Extended-release naltrexone for treatment of alcohol dependence in primary care

The feasibility of using extended-release injectable naltrexone (XR-NTX) to treat alcohol dependence in routine primary care settings is unknown. An open-label, observational cohort study evaluated 3-month treatment retention, patient satisfaction, and alcohol use among alcohol-dependent patients in two urban public hospital medical clinics. Adults seeking treatment were offered monthly medical management (MM) and three XR-NTX injections (380 mg, intramuscular). Physician-delivered MM emphasized alcohol abstinence, medication effects, and accessing mutual help and counseling resources. Seventy-two alcohol-dependent patients were enrolled; 90% (65 of 72) of eligible subjects received the first XR-NTX injection; 75% (49 of 65) initiating treatment received the second XR-NTX injection; 62% (40 of 65), the third. Among the 56% (n = 40) receiving three injections, median drinks per day decreased from 4.1 (95% confidence interval = 2.9–6) at baseline to 0.5 (0–1.7) during Month 3. Extended-release naltrexone delivered in a primary care MM model appears a feasible and acceptable treatment for alcohol dependence.     

Personality disorders and the prediction of alcohol use outcomes for women: Dimensional versus categorical classification

The impending shift in the fifth edition of Diagnostic and Statistical Manual of Mental Disorders from categorical to a hybrid categorical-dimensional diagnosis scheme has generated considerable interest in the relative merits of these respective approaches. This is particularly true for the diagnostically complex category of personality disorders (PDs). The present study assessed whether categorical or dimensional measures better predicted alcohol consumption in a sample of 102 women enrolled in a clinical trial comparing individual cognitive behavioral therapy (CBT) to conjoint CBT for alcohol use disorders (AUDs). Linear regression was used to evaluate whether each PD diagnosis (categorical), or the number of PD symptoms endorsed per PD (dimensional) better predicted percent days drinking over the course of six months of treatment. PD criteria (dimensional) better predicted drinking for Paranoid, Borderline, and Obsessive-Compulsive PDs, while diagnosis (categorical) was a better predictor only for passive-aggressive PD. Both schemes predicted drinking outcomes for avoidant, dependent, and depressive PDs, and neither was predictive for narcissistic PD. These findings suggest that the addition of a dimensional approach for PDs potentially enhances the prediction of alcohol use outcomes.     

酒精使用相关障碍的临床治疗指南综述

酒精是世界范围内使用最广泛的精神活性物质之一,而酒精的有害使用也造成了巨大的疾病、社会及经济负担,因此目前酒精使用相关障碍受到广泛的关注。本文将综述国内外相关临床指南对酒精使用相关障碍的治疗方案及建议,为临床实践提供更清晰的理论基础。     

Effect of naltrexone on subjective alcohol response in subjects at high and low risk for future alcohol dependence

We investigated specific subjective effects of naltrexone pretreatment or placebo during various intervals on the breath alcohol level (BAL) curve in nonalcoholic volunteers. Fifteen high-risk (social drinkers with an alcoholic father) and 14 low-risk (no alcoholic relatives in at least two generations) subjects were tested in a double-blind, placebo-controlled study of the effects of 50 mg oral naltrexone on response to a moderate dose of alcohol. Dependent measures included subjective stimulation and sedation subscales from the Biphasic Alcohol Effects Scale (BAES) and mood subscales from the Profile of Mood States (POMS). At rising BALs, high-risk subjects showed a naltrexone-related attenuation of BAES stimulation. This effect was not evident in low-risk subjects, who directionally showed the opposite effect, although nonsignificant. For both groups, there were no significant naltrexone-related effects for BAES sedation; however, naltrexone did affect several POMS scales on alcohol response, such as decreased vigor, and increased fatigue, tension, and confusion. Confusion was significantly elevated for the high-risk group during rising BALs of the naltrexone session. The results suggest a differential response to naltrexone, based on paternal history of alcoholism and level of stimulation experienced during alcohol drinking. Received: 22 August 1995 / Final version: 25 July 1996     

健康儿童作为药物动力学研究受试者的伦理学辩论

儿童是否允许作为健康受试参加药物动力学研究，目前存在较大分歧。本列出截然不同的两种观点，旨在防范这类研究在健康儿童的不适当实施，以保证其符合国际共认的伦理学要求。     

Nalmefene for the treatment of alcohol use disorders: recent data and clinical potential

Introduction: Few pharmacotherapies are available for alcoholism. Numerous studies indicate the involvement of the opioid-endorphin system in mediating the reinforcing effects of alcohol via dopaminergic neurons. The opioid antagonist naltrexone was found to be effective in alcohol treatment, and the European Medicines Agency has now approved the mu-opioid antagonist und partial kappa agonist nalmefene.

Areas covered: This article presents background information on the chemistry of nalmefene and pre-clinical and clinical findings. The three relevant Phase III studies, all of which followed a harm-reduction, “as needed” approach and found reduced alcohol consumption with nalmefene 18 (20) mg, are discussed in detail.

Expert opinion: The integration of the “as needed” approach into conventional psychosocial alcohol therapies may be challenging but offers the opportunity to reach otherwise not treated patients. Nalmefene is the first medication to be approved specifically in this indication and seems to be most suitable for patients with alcohol misuse or a rather low physical dependence on alcohol who do not require immediate detoxification or inpatient treatment. Although a categorical distinction between patients who want to stop heavy drinking or drinking at all over time may be somewhat hypothetical, nalmefene offers new treatment options to patients with alcohol use disorder.     

Psychological Predictors of Retention in a Low-Threshold Methadone Maintenance Treatment for Opioid Addicts: A 1-Year Follow-Up Study

This study investigated the role of psychological variables and judicial problems in treatment retention for a low-threshold methadone program in Montreal, Canada. Logistic regression analyses were computed to examine associations between psychological variables (psychological distress, self-esteem, stages of change), criminal justice involvement, and treatment retention for 106 highly-disorganized opioid users. Higher methadone dosage was associated with increased odds of treatment retention, whereas criminal charges and lower self-esteem decreased these odds. Psychological variables could be identified early in treatment and targeted to increase potential treatment retention. Financial support for this study was provided by the Fonds de Recherche en Santé du Québec.     

Bupropion and naltrexone: a review of their use individually and in combination for the treatment of obesity

Background: Bupropion and naltrexone are centrally active drugs that have shown potential efficacy – alone and in combination – for the treatment of obesity. Objective: To explore the efficacy and safety of naltrexone and bupropion alone and in a novel combination drug that utilizes sustained-release (SR) formulations of both drugs and to evaluate their efficacy in promoting weight loss. The mechanisms of action of these centrally acting drugs are discussed. Preclinical and clinical studies of bupropion and naltrexone alone and in combination are reviewed. Results/conclusions: Both bupropion and naltrexone have been shown individually to induce weight loss. Bupropion has greater efficacy as monotherapy. Naltrexone SR potentiates the effects of bupropion SR; thus, this synergistic combination has the potential for additional weight loss compared to monotherapy. Current Phase III trials will yield further safety and efficacy information regarding these drugs in combination.     

Depressive symptoms as a predictor of alcohol relapse after residential treatment programs for alcohol use disorder

Alcohol use disorder (AUD) and depressive disorders often co-occur. Findings on the effects of major depressive disorder (MDD) or depressive symptoms on posttreatment alcohol relapse are controversial. The study's aim is to examine the association of MDD and depressive symptoms with treatment outcomes after residential AUD programs. In a naturalistic-prospective, multisite study with 12 residential AUD treatment programs in the German-speaking part of Switzerland, 64 patients with AUD with MDD, 283 patients with AUD with clinically significant depressive symptoms at admission, and 81 patients with AUD with such problems at discharge were compared with patients with AUD only on alcohol use, depressive symptoms, and treatment service utilization. MDD was provisionally identified at admission and definitively defined at discharge. Whereas patients with MDD did not differ from patients with AUD only at 1-year follow-up, patients with AUD with clinically significant depressive symptoms had significantly shorter time-to-first-drink and a lower abstinence rate. These patients also had elevated AUD indices and treatment service utilization for psychiatric disorders. Our results suggest that clinically significant depressive symptoms are a substantial risk factor for relapse so that it may be important to treat them during and after residential AUD treatment programs.     

Emerging drugs for the treatment of cocaine use disorder: a review of neurobiological targets and pharmacotherapy

Introduction: Cocaine use is a global public health concern of significant magnitude, negatively impacting both the individual as well as larger society. Despite numerous trials, the discovery of an effective medication for treatment of cocaine use disorder remains elusive.

Areas covered: This article reviews the emerging pharmacotherapies for treatment of cocaine use disorder, focusing on those medications that are currently in Phase II or III human clinical trials. Articles reviewed were obtained through searches of PubMed, Ovid MEDLINE, Clinicaltrials.gov and the Pharmaprojects database.

Expert opinion: Research into cocaine pharmacotherapy must continue to show innovation. Given that medications targeting single neurotransmitter systems have demonstrated little efficacy in treatment of cocaine use disorder, the recent focus on pharmacotherapeutic agents with multiple neurobiochemical targets represents an exciting shift in trial design and approach. Additionally, consideration of pharmacogenetics may be helpful in identification of subpopulations of cocaine-dependent individuals who may preferentially respond to medications.     

临床路径管理与合理用药的探讨

目的:探讨临床路径管理对于安全、合理用药的作用。方法:查阅临床药物咨询记录及用药安全监测系统(PASS)中的医嘱,对不规范处方进行分析,阐述临床路径管理对不合理医嘱的监管。结果和结论:临床路径管理对安全、合理用药有积极的作用,可以降低治疗费用,值得推广应用。     

Fosphenytoin for the treatment of status epilepticus: an evidence-based assessment of its clinical and economic outcomes

INTRODUCTION: Status epilepticus (SE) is a life-threatening condition requiring prompt treatment in the emergency department to control seizures and limit potential neurologic damage. Fosphenytoin is a water-soluble prodrug of phenytoin (an established treatment option for SE) that has been developed to overcome the often severe venous adverse events that can occur following the intravenous administration of phenytoin. AIMS: The objective of this article is to review the evidence for the use of fosphenytoin in the treatment of SE. EVIDENCE REVIEW: Fosphenytoin can be infused more rapidly than phenytoin and there is evidence that therapeutic drug levels are achieved at least at a similar rate. Although few studies have been conducted in SE patients, there is evidence that fosphenytoin is at least as effective as phenytoin in terms of response and control of SE. There is also moderate evidence that there are fewer vascular adverse events following intravenous fosphenytoin compared with phenytoin administration when both drugs are infused at the recommended dosage and rate. Evidence from pharmacoeconomic studies indicates that a reduction in the incidence of adverse events and their subsequent management are critical factors for cost-effectiveness with fosphenytoin. CLINICAL VALUE: In conclusion, fosphenytoin is a valuable treatment option for the rapid treatment of SE; the risk of venous adverse events is lower than with phenytoin when administered at the recommended rate.     

临床合理用药质询在医院药事管理工作中的应用效果

目的 总结临床合理用药质询在医院药事管理工作中的应用效果.方法 统计分析2010年1月～2011年1月本院发现的一些不合理用药处方以及金额超高处方,总结2011年后本院开展临床合理用药质询工作前后临床用药情况.结果 2011年Ⅰ类切口抗菌药物应用不合理发生率为3.00％,明显低于2010年的11.11％,差异有统计学意义（P＜0.05）;2011年中药注射剂用药不合理发生率为5.43％,明显低于2010年的14.63％,差异有统计学意义（P＜0.05）.结论 临床合理用药质询在药事管理及医疗行政等方面均有效地改善了临床用药不合理、不规范的现象,提高了医院工作的合法、合规性,值得推广应用.     

Nicorandil improves clinical outcomes in patients with stable angina pectoris requiring PCI: a systematic review and meta-analysis of 14 randomized trials

Introduction: Clinical trials concerning the effects of nicorandil in stable coronary artery disease (CAD) remain controversial. This study sought to evaluate the clinical outcomes of nicorandil following elective percutaneous coronary intervention (PCI).

Areas covered: A meta-analysis including eligible randomized controlled trials (RCTs) with data on the nicorandil in stable CAD from Pubmed, EMBase, and Cochrane library (up to March 2018) was conducted. The primary end points were postprocedural incidence of myocardial infarction (MI) and contrast-induced nephropathy (CIN). The second end point was major adverse cerebrovascular and cardiovascular events (MACCE). Fourteen RCTs with a total of 1947 elective CAD patients were selected. Nicorandil significantly reduced the incidence of MI [n = 8; relative risk (RR) = 0.58; P = 0.001; I² = 33.7%], and CIN (n = 5; RR = 0.36; P < 0.00001; I² = 15.4%). However, There was no lowered risk of MACCE in nicorandil-treated patients [n = 10; odds RR = 0.75; P = 0.19; I² = 0.0%]. Subsequent trial sequential analyses confirmed the effect of nicorandil on MI and CIN in PCI.

Expert commentary: The present systematic review and meta-analysis suggests that nicorandil could improve clinical outcomes in terms of perioperative MI and CIN. However, the effect of nicorandil on the MACCE risk is not obvious. Future high-quality, large-scale clinical trials should majorly concern about the long-term clinical effect of nicorandil.     

Adapting substance use motives measures for a clinical population of opiate,alcohol, and stimulant users

Background: Understanding underlying mechanisms that lead to substance use can provide insight into targets for treatment. A wealth of research has evaluated substance use motives as one such mechanism. However, popular motive measures are substance-specific and developed within a younger, non-clinical population. The current study utilizes a mixed-method approach to modify existing measures for use with a clinical polysubstance-using population and evaluates relationships with measures of use and problems by substance of choice.

Methods: Participants (n?=?120) were recruited from a 28-day inpatient Veterans Affairs program. Fourteen patients participated in Phase 1 focus groups to discuss underlying reasons for use and changes in motives over time and progression into hazardous use. The motives scale was adapted based on participant responses. In Phase 2, 106 participants reported on motives and other indices of use.

Results: Results supported an 8-factor measure with the following subscales: to help with withdrawal symptoms, to counteract other substance use, to cope with loneliness, to deal with my pain/sleep, to be social/to enhance positive emotions, to cope with anxiety, to cope with depression, and to relieve boredom/get energy. Social/enhancement, withdrawal, coping with depression, and boredom/energy motives were associated with substance use disorder symptomatology. Multivariate analyzes of motive endorsement by substance of choice revealed that individuals who used opiates were more likely to endorse withdrawal and pain/sleep motives, and coping with anxiety was uncommon among stimulant users.

Conclusions: Findings highlight the progression of use motives over time and suggest further avenues of research and potential areas of earlier intervention.     

Impulsivity as a vulnerability factor for poor addiction treatment outcomes: A review of neurocognitive findings among individuals with substance use disorders

With the current review, we explore the hypothesis that individual differences in neurocognitive aspects of impulsivity (i.e., cognitive and motor disinhibition, delay discounting and impulsive decision-making) among individuals with a substance use disorder are linked to unfavorable addiction treatment outcomes, including high drop-out rates and difficulties in achieving and maintaining abstinence. A systematic review of the literature was carried out using PubMed, PsycINFO and Web of Knowledge searches. Twenty-five unique empirical papers were identified and findings were considered in relation to the different impulsivity dimensions. Although conceptual/methodological heterogeneity and lack of replication are key limitations of studies in this area, findings speak for a prominent role of cognitive disinhibition, delay discounting and impulsive decision-making in the ability to successfully achieve and maintain abstinence during and following addiction treatment. In contrast, indices of motor disinhibition appear to be unrelated to abstinence levels. Whereas the relationship between impulsivity and treatment retention needs to be examined more extensively, preliminary evidence suggests that impulsive/risky decision-making is unrelated to premature treatment drop-out among individuals with a substance use disorder. The reviewed findings are discussed in terms of their clinical implications.     

The use of patient-reported outcomes in advanced breast cancer clinical trials: a review of the published literature

Objective: As a means to measure quantifiable signs, symptoms, and impacts of a disease or its treatment, patient-reported outcome (PRO) instruments can be applied to numerous settings, including use in drug development to support labeling claims. This research summarizes the use of PROs in trials for 16 commonly used regulatory approved treatments for advanced or metastatic breast cancer.

Methods: For each treatment (n?=?16), a literature search was conducted in MEDLINE, Embase, and PsycINFO. The primary criterion for selection was the report of studies that used PROs to evaluate treatment benefit and/or toxicity in advanced or metastatic breast cancer. From this, a sub-set of articles for each treatment were selected for full-text review where PRO-related information was extracted and summarized.

Results: The searches yielded 1727 publications. Following abstract review, 1702 were excluded because they failed to meet criteria, or were duplicates or less relevant for PRO information reported. Thus, 25 articles were reviewed in detail for this evaluation. Eleven PRO instruments were identified from these publications. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire – Core (EORTC QLQ-C30) was utilized the most frequently (n?=?13, 52.0%). Most publications reported PROs positioned as secondary endpoints (n?=?20, 80.0%); described some of the statistical analyses applied to PRO data (n?=?21, 84.0%); and specified PRO results (n?=?23, 92.0%).

Conclusions: While several of the publications provided some information on how PROs were utilized, many did not describe details for PRO administration, scoring, analyses, and results interpretation. While it is encouraging that PROs are often used in clinical trials for patients with metastatic breast cancer, they are not commonly used to support endpoints that establish the basis for label claims. Because they yield direct insight into the patient experience of a condition, PROs may be used to provide a more comprehensive perspective of the benefits and risks from treatment.     

Nonparametric randomization-based covariate adjustment for stratified analysis of time-to-event or dichotomous outcomes

Time-to-event or dichotomous outcomes in randomized clinical trials often have analyses using the Cox proportional hazards model or conditional logistic regression, respectively, to obtain covariate-adjusted log hazard (or odds) ratios. Nonparametric Randomization-Based Analysis of Covariance (NPANCOVA) can be applied to unadjusted log hazard (or odds) ratios estimated from a model containing treatment as the only explanatory variable. These adjusted estimates are stratified population-averaged treatment effects and only require a valid randomization to the two treatment groups and avoid key modeling assumptions (e.g., proportional hazards in the case of a Cox model) for the adjustment variables. The methodology has application in the regulatory environment where such assumptions cannot be verified a priori. Application of the methodology is illustrated through three examples on real data from two randomized trials.     

Effect of quality chronic disease management for alcohol and drug dependence on addiction outcomes

We examined the effect of the quality of primary care-based chronic disease management (CDM) for alcohol and/or other drug (AOD) dependence on addiction outcomes. We assessed quality using (1) a visit frequency based measure and (2) a self-reported assessment measuring alignment with the chronic care model. The visit frequency based measure had no significant association with addiction outcomes. The self-reported measure of care—when care was at a CDM clinic—was associated with lower drug addiction severity. The self-reported assessment of care from any healthcare source (CDM clinic or elsewhere) was associated with lower alcohol addiction severity and abstinence. These findings suggest that high quality CDM for AOD dependence may improve addiction outcomes. Quality measures based upon alignment with the chronic care model may better capture features of effective CDM care than a visit frequency measure.