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Huang MC, Tsai K, Shao YHJ. The use of baclofen to reduce alcohol-attributable hospitalizations and emergency department admissions. Alcohol 2025; 125:35-41. [PMID: 40097079 DOI: 10.1016/j.alcohol.2025.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2024] [Revised: 02/27/2025] [Accepted: 03/12/2025] [Indexed: 03/19/2025]
Abstract
AIMS The potential benefit of baclofen in reducing hospitalizations and emergency department (ED) admissions attributed to alcohol-related diagnoses has not been conclusively established. This study aimed to examine the relationship between baclofen use and the incidence of alcohol-attributable hospitalizations and ED admissions in the general population. METHODS We conducted a self-controlled case series study (SCCS) using data from the Taiwan National Health Insurance Research Database. 2904 patients who had at least one alcohol-attributable hospitalization or emergency department admission and were prescribed 28 or more days of baclofen unrelated to alcohol were included. Conditional Poisson regression was used to estimate the incidence rate ratio (IRR) and 95% confidence interval (CI) for the risk of alcohol-attributable hospitalizations and ED admissions during exposure to baclofen, as well as the pre- and post-exposure periods, relative to the baseline period. The contribution of concomitant psychotropic medication use was also assessed. RESULTS Baclofen was associated with a reduced incidence of alcohol-attributable hospitalizations (IRR = 0.64; 95% CI: 0.53∼0.77) and ED admissions (IRR = 0.56; 95% CI: 0.49∼0.65) in multivariate models. No statistically significant reduction was observed in any admission method in either the pre- or post-exposure period. A dose-dependent response in ED admissions was observed with baclofen, i.e. >60 mg/day associated with a greater decrease in the IRR (0.25, 95% CI: 0.10∼0.62) relative to doses of <30 (0.63, 95% CI: 0.53∼0.75) and 30-60 mg/day (IRR = 0.50, 95% CI: 0.40∼0.63). CONCLUSIONS These findings suggest a possible beneficial effect of baclofen in reducing the incidence of alcohol-attributable hospitalizations and ED admissions.
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Affiliation(s)
- Ming-Chyi Huang
- Department of Addiction Sciences, Taipei City Psychiatric Center, Taipei City Hospital, Taipei 110, Taiwan; Department of Psychiatry, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan; Psychiatric Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan
| | - Kevin Tsai
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, New Taipei City 235, Taiwan; Department of Epidemiology, University of Washington, Seattle, WA 98195, United States
| | - Yu-Hsuan Joni Shao
- Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University, New Taipei City 235, Taiwan; Clinical Big Data Research Center, Taipei Medical University Hospital, Taipei 110, Taiwan.
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Kotake K, So R, Hashimoto N, Imai E, Kaneko T, Banno M, Furukawa Y. Optimal Dose of Baclofen for the Treatment of Alcohol Use Disorder: A Systematic Review and Dose-Response Meta-analysis. CNS Drugs 2025:10.1007/s40263-025-01188-2. [PMID: 40347309 DOI: 10.1007/s40263-025-01188-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/17/2025] [Indexed: 05/12/2025]
Abstract
BACKGROUND AND OBJECTIVES Baclofen, a traditional treatment for spasticity, is gaining interest for its use in alcohol use disorder (AUD). To assist clinicians in using baclofen for effective and safe treatment of AUD, we investigated the optimal target dosage of baclofen through a systematic review and dose-response meta-analysis. METHODS We searched Cochrane, EMBASE, MEDLINE via PubMed, PsycINFO, ClinicalTrials.gov, and the International Clinical Trials Registry Platform for randomized controlled trials on 1 and 2 April 2024. Inclusion criteria were patients aged ≥ 18 years diagnosed with AUD according to Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV, DSM-IV-TR, or International Classification of Diseases (ICD)-10, and treated with baclofen monotherapy. Continuous outcomes-percent days abstinent, drinks per drinking day, heavy drinking days (HDDs), craving, and anxiety-were analyzed as mean or standardized mean differences. Binary outcomes-relapse and dropout, including due to adverse events-were analyzed as odds ratios. Each outcome was assessed using the Cochrane Risk of Bias 2.0 tool. A one-stage random-effects dose-response meta-analysis was performed using restricted cubic splines with fixed knots at 10%, 50%, and 90% percentiles. RESULTS A total of 14 trials (1344 patients) were included. Increasing the dose of baclofen up to 50-60 mg/day was associated with a higher percent days abstinent and reduced craving. However, a higher baclofen dose increases the risk of dropout due to adverse events. Commonly observed adverse events were drowsiness, sedation, somnolence and fatigue. Baclofen up to 50-60 mg/day did not significantly affect drinks per drinking day, HDDs, anxiety, relapse or dropout. Doses > 60 mg/day lacked reliable evaluation due to limited data and study heterogeneity. CONCLUSIONS Baclofen up to 50-60 mg/day may increase percent days abstinent and reduce craving, but may increase dropout due to adverse events. Clinicians should carefully consider individual patient factors when prescribing baclofen to patients with AUD.
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Affiliation(s)
- Kazumasa Kotake
- Department of Pharmacy, Zikei Hospital/Zikei Institute of Psychiatry, 100-2 Urayasu Honmachi, Minami-Ku, Okayama-shi, Okayama, 702-8508, Japan.
- Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan.
| | - Ryuhei So
- Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Psychiatry, Okayama Psychiatric Medical Center, Okayama, Japan
- CureApp, Inc., Tokyo, Japan
| | - Nozomu Hashimoto
- Department of Psychiatry, Okayama Psychiatric Medical Center, Okayama, Japan
- Department of Neuropsychiatry, Dentistry and Pharmaceutical Sciences, Okayama University Graduate School of Medicine, Okayama, Japan
| | - Eriya Imai
- Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan
- Division of Anesthesia, Mitsui Memorial Hospital, Tokyo, Japan
| | - Takao Kaneko
- Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Rehabilitation, Yamagata Prefectural Central Hospital, Yamagata, Japan
| | - Masahiro Banno
- Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Psychiatry, Seichiryo Hospital, Nagoya, Japan
| | - Yuki Furukawa
- Scientific Research WorkS Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Neuropsychiatry, University of Tokyo, Tokyo, Japan
- Department of Psychiatry and Psychotherapy, TUM School of Medicine and Health, Technical University of Munich, Munich, Bayern, Germany
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Wilson MA, Sumera A, Taylor LW, Meftah S, McGeachan RI, Modebadze T, Jayasekera BAP, Cowie CJA, LeBeau FEN, Liaquat I, Durrant CS, Brennan PM, Booker SA. Phylogenetic divergence of GABA B receptor signaling in neocortical networks over adult life. Nat Commun 2025; 16:4194. [PMID: 40328769 PMCID: PMC12056048 DOI: 10.1038/s41467-025-59262-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 04/15/2025] [Indexed: 05/08/2025] Open
Abstract
Cortical circuit activity is controlled by GABA-mediated inhibition in a spatiotemporally restricted manner. GABAB receptor (GABABR) signalling exerts powerful slow inhibition that controls synaptic, dendritic and neuronal activity. But, how GABABRs contribute to circuit-level inhibition over the lifespan of rodents and humans is poorly understood. In this study, we quantitatively determined the functional contribution of GABABR signalling to pre- and postsynaptic domains in rat and human cortical principal cells. We find that postsynaptic GABABR differentially control pyramidal cell activity within the cortical column as a function of age in rodents, but minimally change over adult life in humans. Presynaptic GABABRs exert stronger inhibition in humans than rodents. Pre- and postsynaptic GABABRs contribute to co-ordination of local information processing in a layer- and species-dependent manner. Finally, we show that GABABR signalling is elevated in patients that have received the anti-seizure medication Levetiracetam. These data directly increase our knowledge of translationally relevant local circuit dynamics, with direct impact on understanding the role of GABABRs in the treatment of seizure disorders.
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Affiliation(s)
- Max A Wilson
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK
- Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, EH8 9XD, UK
- Patrick Wild Centre, University of Edinburgh, Edinburgh, EH8 9XD, UK
| | - Anna Sumera
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK
- Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, EH8 9XD, UK
- Patrick Wild Centre, University of Edinburgh, Edinburgh, EH8 9XD, UK
| | - Lewis W Taylor
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK
- UK Dementia Research Institute at the University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Soraya Meftah
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK
- UK Dementia Research Institute at the University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Robert I McGeachan
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK
- UK Dementia Research Institute at the University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Tamara Modebadze
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, NE2 4HH, UK
| | - B Ashan P Jayasekera
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, NE2 4HH, UK
| | - Christopher J A Cowie
- Department of Neurosurgery, Royal Victoria Infirmary, Newcastle upon Tyne, NE1 4LP, UK
| | - Fiona E N LeBeau
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, NE2 4HH, UK
| | - Imran Liaquat
- Department for Clinical Neuroscience, NHS Lothian, Royal Infirmary Edinburgh, Edinburgh, EH16 4SB, UK
| | - Claire S Durrant
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK
- UK Dementia Research Institute at the University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Paul M Brennan
- Department for Clinical Neuroscience, NHS Lothian, Royal Infirmary Edinburgh, Edinburgh, EH16 4SB, UK
- Translational Neurosurgery, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK
| | - Sam A Booker
- Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, EH8 9XD, UK.
- Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, EH8 9XD, UK.
- Patrick Wild Centre, University of Edinburgh, Edinburgh, EH8 9XD, UK.
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Schacht JP, Ray LA, Miranda R, Falk DE, Ryan ML, Sakai JT, Miotto K, Chun T, Scott C, Ransom J, Alsharif N, Ito M, Litten RZ. Effects of a novel GABA-B positive allosteric modulator, ASP8062, on alcohol cue-elicited craving and naturalistic alcohol consumption in a multisite randomized, double-blind, placebo-controlled trial. ALCOHOL, CLINICAL & EXPERIMENTAL RESEARCH 2024; 48:2352-2363. [PMID: 39623527 DOI: 10.1111/acer.15468] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Revised: 08/22/2024] [Accepted: 09/30/2024] [Indexed: 12/11/2024]
Abstract
BACKGROUND The γ-aminobutyric acid-B (GABAB) receptor is a promising target for the development of new medications to treat alcohol use disorder (AUD). The GABAB agonist baclofen has been reported to reduce alcohol consumption but is associated with some undesirable side effects, including sedation. ASP8062 is a novel compound that acts as a positive allosteric modulator at the GABAB receptor and may be more tolerable than baclofen. This proof-of-concept human laboratory clinical trial evaluated the safety profile of ASP8062 and tested its effects on cue-elicited alcohol craving and alcohol use among treatment-seeking individuals with AUD. METHODS This double-blind, randomized, multisite trial tested the effect of ASP8062 (25 mg once daily), relative to placebo, on alcohol cue-elicited craving in a laboratory setting and alcohol consumption, craving, mood, sleep, cigarette smoking, and alcohol-related consequences in the natural environment over a 6-week treatment period. Participants were 60 individuals (26 females and 34 males) with moderate or severe AUD. RESULTS ASP8062, relative to placebo, was well tolerated, and there were no adverse events (AEs) that significantly differed between treatment groups. Most AEs were mild/moderate, and there were no serious AEs among individuals treated with ASP8062. However, ASP8062 did not attenuate alcohol cue-elicited craving compared with placebo. Moreover, exploratory analyses indicated that ASP8062, relative to placebo, did not significantly affect alcohol consumption, naturalistic alcohol craving, mood, sleep, cigarette smoking, or alcohol-related negative consequences during the 6-week treatment period. CONCLUSIONS Although ASP8062 was well tolerated with no serious AEs, the novel compound did not significantly dampen alcohol cue-elicited craving or improve other AUD-related outcome measures. These data indicate positive allosteric modulation of the GABAB receptor at the dose evaluated here may not blunt alcohol cue-elicited craving, and preliminary drinking outcome data suggest it may not be an efficacious treatment strategy for AUD.
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Affiliation(s)
- Joseph P Schacht
- Department of Psychiatry, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Lara A Ray
- Department of Psychology, University of California, Los Angeles, California, USA
| | - Robert Miranda
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA
| | - Daniel E Falk
- Division of Medications Development, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - Megan L Ryan
- Division of Medications Development, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
| | - Joseph T Sakai
- Department of Psychiatry, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Karen Miotto
- Department of Psychology, University of California, Los Angeles, California, USA
| | - Thomas Chun
- Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, California, USA
| | - Charles Scott
- Fast-Track Drugs & Biologics, LLC, Poolesville, Maryland, USA
| | - Janet Ransom
- Fast-Track Drugs & Biologics, LLC, Poolesville, Maryland, USA
| | - Nour Alsharif
- Astellas Pharma Global Development Inc., Northbrook, Illinois, USA
| | - Mototsugu Ito
- Astellas Pharma Global Development Inc., Northbrook, Illinois, USA
| | - Raye Z Litten
- Division of Medications Development, National Institute on Alcohol Abuse and Alcoholism, Bethesda, Maryland, USA
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Agabio R, Lopez-Pelayo H, Bruguera P, Huang SY, Sardo S, Pecina M, Krupitsky EM, Fitzmaurice GM, Lin Z. Efficacy of medications for the treatment of alcohol use disorder (AUD): A systematic review and meta-analysis considering baseline AUD severity. Pharmacol Res 2024; 209:107454. [PMID: 39396764 DOI: 10.1016/j.phrs.2024.107454] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 10/05/2024] [Accepted: 10/06/2024] [Indexed: 10/15/2024]
Abstract
Baseline severity of alcohol use disorder (AUD) is an influencing factor in the response to medications recommended for the treatment of AUD. The scarce efficacy of AUD medications partly justifies their limited uses. We were interested in evaluating the efficacy of approved and recommended AUD medications using generic inverse-variance, an analysis facilitating comparison between medications and placebo both at the end of the study and, concomitantly, to baseline values for the same participants. We conducted a systematic review to include randomized controlled trials (RCTs) comparing any medication to placebo providing, both at baseline and end of treatment, percent heavy drinking days (%HDD), percent drinking days (%DD), and/or drinks per drinking day (DDD). We searched PubMed, Embase, PMC, and three CT registers from inception to April 2023. A total of 79 RCTs (11,737 AUD participants; 30 different medications) were included: 47 RCTs (8465 participants) used AUD medications, and 32 RCTs (3272 participants) used other medications. At baseline, participants consumed on average approximately 12 DDD, and experienced 70 % DD, and 61 % HDD. Placebo halved or reduced these values to a third. Compared to placebo, AUD medications further reduced these outcomes (moderate to high certainty evidence). Other medications reduced the DDD without modifying other alcohol outcomes. AUD medications increased the risk of developing adverse events (high-certainty evidence). Despite the large placebo effects, our results support the benefits of providing AUD medications to people with AUD, helping them reduce alcohol consumption.
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Affiliation(s)
- Roberta Agabio
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, CA, Italy.
| | - Hugo Lopez-Pelayo
- Health and Addictions Research Group, IDIBAPS, Addictions Unit. Psychiatry and Psychology Service, ICN, Hospital Clinic Barcelona, Barcelona, Spain
| | - Pol Bruguera
- Health and Addictions Research Group, IDIBAPS, Addictions Unit. Psychiatry and Psychology Service, ICN, Hospital Clinic Barcelona, Barcelona, Spain
| | - San-Yuan Huang
- Department of Psychiatry, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan
| | - Salvatore Sardo
- Department of Medical Sciences and Public Health, University of Cagliari, Monserrato, CA, Italy
| | - Marta Pecina
- Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
| | - Evgeny M Krupitsky
- Department of Addictions, Bekhterev National Medical Research Center for Psychiatry and Neurology, Bekhtereva street, 3, St. Petersburg 192019, Russia; Valdman Institute of Pharmacology, First St.-Petersburg Pavlov State Medical University, Lev Tolstoy Street, 6-8, St-Petersburg 197022, Russia
| | - Garrett M Fitzmaurice
- Laboratory for Psychiatric Biostatistics, McLean Hospital, Belmont, MA, USA; Department of Psychiatry, Harvard Medical School, Boston, MA, USA
| | - Zhicheng Lin
- Department of Psychiatry, Harvard Medical School, Boston, MA, USA; Laboratory for Psychiatric Neurogenomics, McLean Hospital, Belmont, MA, USA
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Stewart C, Simonsen H, Satyasi SK, Ashraf N, Sukpraprut-Braaten S. A Systematic Review of Phenibut Withdrawals. Cureus 2024; 16:e68775. [PMID: 39376891 PMCID: PMC11456982 DOI: 10.7759/cureus.68775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2024] [Indexed: 10/09/2024] Open
Abstract
Phenibut is an anxiolytic agent that was originally used as a treatment for anxiety, depression, post-traumatic stress disorder (PTSD), and insomnia. It is a gamma-aminobutyric acid (GABA) mimetic, which stimulates GABA receptors in the brain. This increases the inhibitory effects of GABA leading to a greater chance of a sedative response and risk for abuse. It is not currently registered in Western countries but is easily accessible online as a supplement. This is a systematic review of case reports of phenibut patients with withdrawal symptoms published in the PubMed database between January 2010 and October 2023. Following the inclusion criteria application, 15 articles were included. Descriptive statistics were used to analyze the results. The average age of patients with phenibut withdrawals was 31.8 years (SD=12.66 years), and 13 cases (87%) were males. The average dosage was 13.6 g/day (SD=8 g), ranging from 1.5 to 28.5 g/day. Nine cases (60%) presented at an emergency department, and three cases (17%) were presented at a clinic setting facility. The most common history of patients who took phenibut was alcohol or drug abuse (73%). A history of anxiety and depression (60%) was also seen in the majority of patient presentations. Phenibut is never prescribed in the United States, and there are no official guidelines for phenibut use. Educating all physicians about the potentially harmful supplements available to patients and their biological mechanisms is essential. This review highlights the importance of collecting a thorough patient history, including supplements, to help prevent phenibut misuse and subsequent withdrawals.
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Kotake K, Hosokawa T, Tanaka M, So R, Banno M, Kataoka Y, Shiroshita A, Hashimoto Y. Efficacy and safety of alcohol reduction pharmacotherapy according to treatment duration in patients with alcohol dependence or alcohol use disorder: A systematic review and network meta-analysis. Addiction 2024; 119:815-832. [PMID: 38173342 DOI: 10.1111/add.16421] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Accepted: 11/16/2023] [Indexed: 01/05/2024]
Abstract
BACKGROUND AND AIMS Relapse is common in alcohol dependence (AD) and alcohol use disorder (AUD), so alcohol reduction therapy should be measured over as long a period as possible; however, existing reviews do not consider the duration of treatment and therefore alcohol reduction therapy may not have been appropriately evaluated. This review evaluated the efficacy and safety of alcohol reduction pharmacotherapy in patients with AD or AUD according to the duration of treatment. METHODS We conducted a systematic review and network meta-analysis of randomized controlled trials (RCTs) that assessed 15 pharmacological agents. MEDLINE, Embase, PsycINFO, the Cochrane Central Register of Controlled Trials, the ClinicalTrials.gov and the International Clinical Trials Registry Platform were searched for eligible trials through to May 2021. Outcomes were heavy drinking days (HDD), total alcohol consumption (TAC), any adverse event and days without drinking. RESULTS Fifty-five RCTs (n = 8891) were included. Nalmefene was superior to placebo for reducing HDD (standard mean difference [SMD] -0.28, 95% confidence interval [CI] -0.37, -0.18) and TAC (SMD -0.25, 95% CI -0.35, -0.16) in the long-term, but not in the short-term. Topiramate was superior to placebo for reducing HDD (SMD -0.35, 95% CI -0.59, -0.12) and days without drinking (SMD 0.46, 95% CI 0.11, 0.82), and baclofen was superior for reducing TAC (SMD -0.70, 95% CI -1.29, -0.11), in the short-term. The frequency of adverse events was higher with nalmefene and topiramate than with placebo. CONCLUSION Nalmefene, topiramate and baclofen may be effective as alcohol reduction pharmacotherapy; however, only nalmefene has demonstrated long-term efficacy, and nalmefene and topiramate have a significantly higher frequency of adverse events compared with placebo.
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Affiliation(s)
- Kazumasa Kotake
- Department of Pharmacy, Okayama Saiseikai General Hospital, Okayama, Japan
- Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
| | - Tomonari Hosokawa
- Department of Psychiatry, Zikei Hospital/Zikei Institute of Psychiatry, Okayama, Japan
| | - Masuo Tanaka
- Department of Psychiatry, Zikei Hospital/Zikei Institute of Psychiatry, Okayama, Japan
| | - Ryuhei So
- Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Psychiatry, Okayama Psychiatric Medical Center, Okayama, Japan
| | - Masahiro Banno
- Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Psychiatry, Seichiryo Hospital, Nagoya, Japan
- Department of Psychiatry, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuki Kataoka
- Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
- Department of Internal Medicine, Kyoto Min-iren Asukai Hospital, Kyoto, Japan
- Department of Healthcare Epidemiology, Kyoto University Graduate School of Medicine/School of Public Health, Kyoto, Japan
- Section of Clinical Epidemiology, Department of Community Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Akihiro Shiroshita
- Scientific Research Works Peer Support Group (SRWS-PSG), Osaka, Japan
- Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA
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Guiraud J, Spanagel R, van den Brink W. Substitution therapy for patients with alcohol dependence: Mechanisms of action and efficacy. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2024; 175:187-239. [PMID: 38555116 DOI: 10.1016/bs.irn.2024.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/02/2024]
Abstract
New approaches for the treatment of alcohol dependence (AD) may improve patient outcomes. Substitution maintenance therapy is one of the most effective treatment options for opioid and nicotine use disorders. So far, there has been little attention to substitution therapy for the treatment of AD. Here, we explain the mechanistic foundations of alcohol substitution maintenance therapy. Alcohol has many primary targets in the brain (and other organs) and the physical interaction of ethanol molecules with these specific ethanol-sensitive sites on a variety of ionotropic receptors (e.g. GABA-A, NMDA, and nicotinic acetylcholine (nACh) receptors) and ion channels provides the rationale for substitution. As such, a variety of compounds can interact with those ethanol-sensitive sites and can thus substitute for some of the effects of alcohol. For some of these compounds, alcohol discrimination studies have shown their substitution potential. Accordingly, potential substitution treatments include agonists acting at GABA receptors such as sodium oxybate, baclofen and benzodiazepines, NMDA receptor antagonists such as ketamine and memantine, or nAChRs agonists such as varenicline. All these compounds are already approved for other indications and we present clinical evidence for these drugs in the treatment of alcohol withdrawal syndrome (AWS) and in the long-term treatment of AD, and outline future steps for their acceptance as substitution treatment in AD. Finally, we discuss the substitution approach of managed alcohol programs for the most severely affected homeless populations. Results showed that sodium oxybate is probably the closest to a substitution therapy for AD and is already approved for the treatment of AWS and in the long-term treatment of AD in some countries. In conclusion, we argue that better AD treatment can be provided if substitution maintenance treatments for alcohol are implemented at a similar scale as for opioid and nicotine use disorder.
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Affiliation(s)
- Julien Guiraud
- Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, Amsterdam, The Netherlands; Vergio, Clichy, France.
| | - Rainer Spanagel
- Institute of Psychopharmacology, Central Institute of Mental Health, Heidelberg University, Mannheim, Germany
| | - Wim van den Brink
- Amsterdam UMC, Location Academic Medical Center, University of Amsterdam, Department of Psychiatry, Amsterdam Neuroscience, Amsterdam, The Netherlands
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Hudson D, Howarth N, Idalsoaga F, Song YN, Islam A, Theiventhiran S, Díaz LA, Arab JP. Addiction and Liver Disease: Exploring the Complex Relationship and Implications for Clinical Management. CURRENT HEPATOLOGY REPORTS 2024; 23:110-122. [DOI: 10.1007/s11901-024-00630-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Accepted: 01/01/2024] [Indexed: 01/12/2025]
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10
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de Beaurepaire R, Jaury P. Baclofen in the treatment of alcohol use disorder: tailored doses matter. Alcohol Alcohol 2024; 59:agad090. [PMID: 38266071 PMCID: PMC10807704 DOI: 10.1093/alcalc/agad090] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 12/03/2023] [Accepted: 12/16/2023] [Indexed: 01/26/2024] Open
Abstract
AIMS To address the question of tailored baclofen prescribing in alcohol use disorder (AUD) in relation to dose-dependent efficacy and the potential danger of high doses and to provide suggestions for the use of high doses of baclofen in the treatment of AUD. The context is the approvement in France of baclofen in the treatment of AUD without dose limitation, making French physicians, who usually prescribe baclofen in a tailored manner, often use high or very high doses. METHODS A narrative review of the results of randomized controlled trials (RCTs) and observational studies that used tailored baclofen prescribing and of the severe adverse effects of baclofen that have been reported in the literature. RESULTS The results show that RCTs using tailored doses of baclofen in AUD are not completely demonstrative, though they are encouraging according to certain meta-analyses, while observational studies that used tailored doses constantly show a good effectiveness of baclofen treatment. The results suggest that many severe adverse effects of baclofen could be related to a nonrespect by physicians of prescription rules and appropriate treatment monitoring. CONCLUSIONS The use of tailored doses shows that the dose required to suppress cravings is highly variable, low or high, depending on each case. Analysis of the circumstances in which severe adverse effects occur suggest that a careful monitoring of baclofen prescribing might prevent a large majority of severe adverse effects. We propose that the education of the patients and the prescription skills, seriousness, and availability of the prescribing physicians are of major importance in the managing of tailored baclofen treatment of AUD.
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Affiliation(s)
- Renaud de Beaurepaire
- Renaud de Beaurepaire, GH Paul-Guiraud, 54 Avenue de La République, 94806 Villejuif, France
| | - Philippe Jaury
- Faculté de Médecine, Université Paris Cité, Paris, France
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Akimova VD, Barsegyan SS, Pleteneva TV. [Personalized character of toxic effects through mass nonlethal poisoning by phenazepam and other psychoactive substances]. Sud Med Ekspert 2024; 67:47-55. [PMID: 38353015 DOI: 10.17116/sudmed20246701147] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Over several months, 14 people were admitted in 6 hospitals with severe symptoms of intoxication with psychoactive substances as a result of mass poisoning. All symptoms occurred after taking a drink that contained crushed phenazepam tablets. Samples of blood (n=10) and urine (n=6) taken from 14 sufferers for forensic, chemical and toxicological examination were analyzed using the HPLC-MS/MS method. Phenazepam was detected in the biomaterial of all 14 patients. Other psychoactive substances (baclofen, pregabalin, chlorprothixene, chlorpromazine, phenibut, tramadol, diazepam), narcotic substances and ethanol were also found in the sufferers. The phenazepam concentration in the blood was in the range of 109.75-786.50 ng/ml, in the urine - 8.97-101.28 ng/ml. The pharmacokinetic and toxicokinetic characteristics of toxicants as well as additional factors characterizing the phenotype of the sufferer in addition to drug's content in the biological material must be taken into account to determine the toxicity level of phenazepam against the background of combined action with other psychoactive substances.
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Affiliation(s)
- V D Akimova
- Russian Center of Forensic Medical Expertise, Moscow, Russia
| | - S S Barsegyan
- Russian Center of Forensic Medical Expertise, Moscow, Russia
- Peoples' Friendship University of Russia, Moscow, Russia
| | - T V Pleteneva
- Serbsky Federal Medical Research Centre of Psychiatry and Narcology, Moscow, Russia
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Marin MCD, Pedro MOP, Perrotte G, Martins-da-Silva AS, Lassi DLS, Blaas IK, Castaldelli FI, Brisola dos Santos MB, Kortas GT, Campos MW, Torales J, Ventriglio A, Périco CDAM, Negrão AB, Leopoldo K, de Andrade AG, Malbergier A, Castaldelli-Maia JM. Pharmacological Treatment of Alcohol Cravings. Brain Sci 2023; 13:1206. [PMID: 37626562 PMCID: PMC10452441 DOI: 10.3390/brainsci13081206] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2023] [Revised: 08/03/2023] [Accepted: 08/04/2023] [Indexed: 08/27/2023] Open
Abstract
(1) Background: The treatment of substance addiction is challenging and has persisted for decades, with only a few therapeutic options. Although there are some recommendations for specific treatments for Alcohol Use Disorder (AUD), there is no specific medication used to treat alcohol cravings, which could benefit millions of patients that are suffering from alcoholism. Cravings, or the urge to use drugs, refer to the desire to experience the effects of a previously experienced psychoactive substance. (2) Methods: We included original studies of alcohol abuse or dependence extracted from a controlled, blind, pharmacological treatment study which presented measures and outcomes related to alcohol cravings. (3) Results: Specific drugs used for the treatment of alcoholism, such as Naltrexone and Acamprosate, have had the best results in relieving craving symptoms, as well as promoting abstinence. Baclofen and anticonvulsants such as Gabapentin and Topiramate have shown good results in promoting abstinence and the cessation of cravings. (4) Conclusions: Specific drugs used for the treatment of alcoholism to obtain the best results can be considered the gold standard for promoting abstinence and relieving cravings. Anticonvulsants and Baclofen also had good results, with these medications being considered as second-line ones. Varenicline is an option for alcohol dependents who also concomitantly ingest tobacco.
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Affiliation(s)
- Matheus Cheibub David Marin
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
- Hospital Sírio-Libanês, São Paulo 01308-050, Brazil; (M.O.P.P.); (M.B.B.d.S.)
| | - Maria Olívia Pozzolo Pedro
- Hospital Sírio-Libanês, São Paulo 01308-050, Brazil; (M.O.P.P.); (M.B.B.d.S.)
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
| | - Giuliana Perrotte
- Department of Neuroscience, Medical School, FMABC University Center, Santo André 09060-870, Brazil; (G.P.); (C.d.A.-M.P.)
| | - Anderson S. Martins-da-Silva
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
| | - Dangela L. S. Lassi
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
| | - Israel Kanaan Blaas
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
- Department of Neuroscience, Medical School, FMABC University Center, Santo André 09060-870, Brazil; (G.P.); (C.d.A.-M.P.)
| | | | | | - Guilherme Trevizan Kortas
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
- Hospital Sírio-Libanês, São Paulo 01308-050, Brazil; (M.O.P.P.); (M.B.B.d.S.)
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
| | - Marcela Waisman Campos
- Department of Cognitive Neurology, Neuropsychiatry, and Neuropsychology, Fleni, Buenos Aires C1428AQK, Argentina;
| | - Julio Torales
- Department of Medical Psychology, School of Medical Sciences, Universidad Nacional de Asunción, San Lorenzo 111454, Paraguay;
- Regional Institute of Health Research, Universidad Nacional de Caaguazú, Coronel Oviedo 050106, Paraguay
- School of Health Sciences, Universidad Sudamericana, Pedro Juan Caballero 130112, Paraguay
| | - Antonio Ventriglio
- Department of Experimental Medicine, Medical School, University of Foggia, 71100 Foggia, Italy;
| | | | - André B. Negrão
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
| | - Kae Leopoldo
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
| | - Arthur Guerra de Andrade
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
- Hospital Sírio-Libanês, São Paulo 01308-050, Brazil; (M.O.P.P.); (M.B.B.d.S.)
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
- Department of Neuroscience, Medical School, FMABC University Center, Santo André 09060-870, Brazil; (G.P.); (C.d.A.-M.P.)
| | - André Malbergier
- Perdizes Institute (IPer), Clinics Hospital of the Medical School (HCFMUSP), University of São Paulo, São Paulo 05021-001, Brazil; (M.C.D.M.); (D.L.S.L.); (I.K.B.); (G.T.K.); (A.B.N.); (A.G.d.A.); (A.M.)
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
| | - João Maurício Castaldelli-Maia
- Hospital Sírio-Libanês, São Paulo 01308-050, Brazil; (M.O.P.P.); (M.B.B.d.S.)
- Department of Psychiatry, Medical School, University of São Paulo, São Paulo 05403-903, Brazil; (A.S.M.-d.-S.); (K.L.)
- Department of Neuroscience, Medical School, FMABC University Center, Santo André 09060-870, Brazil; (G.P.); (C.d.A.-M.P.)
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Heilig M. Stress-related neuropeptide systems as targets for treatment of alcohol addiction: A clinical perspective. J Intern Med 2023; 293:559-573. [PMID: 37052145 DOI: 10.1111/joim.13636] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/14/2023]
Abstract
Alcohol use is a major cause of disability and death globally. These negative consequences disproportionately affect people who develop alcohol addiction, a chronic relapsing condition characterized by increased motivation to use alcohol, choice of alcohol over healthy, natural rewards, and continued use despite negative consequences. Available pharmacotherapies for alcohol addiction are few, have effect sizes in need of improvement, and remain infrequently prescribed. Research aimed at developing novel therapeutics has in large part focused on attenuating pleasurable or "rewarding" properties of alcohol, but this targets processes that primarily play a role as initiation factors. As clinical alcohol addiction develops, long-term changes in brain function result in a shift of affective homeostasis, and rewarding alcohol effects become progressively reduced. Instead, increased stress sensitivity and negative affective states emerge in the absence of alcohol and create powerful incentives for relapse and continued use through negative reinforcement, or "relief." Based on research in animal models, several neuropeptide systems have been proposed to play an important role in this shift, suggesting that these systems could be targeted by novel medications. Two mechanisms in this category, antagonism at corticotropin-releasing factor type 1, and neurokinin 1/substance P receptors, have been subject to initial evaluation in humans. A third, kappa-opioid receptor antagonism, has been evaluated in nicotine addiction and could soon be tested for alcohol. This paper discusses findings with these mechanisms to date, and their prospects as future targets for novel medications.
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Affiliation(s)
- Markus Heilig
- Center for Social and Affective Neuroscience, BKV, Linköping University and Department of Psychiatry, Linköping University Hospital, Linköping, Sweden
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Phimarn W, Sakhancord R, Paitoon P, Saramunee K, Sungthong B. Efficacy of Varenicline in the Treatment of Alcohol Dependence: An Updated Meta-Analysis and Meta-Regression. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2023; 20:4091. [PMID: 36901103 PMCID: PMC10001935 DOI: 10.3390/ijerph20054091] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 02/19/2023] [Accepted: 02/23/2023] [Indexed: 06/18/2023]
Abstract
BACKGROUND Although varenicline has been used for alcohol dependence (AD) treatment, its efficacy for this condition remains controversial. AIMS This systematic review and meta-analysis of randomized controlled trials (RCTs) assesses the efficacy and safety of varenicline in patients with AD. METHODS PubMed, Cochrane Library, ScienceDirect, Web of Science, and ThaiLis were systematically searched. RCTs investigating the efficacy and safety of varenicline in patients with AD were included. Study selection, data extraction, and quality assessment were independently performed by two authors. The Jadad score and Cochrane risk of bias were used to assess the quality of the included studies. Heterogeneity was assessed using I2 and chi-squared tests. RESULTS Twenty-two high-quality RCTs on 1421 participants were included. Varenicline significantly reduced alcohol-related outcomes compared with placebo based on percentage of abstinent days (standardized mean difference [SMD] 4.20 days; 95% confidence interval [CI]: 0.21, 8.19; p = 0.04), drinks per day (SMD -0.23 drinks; 95% CI: -0.43, -0.04; p = 0.02), drinks per drinking day (SMD -0.24 drinks; 95% CI: -0.44, -0.05; p = 0.01), craving assessed using the Penn alcohol craving scale (SMD -0.35; 95% CI: -0.59, -0.12; p = 0.003), and craving assessed using the alcohol urge questionnaire (SMD -1.41; 95% CI: -2.12, -0.71; p < 0.0001). However, there were no significant effects on abstinence rate, percentage of drinking days, percentage of heavy drinking days, alcohol intoxication, or drug compliance. Serious side effects were not observed in the varenicline or placebo groups. CONCLUSION Our results indicated that AD patients treated with varenicline showed improvement in percentage of very heavy drinking days, percentage of abstinent days, drinks per day, drinks per drinking day, and craving. However, well-designed RCTs with a large sample size and long duration on varenicline treatment in AD remain warranted to confirm our findings.
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Affiliation(s)
- Wiraphol Phimarn
- Social Pharmacy Research Unit, Faculty of Pharmacy, Mahasarakham University, Kantharawichai District, Maha Sarakham 44150, Thailand
| | - Rotjanawat Sakhancord
- Social Pharmacy Research Unit, Faculty of Pharmacy, Mahasarakham University, Kantharawichai District, Maha Sarakham 44150, Thailand
| | - Peerasaran Paitoon
- Social Pharmacy Research Unit, Faculty of Pharmacy, Mahasarakham University, Kantharawichai District, Maha Sarakham 44150, Thailand
| | - Kritsanee Saramunee
- Social Pharmacy Research Unit, Faculty of Pharmacy, Mahasarakham University, Kantharawichai District, Maha Sarakham 44150, Thailand
| | - Bunleu Sungthong
- Integrative Pharmaceuticals and Innovative of Pharmaceutical Technology Research Unit, Faculty of Pharmacy, Mahasarakham University, Kantharawichai District, Maha Sarakham 44150, Thailand
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Abstract
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.
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Affiliation(s)
- Roberta Agabio
- Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato (CA), Italy
| | - Rosella Saulle
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
| | | | - Silvia Minozzi
- Department of Epidemiology, Lazio Regional Health Service, Rome, Italy
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Logge W, Baillie A, Haber P, Towers E, Riordan BC, Morley K. Sex differences in the interrelations between stress, craving and alcohol consumption across individuals and time during baclofen treatment for alcohol dependence. Addict Behav 2023; 136:107462. [PMID: 36084413 DOI: 10.1016/j.addbeh.2022.107462] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2022] [Revised: 07/21/2022] [Accepted: 08/08/2022] [Indexed: 02/03/2023]
Abstract
AIMS Recent studies have suggested that females respond more favourably to baclofen treatment for alcohol use disorder. Females are generally more likely to drink to regulate stress reactivity and negative affect. This study thus aimed to evaluate the role of sex on the effect of baclofen on the relationship between daily alcohol consumption, stress and craving. METHODS A network analysis of fluctuations using vectorized autoregressive modelling was used to explore the relationship between daily surveys of alcohol consumption, stress and craving from daily diary data over 84 days from a randomised controlled trial of baclofen (30 mg or 75 mg per day) versus placebo in 104 participants with alcohol dependence (1, 2). Symptom interrelations across patients and across time were examined including temporal networks (time lagged), contemporaneous and between-subjects networks, and were examined for placebo and baclofen stratified by sex. RESULTS Overall, between persons, there was a significant relationship between stress and drinking in placebo treated individuals in females (r = -0.70, p < 0.001) but not males (r = 0.32, p = 0.054) that was not observed in baclofen treated individuals. No relationship was observed between stress and drinking in the baclofen group for either sex (p's < 0.45). DISCUSSION There appears to be some sex-specific differences whereby baclofen abolishes an overall association between stress and drinking in females, but this is not observed in males. Network analyses may assist in elucidating the mechanism of action of alcohol pharmacotherapies such as baclofen and understanding which symptoms and mechanisms are key for effective interventions.
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Affiliation(s)
- Warren Logge
- Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Edith Collins Centre for Translational Research, Sydney Local Health District NSW, Australia
| | - Andrew Baillie
- Sydney School of Health Sciences, the University of Sydney, Australia
| | - Paul Haber
- Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Edith Collins Centre for Translational Research, Sydney Local Health District NSW, Australia
| | - Ellen Towers
- Clinical School, Sydney Medical School, University of Sydney, NSW, Australia
| | - Benjamin C Riordan
- Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Centre for Alcohol Policy Research (CAPR), La Trobe University, VIC, Australia
| | - Kirsten Morley
- Clinical School, Sydney Medical School, University of Sydney, NSW, Australia; Edith Collins Centre for Translational Research, Sydney Local Health District NSW, Australia.
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Pelz P, Genauck A, Lorenz RC, Wüstenberg T, Wackerhagen C, Charlet K, Gleich T, Geisel O, Heinz A, Müller CA, Beck A. Effects of baclofen on insular gain anticipation in alcohol-dependent patients - a randomized, placebo-controlled, pharmaco-fMRI pilot trial. Psychopharmacology (Berl) 2023; 240:171-183. [PMID: 36538099 PMCID: PMC9816215 DOI: 10.1007/s00213-022-06291-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 12/05/2022] [Indexed: 12/24/2022]
Abstract
RATIONALE One hallmark of addiction is an altered neuronal reward processing. In healthy individuals (HC), reduced activity in fronto-striatal regions including the insula has been observed when a reward anticipation task was performed repeatedly. This effect could indicate a desensitization of the neural reward system due to repetition. Here, we investigated this hypothesis in a cohort of patients with alcohol use disorder (AUD), who have been treated with baclofen or a placebo. The efficacy of baclofen in AUD patients has been shown to have positive clinical effects, possibly via indirectly affecting structures within the neuronal reward system. OBJECTIVES Twenty-eight recently detoxified patients (13 receiving baclofen (BAC), 15 receiving placebo (PLA)) were investigated within a longitudinal, double-blind, and randomized pharmaco-fMRI design with an individually adjusted daily dosage of 30-270 mg. METHODS Brain responses were captured by functional magnetic resonance imaging (fMRI) during reward anticipation while participating in a slot machine paradigm before (t1) and after 2 weeks of individual high-dose medication (t2). RESULTS Abstinence rates were significantly higher in the BAC compared to the PLA group during the 12-week high-dose medication phase. At t1, all patients showed significant bilateral striatal activation. At t2, the BAC group showed a significant decrease in insular activation compared to the PLA group. CONCLUSIONS By affecting insular information processing, baclofen might enable a more flexible neuronal adaptation during recurrent reward anticipation, which could resemble a desensitization as previously observed in HC. This result strengthens the modulation of the reward system as a potential mechanism of action of baclofen. TRIAL REGISTRATION Identifier of the main trial (the BACLAD study) at clinical.gov: NCT0126665.
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Affiliation(s)
- Patricia Pelz
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany.
| | - Alexander Genauck
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Bernstein Center for Computational Neuroscience Berlin (BCCN), Unter Den Linden 6, 10099, Berlin, Germany
| | - Robert C Lorenz
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Lise Meitner Group for Environmental Neuroscience, Max Planck Institute for Human Development, Lentzallee 94, 14195, Berlin, Germany
| | - Torsten Wüstenberg
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Research Council Field of Focus IV, Core Facility for Neuroscience of Self-Regulation (CNSR), Heidelberg University, Hauptstr. 51, Building 3011, 69117, Heidelberg, Germany
| | - Carolin Wackerhagen
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Katrin Charlet
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Section On Clinical Genomics and Experimental Therapeutics (CGET), National Institute On Alcohol Abuse and Alcoholism (NIAAA), National Institutes of Health (NIH), 10 Center Drive, Bethesda, MD, 20892-1540, USA
| | - Tobias Gleich
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Epilepsy-Center Berlin-Brandenburg, Evangelisches Krankenhaus Königin Elisabeth Herzberge, Herzbergstr. 79, 10365, Berlin, Germany
| | - Olga Geisel
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Andreas Heinz
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Christian A Müller
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
| | - Anne Beck
- Department of Psychiatry and Neurosciences | CCM, Charité - Universitätsmedizin Berlin, Charitéplatz 1, 10117, Berlin, Germany
- Health and Medical University, Campus Potsdam, Olympischer Weg 1, 14471, Potsdam, Germany
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Paterson LM, Barker D, Cro S, Mozgunov P, Phillips R, Smith C, Nahar L, Paterson S, Lingford-Hughes AR. FORWARDS-1: an adaptive, single-blind, placebo-controlled ascending dose study of acute baclofen on safety parameters in opioid dependence during methadone-maintenance treatment-a pharmacokinetic-pharmacodynamic study. Trials 2022; 23:880. [PMID: 36258248 PMCID: PMC9579625 DOI: 10.1186/s13063-022-06821-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 10/05/2022] [Indexed: 11/17/2022] Open
Abstract
Background Treatment of opiate addiction with opiate substitution treatment (e.g. methadone) is beneficial. However, some individuals desire or would benefit from abstinence but there are limited options to attenuate problems with opiate withdrawal. Preclinical and preliminary clinical evidence suggests that the GABA-B agonist, baclofen, has the desired properties to facilitate opiate detoxification and prevent relapse. This study aims to understand whether there are any safety issues in administering baclofen to opioid-dependent individuals receiving methadone. Methods Opiate-dependent individuals (DSM-5 severe opioid use disorder) maintained on methadone will be recruited from addiction services in northwest London (NHS and third sector providers). Participants will be medically healthy with no severe chronic obstructive pulmonary disease or type 2 respiratory failure, no current dependence on other substances (excluding nicotine), no current severe DSM-5 psychiatric disorders, and no contraindications for baclofen or 4800 IU vitamin D (placebo). Eligible participants will be randomised in a 3:1 ratio to receive baclofen or placebo in an adaptive, single-blind, ascending dose design. A Bayesian dose-escalation model will inform the baclofen dose (10, 30, 60, or 90 mg) based on the incidence of ‘dose-limiting toxicity’ (DLT) events and participant-specific methadone dose. A range of respiratory, cardiovascular, and sedative measures including the National Early Warning Score (NEWS2) and Glasgow Coma Scale will determine DLT. On the experimental day, participants will consume their usual daily dose of methadone followed by an acute dose of baclofen or placebo (vitamin D3) ~ 1 h later. Measures including oxygen saturation, transcutaneous CO2, respiratory rate, QTc interval, subjective effects (sedation, drug liking, craving), plasma levels (baclofen, methadone), and adverse events will be obtained using validated questionnaires and examinations periodically for 5 h after dosing. Discussion Study outcomes will determine what dose of baclofen is safe to prescribe to those receiving methadone, to inform a subsequent proof-of-concept trial of the efficacy baclofen to facilitate opiate detoxification. To proceed, the minimum acceptable dose is 30 mg of baclofen in patients receiving ≤ 60 mg/day methadone based on the clinical experience of baclofen’s use in alcoholism and guidelines for the management of opiate dependence. Trial registration Clinicaltrials.gov NCT05161351. Registered on 16 December 2021. Supplementary Information The online version contains supplementary material available at 10.1186/s13063-022-06821-9.
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Affiliation(s)
- L M Paterson
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK.
| | - D Barker
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK
| | - S Cro
- Imperial Clinical Trials Unit, Imperial College London, London, UK
| | - P Mozgunov
- MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - R Phillips
- Imperial Clinical Trials Unit, Imperial College London, London, UK
| | - C Smith
- Imperial Clinical Trials Unit, Imperial College London, London, UK
| | - L Nahar
- Toxicology Unit, Imperial College London, London, UK
| | - S Paterson
- Toxicology Unit, Imperial College London, London, UK
| | - A R Lingford-Hughes
- Division of Psychiatry, Department of Brain Sciences, Imperial College London, London, UK
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19
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Fischler PV, Soyka M, Seifritz E, Mutschler J. Off-label and investigational drugs in the treatment of alcohol use disorder: A critical review. Front Pharmacol 2022; 13:927703. [PMID: 36263121 PMCID: PMC9574013 DOI: 10.3389/fphar.2022.927703] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Accepted: 06/30/2022] [Indexed: 11/13/2022] Open
Abstract
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.
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Affiliation(s)
- Pascal Valentin Fischler
- Department for Gynecology and Obstetrics, Women’s Clinic Lucerne, Cantonal Hospital of Lucerne, Lucerne, Switzerland
- *Correspondence: Pascal Valentin Fischler,
| | - Michael Soyka
- Psychiatric Hospital University of Munich, Munich, Germany
| | - Erich Seifritz
- Director of the Clinic for Psychiatry, Psychotherapy and Psychosomatics, Psychiatric University Clinic Zürich, Zürich, Switzerland
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20
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Martins B, Rutland W, De Aquino JP, Kazer BL, Funaro M, Potenza MN, Angarita GA. Helpful or Harmful? The Therapeutic Potential of Medications with Varying Degrees of Abuse Liability in the Treatment of Substance Use Disorders. CURRENT ADDICTION REPORTS 2022; 9:647-659. [PMID: 35990796 PMCID: PMC9376579 DOI: 10.1007/s40429-022-00432-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/26/2022] [Indexed: 11/06/2022]
Abstract
Purpose of Review This review summarizes recent clinical trial research on pharmacological treatments for substance use disorders, with a specific focus on agents with potential abuse liability. Recent Findings Pharmacological treatments for substance use disorders may include gabapentinoids, baclofen, modafinil, ketamine, cannabinoids, gamma-hydroxybutyrate, and psychedelics. Gabapentinoids may decrease negative subjective effects of withdrawal in alcohol and cannabis use disorders. Cannabinoids similarly appear to decrease use and withdrawal symptoms in cannabis use disorder, while research shows stimulant medications may reduce cravings and increase abstinence in cocaine use disorder. Ketamine and psychedelics may help treat multiple substance use disorders. Ketamine may reduce withdrawal symptoms, promote abstinence, and diminish cravings in alcohol and cocaine use disorders and psychedelics may promote remission, decrease use, and reduce cravings in alcohol and opioid use disorders. Summary Regardless of current regulatory approval statuses and potentials for abuse, multiple agents should not be dismissed prematurely as possible treatments for substance use disorders. However, further clinical research is needed before effective implementation can begin in practice. Supplementary Information The online version contains supplementary material available at 10.1007/s40429-022-00432-9.
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Affiliation(s)
- Bradford Martins
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519 USA
| | - Will Rutland
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519 USA
| | - Joao P. De Aquino
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519 USA
| | - Benjamin L. Kazer
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519 USA
| | - Melissa Funaro
- Harvey Cushing/John Hay Whitney Medical Library, Yale University, New Haven, CT 06510 USA
| | - Marc N. Potenza
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
- Child Study Center, Yale University School of Medicine, New Haven, CT 06510 USA
- Department of Neuroscience, Yale University, New Haven, CT 06510 USA
- Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519 USA
- Connecticut Council On Problem Gambling, Wethersfield, CT 06109 USA
- Wu Tsai Institute, Yale University, New Haven, CT 06510 USA
| | - Gustavo A. Angarita
- Department of Psychiatry, Yale University School of Medicine, 300 George Street, Suite 901, New Haven, CT 06511 USA
- Clinical Neuroscience Research Unit, Connecticut Mental Health Center, 34 Park Street, New Haven, CT 06519 USA
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21
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McKee SA, McRae-Clark AL. Consideration of sex and gender differences in addiction medication response. Biol Sex Differ 2022; 13:34. [PMID: 35761351 PMCID: PMC9235243 DOI: 10.1186/s13293-022-00441-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/08/2022] [Indexed: 12/22/2022] Open
Abstract
Substance use continues to contribute to significant morbidity and mortality in the United States, for both women and men, more so than another other preventable health condition. To reduce the public health burden attributable to substances, the National Institute on Drug Abuse and the National Institute on Alcohol Abuse and Alcoholism have identified that medication development for substance use disorder is a high priority research area. Furthermore, both Institutes have stated that research on sex and gender differences in substance use medication development is a critical area. The purpose of the current narrative review is to highlight how sex and gender have been considered (or not) in medication trials for substance use disorders to clarify and summarize what is known regarding sex and gender differences in efficacy and to provide direction to the field to advance medication development that is consistent with current NIH 'sex as a biological variable' (SABV) policy. To that end, we reviewed major classes of abused substances (nicotine, alcohol, cocaine, cannabis, opioids) demonstrating that, sex and gender have not been well-considered in addiction medication development research. However, when adequate data on sex and gender differences have been evaluated (i.e., in tobacco cessation), clinically significant differences in response have been identified between women and men. Across the other drugs of abuse reviewed, data also suggest sex and gender may be predictive of outcome for some agents, although the relatively low representation of women in clinical research samples limits making definitive conclusions. We recommend the incorporation of sex and gender into clinical care guidelines and improved access to publicly available sex-stratified data from medication development investigations.
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Affiliation(s)
- Sherry A. McKee
- Yale School of Medicine, 2 Church St South, Suite 109, New Haven, CT 06519 USA
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22
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Dhanda AD, Allende H, Allgar V, Andrade J, Bailey MP, Callaghan L, Cocking L, Goodwin E, Hawton A, Hayward C, Hudson B, Jeffery A, King A, Lavers V, Lomax J, McCune CA, Parker R, Rollinson C, Wilks J, Creanor ES. Mental Imagery to Reduce Alcohol-related harm in patients with alcohol dependence and alcohol-related liver damaGE: the MIRAGE pilot trial protocol. BMJ Open 2022; 12:e060498. [PMID: 35584873 PMCID: PMC9119183 DOI: 10.1136/bmjopen-2021-060498] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
INTRODUCTION In the UK, alcohol use is the main driver of chronic liver disease and each year results in over 1 million unplanned hospital admissions and over 25 000 deaths from alcohol-related liver disease (ArLD). The only effective treatment to prevent progression of liver damage is reducing or ceasing alcohol consumption. Psychological and pharmacological therapies for alcohol misuse are ineffective in patients with ArLD. Functional imagery training (FIT) is a novel psychological therapy that builds on motivational interviewing techniques with multisensory imagery. This pilot trial aims to test the feasibility of training alcohol liaison nurses to deliver FIT therapy and of recruiting and retaining patients with ArLD and alcohol dependence to a randomised trial of FIT and treatment as usual (TAU) versus TAU alone. METHODS AND ANALYSIS This is a randomised pilot trial of FIT and TAU versus TAU alone in 90 patients with ArLD and alcohol dependence admitted to one of four UK centres. The primary objectives are to estimate rates of screening, recruitment, randomisation, retention, adherence to FIT/TAU and a preliminary assessment of the FIT intervention in the ArLD population. Data from the pilot study will be used to finalise the design of a definitive randomised controlled trial to assess the effectiveness and cost-effectiveness of FIT. The proposed primary outcome measure for the definitive trial is self-reported alcohol use assessed using timeline follow-back. ETHICS AND DISSEMINATION Research ethics approval was given by the Yorkshire and Humber-Bradford Leeds Research Ethics Committee (reference: 21/YH/0044). Eligible patients will be approached and written informed consent obtained prior to participation. Results will be disseminated through peer-reviewed open access journals, international conferences and a lay summary published on the Trials Unit website and made available to patient groups. TRIAL REGISTRATION NUMBER ISRCTN41353774.
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Affiliation(s)
- Ashwin D Dhanda
- South West Liver Unit, University Hospitals Plymouth NHS Trust, Plymouth, UK
- Peninsula Medical School, University of Plymouth, Plymouth, UK
| | - Hannah Allende
- Research, Development and Innovation, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Victoria Allgar
- Peninsula Clinical Trials Unit, University of Plymouth, Plymouth, UK
| | - Jackie Andrade
- School of Psychology, University of Plymouth, Plymouth, UK
| | | | - Lynne Callaghan
- NIHR Peninsula ARC (PenARC), Peninsula Medical School, Plymouth, UK
| | - Laura Cocking
- Peninsula Clinical Trials Unit, University of Plymouth, Plymouth, UK
| | - Elizabeth Goodwin
- Health Economics Group, University of Exeter Medical School, Exeter, UK
| | - Annie Hawton
- Health Economics Group, University of Exeter Medical School, Exeter, UK
| | | | - Ben Hudson
- Department of Hepatology, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Alison Jeffery
- Peninsula Clinical Trials Unit, University of Plymouth, Plymouth, UK
| | - Angela King
- Peninsula Clinical Trials Unit, University of Plymouth, Plymouth, UK
| | | | - Joe Lomax
- Peninsula Clinical Trials Unit, University of Plymouth, Plymouth, UK
| | - C Anne McCune
- Department of Liver Medicine, University Hospitals Bristol and Weston NHS Foundation Trust, Bristol, UK
| | - Richard Parker
- Liver Unit, Leeds Teaching Hospitals NHS Trust, Leeds, UK
| | - Christopher Rollinson
- Research, Development and Innovation, University Hospitals Plymouth NHS Trust, Plymouth, UK
| | - Jonny Wilks
- Peninsula Clinical Trials Unit, University of Plymouth, Plymouth, UK
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23
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Abstract
Alcohol use disorder (AUD) is a highly prevalent but severely under-treated disorder, with only three widely-approved pharmacotherapies. Given that AUD is a very heterogeneous disorder, it is unlikely that one single medication will be effective for all individuals with an AUD. As such, there is a need to develop new, more effective, and diverse pharmacological treatment options for AUD with the hopes of increasing utilization and improving care. In this qualitative literature review, we discuss the efficacy, mechanism of action, and tolerability of approved, repurposed, and novel pharmacotherapies for the treatment of AUD with a clinical perspective. Pharmacotherapies discussed include: disulfiram, acamprosate, naltrexone, nalmefene, topiramate, gabapentin, varenicline, baclofen, sodium oxybate, aripiprazole, ondansetron, mifepristone, ibudilast, suvorexant, prazosin, doxazosin, N-acetylcysteine, GET73, ASP8062, ABT-436, PF-5190457, and cannabidiol. Overall, many repurposed and novel agents discussed in this review demonstrate clinical effectiveness and promise for the future of AUD treatment. Importantly, these medications also offer potential improvements towards the advancement of precision medicine and personalized treatment for the heterogeneous AUD population. However, there remains a great need to improve access to treatment, increase the menu of approved pharmacological treatments, and de-stigmatize and increase treatment-seeking for AUD.
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24
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Grabski M, McAndrew A, Lawn W, Marsh B, Raymen L, Stevens T, Hardy L, Warren F, Bloomfield M, Borissova A, Maschauer E, Broomby R, Price R, Coathup R, Gilhooly D, Palmer E, Gordon-Williams R, Hill R, Harris J, Mollaahmetoglu OM, Curran HV, Brandner B, Lingford-Hughes A, Morgan CJA. Adjunctive Ketamine With Relapse Prevention-Based Psychological Therapy in the Treatment of Alcohol Use Disorder. Am J Psychiatry 2022; 179:152-162. [PMID: 35012326 DOI: 10.1176/appi.ajp.2021.21030277] [Citation(s) in RCA: 78] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Early evidence suggests that ketamine may be an effective treatment to sustain abstinence from alcohol. The authors investigated the safety and efficacy of ketamine compared with placebo in increasing abstinence in patients with alcohol use disorder. An additional aim was to pilot ketamine combined with mindfulness-based relapse prevention therapy compared with ketamine and alcohol education as a therapy control. METHODS In a double-blind placebo-controlled phase 2 clinical trial, 96 patients with severe alcohol use disorder were randomly assigned to one of four conditions: 1) three weekly ketamine infusions (0.8 mg/kg i.v. over 40 minutes) plus psychological therapy, 2) three saline infusions plus psychological therapy, 3) three ketamine infusions plus alcohol education, or 4) three saline infusions plus alcohol education. The primary outcomes were self-reported percentage of days abstinent and confirmed alcohol relapse at 6-month follow-up. RESULTS Ninety-six participants (35 women; mean age, 44.07 years [SD=10.59]) were included in the intention-to-treat analysis. The treatment was well tolerated, and no serious adverse events were associated with the study drug. Although confidence intervals were wide, consistent with a proof-of-concept study, there were a significantly greater number of days abstinent from alcohol in the ketamine group compared with the placebo group at 6-month follow-up (mean difference=10.1%, 95% CI=1.1, 19.0), with the greatest reduction in the ketamine plus therapy group compared with the saline plus education group (15.9%, 95% CI=3.8, 28.1). There was no significant difference in relapse rate between the ketamine and placebo groups. CONCLUSIONS This study demonstrated that treatment with three infusions of ketamine was well tolerated in patients with alcohol use disorder and was associated with more days of abstinence from alcohol at 6-month follow-up. The findings suggest a possible beneficial effect of adding psychological therapy alongside ketamine treatment.
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Affiliation(s)
- Meryem Grabski
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Amy McAndrew
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Will Lawn
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Beth Marsh
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Laura Raymen
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Tobias Stevens
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Lorna Hardy
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Fiona Warren
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Michael Bloomfield
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Anya Borissova
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Emily Maschauer
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Rupert Broomby
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Robert Price
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Rachel Coathup
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - David Gilhooly
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Edward Palmer
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Richard Gordon-Williams
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Robert Hill
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Jen Harris
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - O Merve Mollaahmetoglu
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - H Valerie Curran
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Brigitta Brandner
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Anne Lingford-Hughes
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
| | - Celia J A Morgan
- Psychopharmacology and Addiction Research Centre (Grabski, McAndrew, Marsh, Raymen, Stevens, Hardy, Maschauer, Palmer, Mollaahmetoglu, Morgan) and College of Medicine and Health (Warren), University of Exeter, Exeter, U.K.; Clinical Psychopharmacology Unit (Grabski, Lawn, Marsh, Bloomfield, Borissova, Curran) and Translational Psychiatry Research Group (Bloomfield), University College London; Royal Devon and Exeter NHS Foundation Trust, Exeter, U.K. (Broomby, Price); University College London Hospitals NHS Foundation Trust, London (Coathup, Gilhooly, Gordon-Williams, Brandner); South London and Maudsley NHS Foundation Trust, London (Hill, Harris); Faculty of Medicine, Department of Brain Sciences, Imperial College London (Lingford-Hughes)
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25
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Nielsen AS, Askgaard G, Thiele M. Treatment of alcohol use disorder in patients with liver disease. Curr Opin Pharmacol 2022; 62:145-151. [PMID: 34999372 DOI: 10.1016/j.coph.2021.11.012] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 11/28/2021] [Accepted: 11/30/2021] [Indexed: 12/18/2022]
Abstract
Alcohol contributes to more than 5% of global mortality, and causes more than half of all liver-related deaths. The Alcohol Use Disorders Identification Test (AUDIT) can be used to detect those patients with hazardous drinking and alcohol dependence who will benefit from psychosocial and pharmacological alcohol treatment. Psychosocial treatments range from brief interventions and cognitive behavioral therapy, to experimental neuropsychological treatments. Psychosocial intervention can be combined with acamprosate or naltrexone as first line pharmacological treatments. For patients with liver disease, abstinence increases survival and is therefore an important treatment goal. Acamprosate is a good choice, as it prevents relapse to drinking with a number needed to treat of 12. There are no reports indicating high risks of liver toxicity for acamprosate or naltrexone, but evidence is scarce. We recommend vigorous screening for alcohol use disorder in liver disease patients, followed by psychosocial intervention and complemented by pharmaceutical therapy.
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Affiliation(s)
- Anette Søgaard Nielsen
- Research Unit of Alcohol Research, Department of Clinical Research, University of Southern Denmark, Odense, Denmark
| | - Gro Askgaard
- Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark; Department of Medicine, Zealand University Hospital, Køge, Denmark; Center for Clinical Research and Prevention, Frederiksberg University Hospital, Copenhagen, Denmark
| | - Maja Thiele
- Center for Liver Research, Department of Gastroenterology and Hepatology, Odense University Hospital, Odense, Denmark; Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
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26
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Management of alcohol use disorder in patients with cirrhosis in the setting of liver transplantation. Nat Rev Gastroenterol Hepatol 2022; 19:45-59. [PMID: 34725498 PMCID: PMC8559139 DOI: 10.1038/s41575-021-00527-0] [Citation(s) in RCA: 77] [Impact Index Per Article: 25.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/21/2021] [Indexed: 02/07/2023]
Abstract
The prevalence of alcohol use disorder (AUD) has been steadily increasing over the past decade. In parallel, alcohol-associated liver disease (ALD) has been increasing at an alarming rate, especially among young patients. Data suggest that most patients with ALD do not receive AUD therapy. Although liver transplantation is the only curative therapy for end-stage ALD, transplant candidacy is often a matter of debate given concerns about patients being under-treated for AUD and fears of post-transplantation relapse affecting the allograft. In this Review, we discuss diagnosis, predictors and effects of relapse, behavioural therapies and pharmacotherapies, and we also propose an integrative, multidisciplinary and multimodality approach for treating AUD in patients with cirrhosis, especially in the setting of liver transplantation. Notably, this approach takes into account the utility of AUD pharmacotherapy in patients on immunosuppressive medications and those with renal impairment after liver transplantation. We also propose a comprehensive and objective definition of relapse utilizing contemporary biomarkers to guide future clinical trials. Future research using the proposed approach and definition is warranted with the goal of optimizing AUD treatment in patients with cirrhosis, the transplant selection process and post-transplantation care of patients with AUD.
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Bareli T, Ahdoot HL, Ben Moshe H, Barnea R, Warhaftig G, Gispan I, Maayan R, Rosca P, Weizman A, Yadid G. Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder-An Animal Model and a Human Study. Front Behav Neurosci 2021; 15:788708. [PMID: 35002647 PMCID: PMC8733380 DOI: 10.3389/fnbeh.2021.788708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28-60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.
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Affiliation(s)
- Tzofnat Bareli
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Hadas Levi Ahdoot
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Hila Ben Moshe
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Royi Barnea
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Gal Warhaftig
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Iris Gispan
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Rachel Maayan
- The Laboratory of Molecular Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Paola Rosca
- Department for the Treatment of Substance Abuse and Mental Health Services, Israeli Ministry of Health, Jerusalem, Israel
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abraham Weizman
- The Laboratory of Molecular Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Research Unit, Geha Mental Health Center, Petah Tikva, Israel
| | - Gal Yadid
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
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Garbutt JC, Kampov-Polevoy AB, Pedersen C, Stansbury M, Jordan R, Willing L, Gallop RJ. Efficacy and tolerability of baclofen in a U.S. community population with alcohol use disorder: a dose-response, randomized, controlled trial. Neuropsychopharmacology 2021; 46:2250-2256. [PMID: 34155332 PMCID: PMC8580979 DOI: 10.1038/s41386-021-01055-w] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 05/30/2021] [Accepted: 06/01/2021] [Indexed: 02/06/2023]
Abstract
Identification of new medications for alcohol use disorder (AUD) is important for improving treatment options. Baclofen, a GABAB agonist, has been identified as a potential pharmacotherapy for AUD. In a 16-week double-blind, randomized, placebo-controlled trial, we investigated 30 and 90 mg/day of baclofen compared to placebo and examined effects of dose, sex, and level of pretreatment drinking. One hundred and twenty participants with DSM-IV alcohol dependence (age 46.1 (sd = 10.1) years, 51.7% male) were randomized after exclusion for unstable medical/psychiatric illness and/or dependence on drugs other than nicotine. Seventy-three participants completed the trial. A main effect of baclofen was found [%HDD (F(2,112) = 4.16, p = 0.018, d = 0.51 95%CI (0.06-0.95), 13.6 fewer HDD) and %ABST (F(2,112) = 3.68, p = 0.028, d = 0.49 95%CI (0.04-0.93), 12.9 more abstinent days)] and was driven by the 90 mg/day dose. A sex × dose interaction effect was present for both %HDD (F(2,110) = 5.48, p = 0.005) and %ABST (F(2,110) = 3.19, p = 0.045). Men showed a marginally positive effect for 90 mg/day compared to PBO (%HDD t(110) = 1.88, p = 0.063, d = 0.36 95%CI (-0.09-0.80), 15.8 fewer HDD days; %ABST t(110) = 1.68 (p = 0.096, d = 0.32 95%CI (-0.12-0.76), 15.7 more ABST)) with no effect for 30 mg/day. Women showed a positive effect for 30 mg/day (%HDD, t(110) = 3.19, p = 0.002, d = 0.61 95%CI (0.16-1.05), 26.3 fewer HDD days; %ABST t(110) = 2.73, p = 0.007, d = 0.52 95%CI (0.07-0.96), 25.4 more ABST days) with marginal effects for 90 mg/day on %ABST (p = 0.06) with drop-outs/dose reduction from sedative side-effects of 59% in women at 90 mg/day compared to 5% for men. These findings support the hypothesis that baclofen has efficacy in AUD and suggest that dose and sex be further explored as potential moderators of baclofen response and tolerability.
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Affiliation(s)
- James C. Garbutt
- grid.10698.360000000122483208Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA ,grid.10698.360000000122483208Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Alexei B. Kampov-Polevoy
- grid.10698.360000000122483208Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA ,grid.10698.360000000122483208Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Cort Pedersen
- grid.10698.360000000122483208Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Melissa Stansbury
- grid.10698.360000000122483208Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Robyn Jordan
- grid.10698.360000000122483208Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Laura Willing
- grid.10698.360000000122483208Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC USA
| | - Robert J. Gallop
- grid.268132.c0000 0001 0701 2416Department of Mathematics, Applied Statistics Program, West Chester University, West Chester, PA USA
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Leggio L, Litten RZ. The GABA-B receptor agonist baclofen helps patients with alcohol use disorder: why these findings matter. Neuropsychopharmacology 2021; 46:2228-2229. [PMID: 34400781 PMCID: PMC8581012 DOI: 10.1038/s41386-021-01142-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 07/25/2021] [Accepted: 08/01/2021] [Indexed: 02/06/2023]
Affiliation(s)
- Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse and National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Baltimore and Bethesda, MD, USA. .,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA. .,Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, RI, USA. .,Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA. .,Department of Neuroscience, Georgetown University Medical Center, Washington, DC, USA.
| | - Raye Z. Litten
- grid.420085.b0000 0004 0481 4802Division of Treatment and Recovery, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD USA
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Cheron J, Kerchove d'Exaerde AD. Drug addiction: from bench to bedside. Transl Psychiatry 2021; 11:424. [PMID: 34385417 PMCID: PMC8361217 DOI: 10.1038/s41398-021-01542-0] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 07/14/2021] [Accepted: 07/23/2021] [Indexed: 02/06/2023] Open
Abstract
Drug addiction is responsible for millions of deaths per year around the world. Still, its management as a chronic disease is shadowed by misconceptions from the general public. Indeed, drug consumers are often labelled as "weak", "immoral" or "depraved". Consequently, drug addiction is often perceived as an individual problem and not societal. In technical terms, drug addiction is defined as a chronic, relapsing disease resulting from sustained effects of drugs on the brain. Through a better characterisation of the cerebral circuits involved, and the long-term modifications of the brain induced by addictive drugs administrations, first, we might be able to change the way the general public see the patient who is suffering from drug addiction, and second, we might be able to find new treatments to normalise the altered brain homeostasis. In this review, we synthetise the contribution of fundamental research to the understanding drug addiction and its contribution to potential novel therapeutics. Mostly based on drug-induced modifications of synaptic plasticity and epigenetic mechanisms (and their behavioural correlates) and after demonstration of their reversibility, we tried to highlight promising therapeutics. We also underline the specific temporal dynamics and psychosocial aspects of this complex psychiatric disease adding parameters to be considered in clinical trials and paving the way to test new therapeutic venues.
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Affiliation(s)
- Julian Cheron
- Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels, B-1070, Belgium
| | - Alban de Kerchove d'Exaerde
- Laboratory of Neurophysiology, ULB Neuroscience Institute, Université Libre de Bruxelles (ULB), Brussels, B-1070, Belgium.
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31
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Romito JW, Turner ER, Rosener JA, Coldiron L, Udipi A, Nohrn L, Tausiani J, Romito BT. Baclofen therapeutics, toxicity, and withdrawal: A narrative review. SAGE Open Med 2021; 9:20503121211022197. [PMID: 34158937 PMCID: PMC8182184 DOI: 10.1177/20503121211022197] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2021] [Accepted: 05/13/2021] [Indexed: 12/11/2022] Open
Abstract
Baclofen is an effective therapeutic for the treatment of spasticity related to multiple sclerosis, spinal cord injuries, and other spinal cord pathologies. It has been increasingly used off-label for the management of several disorders, including musculoskeletal pain, gastroesophageal reflux disease, and alcohol use disorder. Baclofen therapy is associated with potential complications, including life-threatening toxicity and withdrawal syndrome. These disorders require prompt recognition and a high index of suspicion. While these complications can develop following administration of either oral or intrathecal baclofen, the risk is greater with the intrathecal route. The management of baclofen toxicity is largely supportive while baclofen withdrawal syndrome is most effectively treated with re-initiation or supplementation of baclofen dosing. Administration of other pharmacologic adjuncts may be required to effectively treat associated withdrawal symptoms. This narrative review provides an overview of the historical and emerging uses of baclofen, offers practical dosing recommendations for both oral and intrathecal routes of administration, and reviews the diagnosis and management of both baclofen toxicity and withdrawal.
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Affiliation(s)
- Jia W Romito
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
- Department of Neurological Surgery, The
University of Texas Southwestern Medical Center, Dallas, TX, USA
- Department of Neurology, The University
of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Emily R Turner
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - John A Rosener
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Landon Coldiron
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Ashutosh Udipi
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Linsey Nohrn
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Jacob Tausiani
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
| | - Bryan T Romito
- Department of Anesthesiology and Pain
Management, The University of Texas Southwestern Medical Center, Dallas, TX,
USA
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32
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Logge WB, Morris RW, Baillie AJ, Haber PS, Morley KC. Baclofen attenuates fMRI alcohol cue reactivity in treatment-seeking alcohol dependent individuals. Psychopharmacology (Berl) 2021; 238:1291-1302. [PMID: 30788529 DOI: 10.1007/s00213-019-05192-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2018] [Accepted: 02/04/2019] [Indexed: 12/20/2022]
Abstract
RATIONALE Baclofen has been shown to effect fMRI alcohol cue reactivity in alcohol dependence, but potential varying effects related to baclofen dose levels have not been examined. OBJECTIVE This study investigated whether baclofen attenuates craving and alcohol cue-elicited activation in alcohol-dependent treatment seekers, and the relationship between this response and clinical outcomes (Morley et al. 2018; Morley et al. 2013). METHODS Participants included 30 alcohol-dependent individuals who had received daily baclofen 30 mg (n = 11), 75 mg (n = 8) or placebo (n = 11) for at least 2 weeks. Using functional magnetic resonance imaging (fMRI), we examined alcohol cue-elicited neural activation during a visual alcohol cue reactivity task 120 min following treatment administration, and alcohol cue reactivity and percentage of heavy drinking days (% HDD) associations were assessed. RESULTS Both baclofen-treated groups reported fewer post-scan % HDD when compared to the placebo-treated group, but no subjective craving group differences were found. Increased alcohol cue-elicited activation was seen in placebo compared to the 75 mg/day baclofen participants in two clusters spanning prefrontal regions implicated in cue reactivity, chiefly frontal regions (i.e., frontal and precentral gyri, anterior cingulate cortex), but no observed alcohol cue reactivity differences between placebo and 30 mg/day baclofen groups. Post-scan % HDD was positively correlated with increased alcohol cue-elicited activation in a cluster encompassing the bilateral caudate nucleus and dorsal anterior cingulate cortex when comparing placebo versus 75 mg/day baclofen groups, and several clusters including prefrontal and mesolimbic regions when comparing placebo versus 30 mg/day baclofen groups. CONCLUSIONS Baclofen administration attenuates alcohol cue-elicited activation and reduced the association in baclofen-treated participants between increased activity in key drug cue reactivity regions and higher post-scan % HDD observed in placebo-treated participants, suggesting a dose-specific response effect that may lead to reduced heavy drinking in chronic alcohol-dependent individuals. TRIAL REGISTRATION ClinicalTrials.gov , NCT01711125, https://clinicaltrials.gov/ct2/show /NCT01711125.
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Affiliation(s)
- Warren B Logge
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Lv 6, King George V Building, 83-117 Missenden Rd, Camperdown, NSW, 2050, Australia.
| | - Richard W Morris
- Central Clinical School, Faculty of Medicine and Health, & Centre for Translational Data Science, University of Sydney, Sydney, NSW, Australia
| | - Andrew J Baillie
- Faculty of Health Sciences, University of Sydney, Sydney, NSW, Australia
| | - Paul S Haber
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Lv 6, King George V Building, 83-117 Missenden Rd, Camperdown, NSW, 2050, Australia
- Drug Health Services, Royal Prince Alfred Hospital, Camperdown, NSW, Australia
| | - Kirsten C Morley
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, Lv 6, King George V Building, 83-117 Missenden Rd, Camperdown, NSW, 2050, Australia
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Morley KC, Logge WB, Fraser I, Morris RW, Baillie AJ, Haber PS. High-dose baclofen attenuates insula activation during anticipatory anxiety in treatment-seeking alcohol dependant individuals: Preliminary findings from a pharmaco-fMRI study. Eur Neuropsychopharmacol 2021; 46:28-36. [PMID: 33735709 DOI: 10.1016/j.euroneuro.2021.02.010] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 01/28/2021] [Accepted: 02/17/2021] [Indexed: 02/06/2023]
Abstract
The GABA B agonist, baclofen, has been shown to reduce alcohol consumption in patients with alcohol use disorder and also those with comorbid anxiety. This study aimed to evaluate the effect of baclofen versus placebo on the BOLD response during an anticipatory anxiety fMRI task in treatment seeking alcohol patients. Participants included 28 alcohol dependant individuals who had received daily baclofen 30 mg (n = 10), 75 mg (n = 8) or placebo (n = 10) for at least 2 week on a randomized controlled trial (Morley, Leung et al. 2013, Morley, Baillie et al. 2018). Using functional magnetic resonance imaging (fMRI), we examined threat cue-elicited neural activation during a threat reactivity task 120 min following administration of BAC (30 mg or 75 mg) or placebo. Whole-brain analyses revealed no significant differences between the combined BAC doses versus PL. However, there were significant decreases in anticipatory threat cue-elicited activation observed in BAC 75 mg/day compared to PL participants in the insula. In response to threat cues, high dose (75 mg/day) baclofen administration attenuates activation in the insula and inferior frontal gyrus, relative to placebo. These preliminary findings suggests that modulating emotional regulation and attentional allocation during high threat stimuli may be mediated by GABA B receptors and may be a potential mechanism of action for baclofen's beneficial treatment effects for alcohol use disorder.
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Affiliation(s)
- Kirsten C Morley
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Edith Collins Centre (Translational Research in Alcohol, Drugs and Toxicology), Sydney Local Health District, Sydney, NSW, Australia.
| | - Warren B Logge
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Drug Health Services, Royal Prince Alfred Hospital, NSW, Australia; Edith Collins Centre (Translational Research in Alcohol, Drugs and Toxicology), Sydney Local Health District, Sydney, NSW, Australia
| | - Isabel Fraser
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia
| | - Richard W Morris
- Psychological Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia
| | - Andrew J Baillie
- Faculty of Health Sciences, University of Sydney, NSW, Australia
| | - Paul S Haber
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Australia; Drug Health Services, Royal Prince Alfred Hospital, NSW, Australia; Edith Collins Centre (Translational Research in Alcohol, Drugs and Toxicology), Sydney Local Health District, Sydney, NSW, Australia
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Minnaard AM, Ramakers GM, Vanderschuren LJ, Lesscher HM. Baclofen and naltrexone, but not N-acetylcysteine, affect voluntary alcohol drinking in rats regardless of individual levels of alcohol intake. Behav Pharmacol 2021; 32:251-257. [PMID: 33315615 PMCID: PMC7960148 DOI: 10.1097/fbp.0000000000000615] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Accepted: 11/20/2020] [Indexed: 11/25/2022]
Abstract
In humans, there is profound individual variation in the risk of alcohol use disorder (AUD). Because GABA, opioid and glutamate neurotransmission have been implicated in AUD, functional differences in these neural systems may underlie the individual vulnerability to AUD. We therefore determined the effects of drugs affecting GABA, opioid and glutamatergic neurotransmission on alcohol consumption in rats that differed in baseline alcohol intake. Subgroups of low-, medium- and high-alcohol-drinking rats were selected on the basis of alcohol consumption using an intermittent alcohol access procedure. The subgroups were treated with the GABAB receptor agonist baclofen, the opioid receptor antagonist naltrexone and the cysteine precursor N-acetylcysteine, and the effects on alcohol intake and preference were determined. Both baclofen and naltrexone reduced alcohol consumption, but N-acetylcysteine did not. These effects were comparable for low-, medium- and high-alcohol-drinking rats. However, there was a substantial degree of individual variation in the responsivity to baclofen and naltrexone, across the subgroups. Taken together, these results suggest that variation in alcohol consumption does not predict the responsivity to baclofen and naltrexone. This implies that individual variability in alcohol consumption on the one hand and sensitivity to treatment with these drugs on the other hand represent separate processes that likely involve distinct biological mechanisms.
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Affiliation(s)
- A. Maryse Minnaard
- Department of Population Health Sciences, Unit Animals in Science and Society, Faculty of Veterinary Medicine
| | - Geert M.J. Ramakers
- Department of Translational Neuroscience, University Medical Center Utrecht Brain Center, Utrecht University, The Netherlands
| | - Louk J.M.J. Vanderschuren
- Department of Population Health Sciences, Unit Animals in Science and Society, Faculty of Veterinary Medicine
| | - Heidi M.B. Lesscher
- Department of Population Health Sciences, Unit Animals in Science and Society, Faculty of Veterinary Medicine
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Drug addiction co-morbidity with alcohol: Neurobiological insights. INTERNATIONAL REVIEW OF NEUROBIOLOGY 2021; 157:409-472. [PMID: 33648675 DOI: 10.1016/bs.irn.2020.11.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Addiction is a chronic disorder that consists of a three-stage cycle of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. These stages involve, respectively, neuroadaptations in brain circuits involved in incentive salience and habit formation, stress surfeit and reward deficit, and executive function. Much research on addiction focuses on the neurobiology underlying single drug use. However, alcohol use disorder (AUD) can be co-morbid with substance use disorder (SUD), called dual dependence. The limited epidemiological data on dual dependence indicates that there is a large population of individuals suffering from addiction who are dependent on more than one drug and/or alcohol, yet dual dependence remains understudied in addiction research. Here, we review neurobiological data on neurotransmitter and neuropeptide systems that are known to contribute to addiction pathology and how the involvement of these systems is consistent or divergent across drug classes. In particular, we highlight the dopamine, opioid, corticotropin-releasing factor, norepinephrine, hypocretin/orexin, glucocorticoid, neuroimmune signaling, endocannabinoid, glutamate, and GABA systems. We also discuss the limited research on these systems in dual dependence. Collectively, these studies demonstrate that the use of multiple drugs can produce neuroadaptations that are distinct from single drug use. Further investigation into the neurobiology of dual dependence is necessary to develop effective treatments for addiction to multiple drugs.
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Augier E. Recent Advances in the Potential of Positive Allosteric Modulators of the GABAB Receptor to Treat Alcohol Use Disorder. Alcohol Alcohol 2021; 56:139-148. [PMID: 33561865 PMCID: PMC7906877 DOI: 10.1093/alcalc/agab003] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 01/04/2021] [Accepted: 01/05/2021] [Indexed: 12/11/2022] Open
Abstract
Aims The effects of alcohol on gamma-aminobutyric acid (GABA) transmission are key for the development and maintenance of alcohol use disorder (AUD). Previous research consistently indicates that GABAB receptor agonists such as baclofen can attenuate addiction-related behaviors in preclinical models of AUD. More importantly, baclofen has also shown promise in clinical studies, particularly in severely alcohol-dependent patients. However, despite this promise, other clinical studies have not confirmed its efficacy and chiefly, larger clinical trials have not been conducted. Therefore, with the exception of France, baclofen is not approved for the treatment of AUD in any other country. Furthermore, it is also important to keep in mind that some patients treated with baclofen may experience important side-effects, including sedation, drowsiness and sleepiness. Methods This short review will first discuss the history of baclofen for AUD treatment. We will then summarize preclinical behavioral results that have investigated the efficacy of GABAB PAMs for addiction treatment, with a special focus on our recent work that investigated the effects of ADX71441, a novel GABAB PAM, on several alcohol-related behaviors in rats that model important aspects of human AUD. Finally, in light of the recent criticism about the translational value of animal models of addiction, the specific translational potential of our work and of other preclinical studies that have unanimously reported the efficacy of GABAB PAMs to attenuate multiple alcohol-related behaviors will be discussed. Results Positive allosteric modulators (PAMs) of the GABAB receptor offer an attractive alternative approach to baclofen and have the potential to achieve mechanistic and therapeutic effects similar to GABAB agonists, while avoiding the tolerance and toxicity issues associated with baclofen. To date, all preclinical behavioral results have invariably shown the efficacy of GABAB PAMs for addiction treatment. Conclusions Preclinical studies indicate that GABAB PAMs have a higher therapeutic index than orthosteric agonists, at least in terms of mitigating the sedative effects of GABAB agonism. This predicts that GABAB PAMs have a high translational potential in humans and merit being tested clinically, in particular in patients with severe AUD.
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Affiliation(s)
- Eric Augier
- Center for Social and Affective Neuroscience, BKV, Linköping University, Linköping 58183, Sweden
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Farokhnia M, Deschaine SL, Sadighi A, Farinelli LA, Lee MR, Akhlaghi F, Leggio L. A deeper insight into how GABA-B receptor agonism via baclofen may affect alcohol seeking and consumption: lessons learned from a human laboratory investigation. Mol Psychiatry 2021; 26:545-555. [PMID: 30382188 PMCID: PMC6494745 DOI: 10.1038/s41380-018-0287-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Revised: 08/16/2018] [Accepted: 09/26/2018] [Indexed: 12/15/2022]
Abstract
Previous studies suggest that GABA-B receptor agonism may represent an effective pharmacological approach to treat addictive disorders. Baclofen is a selective GABA-B receptor agonist which has been investigated as a potential treatment for alcohol use disorder. However, research is needed to understand the biobehavioral mechanisms underlying baclofen's effect on alcohol use. In the present randomized, double-blind, placebo-controlled study, thirty-four alcohol-dependent individuals were randomized to receive baclofen (30 mg/d) or placebo for a week, and then participated in a laboratory experiment consisting of three procedures: alcohol cue-reactivity, priming, and self-administration. During the experiment, craving and other subjective responses to alcohol were assessed, and blood samples were collected for pharmacokinetic measurements. The effects of baclofen on the relationships between different alcohol-related laboratory parameters were investigated. Baclofen pharmacokinetic parameters and their correlations with behavioral measures were also examined. Results showed that baclofen disrupted the link between alcohol priming and self-administration, as indicated by significant interaction effects between drug condition (baclofen vs. placebo) and some of the priming variables (alcohol craving: F3,9 = 6.03, p = 0.01; alcohol sedation: F3,6 = 7.16, p = 0.01) on the total amount of alcohol self-administered. Considerable interindividual variability in baclofen pharmacokinetic parameters was observed. Maximum plasma concentrations of baclofen negatively correlated with cue-induced alcohol craving (r = -0.57, p = 0.03) and priming-induced ratings of 'like more' (r = -0.59, p = 0.02). In conclusion, baclofen may work by dissociating the link between an initial drink (priming) and subsequent alcohol consumption (self-administration). Considerable pharmacokinetic variability is an important factor to take into account when employing baclofen as a treatment for alcohol use disorder.
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Affiliation(s)
- Mehdi Farokhnia
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Sara L Deschaine
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Armin Sadighi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Lisa A Farinelli
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Mary R Lee
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI, USA
| | - Lorenzo Leggio
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA.
- Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, Brown University, Providence, RI, USA.
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Abstract
Bislang sind nur wenige Medikamente zur pharmakologischen Rückfallprophylaxe der Alkoholabhängigkeit zugelassen. Neben dem in Deutschland nicht mehr vertriebenen Disulfiram sind es die Opioidantagonisten Naltrexon und Nalmefen sowie das vermutlich über glutamaterge Neurone wirkende Acamprosat. Baclofen und γ‑Hydroxybutyrat (GHB) sind in einzelnen Ländern zugelassen. Wirkstoffe wie z. B. Vareniclin, Gabapentin und Topiramat können für die Rückfallprophylaxe der Alkoholabhängigkeit von Interesse sein, jedoch ist bislang keine Zulassung erfolgt. Vor dem Hintergrund der zur Revision anstehenden S3-Leitlinie zur Diagnose und Behandlung alkoholbezogener Störungen wird der heutige Kenntnisstand zur Pharmakotherapie der Alkoholabhängigkeit dargestellt.
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Agabio R, Baldwin DS, Amaro H, Leggio L, Sinclair JMA. The influence of anxiety symptoms on clinical outcomes during baclofen treatment of alcohol use disorder: A systematic review and meta-analysis. Neurosci Biobehav Rev 2021; 125:296-313. [PMID: 33454289 DOI: 10.1016/j.neubiorev.2020.12.030] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 12/17/2020] [Accepted: 12/27/2020] [Indexed: 12/22/2022]
Abstract
Given the high coexistence of anxiety symptoms in people with alcohol use disorder (AUD), we aimed to determine the influence of anxiety symptoms on outcomes in patients with AUD treated with the GABAB receptor agonist baclofen. A meta-analysis of 13 comparisons (published 2010-2020) including baseline and outcome data on alcohol consumption and anxiety after 12 weeks was undertaken. There were significantly higher rates of abstinent days in patients treated with baclofen compared to placebo (p = 0.004; high certainty evidence); specifically in those with higher baseline anxiety levels (p < 0.00001; high certainty evidence) compared to those with lower baseline anxiety levels (p = 0.20; moderate certainty evidence). The change in anxiety ratings over 12 weeks did not differ between those treated with baclofen or placebo (p = 0.84; moderate certainty evidence). This may be due to different anxiety constructs being measured by scales not validated in this patient group, or that anxiety is not a biobehavioral mechanism by which baclofen may reduce alcohol drinking. Given the prevalence of anxiety symptoms in AUD all these factors warrant further research.
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Affiliation(s)
- Roberta Agabio
- Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, Italy.
| | - David S Baldwin
- Faculty of Medicine, University of Southampton, Southampton, UK; University Department of Psychiatry and Mental Health, University of Cape Town, South Africa.
| | - Hugo Amaro
- Faculty of Medicine, University of Southampton, Southampton, UK
| | - Lorenzo Leggio
- Clinical Psychoneuroendocrinology and Neuropsychopharmacology Section, Translational Addiction Medicine Branch, National Institute on Drug Abuse Intramural Research Program and National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research, National Institutes of Health, Baltimore and Bethesda, MD, United States; Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, United States; Center for Alcohol and Addiction Studies, Department of Behavioral and Social Sciences, School of Public Health, Brown University, Providence, RI, United States; Division of Addiction Medicine, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States; Department of Neuroscience, Georgetown University Medical Center, Washington DC, United States.
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Cobbina E, Lee MR, Leggio L, Akhlaghi F. A Population Pharmacokinetic Analysis of PF-5190457, a Novel Ghrelin Receptor Inverse Agonist in Healthy Volunteers and in Heavy Alcohol Drinkers. Clin Pharmacokinet 2020; 60:471-484. [PMID: 33155163 DOI: 10.1007/s40262-020-00942-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/29/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND OBJECTIVES The ghrelin receptor (GHS-R1a) is a potential target for alcohol use disorders. PF-5190457 is the first inverse agonist of GHS-R1a to progress to clinical development with potential to treat alcohol use disorder. We present a population pharmacokinetic model for PF-5190457 in non-heavy (alcohol consumption status = 0) and heavy alcohol drinkers (alcohol consumption status = 1), and identify relevant factors that can influence its pharmacokinetics. METHODS Plasma concentration-time data from non-heavy (n = 35) and heavy drinkers (n = 12) were pooled for the population pharmacokinetic model development. The influence of various covariates including alcohol consumption status was evaluated. The accuracy, precision, and robustness of the model were also evaluated using bootstrapping and visual predictive checks. RESULTS A two-compartment model best described the pharmacokinetics of PF-5190457. The apparent volume of distribution of 44.5 L, apparent clearance of 72.0 L/h, apparent peripheral volume of distribution of 271 L, apparent distributional clearance of 28.7 L/h, and first-order absorption rate constant of 0.27/h were accurate and precise. The apparent volume of distribution was 3.8-fold higher (169 L) in heavy drinkers, and correlated with a lower maximum plasma concentration in heavy drinkers compared with non-heavy drinkers at the same dose; and a corresponding reduced incidence of somnolence in heavy drinkers at doses > 50 mg. CONCLUSIONS This work provides an accurate, precise, and robust two-compartment model that describes the pharmacokinetics of PF-5190457 and suggests a possible link of PF-5190457 pharmacokinetics with somnolence. TRIAL REGISTRATION ClinicalTrials.gov identifier numbers NCT01247896 and NCT02039349.
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Affiliation(s)
- Enoch Cobbina
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Office 495 A, Avedisian Hall, 7 Greenhouse Road, Kingston, RI, 02881, USA
| | - Mary R Lee
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, USA
| | - Lorenzo Leggio
- Section on Clinical Psychoneuroendocrinology and Neuropsychopharmacology, National Institute on Alcohol Abuse and Alcoholism Division of Intramural Clinical and Biological Research and National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Bethesda, MD, USA.,Medication Development Program, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Baltimore, MD, USA.,Department of Behavioral and Social Sciences, Center for Alcohol and Addiction Studies, Brown University, Providence, RI, USA
| | - Fatemeh Akhlaghi
- Clinical Pharmacokinetics Research Laboratory, Department of Biomedical and Pharmaceutical Sciences, University of Rhode Island, Office 495 A, Avedisian Hall, 7 Greenhouse Road, Kingston, RI, 02881, USA.
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Kumar A, Sharma A, Bansal PD, Bahetra M, Gill HK, Kumar R. A comparative study on the safety and efficacy of naltrexone versus baclofen versus acamprosate in the management of alcohol dependence. Indian J Psychiatry 2020; 62:650-658. [PMID: 33896969 PMCID: PMC8052868 DOI: 10.4103/psychiatry.indianjpsychiatry_201_19] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 10/06/2019] [Accepted: 06/10/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND The efficacy of naltrexone, baclofen, and acamprosate in the treatment of alcohol dependence has been successfully established over the past several years. The knowledge about their relative efficacies can facilitate in developing relapse prevention strategies that would give rise to a greater personal and socioeconomic benefits. AIMS AND OBJECTIVE To assess and compare the safety and efficacy profile of naltrexone, baclofen, and acamprosate in the treatment of alcohol dependence. In addition to this, the pattern of relapse and attitude of patients toward the treatment were also assessed. MATERIALS AND METHODS This was a prospective study carried out at a tertiary care center. It comprised of thirty alcohol-dependent patients each assigned to naltrexone, baclofen, and acamprosate group after detoxification. The patients were assessed for craving, relapse risk, and medication adherence using the respective scales and questionnaires. RESULTS In terms of Obsessive Compulsive Drinking Scale score decline, the decline seen in the naltrexone group (26.72 ± 13.05) was maximum, followed by baclofen and acamprosate. In terms of decreasing Advance Warning of Relapse (AWARE) questionnaire score, again naltrexone was most effective, with the maximum decline in AWARE score (64.72 ± 45.65), followed by baclofen and acamprosate. The attitude toward treatment with all the three medications was positive, as per the Hogan Drug Attitude Inventory score. CONCLUSION Naltrexone was most effective in decreasing craving and drinking behavior. Baclofen showed best tolerability in terms of liver function tests and least number of side effects reported. Naltrexone group reported the least number of relapses but maximum number of side effects. Acamprosate group had the maximum dropout rate.
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Affiliation(s)
- Arun Kumar
- Department of Psychiatry, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
| | - Arvind Sharma
- Department of Psychiatry, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
| | - P D Bansal
- Department of Psychiatry, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
| | - Mamta Bahetra
- Department of Psychiatry, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
| | - Harkamal K Gill
- Department of Psychiatry, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
| | - Rakesh Kumar
- Department of Psychiatry, Guru Gobind Singh Medical College and Hospital, Faridkot, Punjab, India
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Rigal L, Sidorkiewicz S, Tréluyer JM, Perrodeau E, Le Jeunne C, Porcher R, Jaury P. Titrated baclofen for high-risk alcohol consumption: a randomized placebo-controlled trial in out-patients with 1-year follow-up. Addiction 2020; 115:1265-1276. [PMID: 31833590 DOI: 10.1111/add.14927] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 06/14/2019] [Accepted: 12/02/2019] [Indexed: 02/06/2023]
Affiliation(s)
- Laurent Rigal
- Université Paris-Saclay, UVSQ, Inserm, CESP, Villejuif, France.,Université Paris-Saclay, Département de Médecine Générale, Le Kremlin-Bicêtre, France.,Institut national d'études démographiques (INED), Paris, France
| | - Stéphanie Sidorkiewicz
- Université de Paris, Faculté de Santé, UFR de Médecine, Département de Médecine Générale, Paris, France.,Université de Paris, CRESS, INSERM, INRA, Paris, France
| | - Jean-Marc Tréluyer
- Unité de recherche clinique, School of Medicine, Paris Descartes University, Sorbonne Paris Cité, Paris, France
| | - Elodie Perrodeau
- Université de Paris, CRESS, INSERM, INRA, Paris, France.,Centre d'épidémiologie clinique, AP-HP, Hôpital Hôtel-Dieu, Paris, France
| | - Claire Le Jeunne
- Service de médecine interne APHP-Hôpital Cochin, Paris, France.,Université de Paris, Paris, France
| | - Raphaël Porcher
- Université de Paris, CRESS, INSERM, INRA, Paris, France.,Centre d'épidémiologie clinique, AP-HP, Hôpital Hôtel-Dieu, Paris, France
| | - Philippe Jaury
- Université de Paris, Faculté de Santé, UFR de Médecine, Département de Médecine Générale, Paris, France
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Reynoard J, Schmitt C, Torrents R, Simon N. Toxicological considerations in the prescription of baclofen for the treatment of substance use disorders. Expert Opin Drug Metab Toxicol 2020; 16:309-317. [PMID: 32149546 DOI: 10.1080/17425255.2020.1740681] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Introduction: For many years, applications for baclofen have widened in the treatment of substance abuse disorder (SUD), mainly alcohol use disorder, with a growing rate of off-label prescriptions in Europe. Clinical effects seem to be both a decrease of craving and anxiety, leading to a decrease of drug or alcohol consumption. We described baclofen poisoning circumstances, therapeutic options and outcomes when used in substance use disorders.Areas covered: This review summarizes the toxicological considerations where baclofen was prescribed in humans for substance use or abuse disorder in randomized clinical trials, case series, case reports and observational studies between 1990 and 2020 according to the Preferred Reporting Items for Systemic reviews and Meta-Analysis.Expert opinion: The most frequent cause of severe intoxication is self-poisoning. A dose above 180 mg are expected to cause severe toxicity and death. The treatment is only symptomatic as no antidote is available. Off-label prescription remains unsafe because the optimal dose is not known and varies greatly between patients. As SUD are frequently associated with psychiatric disorders and such patients may have suicidal thoughts, the risk of self-poisoning is high. Potential co-ingestants should also be considered, especially CNS depressants, and they need to be closely monitored.
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Affiliation(s)
- Julien Reynoard
- Pharmacologie Clinique CAP-TV, APHM, Hôpitaux Sud, Marseille, France
| | - Corinne Schmitt
- Pharmacologie Clinique CAP-TV, APHM, Hôpitaux Sud, Marseille, France
| | - Romain Torrents
- APHM, INSERM, IRD, SESSTIM, Hôpital Sainte Marguerite Pharmacologie Clinique CAP-TV, Aix Marseille Univ, Marseille, France
| | - Nicolas Simon
- APHM, INSERM, IRD, SESSTIM, Hôpital Sainte Marguerite Pharmacologie Clinique CAP-TV, Aix Marseille Univ, Marseille, France
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Logge WB, Baillie AJ, Haber PS, Morley KC. Baclofen modulates cardiovascular responses to appetitive cues in treatment-seeking alcohol use disorder individuals. Hum Psychopharmacol 2020; 35:e2722. [PMID: 32045501 DOI: 10.1002/hup.2722] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 11/25/2019] [Accepted: 01/06/2020] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To assess whether baclofen-treated alcohol dependent participants show different subjective and psychophysiological responses to appetitive cues during an alcohol cue reactivity task compared to placebo, and whether these responses are associated with prospective drinking outcomes. METHODS Forty-two alcohol dependent participants (placebo: n = 12, low-dose baclofen [30 mg/day] n = 18, high-dose baclofen [75 mg/day]: n = 12) completed an alcohol cue reactivity task, whereby water and alcohol beverage cues were presented, with subsequent recovery periods, and subjective alcohol craving and psychophysiological indices (skin conductance; cardiovascular measures: heart rate, high-frequency heart rate variability) were recorded. RESULTS High-dose baclofen-treated participants showed both overall cue reactivity to water and alcohol cues and greater recovery effects during recovery periods, revealed by high-frequency heart rate variability, when compared to low-dose- and placebo-treated participants. There were no medication effects on subjective craving. In high-dose baclofen participants only, there was a predictive effect of lower baseline heart rate variability and fewer post-test percentage of heavy drinking days. CONCLUSION There was a dose-specific rescuing effect of high-dose baclofen on the dynamic modulation of cardiovascular responses to eliciting cues. Investigation of treatment responses using psychophysiological techniques may elucidate baclofen's mechanisms of action, and identify subgroups amenable to treatment.
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Affiliation(s)
- Warren B Logge
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.,Drug Health Services, Royal Prince Alfred Hospital, New South Wales, Australia
| | - Andrew J Baillie
- Faculty of Health Sciences, University of Sydney, New South Wales, Australia
| | - Paul S Haber
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia.,Drug Health Services, Royal Prince Alfred Hospital, New South Wales, Australia
| | - Kirsten C Morley
- Discipline of Addiction Medicine, Central Clinical School, Faculty of Medicine and Health, University of Sydney, New South Wales, Australia
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Abstract
Harmful alcohol use and alcohol use disorders (AUD) result in major health and community burden worldwide, yet treatment options are limited. Novel pharmacotherapies are urgently required, and treatments involving GABAB receptors have been used in treating alcohol-related disorders. This chapter will review the clinical evidence of GABAB pharmacotherapies, such as baclofen and γ-hydroxybutyric acid. This includes the use of these treatments in individuals experiencing alcohol withdrawal symptoms and outlining the outcomes of studies of alcohol relapse prevention relapse including case studies, comparative studies and randomised controlled trials. Laboratory research investigating biobehavioural effects of baclofen will also be summarised and polymorphisms associated with baclofen treatment, and safety concerns of GABAB treatments will be addressed. In summary, pharmacological treatments targeting GABAB receptors such as baclofen may be modestly effective in the management of alcohol use disorder, but safety concerns limit the widespread applicability of the currently available agents.
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Baclofen as an adjuvant therapy for autism: a randomized, double-blind, placebo-controlled trial. Eur Child Adolesc Psychiatry 2019; 28:1619-1628. [PMID: 30980177 DOI: 10.1007/s00787-019-01333-5] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 04/03/2019] [Indexed: 10/27/2022]
Abstract
Increasing evidence suggests that the function of the GABAergic system is abnormally low in autism spectrum disorder (ASD). Baclofen, which functions as a selective agonist for GABAB receptors, does appear promising for the treatment of ASD. We conducted a 10-week randomized-controlled study aimed at evaluating the potential of baclofen as an adjuvant therapy to enhance the effect of risperidone in children with ASD. Sixty-four children (3-12 years) with moderate-to-severe irritability symptoms of ASD were included. We used the Aberrant Behavior Checklist-Community Edition (ABC-C) for the outcome measures on each of the follow-up visits (weeks 0, 5, and 10). Analysis of the combined data revealed significant improvement for all the ABC subscales (irritability: F = 51.644, df = 1.66, p < 0.001, lethargy: F = 39.734, df = 1.38, p < 0.001, stereotypic behavior: F = 25.495, df = 1.56, p < 0.001, hyperactivity: F = 54.135, df = 1.35, p < 0.001, and inappropriate speech: F = 19.277, df = 1.47, p = 0.004). Combined treatment with baclofen and risperidone exerted a greater effect on improvement of hyperactivity symptoms at both midpoint [Cohen's d, 95% confidence interval (CI) = - 3.14, - 5.56 to - 0.72] and endpoint (d, 95% CI = - 4.45, - 8.74 to - 0.16) when compared with treatment with placebo plus risperidone. The two treatments achieved comparable results for other outcome measures. Our data support safety and efficacy of baclofen as an adjuvant to risperidone for improvement of hyperactivity symptoms in children with ASD.
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Abstract
BACKGROUND Alcohol withdrawal syndrome (AWS) is a distressing and life-threatening condition that usually affects people who are alcohol dependent when they discontinue or decrease their alcohol consumption. Baclofen shows potential for rapidly reducing symptoms of severe AWS in people with alcoholism. Treatment with baclofen is easy to manage and rarely produces euphoria or other pleasant effects, or craving for the drug. This is an updated version of the original Cochrane Review first published in 2011 and last updated in 2017. OBJECTIVES To assess the efficacy and safety of baclofen for people with AWS. SEARCH METHODS We updated our searches of the following databases to June 2019: the Cochrane Drugs and Alcohol Group Specialised Register, CENTRAL, PubMed, Embase, and CINAHL. We also searched registers of ongoing trials. We handsearched the references quoted in the identified trials, and sought information from researchers, pharmaceutical companies, and relevant trial authors about unpublished or uncompleted trials. We placed no restrictions on language. SELECTION CRITERIA We included all randomised controlled clinical trials (RCTs) evaluating baclofen versus placebo or any other treatment for people with AWS. We excluded uncontrolled, non-randomised, or quasi-randomised trials. We included both parallel group and cross-over studies. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by Cochrane. MAIN RESULTS We included four RCTs with 189 randomised participants (one RCT new for this update). None of the included studies reported the primary outcomes of alcohol withdrawal seizures, alcohol withdrawal delirium, or craving. For the comparison of baclofen and placebo (1 study, 31 participants), there was no evidence of a difference in Clinical Institute Withdrawal Assessment of Alcohol Scale, Revised (CIWA-Ar) scores in eight-hour periods from days one to five (very low-quality evidence). For the comparison of baclofen and diazepam (2 studies, 85 participants), there was no evidence of a difference in change from baseline to days 10 to 15 on CIWA-Ar scores (very low-quality evidence, meta-analysis was not performed due to insufficient data). In one study (37 participants), there was no evidence of a difference in participants with at least one adverse event (risk difference (RD) 0.00, 95% confidence interval (CI) -0.10 to 0.10; very low-quality evidence), dropouts (RD 0.00, 95% CI -0.10 to 0.10; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.10 to 0.10; very low-quality evidence). For the comparison of baclofen and chlordiazepoxide (1 study, 60 participants), there was no evidence of a difference in difference from baseline to nine-day decremental fixed-dose intervention: CIWA-Ar scores (mean difference (MD) 1.00, 95% CI 0.70 to 1.30; very low-quality evidence), global improvement (MD 0.10, 95% CI -0.03 to 0.23; very low-quality evidence), 14/60 participants with adverse events (RD 2.50, 95% CI 0.88 to 7.10; very low-quality of evidence), dropouts (RD 0.00, 95% CI -0.06 to 0.06; very low-quality evidence), and dropouts due to adverse events (RD 0.00, 95% CI -0.06 to 0.06; very low-quality evidence). None of the RCTs provided information on random sequence generation or allocation concealment, therefore, we assessed them at unclear risk of bias. Two RCTs were not of double-blind design and had a high risk of bias in blinding (Addolorato 2006; Girish 2016). One RCT had more than 5% dropouts with high risk of attrition bias (Lyon 2011). We could not assess reporting bias as none of the prepublished protocols were available. AUTHORS' CONCLUSIONS No conclusions can be drawn about the efficacy and safety of baclofen for the management of alcohol withdrawal because we found insufficient and very low-quality evidence.
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Affiliation(s)
- Jia Liu
- Xuanwu Hospital, Capital Medical UniversityDepartment of NeurologyChangchun Street 45BeijingChina100053
| | - Lu‐Ning Wang
- Chinese PLA General HospitalDepartment of Geriatric NeurologyFuxing Road 28Haidian DistrictBeijingChina100853
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Miguel E, Vekovischeva O, Kuokkanen K, Vesajoki M, Paasikoski N, Kaskinoro J, Myllymäki M, Lainiola M, Janhunen SK, Hyytiä P, Linden A, Korpi ER. GABA B receptor positive allosteric modulators with different efficacies affect neuroadaptation to and self-administration of alcohol and cocaine. Addict Biol 2019; 24:1191-1203. [PMID: 30421860 DOI: 10.1111/adb.12688] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 09/28/2018] [Accepted: 10/04/2018] [Indexed: 01/14/2023]
Abstract
Drugs of abuse induce widespread synaptic adaptations in the mesolimbic dopamine (DA) neurons. Such drug-induced neuroadaptations may constitute an initial cellular mechanism eventually leading to compulsive drug-seeking behavior. To evaluate the impact of GABAB receptors on addiction-related persistent neuroplasticity, we tested the ability of orthosteric agonist baclofen and two positive allosteric modulators (PAMs) of GABAB receptors to suppress neuroadaptations in the ventral tegmental area (VTA) and reward-related behaviors induced by ethanol and cocaine. A novel compound (S)-1-(5-fluoro-2,3-dihydro-1H-inden-2-yl)-4-methyl-6,7,8,9-tetrahydro-[1,2,4]triazolo[4,3-a]quinazolin-5(4H)-one (ORM-27669) was found to be a GABAB PAM of low efficacy as agonist, whereas the reference compound (R,S)-5,7-di-tert-butyl-3-hydroxy-3-trifluoromethyl-3H-benzofuran-2-one (rac-BHFF) had a different allosteric profile being a more potent PAM in the calcium-based assay and an agonist, coupled with potent PAM activity, in the [35 S] GTPγS binding assay in rat and human recombinant receptors. Using autoradiography, the high-efficacy rac-BHFF and the low-efficacy ORM-27669 potentiated the effects of baclofen on [35 S] GTPγS binding with identical brain regional distribution. Treatment of mice with baclofen, rac-BHFF, or ORM-27669 failed to induce glutamate receptor neuroplasticity in the VTA DA neurons. Pretreatment with rac-BHFF at non-sedative doses effectively reversed both ethanol- and cocaine-induced plasticity and attenuated cocaine i.v. self-administration and ethanol drinking. Pretreatment with ORM-27669 only reversed ethanol-induced neuroplasticity and attenuated ethanol drinking but had no effects on cocaine-induced neuroplasticity or self-administration. These findings encourage further investigation of GABAB receptor PAMs with different efficacies in addiction models to develop novel treatment strategies for drug addiction.
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Affiliation(s)
- Elena Miguel
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
| | - Olga Vekovischeva
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
| | - Katja Kuokkanen
- Research and Development, Orion Pharma, Orion Corporation Finland
| | - Marja Vesajoki
- Research and Development, Orion Pharma, Orion Corporation Finland
| | - Nelli Paasikoski
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
| | - Janne Kaskinoro
- Research and Development, Orion Pharma, Orion Corporation Finland
| | - Mikko Myllymäki
- Research and Development, Orion Pharma, Orion Corporation Finland
| | - Mira Lainiola
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
| | | | - Petri Hyytiä
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
| | - Anni‐Maija Linden
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
| | - Esa R. Korpi
- Department of Pharmacology, Faculty of MedicineUniversity of Helsinki Finland
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Heilig M, Augier E, Pfarr S, Sommer WH. Developing neuroscience-based treatments for alcohol addiction: A matter of choice? Transl Psychiatry 2019; 9:255. [PMID: 31594920 PMCID: PMC6783461 DOI: 10.1038/s41398-019-0591-6] [Citation(s) in RCA: 58] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 07/05/2019] [Accepted: 08/08/2019] [Indexed: 12/15/2022] Open
Abstract
Excessive alcohol use is the cause of an ongoing public health crisis, and accounts for ~5% of global disease burden. A minority of people with recreational alcohol use develop alcohol addiction (hereafter equated with "alcohol dependence" or simply "alcoholism"), a condition characterized by a systematically biased choice preference for alcohol at the expense of healthy rewards, and continued use despite adverse consequences ("compulsivity"). Alcoholism is arguably the most pressing area of unmet medical needs in psychiatry, with only a small fraction of patients receiving effective, evidence-based treatments. Medications currently approved for the treatment of alcoholism have small effect sizes, and their clinical uptake is negligible. No mechanistically new medications have been approved since 2004, and promising preclinical results have failed to translate into novel treatments. This has contributed to a reemerging debate whether and to what extent alcohol addiction represents a medical condition, or reflects maladaptive choices without an underlying brain pathology. Here, we review this landscape, and discuss the challenges, lessons learned, and opportunities to retool drug development in this important therapeutic area.
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Affiliation(s)
- Markus Heilig
- Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, S-581 83, Linköping, Sweden.
| | - Eric Augier
- 0000 0001 2162 9922grid.5640.7Center for Social and Affective Neuroscience, Department of Clinical and Experimental Medicine, Linköping University, S-581 83 Linköping, Sweden
| | - Simone Pfarr
- 0000 0004 0477 2235grid.413757.3Institute of Psychopharmacology, Central Institute of Mental Health (CIMH), J 5, 68159 Mannheim, Germany
| | - Wolfgang H. Sommer
- 0000 0004 0477 2235grid.413757.3Institute of Psychopharmacology, Central Institute of Mental Health (CIMH), J 5, 68159 Mannheim, Germany ,0000 0004 0477 2235grid.413757.3Department of Addiction Medicine, Central Institute of Mental Health (CIMH), J 5, 68159 Mannheim, Germany
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Abstract
Zusammenfassung. Hintergrund: Unterschiede in der Therapiezielfindung bei der Behandlung von Alkoholkonsumstörungen, die sich zwischen völliger Abstinenz, vermindertem Konsum (Schadensvermeidung) und „kontrolliertem Konsum“ aufspannen, werden seit vielen Jahren z. T. kontrovers diskutiert. Ziel: Ziel der Stellungnahme der Dachgesellschaft Sucht ist es, vorhandene empirische Erkenntnisse zu diesem Themenbereich zusammenzutragen und daraus Empfehlungen für den praktischen Umgang mit verschiedenen Therapiezielen wie Trinkmengenreduktion oder Abstinenz für die Patienten oder Klienten abzuleiten. An der Erstellung des Positionspapiers haben sich Vertreter verschiedener Fachgesellschaften (DG Suchtmedizin, der DG Suchtforschung und Suchttherapie sowie die Deutsche Gesellschaft für Suchtpsychologie) beteiligt. Eine Reihe von Forschungsdesideraten wird benannt.
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Affiliation(s)
- Gallus Bischof
- Universität zu Lübeck, Klinik für Psychiatrie und Psychotherapie
| | - Nikolaus Lange
- Baden-Württembergischer Landesverband für Prävention und Rehabilitation (bwlv), Renchen
| | | | - Ulrich W. Preuss
- Vitos-Klinikum Psychiatrie und Psychotherapie, Herborn, Martin-Luther Universität, Halle-Wittenberg, Klinik für Psychiatrie, Psychotherapie und Psychosomatik
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