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Postgraduate Medical Journal May 2000Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK.... (Review)
Review
Alcohol is a major cause of liver cirrhosis in the Western world and accounts for the majority of cases of liver cirrhosis seen in district general hospitals in the UK. The three most widely recognised forms of alcoholic liver disease are alcoholic fatty liver (steatosis), acute alcoholic hepatitis, and alcoholic cirrhosis. The exact pathogenesis of alcoholic liver injury is still not clear but immune mediated and free radical hepatic injury are thought to be important. There is increasing interest in genetic factors predisposing to hepatic injury in susceptible individuals. Diagnosis is based on accurate history, raised serum markers such as gamma-glutamyltransferase, mean corpuscular volume, and IgA and liver histology when obtainable. Abstinence is the most important aspect of treatment. Newer drugs such as acamprosate and naltrexone are used to reduce alcohol craving. Vitamin supplements and nutrition are vital while corticosteroids have a role in acute alcoholic hepatitis where there is no evidence of gastrointestinal haemorrhage or sepsis. Liver transplantation has excellent results in abstinent patients with end stage liver disease but there are concerns about recidivism after transplant.
Topics: Cytokines; Female; Humans; Liver Diseases, Alcoholic; Male; Risk Factors
PubMed: 10775280
DOI: 10.1136/pmj.76.895.280 -
Frontiers in Pharmacology 2022Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist,... (Review)
Review
Compounds known to be successful in the treatment of alcohol use disorder include the aversive agent, Disulfiram, the glutamatergic NMDA receptor antagonist, Acamprosate, and the opioid receptor antagonists, Naltrexone and Nalmefene. Although all four are effective in maintaining abstinence or reduction of alcohol consumption, only a small percentage of patients receive pharmacological treatment. In addition, many other medications have been investigated for their therapeutic potential in the treatment of alcohol use disorder. In this review we summarize and compare Baclofen, Gabapentin, Topiramate, Ondansetron, Varenicline, Aripiprazole, Quetiapine, Clozapine, Antidepressants, Lithium, Neuropeptide Y, Neuropeptide S, Corticotropin-releasing factor antagonists, Oxytocin, PF-05190457, Memantine, Ifenprodil, Samidorphan, Ondelopran, ABT-436, SSR149415, Mifepristone, Ibudilast, Citicoline, Rimonabant, Surinabant, AM4113 and Gamma-hydroxybutyrate While some have shown promising results in the treatment of alcohol use disorder, others have disappointed and should be excluded from further investigation. Here we discuss the most promising results and highlight medications that deserve further preclinical or clinical study. Effective, patient-tailored treatment will require greater understanding provided by many more preclinical and clinical studies.
PubMed: 36263121
DOI: 10.3389/fphar.2022.927703 -
EClinicalMedicine Sep 2021Although tinnitus has a prevalence between 20 and 42.8%, the currently recommended management for tinnitus, such as tinnitus support and psychologic therapies, are...
BACKGROUND
Although tinnitus has a prevalence between 20 and 42.8%, the currently recommended management for tinnitus, such as tinnitus support and psychologic therapies, are relatively time-consuming and expensive. Several new pharmacologic treatments designed for tinnitus patients without specific origin had been developed but their efficacy remains unclear.
METHODS
The current Network Meta-Analysis (NMA) of randomised controlled trials (RCTs) was conducted to evaluate the efficacy of different pharmacologic treatments for tinnitus management in tinnitus patients without specific or treatable origin (i.e. primary tinnitus). Databases were searched from inception to April 5, 2021. All network meta-analytic procedures were conducted under the frequentist model. We calculated the effect size of outcomes with different rating scales with standardized mean difference. PROSPERO registration: CRD42020177742.
FINDINGS
Overall, 36 RCTs were included with 2,761 participants. The main results revealed that pharmacologic interventions with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) and those with anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) were associated with superior improvement in tinnitus severity and response rate compared to placebo/control. Oral amitriptyline were associated with the highest improvement in tinnitus severity and the fourth highest response rate. None of the investigated interventions was associated with different changes in quality of life compared to placebo/control. All the investigated treatments were associated with similar drop-out rate to placebo/control.
INTERPRETATION
The current NMA suggests a potential role for treatments with brain-acting effect (for example, amitriptyline, acamprosate, and gabapentin) or anti-inflammation/anti-oxidant effect (for example, intra-tympanic dexamethasone injection plus oral melatonin) as the preferable effective treatments for tinnitus without specific or treatable origin.
FUNDING
none.
PubMed: 34611615
DOI: 10.1016/j.eclinm.2021.101080 -
Psychiatria Polska 2015Dear Readers We are happy and proud to announce that we managed to achieve intention announced in the last issue: for the first time in PubMed there is a possibility of...
Dear Readers We are happy and proud to announce that we managed to achieve intention announced in the last issue: for the first time in PubMed there is a possibility of direct and free access to the full texts published in Polish Psychiatry (Polish and English language versions are available)!!! For the issue 6/2014 they have been downloaded by Medline users already 500 times. Owing to this, papers by Polish scientists-psychiatrists are more readily available to colleagues from around the world interested in them, and Polish Psychiatry actually becomes journal of international scope. We hope that it will result in a marked improvement in the bibliometric indicators (which, however, is unrealistic to expect in the current or next year) in the following years. Spring issue of Polish Psychiatry touches several important problems. We pay attention to the texts on addiction - behavioural (Internet addiction) and alcohol. Two papers by prof. M. Wojnar's team summarize the issues related to the coexistence of alcohol dependence with other psychiatric disorders. The issue of dual diagnosis has already appeared in our magazine (for example [1]). This is an extremely difficult problem, and patients are a real challenge, both therapeutic and diagnostic. They often require a comprehensive approach: pharmacotherapy of comorbid mental illness, psychoeducation, addiction treatment programmes. For these patients the maintenance of abstinence is particularly difficult, especially in a situation of exacerbation of psychopathological symptoms. An important direction is searching for additional pharmacotherapeutic methods which help to reduce the degree of alcohol abuse and the resulting damage. These include: acamprosate, drugs which are opioid receptor antagonists [2], and in the current issue the authors from the University of Cagliari focused on baclofen. (...).
Topics: Humans; Information Dissemination; Journalism, Medical; Mental Disorders; Periodicals as Topic; Poland; Psychiatry; Publishing; Research; Societies, Medical
PubMed: 26093586
DOI: 10.12740/PP/42177 -
Pharmacology & Therapeutics Dec 2022Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a... (Review)
Review
Alcohol Use Disorder (AUD) is a multifaceted relapsing disorder that is commonly comorbid with psychiatric disorders, including anxiety. Alcohol exposure produces a plethora of effects on neurobiology. Currently, therapeutic strategies are limited, and only a few treatments - disulfiram, acamprosate, and naltrexone - are available. Given the complexity of this disorder, there is a great need for the identification of novel targets to develop new pharmacotherapy. The GABAergic system, the primary inhibitory system in the brain, is one of the well-known targets for alcohol and is responsible for the anxiolytic effects of alcohol. Interestingly, GABAergic neurotransmission is fine-tuned by neuroactive steroids that exert a regulatory role on several endocrine systems involved in neuropsychiatric disorders including AUD. Mounting evidence indicates that alcohol alters the biosynthesis of neurosteroids, whereas acute alcohol increases and chronic alcohol decreases allopregnanolone levels. Our recent work highlighted that chronic alcohol-induced changes in neurosteroid levels are mediated by epigenetic modifications, e.g., DNA methylation, affecting key enzymes involved in neurosteroid biosynthesis. These changes were associated with changes in GABA receptor subunit expression, suggesting an imbalance between excitatory and inhibitory signaling in AUD. This review will recapitulate the role of neurosteroids in the regulation of the neuroendocrine system, highlight their role in the observed allostatic load in AUD, and develop a framework from mechanisms to potential pharmacotherapy.
Topics: Humans; Pregnanolone; Neurosteroids; Alcoholism; Receptors, GABA-A; Anxiety; Ethanol
PubMed: 36323379
DOI: 10.1016/j.pharmthera.2022.108299 -
Expert Opinion on Drug Discovery Nov 2014Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate... (Review)
Review
INTRODUCTION
Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism.
AREAS COVERED
Herein, the authors review the preclinical studies which have assessed the efficacy of acamprosate in various animal models of alcohol dependence and discuss the disparate findings from the major clinical trials. Moreover, the authors discuss the major limitations of these preclinical and clinical studies and offer explanations for the often-contradictory findings. The article also looks at the importance of the calcium moiety that accompanies the salt form of acamprosate and its relevance to its activity.
EXPERT OPINION
The recent discovery that large doses of calcium largely duplicate the effects of acamprosate in animal models has introduced a serious challenge to the widely held functional association between this drug and the glutamate neurotransmission system. Future research on acamprosate or newer pharmacotherapeutics should consider assessing plasma and/or brain levels of calcium as a correlate or mediating factor in anti-relapse efficacy. Further, preclinical research on acamprosate has thus far lacked animal models of chemical dependence on alcohol, and the testing of rodents with histories of alcohol intoxication and withdrawal is suggested.
Topics: Acamprosate; Alcohol Deterrents; Alcoholism; Animals; Humans; Recurrence; Taurine
PubMed: 25258174
DOI: 10.1517/17460441.2014.960840 -
The Cochrane Database of Systematic... Sep 2010Alcohol dependence is among the main leading health risk factors in most developed and developing countries. Therapeutic success of psychosocial programs for relapse... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Alcohol dependence is among the main leading health risk factors in most developed and developing countries. Therapeutic success of psychosocial programs for relapse prevention is moderate, but could potentially be increased by an adjuvant treatment with the glutamate antagonist acamprosate.
OBJECTIVES
To determine the effectiveness and tolerability of acamprosate in comparison to placebo and other pharmacological agents.
SEARCH STRATEGY
We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE and CINAHL in January 2009 and inquired manufacturers and researchers for unpublished trials.
SELECTION CRITERIA
All double-blind randomised controlled trials (RCTs) which compare the effects of acamprosate with placebo or active control on drinking-related outcomes.
DATA COLLECTION AND ANALYSIS
Two authors independently extracted data. Trial quality was assessed by one author and cross-checked by a second author. Individual patient data (IPD) meta-analyses were used to verify the primary effectiveness outcomes.
MAIN RESULTS
24 RCTs with 6915 participants fulfilled the criteria of inclusion and were included in the review. Compared to placebo, acamprosate was shown to significantly reduce the risk of any drinking RR 0.86 (95% CI 0.81 to 0.91); NNT 9.09 (95% CI 6.66 to 14.28) and to significantly increase the cumulative abstinence duration MD 10.94 (95% CI 5.08 to 16.81), while secondary outcomes (gamma-glutamyltransferase, heavy drinking) did not reach statistical significance. Diarrhea was the only side effect that was more frequently reported under acamprosate than placebo RD 0.11 (95% 0.09 to 0.13); NNTB 9.09 (95% CI 7.69 to 11.11). Effects of industry-sponsored trials RR 0.88 (95% 0.80 to 0.97) did not significantly differ from those of non-profit funded trials RR 0.88 (95% CI 0.81 to 0.96). In addition, the linear regression test did not indicate a significant risk of publication bias (p = 0.861).
AUTHORS' CONCLUSIONS
Acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients. Even though the sizes of treatment effects appear to be rather moderate in their magnitude, they should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment.
Topics: Acamprosate; Adult; Alcohol Deterrents; Alcohol-Related Disorders; Diarrhea; Humans; Placebo Effect; Randomized Controlled Trials as Topic; Taurine
PubMed: 20824837
DOI: 10.1002/14651858.CD004332.pub2 -
The Cochrane Database of Systematic... Jan 2023Alcohol use disorder (AUD) is one of the most widespread psychiatric disorders leading to detrimental consequences to people with this disorder and others. Worldwide,... (Review)
Review
BACKGROUND
Alcohol use disorder (AUD) is one of the most widespread psychiatric disorders leading to detrimental consequences to people with this disorder and others. Worldwide, the prevalence of heavy episodic drinking (30-day prevalence of at least one occasion of 60 g of pure alcohol intake among current drinkers) is estimated at 20% and the prevalence of AUD at 5% of the adult general population, with highest prevalence in Europe and North America. Therapeutic approaches, including pharmacotherapy, play an important role in treating people with AUD. This is an update of a Cochrane Review first published in 2018.
OBJECTIVES
To evaluate the benefits and harms of baclofen on achieving and maintaining abstinence or reducing alcohol consumption in people with AUD compared to placebo, no treatment or any other pharmacological relapse prevention treatment.
SEARCH METHODS
We used standard, extensive Cochrane search methods. The latest search was 22 November 2021.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of at least four weeks' treatment duration and 12 weeks' overall study duration comparing baclofen for AUD treatment with placebo, no treatment or other treatments.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Our primary outcomes were 1. relapse, 2. frequency of use, 3. amount of use, 4. adverse events, 5. dropouts from treatment and 6. dropouts from treatment due to adverse events. Our secondary outcomes were 7. craving, 8. anxiety, 9. depression and 10. frequency of most relevant adverse events.
MAIN RESULTS
We included 17 RCTs (1818 participants) with a diagnosis of alcohol dependence according to the Diagnostic and Statistical Manual of Mental Disorders, 4th edition or International Classification of Diseases 10th edition criteria. Mean age was 46.5 years and 70% were men. Ten studies compared baclofen to placebo or another medication; seven compared two baclofen doses to placebo or another medication. Globally, 15 studies compared baclofen to placebo, two baclofen to acamprosate and two baclofen to naltrexone. In 16 studies, participants received psychosocial treatments. We judged most studies at low risk of selection, performance, detection (subjective outcome), attrition and reporting bias. Ten studies detoxified participants before treatment; in seven studies, participants were still drinking at the beginning of treatment. Treatment duration was 12 weeks for 15 RCTs and longer in two studies. Baclofen daily dose was 30 mg to 300 mg: 10 RCTs used low doses (30 mg or less); eight RCTs medium doses (above 30 and 100 mg or less) and four RCTs high doses (above 100 mg). Compared to placebo, moderate-certainty evidence found that baclofen probably decreases the risk to relapse (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.77 to 0.99; 12 studies, 1057 participants). This result was confirmed among detoxified participants but not among other subgroups of participants. High-certainty evidence found that baclofen increases the percentage of days abstinent (mean difference (MD) 9.07, 95% CI 3.30 to 14.85; 16 studies, 1273 participants). This result was confirmed among all subgroups of participants except non-detoxified or those who received medium doses. There was no difference between baclofen and placebo in the other primary outcomes: heavy drinking days (standardised mean difference (SMD) -0.18, 95% CI -0.48 to 0.11; 13 studies, 840 participants; moderate-certainty evidence); number of drinks per drinking days (MD -0.45, 95% CI -1.20 to 0.30; 9 studies, 392 participants; moderate-certainty evidence); number of participants with at least one adverse event (RR 1.05, 95% CI 0.99 to 1.11; 10 studies, 738 participants; high-certainty evidence); dropouts (RR 0.88, 95% CI 0.74 to 1.03; 17 studies, 1563 participants; high-certainty evidence); dropouts due to adverse events (RR 1.39, 95% CI 0.89 to 2.18; 16 studies, 1499 participants; high-certainty evidence). These results were confirmed by subgroup analyses except than for the dropouts that resulted lower among participants who received high doses of baclofen and studies longer than 12 weeks. Compared to placebo, there was no difference in craving (SMD -0.16, 95% CI -0.37 to 0.04; 17 studies, 1275 participants), anxiety (MD -0.01, 95% CI -0.14 to 0.11; 15 studies, 1123 participants) and depression (SMD 0.07, 95% CI -0.12 to 0.27; 11 studies, 1029 participants). Concerning the specific adverse events, baclofen increases fatigue, dizziness, somnolence/sedation, dry mouth, paraesthesia and muscle spasms/rigidity. There was no difference in the other adverse events. Compared to acamprosate, one study (60 participants) found no differences in any outcomes but the evidence was very uncertain: relapse (RR 1.25, 95% CI 0.71 to 2.20; very low-certainty evidence); number of participants with at least one adverse event (RR 0.63, 95% CI 0.23 to 1.69; very low-certainty evidence); dropouts (RR 0.56, 95% CI 0.21 to 1.46; very low-certainty evidence); dropouts due to adverse events (RR 0.33, 95% CI 0.01 to 7.87; very low-certainty evidence) and craving (MD 5.80, 95% CI -11.84 to 23.44); and all the adverse events evaluated. Compared to naltrexone, baclofen may increase the risk of relapse (RR 2.50, 95% CI 1.12 to 5.56; 1 study, 60 participants; very low-certainty evidence) and decrease the number of participants with at least one adverse event (RR 0.35, 95% CI 0.15 to 0.80; 2 studies, 80 participants; very low-certainty evidence) but the evidence is very uncertain. One study (60 participants) found no difference between baclofen and naltrexone in the dropouts at the end of treatment (RR 1.00, 95% CI 0.32 to 3.10; very low-certainty evidence), craving (MD 2.08, 95% CI -3.71 to 7.87), and all the adverse events evaluated.
AUTHORS' CONCLUSIONS
Baclofen likely reduces the risk of relapse to any drinking and increases the percentage of abstinent days, mainly among detoxified participants. It does not increase the number of participants with at least one adverse event, those who dropout for any reason or due to adverse events. It probably does not reduce number of heavy drinking days and the number of drinks per drinking days. Current evidence suggests that baclofen may help people with AUD in maintaining abstinence. The results of comparisons of baclofen with acamprosate and naltrexone were mainly based on only one study.
Topics: Adult; Female; Humans; Male; Middle Aged; Acamprosate; Alcohol Drinking; Alcoholism; Baclofen; Chronic Disease; Naltrexone
PubMed: 36637087
DOI: 10.1002/14651858.CD012557.pub3 -
Drug and Alcohol Dependence Jan 2023Acamprosate and naltrexone, evidence-based pharmacotherapies for alcohol use disorder (AUD), are publicly covered by the Ontario Drug Benefit (ODB) programs; however,...
BACKGROUND
Acamprosate and naltrexone, evidence-based pharmacotherapies for alcohol use disorder (AUD), are publicly covered by the Ontario Drug Benefit (ODB) programs; however, their availability has changed over time, with expanded formulary access in July 2018, followed by an acamprosate shortage in February 2019 and ending in July 2020. We evaluated the impact of these events on the use of these medications in Ontario, Canada.
METHODS
We conducted a time-series analysis among individuals with AUD dispensed acamprosate or naltrexone through the ODB from July 2016 to December 2020. Outcomes included monthly rates of those with AUD on therapy (primary), and rate of initiation (secondary) overall and by treatment type. We used autoregressive moving average models to evaluate the impact of expanded coverage and the acamprosate shortage on rates of use, and reported characteristics at first dispensation.
RESULTS
Over the study period, 10,637 individuals (61.0% male) initiated acamprosate or naltrexone. Expanded coverage increased monthly utilization rates of acamprosate (p = 0.0004), naltrexone (p < 0.0001), and either AUD pharmacotherapy (p < 0.0001). The acamprosate shortage led to a 98.1% reduction in acamprosate use (p = 0.0003) but did not impact naltrexone (p = 0.51). Our secondary analysis yielded consistent results with respect to the shortage; however, the expanded formulary listing did not impact the rate of new acamprosate patients (p = 0.3). By December 2020, 5.3% of ODB recipients with AUD were accessing pharmacotherapy.
CONCLUSIONS
Although coverage expansion increased access to medications that treat AUD, the shortage of acamprosate led to large reductions in its use, with no responsive increase in naltrexone prescribing.
Topics: Humans; Male; Female; Acamprosate; Naltrexone; Alcohol Deterrents; Ontario; Taurine; Alcoholism
PubMed: 36463765
DOI: 10.1016/j.drugalcdep.2022.109705