Addiction Consult Service and Inpatient Outcomes Among Patients with Alcohol Use Disorder.

BACKGROUND: Alcohol use disorder (AUD) is the most prevalent substance use disorder, but evidence-based medications to treat AUD (MAUD), including naltrexone and acamprosate, are substantially underutilized. Hospitalization provides an opportunity to start MAUD for patients who may not otherwise seek treatment. Addiction consultation services (ACSs) have been increasingly utilized to ensure appropriate treatment. There is little research examining the effect of an ACS on health outcomes among patients with AUD. OBJECTIVE: To determine the association between an ACS consultation and provision of MAUD during admission and MAUD at discharge among admissions with AUD. DESIGN: Retrospective study comparing admissions which received an ACS consult and propensity score-matched historical control admissions. Subjects A total of 215 admissions with a primary or secondary diagnosis of AUD who received an ACS consult and 215 matched historical control admissions. Intervention ACS consultation from a multidisciplinary team offering withdrawal management, substance use disorder treatment, patient-centered counseling, discharge planning, and linkage to outpatient care for patients with substance use disorders, including AUD. Main Measures Primary outcomes were initiation of new MAUD during admission and new MAUD at discharge. Secondary outcomes were patient-directed discharge, time to 7- and 30-day readmission, and time to 7- and 30-day post-discharge ER visit. Key Results Among 430 admissions with AUD, those that received an ACS consultation were significantly more likely to receive new inpatient MAUD (33.0% vs 0.9%; OR 52.5 [CI 12.6-218.6]) and significantly more likely to receive new MAUD at discharge (41.4% vs 1.9%; OR 37.3 [13.3-104.6]), compared with historical controls. ACS was not significantly associated with patient-directed discharge, time to readmission, or time to post-discharge ER visit. CONCLUSIONS: ACS was associated with a large increase in provision of new inpatient MAUD and new MAUD at discharge when compared to propensity-matched historical controls.

Low-dose buprenorphine initiation and treatment continuation among hospitalized patients with opioid dependence: A retrospective cohort study.

BACKGROUND: Buprenorphine is an effective treatment for both opioid use disorder (OUD) and chronic pain, but buprenorphine's pharmacology complicates treatment initiation for some patients. Low-dose buprenorphine initiation is a novel strategy that may reduce precipitated withdrawal. Few studies describe what patient populations benefit most from low-dose initiations and the clinical parameters that impact treatment continuation. This study aimed to 1) describe experiences with low-dose buprenorphine initiation, including both successes and failures among hospitalized patients in an urban underserved community; 2) identify patient- and treatment-related characteristics associated with unsuccessful initiation and treatment discontinuation; and 3) assess buprenorphine treatment continuation after discharge. METHODS: This is a retrospective cohort study with opioid-dependent (meaning OUD or receiving long-term opioid therapy for chronic pain) patients who underwent low-dose buprenorphine initiation during hospital admission from October 2021 through April 2022. The primary outcome was successful completion of low-dose initiation. Bivariate analysis identified patient- and treatment-related factors associated with unsuccessful initiation. Secondary outcomes were buprenorphine treatment discontinuation at post-discharge follow-up, 30- and 90-days. RESULTS: Of 28 patients who underwent low-dose buprenorphine initiation, 68 % successfully completed initiation. Unsuccessful initiation was associated with receipt of methadone during admission and higher morphine milligram equivalents (MME) of supplemental opioids. Of 22 patients with OUD, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 46 %, 36 %, and 36 %. Of 6 patients with chronic pain, the percent receiving a buprenorphine prescription at a follow-up visit, 30 days, and 90 days, respectively, was 100 %, 100 %, and 83 %. CONCLUSION: Low-dose buprenorphine initiation can be successful in opioid-dependent hospitalized patients. Patients taking methadone or requiring higher MME of supplemental opioids may have more difficulty with the low-dose buprenorphine initiation approach, but these findings should be replicated in larger studies. This study suggests patient- and treatment-related factors that clinicians could consider when determining the optimal treatment strategy for patients wishing to transition to buprenorphine.

Hospital-based clinicians lack knowledge and comfort in initiating medications for opioid use disorder: opportunities for training innovation.

BACKGROUND: Hospital-based clinicians infrequently initiate medications for opioid use disorder (MOUD) for hospitalized patients. Our objective was to understand hospital-based clinicians' knowledge, comfort, attitudes, and motivations regarding MOUD initiation to target quality improvement initiatives. METHODS: General medicine attending physicians and physician assistants at an academic medical center completed questionnaires eliciting barriers to MOUD initiation, including knowledge, comfort, attitudes and motivations regarding MOUD. We explored whether clinicians who had initiated MOUD in the prior 12 months differed in knowledge, comfort, attitudes, and motivations from those who had not. RESULTS: One-hundred forty-three clinicians completed the survey with 55% reporting having initiated MOUD for a hospitalized patient during the prior 12 months. Common barriers to MOUD initiation were: (1) Not enough experience (86%); (2) Not enough training (82%); (3) Need for more addiction specialist support (76%). Overall, knowledge of and comfort with MOUD was low, but motivation to address OUD was high. Compared to MOUD non-initiators, a greater proportion of MOUD initiators answered knowledge questions correctly, agreed or strongly agreed that they wanted to treat OUD (86% vs. 68%, p = 0.009), and agreed or strongly agreed that treatment of OUD with medication was more effective than without medication (90% vs. 75%, p = 0.022). CONCLUSIONS: Hospital-based clinicians had favorable attitudes toward MOUD and are motivated to initiate MOUD, but they lacked knowledge of and comfort with MOUD initiation. To increase MOUD initiation for hospitalized patients, clinicians will need additional training and specialist support.

Clinical Management of Opioid Withdrawal.

Appropriate clinical management of opioid withdrawal is a crucial bridge to long-term treatment for opioid use disorder (OUD), because it is a high-risk time for potential opioid overdose and relapse. We provide a narrative review of evidence-based opioid withdrawal management strategies applicable to a variety of treatment settings and geographies. The goals of opioid withdrawal management include relieving suffering associated with withdrawal, providing appropriate diagnosis and screening, engaging patients in initiation of OUD treatment, and using harm reduction strategies, all guided by a patient-centered approach to care. In addition, we discuss complex cases, relapse prevention strategies, and new developments in opioid withdrawal management.

A comparison of office-based buprenorphine treatment outcomes in Bronx community clinics before versus during the COVID-19 pandemic.

INTRODUCTION: In 2020, the US and New York City experienced unprecedented deaths due to the COVID-19 pandemic and drug overdoses. Policy changes reduced burdensome regulations for medication treatment for opioid use disorder (OUD). Despite these policy changes, few studies examined buprenorphine treatment outcomes during the pandemic. We compared treatment outcomes among Bronx patients referred to office-based buprenorphine treatment before versus during the pandemic. METHODS: In a retrospective cohort study, we compared patients referred to buprenorphine treatment in a Bronx community clinic before (March-August 2019) versus during (March-August 2020) the pandemic. We describe changes to buprenorphine treatment during the pandemic, including telehealth and prioritizing harm reduction. Using data from medical records and program logs, main outcomes included steps of the OUD treatment cascade of care-initial visit scheduled and completed, treatment initiated, and retained in treatment at 90 days. Using chi square and t-tests, we examined differences in patient characteristics and OUD treatment cascade steps before versus during the pandemic. RESULTS: Before and during the pandemic, 72 and 35 patients were referred to buprenorphine treatment, respectively. Patients' mean age was 46 years, most were male (67.3%) or Hispanic (52.3%), and few had private insurance (19.6%). Patients referred during (vs. before) the pandemic were more likely to have private insurance (31.4% vs. 13.9%, p < 0.05) and be referred from acute care settings (37.1% vs. 19.4%, p < 0.05). No significant differences in OUD cascade of care outcomes existed between those referred during versus before the pandemic. However, among patients who initiated buprenorphine treatment, those referred during (vs. before) the pandemic were more likely to be retained in treatment at 90 days (68.0% vs. 42.9%, p < 0.05). CONCLUSIONS: Despite the COVID-19 pandemic's unprecedented devastation to the Bronx, along with worsening drug overdose deaths, OUD cascade of care outcomes were similar among patients referred to buprenorphine treatment before versus during the pandemic. Among patients who initiated buprenorphine treatment, treatment retention was better during (versus before) the pandemic. During a public health emergency, incorporating telehealth and prioritizing harm reduction are key strategies to maintain optimal OUD treatment outcomes.

Management of opioid use disorder, opioid withdrawal, and opioid overdose prevention in hospitalized adults: A systematic review of existing guidelines.

BACKGROUND: Hospitalizations related to the consequences of opioid use are rising. National guidelines directing in-hospital opioid use disorder (OUD) management do not exist. OUD treatment guidelines intended for other treatment settings could inform in-hospital OUD management. OBJECTIVE: Evaluate the quality and content of existing guidelines for OUD treatment and management. DATA SOURCES: OVID MEDLINE, PubMed, Ovid PsychINFO, EBSCOhost CINHAL, ERCI Guidelines Trust, websites of relevant societies and advocacy organizations, and selected international search engines. STUDY SELECTION: Guidelines published between January 2010 to June 2020 addressing OUD treatment, opioid withdrawal management, opioid overdose prevention, and care transitions among adults. DATA EXTRACTION: We assessed quality using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. DATA SYNTHESIS: Nineteen guidelines met the selection criteria. Most recommendations were based on observational studies or expert consensus. Guidelines recommended the use of nonstigmatizing language among patients with OUD; to assess patients with unhealthy opioid use for OUD using the Diagnostic Statistical Manual of Diseases-5th Edition criteria; use of methadone or buprenorphine to treat OUD and opioid withdrawal; use of multimodal, nonopioid therapy, and when needed, short-acting opioid analgesics in addition to buprenorphine or methadone, for acute pain management; ensuring linkage to ongoing methadone or buprenorphine treatment; referring patients to psychosocial treatment; and ensuring access to naloxone for opioid overdose reversal. CONCLUSIONS: Included guidelines were informed by studies with various levels of rigor and quality. Future research should systematically study buprenorphine and methadone initiation and titration among people using fentanyl and people with pain, especially during hospitalization.

Reimagining patient-centered care in opioid treatment programs: Lessons from the Bronx during COVID-19.

Opioid treatment programs (OTPs) operate within a rigid set of clinical guidelines and regulations that specify the number of required OTP visits for supervised administration of methadone. To ensure physical distancing in light of COVID-19, the federal government loosened regulations to allow for additional flexibility. As OTP providers in the Bronx, NY, caring for more than 3600 patients in the epicenter of both the overdose and COVID-19 pandemics, we describe how our clinical practice changed with COVID-19. We halted toxicology testing, and to promote physical distancing and prevent interruptions in access to treatment for medications for opioid use disorder (MOUD), we drastically increased unsupervised take-home doses of MOUD. Within two weeks, we reduced the proportion of patients with 5-6 OTP visits per week from 47.2% to 9.4%. To guide treatment decision-making, we shifted focus from toxicology tests to other patient-centered measures, such as engagement in care and patient goals. In the initial three months, our patients experienced six nonfatal overdoses, no fatal overdoses, and 20 deaths attributable to COVID-19. This experience provides an opportunity to re-imagine care in OTPs going forward. We advocate that OTPs rely less on toxicology testing and more on the other patient-centered measures to guide decisions about distribution of take-home doses of MOUD. To minimize financial risk to OTPs and facilitate their transition to a more flexible model of care, we advocate for the reassessment of OTP reimbursement models.

Mcl-1 and FBW7 control a dominant survival pathway underlying HDAC and Bcl-2 inhibitor synergy in squamous cell carcinoma.

Effective targeted therapeutics for squamous cell carcinoma (SCC) are lacking. Here, we uncover Mcl-1 as a dominant and tissue-specific survival factor in SCC, providing a roadmap for a new therapeutic approach. Treatment with the histone deacetylase (HDAC) inhibitor vorinostat regulates Bcl-2 family member expression to disable the Mcl-1 axis and thereby induce apoptosis in SCC cells. Although Mcl-1 dominance renders SCC cells resistant to the BH3-mimetic ABT-737, vorinostat primes them for sensitivity to ABT-737 by shuttling Bim from Mcl-1 to Bcl-2/Bcl-xl, resulting in dramatic synergy for this combination and sustained tumor regression in vivo. Moreover, somatic FBW7 mutation in SCC is associated with stabilized Mcl-1 and high Bim levels, resulting in a poor response to standard chemotherapy but a robust response to HDAC inhibitors and enhanced synergy with the combination vorinostat/ABT-737. Collectively, our findings provide a biochemical rationale and predictive markers for the application of this therapeutic combination in SCC.

PI3K inhibition impairs BRCA1/2 expression and sensitizes BRCA-proficient triple-negative breast cancer to PARP inhibition.

UNLABELLED: PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient-derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal-regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. SIGNIFICANCE: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs.