Abstinent Patients Research Articles

Opioid treatment program prescribing of methadone with community pharmacy dispensing: Pilot study of feasibility and acceptability

Access to methadone for opioid use disorder (OUD) in the United States remains limited to regulated and certified Opioid Treatment Programs (OTPs). Collaboration between OTPs and community pharmacies would increase access to and potentially satisfaction with methadone delivery. While it remains illegal for prescribers to write, and pharmacies to dispense, methadone when the indication is OUD, the present pilot study evaluates the feasibility, acceptability, and outcomes of using community pharmacies to dispense methadone prescribed by OTP physicians (in tablet formulation) to a subset of clinically stable OTP patients; all other treatment services were delivered within the OTP. Necessary Drug Enforcement Administration (DEA) exceptions for OTP prescribers and the pharmacies, along with required Substance Abuse and Mental Health Services Administration (SAMHSA) waiver for OTP participation were obtained. A final sample of 11 patients enrolled in the study and were followed for three months; one left treatment due to dissatisfaction with the tablet formulation. All remaining participants produced drug-negative urine specimens, attended all pharmacy visits and OTP counseling sessions, and completed the evaluation. Participant satisfaction was high. These findings clearly support the feasibility and acceptability of OTP physician prescribing and community pharmacy dispensing of methadone in a subset of abstinent OTP patients, and encourage full scale trials evaluating a broader array of OTPs, pharmacies and patients, in urban and, perhaps most importantly, rural settings.

Plasma Amino Acid Concentrations in Patients with Alcohol and/or Cocaine Use Disorders and Their Association with Psychiatric Comorbidity and Sex.

(1) Background: Co-occurrence of mental and substance use disorders (SUD) is prevalent, but complicates their clinical courses, and specific biomarkers are required. Amino acids are altered in primary mental disorders; however, little is known about SUD and psychiatric comorbidity. Because most psychiatric disorders and biomarkers show sex differences, we investigated amino acids in men and women with alcohol and/or cocaine use disorders (AUD and/or CUD) and psychiatric comorbidity. (2) Methods: A cross-sectional study was conducted in 295 participants, who were divided into four groups (AUD, n = 60; CUD, n = 41; AUD + CUD, n = 64; and control, n = 130). Participants were clinically assessed, and plasma amino acid concentrations were analyzed in relation to sex, diagnosis of SUD and psychiatric comorbidity (3) Results: In the total sample, there were sex differences, and women showed lower Iso, Leu, Gln and Glu than men. While patients with CUD and AUD + CUD had higher Glu, Gly, Orn and Ser than controls, patients with AUD showed no differences. In SUD, patients with psychiatric comorbidity had lower Orn and higher Ala than non-comorbid patients in the AUD group. (4) Conclusions: There was a dysregulation of plasma amino acids in abstinent patients with SUD. However, our results suggest the importance of considering the clinical characteristics and sex in the validity of amino acids as potential biomarkers for SUD.

Debating capabilities of biochemical markers of liver function in patients with alcoholic liver cirrhosis

Introduction. The diagnosis of alcohol-related liver disease is limited by the lack of a tool to reliably identify whether the present deterioration in the patient’s condition is due to alcohol consumption or other causes.Purpose. to conduct a comparative assessment of the clinical and diagnostic significance of liver function biochemical indicators (AST, ALT, GGT, ALP) and their calculated derivatives (AST/ALT, GGT/ALP, GGT/GGTn, ALP/ALPn) as markers of alcohol consumption in patients with alcoholic liver cirrhosis.Material and methods. The observational study included 112 men over 18 years of age with alcohol-related liver cirrhosis. The patients were assessed the severity of liver cirrhosis according to the Child-Pugh scale, performed general and biochemical blood tests, coagulation test, assessment of the fact of alcohol consumption by the level of phosphatidylethanol. An analysis was made of the relationship between alcohol consumption and changes in laboratory parameters of liver function, with the determination of their sensitivity and specificity.Results. Patients with Child-Pugh B cirrhosis who consumed alcohol on phosphatidylethanol had higher levels of plasma albumin, GGT, and lower values of creatinine, direct and total bilirubin, urea, and aPTT compared with patients who did not drink alcohol (p < 0.05). Alcohol-drinking patients with class C cirrhosis have higher ALT levels compared with abstinent patients with the same severity of cirrhosis (p < 0.05). The relationship between the fact of alcohol consumption, determined by the level of phosphatidylethanol, and the ratio of GGT of patients to the normal GGT value, as well as between the ratio of GGT to alkaline phosphatase and the degree of increase in GGT, turned out to be statistically significant. To assess the fact of alcohol consumption, the level of serum GGT > 65 IU/ l (75.5%) has the highest sensitivity, the highest specificity is the ratio of the patient’s GGT to the normal value of GGT > 2 (82.9%).Conclusion. Compared with the known 100% sensitivity and > 92% specificity of Peth as a alcohol biomarker, among the biochemical indicators of liver function and their calculated derivatives, GGT > 65 IU/l have the greatest sensitivity or specificity (respectively, 75.5% and 65%) and GGTnorm. > 2 (37.7% and 82.9%, respectively), which makes it possible to use the totality of these parameters as an indicator of the continued impact on the patient of the main etiological factor of alcohol-related liver cirrhosis in the routine practice of most medical organizations of the Russian Federation.

Implicit measures of alcohol approach and drinking identity in alcohol use disorder: A preregistered double‐blind randomized trial with cathodal transcranial direct current stimulation (tDCS)

Alcohol use disorder (AUD) is a severe and widespread mental disorder with a huge negative impact on the social, economic and health dimensions. The identification of risk factors for the development of AUD and for relapse in existing AUD are crucial for prevention and treatment approaches. Alcohol-related implicit associations have been shown to contribute to drinking and might partially explain sudden relapses. The aims of this study are to investigate implicit associations in abstinent AUD patients and to test whether cathodal transcranial direct current stimulation (tDCS) modulates implicit associations. We measured performance in two alcohol-related implicit association tests (IATs) and two control tasks (flower-insect IAT, Stroop task) in 27 abstinent AUD patients with 31.5 (SD =36) days of abstinence on average. During the execution of the tasks, we applied 1mA cathodal or sham tDCS over the left dorsolateral prefrontal cortex (dlPFC) in a sham-controlled within-subject design. Results show an implicit bias of alcohol avoidance and implicit nondrinking identity for abstinent AUD patients. Cathodal tDCS modulated neither alcohol-related implicit associations nor the control tasks. This study complements knowledge about implicit alcohol-related association in AUD patients and shows no effect of a neuromodulatory intervention to alter implicit associations with the present parameters.

Sex Differences in Plasma Lysophosphatidic Acid Species in Patients with Alcohol and Cocaine Use Disorders.

Preclinical evidence suggests a main role of lysophosphatidic acid (LPA) signaling in drug addiction. Recently, we reported alterations in the plasma concentrations of LPA species in patients with alcohol use disorder (AUD). As there are sex differences in drug addiction, the main aim of the present study was to investigate whether relevant LPA species (16:0-LPA, 18:0-LPA, 18:1-LPA, 18:2-LPA and 20:4-LPA) were associated with sex and/or substance use disorder (SUD). This exploratory study was conducted in 214 abstinent patients with lifetime SUD, and 91 healthy control subjects. The SUD group was divided according to the diagnosis of AUD and/or cocaine use disorder (CUD). Participants were clinically assessed, and plasma samples were collected to determine LPA species and total LPA. We found that LPA concentrations were significantly affected by sex, and women showed higher concentrations than men. In addition, there were significantly lower 16:0-LPA, 18:2-LPA and total LPA concentrations in patients with SUD than in controls. Namely, patients with CUD and AUD + CUD showed lower LPA concentrations than controls or patients with AUD. In conclusion, our data suggest that LPA species could be potential biomarkers for SUD in women and men, which could contribute to a better stratification of these patients in treatment programs.

Severe liver fibrosis in the HCV cure era: Major effects of social vulnerability, diabetes, and unhealthy behaviors

Background & AimsAfter HCV cure, not all patients achieve significant liver fibrosis regression. We explored the effects of clinical and socio-behavioral factors on liver fibrosis, before and after HCV cure with direct-acting antivirals.MethodsWe analyzed data from the ongoing ANRS CO22 HEPATHER cohort, which prospectively collects clinical and socio-behavioral data on HCV-infected patients. Mixed-effects logistic regression models helped identify predictors of longitudinal measures of severe liver fibrosis, defined as a fibrosis-4 index >3.25. We also estimated the adjusted population attributable fractions (PAFs) for modifiable risk factors.ResultsAmong the 9,692 study patients (accounting for 24,687 visits over 4 years of follow-up, 48.5% of which were post-HCV cure), 26% had severe fibrosis at enrolment. After multivariable adjustment, HCV-cured patients had an 87% lower risk of severe fibrosis. An inverse dose-response relationship was found for coffee consumption, with the risk of severe fibrosis diminishing by 58% per additional cup/day (adjusted odds ratio (aOR 0.42; 95% CI 0.38-0.46). Unemployment, low educational level, and diabetes were associated with a higher severe fibrosis risk (aOR 1.69; 95% CI 1.32-2.16, aOR 1.50; 95% CI 1.20-1.86, and aOR 4.27; 95% CI 3.15-5.77, respectively). Severe fibrosis risk was 3.6/4.6-fold higher in individuals with previous/current unhealthy alcohol use than in abstinent patients. All these associations remained valid after HCV cure. The risk factors accounting for the greatest severe fibrosis burden were unemployment, low education level, and diabetes (PAFs: 29%, 21%, and 17%, respectively).ConclusionsMonitoring liver fibrosis after HCV cure is crucial for patients with low socioeconomic status, previous/current unhealthy alcohol use, and diabetes. Innovative HCV care models for the most socially vulnerable individuals and interventions for healthier lifestyles are needed to reinforce the positive effects of HCV cure on liver health.Lay summaryAfter hepatitis C virus (HCV) cure, not all patients achieve significant liver fibrosis regression. Herein, we studied the effects of clinical and socio-behavioral factors on the risk of severe liver fibrosis. Coffee consumption was strongly inversely associated with severe fibrosis, while diabetes, previous and current unhealthy alcohol use were associated with a 4.3-, 3.6- and 4.6-fold higher risk of severe fibrosis, respectively. Unemployment and low educational level were also associated with a higher risk of severe fibrosis. All these associations remained valid after HCV cure. These results demonstrate the need to continue liver fibrosis monitoring in at-risk groups, and to facilitate healthier lifestyles after HCV cure as a clinical and public health priority.

Reduced structural connectivity of the amygdala is associated with childhood trauma in adult patients with alcohol use disorder.

Childhood trauma (CT) is frequent in patients with alcohol use disorder (AUD) and may impact on adult drinking behaviour and treatment outcome. This study aimed to investigate the structural correlates of CT in AUD, focusing on the amygdala, which plays a crucial role in the neurobiology of trauma. We hypothesized reduced amygdala volume and reduced structural connectivity as quantified by fractional anisotropy (FA) and by number of streamlines in those AUD patients with a history of moderate to severe CT (AUD‐CT). T1‐weighted MP2RAGE and diffusion‐weighted imaging (DWI) 3‐Tesla MRI‐scans were acquired in 41 recently abstinent patients with AUD. We compared bilateral amygdala volume and structural connectivity (FA and number of streamlines) of pathways emanating from the amygdala between AUD‐CT (n = 20) and AUD without CT (AUD‐NT, n = 21) using a mixed model multivariate analysis of variance (MANCOVA) controlling for age and gender. AUD‐CT displayed reduced FA and reduced number of streamlines of amygdalar tracts. There were no differences regarding amygdala volume. The severity of physical abuse, a subscale of the childhood trauma questionnaire, was negatively correlated with FA and with number of streamlines. AUD‐CT and AUD‐NT differ regarding structural connectivity of pathways projecting to and from the amygdala, but not regarding amygdala volume. Those alterations of structural connectivity in AUD‐CT may represent a distinguishable neurobiological subtype of AUD, which might be associated with the complex clinical picture and poorer outcome that patients with CT and AUD often present.

Repetitive Transcranial Magnetic Stimulation in Alcohol Dependence: A Randomized, Double-Blind, Sham-Controlled Proof-of-Concept Trial Targeting the Medial Prefrontal and Anterior Cingulate Cortices

BackgroundAlcohol addiction is associated with a high disease burden, and treatment options are limited. In a proof-of-concept study, we used deep repetitive transcranial magnetic stimulation (dTMS) to target circuitry associated with the pathophysiology of alcohol addiction. We evaluated clinical outcomes and explored associated neural signatures using functional magnetic resonance imaging. MethodsThis was a double-blind, randomized, sham-controlled trial. A total of 51 recently abstinent treatment-seeking patients with alcohol use disorder (moderate to severe) were randomized to sham or active dTMS, using an H7 coil targeting midline frontocortical areas, including the medial prefrontal and anterior cingulate cortices. Treatment included 15 sessions over 3 weeks, followed by five sessions over 3 months of follow-up. Each session delivered 100 trains of 30 pulses at 10 Hz. The primary predefined outcome was reduction in percentage of heavy drinking days, obtained using timeline follow-back interviews. Secondary analyses included self-reports of craving, ethyl glucuronide in urine, and brain imaging measures. ResultsBoth craving after treatment and percentage of heavy drinking days during follow-up were significantly lower in the active versus sham control group (percentage of heavy drinking days = 2.9 ± 0.8% vs. 10.6 ± 1.9%, p = .037). Active dTMS was associated with decreased resting-state functional connectivity of the dorsal anterior cingulate cortex with the caudate nucleus and decreased connectivity of the medial prefrontal cortex to the subgenual anterior cingulate cortex. ConclusionsWe provide initial proof-of-concept for dTMS targeting midline frontocortical structures as a treatment for alcohol addiction. These data strongly support a rationale for a full-scale confirmatory multicenter trial. Therapeutic benefits of dTMS appear to be associated with persistent changes in brain network activity.

Plasma Concentrations of Lysophosphatidic Acid and Autotaxin in Abstinent Patients with Alcohol Use Disorder and Comorbid Liver Disease.

Lysophosphatidic acid (LPA) is an endogenous lysophospholipid and a bioactive lipid that is synthesized by the enzyme autotaxin (ATX). The ATX–LPA axis has been associated with cognitive dysfunction and inflammatory diseases, mainly in a range of nonalcoholic liver diseases. Recently, preclinical and clinical evidence has suggested a role of LPA signaling in alcohol use disorder (AUD) and AUD-related cognitive function. However, the ATX–LPA axis has not been sufficiently investigated in alcoholic liver diseases. An exploratory study was conducted in 136 participants, 66 abstinent patients with AUD seeking treatment for alcohol (alcohol group), and 70 healthy control subjects (control group). The alcohol group was divided according to the presence of comorbid liver diseases (i.e., fatty liver/steatosis, alcoholic steatohepatitis, or cirrhosis). All participants were clinically evaluated, and plasma concentrations of total LPA and ATX were measured using enzyme-linked immunosorbent assays. Data were primarily analyzed using analysis of covariance (ANCOVA) while controlling for age, body mass index, and sex. Logistic regression models were created to assess the association of the ATX–LPA axis and AUD or liver disease. LPA and ATX were log10-transformed to fit the assumptions of parametric testing.The main results were as follows: total LPA and ATX concentrations were dysregulated in the alcohol group, and patients with AUD had significantly lower LPA (F(1,131) = 10.677, p = 0.001) and higher ATX (F(1,131) = 8.327, p = 0.005) concentrations than control subjects; patients with AUD and liver disease had significantly higher ATX concentrations (post hoc test, p < 0.05) than patients with AUD but not liver disease; significant correlations between AUD-related variables and concentrations of LPA and ATX were only found in the non-liver disease subgroup (the duration of alcohol abstinence with LPA and ATX (r = +0.33, p < 0.05); and the severity of AUD with ATX (rho = −0.33, p < 0.05)); and a logistic regression model with LPA, ATX, and AUD-related variables showed an excellent discriminative power (area under the curve (AUC) = 0.915, p < 0.001) for distinguishing patients with AUD and comorbid liver disease. In conclusion, our data show that the ATX–LPA axis is dysregulated in AUD and suggest this lipid signaling, in combination with relevant AUD-related variables, as a reliable biomarker of alcoholic liver diseases.

The Higher Parietal Cortical Thickness in Abstinent Methamphetamine Patients Is Correlated With Functional Connectivity and Age of First Usage.

AimThis study aimed to explore the changes of cortical thickness in abstinent methamphetamine (MA) patients compared with healthy controls.Materials and MethodsThree-tesla structural and functional magnetic resonance imaging (MRI) was obtained from 38 abstinent methamphetamine-dependent (AMD) patients and 32 demographically equivalent healthy controls. The cortical thickness was assessed using FreeSurfer software. General linear model was used to get brain regions with significant different cortical thickness between groups (p < 0.05, Monte Carlo simulation corrected). The mean cortical thickness value and functional connectivity with all other brain regions was extracted from those significant regions. Moreover, correlation coefficients were calculated in the AMD group to assess the relations between the mean cortical thickness, functional connectivity and age when they first took MA and the duration of both MA use and abstinence.ResultsThe AMD group showed significant cortical thickness increase in one cluster located in the parietal cortex, including right posterior central gyrus, supramarginal gyrus, and superior parietal lobule. In addition, cortical thickness values of those regions were all significant and negatively correlated with the age when patients first used MA. The cortical thickness of right posterior gyrus were positively correlated with its functional connectivities with left middle frontal gyrus and both left and right medial orbitofrontal gyrus.ConclusionThe higher cortical thickness in the parietal cortex of the AMD group is in agreement with findings in related studies of increased glucose metabolism and gray matter volume. Importantly, the negative correlation between parietal cortical thickness and age of first MA suggested that adolescent brains are more vulnerable to MA’s neurotoxic effect.

Impact of Alcohol Abstinence on the Risk of Hepatocellular Carcinoma in Patients With Alcohol-Related Liver Cirrhosis.

Although alcohol cessation is the only effective treatment for alcohol-related liver disease, few data exist concerning its influence on the risk of hepatocellular carcinoma (HCC). We aimed to evaluate the effect of alcohol abstinence on the incidence of HCC in patients with alcohol-related cirrhosis. We studied 727 patients with alcohol-related cirrhosis (247 with compensated disease and 480 with previous decompensation) who were included in a surveillance program for the early detection of HCC and prospectively followed. Baseline clinical and biological parameters and alcohol consumption during follow-up were recorded. Abstinence was defined as the absence of any alcohol use. During follow-up (median 54 months), 354 patients (48.7%) remained abstinent and 104 developed HCC (2.3 per 100 person-years). Factors independently associated with the risk of HCC among patients with previous decompensation were age, male gender, and aspartate aminotransferase, whereas abstinence was not linked to a reduced risk (hazard ratio 0.95; 95% confidence interval 0.59-1.52). However, among patients without previous decompensation, prothrombin activity and abstinence were independently associated with the risk of HCC. Abstinent patients had a significant decrease in the risk of developing tumor (hazard ratio 0.35; 95% confidence interval 0.13-0.94). These results did not change after applying a competing risk analysis where death and liver transplantation were considered as competing events. Alcohol abstinence reduced the risk of HCC in patients with alcohol-related cirrhosis, but only in those without a history of decompensated disease. This finding emphasizes the need for an early diagnosis of alcohol-related liver disease and for implementing strategies leading to an increase in the rate of achieving and maintaining abstinence among this population.

Role of inflammation in alcohol-related brain abnormalities: a translational study.

Brain abnormalities observed in alcohol use disorder are highly heterogeneous in nature and severity, possibly because chronic alcohol consumption also affects peripheral organs leading to comorbidities that can result in exacerbated brain alterations. Despite numerous studies focussing on the effects of alcohol on the brain or liver, few studies have simultaneously examined liver function and brain damage in alcohol use disorder, and even fewer investigated the relationship between them except in hepatic encephalopathy. And yet, liver dysfunction may be a risk factor for the development of alcohol-related neuropsychological deficits and brain damage well before the development of liver cirrhosis, and potentially through inflammatory responses. The use of animal models enables a better understanding of the pathophysiological mechanisms underlying liver–brain relationships in alcohol use disorder, and more particularly of the inflammatory response at the tissue, cerebral and hepatic levels. The objective of this translational study was to investigate, both in alcohol use disorder patients and in a validated animal model of alcohol use disorder, the links between peripheral inflammation, liver damage and brain alterations. To do this, we conducted an in vivo neuroimaging examination and biological measures to evaluate brain volumes, liver fibrosis and peripheral cytokines in alcohol use disorder patients. In selectively bred Sardinian alcohol-preferring rats, we carried out ex vivo neuroimaging examination and immunohistochemistry to evaluate brain and liver inflammatory responses after chronic (50 consecutive weeks) alcohol drinking. In recently abstinent and non-cirrhotic alcohol use disorder patients, the score of liver fibrosis positively correlated with subcortical regions volumes (especially in right and left putamen) and level of circulating proinflammatory cytokines. In Sardinian alcohol-preferring rats, we found macrostructural brain damage and microstructural white matter abnormalities similar to those found in alcohol use disorder patients. In addition, in agreement with the results of peripheral inflammation observed in the patients, we revealed, in Sardinian alcohol-preferring rats, inflammatory responses in the brain and liver were caused by chronic alcohol consumption. Since the liver is the main source of cytokines in the human body, these results suggest a relationship between liver dysfunction and brain damage in alcohol use disorder patients, even in the absence of major liver disease. These findings encourage considering new therapeutic strategies aiming at treating peripheral organs to limit alcohol-related brain damage.

I feel good? Anhedonia might not mean "without pleasure" for people treated for opioid use disorder.

Anhedonia is usually defined as partial or total loss of the capacity for pleasure. People with anhedonia in the context of major depressive disorder may have an unexpected capacity for event-related mood brightening, observable when mood is assessed dynamically (with smartphone-based ecological momentary assessment [EMA]) rather than only statically via questionnaire. We used EMA to monitor mood and pleasant events for 4 weeks in 54 people being treated with opioid agonist medication for opioid-use disorder (OUD), which is also associated with anhedonia, said to manifest especially as loss of pleasure from nondrug reward. We compared OUD patients' EMA reports with those of 47 demographically similar controls. Background positive mood was lower in OUD patients than in controls, as we hypothesized (Cohen ds = .85 to 1.32, 95% CIs [.66, 1.55]), although, contrary to our hypothesis, background negative mood was also lower (ds = .82 to .85, 95% CIs [.73, .94]). As hypothesized, instances of nondrug pleasure were as frequent in OUD patients as in controls-and were not rated much less pleasurable (d = .18, 95% CI [-.03, .35]). Event-related mood brightening occurred in both abstinent and nonabstinent OUD patients (ds = .18 to .37, CIs [-.01, .57]) and controls (ds = .04 to .60, CIs [-.17, .79]), brightening before each event began earlier for controls than OUD patients, but faded similarly postevent across groups. Our findings add to the evidence that anhedonia does not rule out reactive mood brightening, which, for people with OUD being treated on opioid agonist medication, can be elicited by nondrug activities. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Kappa opioid receptor blockade in the nucleus accumbens shell prevents sex-dependent alcohol deprivation effect induced by inflammatory pain.

Pain-induced negative affect reduces life quality of patients by increasing psychiatric comorbidities, including alcohol use disorders (AUDs). Indeed, clinical data suggest pain as a risk factor to suffer AUDs, predicting relapse drinking in abstinent patients. Here, we analyse the impact of pain on alcohol relapse and the role of kappa opioid receptor (KOR) activation in mediating these pain-induced effects because KORs play an important role in pain-driven negative affect and AUD. Female and male Sprague-Dawley rats underwent 2 alcohol intermittent access periods separated by a forced abstinence period. The complete Freund adjuvant model of inflammatory pain was introduced during abstinence, and alcohol intake before and after alcohol reintroduction was assessed. In addition, we used behavioural approaches to measure stress and memory impairment and biochemical assays to measure KOR expression in abstinence and reintroduction periods. Only female CFA-treated rats increased alcohol intake during the reintroduction period. Concomitantly, this group showed enhanced anxiety-like behaviour and increased KOR expression in the nucleus accumbens shell that was developed during abstinence and remained during the reintroduction period. Finally, KOR antagonist norbinaltorphimine was administered in the nucleus accumbens shell during abstinence to prevent a pain-induced alcohol deprivation effect, a phenomenon observed in CFA-female rats. The administration of norbinaltorphimine effectively blocked a pain-induced alcohol deprivation effect in female rats. Our data evidenced that inflammatory pain constitutes a risk factor to increase alcohol consumption during a reintroduction phase only in female rats by the rise and maintenance of stress probably mediated by KOR signalling in the nucleus accumbens.

The role of the orbitofrontal cortex and the nucleus accumbens for craving in alcohol use disorder

This study aimed to investigate structural and functional alterations of the reward system and the neurobiology of craving in alcohol use disorder (AUD). We hypothesized reduced volume of the nucleus accumbens (NAcc), reduced structural connectivity of the segment of the supero-lateral medial forebrain bundle connecting the orbitofrontal cortex (OFC) with the NAcc (OFC-NAcc), and reduced resting-state OFC-NAcc functional connectivity (FC). Furthermore, we hypothesized that craving is related to an increase of OFC-NAcc FC. Thirty-nine recently abstinent patients with AUD and 18 healthy controls (HC) underwent structural (T1w-MP2RAGE, diffusion-weighted imaging (DWI)) and functional (resting-state fMRI) MRI-scans. Gray matter volume of the NAcc, white matter microstructure (fractional anisotropy (FA)) and macrostructure (tract length) of the OFC-NAcc connection and OFC-NAcc FC were compared between AUD and HC using a mixed model MANCOVA controlling for age and gender. Craving was assessed using the thoughts subscale of the obsessive-compulsive drinking scale (OCDS) scale and was correlated with OFC-NAcc FC. There was a significant main effect of group. Results were driven by a volume reduction of bilateral NAcc, reduced FA in the left hemisphere, and reduced tract length of bilateral OFC-NAcc connections in AUD patients. OFC-NAcc FC did not differ between groups. Craving was associated with increased bilateral OFC-NAcc FC. In conclusion, reduced volume of the NAcc and reduced FA and tract length of the OFC-NAcc network suggest structural alterations of the reward network in AUD. Increased OFC-NAcc FC is associated with craving in AUD, and may contribute to situational alcohol-seeking behavior in AUD.

FMRI-based prediction of naltrexone response in alcohol use disorder: a replication study

Pharmacological treatment in alcohol use disorder suffers from modest effect sizes. Efforts have been undertaken to identify patient characteristics that help to select individuals that benefit from pharmacological treatment. Previous studies indicated that neural alcohol cue-reactivity (CR) might provide a marker that identifies patients, which benefit from naltrexone treatment.We investigated the reproducibility of the association between ventral striatum (VS) activation and naltrexone (NTX) treatment response by analyzing data from a recent longitudinal clinical trial in N = 44 abstinent treatment-seeking alcohol-dependent patients. A follow-up was conducted over 3 months. We computed the percentage of significant voxels in VS and tested main effects and interactions with NTX treatment on relapse risk using Cox Regression models.We found a significant interaction effect between pre-treatment cue reactivity in the VS and NTX treatment on time to first heavy relapse (Hazard Ratio = 7.406, 95% CI 1.17–46.56, p = 0.033), such that the patient group with high VS activation (defined by a mean split) showed a significant medication effect (Hazard Ratio = 0.140, 95% CI 0.02–0.75, p = 0.022) with a number needed to treat of 3.4 [95% CI 2.413.5], while there was no significant effect in the group with low VS activation (Hazard Ratio = 0.726, p = 0.454).Thus, using an independent sample we replicated the previously described positive association between VS activation and NTX efficacy. Although our results should be considered cautiously in light of the small sample size, our results support the potential of neural alcohol CR as a tool for precision medicine approaches in alcohol dependence.

Neurobiology of alcohol seeking behavior.

Alcohol addiction is a chronic relapsing brain disease characterized by an impaired ability to stop or control alcohol use despite adverse consequences. A main challenge of addiction treatment is to prevent relapse, which occurs in more than >50% of newly abstinent patients with alcohol disorder within 3months. In people suffering from alcohol addiction, stressful events, drug-associated cues and contexts, or re-exposure to a small amount of alcohol trigger a chain of behaviors that frequently culminates in relapse. In this review, we first present the preclinical models that were developed for the study of alcohol seeking behavior, namely the reinstatement model of alcohol relapse and compulsive alcohol seeking under a chained schedule of reinforcement. We then provide an overview of the neurobiological findings obtained using these animal models, focusing on the role of opioids systems, corticotropin-release hormone and neurokinins, followed by dopaminergic, glutamatergic, and GABAergic neurotransmissions in alcohol seeking behavior.

Neurophysiological correlates of alcohol-specific inhibition in alcohol use disorder and its association with craving and relapse

ObjectiveThis study investigates neurophysiological correlates of general and alcohol-specific inhibitory control in patients with Alcohol Use Disorder (AUD), focusing on its association with individual craving levels and with relapse at three-month follow-up. Methods59 abstinent AUD patients and 20 healthy controls performed a Go/NoGo task incorporating alcohol-related and neutral stimuli during 64-channel electroencephalography (EEG) recording, yielding four event-related potentials (ERP) per participant (NoGo-Alcohol, Go-Alcohol, NoGo-Neutral, Go-Neutral). Whole-scalp randomization-based statistics assessed effects of the factors group (patients/controls or relapsers/abstainers), craving level, response type (NoGo/Go) and picture type (alcohol/neutral) on topography and signal strength of the ERP components N2 and P3. ResultsNo differences on group level were observed between patients and controls. However, analyses incorporating individual craving indicated that the topographic difference between alcohol-related and neutral NoGo-N2 components increased with craving. Moreover, topographic differences in the alcohol-related and neutral NoGo-P3 component allowed for differentiation between relapsers and abstainers. ConclusionsIn alcohol-related contexts, the response inhibition conflict reflected in the NoGo-N2 seems enhanced in patients with high craving. The inhibition-sensitive NoGo-P3 varies in relapsers but not in abstainers between neutral and alcohol-related contexts. SignificanceIn AUD patients, neurophysiological correlates of inhibition vary with alcohol-related contexts and craving, and might be indicative of relapse risk.

Neurofeedback Training versus Treatment-as-Usual for Alcohol Dependence: Results of an Early-Phase Randomized Controlled Trial and Neuroimaging Correlates

Introduction: Alcohol dependence is one of the most common substance use disorders, and novel treatment options are urgently needed. Neurofeedback training (NFT) based on real-time functional magnetic resonance imaging (rtf­MRI) has emerged as an attractive candidate for add-on treatments in psychiatry, but its use in alcohol dependence has not been formally investigated in a clinical trial. We investigated the use of rtfMRI-based NFT to prevent relapse in alcohol dependence. Methods: Fifty-two alcohol-dependent patients from the UK who had completed a detoxification program were randomly assigned to a treatment group (receiving rtfMRI NFT in addition to standard care) or the control group (receiving standard care only). At baseline, alcohol consumption was assessed as the primary outcome measure and a variety of psychological, behavioral, and neural parameters as secondary outcome measures to determine feasibility and secondary training effects. Participants in the treatment group underwent 6 NFT sessions over 4 months and were trained to downregulate their brain activation in the salience network in the presence of alcohol stimuli and to upregulate frontal activation in response to pictures related to positive goals. Four, 8, and 12 months after baseline assessment, both groups were followed up with a battery of clinical and psychometric tests. Results: Primary outcome measures showed very low relapse rates for both groups. Analysis of neural secondary outcome measures indicated that the majority of patients modulated the salience system in the desired directions, by decreasing activity in response to alcohol stimuli and increasing activation in response to positive goals. The intervention had a good safety and acceptability profile. Conclusion: We demonstrated that rtfMRI-neurofeedback targeting hyperactivity of the salience network in response to alcohol cues is feasible in currently abstinent patients with alcohol dependence.

Modafinil reduces smoked cocaine self-administration in humans: effects vary as a function of cocaine ‘priming’ and cost

BackgroundThe absence of an FDA-approved medication for the treatment of cocaine use disorder (CUD) may, in part, reflect the varying conditions present when the decision to use cocaine is made, with one medication unlikely to work under all conditions. The objective of this double-blind, placebo-controlled, human laboratory study was to test the effects of modafinil, a medication with mixed efficacy for the treatment of CUD, using a novel self-administration procedure designed to model distinct clinical scenarios. MethodsDuring modafinil maintenance (0, 300 mg/day), participants chose to self-administer up to 7 doses of smoked cocaine (25 mg) under 9 conditions: immediately after exposure to: (a) cues associated with cocaine and a non-contingent cocaine administration, i.e. 'prime' (25 mg), (b) only cocaine cues, and (c) neither cues nor cocaine. Each condition was tested when self-administered cocaine cost $5, $10 and $15/dose. ResultsNontreatment-seeking cocaine smokers (3 F,13 M), spending $388 ± 218/week on cocaine and with no history of alcohol use disorder, completed the study. Relative to placebo, modafinil robustly attenuated self-administration when cocaine was expensive ($10,$15/dose) and when there was no 'prime.' Modafinil had no effect on self-administration when cocaine was inexpensive ($5/dose) or when participants received a 'prime.' ConclusionsModafinil's effects on cocaine-taking varied substantially as a function of recent cocaine exposure and cost, which may help explain the mixed clinical findings. Modafinil may be most effective for preventing relapse in abstinent patients, particularly under conditions in which cocaine is costly, rather than initiating abstinence for those continuing to use cocaine.