mann et al., 2009) statistical significance was not reached (P = 0.068). However, significance was noted for GRIN2B SNP rs2300272 in the replication sample, with presence of the minor allele (frequency = 0.48) associated with shorter abstinence. These are novel findings in humans, and work is required to replicate results and further understand the biological mechanisms involved.
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ACCEPTED MANUSCRIPT Several plausible rationales were presented by the authors including increased GluN2Bcontaining NMDA subunit expression and changes in calcium influx.
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A 21-day study with 126 participants reported that compared with naltrexone, those on acamprosate who were homozygous for the C allele (T1519C) in gamma-aminobutyric acid
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receptor subunit alpha-6 (GABRA6) and homozygous for the A1 allele in the dopamine receptor D2 (DRD2) Taq1A (rs1800497) polymorphism had lower cue-induced craving
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(Ooteman et al., 2009). However, the Taq1A polymorphism is actually located 10 kb downstream of DRD2 in the last exon of ANKK1 (Neville et al., 2004). The interaction
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between genes in this chromosomal region and alcohol dependence remains unclear (Dick et al., 2007). It is hypothesised that the A1 allele of the Taq1A polymorphism may exert its
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effects via alterations in brain opiate receptor expression and it has been shown that naloxone, an opioid antagonist like naltrexone, has lower binding affinity in A1 allele carriers
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(Ritchie and Noble, 1996). The study by Ooteman and Colleagues (2009) also found that those who were homozygous for the T allele (C1412T) in the gamma-aminobutyric acid
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receptor subunit beta-2 (GABRB2) and allocated acamprosate had reduced physiological cue reactivity to alcohol, as indexed by heart rate. Of interest, naltrexone administration resulted in lower cue-induced craving in Taq1A A2 allele homozygotes and reduced physiological cue reactivity in OPRM1 rs1799971 G allele carriers. 5. Disulfiram Mechanism of action: Disulfiram is an aversive medication that blocks the enzyme aldehyde dehydrogenase. Thus, when alcohol is consumed there is an accumulation of acetaldehyde that cannot be metabolised (Figure 1), which results in an unpleasant reaction. Due to this potential reaction, disulfiram’s mechanism of action is considered primarily psychological
18
ACCEPTED MANUSCRIPT (Fuller and Gordis, 2004; Skinner et al., 2010). Alternatively, plausible pharmacodynamic mechanisms of action have been proposed from cocaine addiction research. Blocking of
metabolite
3,4-dihydroxyphenylacetaldehyde
(DOPAL)
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dopamine
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ALDH2 by a specific inhibitor released by disulfiram, ALDH2i, prevents the conversion of the to
3,4-
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dihydroxyphenylacetic acid (DOPAC). Condensing of increased DOPAL and dopamine in the ventral tegmental area neurons produces tetrahydropapaveroline, which inhibits tyrosine
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hydroxylase and subsequent dopamine production (Weinshenker, 2010; Yao et al., 2010). A reduction in dopamine is known to blunt the reward/reinforcement pathway. The role this
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effect plays in the treatment of alcohol dependence is unknown. It should be noted that disulfiram has been associated with hepatotoxicity (Chick, 1999), and should therefore be
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used with caution in patients either with or at risk of liver disease. Efficacy: A recent meta-analysis of 22 studies found that disulfiram was more successful
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than comparator conditions at improving drinking status. Although when study design was considered, only open-label RCTs had significantly enhanced outcomes (Skinner et al., 2014).
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The most likely explanation for this observation is that placebo groups in double blind trials are exposed to the same message about potential alcohol-induced adverse reactions, which results in the same mode of action between groups. It is also easy for participants to unmask treatment allocation by consuming a small quantity of alcohol and observing the effect. Pharmacogenetics: Two recent original articles investigating disulfiram’s efficacy are of relevance to this review. The first used a four-group single-blind design and genotyped for ALDH2 in 109 Japanese alcohol dependent individuals (Yoshimura et al., 2014). Overall, there were no significant differences between any of the groups for abstinence or dropouts. 19
ACCEPTED MANUSCRIPT However, when genotyping was considered, all participants with the inactive form of ALDH2 who were allocated disulfiram (n=5) remained abstinent during the study period. The
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inactive ALDH2 allele is common in East Asians (~35%) (Eng et al., 2007; Higuchi et al., 1996)
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and leads to a ‘natural’ adverse reaction to alcohol, which is similar to that produced by
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disulfiram but of smaller magnitude. Further exploration in larger samples is required to delineate whether innate inactivation of ALDH2 augments the aforementioned
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psychological and/or physiological responses to disulfiram to produce a subgroup of ‘super responders’. The second study investigated the moderating effects of OPRM1 rs1799971
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(Asn40Asp) and dopamine beta-hydroxylase (DBH) rs1611115 (C-1021T) genotypes in alcohol dependent individuals of European ancestry (n=107). Participants who were
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allocated disulfiram and continued to drink alcohol were likely to consume less if they were
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homozygous C allele carriers for the rs1611115 genotype (Arias et al., 2014). The authors
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speculated that this might result from T allele carriers having a more pronounced addictionprone and reward seeking phenotype. However, this is preliminary data and replication is
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required. 6. Nalmefene
Mechanism of action: Nalmefene, like naltrexone, modulates activity in the opioid receptor system. It acts as an antagonist at the mu and delta receptor and as a partial agonist at the kappa receptor (Bart et al., 2005). Like naltrexone, nalmefene is reported to suppress both craving and pleasure associated with alcohol and, as such, can be considered an anti-craving mediation rather than relapse preventing (Drobes et al., 2004), although reductions in relapse rates have been reported (e.g., Mason et al., 1999). Nalmefene was originally approved for the treatment of opioid overdose but recently received approval for alcohol
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ACCEPTED MANUSCRIPT dependence by the European Medicines Agency. However, correspondents in The British Medical Journal have criticised this move, citing possible reasons for reassessing this
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decision, including a poorly defined primary outcome measure, use of surrogate markers
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and conflicts of interest in the trials submitted for evaluation (Braillon, 2014; McNulty and
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Williams, 2014; Spence, 2014).
Efficacy: To date, seven RCTs have been published on the efficacy of nalmefene for treating
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alcohol-related disorders, with all but one reporting reduced heavy drinking (Anton et al., 2004). The findings from six randomised controlled trials (Anton et al., 2004; Gual et al.,
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2013; Karhuvaara et al., 2007; Mann, Bladström, et al., 2013; Mason et al., 1994; Mason et al., 1999) have been extensively reviewed elsewhere (Soyka, 2014). The most recent
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publication, the third prospective study from the (E)SENSE project, evaluated the efficacy and tolerability of nalmefene ‘as-needed’ treatment over 12 months in 675 alcohol
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dependent patients (van den Brink et al., 2014). One-hundred and twelve patients in the placebo group and 310 in the nalmefene group completed the study. There were
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statistically significant reductions in the number of heavy drinking days (1.6 days/month) and total alcohol consumed (6.5 g/day) in the nalmefene group compared with placebo; although neither primary outcome variable reached statistical significance at 6 months. This later finding contradicts previous results (Gual et al., 2013; Mann, Bladström, et al., 2013). Both of these studies found that the nalmefene group significantly reduced their heavy drinking days after 6 months, and one (Gual et al., 2013) reported that total alcohol consumption was lower at this time point. However, when Van den Brink and colleagues considered higher risk drinkers only, indexed by Timeline Follow-back data from the month preceding the screening visit, total alcohol consumption was significantly reduced at 6
21
ACCEPTED MANUSCRIPT months, whilst both primary measures were significantly improved at the end of the study in this subgroup. These findings are in agreement with similar subgroup analysis from the
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first two studies (van den Brink et al., 2013). Further prospective RCTs are required in different subgroups of the population to acquire
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knowledge about global efficacy. To date, all studies have recruited predominately white, middle-aged males and many have excluded those with comorbidities. One study (van den
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Brink et al., 2014) included patients with comorbid psychiatric disorders, although the number recruited with such conditions was substantially lower than population estimates
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(Kessler et al., 1996).
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Pharmacogenetics: Secondary analysis of the Karhuvaara study (Karhuvaara et al., 2007)
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investigated pharmacogenetic moderators of nalmefene’s efficacy in 166 patients. A total of
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five SNPs were genotyped; two each in OPRM1 (including rs1799971) and OPRD1 and one in opioid receptor kappa-1 (OPRK1). The authors reported no main or moderating effects of
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these genotypes (Arias et al., 2008). 7. Baclofen
Mechanism of action: Baclofen is a γ-aminobutyric acid (GABA) β-receptor agonist that is primarily marketed as an anti-spasticity agent. More recently, several groups have investigated baclofen as potential pharmacological aid for treatment of alcohol dependence. The stimulation of GABAB-receptors by baclofen is thought to inhibit the release of the excitatory amino acids, glutamate and aspartate, which reduce the rewarding/pleasurable effects of alcohol. The activation of GABAB-receptors may also reduce the anxiogenic effects of alcohol (Addolorato et al., 2009). Importantly, excretion of
22
ACCEPTED MANUSCRIPT baclofen in mainly via the kidneys (Wuis et al., 1990), and is therefore not contraindicated in patients with liver disease.
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Efficacy: As mentioned previously, alcohol dependent patients with comorbidities are often excluded from research, despite high prevalence of conditions such as alcoholic liver disease
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in this population (Mann et al., 2003). In a pioneering RCT, 84 patients with alcohol dependence and comorbid liver cirrhosis were randomised to receive baclofen 30 mg/day or
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placebo (1:1) for 12 weeks (Addolorato et al., 2007). Those allocated baclofen had significantly higher rates of abstinence (OR 6.3 [95% CI: 2.4-16.1]; P = 0.0001) and a greater
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number of cumulative days without consuming alcohol (62.8 vs 30.8 days). There were also significant reductions in several markers of liver injury. The placebo group had more
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dropouts (31% vs 14%) but this was statistically similar between groups, likely attributable to lack of statistical power due to the small sample size. Although it is worth noting, as per
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intention to treat analysis, these dropouts were considered to have relapsed in the final analysis, which may have influenced the magnitude of the true results. Baclofen was well
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tolerated both during the intervention phase and subsequent four week withdrawal period. Although liver cirrhosis was not used as a moderator of baclofen’s efficacy, this study provides insight into possible treatment stratification as well as scope for future research in this population; a related study protocol was recently published (Morley et al., 2013), and the results should hopefully provide further insight. Separate findings from post-hoc analysis of patients with hepatitis C were consistent with the main study; baclofen resulted in more patients achieving and maintaining abstinence than those allocated placebo (83.3% vs 25.0%) (Leggio et al., 2012). In contrast, Garbutt et al. (2010) found no significant effect of baclofen in several drink-related outcome measures.
23
ACCEPTED MANUSCRIPT Although the findings are not consistent across the aforementioned studies, some evidence suggests that a greater number of mean daily drinks on drinking days and higher anxiety are
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moderators of baclofen’s efficacy. Also, preliminary data from a small open label trial found
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that female alcohol dependent patients may respond more positively to baclofen treatment
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(Flannery et al., 2004), however, these findings were not confirmed in a larger RCT (Garbutt et al., 2010). A French-language meta-analysis concluded there is weak support for the
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efficacy of low dose baclofen in maintaining abstinence, but reported a significant increase of 179% in patients abstinent at the end of trails compared with placebo (Lesouef et al.,
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2014).
Two small RCTs have been published from an international project (The International
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Baclofen Intervention Study) that initially aimed to conduct a large, multisite, double-blind, RCT investigating the efficacy of baclofen for alcohol dependence, but the recruitment
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target was not achieved. The first publication reported that a 60 mg/day dose of baclofen was significantly more effective at reducing the number of drinks per day than both 30
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mg/day and placebo; 30 mg/day was superior to placebo (Addolorato et al., 2011). The subsequent study found no significant treatment differences in any primary efficacy outcomes (e.g., days to relapse, drinks per drinking day, heavy drinking days during previous week), but alcohol consumption did significantly decrease over the treatment period (Morley et al., 2014). Each study began with a sample size of 42, which was then reduced as patients were lost to follow-up, these small sample sizes likely explain a number of nonsignificant trends towards improved outcomes for participants allocated either dose of baclofen. The study from Morley and Colleagues noted that patients with comorbid anxiety who were allocated baclofen generally reported significantly increased time to first drink
24
ACCEPTED MANUSCRIPT (lapse) and first heavy drinking day (relapse) compared with placebo; the only nonsignificant post hoc difference was found between 60 mg/day and placebo.
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Whether high dose baclofen is more effective in the treatment of alcohol dependence is currently unknown and concerns have been raised about its tolerability and safety
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(Enserink, 2011). An observational study of 100 alcohol dependent individuals found that baclofen treatment with no superior dose limit (average maximal dose was 147 mg/day)
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was effective at reducing the risk of heavy drinking (De Beaurepaire, 2012). Interestingly, a significant relationship was observed between the amount of alcohol taken before
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treatment and the maximal dose of baclofen required, those with higher alcohol consumption required increased baclofen. Some trials studying high dose baclofen are
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ongoing (e.g., ClinicalTrials.gov Identifier: NCT01266655; NCT01980706).
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Pharmacogenetics: To date there have been no relevant pharmacogenetic studies for baclofen in alcohol dependence treatment.
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8. Ondansetron
Mechanism of action: Ondansetron, a serotonin 5-HT3 receptor antagonist, is predominately indicated for use as an antiemetic drug. However, due to its pharmacological properties it has been proposed as a treatment for alcohol dependence. 5-HT3 receptors are densely distributed in the mesocorticolimbic neuronal terminals, which regulate dopamine release (Chen et al., 1991). Ondansetron antagonises these receptors and blocks the pleasurable stimulation from alcohol and thereby reduces the urge to drink (Johnson, 2004). Efficacy: Ondansetron has been shown to be effective in early onset alcohol dependent patients in several studies (Johnson et al., 2002; Johnson et al., 2000; Kranzler et al., 2003).
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ACCEPTED MANUSCRIPT For this patient subgroup, a dose of 4 µg/kg twice per day for 11 weeks in a sample of 271 was found to be most efficacious for reducing drinks per day and drinks per drinking day,
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alongside increasing the percentage of days abstinent and total days abstinent, compared
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with doses of 1 and 16 µg/kg twice per day (Johnson et al., 2000). Other results have
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complemented these inverted U-shaped findings (Johnson et al., 2002). Subsequent analysis of the same dataset revealed that Babor type B alcohol dependent patients responded
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significantly better to ondansetron (4 μg/kg) than type A; however, early- vs. late-onset classification was still a better predictor of outcomes overall (Roache et al., 2008).
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A more recent study with a total sample size of 280 showed no association between age at onset of alcohol problems and response to ondansetron (Johnson et al., 2011), which is
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paradoxical to the earlier findings by the same research group. This finding, combined with some of the results from sertraline research (see section 9), has prompted a call for further
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exploration into the biological mechanisms underpinning age of onset and how different phenotypes interact with serotonin transporters (Roache, 2012). Moreover, consensus
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needs to be reached on the limits that define the upper and lower bounds of this dichotomous variable. If age of onset is found to be a reliable moderator for any alcohol dependence medication it likely would be welcomed by prescribers as it represents a cheap and relatively easy to determine variable. A pilot RCT in Brazil assessed the efficacy and safety of full dose ondansetron (16 mg/day) in severely dependent male alcohol dependent patients (Correa Filho and Baltieri, 2013). Of the 102 participants recruited almost half dropped out of the study. Of those retained, no significant differences were observed in percentage of days abstinent or heavy drinking days between the treatment and placebo groups; it should be noted that both groups had good
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ACCEPTED MANUSCRIPT outcomes for each variable. Multiple-imputation analysis was used to include those not retained in the study. This resulted in a small (3.8%), but statistically significant, reduction in
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the percentage of heavy drinking days for those treated with ondansetron compared with
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placebo. The authors openly criticise this approach and recommend future studies should
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account for substantial attrition in their sample size. There were trends to suggest that early- vs late-onset typology may have influenced results but these findings were not fully
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explained. Only minor adverse effects were reported, with no difference between groups. Although not overtly referred to in alcohol research to date, there are some concerns
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regarding ondansetron inducing QT prolongation. This needs to be considered when treating patients at risk of cardiac arrhythmias or where inducing QT prolongation may
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impact clinical management of any comorbidity (e.g. patients at risk of seizures).
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Pharmacogenetics: Differences at gene level have been explored in an attempted to explain individual variation in ondansetron response. In an 11 week two-site RCT, Johnson et al. (2011) initially stratified 283 patients based on their 5’-serotonin-transporter-linked
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polymorphic region (5’-HTTLPR) (LL/LS/SS), with additional genotyping for rs1042173 (T/G); both are found in the serotonin transporter gene, SLC6A4. When 5’-HTTLPR is considered alone, carriers of the LL genotype on ondansetron had a lower number of drinks per drinking day (−1.45) and a higher percentage of days abstinent (9.65%) than all other genotypes and treatment groups combined. When considered together, LL/TT carriers showed the biggest improvement in outcome measures with 2.63 less drinks per drinking day and a 16.99% increase in days abstinent. The ondansetron group reported significantly more fatigue.
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ACCEPTED MANUSCRIPT Secondary analysis of the aforementioned study by Johnson and colleagues (2011) explored the role of two further genes in predicting ondansetron’s efficacy, hydroxytryptamine
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receptor 3A (HTR3A) and hydroxytryptamine receptor 3B (HTR3B) (Johnson et al., 2013).
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Three genotypes (HTR3A-rs1150226-AG, HTR3A-rs1176713-GG, and HTR3B-rs17614942-AC)
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were found to be associated with positive outcomes (as above, plus percentage of days abstinent) when taking ondansetron. Approximately 34% of the study cohort carried one or
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a combination of the SLC6A4-LL/T and HTR3 genotypes that were associated with the largest ondansetron-induced reductions in drinking. Of the defined combinations presented in the
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study, one was considered a group of potential “super-responders” (possessing any one, two, or all three of the identified HTR3 genotypes; n=29/133) with a fivefold increase in
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percentage of subjects with no heavy drinking days when treatment groups were compared. 9. Sertraline
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Mechanism of action: Sertraline is a selective serotonin reuptake inhibitor (SSRI). As such, it acts as a 5-hydroxytryptamine (5-HT) agonist and may reduce the urge to drink and the
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pleasurable effects associated with alcohol. However, the routine use of SSRIs in clinical practice for alcohol dependence treatment is not recommended in certain countries, for example the UK (NICE, 2009). Nevertheless, several groups have conducted clinical research into sertraline’s efficacy for the treatment of alcohol dependence. Efficacy: In the first such study, 100 patients were randomised either to sertraline (maximum dose 200 mg/day) or placebo for 14 weeks and stratified according to lower risk/severity (type A) and higher risk/severity (type B) (Pettinati et al., 2000). Sertraline treatment in type A alcohol dependent patients (n=30) was associated with fewer drinking days (0.0% vs 22.4%) and increased likelihood of continuous abstinence (53.3% vs 16.0%)
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ACCEPTED MANUSCRIPT compared with placebo (n=25). There was also a trend to suggest that the same subgroup had a greater number of weeks to relapse. These findings were later reported to only be
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evident in type A men (Pettinati et al., 2004). Conversely, those defined as type B alcohol
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dependent patients and treated with sertraline (n=20) deteriorated compared with placebo
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(n=25), with more drinking days (8.2% vs 4.1%) and reduced likelihood of maintaining abstinence (10.0% vs 24.0%) (Pettinati et al., 2000). These effects persisted during the 6-
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month follow-up period (Dundon et al., 2004). Further exploration of the original data found that sertraline was not effective in alcohol dependent patients with current or lifelong
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comorbid depression (n=53) compared with those without depression (n=47) (Pettinati et al., 2001).
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Pharmacogenetics: In another series of studies utilising a single data set, Kranzler et al (2011) explored the moderating effect of age of onset and the 5’-HTTLPR polymorphism on
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sertraline response. The 5’-HTTLPR polymorphism has long-(L) and short-repeat (S) alleles. The long-repeat can be further divided according to the A→G SNP at rs25531, which alters
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the function of the allele. The function of LG is similar to that of S, and for the purposes of this study were grouped as S’; The LA allele was labelled L’. One-hundred and thirty four participants were randomised to either placebo (n=71) or sertraline (n=63), which was titrated from 50 mg/day to a maximum dose of 200 mg/day depending on tolerability. Completion rate for the study was 61.9%, although those who were early onset alcohol dependent patients with L’ and treated with sertraline had a high attrition rate, only 14.3% completed. Three participants receiving sertraline experienced serious adverse reactions that resulted in hospitalisation. At the end of the treatment period, late onset alcohol dependent patients who were L’ allele homozygous and treated with sertraline significantly
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ACCEPTED MANUSCRIPT reduced their number of drinking days compared with placebo (Cohen’s d = 0.48). Conversely, early onset alcohol dependent patients who carried the same allele make-up
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and treated with sertraline significantly increased their number of drinking days compared
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with placebo (Cohen’s d = 0.98). Similar trends were observed for the number of heavy
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drinking days but this variable did not reach statistical significance for late onset alcohol dependent patients. There were no observed effects for S’ allele carriers (Kranzler et al.,
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2011). Subsequent analysis used other typologies to stratify participants (Kranzler et al., 2012). Again, carriers of the S’ allele demonstrated no significant effect for either drinking
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outcome measure (drinking days and heavy drinking days). When L’ allele homozygotes were stratified according to Babor and two age of onset typologies, type A and late onset
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alcohol dependent patients on sertraline had significantly improved drinking behaviour
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compared with placebo. Conversely, type B and early onset alcohol dependent patients
10. Topiramate
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significantly deteriorated on sertraline compared with placebo.
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Mechanism of action: Topiramate is a broad-spectrum antiepileptic drug. It is hypothesised that the positive effects of topiramate on alcohol consumption manifest through neuronal stabilisation (Johnson and Ait-Daoud, 2010), which may result from inhibition of AMPA and kainate subtypes of glutamate receptors alongside up-regulation of GABAA receptor function (Shank and Maryanoff, 2008; White et al., 2000).Efficacy: Data from early clinical trials has been encouraging, with improvements in alcohol consumption outcomes and quality of life, and no serious adverse reactions (Olmsted and Kockler, 2008). A seven study meta-analysis (Blodgett et al., 2014) found that topiramate had superior effects on abstinence, heavy drinking, GGT and craving outcomes compared with results for both naltrexone and
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ACCEPTED MANUSCRIPT acamprosate, published elsewhere (Maisel et al., 2013). However, the total sample size of 1225 in the topiramate meta-analysis was too small to conduct any formal moderator tests.
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A drug utilisation study suggests that the use of topiramate to treat alcohol use disorders in
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USA Veterans has almost doubled between fiscal years 2009 and 2012 (Del Re et al., 2013),
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although total use is still under 2%.
In a 12 week double-blind trial, 150 treatment seeking alcohol dependent individuals were
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randomised to either topiramate (titrated from 25 to 300 mg/day) or placebo (1:1) (Johnson et al., 2003). Both groups demonstrated improvements in study outcomes from baseline but
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those reported in the topiramate group were statistically superior to placebo. Those receiving topiramate had 2.88 fewer drinks per day, 3.10 fewer drinks per drinking day,
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27.6% fewer heavy drinking days, 26.2% more days abstinent, and a -0.07 lower log plasma gamma-glutamyl transferase ratio, compared with placebo. Abstinence prior to study entry
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was not required, although the biggest reduction in drinking was seen between screening and enrolment. This pre-treatment decline in drinking is sometimes a caveat to finding
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statistically significant results, and is often cited as a limitation, however, within this study (Johnson et al., 2003), it demonstrates how topiramate could be used as an effective adjunct for individuals who are self-motivated to decrease alcohol consumption. There is also evidence from a laboratory-based study to suggest that topiramate (titrated to 200 and 300 mg/day) reduced heavy drinking in 61 non-treatment seeking drinkers (Miranda et al., 2008). There were no severe adverse reactions to topiramate but a substantial number of mild-moderate reactions were reported. In addition, several studies have been published using the same data set of 150 alcohol dependent patients. Compared with placebo, topiramate increased quality of life and
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ACCEPTED MANUSCRIPT overall well-being alongside reducing the level of dependence and harmful consequences of drinking (Johnson et al., 2004). Utilisation of a holistic (subjective and objective drinking to
analysing the
effects of
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measures and psychological outcomes) approach
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pharmacotherapy in this population is rare, but doing so adds strength to potential clinical
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effectiveness and should be encouraged.
Similar results were reported in a larger multi-site study (n=371) by the same group
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(Johnson et al., 2008; Johnson et al., 2007). Again there were significant improvements in all subjective and objective measures (same outcomes as Johnson et al., 2004), using both pre-
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specified and imputed models to account for dropout. Furthermore, improvements in physical and mental well-being were noted (Johnson et al., 2008). Unlike the previous study,
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this cohort had low representation from non-Caucasian groups (85% Caucasian). Participants on topiramate reported a large number of adverse reactions, many of which
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occurred significantly less in the comparator condition. Pharmacogenetics: In a pharmacogenetic study, 138 treatment seeking heavy drinkers
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(>90% met the DSM-IV criteria of current alcohol dependence) were allocated either topiramate (max dose 200 mg/day) or placebo (Kranzler, Covault, et al., 2014). The moderating effects of a noncoding intronic SNP in glutamate receptor ionotropic kainate-1 (GRIK1), rs2832407, were investigated in self-identified European American patients (n=122) only because of differences in allele frequency between ethnicities. In the entire cohort, the topiramate group had significantly better outcomes for the number of heavy drinking days (no heavy drinking days in last 4 weeks: OR = 2.75, 95% CI = 1.24 to 6.10) and days abstinent (abstaining from alcohol during the final week of treatment: OR = 2.57, 1.13-5.84). In the genotyped cohort, C allele homozygotes had a significant reduction in heavy drinking and
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ACCEPTED MANUSCRIPT there was trend to suggest an increase in number of days abstinent compared with placebo, whereas those carrying the A allele showed negligible differences. These positive results
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were confirmed through the analysis of daily interactive voice response surveys in the same
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cohort (Kranzler, Armeli, et al., 2014). There was a trend to suggest that topiramate
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mediated a significant reduction in drinks/day (β = -0.547, 95%CI: -1.153 to 0.059, P = 0.076), however a significant interaction was observed for medication group x genotype (β =
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topiramate reporting the best outcomes.
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-1.506, 95%CI: -2.719 to -0.293, P = 0.015), with those homozygous for the C allele on
11. Relationship between genes: A network pathway analysis
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It is clear that the relationship between genes and therapeutic response is complex. We
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attempted elucidation of relationship between various genes involved in treatment
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response to alcohol dependence by undertaking a network pathway analysis (Figure 2). We used Ingenuity Pathway Analysis software (http://www.ingenuity.com/products/ipa) and
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only included genes implicated in therapeutic response as outlined in this review. The pathway is based on both experimental data and prediction (high threshold only), and it draws information from a large number of databases and literature contained in the Ingenuity Knowledge Database. The information utilised includes published experimental data in human, rat and mouse models, and in vitro studies that include, but are not limited to, cells related to the brain and central nervous system. The aim of this analysis is to highlight various genes or pathways that may act alone or together to influence therapeutic response.
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ACCEPTED MANUSCRIPT Interestingly, the network analysis not only identified connections between treatment response pathways but also highlighted how these pathways are closely interlinked with
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genes that are important in susceptibility to alcohol dependence. Figure 2 shows the
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crosstalk between various receptors, transporters, cytoplasmic mediators and nuclear
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transcription factors involved in treatment response and alcohol dependence. Some key common regulators such as GATA4 and NFATc2, a calcium dependent factor, correlate with
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the calcium signalling pathway reported to be associated with alcohol phenotypes by Li and Colleagues (2014); and FOS interacts with multiple receptors that are important in alcohol
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dependence or therapeutic response. Various secreted mediators such as BDNF and IL4 are also shown here. Another important observation is the potential relevance of CYP enzymes
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such as CYP19A1 (aromatase), of which genetic variants are associated with craving for
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alcohol (Lenz et al., 2011). We acknowledge that this analysis may not be complete and we
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are limited by the curated information present in the Ingenuity database. We also acknowledge that some of the network connections are generated based on predictions and
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therefore require experimental validation. Nevertheless, it is sensible to speculate that mediators which are involved in the susceptibility to alcohol dependence may also play a significantly important role in modulating response to various drugs utilised in the treatment of this disorder.
12. Conclusion A growing collection of evidence is now available for pharmacotherapy-based treatment of alcohol dependence, which has contributed to positive clinical progress. However, barriers to utilisation in practice remain. Pragmatic approaches are required to ensure that evidence
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ACCEPTED MANUSCRIPT gathering is patient-centric and that healthcare practitioners willingly engage with treatment pathways as prescribing for alcohol dependence treatment remains low.
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Research in this discipline is buoyed by emerging therapeutic targets/agents alongside the possibility of stratified/personalised approaches to treatment which translate to positive
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real-world outcomes. To date, GWAS and associated meta-analyses have reported a number of risk alleles for alcohol dependence, but replication of these results has been limited.
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Network-based analysis has produced some promising initial findings, and combined with a multi -omics approach could provide the next frontier in the identification of risk factors and
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therapeutic candidates. This strategy has proven successful in other complex conditions, such as cancer. Furthermore, links with industry, advances in technology and novel
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analytical methods, such as the recently proposed Bayesian mixed treatment comparison meta-analysis in alcohol dependence (DeSantis and Zhu, 2014), are providing new direction
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in this and other research areas.
Treatment stratification aims to reduce adverse reactions and augment effectiveness. The
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modest global efficacy for acamprosate and naltrexone alongside the exploration of more contemporary drugs have benefited from this approach. However, many areas lack strong empirical evidence and current literature is often hampered by methodological limitations, including patient phenotype heterogeneity, inadequate sample sizes and serial use of cohorts. It would be unwise to suggest that RCTs are the only method that we can use to validate findings, as other designs have shown clinical utility (e.g. enrichment studies) and need to be evaluated in an integrative and intelligent manner. Prior to any future (clinical) trials the following would be useful to consider: i) the use of prospective stratification and justification for any subsequent subgroup analysis at the design stage; ii) the challenges
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ACCEPTED MANUSCRIPT associated with analytical methods, including the issue of assessment reactivity; iii) techniques to ensure adequate recruitment to the “minor” group(s); and iv) how
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stratification technique(s) could be implemented into clinical practice. Although there are many opportunities, there are also many challenges to the treatment of
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alcohol dependence. Barriers to treatment in this patient group include: low numbers attending services, stigmatisation, uncertainty surrounding the efficacy of all treatments,
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and lack of specialist knowledge. Furthermore, the gap between onset of dependence and treatment needs to be reduced to help optimise treatment success. Current
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identification/screening techniques are inadequate and represent a missed opportunity to
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provide early intervention.
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In summary, pharmacotherapy represents an important treatment modality in this
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population. Development of new therapeutic agents alongside ongoing empirical investigations into stratification of existing drugs should be an important research goal. Such work will hopefully lead to improved clinical outcomes, increased treatment utilisation and
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reduced costs.
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Figure 1. Alcohol metabolism pathway. Alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and catalase oxidise ethanol to acetaldehyde. Acetaldehyde is toxic and along with the byproducts produced during ethanol oxidation induces much of damage associated with alcohol consumption. Acetaldehyde is converted to acetate by aldehyde dehydrogenase (ALDH).
Figure 2. Crosstalk between genes that are involved in alcohol dependence (given in green) and those that modulate the drug response (in blue). The pink lines show relationships which are important in alcohol dependence (continuous lines show direct relationship; broken lines show 45
ACCEPTED MANUSCRIPT indirect relationship). Receptors or transporters: OPRM1: opioid receptor, mu 1; OPRK1: opioid receptor, kappa 1; SLC6A3: solute carrier family 6 (also called DAT – dopamine transporter); DRD2: Dopamine receptor,D2; GABRB2: gammaaminobutyric acid (GABA) A receptor, beta 2; GRIN2B: glutamate receptor, ionotropic, N-methyl D-aspartate 2B; HTR7: 5-
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hydroxytryptamine (serotonin) receptor 7; GRIK1: glutamate receptor, ionotropic, kainate 1; Cytoplasmic proteins: CRH:
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corticotropin releasing hormone; IL4: interleukin 4; BDNF: brain-derived neurotrophic factor; CYP11A1: cytochrome P450,
SC R
family 11, subfamily A, polypeptide 1; CYP19A1: cytochrome P450, family 19, subfamily A, polypeptide 1; TNF: tumor necrosis factor; PLAT: plasminogen activator, tissue; NPPA: natriuretic peptide A; Transcription factors: GATA4: GATA binding protein 4; NFATc2: nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 2; ATM: ATM
AC
CE P
TE
D
MA
NU
serine/threonine kinase; SP1: Sp1 transcription factor; FOS: FBJ murine osteosarcoma viral oncogene homolog.
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Table 1. Common variables used in the stratification of alcohol dependence
T
IP
Age
Comment The majority of research in this field is conducted in males. Alcohol dependence is more prevalent in males but alcohol generally affects females more severely. The majority of alcohol abusers are in their teens or twenty’s, with the highest prevalence of those undertaking treatment for AD being in their 40’s. The majority of sample populations have mean ages in their 40’s.
CR
Variable Gender
The availability of alcohol varies depending on societal, cultural and religious views. The majority of research has been conducted in those of European descent. Non-Caucasian populations are underrepresented in alcohol research, making universal application of results difficult. A subgroup of East Asians experience an adverse reaction to alcohol associated with a mutation in ALDH2 which has been hypothesised to be protective against alcohol misuse.
Family History
Alcohol dependence has a substantial hereditary component, 40-60%. However, a consensus is yet to be reached on the optimal description of positive family in this area of research. This lack of uniformity and the small number of studies negatively impacts on the overall strength of the evidence. In typology research, attempts are made to group individuals depending on the characteristics of their alcohol dependence, with the aim to guide diagnosis, predict prognosis and provide targeted treatments. The typologies discussed within this review are presented in table 3 (for a dedicated review see Leggio, Kenna et al. 2009). Excessive alcohol consumption is a risk factor for ~60 diseases/conditions. Also, those with alcohol use disorders can have underlying mental-health disorders that are caused by or are responsible for their alcohol misuse. Individuals with comorbidities are often excluded from research for reasons relating to safety, inherent complexity and maintaining sample homogeneity. The majority of medications utilised in alcohol dependence are metabolised in liver which is often compromised with excessive alcohol consumption (e.g., alcoholic liver disease). Baclofen has received some interest an alternative treatment for alcohol dependence as it is predominantly excreted by the kidneys. Please see pharmacogenetics sections and table 2.
Genetics
AC
CE P
Co-morbidities
TE D
Typology
MA N
US
Ethnicity
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Table 2. Primary findings from pharmacogenetic studies on the treatment of alcohol dependence that were longer than 10 weeks in duration
Kim et al, 2009
Rubio et al, 2002 Coller et al, 2011 Arias et al, 2014
Oslin et al, 2015 Kiefer et al, 2011
Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Naltrexone 50 mg/day 12 weeks Acamprosate 1998 mg/day 12 weeks
149 European American and African American 32 Asian
OPRM1 (rs1799971) OPRM1 (rs648893) OPRK1 (rs963549) OPRD1 (rs2234918) OPRD1 (rs678849) OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) DBH (rs1611115) CC CT:TT OPRM1 (rs1799971) AA AG:GG GATA4 (rs13273672) AA AG:GG
45 Spanish
100 Australian Caucasian c 107 Caucasian
221 (98.2% White) 147
Relapse to heavy drinking
48 23 115 31
Good clinical outcome (abstinent or moderate drinker with no problems Rate of relapse to heavy drinking
Time to first relapse to heavy drinking
16 16
Relapse
29 16 Time to first relapse to heavy drinking
65 35
Abstinence from heavy drinking 15 17 Relapse to heavy drinking Relapse to heavy drinking
60 87
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Finding
T IP
OPRM1 (rs1799971) AA AG:GG OPRM1 (rs1799971) AA AG:GG
Outcome measure
CR
71 European American 146 European American
N per b genotype
US
Genetic variation
MA N
Gelernter et al, 2007
a
TE D
Anton et al, 2008
N
CE P
Oslin et al, 2003
Medication/dose/ Treatment duration Naltrexone 50-100 mg/day 11-24 weeks Naltrexone Titrated up to 100 mg/day 16 weeks Naltrexone 50 mg/day 13 weeks
AC
Study
OR = 3.52 (CI = 1.03-11.96) 47.9% for AA 26.1% for AG:GG OR = 5.75 (CI = 1.88-17.54) 48.6% for AA 87.1% for AG:GG NS NS NS NS NS HR = 13.65 (CI: 1.68 – 110.20) 59.9 days for AA 73.3 days for AG:GG OR = 1.19 31% for AA 25% for AG:GG NS 11 days 10 days NS for rs1799971 T allele carriers reported greater abstinence from heavy drinking the “CC” genotype
NS NS A allele carriers were less likely to relapse compared with placebo OR = 2.26 (1.36-3.67; P = 0.0013)
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Johnson et al, 2013
Ondansetron 8 µg/kg of body weight/day 11 weeks
140 Caucasian and Hispanic
Kranzler et al, 2011
Sertraline Titrated to 200 mg/day 12 weeks
63 (21 EOA, 42 LOA)
Kranzler et al, 2014
Topiramate Titrated to 200 mg/day 12 weeks
56 European American
T
IP
Drinks per drinking day 7 3
CR
140 Caucasian and Hispanic
Abstinence
Heavy drinking days per week, abstinent days per week
US
Ondansetron 8 µg/kg of body weight/day 11 weeks
166 Finnish
DBH (rs1611115) CC CT:TT OPRM1 (rs1799971) OPRM1 (rs648893) OPRK1 (rs963549) OPRD1 (rs2234918) OPRD1 (rs678849) SLC6A4 L’L’ L’S’:S’S’ SLC6A4 (rs1042173) TT TG:GG HTR3A (rs1150226) AG HTR3A (rs1176713) GG HTR3B (rs17614942) AC
5
MA N
Johnson et al, 2011
c
107 Caucasian
Inactive ALDH2
49 91
SLC6A4 L’L’ (EOA) L’S’:S’S’ (EOA) L’L’ (LOA) L’S’:S’S’ (LOA) GRIK1 (rs2832407) CC CA:AA
Drinks/drinking day Percentage of days abstinent
42 95
TE D
Arias et al, 2008
54 East Asian
CE P
Arias et al, 2014
Disulfiram 200 mg/day 26 weeks Disulfiram 250 mg/day 12 weeks Nalmefene Titrated to max dose of 40 mg/day 28 weeks
AC
Yoshimura et al, 2014
Drinks/drinking day
20 Percentage of days abstinent
6 17
Percentage of heavy drinking days Number of drinking days
7 14 12 30 Heavy drinking days
All 5 patients on disulfiram with inactive ALDH2 remained abstinent. Significant interaction between DBH rs1611115 and disulfiram, C allele homozygotes likely to consume less alcohol on drinking days NS NS NS NS NS Significantly lower drinks/drinking day in LL than S carriers -1.53 (CI: -2.59 to 0.47; effect size = 0.47). Significantly greater days abstinent 9.73% (CI: 0.95 to 18.50%; effect size = 0.29). Those with LL/TT had superior outcomes compared with other genotypes. Significant associations with improved outcomes in rs1150226 (AG) and rs17614942 (AC) genotypes. Significant association for drinks/drinking day in rs1176713 (GG).
Drinking days reduced for L allele homozygous (LOAs) treated with sertraline compared with placebo (d = 0.48). L allele homozygous (EOA) increased for the same measure (d = 0.98
Those with CC had significantly less heavy drinking days compared with placebo. There was a trend to Days abstinent suggest a similar outcome in days abstinent but this didn’t reach significance. Negligible differences were seen in A allele carriers. a Number of participants genotyped in the medication group; b Number of participants not presented for NS results; c Unable to extract the number of participants in each group from the original manuscript; EOA = Early Onset Alcohol Dependent Patients; LOA = Late Onset Alcohol Dependent Patients. 21 35
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Cloninger
Type I Later onset of dependence Men and women affected equally Likely binge drinkers: have periods of abstinence Rapid progression from mild to severe alc abuse High harm avoidance Type I Occasional/social drinking progresses into habitual drinking Increased alc craving and loss of control Alc consumed to counteract withdrawal symptoms “Normal” childhood and interpersonal relationships Positive FH Frequent outpatient treatment, eventually admitted for detoxification Alc consumption has minimal impact on social behaviour
Type B Cont. Poly drug use History of frequent treatment for substance misuse High life stress
US
MA N
TE D
CE P
AC
Lesch
Late-Onset Age of onset >25 years Type B Early onset of dependence Significant number of childhood risk factors Greater severe dependence Positive FH Greater psychopathological dysfunction Type I Cont. Low novelty seekers High award dependence Often accompanied by the development of ALD Respond better to treatment Experience losses of control and often feel guilty about drinking Type II Alc consumed for sedative effect (i.e. ‘self-medicating’) Pattern of consumption changes depending on environment Behavioural changes when intoxicated Decreased activity during leisure time Impaired interpersonal relationships Exhibits self-destructive tendencies when intoxicated Use of sedative drugs No severe somatic disorders No severe withdrawal symptoms
IP
Early-Onset Age of onset ≤25 years Type A Later onset of dependence Fewer childhood risk factors Less severe dependence Fewer alc-related problems Less psychopathological dysfunction
CR
Early vs. Late Onset Alcoholism Babor
T
Table 3. Alcohol misuse typologies and their characteristics that are relevant to the present review
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Type II Early onset of dependence Primarily affects males Strong inheritable influences, often from father Unable to abstain, even though may desire to do so Are often impulsive and take risks Type III Alc Consumption to ‘self-mediate’ psychiatric disorders Alc free periods: patient drinks when psychiatric disorders are active Positive FH for psychiatric disorders Significantly impaired interpersonal relationships Aggressive behaviour whether intoxicated or sober Self-destructive whether intoxicated or sober Mild to moderate somatic symptoms of withdrawal
Type II Cont. Low harm avoidance High novelty seeking Low reward dependence Often manifest antisocial behaviour Often non-responders to treatment Type IV Severe intoxication following low alc consumption Brain damage
