Effect of the Communities that HEAL intervention on receipt of behavioral therapies for opioid use disorder: A cluster randomized wait-list controlled trial.

BACKGROUND: The U.S. opioid overdose crisis persists. Outpatient behavioral health services (BHS) are essential components of a comprehensive response to opioid use disorder and overdose fatalities. The Helping to End Addiction Long-Term® (HEALing) Communities Study developed the Communities That HEAL (CTH) intervention to reduce opioid overdose deaths in 67 communities in Kentucky, Ohio, New York, and Massachusetts through the implementation of evidence-based practices (EBPs), including BHS. This paper compares the rate of individuals receiving outpatient BHS in Wave 1 intervention communities (n = 34) to waitlisted Wave 2 communities (n = 33). METHODS: Medicaid data included individuals ≥18 years of age receiving any of five BHS categories: intensive outpatient, outpatient, case management, peer support, and case management or peer support. Negative binomial regression models estimated the rate of receiving each BHS for Wave 1 and Wave 2. Effect modification analyses evaluated changes in the effect of the CTH intervention between Wave 1 and Wave 2 by research site, rurality, age, sex, and race/ethnicity. RESULTS: No significant differences were detected between intervention and waitlisted communities in the rate of individuals receiving any of the five BHS categories. None of the interaction effects used to test the effect modification were significant. CONCLUSIONS: Several factors should be considered when interpreting results-no significant intervention effects were observed through Medicaid claims data, the best available data source but limited in terms of capturing individuals reached by the intervention. Also, the 12-month evaluation window may have been too brief to see improved outcomes considering the time required to stand-up BHS. TRIAL REGISTRATION: Clinical Trials.gov http://www. CLINICALTRIALS: gov: Identifier: NCT04111939.

An Approach to Enhancing Medication Treatment for Opioid Use Disorder in the HEALing Communities Study.

The HEALing (Helping to End Addiction Long-term) Communities Study (HCS) aims to test the effectiveness of the Communities That HEAL intervention in decreasing opioid overdose deaths in 67 communities across four U.S. states. This intervention enlists a collaborative team of researchers, academic experts, and community coalitions to select and implement interventions from a menu of evidence-based practices, including medications for opioid use disorder (MOUD). The HCS's New York team developed an integrated network systems (INS) approach with a mapping tool to coach coalitions in the selection of strategies to enhance medication treatment. With the INS approach, community coalitions develop a map of service delivery venues in their local county to better engage people with medication treatment wherever this need arises. The map is structured around core services that can provide maintenance MOUD and satellite services, which include all settings where people with opioid use disorder are encountered and can be identified, possibly given medication, and referred to core programs for ongoing MOUD care. This article describes the rationale for the INS mapping tool, with a discussion framed by the consolidated framework for implementation research, and provides a case example of its application.

Impact of the Communities That HEAL Intervention on Buprenorphine-Waivered Practitioners and Buprenorphine Prescribing: A Prespecified Secondary Analysis of the HCS Randomized Clinical Trial.

Importance: Buprenorphine significantly reduces opioid-related overdose mortality. From 2002 to 2022, the Drug Addiction Treatment Act of 2000 (DATA 2000) required qualified practitioners to receive a waiver from the Drug Enforcement Agency to prescribe buprenorphine for treatment of opioid use disorder. During this period, waiver uptake among practitioners was modest; subsequent changes need to be examined. Objective: To determine whether the Communities That HEAL (CTH) intervention increased the rate of practitioners with DATA 2000 waivers and buprenorphine prescribing. Design, Setting, and Participants: This prespecified secondary analysis of the HEALing Communities Study, a multisite, 2-arm, parallel, community-level, cluster randomized, open, wait-list-controlled comparison clinical trial was designed to assess the effectiveness of the CTH intervention and was conducted between January 1, 2020, to December 31, 2023, in 67 communities in Kentucky, Massachusetts, New York, and Ohio, accounting for approximately 8.2 million adults. The participants in this trial were communities consisting of counties (n = 48) and municipalities (n = 19). Trial arm randomization was conducted using a covariate constrained randomization procedure stratified by state. Each state was balanced by community characteristics including urban/rural classification, fatal opioid overdose rate, and community population. Thirty-four communities were randomized to the intervention and 33 to wait-list control arms. Data analysis was conducted between March 20 and September 29, 2023, with a focus on the comparison period from July 1, 2021, to June 30, 2022. Intervention: Waiver trainings and other educational trainings were offered or supported by the HEALing Communities Study research sites in each state to help build practitioner capacity. Main Outcomes and Measures: The rate of practitioners with a DATA 2000 waiver (overall, and stratified by 30-, 100-, and 275-patient limits) per 100 000 adult residents aged 18 years or older during July 1, 2021, to June 30, 2022, were compared between the intervention and wait-list control communities. The rate of buprenorphine prescribing among those waivered practitioners was also compared between the intervention and wait-list control communities. Intention-to-treat and per-protocol analyses were performed. Results: A total of 8 166 963 individuals aged 18 years or older were residents of the 67 communities studied. There was no evidence of an effect of the CTH intervention on the adjusted rate of practitioners with a DATA 2000 waiver (adjusted relative rate [ARR], 1.04; 95% CI, 0.94-1.14) or the adjusted rate of practitioners with a DATA 2000 waiver who actively prescribed buprenorphine (ARR, 0.97; 95% CI, 0.86-1.10). Conclusions and Relevance: In this randomized clinical trial, the CTH intervention was not associated with increases in the rate of practitioners with a DATA 2000 waiver or buprenorphine prescribing among those waivered practitioners. Supporting practitioners to prescribe buprenorphine remains a critical yet challenging step in the continuum of care to treat opioid use disorder. Trial Registration: ClinicalTrials.gov Identifier: NCT04111939.

State alignment with federal regulations in 2022 to relax buprenorphine 30-patient waiver requirements.

Background: In 2021, the Department of Health and Human Services released guidelines allowing waiver-eligible providers seeking to treat up to 30 patients to be exempt from waiver training (WT) and the counseling and other ancillary services (CAS) attestation. This study evaluates if states and the District of Columbia had more restrictive policies preventing adoption of the 2021 federal guidelines. Methods: First, the Westlaw database was searched for buprenorphine regulations. Second, state medical, osteopathic, physician assistant, nursing boards, and single state agencies (SSA) were surveyed to assess for the WT and CAS requirements and if they were discussing the 2021 guidelines. Results were recorded and compared by state and waiver-eligible provider types. Results: The Westlaw search revealed seven states with regulations requiring the WT and ten states requiring CAS. Survey results showed ten state boards/SSAs required WT for at least one waiver-eligible practitioner type and eleven state boards/SSAs required CAS. In some states, the WT and CAS requirements only applied in special circumstances. Eleven states had discrepancies between the Westlaw and survey results among three waiver-eligible provider types. Conclusions: Despite the 2021 federal change intended to increase access to buprenorphine, several states had regulations and/or provider boards and SSAs that were not supportive. Now, the Mainstreaming Addiction Treatment (MAT) Act of 2022 eliminated the federal x-waiver requirement to prescribe buprenorphine. However, these states may continue to have barriers to treatment access despite the MAT Act. Strategies to engage states with these restrictive policies are needed to improve buprenorphine treatment capacity.

Adaptations to Opioid Use Disorder Care During the COVID-19 Pandemic: A National Survey of Prescribers.

OBJECTIVES: Among opioid use disorder (OUD)-treating providers, to characterize adaptations used to provide medications for OUD (MOUD) and factors associated with desire to continue virtual visits post-COVID-19 pandemic. METHODS: In a national electronic survey of OUD-treating prescribers (July-August 2020), analyses restricted to X-waivered buprenorphine prescribers providing outpatient, longitudinal care for adults with OUD, quantitative and qualitative analyses of survey items and free text responses were conducted. RESULTS: Among 797 respondents, 49% were men, 57% ≥50 years, 76% White, 68% physicians. Respondents widely used virtual visits to continue prescribing existing MOUD regimens (79%), provide behavioral healthcare (71%), and initiate new MOUD prescriptions (49%). Most prescribers preferred to continue/expand use of virtual visits after COVID-19. In multivariable models, factors associated with preference to continue/expand virtual visits to initiate MOUD postpandemic were treating a moderate number of patients prepandemic (aOR = 1.67; 95%[CI] = 1.06,2.62) and practicing in an urban setting (aOR = 2.17; 95%[CI] = 1.48,3.18). Prescribing buprenorphine prepandemic (aOR = 2.06; 95%[CI] = 1.11,3.82) and working in an academic medical center (aOR = 2.47; 95%[CI] = 1.30,4.68) were associated with preference to continue/expand use of virtual visits to continue MOUD postpandemic. Prescribing naltrexone extended-release injection prepandemic was associated with preference to continue/expand virtual visits to initiate and continue MOUD (aOR = 1.51; 95%[CI] = 1.10,2.07; aOR = 1.74; 95%[CI] = 1.19,2.54). Qualitative findings suggest that providers appreciated virtual visits due to convenience and patient accessibility, but were concerned about liability and technological barriers. CONCLUSIONS: Surveyed prescribers widely used virtual visits to provide MOUD with overall positive experiences. Future studies should evaluate the impact of virtual visits on MOUD access and retention and clinical outcomes.

Well-Being of Health Care Professionals Treating Opioid Use Disorder During the COVID-19 Pandemic: Results From a National Survey.

OBJECTIVE: The COVID-19 pandemic has dramatically affected health care delivery, effects that are juxtaposed with health care professional (HCP) burnout and mental distress. The Opioid Use Disorder Provider COVID-19 Survey was conducted to better understand the impact of COVID-19 on clinical practice and HCP well-being. METHODS: The cross-sectional survey was e-mailed to listservs with approximately 157,000 subscribers of diverse professions between July 14 and August 15, 2020. Two dependent variables evaluated HCP functioning and work-life balance. Independent variables assessed organizational practices and HCP experiences. Covariates included participant demographic characteristics, addiction board certification, and practice setting. Multilevel multivariate logistic regression models were used. RESULTS: Among 812 survey respondents, most were men, White, and physicians, with 46% located in urban settings. Function-impairing anxiety was reported by 17%, and 28% reported more difficulty with work-life balance. Difficulty with functioning was positively associated with having staff who were sick with COVID-19 and feeling close to patients, and was negatively associated with being male and having no staff changes. Difficulty with work-life balance was positively associated with addiction board certification; working in multiple settings; having layoffs, furloughs, or reduced hours; staff illness with COVID-19; and group well-being check-ins. It was negatively associated with male gender, older age, and no staff changes. CONCLUSIONS: Demographic, provider, and organizational-practice variables were associated with reporting negative measures of well-being during the COVID-19 pandemic. These results should inform HCPs and their organizations on factors that may lead to burnout, with particular focus on gender and age-related concerns and the role of well-being check-ins.

A randomized, double-blind, placebo-controlled trial of ondansetron for the treatment of cocaine use disorder with post hoc pharmacogenetic analysis.

BACKGROUND: Cocaine use disorder (CUD) has significant consequences and there remain no FDA-approved pharmacotherapies. Ondansetron is an indirect dopaminergic modulator that has shown efficacy in alcohol use disorder, particularly in phenotypic and genotypic subgroups, and was found to be efficacious in a pilot dose-finding trial for CUD. METHODS: One-hundred eight (108) adults with CUD were randomized to ondansetron 4 mg twice daily or placebo for 9 weeks and assessed up to thrice weekly to evaluate self-reported cocaine use and urine benzoylecgonine. Participants received cognitive-behavioral therapy and brief behavioral compliance enhancement therapy. Consenting participants (N = 79) provided blood samples for exploratory pharmacogenetic analyses. RESULTS: Participants in both arms reduced cocaine use over time, but there was no statistically significant difference on percentage of cocaine-free days (PCFD; p = 0.972) or percentage of cocaine-free urine samples (PCFU; p = 0.909). Participants with early-onset CUD had greater improvement regardless of study arm (p = 0.002). Post hoc pharmacogenetic analyses demonstrated an interaction effect between treatment and rs1176713 SNP on PCFU in the total sample (p = 0.040) and African ancestry subset (p = 0.03). Constipation, fatigue, and somnolence were more common among ondansetron-treated participants (Fisher exact p < 0.05). Those who developed constipation were mostly rs1176713:GG carriers (Fisher exact p = 0.029). CONCLUSIONS: Ondansetron did not demonstrate efficacy in the treatment of CUD. However, these preliminary results suggest a genotype-based variance in response to ondansetron in African ancestry individuals with CUD. Further studies are needed to validate findings for developing a personalized genomic approach for CUD treatment in racially and ethnically diverse populations.

An adaptive clinical trial design for cocaine use disorder: Extended-release amphetamine salts for early behavioral intervention non-responders.

BACKGROUND/AIMS: Cocaine use disorder (CUD) persists as a major public health problem in the United States. Response to evidence-based behavioral treatment has been shown to be predicted by dopaminergic dysfunction. Amphetamine formulations modulate dopaminergic systems and are one of the few agents with positive clinical findings but are associated with unique risks. We aimed to find a model for determining the most appropriate patients for treatment with mixed amphetamine salts-extended-release (MAS-ER) for CUD using an adaptive trial design. METHODS: We are enrolling treatment-seeking adults ages 18-60 years. All eligible participants receive bi-weekly individual counseling augmented with a computer-based intervention based on the community reinforcement approach with contingency management (CRA + CM) for 4 weeks. Participants who fail to achieve abstinence are additionally randomly assigned to 10 weeks of either MAS-ER, titrated up to 80 mg daily, or placebo. All participants complete a follow-up assessment after 12 weeks. RESULTS: Frequency and amount of cocaine use, cravings, retention, and quality of life will be compared between groups. The primary outcome will be having at least 3 weeks of urine toxicology-confirmed self-reported abstinence. Analyses will also be conducted to identify variables that may help identify who is more or less likely respond to the behavioral intervention during the first 4-weeks of treatment. CONCLUSIONS: This trial more closely mimics a personalized medicine approach that is often used in clinical practice. It will help us understand who may be appropriate for psychostimulant therapy as an enhancement to evidence-based behavioral interventions, while limiting exposure to those who would respond to a psychosocial intervention alone. ClinicalTrials.gov Identifier: NCT01986075.

Impulsiveness as a moderator of amphetamine treatment response for cocaine use disorder among ADHD patients.

BACKGROUND: Amphetamines are a first-line treatment for ADHD and have shown promise for the treatment of cocaine use disorder (CUD), both alone and with comorbid ADHD. Impulsiveness is a key aspect of both ADHD and substance use disorders. We sought to understand the role of baseline impulsiveness in the treatment of comorbid CUD and ADHD. METHODS: In a post hoc analysis (N = 76) of a 14-week, double-blind, randomized, placebo-controlled trial of mixed amphetamine salts-extended release (MAS-ER) for comorbid ADHD and CUD, we examined the relationship between treatment response and participants' baseline Barratt Impulsiveness Scale (BIS-11) score by comparing those with scores below versus above the median. In the original trial, participants received daily 60 mg MAS-ER, 80 mg MAS-ER, or placebo, in conjunction with cognitive behavioral therapy. RESULTS: The odds of a cocaine-abstinent week over time were significantly greater in the high BIS group compared to the low BIS group, both when missing data was treated as missing (p = .0155; OR = 1.23, 95% CI: 1.13, 1.35 versus OR = 1.04, 95% CI: 0.95, 1.15) and when missing data was treated as cocaine-positive (p = .003; OR = 1.15, 95% CI: 1.06, 1.24 versus OR = 0.96, 95% CI: 0.88, 1.05). CONCLUSIONS: The results show an association between higher within-group trait impulsiveness, as measured by the BIS-11, and response to MAS-ER for CUD in a cohort with comorbid ADHD. This result further demonstrates that impulsiveness is an important factor when considering treatment options for patients with CUD and that higher baseline impulsiveness may predict response to treatment with psychostimulants for CUD.

In Vitro Assessment of Putative PD-1/PD-L1 Inhibitors: Suggestions of an Alternative Mode of Action.

The programmed cell death protein 1 (PD-1) signaling axis is among the most important therapeutic targets in modern oncology. Aurigene Discovery Technologies Ltd. (Aurigene) has patented a series of peptidomimetic small molecules derived from the PD-1 protein sequence for use in targeting the interaction between PD-1 and its ligand, PD-L1. We evaluated three of Aurigene's most potent compounds in SPR binding assays. Our results showed that these compounds-each of which is known to be potently effective in a splenocyte recovery assay-do not directly inhibit the PD-1/PD-L1 interaction nor do they appear to bind to either of the constituent proteins, indicating that another mechanism is at play. As a result of these studies and upon consideration of structural features within the PD-1/PD-L1 complex, we hypothesize that the Aurigene molecules may interact with a currently unknown protein capable of regulating the PD-1 axis.

Women and Addiction: An Update.

Gender-related alcohol and drug abuse problems are related not only to biological differences, but also to social and environmental factors, which can influence the clinical presentation, consequences of use, and treatment approaches. Women are becoming the fastest-growing population of substance abusers in the United States. Given that women experience a more rapid progression of their addiction than men, it is important that we understand and address the differences to help develop prevention and treatment programs that are tailored for women, incorporating trauma assessment and management, identification and intervention for medical and psychiatric comorbidities, financial independence, pregnancy, and child care.

Impulsiveness as a predictor of topiramate response for cocaine use disorder.

BACKGROUND/OBJECTIVES: Topiramate has been studied in the treatment of substance use disorders and is often used off-label in the treatment of other disorders with impaired impulse control. We sought to determine whether impulsiveness could predict topiramate treatment response in individuals with cocaine use disorder (CUD). METHODS: In a post-hoc analysis of a 12-week, double-blind, randomized, placebo-controlled trial of topiramate for CUD, we examined the relationship between response to treatment and participants' baseline score on the Barrett Impulsiveness Scale (BIS-11). During the original trial, topiramate was titrated up to 300 mg/day over 6 weeks and maintained for 6 weeks. All participants received weekly cognitive behavioral therapy. RESULTS: Individuals with total BIS-11 scores above the median had 11.2% more cocaine-free days with topiramate versus placebo (Bonferroni corrected p = 0.047). Individuals with first-order factor scores above the median in self-control (Bonferroni corrected p = 0.020) and at or below the median in attention (Bonferroni corrected p = 0.022), and second-order factor scores at or below the median in attentional (Bonferroni corrected p = 0.024) and motor impulsiveness (Bonferroni corrected p = 0.046) were all associated with a greater improvement with topiramate. DISCUSSION/CONCLUSION: The results indicate an association between higher within-group impulsiveness and response to topiramate for CUD. The subscore findings may suggest a complex interaction between effectiveness and known cognitive side effects. The finding that trait impulsiveness is associated with treatment response is a promising discovery that may help guide treatment for CUD. SCIENTIFIC SIGNIFICANCE: This analysis suggests a possible endophenotype based on impulsiveness that can predict treatment response to topiramate. (Am J Addict 2019;XX:1-6).

A Review of Alprazolam Use, Misuse, and Withdrawal.

: Alprazolam is one of the most widely prescribed benzodiazepines for the treatment of generalized anxiety disorder and panic disorder. Its clinical use has been a point of contention as most addiction specialists consider it to be highly addictive, given its unique psychodynamic properties which limit its clinical usefulness, whereas many primary care physicians continue to prescribe it for longer periods than recommended. Clinical research data has not fully shed light on its "abuse liability," yet it is one of the most frequently prescribed benzodiazepines. "Abuse liability" is the degree to which a psychoactive drug has properties that facilitate people misusing it, or becoming addicted to it, and is commonly used in the literature. We have replaced it in our manuscript with "misuse liability" as it reflects a more updated terminology consistent with the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). In this paper, we have reviewed alprazolam's indications for use, its effect on pregnant women, misuse liability, withdrawal syndrome, pharmacodynamic properties, and suggest better clinical prescription practice of alprazolam by presenting an indepth theory of its clinical effects with use and withdrawal.

Women and Addiction.

Gender-related alcohol and drug abuse problems are related not only to biological differences, but also to social and environmental factors, which can influence the clinical presentation, consequences of use, and treatment approaches. Women are becoming the fastest-growing population of substance abusers in the United States. Given that women experience a more rapid progression of their addiction than men, it is important that we understand and address the differences to help develop prevention and treatment programs that are tailored for women, incorporating trauma assessment and management, identification and intervention for medical and psychiatric comorbidities, financial independence, pregnancy, and child care.