PHARMACOLOGICAL TREATMENT

OPTIONS FOR ALCOHOL USE DISORDER

Alcohol Use Disorder (AUD) and other alcohol-related health problems are a significant public health issue all over the world. The World Health Organization (WHO) reports that each year 3.3 million people lose their lives due to harmful alcohol use, with 5.9% of all deaths being related to alcohol consumption (1). It has been estimated that in 2010, the economic burden of alcohol-related costs was 155.8 billion Euro, of which 60% were connected to alcohol addiction (2).

In AUD, after the end of the withdrawal phase, when having reached a state of abstinence, the main aim is to maintain this abstinence by reducing craving and preventing relapse (3). During treatment, especially all severe cases of AUD need to be assessed from the angle of pharmacologic therapy. Drugs licensed for the treatment of AUD, worldwide as well as in Turkey, are disulfiram, acamprosate, naltrexone, and nalmefene. Long-term release naltrexone has not yet been approved in Turkey. Nalmefene, licensed in Europe and Turkey, has recently (November 2014) been approved for reducing the amount of alcohol consumed in AUD (4-6). In some European countries, baclofen and sodium oxybate have been approved (7,8). In this paper, we assess information obtained from studies regarding drug treatments used in clinical practice today, which are summarized in Table 1. However, when examining study results for pharmacological treatments, we immediately have to remember that all of those treatments need to be used together with psychosocial support; in particular, it should be recommended that patients be placed in a psychosocial support program suitable to them individually for the duration of therapy.

APPROVED PHARMACOTHERAPIES FOR

ALCOHOL USE DISORDER

Acamprosate

Acamprosate is a synthetic glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, approved by the Turkish Health Ministry in 2003 and by the FDA in 2004 (9). Acamprosate blocks the extracellular dopamine increase in the Nucleus accumbens (NAc) (10) and plays a protective role against neurotoxicity during alcohol withdrawal (11).

A number of systematic reviews and meta-analyses agree that acamprosate is effective in the prevention of relapse after detoxification (12-17). Among these studies, the National Institute for Health and Clinical Excellence (NICE) (18) found a relative risk (RR) value of 0.83 (95% confidence interval [CI]=0.77-0.88), while Rösner et al. (12) report an RR of 0.86 (95% CI=0.81-0.91). The number needed to treat was calculated as 9-11 (12,13). The rate of withdrawal from treatment because of side effects was higher in acamprosate users compared to placebo, but the difference was not statistically significant (18).

According to one meta-analysis, acamprosate is an effective drug for all AUD patients irrespective of gender, starting age, family history, presence of anxiety, and intensity of craving and dependence (19). However, there are studies showing genetic and individual characteristics playing a role in the response to acamprosate. For example, it is thought that variations in the N-methyl-D-aspartate (NMDA) mGluR5 receptor affect the response to acamprosate (20). In addition, the intronic single nucleotide polymorphism (SNP) rs13273672, coded by the GATA4 (GATA binding protein 4) gene, is reported to be related with relapse in acamprosate users (21). Furthermore, a study researching SNPs and duration of abstinence reported a correlation for GRIN2B rs2300272, rs2058878 and most strongly rs2058878 (22).

It has been reported that acamprosate is more beneficial in patients experiencing relief craving related to irregularities in the gamma-aminobutyric acid (GABA) and glutamate systems (11,23). A recent study showed that acamprosate is more effective in patients who at the beginning of treatment had a high serum level of glutamate (24). Further, it is seen that acamprosate is more effective in Lesch type I and type II alcohol dependents than in type III and type IV (25). It has been pointed out that acamprosate is beneficial especially in Lesch type I alcohol dependents, while there was no correlation between craving and acamprosate response (26).

Acamprosate is more effective in patients whose therapy goal is total abstinence than in those who aim at reducing their drinking without total abstinence (17,27). Given that drug interaction is very low, it is suitable for patients who are using further drugs for other diseases, and it can be administered to patients under opioid analgesic treatment (28). As it is excreted by the kidneys unchanged, there is no risk of hepatotoxicity, but it should not be used in patients with a high degree of kidney insufficiency (creatinine clearance <30ml/min) (29). The drug may however be used in patients with compensated cirrhosis (30).

Acamprosate is formulated in tablets of 333mg. Due to its low bioavailability, it needs to be administered in high doses (for persons below 60kg 1332mg, above 60kg 1998mg) (9,31). Most commonly observed side effects regard the gastrointestinal system. Less common are stomach ache, rash, itching, paresthesia, changes in libido, confusion, and suicidal ideation (27,37). Therapy can continue for between 3 and 12 months (18,27,33,34). The most appropriate strategy is a joint decision about the duration of therapy by doctor and patient according to the observed side effects, relapse history, and social and familial characteristics.

Naltrexone

Naltrexone is an unspecific opioid receptor antagonist. It particularly blocks the μ-opioid receptors, leading to a reduction of the increase in dopamine occurring after the use of alcohol and thus reducing its rewarding effect (18,35). Blocking the dopaminergic effect of the endorphins secreted after alcohol use, it reduces the stimulating and positively enhancing effect of alcohol. Further, it increases the sedative effect of alcohol and reduces alcohol craving (36).

Naltrexone was approved in 1994 for use in alcohol dependence (28). The evidence for its effectiveness in AUD is of level A (31). Naltrexone reduces the relapse rate in AUD and lengthens the abstinence period. Meta-analyses show that it reduces the relative risk, compared to placebo, by 36%. On average, the number needed to treat is 7, which indicates a moderate effect size (27). Naltrexone has also been shown to reduce craving and frequency of drinking after relapse. It is more effective in reducing intensity and rate of relapse than in extending the period of abstinence (27). One meta-analysis showed that in short-term treatment (12-16 weeks) jointly with psychotherapy, 50 mg naltrexone was clinically highly beneficial in maintaining abstinence, while the safety profile was similar to that of a placebo (37).

A meta-analysis of 19 studies found that complete abstinence was reached more frequently in the naltrexone group, but the difference was not statistically significant (14). However, among the naltrexone users the period until relapse was longer, the number of drinking days, number of drinks consumed per day, total amount of alcohol consumed during the treatment, as well as the gamma-glutamyl transferase (GGT) and aspartate aminotransferase (AST) levels were lower (14).

Naltrexone is more beneficial for patients wanting to prevent relapse to heavy drinking and high alcohol intake rather than for those aiming at abstinence (17,27). Further, it was shown that naltrexone is more beneficial in patients experiencing a high level of craving during therapy (38-41), those with a family history of AUD (41-43), and for heavy drinkers (44). It is also thought that the μ-opioid receptor polymorphism affects the response to naltrexone therapy (45). In carriers of the “G” allel, it has been reported that SNP (rs179919 or A118G) on the μ-opioid receptor correlates with a better response to naltrexone (46).

It is assumed that naltrexone is more beneficial in patients experiencing “reward craving” related with the dopamine and opioid system (23). Naltrexone is more successful in Babor type-A alcohol dependents (less severe, late-onset, no family history, fewer psychiatric comorbidities) compared to type-B (47). It has been reported that patients with depression at the beginning of the therapy and Lesch type III and type IV dependents respond better to naltrexone (26). According to Cloninger’s typology, early-onset type 2 alcohol dependents with more serious alcohol-related problems and comorbid psychopathologies benefit more from naltrexone than type 1 dependents (48).

For patients with comorbid opioid use disorder and AUD, naltrexone is a favorable therapeutic option in order to reduce the craving for either substance. However, for patients continuing opioid use or requiring opioid analgesic treatment, it is not a suitable drug (28). It also may not be used with acute hepatitis, liver insufficiency, or in patients with a history of hypersensitivity to naltrexone (29).

It is recommended to wait until the decline of withdrawal symptoms, 3 to 7 days after the patient had the last drink, to start naltrexone treatment (27). Recommended therapeutic dose is 50mg/day (18). While naltrexone is usually well tolerated, in 10% of the patients emesis, headache, dizziness, malaise, irritability, insomnia, or anxiety can be seen (27). More rarely, chest pain, muscle and joint pain, loss of appetite, constipation, rash, insomnia, increased thirst, depression, or delayed ejaculation can be found (29,49). While hepatotoxicity has been reported in high doses (300mg/day), this effect is rare in the recommended dose of 50mg/day (50). It is recommended to continue the drug for 3-6 months, but the best course of action is to decide about the duration of treatment jointly with the patient (18,34).

Intramuscular Naltrexone

To increase compliance and bioavailability, in 2006 the FDA approved intramuscular (IM) naltrexone, but in Turkey, this form has not yet been licensed. The FDA-licensed IM form contains 380mg and the recommended application rate is once per month (28). An open cohort study showed IM naltrexone to be useful in the first stage treatment for maintaining abstinence (51). In addition, the rate of IM-naltrexone-users continuing the therapy was higher than among patients using oral naltrexone, acamprosate, or disulfiram (52). IM naltrexone did not reduce the risk of heavy drinking; however, it increased the total number of days of abstinence, and the number of patients remaining abstemious for 12 weeks was twice higher (53). The side effect profile of the IM form, apart from reactions to the injection, looked similar to that of the oral form (54).

Combination of Naltrexone and Acamprosate

A meta-analysis of 64 studies concluded that acamprosate is more effective in reaching abstinence and naltrexone in reducing heavy drinking and craving (17). It could be assumed that a combined use of these two drugs with their different target neurotransmitters and modes of action might be clinically more beneficial. A randomized double-blind placebo-controlled study by Kiefer et al. (55) did not find that a combined use of the two drugs produced better results in the prevention of relapse compared to the single use of naltrexone. Therefore, it has been said that naltrexone can be added to the treatment if the desired effects of acamprosate are not seen (33). The combination of the two drugs is safe, the most frequently seen side effects being diarrhea and nausea (33,56).

Even though so far there is no study investigating the safety and efficacy of a combination of acamprosate and nalmefene, given the similarity with naltrexone and the fact that the drug does not affect the liver, it can be assumed that nalmefene can be used as supplement to acamprosate when needed or on a regular basis.

Disulfiram

Disulfiram blocks the enzyme aldehyde dehydrogenase that converts acetaldehyde to acetate in the second step of alcohol metabolism. In case of alcohol intake, acetaldehyde accumulation leads to symptoms like nausea, emesis, dizziness, flushing, headache, diarrhea, shortness of breath, and cardiac arrhythmia. This effect is a deterrent for people who know that they are bound to encounter these negative effects if they consume alcohol. Disulfiram is effective especially when taken under supervision (57,58).

As the side effects of disulfiram when taken with alcohol can be life threatening, most of the relevant studies have been carried out as open label, in which the patients and doctor knew which drug was being used. This fact reduces the reliability of the data (18).

There are studies showing that disulfiram increases the number of days to relapse compared to naltrexone, acamprosate, and topiramate (59-61). It has also been shown that disulfiram used for 12 weeks not only extends the time until first alcohol intake compared to naltrexone and acamprosate, but it also reduces the number of days of heavy drinking (62). In the meta-analysis by NICE (18), it is reported that disulfiram is not different from placebo for relapse to alcohol use, while the study by Brewer et al. (63) reports that disulfiram taken under supervision increased compliance with treatment and reduced drinking in comparison with taking disulfiram without supervision or with the control group not taking disulfiram. Another systematic review reported that disulfiram in the short term was more effective than placebo in maintaining abstinence, increasing duration till relapse and number of days drinking (64).

Because of its lower level of safety, disulfiram was suggested to be considered as a second-stage treatment (31,65) that can be used together with naltrexone or acamprosate (31). It has been reported that disulfiram used daily under supervision together with acamprosate is more effective than acamprosate on its own (66). The combination of naltrexone and disulfiram has been studied in patients with comorbid psychiatric diseases; however, for this drug combination no advantage compared to the single use of naltrexone or disulfiram was found (67-69).

Disulfiram is not a suitable option for patients with impaired judgment, high-level of impulsivity or self-harm, severe cardiac, hepatic, or respiratory problems (27). As one of the metabolites of disulfiram blocks dopamine beta-hydroxylase, which converts dopamine into norepinephrine, it can aggravate symptoms in patients with psychotic disorder (28,70).

Disulfiram is formulated in 500mg tablets, and the recommended daily dose is 250-500mg (27). It is suggested to start disulfiram at least 24 hours after stopping alcohol consumption (18). Cross-reaction with more than 40 drugs, including benzodiazepines, isoniazid, rifampin, metronidazole, warfarin, oral hypoglycemics, phenytoin, theophylline, tricyclic antidepressants, and desipramine need to be considered (29,71). Light side effects are feeling of dizziness, headache, fatigue, acneiform eruptions, impotence, and alterations in taste sensations (29,72). More rarely seen more serious side effects are icterus, hepatitis, peripheral neuropathy, psychosis, confusion, optic neuritis, and blood dyscrasia (27,28). During disulfiram treatment, cardiac and hepatic side effects need to be closely monitored (29). It is recommended to continue the therapy for 3-6 months, but the best way is to decide about the duration of treatment with the patient, depending upon personal characteristics (18,27,34).

Nalmefene

Nalmefene is used to reduce alcohol consumption in adult alcohol addicts with a high “drinking risk level” who do not show physical withdrawal symptoms and do not require urgent withdrawal treatment. Detailed information about nalmefene can be found in the section “Reduction of heavy drinking (harm reduction)” below.

OTHER PHARMACOTHERAPIES

APPROVED IN THE COUNTRIES OF THE

EUROPEAN UNION

Sodium Oxybate

Sodium oxybate, a form of gamma-hydroxybutyric acid (GHB), has been approved in some countries, such as Austria, Italy, and France, for use in alcohol withdrawal and AUD (73). It is thought that sodium oxybate reacts like alcohol, reducing symptoms of craving and withdrawal (74). However, 30-40% of patients do not respond to GHB treatment (75). For this reason, in one study GHB and disulfiram were used in combination, finding that the combination therapy increased the number of days staying in treatment and the number of days of abstinence compared to GHB therapy on its own (76). However, especially in patients with psychiatric comorbidities and other substance use disorders, sodium oxybate craving and sodium oxybate abuse were observed (77). In view of these risks, this therapy cannot be recommended commonly in the first stage of AUD treatment (78), but it is indicated for use under close supervision in patients who are able to comply with the dosage recommendations (79).

Baclofen

Baclofen is a GABA-B receptor agonist approved for the treatment of spasticity (80) with anxiolytic effect (81). In France, Baclofen has a temporary license for reduction of alcohol consumption and reaching abstinence (8).

It seems to be effective in maintaining abstinence, reducing craving (82,83), and reducing amount of alcohol and anxiety in patients who are unable to maintain abstinence (82). In a placebo-controlled double-blind study, alcohol consumption declined in each of three groups: those taking 30mg and 60mg baclofen, respectively, or placebo, but there was a significant difference between the groups (84). A placebo-controlled study by Garbutt et al. (85), while not showing a positive effect of baclofen on craving, abstinence, or amount of alcohol, demonstrated a reduction of anxiety scores. As it is known that baclofen is more effective in populations of severely addicted patients, the fact that Garbutt et al. (85) included patients at a lighter level might be related to the negative results (81). Even if results regarding the effectiveness of baclofen are mixed, it is seen as a safe drug to use in AUD patients, even with cirrhosis (78,83).

PPHARMACOTHERAPIES THAT HAVE

ACHIEVED FAVORABLE RESULTS IN

STUDIES BUT HAVE NOT BEEN APPROVED

Even without approval for use in AUD, some drug therapies are being used in clinical application. With an increase in studies regarding these therapies, available data are growing, and assessments of their effectiveness can be made more explicitly.

Anticonvulsants

It is assumed that topiramate, an AMPA-glutamate antagonist, reduces the rewarding effect of alcohol by blocking dopamine activity in the mesolimbic cortical area (86). A systematic review of seven randomized controlled studies showed that topiramate has the greatest effect on abstinence, observing a reduction in heavy drinking, while no effect on craving was found (87). A double-blind placebo-controlled study showed that topiramate reduced the amount of alcohol consumed by heavy drinkers on drinking days and the craving during the drinking period but was not effective regarding craving outside drinking periods (88). However, there are also studies that have not found topiramate to be effective in AUD (89). Topiramate has no FDA license for AUD, but the National Institute on Alcohol Abuse and Alcoholism (NIAAA) supports its use on the basis of strong evidence (50).

Gabapentin is an anticonvulsant inhibiting excitatory Ca ion channels and stimulating inhibitory GABA-B receptors (90). A systematic review reached the conclusion that gabapentin reduces heavy drinking but is not effective regarding abstinence, craving, and GGT (91). Another 12-week placebo-controlled study not included in the review, however, showed that gabapentin increased the abstinence rate and reduced heavy drinking (92). The same study showed that the positive effect of 1800mg/day gabapentin on craving, insomnia, and dysphoria was better than with 900mg/day, concluding that gabapentin, especially at a daily dose of 1800mg, could be a treatment option (92).

It has been reported that carbamazepine reduces the alcohol amount consumed on drinking days and extends the period to the first drink in abstinent patients (93,94). Studies with valproate also predict a prevention of relapse into heavy drinking and support of abstinence (95,96). It has also been seen that the use of valproate together with lithium in patients with bipolar mood disorder and AUD reduces the amount of alcohol used on drinking days (97). Soyka et al. (31) assessed these studies and proposed a level of evidence of C for carbamazepine and D for valproate. It has been reported that oxcarbamazepine, especially at high doses of around 1500-1800mg/day, is effective in maintaining abstinence (98). It is thought that the anticonvulsant topiramate is more beneficial in patients experiencing compulsive craving, while gabapentin is more useful in persons experiencing relief craving (99).

Varenicline

Varenicline has been licensed by the FDA for treating nicotine use disorder (100). It has been reported to have a potential for reducing the amount of alcohol used by increasing the negative effects of alcohol and reducing the rewarding effects (101) and reducing craving (102). A systematic review showed a moderate effect size of varenicline therapy (103). In 4 studies (100,104-106), a reduction of alcohol use with varenicline was observed, while in another study, a reduction of alcohol use was only reported in a group of smokers (107). In the light of these studies, we may assume that varenicline does not so much inhibit first use of alcohol but rather reduces cumulative alcohol consumption after first use (100,102,104-106).

Ondansetron

Ondansetron is a selective 5-HT3 receptor antagonist used in the treatment of nausea. Studies with ondansetron have shown a reduction in the amount of alcohol used and a longer remission in persons with early-onset AUD (108). In addition, a polymorphism in the starting region of the serotonin carrier gene has been shown to affect the response to ondansetron, and in carriers of the long LL allele, ondansetron reduced the amount of alcohol used (109). Another experimental study reported that ondansetron might reduce alcohol consumption in women with the LL 5-HTTLPR genotype, while it was not effective in women with the SS/SL 5-HTTLPR genotype (110). It has been pointed out that ondansetron is more beneficial in persons experiencing reward craving (99).

Dopamine Receptor Antagonists

It is known that the dopamine D2 receptor antagonist haloperidol reduces alcohol craving, the amount of alcohol used, and impulsivity (111); however, because of side effects, the use of classic antipsychotics in AUD therapy is limited (112).

In a double-blind comparative study, it has been reported that aripiprazole reduces craving (113). It was found to be as effective as naltrexone regarding relapse rate and number of days keeping up abstinence, but naltrexone reduced craving more than aripiprazole (114). Another randomized controlled trial did not find any difference between aripiprazole and placebo regarding number of abstinent days, rate of heavy drinking days, and period until first drinking, but it found the amount of alcohol consumed per drinking day and the severity of alcohol dependence at the end of the study to be reduced more than in the placebo group (115). It has also been shown that a 14-day use of aripiprazole reduced the response to alcohol-related stimuli in the right ventral striatum (116).

The abstinence period was longer in AUD patients who were using quetiapine for insomnia (117). The drug also reduced craving, total amount of alcohol used, and severity of psychiatric symptoms in patients with comorbid mood disorder and schizophrenia (118). In addition, it has been shown to reduce craving in persons with Babor type B alcohol dependence (119). Long-release form of quetiapine, however, has been found to be ineffective in the reduction of craving or prevention of heavy drinking (120).

A randomized controlled study demonstrated that a single dose of olanzapine reduced desire to drink and loss of control after alcohol-related stimuli (121). It was found that the use of 5mg olanzapine for 12 weeks reduced craving, while 2.5mg olanzapine reduced the number of drinking days and increased the control over alcohol drinking (122). In persons who were homozygous or heterozygous with seven or more repeats of the DRD4 repeat allele, olanzapine reduced alcohol consumption and craving, whereas in patients with a shorter allele, no benefit of olanzapine was found (123).

Finally, even if data regarding dopamine receptor antagonists are not entirely consistent, it can be said that these substances can be beneficial especially in AUD patients with comorbid psychiatric conditions (112).

Selective Serotonin Reuptake Inhibitors

Selective Serotonin Reuptake Inhibitors (SSRI) are used frequently in AUD patients to reduce signs of depression and anxiety. While the first studies showed that the SSRI fluoxetine reduced craving and heavy drinking (124), a later placebo-controlled study demonstrated that in patients without depression, fluoxetine had no effect on drinking (125). Another study showed that fluoxetine reduced craving but had no effect on drinking (127). It has been shown that sertraline is beneficial for Babor type B alcohol dependents (125,127). An experimental study found that sertraline reduced alcohol consumption in women with an SS/SL 5-HTTLPR genotype but was not useful in women with an LL 5-HTTLPR genotype (110). A randomized controlled trial found fluvoxamine ineffective regarding alcohol-related therapeutic aims (128).

It has been found that SSRI are more beneficial in persons experiencing obsessive craving (99). However, SSRI are not recommended as first-stage agents in AUD, but in case of additional depression or anxiety disorder, their usefulness has been established (71).

Kudzu

Kudzu is a plant used in Chinese herbal medicine; while its mode of action is not entirely known, it is thought to be operating through the aldehyde dehydrogenase of monoamine oxidase-acetaldehyde pathways (129). It causes a rapid fall in blood alcohol level after alcohol use, greater access to alcohol for the central nervous system, and an increase of alcohol-related reward from the first drink (130). In a double-blind, placebo-controlled 4-week study, kudzu reduced the amount of alcohol used in heavy drinkers (131). There are also studies showing that after 7 days of using kudzu, the amount of alcohol used in a laboratory setting is reduced (132,133).

Other Therapies

CRF antagonists and drugs affecting neuropeptide Y are still under investigation in AUD therapy (78). In particular, it has been shown that CRF-1 antagonists may have positive effects in anxious alcoholics (134). The steroid secretion inhibitor finasteride and the progesterone antagonist mifepristone reduced alcohol consumption in animal models (135). Additionally, in humans, the use of finasteride reduced alcohol consumption (136), and mifepristone reduced the amount of alcohol used in the short term (137).

The alpha-1 adrenergic antagonist prazosin has been reported to reduce the quantity of alcohol used after exposure to stress and to decrease anxiety (138) and, according to a different study, craving (139). It is believed that prazosin is effective especially in the presence of post-traumatic stress disorder comorbidity (140,141).

Metadoxine (pyridoxine-L-2-pyrrolidone-5-carboxylate) accelerates the urinary excretion of ethanol and acetaldehyde (142) and can lead to a reduction of certain biological indicators of alcohol-related liver damage (143). It has been shown that metadoxine users remain longer in therapy and abstinence periods are longer (144).

In animal models, CB1 receptor antagonists reduced the rewarding effect of alcohol and the amount consumed (145). However, studies with humans usually produced negative results (146,147). Considering the hyperglutamatergic state seen in AUD, it was thought that the NMDA receptor antagonist memantine could be useful (50); however, in comparison with placebo, memantine showed no advantage (148-150). Based on studies showing that basal ghrelin levels are correlated with alcohol craving (151), research about the uses of ghrelin antagonists in AUD therapy is still ongoing (50).

REDUCTION OF HEAVY DRINKING

(HARM REDUCTION)

The logic of a strategy of harm reduction is based on the expectation that even a small reduction in the quantity of alcohol used will reduce the disease burden (152) and with the patient’s self-selected treatment goal the treatment outcome will be better (153). It is reported that 78.1% of persons abusing alcohol or being dependent to alcohol are not seeking any kind of therapy (154,155). One of the reasons for avoiding therapy is that some people may want to reduce the amount of alcohol used but are not inclined towards total abstinence (156). To choose harm reduction as a treatment goal can be a important step that may lead to an internalization of consuming less alcohol, possibly leading towards total abstinence (157).

One of the aims of a harm reduction strategy is to reduce heavy drinking. The WHO reports a global rate of 16% for heavy drinking, whereas in Turkey the rate is 0.2% (158). However, the scales used for the concept of heavy drinking differ between various studies. The National Institute on Alcohol Abuse and Alcoholism, NIAAA defines as heavy drinking if women consume more than 4 standard units in a single session and men more than 5 standard units (159). The WHO proposes a measure of more than 60gr (7.5 standard units) ethanol intake for men and more than 40gr (5 standard units) for women to be considered as heavy drinking (160). The Centers for Disease Control and Prevention define the weekly consumption of over 14 standard units by men and over 7 standard units by women as heavy drinking (161), while the Substance Abuse and Mental Health Services (SAMSHA) define as heavy drinking if someone in the previous 30 days consumed 5 or more units in one session on 5 or more days (28).

Nalmefene

Nalmefene was the first drug licensed for reduction of alcohol consumption (162). In the European Union, it is approved for AUD, while in the United States of America approval has not yet been granted (50). In Turkey, it was licensed for use in AUD in November 2014.

Nalmefene is an opioid receptor antagonist like naltrexone. In contrast to naltrexone, it has a partially agonistic characteristic at the kappa-opioid receptor, the dose-dependent hepatotoxicity is lower than that of naltrexone (50), and the bioavailability is higher (163).

Two double-blind placebo-controlled studies with nalmefene have shown that the drug reduces heavy drinking and prevents relapse to heavy drinking (164,165). Another double-blind placebo-controlled study reported that nalmefene is effective and safe for reducing heavy drinking and in addition leads to a reduction of liver enzymes (166). In one study, administration of nalmefene alongside motivational therapy was not found to be superior to placebo (167). Reasons for this result may be that the participants during the study were in an abstinent period, 3 different dosage patterns were applied (5mg, 20mg, and 40mg); the number of participants in each group was low and the monitoring period was short, and because of a rapid dose titration, there may have been an increase in side effects (167).

In three randomized controlled trials carried out recently (ESENSE 1, ESENSE 2, SENSE), the patients were advised to use nalmefene “as needed”, when they felt at risk, and this treatment strategy was applied jointly with the “BRENDA” psychosocial support program. The result of these studies indicated that nalmefene reduced the number of days with heavy drinking as well as the total amount of alcohol consumed, and it also helped improve liver enzyme levels (168-170). In a post-hoc analysis of two of these studies (168,169), it was seen that nalmefene used in the 6th month reduced the amount of alcohol and the number of drinking days (171), and the effect was greater in the group of patients whose alcohol intake had not yet been reduced at the beginning of the treatment (171). Further, it has been reported that nalmefene reduces craving after the first alcohol intake in alcohol dependents who are not seeking treatment (35).

Nalmefene is formulated in 18mg tablets. In all studies, it was found to be safe and well tolerated (164,166,168,169,171,172). There is no difference between regular and intermittent use of nalmefene regarding toleration and safety (173). Most commonly found side effects are nausea, fatigue, headache, insomnia, and a feeling of hangover (167,168), but most of the side effects occur at the beginning of treatment and are temporary (173). No recommendation for the required duration of the nalmefene treatment could be found. Given that at the end of the 1-year SENSE study (170), nalmefene was shown to reduce alcohol amount and number of heavy drinking days we may assume that nalmefene is effective for at least 1 year.

In the light of these studies, it can be assumed that nalmefene is beneficial for reducing the disease load caused by AUD and to close the therapy gap. It seems that nalmefene, in concert with continuous psychosocial support, is an effective treatment strategy for alcohol dependents and high-risk alcohol users who have no physical withdrawal symptoms and do not require urgent withdrawal treatment for the reduction of alcohol use (174). It has also been pointed out that the combination of nalmefene and psychosocial support offers positive outcomes in a cost-benefit analysis as an advantageous and appropriate treatment from the perspective of public health (175).

The only pharmacotherapy approved for the reduction of alcohol use is nalmefene. Thus, it is the drug to be used for the treatment goal of reducing heavy drinking. Considering the importance of harm reduction strategy, role of other drugs, some with approval for AUD and some without, in heavy drinking have been studied. For those drug therapies, below we are assessing data regarding their effectiveness in reducing heavy drinking. However, in order to be able to assess the effectiveness of those therapies in harm reduction strategy, more studies are required.

Naltrexone

Naltrexone is more effective in reducing heavy drinking and reaching controlled drinking than in maintaining abstinence (33). In one meta-analysis, with naltrexone 38% less relapse into heavy drinking was reported (14). Based on 20 randomized controlled studies, it was reported that naltrexone reduces the risk of heavy drinking (RR=0.83, 95% CI=0.76-0.90), number of days drinking (mean difference [MD]=3.89, 95% CI=-5.75–-2.04), and amount of alcohol used (MD=-10.83; 95% CI=-19.69–-1.97) (176). The effect of naltrexone in reducing heavy drinking in AUD is at a moderate level (0.15-0.20) (85). It has also been found that naltrexone has a significant positive effect regarding relapse into heavy drinking, and it also reduced the number of units consumed on days drinking and the number of days with heavy drinking (18). It was also found to be effective in patients using the drug “as needed” when experiencing intensive craving, extending a reduced alcohol intake (177-179).

With extended release naltrexone, the number of days with heavy drinking dropped over 6 months (4). Used together with low-intensity psychotherapy, 380mg IM naltrexone achieved a 25% reduction of heavy drinking compared to placebo, whereas at a dose of 190mg no significant difference was reported (54).

Acamprosate

Acamprosate, which is basically effective in maintaining abstinence, has been found by some meta-analyses to reduce patients’ heavy drinking (18,180,181). In a recent meta-analysis based on 122 randomized controlled studies and one cohort study, interestingly no difference was found between acamprosate and naltrexone in preventing heavy drinking (182).

Other Therapies

It has been said that baclofen, by reducing the positive reward effect, makes people use alcohol in lower doses (183). One small study (82) also shows that baclofen can effectively lead to abstinence and, in those where it does not, reduce the amount of alcohol used. Anticonvulsants also reduce heavy drinking and the number of days with heavy drinking (89). In one placebo-controlled study (184) and in meta-analyses, it has been seen that topiramate reduces heavy drinking (87-182). It has also been reported that being homozygous for the rs2832407 C allele coding for the GluK1 subunit of the glutamate kainate receptor leads to a better response to topiramate in heavy drinkers (185). Gabapentin increases the abstinence rate and reduces heavy drinking (92). A study comparing a combination of gabapentin and naltrexone with naltrexone only found that the combination of two drugs, compared to naltrexone only and placebo, extended the period until heavy drinking and reduced the number of days with heavy drinking and the amount of alcohol used on days with drinking; in addition, gabapentin is reported to have a positive effect on sleep (186). A small study with aripiprazole showed a significant reduction in the number of days with heavy drinking compared to placebo (116).

Considering the chronic course and the disease load caused by AUD, its therapy has a great significance. Drug treatments aimed at preventing relapses are successful in some patients but not in others. Therefore, on the one hand research into new therapies continues, while on the other hand the great issue is personalization of treatment, to understand which drug is most effective in what type of patient. As the researches in this area increase, more useful evidence based medicines can be introduced to patients.

REFERENCES

1.WHO, World Health Organisation. Global Status Report on Alcohol and Health 2014. http://www.who.int/substance_abuse/publications/global_alcohol_report/msb_gsr_2014_1.pdf?ua=1 Accessed: 23.11.15.

2.Rehm J, Shield KD. Alcohol consumption, alcohol dependence and attributable burden of disease in Europe. Centre for Addiction and Mental Health. 2012.

3.Crowly P. Long-term drug treatment of patients with alcohol dependence. Australian Prescriber 2015; 38:41-43.

4.Mann K. Pharmacotherapy of alcohol dependence: a review of the clinical data. CNS Drugs 2004; 18:485-504. [CrossRef]

5.Niciu MJ, Arias AJ. Targeted opioid receptor antagonists in the treatment of alcohol use disorders. CNS Drugs 2013; 27:777-787. [CrossRef]

6.Evren C. Nalmefene for Reduced-Risk Drinking: it is not Only Fancy Term For Harm Reduction. Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2014; 27:275-280.

7.Mirijello A, Caputo F, Vassallo G, Rolland B, Tarli C, Gasbarrini A, Addolorato G. GABAB Agonists for the Treatment of Alcohol Use Disorder. Curr Pharm Des 2015; 21: 3367-72. [CrossRef]

8.Reynaud M. Baclofen SAGA: From myths to evidence. ECNP Berlin, 21 October 2014. http://www.ecnp.eu/presentationpdfs/7/S_23_04.pdf

9.Evren C. Alcohol craving, glutamate and acamprosate. Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2012; 25:189-197.

10.Cano-Cebrian MJ, Zornoza-Sabina T, Guerri C, Polache A, Granero L. Acamprosate blocks the increase of dopamine extracellular levels in nucleus accumbens evoked by chemical stimulation of the ventral hippocampus. Naunyn Schmiedebergs Arch Pharmacol 2003; 368:324-327.[CrossRef]

11.Mann K, Kiefer F, Spanagel R, Littleton J. Acamprosate: recent findings and future research directions. Alcohol Clin Exp Res 2008; 32:1105-1110. [CrossRef]

12.Rösner S, Hackl-Herrwerth A, Leucht S, Lehert P, Vecchi S, Soyka M. Acamprosate for alcohol dependence. Cochrane Database Syst Rev 2010; 9:CD004332. [CrossRef]

13.Slattery J, Chick J, Cochrane M, Craig J, Godfrey C, Kohli H. Prevention of relapse in alcohol dependence. Health Technology Assessment Report 3. Glasgow: Health Technology Board for Scotland. 2003.

14.Bouza C, Angeles M, Mu-oz A, Amate JM. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 2004; 99:811-828. [CrossRef]

15.Kranzler HR, Van Kirk J. Efficacy of naltrexone and acamprosate for alcoholism treatment: a meta-analysis. Alcohol Clin Exp Res 2001; 25:1335-1341. [CrossRef]

16.Mann K, Lehert P, Morgan MY. The efficacy of acamprosate in the maintenance of abstinence in alcohol-dependent individuals: results of a meta-analysis. Alcohol Clin Exp Res 2004; 28: 51-63. [CrossRef]

17.Maisel NC, Blodgett JC, Wilbourne PL, Humphreys K, Finney JW. Meta-analysis of naltrexone and acamprosate for treating alcohol use disorders: when are these medications most helpful? Addiction 2013; 108:275-293. [CrossRef]

18.NICE, National Institute for Health and Clinical Excellence. Alcohol dependence and harmful alcohol use. NICE clinical guideline 115. London: National Institute for Health and Clinical Excellence. 2011

19.Verheul R, Lehert P, Geerlings PJ, Koeter MW, van den Brink W. Predictors of acamprosate efficacy: results from a pooled analysis of seven European trials including 1485 alcohol-dependent patients. Psychopharmacology 2005; 178:167-173. [CrossRef]

20.Blednov YA, Harris RA. Metabotropic glutamate receptor 5 (mGluR5) regulation of ethanol sedation, dependence and consumption: relationship to acamprosate actions. Int J Neuropsychopharmacol. 2008; 11:775-793. [CrossRef]

21.Kiefer F, Witt SH, Frank J, Richter A, Treutlein J, Lemenager T, Nöthen MM, Cichon S, Batra A, Berner M, Wodarz N, Zimmermann US, Spanagel R, Wiedemann K, Smolka MN, Heinz A, Rietschel M, Mann K. Involvement of the atrial natriuretic peptide transcription factor GATA4 in alcohol dependence, relapse risk and treatment response to acamprosate. Pharmacogenomics J 2011; 11:368-374. [CrossRef]

22.Karpyak VM, Biernacka JM, Geske JR, Jenkins GD, Cunningham JM, Rüegg J, Kononenko O, Leontovich AA, Abulseoud OA, Hall-Flavin DK, Loukianova LL, Schneekloth TD, Skime MK, Frank J, Nöthen MM, Rietschel M, Kiefer F, Mann KF, Weinshilboum RM, Frye MA, Choi DS. Genetic markers associated with abstinence length in alcohol-dependent subjects treated with acamprosate. Transl Psychiatry 2014; 4:e462. [CrossRef]

23.Verheul R, van den Brink W, Geerlings P. A three-pathway psychobiological model of craving for alcohol. Alcohol Alcohol 1999; 34:197-222. [CrossRef]

24.Nam HW, Karpyak VM, Hinton DJ, Geske JR, Ho AM, Prieto ML, Biernacka JM, Frye MA, Weinshilboum RM, Choi DS. Elevated baseline serum glutamate as a pharmacometabolomic biomarker for acamprosate treatment outcome in alcohol-dependent subjects. Transl Psychiatry 2015; 5:e621. [CrossRef]

25.Lesch OM, Walter H. Subtypes of alcoholism and their role in therapy. Alcohol Alcohol Suppl 1996; 31:63-67. [CrossRef]

26.Kiefer F, Helwig H, Tarnaske T, Otte C, Jahn H, Wiedemann K. Pharmacological relapse prevention of alcoholism: clinical predictors of outcome. Eur Addict Res 2005; 11:83-91. [CrossRef]

27.AGDHA, Australian Government Department of Health and Ageing. Guidelines for the treatment of alcohol problems. http://www.drugsandalcohol.ie/20201/1/Gudelines_for_treatment_of_alcohol_problems.pdf. Accessed: September 3, 2015.

28.SAMSHA, Substance Abuse and Mental Health Services Administration and National Institute on Alcohol Abuse and Alcoholism. Medication for the Treatment of Alcohol Use Disorder: A Brief Guide. HHS Publication No. (SMA) 15-4907. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2015.

29. SAMSHA, Substance Abuse and Mental Health Service Administration. Incorporating Alcohol Pharmacotherapies Into Medical Practice. Treatment Improvement Protocol 49. HHS Publication No. (SMA) 12-4389. Rockville, MD: Substance Abuse and Mental Health Services Administration; 2009.

30.Borro P, Leone S, Testino G. Liver disease and hepatocellular carcinoma in alcoholics: the role of anticraving therapy. Curr Drug Targets 2015 (in press).

31.Soyka M, Kranzler HR, Berglund M, Gorelick D, Hesselbrock V, Johnson BA, Möller HJ; WFSBP Task Force on Treatment Guidelines for Substance Use Disorders. World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for biological treatment of substance use and related disorders, Part 1: Alcoholism. World J Biol Psychiatry 2008; 9:6-23. [CrossRef]

32.Witkiewitz K, Saville K, Hamreus K. Acamprosate for treatment of alcohol dependence: mechanisms, efficacy, and clinical utility. Ther Clin Risk Manag 2012; 8:45-53. [CrossRef]

33.Multidisciplinary Guideline Development GGZ [Dutch Mental Health Association]. Multidisciplinary Guideline, Alcohol Use Disorders. Trimbos Institute. 2009.

34.Lingford-Hughes AR, Welch S, Peters L, Nutt DJ. With Expert Reviewersgroup. BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP J Psychopharmacology 2012; 26: 899-952. [CrossRef]

35.Drobes DJ, Anton RF, Thomas SE, Voronin K. Effects of naltrexone and nalmefene on subjective response to alcohol among non-treatment-seeking alcoholics and social drinkers. Alcohol Clin Exp Res 2004; 28:1362-1370. [CrossRef]

36.Johnson BA. Update on neuropharmacological treatments for alcoholism: scientific basis and clinical findings. Biochem Pharmacol 2008; 75:34-56. [CrossRef]

37.Jarosz J, Miernik K, Wąchal M, Walczak J, Krumpl G. Naltrexone (50mg) plus psychotherapy in alcohol-dependent patients: a meta-analysis of randomized controlled trials. Am J Drug Alcohol Abuse. 2013;39:144-160. [CrossRef]

38.Jaffe AJ, Rounsaville B, Chang G, Schottenfeld RS, Meyer RE, O’Malley SS. Naltrexone, relapse prevention, and supportive therapy with alcoholics: an analysis of patient treatment matching. J Consult Clin Psychol 1996; 64:1044-1053. [CrossRef]

39.O’Malley SS, Jaffe AJ, Chang G, Schottenfeld RS, Meyer RE, Rounsaville B. Naltrexone and coping skills therapy for alcohol dependence: a controlled study. Arch Gen Psychiatry 1992; 49:881-887. [CrossRef]

40.Volpicelli JR, Clay KL, Watson NT, O’Brien CP. Naltrexone in the treatment of alcoholism: predicting response to naltrexone. J Clin Psychiatry 1995; 56(Suppl.7):39-44.

41.Monterosso JR, Flannery BA, Pettinati HM, Oslin DW, Rukstalis M, O’Brien CP, Volpicelli JR. Predicting treatment response to naltrexone: the influence of craving and family history. Am J Addict 2001; 10:258-268. [CrossRef]

42.Rubio G, Ponce G, Rodriguez-Jiménez R, Jiménez-Arriero MA, Hoenicka J, Palomo T. Clinical predictors of response to naltrexone in alcoholic patients: who benefits most from treatment with naltrexone? Alcohol Alcohol 2005; 40:227-233. [CrossRef]

43.Krishnan-Sarin S, Krystal JH, Shi J, Pittman B, O’Malley SS. Family history of alcoholism influences naltrexone-induced reduction in alcohol drinking. Biol Psychiatry 2007; 62:694-697. [CrossRef]

44.Davidson D, Wirtz PW, Gulliver SB, Longabaugh R. Naltrexone’s suppressant effects on drinking are limited to the first 3 months of treatment. Psychopharmacology (Berl) 2007; 194:1-10. [CrossRef]

45.Anton RF, Oroszi G, O’Malley S, Couper D, Swift R, Pettinati H, Goldman D. An evaluation of mμ-opioid receptor (OPRM1) as a predictor of naltrexone response in the treatment of alcohol dependence: results from the Combined Pharmacotherapies and Behavioral Interventions for Alcohol Dependence (COMBINE) study. Arch Gen Psychiatry 2008; 65:135-144. [CrossRef]

46.Berrettini W. Opioid pharmacogenetics of alcohol addiction. Cold Spring Harb Perspect Med 2013; 3. [CrossRef]

47.Bogenschutz MP, Scott Tonigan J, Pettinati HM. Effects of alcoholism typology on response to naltrexone in the COMBINE study. Alcohol Clin Exp Res 2009; 33:10-18. [CrossRef]

48.Kiefer F, Jiménez-Arriero MA, Klein O, Diehl A, Rubio G. Cloninger’s typology and treatment outcome in alcohol-dependent subjects during pharmacotherapy with naltrexone. Addict Biol 2008; 13:124-129. [CrossRef]

49.Fishman MJ, Mee-Lee D, Shulman GD, Kolodner G, Wilford BB, eds. ASAM Patient Placement Criteria: Supplement on Pharmacotherapies for Alcohol Use Disorders. Philadelphia, PA: Lippincott, Williams & Wilkins; 2010.

50.Swift RM, Aston ER. Pharmacotherapy for alcohol use disorder: current and emerging therapies. Harv Rev Psychiatry 2015; 23:122-133.[CrossRef]

51.Lee JD, Grossman E, Huben L, Manseau M, McNeely J, Rotrosen J, Stevens D, Gourevitch MN. Extended-release naltrexone plus medical management alcohol treatment in primary care: findings at 15 months. J Subst Abuse Treat 2012; 43:458-462. [CrossRef]

52.Bryson WC, McConnell J, Korthuis PT, McCarty D. Extended-release naltrexone for alcohol dependence: persistence and healthcare costs and utilization. Am J Manag Care 2011; 17(Suppl.8):222-234.

53.Kranzler HR, Wesson DR, Billot L. Naltrexone depot for treatment of alcohol dependence: a multicenter, randomized, placebo-controlled clinical trial. Alcohol Clin Exp Res 2004; 28:1051-9. [CrossRef]

54.Garbutt JC, Kranzler HR, O’Malley SS, Gastfriend DR, Pettinati HM, Silverman BL, Loewy JW, Ehrich EW, Vivitrex Study Group. Efficacy and tolerability of long-acting injectable naltrexone for alcohol dependence: a randomized controlled trial. JAMA 2005; 293:1617-1625. [CrossRef]

55.Kiefer F, Jahn H, Tarnaske T, Helwig H, Briken P, Holzbach R, Kämpf P, Stracke R, Baehr M, Naber D, Wiedemann K. Comparing and combining naltrexon and acamprosate in relapse prevention of alcoholism: a double-blind, placebo-controlled study. Arch Gen Psychiatry 2003; 60:92-99. [CrossRef]

56.Kiefer F, Wiedeman K. Combined therapy: what does acamprosate and naltrexon combination tell us? Alcohol Alcohol 2004; 39:542-547.[CrossRef]

57.Krampe H, Ehrenreich H. Supervised disulfiram as adjunct to psychotherapy in alcoholism treatment. Curr Pharm Des 2010; 16:2076-2090.[CrossRef]

58.Caputo F, Vignoli T, Grignaschi A, Cibin M, Addolorato G, Bernardi M. Pharmacological management of alcohol dependence: from mono-therapy to pharmacogenetics and beyond. Eur Neuropsychopharmacol 2014; 24:181-191. [CrossRef]

59.De Sousa A, De Sousa A. A one-year pragmatic trial of naltrexone vs disulfiram in the treatment of alcohol dependence. Alcohol Alcohol 2004; 39:528-531. [CrossRef]

60.De Sousa A, De Sousa A. An open randomized study comparing disülfiram and acamprosate in the treatment of alcohol dependence. Alcohol Alcohol 2005; 40:545-548. [CrossRef]

61.De Sousa AA, De Sousa J, Kapoor H. An open randomized trial comparing disulfiram and topiramate in the treatment of alcohol dependence. J Subst Abuse Treat 2008; 34:460-463. [CrossRef]

62.Laaksonen E, Koski-Jännes A, Salaspuro M, Ahtinen H, Alho H. A randomized, multicentre, open-label, comparative trial of disulfiram, naltrexone and acamprosate in the treatment of alcohol dependence. Alcohol Alcohol 2008; 43:53-61. [CrossRef]

63.Brewer C, Meyers RJ, Johnsen J. Does disulfiram help to prevent relapse in alcohol abuse? CNS Drugs 2000; 14:329-341. [CrossRef]

64.Jørgensen CH, Pedersen B, Tønnesen H. The efficacy of disulfiram for the treatment of alcohol use disorder. Alcohol Clin Exp Res 2011; 35:1749-1758. [CrossRef]

65.European Federation of addiction Societies (EUFAS). Good Practise Recommendation. Alcohol misuse: screening, diagnosis and treatment According to the “Clinical practice recommendations” method, 2015.

66.Besson J, Aeby F, Kasas A, Lehert P, Potgieter A. Combined efficacy of acamprosate and disulfiram in the treatment of alcoholism: a controlled study. Alcohol Clin Exp Res 1998; 22:573-579. [CrossRef]

67.Petrakis IL, Poling J, Levinson C, Nich C, Carroll K, Rounsaville B; VA New England VISN I MIRECC Study Group. Naltrexone and disulfiram in patients with alcohol dependence and comorbid psychiatric disorders. Biol Psychiatry 2005; 57:1128-1137. [CrossRef]

68.Petrakis IL, Nich C, Ralevski E. Psychotic spectrum disorders and alcohol abuse: a review of pharmacotherapeutic strategies and a report on the effectiveness of naltrexone and disulfiram. Schizophr Bull 2006; 32:644-654. [CrossRef]

69.Petrakis IL, Poling J, Levinson C, Nich C, Carroll K, Ralevski E, Rounsaville B. Naltrexone and disulfiram in patients with alcohol dependence and comorbid post-traumatic stress disorder. Biol Psychiatry 2006; 60:777-783. [CrossRef]

70.Chick J. Safety issues concerning the use of disulfiram in treating alcohol dependence. Drug Saf 1999; 20:427-435. [CrossRef]

71.National Board of Health, Danish Center for Evaluation and Health Technology Assessment. Treatment of alcohol dependence – a Health Technology Assessment Copenhagen: National Board of Health, Danish Center for Evaluation and Health Technology Assessment, 2006; 8(2).

72.Antabuse (disulfiram) prescription drug label. U.S. National Library of Medicine Web site. http://dailymed.nlm.nih.gov/dailymed/lookup.cfm?setid=f0ca0e1f-9641-48d5-9367-e5d1069e8680. Published August 2014. Accessed: September 2, 2015.

73.Keating GM. Sodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence. Clin Drug Investig 2014; 34:63-80. [CrossRef]

74.Addolorato G, Castelli E, Stefanini GF, Casella G, Caputo F, Marsigli L, Bernardi M, Gasbarrini G. An open multicentric study evaluating 4-hydroxybutyric acid sodium salt in the medium-term treatment of 179 alcohol dependent subjects. Alcohol Alcohol 1996; 31:341-345.[CrossRef]

75.Addolorato G, Cibin M, Caputo F, Capristo E, Gessa GL, Stefanini GF, Gasbarrini G. Gamma-hydroxybutyric acid in the treatment of alcoholism: dosage fractioning utility in non-responder alcoholic patients. Drug Alcohol Depend 1998; 53:7-10. [CrossRef]

76.Maremmani AG, Pani PP, Rovai L, Pacini M, Dell’Osso L, Maremmani I. Long-term γ-hydroxybutyric acid (GHB) and disulfiram combination therapy in GHB treatment-resistant chronic alcoholics. Int J Environ Res Public Health 2011; 8:2816-2827. [CrossRef]

77.Skala K, Caputo F, Mirijello A, Vassallo G, Antonelli M, Ferrulli A, Walter H, Lesch O, Addolorato G. Sodium oxybate in the treatment of alcohol dependence: from the alcohol withdrawal syndrome to the alcohol relapse prevention. Expert Opin Pharmacother 2014; 15:245-257.[CrossRef]

78.Addolorato G, Caputo F, Capristo E, Stefanini GF, Gasbarrini G. Gamma-hydroxybutyric acid efficacy, potential abuse, and dependence in the treatment of alcohol addiction. Alcohol 2000; 20:217-222. [CrossRef]

79.Soyka M, Lieb M. Recent developments in pharmacotherapy of alcoholism. Pharmacopsychiatry 2015; 48:123-135. [CrossRef]

80.Brennan JL, Leung JG, Gagliardi JP, Rivelli SK, Muzyk AJ. Clinical effectiveness of baclofen for the treatment of alcohol dependence: a review. Clin Pharmacol 2013; 5:99-107.

81.Addolorato G, Leggio L. Safety and efficacy of baclofen in the treatment of alcohol-dependent patients. Curr Pharm Des 2010; 16:2113-2117. [CrossRef]

82.Addolorato G, Caputo F, Capristo E, Domenicali M, Bernardi M, Janiri L, Agabio R, Colombo G, Gessa GL, Gasbarrini G. Baclofen efficacy in reducing alcohol craving and intake: a preliminary double-blind randomized controlled study. Alcohol Alcohol 2002; 37:504-508.[CrossRef]

83.Addolorato G, Leggio L, Ferrulli A, Cardone S, Vonghia L, Mirijello A, Abenavoli L, D’Angelo C, Caputo F, Zambon A, Haber PS, Gasbarrini G. Effectiveness and safety of baclofen for maintenance of alcohol abstinence in alcohol-dependent patients with liver cirrhosis: randomised, double-blind controlled study. Lancet 2007; 370:1915-1922. [CrossRef]

84.Morley KC, Baillie A, Leung S, Addolorato G, Leggio L, Haber PS. Baclofen for the treatment of alcohol dependence and possible role of comorbid anxiety. Alcohol Alcohol 2014; 49:654-660.

85.Garbutt JC, Kampov-Polevoy AB, Gallop R, Kalka-Juhl L, Flannery BA. Efficacy and safety of baclofen for alcohol dependence: a randomized, double-blind, placebo- controlled trial. Alcohol Clin Exp Res 2010; 34:1849-1857. [CrossRef]

86.Johnson BA, Ait-Daoud N, Akhtar FZ, Ma JZ. Oral topiramate reduces the consequences of drinking and improves the quality of life of alcohol-dependent individuals: a randomized controlled trial. Arch Gen Psychiatry 2004; 61:905-912. [CrossRef]

87.Blodgett JC, Del Re AC, Maisel NC, Finney JW. A meta-analysis of topiramate’s effects for individuals with alcohol use disorders. Alcohol Clin Exp Res 2014; 38:1481-1488. [CrossRef]

88.Miranda R Jr, MacKillop J, Treloar H, Blanchard A, Tidey JW, Swift RM, Chun T, Rohsenow DJ, Monti PM. Biobehavioral mechanisms of topiramate’s effects on alcohol use: an investigation pairing laboratory and ecological momentary assessments. Addict Biol 2014. [CrossRef]

89.Likhitsathian S, Uttawichai K, Booncharoen H, Wittayanookulluk A, Angkurawaranon C, Srisurapanont M. Topiramate treatment for alcoholic outpatients recently receiving residential treatment programs: a 12-week, randomized, placebo-controlled trial. Drug Alcohol Depend 2013; 133:440-446. [CrossRef]

90.Myrick H, Malcolm R, Randall PK, Boyle E, Anton RF, Becker HC, Randall CL. A double-blind trial of gabapentin versus lorazepam in the treatment of alcohol withdrawal. Alcohol Clin Exp Res 2009; 33:1582-1588. [CrossRef]

91.Pani PP, Trogu E, Pacini M, Maremmani I. Anticonvulsants for alcohol dependence. Cochrane Database Syst Rev 2014; 2:CD008544.[CrossRef]

92.Mason BJ, Quello S, Goodell V, Shadan F, Kyle M, Begovic A. Gabapentin treatment for alcohol dependence: a randomized clinical trial. JAMA Intern Med 2014; 174:70-77. [CrossRef]

93.Mueller TI, Stout RL, Rudden S, Brown RA, Gordon A, Solomon DA, Recupero PR. A double-blind, placebo-controlled pilot study of carbamazepine for the treatment of alcohol dependence. Alcohol Clin Exp Res 1997; 21:86-92. [CrossRef]

94.Malcolm R, Myrick H, Roberts J, Wang W, Anton RF, Ballenger JC. The effects of carbamazepine and lorazepam on single versus multiple previous alcohol withdrawals in an outpatient randomized trial. J Gen Intern Med 2002; 17:349-355. [CrossRef]

95.Brady KT, Myrick H, Henderson S, Coffey SF. The use of divalproex in alcohol relapse prevention: a pilot study. Drug Alcohol Depend 2002; 67:323-330. [CrossRef]

96.Longo LP, Campbell T, Hubatch S. Divalproex sodium (Depakote) for alcohol withdrawal and relapse prevention. J Addict Dis 2002; 21:55-64. [CrossRef]

97.Salloum IM, Cornelius JR, Daley DC, Kirisci L, Himmelhoch JM, Thase ME. Efficacy of valproate maintenance in patients with bipolar disorder and alcoholism: a double-blind placebo-controlled study. Arch Gen Psychiatry 2005; 62:37-45. [CrossRef]

98.Martinotti G, Di Nicola M, Romanelli R, Andreoli S, Pozzi G, Moroni N, Janiri L. High and low dosage oxcarbazepine versus naltrexone for the prevention of relapse in alcohol-dependent patients. Hum Psychopharmacol 2007; 22:149-156. [CrossRef]

99.Martinotti G, Di Nicola M, Tedeschi D, Callea A, Di Giannantonio M, Janiri L; Craving Study Group. Craving Typology Questionnaire (CTQ): a scale for alcohol craving in normal controls and alcoholics. Compr Psychiatry. 2013; 54:925-932. [CrossRef]

100.Fucito LM, Toll BA, Wu R, Romano DM, Tek E, O’Malley SS. A preliminary investigation of varenicline for heavy drinking smokers. Psychopharmacology (Berl) 2011; 215:655-663. [CrossRef]

101.Childs E, Roche DJ, King AC, de Wit H. Varenicline potentiates alcohol-induced negative subjective responses and offsets impaired eye movements. Alcohol Clin Exp Res 2012; 36:906-914. [CrossRef]

102.Meszaros ZS, Abdul-Malak Y, Dimmock JA, Wang D, Ajagbe TO, Batki SL. Varenicline treatment of concurrent alcohol and nicotine dependence in schizophrenia: a randomized, placebo-controlled pilot trial. J Clin Psychopharmacol 2013; 33:243-247. [CrossRef]

103.Erwin BL, Slaton RM. Varenicline in the treatment of alcohol use disorders. Ann Pharmacother 2014; 48:1445-1455. [CrossRef]

104.Mitchell JM, Teague CH, Kayser AS, Bartlett SE, Fields HL. Varenicline decreases alcohol consumption in heavy-drinking smokers. Psychopharmacology (Berl) 2012; 223:299-306. [CrossRef]

105.Litten RZ, Ryan ML, Fertig JB, Falk DE, Johnson B, Dunn KE, Green AI, Pettinati HM, Ciraulo DA, Sarid-Segal O, Kampman K, Brunette MF, Strain EC, Tiouririne NA, Ransom J, Scott C, Stout R; NCIG (National Institute on Alcohol Abuse and Alcoholism Clinical Investigations Group) Study Group. A double-blind, placebo-controlled trial assessing the efficacy of varenicline tartrate for alcohol dependence. J Addict Med 2013; 7:277-286. [CrossRef]

106.McKee SA, Harrison EL, O’Malley SS, Krishnan-Sarin S, Shi J, Tetrault JM, Picciotto MR, Petrakis IL, Estevez N, Balchunas E. Varenicline reduces alcohol self-administration in heavy-drinking smokers. Biol Psychiatry 2009; 66:185-190. [CrossRef]

107.Plebani JG, Lynch KG, Rennert L, Pettinati HM, O’Brien CP, Kampman KM. Results from a pilot clinical trial of varenicline for the treatment of alcohol dependence. Drug Alcohol Depend 2013; 133:754-758. [CrossRef]

108.Johnson BA, Roache JD, Javors MA, DiClemente CC, Cloninger CR, Prihoda TJ, Bordnick PS, Ait-Daoud N, Hensler J. Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. JAMA 2000; 284:963-971. [CrossRef]

109.Johnson BA, Seneviratne C, Wang XQ, Ait-Daoud N, Li MD. Determination of genotype combinations that can predict the outcome of the treatment of alcohol dependence using the 5-HT(3) antagonist ondansetron. Am J Psychiatry 2013; 170:1020-1031. [CrossRef]

110.Kenna GA, Zywiak WH, Swift RM, McGeary JE, Clifford JS, Shoaff JR, Fricchione S, Brickley M, Beaucage K, Haass-Koffler CL, Leggio L. Ondansetron and sertraline may interact with 5-HTTLPR and DRD4 polymorphisms to reduce drinking in non-treatment seeking alcohol-dependent women: exploratory findings. Alcohol 2014; 48:515-522. [CrossRef]

111.Modell JG, Mountz JM, Glaser FB, Lee JY. Effect of haloperidol on measures of craving and impaired control in alcoholic subjects. Alcohol Clin Exp Res 1993; 17:234-240. [CrossRef]

112.Haass-Koffler CL, Leggio L, Kenna GA. Pharmacological approaches to reducing craving in patients with alcohol use disorders. CNS Drugs 2014; 28:343-360. [CrossRef]

113.Martinotti G, Di Nicola M, Janiri L. Efficacy and safety of aripiprazole in alcohol dependence. Am J Drug Alcohol Abuse 2007; 33:393-401. [CrossRef]

114.Martinotti G, Di Nicola M, Di Giannantonio M, Janiri L. Aripiprazole in the treatment of patients with alcohol dependence: a double-blind, comparison trial vs. naltrexone. J Psychopharmacol 2009; 23:123-129. [CrossRef]

115.Anton RF, Kranzler H, Breder C, Marcus RN, Carson WH, Han J. A randomized, multicenter, double-blind, placebo-controlled study of the efficacy and safety of aripiprazole for the treatment of alcohol dependence. J Clin Psychopharmacol 2008; 28:5-12. [CrossRef]

116.Myrick H, Li X, Randall PK, Henderson S, Voronin K, Anton RF. The effect of aripiprazole on cue-induced brain activation and drinking parameters in alcoholics. J Clin Psychopharmacol 2010; 30:365-372. [CrossRef]

117.Monnelly EP, Ciraulo DA, Knapp C, LoCastro J, Sepulveda I. Quetiapine for treatment of alcohol dependence. J Clin Psychopharmacol. 2004; 24:532-535. [CrossRef]

118.Martinotti G, Andreoli S, Di Nicola M, Di Giannantonio M, Sarchiapone M, Janiri L. Quetiapine decreases alcohol consumption, craving, and psychiatric symptoms in dually diagnosed alcoholics. Hum Psychopharmacol 2008; 23:417-424. [CrossRef]

119.Kampman KM, Pettinati HM, Lynch KG, Whittingham T, Macfadden W, Dackis C, Tirado C, Oslin DW, Sparkman T, O’Brien CP. A double-blind, placebo-controlled pilot trial of quetiapine for the treatment of type A and Type B alcoholism. J Clin Psychopharmacol 2007; 27:344-351. [CrossRef]

120.Litten RZ, Fertig JB, Falk DE, Ryan ML, Mattson ME, Collins JF, Murtaugh C, Ciraulo D, Green AI, Johnson B, Pettinati H, Swift R, Afshar M, Brunette MF, Tiouririne NA, Kampman K, Stout R; NCIG 001 Study Group. A double-blind, placebo-controlled trial to assess the efficacy of quetiapine fumarate XR in very heavy-drinking alcohol-dependent patients. Alcohol Clin Exp Res 2012; 36:406-416. [CrossRef]

121.Hutchison KE, Swift R, Rohsenow DJ, Monti PM, Davidson D, Almeida A. Olanzapine reduces urge to drink after drinking cues and a priming dose of alcohol. Psychopharmacology (Berl) 2001; 155:27-34. [CrossRef]

122.Littlewood RA, Claus ED, Arenella P, Bogenschutz M, Karoly H, Ewing SW, Bryan AD, Hutchison KE. Dose specific effects of olanzapine in the treatment of alcohol dependence. Psychopharmacology (Berl) 2015; 232:1261-1268. [CrossRef]

123.Hutchison KE, Ray L, Sandman E, Rutter MC, Peters A, Davidson D, Swift R.The effect of olanzapine on craving and alcohol consumption. Neuropsychopharmacology 2006; 31:1310-1317.

124.Naranjo CA, Bremner KE. Clinical pharmacology of serotonin-altering medications for decreasing alcohol consumption. Alcohol Alcohol Suppl 1993; 2:221-229.

125.Kranzler HR, Feinn R, Armeli S, Tennen H. Comparison of alcoholism subtypes as moderators of the response to sertraline treatment. Alcohol Clin Exp Res 2012; 36:509-516. [CrossRef]

126.Kabel DI, Petty F. A placebo-controlled, double-blind study of fluoxetine in severe alcohol dependence: adjunctive pharmacotherapy during and after inpatient treatment. Alcohol Clin Exp Res 1996; 20:780-784. [CrossRef]

127.Pettinati HM, Volpicelli JR, Kranzler HR, Luck G, Rukstalis MR, Cnaan A. Sertraline treatment for alcohol dependence: interactive effects of medication and alcoholic subtype. Alcohol Clin Exp Res 2000; 24:1041-1049. [CrossRef]

128.Chick J, Aschauer H, Hornik K, Investigators’ Group. Efficacy of fluvoxamine in preventing relapse in alcohol dependence: a one-year, double-blind, placebo controlled multicentre study with analysis by typology. Drug Alcohol Depend 2004; 74:61-70. [CrossRef]

129.Keung WM. Anti-dipsotropic isoflavones: the potential therapeutic agents for alcohol dependence. Med Res Rev 2003; 23: 669-696.[CrossRef]

130.Penetar DM, Maclean RR, McNeil JF, Lukas SE. Kudzu extract treatment does not increase the intoxicating effects of acute alcohol in human volunteers. Alcohol Clin Exp Res 2011; 35:726-734. [CrossRef]

131.Lukas SE, Penetar D, Su Z, Geaghan T, Maywalt M, Tracy M, Rodolico J, Palmer C, Ma Z, Lee DY. A standardized kudzu extract (NPI-031) reduces alcohol consumption in non-treatmentseeking male heavy drinkers. Psychopharmacology (Berl) 2013; 226:65-73. [CrossRef]

132.Lukas SE, Penetar D, Berko J, Vicens L, Palmer C, Mallya G, Macklin EA, Lee DY. An extract of the Chinese herbal root kudzu reduces alcohol drinking by heavy drinkers in a naturalistic setting. Alcohol Clin Exp Res 2005; 29:756-762. [CrossRef]

133.Penetar DM, Toto LH, Farmer SL, Lee DY, Ma Z, Liu Y, Lukas SE. The isoflavone puerarin reduces alcohol intake in heavy drinkers: a pilot study. Drug Alcohol Depend 2012; 126:251-6. [CrossRef]

134.Zorrilla EP, Heilig M, de Wit H, Shaham Y. Behavioral, biological, and chemical perspectives on targeting CRF(1) receptor antagonists to treat alcoholism. Drug Alcohol Depend 2013; 128:175-186. [CrossRef]

135.Simms JA, Haass-Koffler CL, Bito-Onon J, Li R, Bartlett SE. Mifepristone in the central nucleus of the amygdala reduces yohimbine stress-induced reinstatement of ethanol-seeking. Neuropsychopharmacology 2012; 37:906-918. [CrossRef]

136.Irwig MS. Decreased alcohol consumption among former male users of finasteride with persistent sexual side effects: a preliminary report. Alcohol Clin Exp Res 2013; 37:1823-1826. [CrossRef]

137.Vendruscolo LF, Estey D, Goodell V, Macshane LG, Logrip ML, Schlosburg JE, McGinn MA, Zamora-Martinez ER, Belanoff JK, Hunt HJ, Sanna PP, George O,Koob GF, Edwards S, Mason BJ. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependentindividuals. J Clin Invest 2015; 125:3193-3197. [CrossRef]

138.Simpson TL, Saxon AJ, Meredith CW, Malte CA, McBride B, Ferguson LC, Gross CA, Hart KL, Raskind M. A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. Alcohol Clin Exp Res 2009; 33:255-263. [CrossRef]

139.Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, Morgan PT, Sinha R. Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res 2012; 36:351-360. [CrossRef]

140.Simpson TL, Malte CA, Dietel B, Tell D, Pocock I, Lyons R, Varon D, Raskind M, Saxon AJ. A pilot trial of prazosin, an alpha-1 adrenergic antagonist, for comorbid alcohol dependence and posttraumatic stress disorder. Alcohol Clin Exp Res 2015; 39:808-817. [CrossRef]

141.Sofuoglu M, Rosenheck R, Petrakis I. Pharmacological treatment of comorbid PTSD and substance use disorder: recent progress. Addict Behav 2014; 39:428-433. [CrossRef]

142.Pellegrini-Giampietro DE, Moroni F, Pistelli A, Palmerani B, Zorn AM, Peruzzi S, Caramelli L, Botti P, Valenza T, Antonini M. Pyrrolidone carboxylic acid in acute and chronic alcoholism. Preclinical and clinical studies. Recenti Prog Med 1989; 80:160-164.

143.Leggio L, Kenna GA, Ferrulli A, Zywiak WH, Caputo F, Swift RM, Addolorato G. Preliminary findings on the use of metadoxine for the treatment of alcohol dependence and alcoholic liver disease. Hum Psychopharmacol 2011; 26:554-559. [CrossRef]

144.Guerrini I, Gentili C, Nelli G, Guazzelli M. A follow up study on the efficacy of metadoxine in the treatment of alcohol dependence. Subst Abuse Treat Prev Policy 2006; 1:35. [CrossRef]

145.Maccioni P, Colombo G, Carai MA. Blockade of the cannabinoid CB1 receptor and alcohol dependence: preclinical evidence and preliminary clinical data. CNS Neurol Disord Drug Targets 2010; 9:55-59. [CrossRef]

146.Soyka M, Koller G, Schmidt P, Lesch OM, Leweke M, Fehr C, Gann H, Mann KF; ACTOL Study Investigators. Cannabinoid receptor 1 blocker rimonabant (SR 141716) for treatment of alcohol dependence: results from a placebo-controlled, double-blind trial. J Clin Psychopharmacol 2008; 28:317-324. [CrossRef]

147.George DT, Herion DW, Jones CL, Phillips MJ, Hersh J, Hill D, Heilig M, Ramchandani VA, Geyer C, Spero DE, Singley ED, O’Malley SS, Bishai R, Rawlings RR, Kunos G. Rimonabant (SR141716) has no effect on alcohol self-administration or endocrine measures in nontreatment-seeking heavy alcohol drinkers. Psychopharmacology (Berl) 2010; 208:37-44. [CrossRef]

148.Evans SM, Levin FR, Brooks DJ, Garawi F. A pilot doubleblind treatment trial of memantine for alcohol dependence. Alcohol Clin Exp Res 2007; 31:775-782. [CrossRef]

149.Muhonen LH, Lönnqvist J, Juva K, Alho H. Double-blind, randomized comparison of memantine and escitalopram for the treatment of major depressive disorder comorbid with alcohol dependence. J Clin Psychiatry 2008; 69:392-399. [CrossRef]

150.Krishnan-Sarin S, O’Malley SS, Franco N, Cavallo DA, Morean M, Shi J, Pittman B, Krystal JH. N-methyl-D-aspartate receptor antagonism has differential effects on alcohol craving and drinking in heavy drinkers. Alcohol Clin Exp Res 2015; 39:300-307. [CrossRef]

151.Leggio L, Ferrulli A, Cardone S, Nesci A, Miceli A, Malandrino N, Capristo E, Canestrelli B, Monteleone P, Kenna GA, Swift RM, Addolorato G. Ghrelin system in alcohol-dependent subjects: role of plasma ghrelin levels in alcohol drinking and craving. Addict Biol 2012; 17:452-464. [CrossRef]

152.Rehm J, Mathers C, Popova S, Thavorncharoensap M, Teerawattananon Y, Patra J. Global burden of disease and injury and economic cost attributable to alcohol use and alcohol-use disorders. Lancet 2009; 373:2223-2233. [CrossRef]

153.Adamson SJ, Heather N, Morton V, Raistrick D, UKATT Research Team. Initial preference for drinking goal in the treatment of alcohol problems: II. Treatment outcomes. Alcohol Alcohol 2010; 45:136-142. [CrossRef]

154.Kohn R, Saxena S, Levav I, Saraceno B. The treatment gap in mental health care. Bull World Health Organ 2004; 82:858-866.

155.Dawson DA, Grant BF, Stinson FS, Chou PS, Huang B, Ruan WJ. Recovery from DSM-IV alcohol dependence: United States, 2001–2002. Addiction 2005; 100:281-292. [CrossRef]

156.Luquiens A, Reynaud M, Aubin HJ. Is controlled drinking an acceptable goal in the treatment of alcohol dependence? A survey of French alcohol specialists. Alcohol Alcohol 2011; 46:586-591. [CrossRef]

157.Gastfriend DR, Garbutt JC, Pettinati HM, Forman RF. Reduction in heavy drinking as a treatment outcome in alcohol dependence. J Subst Abuse Treat 2007; 33:71-80. [CrossRef]

158.WH0, Alcohol Consumptıon: Levels And Patterns, Turkey, 2014. http://www.who.int/substance_abuse/publications/global_alcohol_report/profiles/tur.pdf?ua=1

159.NIAAA, National Institute on Alcohol Abuse and Alcoholism. Helping Patients Who Drink Too Much: A Clinician’s Guide, Updated 2005 Edition. (NIH Publication No. 07-3769.) Bethesda, MD: National Institutes of Health; 2007.

160.NICE, National Institute for Health and Clinical Excellence. Nalmefene for reducing alcohol consumption in people with alcohol dependence. NICE technology appraisal guidance 325. Published: 26 November 2014. https://www.nice.org.uk/guidance/ta325/resources/nalmefene-for-reducing-alcohol-consumption-in-people-with-alcohol-dependence-82602488589253. Accessed: September 3, 2015.

161.CDC, Centers for Disease Control and Prevention. Alcohol use and your health. http://www.cdc.gov/alcohol/pdfs/alcoholyourhealth.pdf Accessed : September 3, 2015.

162.Luquiens A, Aubin HJ. Patient preferences and perspectives regarding reducing alcohol consumption: role of nalmefene. Patient Prefer Adherence 2014; 8:1347-1352.

163.Osborn MD, Lowery JJ, Skorput AG, Giuvelis D, Bilsky EJ. In vivo characterization of the opioid antagonist nalmefene in mice. Life Sci 2010; 86: 624-630. [CrossRef]

164.Mason BJ, Ritvo EC, Morgan RO, Salvato FR, Goldberg G, Welch B, Mantero-Atienza E. A double-blind, placebo-controlled pilot study to evaluate the efficacy and safety of oral nalmefene HCl for alcohol dependence. Alcohol Clin Exp Res 1994;18:1162-1167. [CrossRef]

165.Mason BJ, Salvato FR, Williams LD, Ritvo EC, Cutler RB. A double-blind, placebo-controlled study of oral nalmefene for alcohol dependence. Arch Gen Psychiatry 1999; 56:719-724. [CrossRef]

166.Karhuvaara S, Simojoki K, Virta A, Rosberg M, Löyttyniemi E, Nurminen T, Kallio A, Mäkelä R. Targeted nalmefene with simple medical management in the treatment of heavy drinkers: a randomized double-blind placebo-controlled multicenter study. Alcohol Clin Exp Res 2007; 31:1179-1187. [CrossRef]

167.Anton RF, Pettinati H, Zweben A, Kranzler HR, Johnson B, Bohn MJ, McCaul ME, Anthenelli R, Salloum I, Galloway G, Garbutt J, Swift R, Gastfriend D, Kallio A, Karhuvaara S. A multi-site dose ranging study of nalmefene in the treatment of alcohol dependence. J Clin Psychopharmacol 2004; 24:421-428. [CrossRef]

168.Mann K, Bladström A, Torup L, Gual A, van den Brink W. Extending the treatment options in alcohol dependence: a randomized controlled study of as-needed nalmefene. Biol Psychiatry 2013; 73:706-713. [CrossRef]

169.Gual A, He Y, Torup L, van den Brink W, Mann K; ESENSE 2 Study Group. A randomised, double-blind, placebo-controlled, efficacy study of nalmefene, as-needed use, in patients with alcohol dependence. Eur Neuropsychopharmacol 2013; 23:1432-1442. [CrossRef]

170.van den Brink W, Sørensen P, Torup L, Mann K, Gual A; SENSE Study Group. Long-term efficacy, tolerability and safety of nalmefene as-needed in patients with alcohol dependence: a 1-year, randomised controlled study. J Psychopharmacol. 2014; 28:733-744. [CrossRef]

171.van den Brink W, Aubin HJ, Bladström A, Torup L, Gual A, Mann K. Efficacy of as-needed nalmefene in alcohol-dependent patients with at least a high drinking risk level: results from a subgroup analysis of two randomized controlled 6-month studies. Alcohol Alcohol 2013; 48:570-578. [CrossRef]

172.Ingman K, Hagelberg N, Aalto S, Någren K, Juhakoski A, Karhuvaara S, Kallio A, Oikonen V, Hietala J, Scheinin H. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing. Neuropsychopharmacology 2005; 30:2245-2253. [CrossRef]

173.van den Brink W, Strang J, Gual A, Sørensen P, Jensen TJ, Mann K. Safety and tolerability of as-needed nalmefene in the treatment of alcohol dependence: results from the Phase III clinical programme. Expert Opin Drug Saf 2015; 14:495-504. [CrossRef]

174.Stevenson M, Pandor A, Stevens JW, Rawdin A, Rice P, Thompson J, Morgan MY. Nalmefene for reducing alcohol consumption in people with alcohol dependence: an evidence review group perspective of a NICE single technology appraisal. Pharmacoeconomics 2015; 33:833-47. [CrossRef]

175.Laramée P, Brodtkorb TH, Rahhali N, Knight C, Barbosa C, François C, Toumi M, Daeppen JB, Rehm J. The cost-effectiveness and public health benefit of nalmefene added to psychosocial support for the reduction of alcohol consumption in alcohol-dependent patients with high/very high drinking risk levels: a Markov model. BMJ Open 2014; 4:e005376.

176.Rosner S, Hackl-Herrwerth A, Leucht S, Vecchi S, Srisurapanont M, Soyka M. Opioid antagonists for alcohol dependence. Cochrane Database Syst Rev 2010; (12):CD001867. [CrossRef]

177.Heinala P, Alho H, Kiianmaa K, Lonnqvist J, Kuoppasalmi K, Sinclair JD. Targeted use of naltrexone without prior detoxification in the treatment of alcohol dependence: a factorial double-blind, placebo-controlled trial. J Clin Psychopharmacol 2001; 21:287-292. [CrossRef]

178.Kranzler HR, Tennen H, Penta C, Bohn MJ. Targeted naltrexone treatment of early problem drinkers. Addict Behav 1997; 22:431-436.[CrossRef]

179.Kranzler HR, Tennen H, Armeli S, Chan G, Covault J, Arias A, Oncken C.Targeted naltrexone for problem drinkers. J Clin Psychopharmacol 2009; 29:350-357. [CrossRef]

180.Chick J, Lehert P, Landron F; Plinius Maior Society. Does acamprosate improve reduction of drinking as well as aiding abstinence? J Psychopharmacol 2003; 17:397-402. [CrossRef]

181.Mason BJ, Lehert P. Acamprosate for alcohol dependence: a sex- specific meta-analysis based on individual patient data. Alcohol Clin Exp Res 2012; 36:497-508. [CrossRef]

182.Jonas DE, Amick HR, Feltner C, Bobashev G, Thomas K, Wines R, Kim MM, Shanahan E, Gass CE, Rowe CJ, Garbutt JC. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 2014; 311:1889-1900. [CrossRef]

183.Flannery BA, Garbutt JC, Cody MW, Renn W, Grace K, Osborne M, Crosby K, Morreale M, Trivette A. Baclofen for alcohol dependence: a preliminary open-label study. Alcohol Clin Exp Res 2004; 28:1517-1523. [CrossRef]

184.Johnson BA, Rosenthal N, Capece JA, Wiegand F, Mao L, Beyers K, McKay A, Ait-Daoud N, Anton RF, Ciraulo DA, Kranzler HR, Mann K, O’Malley SS, Swift RM; Topiramate for Alcoholism Advisory Board; Topiramate for Alcoholism Study Group. Topiramate for treating alcohol dependence: a randomized controlled trial. JAMA 2007; 298:1641-1651. [CrossRef]

185.Kranzler HR, Covault J, Feinn R, Armeli S, Tennen H, Arias AJ, Gelernter J, Pond T, Oncken C, Kampman KM. Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry 2014; 171:445-452. [CrossRef]

185.Anton RF, Myrick H, Wright TM, Latham PK, Baros AM, Waid LR, Randall PK. Gabapentin combined with naltrexone for the treatment of alcohol dependence. Am J Psychiatry 2011; 168:709-717. [CrossRef]