A comparison between phase-III trials and a phase-IV study of nalmefene in alcohol use disorder patients. Is there a difference?

Concerns regarding the external validity of phase-III trials are common to many medical disciplines, with relevant discrepancies found between experimental and clinical samples in some diseases such as hypertension. The aim of this study was to compare the samples included in the pivotal, phase-III clinical trials of nalmefene with that of a recently conducted phase-IV trial. Baseline characteristics of the studies were compared through univariate analysis. Significant differences were found in the percentage of low-risk drinkers included. Differences were also found in the prescription and intake pattern of nalmefene, as well as in the rate of psychiatric and addictive comorbidities, which were much higher in the phase-IV study. These data suggest that in the field of alcohol use disorders there are also relevant differences between experimental and clinical samples, a fact that reinforces the need for phase-III trials to be balanced with observational, phase-IV trials

The more you take it, the better it works: six-month results of a nalmefene phase-IV trial

Background: Alcohol use disorders remain a major health problem. Reduced drinking has been increasingly recognized as a valuable alternative to abstinence. Nalmefene has shown in previous, experimental studies to be a useful tool to aid reduced drinking. However, more data from routine practice settings are needed in order to obtain evidence with high external validity. The aim of this study was to conduct a single-arm phase-IV study with alcohol-dependent outpatients starting with nalmefene for the first time. Here, we present the main effectiveness analysis, scheduled at six months. Methods: This was an observational, multisite, single-arm, phase-IV study conducted among adult alcohol-dependent outpatients who received nalmefene for the first time. The study consisted of four visits: Baseline, 1 month, 6 months, and 12 months. At each visit, drinking variables were obtained from the time-line follow-back regarding the previous month. Satisfaction with medication was also assessed from both patients and professionals with the Medication Satisfaction Questionnaire. A repeated measures mixed model was performed for effective analysis regarding drinking outcomes (reduction in total alcohol consumption and the number of heavy drinking days). Regression analyses were performed in order to find predictors of responses to nalmefene. Results: From a total of 110 patients included, 63 reported data at the six-month visit. On average, patients took nalmefene 69% of days during the month previous to the 6-month assessment. Compared to the one month results, the number of heavy drinking days and total alcohol consumption increased. Still, they were significantly lower than baseline values (outcome evolution over time was from 13.5 to 6.8 to 9.4 days/month, and from 169 to 79 to 116 units/month). A total of 23 patients were considered medication responders. The number of days of taking nalmefene was significantly associated in the regression analysis. Satisfaction was globally high for both professionals and patients and, overall, nalmefene was well-tolerated with no serious adverse events reported. Conclusion: The data provided by this phase-IV study suggest that nalmefene is an effective, well-tolerated treatment for alcohol-dependence in real world, clinical settings

Remediation therapy in patients with alcohol use disorders and neurocognitive disorders: A Pilot Study.

Many alcohol-dependent patients suffer from cognitive impairment of variable severity, manifested by alterations in retrograde and anterograde memory, visuospatial processing, cognitive abilities and attention, some of which are reversible. In this context, cognitive remediation therapies could significantly improve patients' performance; therefore, these are considered a valuable alternative. The aim of this study was to implement cognitive remediation therapy in patients with alcohol dependence and cognitive impairment and evaluate its viability and effectiveness. The participants were sixteen abstinent, alcohol-dependent patients (mean age of 59 years, 63% males) from the Addictive Behaviours Unit of a tertiary hospital. Over 6 months, a nurse led 1-hour weekly sessions (24 sessions in total) during which exercises for improving functional, social and cognitive performance were completed. Patients were assessed at baseline, at the end of the study and 6 months later, using the Mini-Mental State Examination (MMSE) and the Memory Alteration Test (M@T). Their respective scores were 26.4 (SD 3.16), 29 (SD 1.67) and 27 (SD 3.1) for the MMSE and 38.7 (SD 6.81), 45.7 (SD 5.6) and 41.1 (SD 7.86) for the M@T. Changes were assessed with both Friedman and Wilcoxon signed-rank tests, with mostly statistically significant differences (p < 0.05). Assistance and satisfaction were high. Therefore, the therapy was viable, widely accepted and effective

The more you take it, the better it works : Six-month results of a nalmefene phase-IV trial

Alcohol use disorders remain a major health problem. Reduced drinking has been increasingly recognized as a valuable alternative to abstinence. Nalmefene has shown in previous, experimental studies to be a useful tool to aid reduced drinking. However, more data from routine practice settings are needed in order to obtain evidence with high external validity. The aim of this study was to conduct a single-arm phase-IV study with alcohol-dependent outpatients starting with nalmefene for the first time. Here, we present the main effectiveness analysis, scheduled at six months. This was an observational, multisite, single-arm, phase-IV study conducted among adult alcohol-dependent outpatients who received nalmefene for the first time. The study consisted of four visits: Baseline, 1 month, 6 months, and 12 months. At each visit, drinking variables were obtained from the time-line follow-back regarding the previous month. Satisfaction with medication was also assessed from both patients and professionals with the Medication Satisfaction Questionnaire. A repeated measures mixed model was performed for effective analysis regarding drinking outcomes (reduction in total alcohol consumption and the number of heavy drinking days). Regression analyses were performed in order to find predictors of responses to nalmefene. From a total of 110 patients included, 63 reported data at the six-month visit. On average, patients took nalmefene 69% of days during the month previous to the 6-month assessment. Compared to the one month results, the number of heavy drinking days and total alcohol consumption increased. Still, they were significantly lower than baseline values (outcome evolution over time was from 13.5 to 6.8 to 9.4 days/month, and from 169 to 79 to 116 units/month). A total of 23 patients were considered medication responders. The number of days of taking nalmefene was significantly associated in the regression analysis. Satisfaction was globally high for both professionals and patients and, overall, nalmefene was well-tolerated with no serious adverse events reported. The data provided by this phase-IV study suggest that nalmefene is an effective, well-tolerated treatment for alcohol-dependence in real world, clinical settings

Identifying Triggers of Alcohol Craving to Develop Effective Virtual Environments for Cue Exposure Therapy

Background: Many studies have indicated that alcohol craving is a core mechanism in the acquisition, maintenance, and precipitation of relapse in alcohol use disorder (AUD). A common treatment approach in AUD is cue exposure therapy (CET). New technologies like virtual reality (VR) have the potential to enhance the effectiveness of CET by creating realistic scenarios in naturalistic environments. In this study, we aimed to determine relevant triggers of alcohol craving in patients with AUD. Methods: We enrolled 75 outpatients diagnosed with AUD according to the DSM-5 criteria Participants completed the Alcohol Use Disorder Identification Test and a self-administered questionnaire to assess alcohol craving. The variables included in the craving questionnaire were as follows: presence of others, situations, time of the day, day of the week, mood, and type of alcoholic beverage. Results: Greater levels of alcohol craving were seen in many situations, including being at a party, in a restaurant, in a bar or pub, and at home. Drinking alone and drinking with two or more friends were equally associated with higher levels of craving. Drinking at night and drinking at weekends also emerged as triggers for alcohol craving. Emotional states like anxiety or tension, sadness, stress, frustration, or irritability were highly associated with urges to drink alcohol. The alcoholic drinks most highly associated with increased levels of craving were beer, wine, and whisky. Gender and age implications were discussed. Conclusion: This study is part of a larger project aiming to develop and validate CET based on VR technology for patients with AUD who are resistant to classical treatment. The identified triggers have been used to develop relevant VR environments for CET, and further research is ongoing to implement our findings

Craving and Anxiety Responses as Indicators of the Efficacy of Virtual Reality-Cue Exposure Therapy in Patients Diagnosed with Alcohol use Disorder

Introduction: Virtual Reality (VR) technology has shown promising results as an assessment and treatment instrument in substance use disorders, particularly in attempts to reduce craving. A common application of the VR technology in treatment is based on cue-exposure therapy (CET). Following from previous results, the present case series is part of a larger project aiming to test the efficacy of the Virtual Reality-Cue Exposure Therapy (VR-CET) versus Cognitive-Behavioral Therapy (CBT). Method: Eight patients between ages 40 and 55 (Mage = 49, SD = 5.54) from the Addictive Behaviors Unit at the Hospital Clinic of Barcelona participated in this study after providing written informed consent. Patients were randomly assigned to the VR-CET group (three patients) or the CBT group (five patients). The protocol of the clinical trial consisted of a pre-treatment session (the initial assessment session), six sessions of CBT or VR-CET, and a post-treatment session (post-assessment session). The VR-CET sessions consisted of exposure to alcohol-related cues and environments aiming to reduce anxiety and craving responses to alcohol-related stimuli. The CBT sessions consisted of classical standardized therapy for the treatment of addictions, as previously applied in other clinical trials. In the pre- and post-treatment sessions, patients completed several measures of alcohol craving and anxiety and visual analog scales (VAS) during VR exposure. Results: Our data indicated a significant reduction in both groups in all scores of craving and anxiety responses, as assessed by the different instruments. In addition, the VR-CET group obtained lower scores on anxiety and craving responses than the CBT group. Conclusions: In this ongoing project, the first phase of the clinical trial showed significant improvements in terms of craving and anxiety reduction in both groups, emphasizing that VR-CET can be as efficient as CBT. In addition, patients in the VR-CET group obtained slightly better scores than patients in the CBT group, suggesting the clinical potential of the VR technology in the treatment of substance use disorders. We propose that VR-based CET can be a useful complement to existing treatment methods for AUD patients

Attentional bias, alcohol craving, and anxiety implications of the virtual reality cue-exposure therapy in severe alcohol use disorder: a case report

Aims: Attentional bias (AB), alcohol craving, and anxiety have important implications in the development and maintenance of alcohol use disorder (AUD). The current study aims to test the effectiveness of a Virtual Reality Cue-Exposure Therapy (VR-CET) to reduce levels of alcohol craving and anxiety and prompt changes in AB toward alcohol content. Method: A 49-year-old male participated in this study, diagnosed with severe AUD, who also used tobacco and illicit substances on an occasional basis and who made several failed attempts to cease substance misuse. The protocol consisted of six VR-CET booster sessions and two assessment sessions (pre- and post-VR-CET) over the course of 5 weeks. The VR-CET program consisted of booster therapy sessions based on virtual reality (VR) exposure to preferred alcohol-related cues and contexts. The initial and final assessment sessions were focused on exploring AB, alcohol craving, and anxiety using paper-and-pencil instruments and the eye-tracking (ET) and VR technologies at different time points. Results: Pre and post assessment sessions indicated falls on the scores of all instruments assessing alcohol craving, anxiety, and AB. Conclusions: This case report, part of a larger project, demonstrates the effectiveness of the VR-CET booster sessions in AUD. In the post-treatment measurements, a variety of instruments showed a change in the AB pattern and an improvement in craving and anxiety responses. As a result of the systematic desensitization, virtual exposure gradually reduced the responses to significant alcohol-related cues and contexts. The implications for AB, anxiety and craving are discussed

Attentional bias assessment in patients with alcohol use disorder: an eye-tracking study

Introduction: Alcohol use disorder (AUD) represents a major general health concern with important consequences for individuals' psycho-social functioning. Many studies suggest that cognitive processes such as attentional bias (AB) are heavily involved in the phases of acquisition, maintenance and relapse precipitation in AUD. AB is described as an implicit selective attention when processing visual information in favor of desired cues, which may elicit craving for alcohol and facilitate drinking-related behaviors. In line with recent studies of the applications of human-computer interaction in the field of psychology, the current study aimed to assess attentional bias towards alcohol-related images using eye-tracking technology. Specifically, we explored the first gaze towards alcohol-related images versus neutral images in patients with short-term and long-term abstinence. Method: 24 outpatients (Mage = 53, SD = 11.65) from the Addictive Behavior Unit of the Hospital Clinic of Barcelona participated in the study. The inclusion criteria were diagnoses of AUD and normal or corrected-to-normal visual acuity. Participants were divided according to their abstinence period, with the cut-off point being set at four months. Fourteen patients had been abstinent for less than four months (M = 1, SD = 0.96), and 10 for longer than this period (M = 14, SD = 8.17). The self-reported abstinence period was supported by the results of urine analyses performed in all patients. Participants completed the Alcohol Use Disorder Identification Test (M = 19.75, SD = 9.34) and the Visual Attention Task (VAT). The VAT consisted of images related to alcohol consumption versus neutral images such as office objects. The EyeTribe eye-tracking technology was used to record eye movement activity during the VAT. Results: Our data indicated a statistically significant difference between patients with short-term and long-term abstinence regarding their first fixation towards alcohol-related and neutral images. Patients abstinent for less than four months had a tendency to look first at images related to alcohol consumption, whereas patients abstinent for more than four months were more likely to look first at neutral images, regardless of their AUDIT score. Conclusions: Patients with short-term abstinence had a greater AB than patients with long-term abstinence. The first gaze seems to be a sensitive parameter for differentiating between patients with low and high AB. The use of eye-tracking technology suggests that AB is important in clinical assessment and should be addressed in treatment as well as in relapse prevention. We consider that the eye- tracking technology is a promising instrument for assessing current addictive behavior

Predictors of Changes in alcohol craving levels during a virtual reality cue exposure treatment among patients with alcohol use disorder

Background/Objective: Determining the predictive variables associated with levels of alcohol craving can ease the identification of patients who can benefit from treatments. This study aimed to describe changes (improvement or no change/deterioration) in alcohol craving levels and explore the predictors of these changes from admission to discharge in outpatients with alcohol use disorder (AUD) undergoing treatment-as-usual (TAU), or treatment-as-usual supplemented with virtual reality cue-exposure therapy (TAU + VR-CET). Method: A prospective cohort study was conducted amongst 42 outpatients with AUD (n = 15 TAU + VR-CET and n = 27 TAU) from a clinical setting. Changes in the levels of alcohol craving between admission and discharge were assessed with the Multidimensional Alcohol Craving Scale. Sociodemographic characteristics (age, gender, education, and socioeconomic and civil status), cognitive-a ective behavioral patterns (AUD severity, abstinence duration, psychiatric comorbidity, state anxiety, attentional bias, and substance use), and type of treatment (TAU + VR-CET and only TAU) were also evaluated. Results: The TAU + VR-CET group showed greater changes of improvement in the levels of alcohol craving than the TAU group ( 2 = 10.996; p = 0.001). Intragroup changes in alcohol craving from pre to post-treatment were significant in the TAU + VR-CET group ( 2 = 13.818; p = 0.003) but not within the TAU group ( 2 = 2.349; p = 0.503). The odds of an improvement in any of the craving levels between pre- and post-test was 18.18 (1/0.055) times higher in the TAU + VR-CET group with respect to the TAU group. The use of illicit drugs in the month prior to the test increased the odds of having a positive change by 18.18 (1/0.055) with respect to not having consumed. Conclusions: Including VR-CET in TAU programs may provide benefits in the treatment of AUDs mainly among patients with intense alcohol craving and individuals having used illicit substances prior to treatment

Association between vitamin D receptor rs731236 (Taq1) polymorphism and risk for restless legs syndrome in the Spanish caucasian population

Varios trabajos recientes sugieren un posible papel de la deficiencia de vitamina D en la etiología o el síndrome de las piernas inquietas (RLS). Hemos analizado la posible relación de 2 polimorfismos de un solo nucleótido (SNP) en el receptor de la vitamina D3 (GEN VDR) con el riesgo de SPI. Hemos estudiado la variante alélica genotipo y frecuencias de VDR rs2228570 y rs731236 VDR SNPs en 205 RLS pacientes y 445 controles sanos mediante un ensayo TaqMan. Las frecuencias de los rs731236AAgenotype y la variante alélica rs731236un SPI fue significativamente inferior en los pacientes que en los controles (P<0,005 y 0,01, respectivamente). El síndrome de las piernas inquietas pacientes portadoras de la variante alélica rs731236G había una edad temprana en el inicio, y los portadores del genotipo GG731236rs tuvieron mayor severidad de RLS, aunque estos datos desaparecieron después de los análisis multivariados. Ninguno de los SNPs estudiados estaba relacionada con la positividad de la historia familiar de SPI. Estos resultados sugieren una modesta, pero significativa asociación entre rs731236 VDR SNP y el riesgo de síndrome de piernas inquietas.Several recent works suggest a possible role of vitamin D deficiency in the etiology or restless legs syndrome (RLS). We analyzed the possible relationship of 2 common single nucleotide polymorphisms (SNPs) in the vitamin D3 receptor (VDR) gene with the risk for RLS. We studied the genotype and allelic variant frequencies of VDR rs2228570 and VDR rs731236 SNPs in 205 RLS patients and 445 healthy controls using a TaqMan essay. The frequencies of the rs731236AAgenotype and the allelic variant rs731236A were significantly lower in RLS patients than in controls (P<0.005 and<0.01, respectively). Restless legs syndrome patients carrying the allelic variant rs731236G had an earlier age at onset, and those carrying the rs731236GG genotype had higher severity of RLS, although these data disappeared after multivariate analyses. None of the SNPs studied was related with the positivity of family history of RLS. These results suggest a modest, but significant association between VDR rs731236 SNP and the risk for RLS.• Instituto de Salud Carlos III, Madrid, Fondo de Investigación Sanitaria: Ayudas PI12/00241, PI12/00324, y RETICS RD12/0013/0002 • Junta de Extremadura: GR15026 y PRIS10016 • Ministerio de Ciencia e Innovación: Ayudas SAF2006-10126 (2006–2009) y SAF2010-22329-C02-01 (2011-2013) • Parciamente financiado con Fondos FEDERpeerReviewe