Donna T. Chen

Extended-Release Naltrexone to Prevent Opioid Relapse in Criminal Justice Offenders

BACKGROUND Extended-release naltrexone, a sustained-release monthly injectable formulation of the full mu-opioid receptor antagonist, is effective for the prevention of relapse to opioid dependence. Data supporting its effectiveness in U.S. criminal justice populations are limited. METHODS In this five-site, open-label, randomized trial, we compared a 24-week course of extended-release naltrexone (Vivitrol) with usual treatment, consisting of brief counseling and referrals for community treatment programs, for the prevention of opioid relapse among adult criminal justice offenders (i.e., persons involved in the U.S. criminal justice system) who had a history of opioid dependence and a preference for opioid-free rather than opioid maintenance treatments and who were abstinent from opioids at the time of randomization. The primary outcome was the time to an opioid-relapse event, which was defined as 10 or more days of opioid use in a 28-day period as assessed by self-report or by testing of urine samples obtained every 2 weeks; a positive or missing sample was computed as 5 days of opioid use. Post-treatment follow-up occurred at weeks 27, 52, and 78. RESULTS A total of 153 participants were assigned to extended-release naltrexone and 155 to usual treatment. During the 24-week treatment phase, participants assigned to extended-release naltrexone had a longer median time to relapse than did those assigned to usual treatment (10.5 vs. 5.0 weeks, P<0.001; hazard ratio, 0.49; 95% confidence interval [CI], 0.36 to 0.68), a lower rate of relapse (43% vs. 64% of participants, P<0.001; odds ratio, 0.43; 95% CI, 0.28 to 0.65), and a higher rate of opioid-negative urine samples (74% vs. 56%, P<0.001; odds ratio, 2.30; 95% CI, 1.48 to 3.54). At week 78 (approximately 1 year after the end of the treatment phase), rates of opioid-negative urine samples were equal (46% in each group, P=0.91). The rates of other prespecified secondary outcome measures--self-reported cocaine, alcohol, and intravenous drug use, unsafe sex, and reincarceration--were not significantly lower with extended-release naltrexone than with usual treatment. Over the total 78 weeks observed, there were no overdose events in the extended-release naltrexone group and seven in the usual-treatment group (P=0.02). CONCLUSIONS In this trial involving criminal justice offenders, extended-release naltrexone was associated with a rate of opioid relapse that was lower than that with usual treatment. Opioid-use prevention effects waned after treatment discontinuation. (Funded by the National Institute on Drug Abuse; ClinicalTrials.gov number, NCT00781898.).

Treatment late effects in long-term survivors of pediatric sarcoma

To assess health and musculoskeletal function in survivors of pediatric sarcomas.

Ethical and Methodological Issues in Pedigree Stroke Research

Background— Stroke is a complex genetic disorder with a variable phenotype. Investigations of heritable factors in complex genetic disorders use pedigree and genetic techniques, which pose different ethical and methodological challenges than those routinely encountered in therapeutic research. Building consensus on acceptable research practices in this field is vital to the success of multicentered collaborations. Summary of Review— We review important ethical and methodological concerns related to the collection, storage, and release of pedigree research information. The human studies aspects of pedigree research are complicated methodologically because individuals can be active or passive participants and pedigrees can be proband derived, partially validated, or fully validated. Current research ethics frameworks do not work well outside of a dyadic researcher-subject relationship. Privacy and confidentiality for family members must be considered in pedigree research. Investigators should anticipate potential conflicts of interest among family members when designing a pedigree research protocol. Conclusions— We propose a “proband-initiated contact” methodology in which the proband or the proband’s designate allows identification of potential families without breaching the privacy of individuals in the family. In situations in which family history data are collected without direct contact between researchers and individuals in the proband’s family, an Institutional Review Board may waive consent by family members after appropriate review of the protocol and application of rules for granting waivers of consent. Certificates of Confidentiality should be considered.

Curricular approaches to research ethics training for psychiatric investigators

RationaleTraining in research ethics is crucial for psychiatric investigators. Addressing ethical dimensions of human subjects research requires knowledge about the rules and norms governing research; sensitivity to ethical implications of actions; and skills in ethics problem solving. Investigators in training who are physicians have the additional challenge of developing identities as investigators that sometimes conflict with their identities as physicians.ObjectivesTo propose a curriculum for psychiatric research ethics training.MethodsReview of literature on ethics education and presentation of a curricular approach to research ethics training for psychiatric investigators.ResultsResearch ethics can be learned and should be taught. Involvement of active investigators in teaching research ethics is important. While core topics of psychiatric research ethics training have not yet been identified, there are available models from which to draw. Research ethics should be introduced early and integrated throughout the research training period. Lack of resources and institutional support can be obstacles to development of comprehensive research ethics curricula. Small-group, case-based discussion is best for teaching ethics problem-solving skills. Examples of teaching module ideas and a fully developed sample teaching module are presented.ConclusionsThere is opportunity for creative models for teaching psychiatric research ethics. Work is needed to identify core topics, target pedagogical strategies to trainees at different levels, and develop evaluation methods.

Enrolling decisionally impaired adults in clinical research.

Progress in diagnosing, treating, and preventing medical conditions that impair decision-making abilities depends on clinical research involving individuals who may be either unable to or have diminished ability to give informed consent. Such research, however, raises ethical concern and controversy about the potential exploitation of these vulnerable individuals. This article addresses a range of ethical and practical issues concerning the enrollment of adults who are decisionally impaired, and those at risk of becoming so, in clinical research. These include (1) the relationship of decision-making capacity to competence, and the framework for determining competence in adults receiving clinical care and making treatment decisions for those who lack competence; (2) the differences between clinical practice and clinical research that influence the criteria for permissible research involving incompetent adults and the applicability of the framework guiding treatment decisions to clinical research decisions; and (3) the regulatory framework developed to guide the ethical participation of children in research and its applicability to determining the scope and limits of research with incompetent adults.

Role of organization ethics in critical care medicine

The authors view the activities involved in critical care medicine as composing a complex adaptive system that is itself operating within a complex adaptive system, the healthcare organization. The authors explain why it is necessary that these systems be viewed this way, and they explain what is necessary to allow them to produce creative or emergent outcomes. They provide a justification for the role of an organization ethics program within this context. They provide a definition of organization ethics and outline the characteristics that an effective organization ethics program would possess.

Extended-release naltrexone to prevent relapse among opioid dependent, criminal justice system involved adults: Rationale and design of a randomized controlled effectiveness trial

BACKGROUND Extended-release naltrexone (XR-NTX, Vivitrol; Alkermes Inc.) is an injectable monthly sustained-release mu opioid receptor antagonist. XR-NTX is a potentially effective intervention for opioid use disorders and as relapse prevention among criminal justice system (CJS) populations. METHODS This 5-site open-label randomized controlled effectiveness trial examines whether XR-NTX reduces opioid relapse compared with treatment as usual (TAU) among community dwelling, non-incarcerated volunteers with current or recent CJS involvement. The XR-NTX arm receives 6 monthly XR-NTX injections at Medical Management visits; the TAU group receives referrals to available community treatment options. Assessments occur every 2 weeks during a 24-week treatment phase and at 12- and 18-month follow-ups. The primary outcome is a relapse event, defined as either self-report or urine toxicology evidence of ≥10 days of opioid use in a 28-day (4 week) period, with a positive or missing urine test counted as 5 days of opioid use. RESULTS We describe the rationale, specific aims, and design of the study. Alternative design considerations and extensive secondary aims and outcomes are discussed. CONCLUSIONS XR-NTX is a potentially important treatment and relapse prevention option among persons with opioid dependence and CJS involvement. ClinicalTrials.gov: NCT00781898.

Tools for tomorrow's health care system: a systems-informed mental model, moral imagination, and physicians' professionalism.

Physician educators have been charged with incorporating systems-based approaches into medical education and residency training to help future physicians understand how their ability to provide high-quality health care depends on other individual and organizational stakeholders with whom and, in some cases, for whom they work. In part, this also requires that physicians accept that they have responsibilities to various system stakeholders. These changes are controversial because some fear they might distract physicians from their primary ethical obligation to their patients. However, systems theories and their applications in organizational management and business ethics support the notions that individuals can maintain primary professional ethical obligations while working within complex systems and that organizational systems can be constructed to support individual professional practice. If physicians are to commit to working within and, ultimately, improving systems of care as part of their ethical practice of medicine, then they will need a new mental model. Leading thinkers have used various models of systems and have highlighted different aspects of systems theories in describing organizations, groups of organizations, and organizational processes. This essay draws from these models some basic concepts and elements and introduces a simple but comprehensive mental model of systems for physicians. If it is used with professionalism and moral imagination, physicians might have a tool that they can use to understand, work with, and, ultimately, improve the systems of care that they rely on in their practice of medicine and that critically affect the welfare of their patients.

Recommendations from the international stroke genetics consortium, part 1: standardized phenotypic data collection.

Risk and clinical outcome of stroke, as for nearly all complex conditions, is polygenic.1 Discovering influential genetic variants offers the promise of new and personalized treatments that will substantially reduce the devastating effects of stroke on global health. Adequate power to detect multiple genetic risk alleles requires large sample sizes. Although stroke is the second leading cause of death worldwide and a major contributor to adult disability,2 no individual center can collect sufficient samples on its own. Recognizing this challenge, in 2007, stroke researchers from around the world formed the International Stroke Genetics Consortium (ISGC, http://www.strokegenetics.org). The ISGC mission is to identify genetic factors influencing stroke risk, prognosis, and treatment response by studying patients enrolled at centers around the globe. Although there has been notable early success,3–5 much work remains not only to achieve the ultimate goal of personalized medicine in stroke, finding genetic risk alleles, but also, more importantly, to develop comprehensive stroke risk assessments with actionable clinical results.6 Judging from developments in other complex diseases, such as diabetes mellitus and coronary artery disease, sample sizes of the order of 100 000 to 200 000 will be needed to identify the full range of genetic variation involved in stroke. Achieving such sample sizes requires even larger collaboration. We propose a standard methodology for data collection in stroke genetics studies to establish a best practice approach, sharing lessons learned through the ISGC. We outline the appropriate selection of case and control subjects and delineate the phenotypic data to collect, including minimum and preferred data points. Minimum requirements are prerequisites for inclusion in basic stroke genetic studies. Preferred data elements enable centers to participate in a broader variety of collaborations, such as those exploring gene–environment interactions, imaging endophenotypes, such as white matter hyperintensities, and functional …

Incidental genetic findings in randomized clinical trials: recommendations from the Genomics and Randomized Trials Network (GARNET)

Recommendations and guidance on how to handle the return of genetic results to patients have offered limited insight into how to approach incidental genetic findings in the context of clinical trials. This paper provides the Genomics and Randomized Trials Network (GARNET) recommendations on incidental genetic findings in the context of clinical trials, and discusses the ethical and practical issues considered in formulating our recommendations. There are arguments in support of as well as against returning incidental genetic findings in clinical trials. For instance, reporting incidental findings in clinical trials may improve the investigator-participant relationship and the satisfaction of participation, but it may also blur the line between clinical care and research. The issues of whether and how to return incidental genetic findings, including the costs of doing so, should be considered when developing clinical trial protocols. Once decided, plans related to sharing individual results from the aim(s) of the trial, as well as incidental findings, should be discussed explicitly in the consent form. Institutional Review Boards (IRBs) and other study-specific governing bodies should be part of the decision as to if, when, and how to return incidental findings, including when plans in this regard are being reconsidered.