Dusunen Adam The Journal of Psychiatry and Neurological Sciences 2015;28:283-300 Editorial / Editoryal DOI: 10.5350/DAJPN20152804001 Pharmacological Treatment Cuneyt Evren1, Muge Bozkurt2 1Assoc. Prof. Dr., 2Psychiatrist, Bakirkoy Training and Options for Alcohol Use Research Hospital for Psychiatry, Neurology and Neurosurgery, Alcohol and Drug Research, Treatment and Training Center (AMATEM), Disorder* Istanbul - Turkey Address reprint requests to / Yazışma adresi: Assoc. Prof. Dr. Cuneyt Evren, Bakirkoy Training and Research Hospital for Psychiatry, Neurology and Neurosurgery, Alcohol and Drug Research, Treatment and Training Center (AMATEM), Istanbul, Turkey Phone / Telefon: +90-212-409-1515/2111, Fax / Faks: +90-212-409-1590, E-mail address / Elektronik posta adresi: [email protected] *Abridged version of the “Therapeutic Guideline for Alcohol Use Disorder” prepared by the Working Group Therapeutic Guideline for Alcohol Use Disorder. PHARMACOLOGICAL TREATMENT assess information obtained from studies regarding OPTIONS FOR ALCOHOL USE DISORDER drug treatments used in clinical practice today, which are summarized in Table 1. However, when examining Alcohol Use Disorder (AUD) and other alcohol- study results for pharmacological treatments, we related health problems are a significant public health immediately have to remember that all of those issue all over the world. The World Health Organization (WHO) reports that each year 3.3 million people lose Table 1: Drugs used for the therapy of alcohol use their lives due to harmful alcohol use, with 5.9% of all disorder (AUD) deaths being related to alcohol consumption (1). It has Drugs for AUD approved in Turkey been estimated that in 2010, the economic burden of Disulfiram Naltrexone alcohol-related costs was 155.8 billion Euro, of which Acamprosate 60% were connected to alcohol addiction (2). Nalmefene In AUD, after the end of the withdrawal phase, Drugs approved in some European countries when having reached a state of abstinence, the main Baclofen (Temporary recommendation of use in France) Sodium oxybate (Austria, Italy, and France) aim is to maintain this abstinence by reducing craving Drugs at research stage for AUD and preventing relapse (3). During treatment, especially Anticonvulsants all severe cases of AUD need to be assessed from the Varenicline angle of pharmacologic therapy. Drugs licensed for the Ondansetron treatment of AUD, worldwide as well as in Turkey, are Dopamine receptor antagonists Selective serotonin reuptake inhibitors disulfiram, acamprosate, naltrexone, and nalmefene. Memantine Long-term release naltrexone has not yet been approved Kudzu in Turkey. Nalmefene, licensed in Europe and Turkey, CB1 receptor antagonists CRF1 antagonists has recently (November 2014) been approved for Finasteride, mifepristone reducing the amount of alcohol consumed in AUD Prazosin (4-6). In some European countries, baclofen and sodium Metadoxine Ghrelin antagonists oxybate have been approved (7,8). In this paper, we Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 28, Number 4, December 2015 283 Pharmacological treatment options for alcohol use disorder treatments need to be used together with psychosocial It has been reported that acamprosate is more support; in particular, it should be recommended that beneficial in patients experiencing relief craving related patients be placed in a psychosocial support program to irregularities in the gamma-aminobutyric acid suitable to them individually for the duration of therapy. (GABA) and glutamate systems (11,23). A recent study showed that acamprosate is more effective in patients APPROVED PHARMACOTHERAPIES FOR who at the beginning of treatment had a high serum ALCOHOL USE DISORDER level of glutamate (24). Further, it is seen that acamprosate is more effective in Lesch type I and type Acamprosate II alcohol dependents than in type III and type IV (25). It has been pointed out that acamprosate is beneficial Acamprosate is a synthetic glutamate N-methyl-D- especially in Lesch type I alcohol dependents, while aspartate (NMDA) receptor antagonist, approved by there was no correlation between craving and the Turkish Health Ministry in 2003 and by the FDA in acamprosate response (26). 2004 (9). Acamprosate blocks the extracellular Acamprosate is more effective in patients whose dopamine increase in the Nucleus accumbens (NAc) therapy goal is total abstinence than in those who aim (10) and plays a protective role against neurotoxicity at reducing their drinking without total abstinence during alcohol withdrawal (11). (17,27). Given that drug interaction is very low, it is A number of systematic reviews and meta-analyses suitable for patients who are using further drugs for agree that acamprosate is effective in the prevention of other diseases, and it can be administered to patients relapse after detoxification (12-17). Among these studies, under opioid analgesic treatment (28). As it is excreted the National Institute for Health and Clinical Excellence by the kidneys unchanged, there is no risk of (NICE) (18) found a relative risk (RR) value of 0.83 (95% hepatotoxicity, but it should not be used in patients confidence interval [CI]=0.77-0.88), while Rösner et al. (12) with a high degree of kidney insufficiency (creatinine report an RR of 0.86 (95% CI=0.81-0.91). The number clearance <30ml/min) (29). The drug may however be needed to treat was calculated as 9-11 (12,13). The rate of used in patients with compensated cirrhosis (30). withdrawal from treatment because of side effects was Acamprosate is formulated in tablets of 333mg. Due higher in acamprosate users compared to placebo, but the to its low bioavailability, it needs to be administered in difference was not statistically significant (18). high doses (for persons below 60kg 1332mg, above According to one meta-analysis, acamprosate is an 60kg 1998mg) (9,31). Most commonly observed side effective drug for all AUD patients irrespective of effects regard the gastrointestinal system. Less common gender, starting age, family history, presence of anxiety, are stomach ache, rash, itching, paresthesia, changes in and intensity of craving and dependence (19). However, libido, confusion, and suicidal ideation (27,37). Therapy there are studies showing genetic and individual can continue for between 3 and 12 months (18,27,33,34). characteristics playing a role in the response to The most appropriate strategy is a joint decision about acamprosate. For example, it is thought that variations the duration of therapy by doctor and patient according in the N-methyl-D-aspartate (NMDA) mGluR5 to the observed side effects, relapse history, and social receptor affect the response to acamprosate (20). In and familial characteristics. addition, the intronic single nucleotide polymorphism (SNP) rs13273672, coded by the GATA4 (GATA Naltrexone binding protein 4) gene, is reported to be related with relapse in acamprosate users (21). Furthermore, a study Naltrexone is an unspecific opioid receptor researching SNPs and duration of abstinence reported a antagonist. It particularly blocks the μ-opioid receptors, correlation for GRIN2B rs2300272, rs2058878 and leading to a reduction of the increase in dopamine most strongly rs2058878 (22). occurring after the use of alcohol and thus reducing its 284 Düşünen Adam The Journal of Psychiatry and Neurological Sciences, Volume 28, Number 4, December 2015 Evren C, Bozkurt M rewarding effect (18,35). Blocking the dopaminergic dopamine and opioid system (23). Naltrexone is more effect of the endorphins secreted after alcohol use, it successful in Babor type-A alcohol dependents (less reduces the stimulating and positively enhancing effect severe, late-onset, no family history, fewer psychiatric of alcohol. Further, it increases the sedative effect of comorbidities) compared to type-B (47). It has been alcohol and reduces alcohol craving (36). reported that patients with depression at the beginning Naltrexone was approved in 1994 for use in alcohol of the therapy and Lesch type III and type IV dependents dependence (28). The evidence for its effectiveness in respond better to naltrexone (26). According to AUD is of level A (31). Naltrexone reduces the relapse Cloninger’s typology, early-onset type 2 alcohol rate in AUD and lengthens the abstinence period. dependents with more serious alcohol-related problems Meta-analyses show that it reduces the relative risk, and comorbid psychopathologies benefit more from compared to placebo, by 36%. On average, the naltrexone than type 1 dependents (48). number needed to treat is 7, which indicates a For patients with comorbid opioid use disorder and moderate effect size (27). Naltrexone has also been AUD, naltrexone is a favorable therapeutic option in shown to reduce craving and frequency of drinking order to reduce the craving for either substance. after relapse. It is more effective in reducing intensity However, for patients continuing opioid use or and rate of relapse than in extending the period of requiring opioid analgesic treatment, it is not a suitable abstinence (27). One meta-analysis showed that in drug (28). It also may not be used with acute hepatitis, short-term treatment (12-16 weeks) jointly with liver insufficiency, or in patients with a history of psychotherapy, 50 mg naltrexone was clinically highly hypersensitivity to naltrexone (29). beneficial in maintaining abstinence, while the safety It is recommended to wait until the decline of profile was similar