Effectiveness of Conditioned Open-label Placebo With Methadone in Treatment of Opioid Use Disorder: A Randomized Clinical Trial.

Importance: Methadone treatment is the most effective evidence-based treatment for opioid use disorder (OUD), but challenges related to dosing and premature treatment dropout argue for adjunct interventions to improve outcomes. One potential behavioral intervention with low risk involves harnessing placebo effects. Objective: To determine the effect of a pharmacologically conditioned open-label placebo (C-OLP) on 90-day methadone dose, retention, drug use, withdrawal, craving, quality of life, and sleep. Design, Setting, and Participants: This 2-arm, open-label, single-blind randomized clinical trial was conducted between December 5, 2017, and August 2, 2019, in an academically affiliated community opioid treatment program. Analyses were conducted between October 1, 2019, and April 30, 2020. A total of 320 newly enrolled adults seeking treatment for moderate to severe OUD were assessed for study eligibility; 131 met eligibility criteria, provided informed consent, and were randomized to either C-OLP or treatment as usual (TAU) in an unequal-block (3:2) manner. Exclusion criteria were pregnancy, hospital/program transfers, and court-ordered treatment. Interventions: Participants randomized to C-OLP received pharmacologic conditioning and a placebo pill and methadone, and participants randomized to TAU were given methadone only. Participants met with the study team 5 times: at baseline (treatment intake) and 2, 4, 8, and 12 weeks postbaseline. Interactions were balanced between the 2 groups. Main Outcomes and Measures: Outcomes included 90-day methadone dose (primary) and treatment retention, drug use, withdrawal, craving, quality of life, and sleep quality (secondary). Analyses were conducted as intention-to-treat. Results: Of the 131 people enrolled in the study, 54 were randomized to TAU and 77 to C-OLP. Mean (SD) age was 45.9 (11.2) years; most of the participants were Black or African American (83 [63.4%]) and male (84 [64.1%]). No significant group differences were observed in the mean (SD) 90-day methadone dose (83.1 [25.1] mg for group TAU, 79.4 [19.6] mg for group C-OLP; t = 0.621991; P = .43), but the groups differed significantly in their retention rates: 33 (61.1%) for TAU and 60 (77.9%) for C-OLP (χ21 = 4.356; P = .04; number needed to treat for the beneficial outcome of 3-month treatment retention, 6; 95% CI, 4-119). C-OLP participants also reported significantly better sleep quality. Conclusions and Relevance: In this randomized clinical trial, C-OLP had no effect on the primary outcome of 90-day methadone dose. However, C-OLP participants were significantly more likely to remain in treatment. These findings support the use of C-OLP as a methadone treatment adjunct, but larger trials are needed to further examine the use of C-OLP. Trial Registration: ClinicalTrials.gov Identifier: NCT02941809.

Race-based differences in drug use prior to onset of opioid use disorder.

Rates of opioid use disorder (OUD) have increased dramatically over the past two decades, a rise that has been accompanied by changing demographics of those affected. Early exposure to drugs is a known risk factor for later development of opioid use disorder; but how and whether this risk factor may differ between racial groups is unknown. Our study seeks to identify race differences in self-report of current and past substance use in OUD-diagnosed treatment-seeking individuals. Patients (n = 157) presenting for methadone maintenance treatment at a racially diverse urban opioid treatment program were approached and consented for study involvement. Participants were administered substance use history questionnaires and urine drug screening at intake. Chi-square, t-tests, and rank-sum were used to assess race differences in demographic variables. Logistic and linear regressions assessed the relationship between race and substance use for binary and continuous variables, respectively. 61% of the population identified as Black and 39% as White. Black participants were significantly older; age was thus included as a covariate. Logistic regressions demonstrated that despite similar urine toxicology at intake, White participants were significantly more likely to report having used prescription opioids and psychedelic, stimulant, and sedative substance classes prior to their first use of non-pharmaceutical opioids. Compared to Black participants, White treatment-seeking OUD-diagnosed individuals reported using a wider range of substances ever and prior to first use of non-pharmaceutical opioids. There were no differences, however, in presentation for OUD treatment, suggesting different pathways to OUD, which may carry important clinical implications.

Emergency Department Drug Surveillance (EDDS) hospital's urinalysis results compared with expanded re-testing by an independent laboratory, a pilot study.

INTRODUCTION: Most hospital urine toxicology screens detect a fixed, limited set of common substances. These tests are fast and accurate but may miss emerging trends in substance use in the community and clinical acumen alone is insufficient for identifying new substances. METHODS: This prospective cohort study examined de-identified urine specimens obtained from patients visiting the Emergency Department (ED) at Prince George's Hospital Center (PGHC), between October 15, 2019 to November 6, 2019 and tested positive for one or more substances. The Emergency Department Drug Surveillance System (EDDS) collects quarterly exports from de-identified electronic health records (EHRs) containing urinalysis results for drug related ED visits. We performed a feasibility study of a new urine specimen submission by collecting a stratified sample of 151 urine specimens from PGHC ED patients. The specimens were tested for 240 drugs using liquid chromatography-tandem mass spectrometry (LC-MS/MS). This paper presents a comparison between the PGHC and expanded testing results. RESULTS: The expanded urinalysis panel found more cocaine (37% vs. 20%; p < 0.01) and benzodiazepine positives (21% vs. 11%; p < 0.05) than would have been detected by the hospital screen. Additionally, the expanded toxicology panel identified fentanyl in 4-14% of the samples. CONCLUSION: The EHR data submitted to EDDS from the hospital urine toxicology screen correctly identified hospital substance use patterns over the approximate 1 month study period. The expanded testing also uncovered drugs that the hospital might consider adding to their routine screen. EDDS is a feasible system for monitoring and confirming recent substance use trends among ED patients.

Toward a National System of Expanded Testing of Existing Urine Specimens: The Drug Outbreak Testing Service (DOTS).

BACKGROUND: NIDA's National Drug Early Warning System (NDEWS) was established in 2014 with the mission of identifying and monitoring emerging drugs in the United States. Identification of emerging drugs has been complicated, however, by the rapid development of novel psychoactive substances such that users often cannot identify and report the drugs they have ingested. Biologic testing of urine, hair or blood is the only way to reliably identify the substances recently used. Unfortunately, the large number of up-to-date tests required is beyond the resources available to most organizations. METHODS: The DOTS study tested the feasibility of recruiting organizations to submit up to 25 de-identified urine specimens for testing for approximately 240 drugs, at no cost to them. The results were for epidemiologic purposes only and not for clinical use. Eleven sites who had questions about their patients or the results of their organization's more limited urinalysis screens participated. These sites included drug treatment programs, medical examiners, hospitals and a criminal justice testing program. RESULTS: Extensive polydrug use and geographic differences in the drugs detected were found. All sites found the DOTS collaborating laboratory's test results to be very useful for understanding the types of drugs being used recently and to assess the adequacy of their testing protocols. CONCLUSIONS: The U.S. should consider establishing a program of expanded testing of already collected de-identified urine specimens in order to identify emerging drugs and track local patterns of use and availability.

Open-label dose-extending placebos for opioid use disorder: a protocol for a randomised controlled clinical trial with methadone treatment.

INTRODUCTION: More than 2 million individuals in the USA have an opioid use disorder (OUD). Methadone maintenance treatment is the gold standard of medication-based treatment for OUD, but high-dose methadone is associated with cardiotoxicity and respiratory complications, among other side effects. These adverse effects make enhancing the effectiveness of lower doses of methadone an attractive therapeutic goal. Long recognised for its capacity to enhance treatment outcomes for a wide range of neuropsychiatric disorders including pain, the placebo effect offers an as-yet untested avenue to such an enhancement. This approach is particularly compelling given that individuals with substance use disorder tend to have higher salience attribution and may thereby be more sensitive to placebo effects. Our study combines two promising clinical methodologies-conditioning/dose-extension and open-label placebo-to investigate whether placebo effects can increase the effective potency of methadone in treatment-seeking OUD patients. METHODS AND ANALYSIS: A total of 120 newly enrolled treatment-seeking OUD patients will be randomly assigned to one of two different groups: either methadone plus daily placebo dose-extension (PDE; treatment group) or methadone/treatment as usual (control). Participants will meet with study team members five times over the course of 3 months of treatment with methadone (baseline, 2 weeks, and 1, 2 and 3 months postbaseline). Throughout this study time period, methadone dosages will be adjusted by an addiction clinician blind to patient assignment, per standard clinical methods. The primary outcome is methadone dose at 3 months. Secondary outcomes include self-report of drug use; 3-month urine toxicology screen results; and treatment retention. Exploratory outcomes include several environmental as well as personality factors associated with OUD and with propensity to demonstrate a placebo effect. ETHICS AND DISSEMINATION: Human subjects oversight for this study is provided by the University of Maryland, Baltimore and University of Maryland, College Park Institutional Review Boards. Additionally, the study protocol is reviewed annually by an independent Data and Safety Monitoring Board. Study results will be disseminated via research conference presentations and peer-reviewed publications. TRIAL REGISTRATION NUMBER: NCT02941809.

Opioid-galanin receptor heteromers mediate the dopaminergic effects of opioids.

Identifying non-addictive opioid medications is a high priority in medical sciences, but µ-opioid receptors mediate both the analgesic and addictive effects of opioids. We found a significant pharmacodynamic difference between morphine and methadone that is determined entirely by heteromerization of µ-opioid receptors with galanin Gal1 receptors, rendering a profound decrease in the potency of methadone. This was explained by methadone's weaker proficiency to activate the dopaminergic system as compared to morphine and predicted a dissociation of therapeutic versus euphoric effects of methadone, which was corroborated by a significantly lower incidence of self-report of "high" in methadone-maintained patients. These results suggest that µ-opioid-Gal1 receptor heteromers mediate the dopaminergic effects of opioids that may lead to a lower addictive liability of opioids with selective low potency for the µ-opioid-Gal1 receptor heteromer, exemplified by methadone.

Assets, challenges, and the potential of technology for nutrition education in rural communities.

OBJECTIVE: To examine assets of and challenges to getting adequate nutrition and physical activity among low-income rural residents, and the potential for technology to provide health education. METHODS: Environmental scans and community stakeholder interviews were conducted in 5 rural counties in Maryland. During environmental scans, stakeholders guided tours around each county to explore community services and resources for nutrition, physical activity and technology. In-depth interviews with stakeholders (n=58) focused on nutrition, physical activity, and technology issues. RESULTS: Low-income residents both benefit from and face challenges in rural settings. Besides attitude and knowledge barriers, lack of affordable resources and public transportation contributed to inattention to nutrition and physical activity. Stakeholders' reactions to a proposed Internet-based intervention were mostly favorable, but questions emerged about providing computers and Internet to individual families. CONCLUSIONS AND IMPLICATIONS: Internet-based education may be a viable option to help low-income rural residents overcome barriers to nutrition and physical activity.

Rural eHealth nutrition education for limited-income families: an iterative and user-centered design approach.

BACKGROUND: Adult women living in rural areas have high rates of obesity. Although rural populations have been deemed hard to reach, Internet-based programming is becoming a viable strategy as rural Internet access increases. However, when people are able to get online, they may not find information designed for them and their needs, especially harder to reach populations. This results in a "content gap" for many users. OBJECTIVE: User-centered design is a methodology that can be used to create appropriate online materials. This research was conducted to apply a user-centered approach to the design and development of a health promotion website for low-income mothers living in rural Maryland. METHODS: Three iterative rounds of concept testing were conducted to (1) identify the name and content needs of the site and assess concerns about registering on a health-related website; (2) determine the tone and look of the website and confirm content and functionality; and (3) determine usability and acceptability. The first two rounds involved focus group and small group discussions, and the third round involved usability testing with individual women as they used the prototype system. RESULTS: The formative research revealed that women with limited incomes were enthusiastic about a website providing nutrition and physical activity information targeted to their incomes and tailored to their personal goals and needs. Other priority content areas identified were budgeting, local resources and information, and content that could be used with their children. Women were able to use the prototype system effectively. CONCLUSIONS: This research demonstrated that user-centered design strategies can help close the "content gap" for at-risk audiences.

Assessment of the nutrition and physical activity education needs of low-income, rural mothers: can technology play a role?

The purpose of this study was to examine the perceptions of low-income, rural mothers regarding their need for nutrition and physical activity education and the role of technology in addressing those needs. Quantitative and qualitative research was combined to examine the nature and scope of the issues faced by this target population. Women who were currently receiving food stamps and had children in nursery school to eighth grade were recruited through a state database to participate in a telephone survey (N = 146) and focus groups (N = 56). Low-income, rural mothers were aware of and practiced many health behaviors related to nutrition and physical activity, but they faced additional barriers due to their income level, rural place of residence, and having children. They reported controlling the fat content in the food they cooked and integrating fruits and vegetables but showed less interest in increasing fiber consumption. They reported knowing little about physical activity recommendations, and their reported activity patterns were likely inflated because of seeing housework and child care as exercise. To stretch their food budget, the majority reported practicing typical shopping and budgeting skills, and many reported skills particularly useful in rural areas: hunting, fishing, and canning. Over two-thirds of the survey respondents reported computer access and previous Internet use, and most of those not yet online intended to use the Internet in the future. Those working in rural communities need to consider technology as a way to reach traditionally underserved populations like low-income mothers.