Reduce Alcohol Relapse Research Articles

Fenofibrate Decreases Ethanol-Induced Neuroinflammation and Oxidative Stress and Reduces Alcohol Relapse in Rats by a PPAR-α-Dependent Mechanism.

High ethanol consumption triggers neuroinflammation, implicated in sustaining chronic alcohol use. This inflammation boosts glutamate, prompting dopamine release in reward centers, driving prolonged drinking and relapse. Fibrate drugs, activating peroxisome proliferator-activated receptor alpha (PPAR-α), counteract neuroinflammation in other contexts, prompting investigation into their impact on ethanol-induced inflammation. Here, we studied, in UChB drinker rats, whether the administration of fenofibrate in the withdrawal stage after chronic ethanol consumption reduces voluntary intake when alcohol is offered again to the animals (relapse-type drinking). Furthermore, we determined if fenofibrate was able to decrease ethanol-induced neuroinflammation and oxidative stress in the brain. Animals treated with fenofibrate decreased alcohol consumption by 80% during post-abstinence relapse. Furthermore, fenofibrate decreased the expression of the proinflammatory cytokines tumor necrosis factor-alpha (TNF-α) and interleukins IL-1β and IL-6, and of an oxidative stress-induced gene (heme oxygenase-1), in the hippocampus, nucleus accumbens, and prefrontal cortex. Animals treated with fenofibrate showed an increase M2-type microglia (with anti-inflammatory proprieties) and a decrease in phagocytic microglia in the hippocampus. A PPAR-α antagonist (GW6471) abrogated the effects of fenofibrate, indicating that they are dependent on PPAR-α activation. These findings highlight the potential of fenofibrate, an FDA-approved dyslipidemia medication, as a supplementary approach to alleviating relapse severity in individuals with alcohol use disorder (AUD) during withdrawal.

Frontal tDCS reduces alcohol relapse rates by increasing connections from left dorsolateral prefrontal cortex to addiction networks

BackgroundBrain-based interventions are needed to address persistent relapse in alcohol use disorder (AUD). Neuroimaging evidence suggests higher frontal connectivity as well as higher within-network connectivity of theoretically defined addiction networks are associated with reduced relapse rates and extended abstinence during follow-up periods. Objective/Hypothesis: A longitudinal randomized double-blind sham-controlled clinical trial investigated whether a non-invasive neuromodulation intervention delivered during early abstinence can (i) modulate connectivity of addiction networks supporting abstinence and (ii) improve relapse rates. Hypotheses: Active transcranial direct current stimulation (tDCS) will (i) increase connectivity of addiction networks known to support abstinence and (ii) reduce relapse rates. MethodsShort-term abstinent AUD participants (n = 60) were assigned to 5 days of either active tDCS or sham during cognitive training. Causal discovery analysis (CDA) examined the directional influence from left dorsolateral prefrontal cortex (LDLPFC, stimulation site) to addiction networks that support abstinence. ResultsActive tDCS had an effect on the average strength of CDA-determined connectivity from LDLPFC to the incentive salience and negative emotionality addiction networks - increasing in the active tDCS group only. Active tDCS had an effect on relapse rates following the intervention, with lower probability of relapse in the active tDCS vs. sham. Active tDCS showed an unexpected sex-dependent effect on relapse rates. ConclusionOur results suggest that LDLPFC stimulation delivered during early abstinence has an effect on addiction networks supporting abstinence and on relapse rates. The unexpected sex-dependent neuromodulation effects need to be further examined in larger clinical trials.

266. Frontal TDCS Reduces Alcohol Relapse Rates by Increasing Connections From Left Dorsolateral Prefrontal Cortex to Addiction Networks

266. Frontal TDCS Reduces Alcohol Relapse Rates by Increasing Connections From Left Dorsolateral Prefrontal Cortex to Addiction Networks

Impaired synaptic transmission in dorsal dentate gyrus increases impulsive alcohol seeking

Both human and animal studies indicate that the dentate gyrus (DG) of the hippocampus is highly exploited by drug and alcohol abuse. Yet, it is poorly understood how DG dysfunction affects addiction-related behaviors. Here, we used an animal model of alcohol use disorder (AUD) in automated IntelliCages and performed local genetic manipulation to investigate how synaptic transmission in the dorsal DG (dDG) affects alcohol-related behaviors. We show that a cue light induces potentiation-like plasticity of dDG synapses in alcohol-naive mice. This process is impaired in mice trained to drink alcohol. Acamprosate (ACA), a drug that reduces alcohol relapse, rescues the impairment of dDG synaptic transmission in alcohol mice. A molecular manipulation that reduces dDG synaptic AMPAR and NMDAR levels increases impulsive alcohol seeking during cue relapse (CR) in alcohol mice but does not affect alcohol reward, motivation or craving. These findings suggest that hindered dDG synaptic transmission specifically underlies impulsive alcohol seeking induced by alcohol cues, a core symptom of AUD.

Integration of addiction treatment and behavioral therapies in comprehensive liver transplantation care to augment adherence and reduce alcohol relapse

BackgroundLiver transplantation (LT) is the only definitive, life-saving treatment for patients with end-stage liver disease (ESLD). Few attempts have been made to summarize the current literature on the delivery of behavioral and addiction therapies to patients, both pre- and post- LT, to increase sobriety (especially in alcohol-related ESLD) and adherence, rendering providers without guidance for ideal timing, treatment components, and duration of aforementioned therapies. MethodsThis review summarizes the literature on alcohol relapse and medical adherence specific to the LT transplant population, and comprehensively compiles and evaluates behavioral therapies and addiction treatment programs instituted in the management of LT patients and those with liver disease etiologies that may lead to LT transplant (primarily alcoholic liver disease). ResultsOptimization of LT outcomes and patient survival depends on interventions focused on addressing alcohol relapse and medical adherence. Modifiable factors contributory to nonadherence and alcohol relapse in ESLD and LT patients should be addressed with systematic integration of behavioral therapies and addiction treatments within comprehensive liver transplant care. ConclusionImplementation of therapies inclusive of individual and/or group approaches to deliver motivational, cognitive-behavioral, self-improvement and pharmacological interventions in an integrated, multidisciplinary fashion is imperative to impart comprehensive care to transplant patients.

Modulation of relapse-like drinking in male Sprague-Dawley rats by ligands targeting the α5GABAA receptor

Preclinical evidence suggests a key role for GABAA receptors containing the α5 subunit (i.e., α5GABAA receptors) in the abuse-related effects of alcohol, including the reinforcing and discriminative stimulus effects, as well as cue-induced alcohol-seeking behavior. However, the contribution of this GABAA receptor subtype to relapse-like drinking behavior remains unknown. The present study evaluated the capacity of ligands targeting α5GABAA receptors to modulate the alcohol deprivation effect (ADE), a model of relapse-like drinking. Groups of Sprague-Dawley rats underwent repeated cycles of long-term access to alcohol solutions (5%, 10%, 20% v/v) and water in the home cage followed by water only deprivation periods. Upon evidence that the ADE could be reliably expressed across cycles, drug treatment was initiated. One group received the α5GABAA receptor-preferring agonist QH-ii-066 and the other group received the α5GABAA receptor-selective inverse agonist L-655,708. At the end of ADE testing, rats underwent testing in the elevated zero maze under vehicle or L-655,708 treatment for assessment of anxiety-like behavior. The ADE was reliably expressed across repeated cycles of alcohol access/deprivation in a subset of rats. Low doses of QH-ii-066 enhanced expression of the ADE; whereas, L-655,708 dose-dependently inhibited expression of the ADE. L-655,708 did not engender anxiogenic effects in the elevated zero maze under the conditions evaluated. These findings suggest a key role for α5GABAA receptor mechanisms in relapse-like drinking. Moreover, they suggest that α5GABAA receptors may represent a novel pharmacological target for the development of medications to prevent or reduce alcohol relapse.

Protocol for the methamphetamine approach-avoidance training (MAAT) trial, a randomised controlled trial of personalised approach bias modification for methamphetamine use disorder

BackgroundGlobally, methamphetamine use has increased in prevalence in recent years. In Australia, there has been a dramatic increase in numbers of people seeking treatment, including residential rehabilitation, for methamphetamine use disorder (MUD). While residential rehabilitation is more effective for MUD than withdrawal treatment (i.e. “detoxification”) alone, relapse rates remain high, with approximately half of rehabilitation clients using methamphetamine within 3 months of rehabilitation. “Approach bias modification” (ABM) is a computerised cognitive training approach that aims to dampen automatically triggered impulses to approach drugs and drug-related stimuli. ABM has been demonstrated to reduce alcohol relapse rates, but no randomised controlled trials of ABM for MUD have yet been conducted. We aim to test whether a novel “personalised” form of ABM, delivered during rehabilitation, reduces post-treatment methamphetamine use, relative to a sham-training control condition. Secondary outcomes will include dependence symptoms, cravings, and approach bias.MethodsWe aim to recruit 100 participants attending residential rehabilitation for MUD at 3 sites in the Melbourne metropolitan area. Participants will complete baseline measures of methamphetamine use, craving, dependence severity, and approach bias before being randomised to receiving 6 sessions of ABM or “sham” training. In the active condition, ABM will be personalised for each participant, using those methamphetamine images that they rate as most relevant to their recent methods of methamphetamine use as “avoidance” images and using positive images representing their goals or healthy sources of pleasure as “approach” images. Approach bias and craving will be re-assessed following completion of training, and methamphetamine use, dependence, and craving will be assessed 4 weeks and 3 months following discharge from residential treatment.DiscussionThis study is the first randomised controlled trial of ABM for MUD and also the first ABM study to test using a personalised set of both approach and avoid images for ABM training. If effective, the low cost and easy implementation of ABM means it could be widely implemented as a standard part of MUD treatment.Trial registrationAustralian New Zealand Clinical Trials Registry ACTRN12620000072910. Registered on 30 January 2020 (prospectively registered): https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=378804&isReview=true

Personalized Approach Bias Modification Smartphone App ("SWIPE") to Reduce Alcohol Use Among People Drinking at Hazardous or Harmful Levels: Protocol for an Open-Label Feasibility Study.

BackgroundAlcohol accounts for 5.1% of the global burden of disease and injury, and approximately 1 in 10 people worldwide develop an alcohol use disorder. Approach bias modification (ABM) is a computerized cognitive training intervention in which patients are trained to “avoid” alcohol-related images and “approach” neutral or positive images. ABM has been shown to reduce alcohol relapse rates when delivered in residential settings (eg, withdrawal management or rehabilitation). However, many people who drink at hazardous or harmful levels do not require residential treatment or choose not to access it (eg, owing to its cost, duration, inconvenience, or concerns about privacy). Smartphone app–delivered ABM could offer a free, convenient intervention to reduce cravings and consumption that is accessible regardless of time and place, and during periods when support is most needed. Importantly, an ABM app could also easily be personalized (eg, allowing participants to select personally relevant images as training stimuli) and gamified (eg, by rewarding participants for the speed and accuracy of responses) to encourage engagement and training completion.ObjectiveWe aim to test the feasibility and acceptability of “SWIPE,” a gamified, personalized alcohol ABM smartphone app, assess its preliminary effectiveness, and explore in which populations the app shows the strongest indicators of effectiveness.MethodsWe aim to recruit 500 people who drink alcohol at hazardous or harmful levels (Alcohol Use Disorders Identification Test score≥8) and who wish to reduce their drinking. Recruitment will be conducted through social media and websites. The participants’ intended alcohol use goal (reduction or abstinence), motivation to change their consumption, and confidence to change their consumption will be measured prior to training. Participants will be instructed to download the SWIPE app and complete at least 2 ABM sessions per week for 4 weeks. Recruitment and completion rates will be used to assess feasibility. Four weeks after downloading SWIPE, participants will be asked to rate SWIPE’s functionality, esthetics, and quality to assess acceptability. Alcohol consumption, craving, and dependence will be measured prior to commencing the first session of ABM and 4 weeks later to assess whether these variables change significantly over the course of ABM.ResultsWe expect to commence recruitment in August 2020 and complete data collection in March 2021.ConclusionsThis will be the first study to test the feasibility, acceptability, and preliminary effectiveness of a personalized, gamified ABM intervention smartphone app for hazardous or harmful drinkers. Results will inform further improvements to the app, as well as the design of a statistically powered randomized controlled trial to test its efficacy relative to a control condition. Ultimately, we hope that SWIPE will extend the benefits of ABM to the millions of individuals who consume alcohol at hazardous levels and wish to reduce their use but cannot or choose not to access treatment.Trial RegistrationAustralian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12620000638932p; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=12620000638932pInternational Registered Report Identifier (IRRID)PRR1-10.2196/21278

Urinary ethyl glucuronide (uEtG) as a marker for alcohol consumption in liver transplant candidates: a real-world cohort.

In order to reduce alcohol relapse after liver transplantation (LT), the German national guidelines for waiting-list maintenance and organ allocation demand a minimum 6-month period of alcohol abstinence pre-LT, confirmed by measuring urinary ethyl glucuronide (uEtG). Between January 2015 and June 2016, uEtG was measured at least once in 339 cirrhotic patients with an indication for LT at the University Medical Center Mainz. uEtG was measured with an enzyme-linked immunosorbent assay (ELISA) screening test (cutoff value: 500 µg/L). For uEtG values ≥ 500 µg/L, liquid chromatography-mass spectrometry (LC-MS/MS) was performed as a confirmatory assay. Data were collected prospectively in a transplant database. Of the 339 potential liver transplant candidates, uEtG was negative in 86.4 %. Most patients were male (64.3 %), with an average age of 56.42 ± 10.1 years. In the multivariate analysis, mean corpuscular volume (p = 0.001), urinary creatinine (p = 0.001), gamma-glutamyl transferase (p = 0.001), and hemoglobin (p = 0.003) were significantly associated with a positive uEtG test result. The sensitivity of the ELISA screening test was 100 % for uEtG values > 2000 µg/L, as confirmed by LC-MS/MS. uEtG is an effective parameter to reveal alcohol consumption by patients on the waiting list for LT. The sensitivity of the ELISA is excellent for uEtG values > 2000 µg/L, for which LC-MS/MS confirmation could be omitted.

Text Messaging to Reduce Alcohol Relapse in Prelisting Liver Transplant Candidates: A Pilot Feasibility Study.

Many liver transplantation programs require documented alcohol sobriety prior to United Network for Organ Sharing (UNOS) listing. This pilot study examined the feasibility of the first mobile, alcohol relapse prevention intervention for liver transplant patients with alcoholic liver disease (ALD). This was a randomized 8-week pilot feasibility trial of a text message-based alcohol intervention. In-treatment assessment was conducted at 4weeks (4W), and immediate posttreatment assessment was conducted at 8W. Participants were liver transplant candidates (N=15) diagnosed with ALD who reported at least 1 drinking episode in the past year. Primary feasibility outcomes were percent of messages responded to and posttreatment intervention satisfaction ratings. Preliminary clinical efficacy outcomes were any biologically confirmed alcohol consumption, stress, abstinence self-efficacy, and alcohol craving. On feasibility outcomes, participants responded to 81% of messages received and reported high rates of intervention satisfaction, looked forward to receiving the messages, and found it easy to complete the intervention. On preliminary efficacy outcomes, zero participants in the text message (TM) had positive urine alcohol tests at 8W. Two of the 6 participants in standard care (SC) tested positive at 8W. No effects were seen on craving. For stress, a condition×time interaction emerged. TM participants had less stress at 4W and 8W compared with SC at baseline. They maintained their stress level during the intervention. For self-efficacy, a trend for condition effect emerged. TM participants had higher self-efficacy than SC participants. Participants reported high satisfaction with the intervention, looked forward to the messages, and found it easy to complete. Participants who received the intervention had better treatment outcomes than those who received standard care. They maintained higher levels of self-efficacy and lower stress. Mobile alcohol interventions may hold significant promise to help ALD liver transplant patients maintain sobriety.

Alcohol Relapse After Liver Transplantation for Alcoholic Cirrhosis-Impact on Liver Graft and Patient Survival: A Meta-analysis.

We performed meta-analysis to determine effect of alcohol relapse after liver transplantation (LT) for alcoholic cirrhosis on graft histology and survival. Studies were selected using following criteria: (a) LT for alcoholic cirrhosis, (b) reporting data on liver histology and/or patient survival among relapsers and abstainers, (c) minimum follow-up of 3 years. Random effects model was used to pool data to compare relapsers and abstainers on liver histology and patient survival. On analysis of seven studies, pooled prevalence of self-reported alcohol relapse was 26.3% (18.0-36.7%) over median (range) follow-up of 6.0 (3.7-8.3) years, with annual alcohol relapse rate of 4.7% (3.0-6.4%) for any alcohol use and 2.9% (0.5-5.3%) for heavy alcohol use. Relapsers compared to abstainers had higher odds for graft steatosis [4.1 (2.4-6.9)], steatohepatitis [4.5 (1.4-14.2)], alcoholic hepatitis [9.3 (1.01-85)], advanced fibrosis or cirrhosis [8.4 (3.5-20)]. Relapsers were over 3-fold more likely to die at 10 years of follow-up: [3.67 (1.42-9.50)] without differences in overall or 5-year survival. Recurrent alcoholic cirrhosis occurring in 9% of biopsied patients and 2% of all transplants was responsible for about 20% of all deaths on follow-up after LT. Extra-hepatic malignancy, and cardiovascular events were common causes for patient mortality. Alcohol relapse after LT for alcoholic cirrhosis negatively impacts the graft and long-term patient survival. Studies are needed to develop strategies to reduce alcohol relapse after LT for alcoholic cirrhosis. Alcohol relapse in liver transplant recipients can negatively affect graft histology and patient survival. Strategies to reduce alcohol relapse are needed to preserve graft function?

V1b Receptor Antagonist SSR149415 and Naltrexone Synergistically Decrease Excessive Alcohol Drinking in Male and Female Mice.

A recent clinical trial found that pharmacological blockade of V1b receptors reduces alcohol relapse in alcohol-dependent patients. SSR149415 is a selective V1b receptor antagonist that has potential for development as an alcohol dependency treatment. In this study, we investigated whether SSR149415 alone or in combination with the mu-opioid receptor (MOP-r) antagonist naltrexone (NTN) would alter excessive alcohol drinking in mice. Both sexes of C57BL/6J (B6) mice were subjected to a chronic intermittent access (IA) drinking paradigm (2-bottle choice, 24-hour access every other day) for 3weeks. Sucrose and saccharin drinking were used as controls for alcohol-specific drug effects. Neuronal proopiomelanocortin (POMC) enhancer (nPE) knockout mice with hypothalamic-specific loss of POMC (including beta-endorphin, the main endogenous ligand of MOP-r) were used as a genetic control for the effects of NTN. Acute administration of SSR149415 (1 to 30mg/kg) reduced alcohol intake and preference in a dose-dependent manner in both male and female B6 mice after IA. To investigate potential synergistic effects between NTN and SSR149415, we tested 6 different combination doses of SSR149415 and NTN, and found that a combination of SSR149415 (3mg/kg) and NTN (1mg/kg) reduced alcohol intake profoundly at doses lower than the individual effective doses in both sexes of B6 mice. We confirmed the effect of SSR149415 on reducing alcohol intake in nPE-/- male mice, consistent with independent mechanisms by which SSR149415 and NTN decrease alcohol drinking. The combination of V1b antagonist SSR149415 with NTN at individual subthreshold doses shows potential in alcoholism treatment, possibly with less adverse effects.

Design and methods of a double blind randomized placebo-controlled trial of extended-release naltrexone for alcohol dependent and hazardous drinking prisoners with HIV who are transitioning to the community

BackgroundHIV-infected prisoners have a high prevalence of alcohol use disorders and commonly relapse to alcohol soon after release to the community which is linked to high morbidity, poor antiretroviral therapy (ART) adherence and increased sexual risk-taking behaviors. Extended-release naltrexone (XR-NTX) effectively reduces relapse to alcohol in alcohol dependent persons, yet it remains unexamined among criminal justice system (CJS) populations transitioning to the community. MethodsA randomized double-blind, placebo-controlled trial of XR-NTX to improve HIV treatment outcomes via reducing relapse to alcohol use after prison release for HIV-infected hazardous drinking and alcohol dependent prisoners is discussed. ResultsAcceptability of study participation is high with 86% of those referred who met eligibility criteria and 85% of those who were able to receive injections prior to release accepted injections, yet important implementation issues are identified and addressed during the study and are discussed in this paper. ConclusionMedication-assisted therapies for prevention of relapse to alcohol use for CJS populations transitioning to the community, especially for HIV-infected patients, are urgently needed in order to reduce alcohol relapse after release and improve HIV treatment outcomes and contribute to improved individual and public health.

Effects of Acamprosate on Neuronal Receptors and Ion Channels Expressed in Xenopus Oocytes

Acamprosate (calcium acetylhomotaurinate) has proven to be a moderately effective pharmacological adjunct for the treatment of alcoholism. However, the central nervous system mechanism by which acamprosate reduces alcohol relapse remains unclear. Here we survey a number of metabotropic receptors, ligand-gated ion channels, and voltage-gated ion channels, to determine if acamprosate has actions at these sites in the central nervous system. Xenopus oocytes were injected with cDNAs or cRNAs encoding metabotropic glutamate receptors 1 and 5, M1 muscarinic receptors, glycine alpha1 homomeric and alpha1beta1 heteromeric receptors, gamma-aminobutyric acid A (GABA(A)alpha4beta3delta, alpha4beta3gamma2s, and alpha1beta2gamma2s) receptors, vanilloid receptor 1, and various combinations of alpha and beta subunits of voltage-gated Na+ channels. Electrophysiological responses were measured using two-electrode voltage clamp parameters after activation with agonists or voltage steps (for the voltage-gated channels). Acamprosate (0.1 to 100 microM) was pre-applied for 1 minute, followed by co-application with agonist. Acamprosate was also applied with ethanol to determine if it altered ethanol responses at some of these receptors and channels. None of the receptors or ion channels responded to acamprosate alone. Acamprosate also failed to alter the activation of receptors or channels by agonists or after activation of voltage-gated channels. There was no effect of acamprosate on ethanol responses at GABA(A)alpha1beta2gamma2s receptors or Na+ channels. Acamprosate does not significantly modulate the function of these receptors and ion channels at clinically relevant concentrations. Thus, the clinical effectiveness of acamprosate in the treatment of alcoholism is not likely due to direct effects on these receptors or ion channels.

Effects of acamprosate on sensitization to the locomotor-stimulant effects of alcohol in mice selectively bred for high and low alcohol preference.

Sensitization to the locomotor-stimulant effects of drugs is thought to play an important role in the development of drug-seeking behaviour. We hypothesized that the ability of acamprosate to reduce alcohol relapse rates in recovering alcoholics, and alcohol consumption in rodents, may be related to its ability to reduce sensitization to the locomotor-stimulant effects of alcohol. The purpose of the present study was to determine whether acamprosate reduces the expression of sensitization to the locomotor-stimulant effects of alcohol in lines of mice selectively bred for high (HAP) and low (LAP) alcohol preference. Mice were given six intraperitoneal (i.p.) injections of alcohol (3 g/kg) or saline at 48 h intervals. The test for sensitization to the locomotor-stimulant effects of alcohol consisted of a challenge dose of 2 g/kg i.p. alcohol followed immediately by assessment of locomotor activity for 20 min. Mice were pretreated with either saline or acamprosate (400 mg/kg) at 14 h and again at 2 h before the alcohol challenge. Both HAP and LAP mice showed sensitization to the locomotor-stimulant effects of alcohol. Acamprosate reduced the expression of sensitization to the locomotor-stimulant effects of alcohol in HAP but not LAP mice. These data suggest complex effects of acamprosate on alcohol-stimulated locomotor activity that depend on genotype.