Faculty Bibliography

OBJECTIVES/OBJECTIVE:To advance our understanding of medication treatments for opioid use disorders (OUDs), identification of distinct subgroups and factors associated with differential treatment response is critical. We examined trajectories of opioid use for patients with OUD who were randomized to (but not in all cases inducted onto) buprenorphine-naloxone (BUP-NX) or extended-release naltrexone (XR-NTX), and identified characteristics associated with each trajectory. METHODS:Growth mixture models (GMMs) were run to identify distinct trajectories of days of opioid use among a subsample of 535 individuals with OUD who participated in a 24-week randomized controlled trial (RCT; 2014-2016) of BUP-NX (n = 281) or XR-NTX (n = 254). RESULTS:Four distinct opioid use trajectory classes were identified for BUP-NX (near abstinent/no use (59%); low use (13.2%); low use, increasing over time (15%); and moderate use, increasing over time (12.8%)). Three distinct opioid use trajectory classes were found for XR-NTX (near abstinent/no use (59.1%); low use (14.6%); and moderate use, increasing over time (26.4%)). Across both BUP-NX and XR-NTX, the near abstinent/no use class had the highest number of medical management visits. Within BUP-NX, the low use class had a greater proportion of individuals with a previous successful treatment history compared with other classes. Within XR-NTX, the moderate use, increasing over time class had the highest proportion of Hispanic participants compared with other classes. CONCLUSIONS:Findings highlight the significant heterogeneity of opioid use during a RCT of BUP-NX and XR-NTX and factors associated with opioid use patterns including medical management visits and history of treatment success.

There is a reciprocal relationship between the circadian and the reward systems. Polymorphisms in several circadian rhythm-related (clock) genes were associated with drug addiction. This study aims to search for associations between 895 variants in 39 circadian rhythm-related genes and opioid addiction (OUD). Genotyping was performed with the Smokescreen® array. Ancestry was verified by principal/MDS component analysis and the sample was limited to European Americans (EA) (OUD; n = 435, controls; n = 138). Nominally significant associations (p < 0.01) were detected for several variants in genes encoding vasoactive intestinal peptide receptor 2 (VIPR2), period circadian regulator 2 (PER2), casein kinase 1 epsilon (CSNK1E), and activator of transcription and developmental regulator (AUTS2), but no signal survived correction for multiple testing. There was intriguing association signal for the untranslated region (3' UTR) variant rs885863 in VIPR2, (p = .0065; OR = 0.51; 95% CI 0.31-0.51). The result was corroborated in an independent EA OUD sample (n = 398, p = 0.0036; for the combined samples). Notably, this SNP is an expression quantitative trait locus (cis-eQTL) for VIPR2 and a long intergenic non-coding RNA, lincRNA 689, in a tissue-specific manner, based on the Genotype-Tissue Expression (GTEx) project. Vasoactive intestinal peptide (VIP) is an important peptide of light-activated suprachiasmatic nucleus cells. It regulates diverse physiological processes including circadian rhythms, learning and memory, and stress response. This is the first report of an association of a VIPR2 variant and OUD. Additionally, analysis of combinations of single nucleotide polymorphisms (SNPs) genotypes revealed an association of PER2 SNP rs80136044, and SNP rs4128839, located 41.6 kb downstream of neuropeptide Y receptor type 1 gene, NPY1R (p = 3.4 × 10-6, OR = 11.4, 95% CI 2.7-48.2). The study provides preliminary insight into the relationship between genetic variants in circadian rhythm genes and long non-coding RNA (lncRNAs) in their vicinity, and opioid addiction.

BACKGROUND:Substance use frequently goes undetected in primary care. Though barriers to implementing systematic screening for alcohol and drug use have been examined in urban settings, less is known about screening in rural primary care. OBJECTIVE:To identify current screening practices, barriers, facilitators, and recommendations for the implementation of substance use screening in rural federally qualified health centers (FQHCs). DESIGN/METHODS:As part of a multi-phase study implementing electronic health record-integrated screening, focus groups (n = 60: all stakeholder groups) and individual interviews (n = 10 primary care providers (PCPs)) were conducted. PARTICIPANTS/METHODS:Three stakeholder groups (PCPs, medical assistants (MAs), and patients) at three rural FQHCs in Maine. APPROACH/METHODS:Focus groups and interviews were recorded, transcribed, and content analyzed. Themes surrounding current substance use screening practices, barriers to screening, and recommendations for implementation were identified and organized by the Knowledge to Action (KTA) Framework. KEY RESULTS/RESULTS:Identifying the problem: Stakeholders unanimously agreed that screening is important, and that universal screening is preferred to targeted approaches. Adapting to the local context: PCPs and MAs agreed that screening should be done annually. Views were mixed regarding the delivery of screening; patients preferred self-administered, tablet-based screening, while MAs and PCPs were divided between self-administered and face-to-face approaches. Assessing barriers: For patients, barriers to screening centered around a perceived lack of rapport with providers, which contributed to concerns about trust, judgment, and privacy. For PCPs and MAs, barriers included lack of comfort, training, and preparedness to address screening results and offer treatment. CONCLUSIONS:Though stakeholders agree on the importance of implementing universal screening, concerns about the patient-provider relationship, the consequences of disclosure, and privacy appear heightened by the rural context. Findings highlight that strong relationships with providers are critical for patients, while in-clinic resources and training are needed to increase provider comfort and preparedness to address substance use.

Aim: Naltrexone is first-line pharmacotherapy for alcohol use disorders (AUD). Oral naltrexone (ONTX) is under-prescribed in primary care and possibly limited by poor adherence. Monthly injectable extended-release naltrexone (XR-NTX) may improve adherence and good clinical outcomes.
Method(s): This is a randomized, open-label, comparative effectiveness trial of 24 weeks of XR-NTX vs. O-NTX as AUD treatment in primary care at a public hospital in New York City. Adults (>18 yo) with AUD randomized to XR-NTX (380 mg/month) vs. O-NTX (50 mg/day) with Medical Management. Self-reported daily drinking recall informed the primary outcome, a Good Clinical Outcome (GCO) across weeks 5-24, defined as abstinence or moderate drinking and 0-2 days of heavy drinking per month. Data & Results: N = 237 adults randomized (n = 117 XR-NTX; n = 120 O-NTX); mean age 48.5 (SD 10.6); 71%male; 54%AA, 21% Hispanic; 41%employed. At baseline mean drinks/day were 9.6 (SD 11.6); 29% abstinent days; 61%heavy drinking days; mean Obsessive Compulsive Drinking Scale (OCDS) scores were 17.6 (SD 7.1) and mean AUDIT scores were 24.2 (SD 8.0). 64%of monthly XR-NTX injections were received and 67%ofmonthly O-NTX refills were provided. The primary GCO across weeks 5-24 was reported by 29%XR-NTX and 23%O-NTX (p = 0.29). Mean months with a GCO was 2.9 XR-NTX, 2.5 O-NTX (p = 0.21). Rates of%days abstinent (70%XRNTX vs. 71%O-NTX; p = 0.77) and %heavy drinking days (20%XR-NTX vs. 16%O-NTX; p = 0.28) were similar weeks 1-24. Mean blood pressure decreased from 127/86 mmHg at baseline to 124/83 mmHg at week 25; there was no change in mean weight (180 lb) pre/post, and there were no differences in BP or weight changes by arm. Declines in OCDS scores (17.6 to 7.6) were similar by arm.
Conclusion(s): Initiation and retention on both forms of naltrexone was robust. Overall, participants reported improved longitudinal drinking outcomes. There was insufficient evidence of any differences in primary and secondary self-reported drinking outcomes between monthly XR-NTX and daily ONTX. Additional analysis will examine CDT and LFT levels during treatment, and interactions with OPMR1 genotype status

Background: Emergency department (ED) visits related to substance use are common. ED patients also have high levels of health-related material needs (HRMNs), such as homelessness and food insecurity. However, little research has examined the intersection between ED patient HRMNs and substance use. Methods: We surveyed a random sample of public hospital ED patients. Surveys included validated single-item screeners for unhealthy alcohol and any drug use and questions on self-reported past-year material needs. We compared individual HRMNs and cumulative number of HRMNs by substance use screening status using bivariate and multivariable analyses. Results: A total of 2312 surveys were completed. Nearly one third of patients (32.3%, n = 747) screened positive for unhealthy alcohol use, and 21.8% (n = 503) screened positive for drug use. Prevalence of HRMNs for all patients-including food insecurity (50.8%), inability to meet essential expenses (40.8%), cost barriers to medical care (24.6%), employment issues (23.8%), and homelessness (21.4%)-was high and was significantly higher for patients with unhealthy alcohol use or drug use. In multivariable analyses, homelessness was independently associated with unhealthy alcohol use (adjusted odds ratio [aOR]: 1.61, 95% confidence interval [CI]: 1.24-2.09) and drug use (aOR: 2.30, 95% CI: 1.74-3.05). There was a significant stepwise increase in the odds of patient unhealthy alcohol or drug use as number of HRMNs increased. Conclusions: ED patients with unhealthy alcohol or drug use have higher prevalence of HRMNs than those without. Our findings suggest that HRMNs may act additively and that homelessness is particularly salient. Patients' comorbid HRMNs may affect the success of ED-based substance use interventions.

Background: Patients with opioid use disorder (OUD) have improved outcomes on buprenorphine (BUP) and are twice as likely to be in treatment if BUP is initiated in the Emergency Department (ED) compared with standard referral. Our objective is to assess staff readiness for ED-initiated BUP with referral in highneed, low-resource community and academic EDs in New Hampshire and Manhattan.
Method(s): As part of an implementation study, in summer 2018, we conducted a mixed-methods formative evaluation using the modified Organizational Readiness to Change Assessment (ORCA) and rulers of readiness to begin ED-BUP on a scale of 0 (not) to 10 (completely), in EDs of one critical access hospital, one community hospital with urban/rural catchment, and one academic public safety-net hospital. ORCAs were administered electronically prior to inperson focus groups with ED physicians, PA/APRNs, nurses, social workers, and community providers. ORCAs and rulers were compared across sites and between EDs and the community providers. We conducted focus groups guided by an implementation framework to identify barriers and facilitators to the implementation of ED-BUP at each site. Findings were reported back to stakeholders, and used to develop site-specific clinical protocols and implementation strategies, along with education and resources designed to enhance uptake of ED-BUP at each site.
Result(s): ORCA completion rates at each site were 32%, 52%, and 17%. The ORCA showed that ED staff at two sites were ambivalent as to whether ED-BUP will improve treatment follow-up; one site agreed. ED staff and community providers reported respective readiness for ED-BUP with referral at each site of 3.5 (N=15) and 6.7 (N=36); 2.0 (N=11) and 6.3(N=28); 3.5 (N=28) and 9.3 (N=6). Nine focus groups of 36 stakeholders identified several barriers (lack of knowledge/experience with BUP, workflow integration, increased time/patient burden, and limited knowledge of local treatment options) and facilitators (improved patient care, a sense of moral imperative, and local champions/leadership buy-in).
Conclusion(s): A mixed-methods formative evaluation with facilitation and stakeholder input identified ambivalence in ED staff, as well as barriers and facilitators, including specific opportunities for education and facilitation, which may enhance site-specific implementation of ED-initiated BUP

BACKGROUND:Extended-release naltrexone (XR-NTX, Vivitrol®) and daily oral naltrexone tablets (O-NTX) are FDA-approved mu opioid receptor antagonist medications for alcohol dependence treatment. Despite the efficacy of O-NTX, non-adherence and poor treatment retention have limited its adoption into primary care. XR-NTX is a once-a-month injectable formulation that offers a potentially more effective treatment option in reducing alcohol consumption and heavy drinking episodes among persons with alcohol use disorders. METHODS:This pragmatic, open-label, randomized controlled trial examines the effectiveness of XR-NTX vs. O-NTX in producing a Good Clinical Outcome, defined as abstinence or moderate drinking (<2 drinks/day, men; <1 drink/day, women; and < 2 heavy drinking occasions/month) during the final 20 of 24 weeks of primary care-based Medical Management treatment for alcohol dependence. Secondary aims will estimate the cost effectiveness of XR-NTX vs. O-NTX, in conjunction with primary-care based Medical Management for both groups, and patient-level characteristics associated with effectiveness in both arms. Alcohol dependent persons are recruited from the community into treatment in a New York City public hospital primary care setting (Bellevue Hospital Center) for 24 weeks of either XR-NTX (n = 117) or O-NTX (n = 120). RESULTS:We describe the rationale, specific aims, design, and recruitment results to date. Alternative design considerations and secondary aims and outcomes are reported. CONCLUSIONS:XR-NTX treatment in a primary care setting is potentially more efficacious, feasible, and cost-effective than oral naltrexone when treating community-dwelling persons with alcohol use disorders. This study will estimate XR-NTX's treatment and cost effectiveness relative to oral naltrexone.