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.

Harm reduction behaviors are associated with carrying naloxone among patients on methadone treatment.

BACKGROUND: Despite the widespread availability of naloxone, US opioid overdose rates continue to rise. The "Cascade of Care" (CoC) is a public health approach that identifies steps in achieving specific outcomes and has been used to identify gaps in naloxone carriage among individuals with opioid use disorder (OUD). We sought to apply this framework to a treatment-seeking population with OUD that may be more inclined to engage in harm reduction behaviors. METHODS: Patients were recruited from an urban methadone program to complete a survey. We assessed naloxone familiarity, availability, obtainability, training, and possession, as well as naloxone carriage rates, demographics, and harm reduction behaviors. A multivariable logistic regression examined associations between naloxone carriage and individual-level factors. RESULTS: Participants (n = 97) were majority male (59%), with a mean age of 48 (SD = 12), 27% had college education or higher, 64% indicated injection drug use, and 84% reported past naloxone training. All participants endorsed familiarity with naloxone, but only 42% regularly carried naloxone. The following variables were associated with carrying naloxone: White race (aOR = 2.94, 95% CI 1.02-8.52), college education (aOR = 8.11, 95% CI 1.76-37.47), and total number of self-reported harm reduction behaviors (aOR = 1.45, 95% CI 1.00-2.11). CONCLUSION: We found low rates of naloxone carriage among methadone-treated patients. Methadone programs provide opportunities for naloxone interventions and should target racial/ethnic minorities and individuals with lower education. The spectrum of harm reduction behaviors should be encouraged among these populations to enhance naloxone carriage.

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.

Co-use of methamphetamine and opioids among people in treatment in Oregon: A qualitative examination of interrelated structural, community, and individual-level factors.

BACKGROUND: Rates of methamphetamine use and methamphetamine-related deaths have increased steadily in the United States in recent years. Methamphetamine is increasingly present in opioid-related deaths. An initial study of de-identified urine specimens (n = 102) collected at a drug treatment program between 2017 and 2018 indicated that 61% of specimens contained methamphetamine; of the specimens containing methamphetamine, people were, on average, five years younger than those who tested negative for methamphetamine; and non-fentanyl opioids were more than three times as common in methamphetamine positive specimens. The National Drug Early Warning System (NDEWS) Coordinating Center initiated a HotSpot Study to assess whether there was an emerging dynamic in the area, or if enhanced data collection could give insights into the co-use of methamphetamine and opioids. METHODS: A qualitative study, grounded in principles of rapid ethnographic assessment and a social science/anthropological framework was conducted and used methodological complementarity to contextualize results from the initial urinalysis study. Targeted sampling was conducted at two treatment sites. Program staff and patients were recruited to participate in focus groups and semi-structured interviews to assess structural, community, and individual-level factors impacting methamphetamine and opioid co-use. RESULTS: Within our broader framework of structural, community, and individual-level factors intersecting co-use, our data yielded three sub-themes: 1) the circulation of stigma regarding methamphetamine use was consistently described by both patients and staff and this intersected structural changes in treatment policy and suggested compounded stigma; 2) community-level factors and temporality were important for understanding patterns of methamphetamine use and for further interpreting the initial urinalysis; 3) patient rationales regarding the co-use of methamphetamine and opioids included strategies to mitigate the harms of heroin, as well as to detox or titrate the effects of heroin. CONCLUSION AND IMPLICATIONS: Using an ethnographically-oriented and social science/anthropological approach and methodological complementarity to contextualize the prior urinalysis study demonstrates how behavioral variables cannot be abstracted from larger socio-structural and community contexts which impact people's decision-making process regarding co-use of methamphetamine and opioids. Further, by grounding our analysis in the meaning-centered and experiential narratives of people who use drugs, our research demonstrates the importance of considering the expertise of people who co-use opioids and methamphetamine as central for informing future sustainable program planning to address co-use that also accounts for the interrelationship between structural, community, and individual-level factors.

Introducing the National Drug Early Warning System.

PURPOSE OF REVIEW: In 2013, NIH NIDA released a special funding opportunity to update and expand their longstanding Community Epidemiology Workgroup (CEWG) by creating a coordinating center for a new type of monitoring system that became the National Drug Early Warning System (NDEWS). This article provides an overview of four primary NDEWS components: core staff; an approach to detecting and monitoring emerging drug trends including community-based epidemiologists and national databases; small rapid follow-up studies; and innovative multimedia approaches for disseminating information. RECENT FINDINGS: The cornerstones for detecting and monitoring are the 1700+ member NDEWS Network and a coalition of local epidemiologists. Follow-up studies are designed with local researchers, practitioners, and policymakers to focus on local trends. Among NDEWS accomplishments are developing protocols for expanded urinalyses in high-risk populations and conducting follow-up studies with local collaborators in New Hampshire, New York, Ohio, Oregon, and a tribal nation in Minnesota. SUMMARY: During its first 6 years, NDEWS has advanced its mission to develop multidisciplinary collaborations and innovative technologies for identifying, monitoring, and following up on emerging drug trends and has contributed to the translation of science into practice. VIDEO ABSTRACT: http://links.lww.com/YCO/A55.

Evidence of fentanyl use is common and frequently missed in a cross-sectional study of emergency department patients in Baltimore, Maryland.

Objective: Fentanyl-associated deaths have risen in Maryland, but the prevalence of illicit fentanyl use is unknown. Our objective was to measure whether fentanyl is present among emergency department (ED) patients seeking care for a drug overdose.Design: The prevalence of fentanyl use was determined using a cross-sectional study of a convenience sample of adult ED patients with complaints of apparent opioid overdose, withdrawal from opioids, and/or requesting treatment for their substance use disorder (SUD) between February and April, 2018. Subjects were consented, interviewed, and underwent urine point-of-care (POC) fentanyl testing.Results: A total of 102 patients met inclusion criteria and were approached, 76 consented, 63 (83%) of whom tested positive for recent fentanyl use. 60 (80%) were male, 26 (34%) had overdosed, 41 (54%) were seeking SUD treatment, and 13 (17%) were in withdrawal (4 had multiple complaints). Of those who underwent both standard hospital urine drug screen and POC fentanyl testing, 56% (22/39) were positive for fentanyl and negative for opiates. Only 5% (4/76) reported knowledge of using fentanyl.Conclusions: Fentanyl use was common and frequently missed among these ED patients. Hospitals who treat patients taking illicit fentanyl should consider adding fentanyl to their urine drugs of abuse panel.

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.

The emerging buprenorphine epidemic in the United States.

The authors sampled for expanded drug testing of 1,061 urine specimens collected by Maryland Division of Parole and Probation staff. They found an increase in the percentage of individuals testing positive for buprenorphine and found that these specimens often contained other drugs, suggesting misuse. Subsequent interviews with 15 probationers and parolees in Baltimore, Maryland, showed wide-scale availability of buprenorphine on the street and in prisons. Medical examiners and drug testing programs should immediately initiate routine testing for buprenorphine to track a possible outbreak of buprenorphine diversion and misuse. Physician education programs should redouble their efforts to teach strategies to deter diversion and misuse of the drug.

The association between early conduct problems and early marijuana use in college students.

Early conduct problems have been linked to early marijuana use in adolescence. The present study examines this association in a sample of 1,076 college students that was divided into three groups: 1) early marijuana users (began marijuana use prior to age 15; n=126), 2) late marijuana users (began marijuana use at or after age 15; n=607), and 3) non-users (never used marijuana; n=343). A conduct problem inventory used in previous studies was adapted for use in the present study. Early conduct problems were associated with early marijuana use but not with late marijuana use, holding constant other risk factors. Results suggest that early conduct problems are a risk factor for early marijuana use even among academically-achieving college-bound students.

Persistent nonmedical use of prescription stimulants among college students: possible association with ADHD symptoms.

OBJECTIVE: To investigate the possible association between untreated ADHD symptoms (as measured by the Adult ADHD Self-Report Scale) and persistent nonmedical use of prescription stimulants. METHOD: Multinomial regression modeling was used to compare ADHD symptoms among three groups of college students enrolled in a longitudinal study over 4 years: (1) persistent nonmedical users of prescription stimulants, (2) persistent users of marijuana who did not use prescription stimulants nonmedically, and (3) consistent nonusers of drugs. RESULTS: ADHD symptoms were associated with being a persistent nonmedical user of prescription stimulants after adjustment for race/ethnicity, sex, socioeconomic status, and other illicit drug use. No associations were observed between ADHD symptoms and being a persistent marijuana user or nonuser. CONCLUSION: ADHD symptoms, and in particular inattention symptoms, appeared to be associated with nonmedical use of prescription stimulants.

Gender differences in the validity of the substance abuse subtle screening inventory--3 (SASSI-3) with a criminal justice population.

The Substance Abuse Subtle Screening Inventory-3 is a brief, self-administered screening tool designed to measure the probability of having a substance dependence disorder. The present study assessed the validity of this instrument with an inmate population using a DSM-IV diagnosis of substance dependence as the criterion measure. The study also examined instrument validity by gender. Findings revealed differences in the prediction of dependence between male and female inmates. The advantages and shortcomings of the instrument are discussed in light of these findings, and suggestions for future research are advanced.

The impact of positive and negative ecstasy-related information on ecstasy use among college students: Results of a longitudinal study.

AIMS: To: 1) estimate the proportion of students exposed to specific types of information regarding the positive and negative effects of ecstasy, 2) test models that quantified the relationship between exposure to these messages and subsequent ecstasy use, controlling for peer drug use and sensation-seeking. METHODS: As part of the College Life Study, 447 students, ages 17-20, from a university in the mid-Atlantic region of the US completed an in person interview plus three follow-up assessments. FINDINGS: Individuals who had heard a greater number of negative messages were significantly more likely to use ecstasy, even controlling for positive messages, prior ecstasy use, peer ecstasy use, perceived harm, sensation-seeking, sex, and race. Some messages were significant at the bivariate level. CONCLUSIONS: Ecstasy use may have been influenced more by the content of the messages than by the quantity or diversity of messages. Interventions should be designed to address both positive and negative perceptions about a particular drug, rather than focusing exclusively on the negative information. Future evaluations should focus on the effectiveness of multi-pronged sustainable prevention programs in reducing adolescent drug use risk.

Increased alcohol consumption, nonmedical prescription drug use, and illicit drug use are associated with energy drink consumption among college students.

OBJECTIVES: This longitudinal study examined the prevalence and correlates of energy drink use among college students, and investigated its possible prospective associations with subsequent drug use, including nonmedical prescription drug use. METHODS: Participants were 1,060 undergraduates from a large, public university who completed three annual interviews, beginning in their first year of college. Use of energy drinks, other caffeinated products, tobacco, alcohol, and other illicit and prescription drugs were assessed, as well as demographic and personality characteristics. RESULTS: Annual weighted prevalence of energy drink use was 22.6%(wt) and 36.5%(wt) in the second and third year of college, respectively. Compared to energy drink non-users, energy drink users had heavier alcohol consumption patterns, and were more likely to have used other drugs, both concurrently and in the preceding assessment. Regression analyses revealed that Year 2 energy drink use was significantly associated with Year 3 nonmedical use of prescription stimulants and prescription analgesics, but not with other Year 3 drug use, holding constant demographics, prior drug use, and other factors. CONCLUSIONS: A substantial and rapidly-growing proportion of college students use energy drinks. Energy drink users tend to have greater involvement in alcohol and other drug use and higher levels of sensation-seeking, relative to non-users of energy drinks. Prospectively, energy drink use has a unique relationship with nonmedical use of prescription stimulants and analgesics. More research is needed regarding the health risks associated with energy drink use in young adults, including their possible role in the development of substance use problems.

Sharing and selling of prescription medications in a college student sample.

OBJECTIVE: To estimate the prevalence of prescription medication diversion among college students; to compare classes of medications with respect to the likelihood of diversion; to document the most common methods of diversion; and to examine the characteristics of students who diverted medications. METHOD: A cross-sectional analysis of personal interview data collected between August 2006 and August 2007 as part of an ongoing longitudinal study. The cohort of students, who were between the ages of 17 and 19 years at study onset, attended a large public university in the mid-Atlantic region. Information was gathered regarding a wide variety of variables, including demographics, diversion of medically prescribed drugs, illicit drug use, and childhood conduct problems. RESULTS: Among 483 students prescribed a medication, 35.8% diverted a medication at least once in their lifetime. The most commonly diverted medication classes were prescription attention-deficit/hyperactivity disorder medication (61.7% diversion rate) and prescription analgesics (35.1% diversion rate). Sharing was the most common method of diversion, with 33.6% of students sharing their medication(s) and 9.3% selling in their lifetime. Comparative analyses revealed that prescription medication diverters had used more illicit drugs in the past year and had more childhood conduct problems than nondiverters. CONCLUSION: If confirmed, these findings have important clinical implications for improved physician-patient communication and vigilance regarding prescribing analgesic and stimulant medications for young adults.

Suicide ideation among college students: a multivariate analysis.

The goal of this study was to develop a multi-dimensional model that might explain suicide ideation among college students. Face-to-face interviews were conducted with 1,249 first-year college students. An estimated 6%(wt) of first-year students at this university had current suicide ideation. Depressive symptoms, low social support, affective dysregulation, and father-child conflict were each independently associated with suicide ideation. Only 40%(wt) of individuals with suicide ideation were classified as depressed according to standard criteria. In the group who reported low levels of depressive symptoms, low social support and affective dysregulation were important predictors of suicide ideation. Alcohol use disorder was also independently associated with suicide ideation, while parental conflict was not. Results highlight potential targets for early intervention among college students.