Doi: 10.1093/alcalc/agq039

Alcohol and Alcoholism Advance Access published June 30, 2010
Alcohol & Alcoholism, pp. 1–7, 2010 Acetyl-L-Carnitine for Alcohol Craving and Relapse Prevention in Anhedonic Alcoholics: A Randomized, Double-Blind, Placebo-Controlled Pilot Trial Giovanni Martinotti1,2,*, Daniela Reina2, Marco Di Nicola2, Sara Andreoli1,2, Daniela Tedeschi2, Ilaria Ortolani2, Gino Pozzi2, Emerenziana Iannoni3, Stefania D’Iddio3 and Luigi Janiri2 1Clinica “Villa Maria Pia”, Rome, Italy, 2Institute of Psychiatry, Catholic University Medical School, Rome, Italy and 3Sigma-Tau SpA, Italy *Corresponding author: Clinica Villa Maria Pia, Via del Forte Trionfale 36, Rome 00135, Italy. Tel: +39-3355627362; Fax: +39-06-3052553; (Received 11 April 2010; accepted 14 June 2010) Abstract — Aim: The study aimed to evaluate the efficacy of acetyl-L-carnitine (ALC), at different doses, in relapse prevention andcraving in anhedonic detoxified alcohol-dependent subjects. Method: Randomized, double-blind, placebo-controlled, pilot study in 64alcohol-dependent anhedonic patients: 23 received ALC at a dose of 3 g/day, 21 received ALC at a dosage of 1 g/day and 20 were givenplacebo. Intensity of alcohol craving was evaluated by Visual Analogue Scale. Subjects were evaluated at the beginning of treatmentand after 10, 30, 60 and 90 days. Results: Survival analysis showed that patients treated with ALC remained completely abstinent forlonger than those treated with placebo (Z=−2.27; P < 0.05). From the 10th day onwards, a greater reduction of craving was observed in the ALC 1 g group than with placebo (P=0.035). The two groups did not differ in the percentage of subjects remaining abstinent for theentire study period or the number of subjects who relapsed (defined as five or more standard drinks (four for women) on a singleoccasion or drinking on five or more days in 1 week). Conclusions: The results of this study suggest that ALC can reduce cravingand the time to first drink. ALC use was safe. Further studies are needed to clarify to confirm, over longer periods, these short-termoutcome benefits.
has an absolute bioavailability ranging between 2.1 and 2.4 Craving, usually defined as the conscious and unbearable desire to use alcohol, is an important heuristic construct with treat- ). ALC has a high bioavailability through IV infusion, ment implications. Because high levels of craving have been while lower plasma levels are usually obtained from oral ad- associated with increased probability of relapse, especially in the early post-treatment period, intervention that reduce crav- As regards the role of ALC in neurotransmission, it may facilitate cholinergic neurotransmission either directly or by shuttling acetyl groups that can be used for acetylcholine syn- Avoiding relapse and decreasing craving are major chal- lenges for people who have weathered detoxification from substances of abuse, and various pharmacological strategies has an excitatory activity on cortical cholinergic neurons have been investigated with partial but not universal consen- sus In the last few years, the mechanism of craving for alcohol has been of interest in alcoholism treat- showed that ALC exerted a mild excitatory effect on cortical cholinergic receptors in vivo, providing further complexities of the concept of craving, researchers have yet evidence of the influence of ALC on the cholinergic system.
to reach a consensus definition of this phenomenon.
With regard to the effect of ALC on dopamine outflow, com- Acetyl-L-carnitine (ALC) is an endogenous compound re- monly implicated in alcohol and substance use disorders (see presenting a small amount of the physiological pool of tation has been shown to increase levels of dopamine in the of ALC is to contribute to the homeostasis of coenzyme A, cortex, hippocampus and striatum of rat brain ( exporting acetyl-CoA groups from the mitochondria while other animal studies have shown that ALC admin- ALC crosses the blood-brain barrier using a low affin- istration persistently increases dopamine outflow in the nucleus ity, carrier-mediated, sodium-dependent active transport and humans suggest that dopaminergic agents may be an im- ically, it acts as a precursor of acetylcholine ( portant class of pharmacotherapies for alcohol dependence ) and stimulates intermediate energy production (and cytochrome oxidase activity in mito- Another system believed to relate to alcohol dependence is N-methyl-D-aspartate (NMDA) neurotransmission. ALC is From a pharmacokinetic viewpoint, there are a number of believed to modulate, either directly or indirectly, through ac- features that distinguish ALC from conventional drugs. First tivation of cholinergic receptors, the NMDA subtype of and foremost, it is an endogenous compound that is present not only in humans but also in most, if not all, animal species.
studies have shown that glutamate receptor ligands alter the The pharmacokinetics of ALC are non-linear, due to the par- reinforcing effects of ethanol: infusion of NMDA receptor an- ticular filtration/active re-absorption process that it undergoes tagonists attenuates oral ethanol consumption in rats The Author 2010. Published by Oxford University Press on behalf of the Medical Council on Alcohol. All rights reserved diction Severity Index ). Axis II diagnosis compounds each believed to influence the NMDA receptor, was divided into Cluster A (paranoid, schizoid, schizotypal), B such as acamprosate, N-acetylcysteine, modafinil, topiramate, (antisocial, borderline, histrionic, narcissistic) and C (avoidant, lamotrigine, gabapentin, pregabalin and memantine, have dependent, obsessive–compulsive), according to DSM-IV. In- promise for the treatment of alcohol withdrawal, craving clusion criteria were age between 18 and 65 years; diagnosis of and relapse prevention although much of the data are in ani- alcohol dependence according to DSM-IV-TR criteria, with a mal rather than human studies (see for review, history of alcohol use disorders for at least 3 years and a daily alcohol intake of at least six drinks (one drink containing 12 g In addition, the acute administration of ALC increases β- ethanol) in the month before the screening; and presence of endorphin levels in healthy subjects and normalizes them in anhedonic symptoms, with SHAPS (Snaith–Hamilton Plea- patients with dementia, Alzheimer’s disease and depression.
Clinical trials with ALC have been performed in Europe Exclusion criteria were the presence of delirium tremens or since the late 1970s and in the USA since 1990. ALC has hallucinosis; a score of over 5 on the Clinical Institute With- been extensively studied in Alzheimer’s disease, and explor- atory work has been conducted in other patient populations ); blood alcohol concentration higher than 0.1 g/L; substance abuse; Axis I diagnosis other than alcohol depen- dence; evidence of a mental disorder severely interfering with ). In all these studies, ALC appeared to be effica- cognitive capacity; epilepsy; severe cardiac failure; diabetes mellitus; severe liver impairment; liver encephalopathy; kid- The aim of this pilot study was to evaluate the efficacy of ney failure; neoplastic disease; lack of cooperating relatives; ALC in relapse prevention and craving in anhedonic detoxi- intake of psychotropic medications such as anticonvulsants, fied alcohol-dependent subjects. Secondary study outcomes antidepressants or antipsychotics; pregnancy or lactation; were the number of abstinent and heavy drinking days during and a history of severe adverse reaction or well-known hy- the study period and the effect of ALC on withdrawal symp- toms. This pilot study was designed as a randomized, double-blind, dose-determining, placebo-controlled trial, stratified by The study was designed to last for 142 days, with a screeningphase (7 days), a treatment phase (90 days) and a follow-up phase (45 days). Subjects were assessed at the following times:at the beginning of treatment (T0) and after 10 (T1), 30 (T2), 60 (T3) and 90 (T4) days of therapy. A follow-up assessment Between December 2004 and September 2008, 205 alcohol- (T5) was carried out 45 days after the last therapy intake.
dependent subjects, referred to the alcohol outpatient treatment During the treatment phase (90 days) patients received the unit of the Psychiatry and Drug Dependence Day-Hospital of treatments described above, according to the allocated group.
the Agostino Gemelli University General Hospital in Rome, Compliance was verified by counting the sachets returned for were consecutively screened for the study. Random allocation each treatment period at the corresponding assessment. Sub- was conducted using a dedicated website, the investigator en- ject flow by treatment group is shown in tering the programme and inserting sex and age after which a During the study period, patients were only given diazepam specific randomization code was generated allowing assign- (20 mg/day or equivalent as required) for insomnia according ment stratified by sex and age (≤ or >35). In this way, 64 In cases in which withdrawal symptoms severely interferedwith the clinical condition, the patients were adequately trea- ALC at a dosage of 3 g/day by slow IV infusion (500 ml of solution infused in 3–4 h) for 10 days and then 3 g For the entire study period, all the patients attended a self- three times a day orally for the remainder of the study help group based on a psychosocial programme twice per week.
Abstinence from alcohol was evaluated on the basis of the or ALC 1 g/day by slow IV infusion for 10 days and then participant’s self-evaluation and a family member interview.
3 g three times a day orally for the remainder of the study Abstinence was confirmed by determining blood alcohol con- centration at each outpatient control, measuring alcohol abuse or placebo (n=20) (all treatments supplied in sachets).
hepatic indices [aspartate aminotransferase (AST), alanineaminotransferase (ALT), gamma glutamyl-transpeptidase The treatment sequence was identical for placebo and ALC (GGT)] and measuring mean cellular volume (MCV). Toxico- groups. The sequence of IV and oral treatment was based on logical urinalysis was performed at baseline and at each previous studies showing a faster increase of plasma level outpatient control in order to identify poly-drug abuse and ALC when IV infusion preceded oral administration ( The intensity of alcohol craving was evaluated by a 10-cm Visual Analogue Scale (VAS) (at the begin- All the patients were evaluated by attending psychiatrists us- ning of treatment (T0) and after 10 (T1), 30 (T2), 60 (T3) ing the Structured Clinical Interviews for Diagnostic and Statistic Manual for Mental Disorders, 4th edition (DSM-IV) Effectiveness measures included the Clinical Global Im- SCID I and II (First et al., 1990, 1995) and the European Ad- pressions scale (CGI) Safety parameters were Acetyl-L-carnitine for Alcohol Craving and Relapse Prevention Patients screened
Patients included
Lost to follow-up: 1
Lost to follow-up: 1
Lost to follow-up: 1
Non-compliance: 2
Withdrawal consent: 1
Withdrawal sympt.:1
Withdrawal consent: 1
Lost to follow-up: 4
Lost to follow-up: 4
Lost to follow-up: 5
Non-compliance: 7
Non-compliance: 4
Non-compliance: 4
Adverse event: 1
Fig. 1. Diagram of subjects flow by treatment group.
monitored throughout all the study and are described in a sep- five (four for women) or more standard drinks on a single oc- arate paper, which also reports the effect of ALC on casion or drinking on five or more days in 1 week. This anhedonic, melancholic and negative symptoms (Martinotti definition is currently reported for research purposes in differ- The study protocol was approved by the Ethical Committee Secondary study outcomes were the number of abstinent days of the Catholic University of Rome and by the Institutional (which includes both the days before the end of abstinence Review Boards in accordance with local requirements. It was and, eventually, those abstinent days following the first alco- conducted according to the Declaration of Helsinki Guidelines hol use), of heavy drinking days (characterized by ≥4 drinks (1964). After receiving information about the drug, any possi- per day for women and ≥5 per day for men) during the study ble side effects and the dosing rate, as well as the possibility period, and the effect of ALC on withdrawal symptoms. In of dropping out of the study at any time, all patients (or their Italy a ‘drink’ is considered to contain 12 g of ethanol.
legal representatives) provided their written informed con- Student’s t and chi-square tests were employed in order to sent prior to randomization. Each patient was informed compare socio-demographic and clinical data.
that an alcohol relapse, non-compliance or the onset of side Primary and secondary efficacy analyses were performed effects would lead to their exclusion from the trial. In any on the per-protocol population, which included all randomly case, patients were free to leave the study at any time. No assigned patients assessed during the entire treatment phase reimbursement was contemplated for the subjects included in (T1–T4). All the drop-out subjects were eliminated from the analysis on application of this method. Time to first drink(survival remaining abstinent) was compared across groups using Kaplan–Meier survival curves and the log rank test.
The primary study outcomes were maintenance of abstinence Safety analysis was performed on the intent-to-treat popu- and the reduction of alcohol craving as measured by VAS. A lation, which included all randomly assigned patients who return to drinking any alcohol, regardless of the quantity, took at least one dose of study medication.
marked the end of the abstinence. Differently from ‘end of ab- Craving data were analysed at baseline and at different stinence’, relapse to drinking was defined as either drinking times by analysis of variance for repeated measures, with time as ‘within’ factor and treatment, age and sex as ‘between’ fac- tors. Where appropriate, a Bonferroni correction was applied The survival curve for time to first drink (duration of absti- to control for the number of comparisons. We defined P va- nence) is shown in . The survival function showed lues of 0.05 or below as statistically significant.
that patients treated with ALC remained abstinent from anyamount of alcohol for a longer time than those treated withplacebo (Z=−2.27; P < 0.05).
In relation to craving, a significant reduction as measured by VASc was found between times in all groups (P=0.039). The global effect of ALC treatment during times was stronger than A total of 205 patients were screened, of whom 141 were treatment with placebo (P=0.035). Greater reduction in anhe- excluded. In 78% of patients excluded, the reason was the donia in the ALC 1 g group than the placebo group was found absence of anhedonia (a SHAPS dychotomic score lower at T1, T2 and T3 (respectively Δ=−3; 95% Confidence inter- than 3). There were no significant differences between the val (CI): −5.1, −0.8; P=0.005; Δ=−2.5; 95% CI: −4.8, −0.1; other baseline characteristics of patients who did not pass P=0.038; Δ=−2.4; 95% CI: −4.6, −0.1; P=0.045). In relation the screening compared with those who were included. The to craving, no differences between patients with and without a three groups of randomized patients did not vary in terms of psychiatric Axis II diagnosis were found.
socio-demographical and clinical characteristics, level of The percentage of subjects remaining abstinent for the entire craving (VASc) and average alcohol consumption in the study period (ALC 1 g = 26%; ALC 3 g = 28.5%; Placebo = month before the assessment (Despite screening 20%) and the number of subjects who relapsed (ALC 1 g = out the patients who at screening had a CIWA-Ar score over 19%; ALC 3 g = 17%; Placebo = 40%) were not significantly 5, some patients presumably had resumed drinking because different (X2=1.16; X2=3.4) between groups, although a trend several had scores over 5 at their baseline interview some towards better outcome in the treated groups was observed. The percentage of subjects excluded from the study due to lack of During the study period two subjects used diazepam, at a compliance (ALC 1 g=24%; ALC 3 g=39%; Placebo=25%) dosage of 20 mg/day, for 2 and 4 days of treatment, respec- was not significantly different between groups.
tively. For both cases the reason was insomnia, as permitted The mean number of abstinent days (ALC 1 g: 72.6 ± 43.7 days; ALC 3 g: 76.1 ± 21.2 days; Placebo: 63.1 ± Table 1. Socio-demographic characteristics, alcohol history and clinical data of the sample. Percentages are given in brackets Duration of alcohol dependence (years: M, SD) a1 drink=12 g or 0.5 oz.
VASc, Visual Analogue Scale for Craving; SHAPS, Snaith–Hamilton Pleasure Scale; CIWA-Ar, Clinical Institute Withdrawal Assessment for Alcohol.
Acetyl-L-carnitine for Alcohol Craving and Relapse Prevention ALC 3g
Cumulative Survival
ALC 1g
* Placebo
Weeks of treatment
Fig. 2. Survival remaining abstinent. *P < 0.05 (Z=−2.27) between Placebo and the ALC groups.
31.2 days) and heavy drinking days (ALC 1 g: 6.8 ± 9.2 days; ALC is difficult because of the diverse typologies of patients ALC 3 g: 4.1 ± 8.2 days; Placebo: 19.2 ± 17.8 days) were not included, the response criteria used and the absence of a pla- significantly different between groups (X2=0.72; X2=3.4).
All the treated patients showed a statistically significant im- provement in scores on the CGI scale (P < 0.01). No The daily dosage of ALC (1 g or 3 g) was defined on the differences were found between groups.
basis of previous clinical studies in other psychopathologicalconditions (; ; Adverse events (whether or not considered treatment related) occurred in six (26.1 %) patients in the ALC 3 g group, eight (38.1 %) in the ALC 1 g group and six (30%) in the placebo was allowed for reasons of safety. Despite few days of treat- group, these differences being non-significant (P=0.42).
ment being characterized by its use in two patients for 2 and Adverse events rated as treatment related occurred in two 4 days, it represents a possible limitation.
(8.7%) patients in the ALC 3 g group, five (23.8%) in the In this study, ALC was associated with prolonging absti- ALC 1 g group and three (15%) in the placebo group, these nence compared to placebo. The efficacy of ALC in differences being non-significant (P=0.42). Events leading to reducing craving may be responsible for these results. This the exclusion of a patient from the study occurred in one sub- magnitude of the effect seemed greatest during the first week of the study and gradually waned over time. With re- No serious adverse events were observed.
gard to relapse to heavy drinking, only a tendency in favour No clinically significant differences between groups (Fish- of ALC was seen. The mean number of abstinent days and er’s exact test) were seen in the mean change from baseline heavy drinking days did not differ significantly between of any vital signs, electrocardiograms (ECGs), haematology, clinical chemistry or urinalysis parameters, between baseline The better outcome of the ALC 1 g group merits further in- vestigations. However, the fact that this did not emerge from Comparing hepatic alcohol abuse indices before and after the ALC 3 g group deserves explanation, because one would treatment administration, we found a significant decrease in have hoped to see a dose–response effect. However, the higher the values of GGT (P < 0.01), AST (P < 0.01), ALT (P < number of subjects excluded from the study due to lack of compliance in the ALC 3 g groups would have reduced thestatistical power for this group.
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Reducing Sensitivity to NoC Latency in NUCA Caches Pierfrancesco Foglia*, Giacomo Gabrielli*, Francesco Panicucci†, Marco Solinas* {foglia, giacomo.gabrielli, marco.solinas}, [email protected] Members of the HiPEAC European Network of Excellence Abstract proposed schemes [4, 5]. Taking into account theconsiderations derived from the performed analysis, we Non Unifo


MESTINON® (pyridostigmine bromide tablets, USP) SYRUP TABLETS and TIMESPAN® TABLETS DESCRIPTION: Mestinon (pyridostigmine bromide tablets, USP) is an orally active cholinesterase inhibitor. Chemically, pyridostigmine bromide is 3-hydroxy-1-methylpyridinium bromide dimethylcarbamate. Its structural formula is: Mestinon is available in the following forms: Syrup containing 60 mg

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