Predictors of Linkage to an Opioid Treatment Program and Methadone Treatment Retention following Hospital Discharge in a Safety-Net Setting.

Background: Methadone is increasingly initiated during hospitalization for the treatment of opioid use disorder (OUD). However, little is known about which factors are associated with linkage to opioid treatment programs (OTP) and retention in methadone maintenance therapy (MMT) following hospital discharge. Materials & Methods: This is a retrospective study of adults with OUD hospitalized in an urban, safety-net hospital referred by inpatient clinicians to an onsite OTP for post-discharge MMT follow-up from October 2017 to July 2019. We used multivariable modified Poisson regression models to generate adjusted risk ratios (aRR) for associations of sociodemographic factors, mental health disorders, alcohol use, stimulant use, and prior care engagement with post-discharge OTP enrollment and MMT retention at 30 and 90-days. Results: Of the 125 patients referred, 40% enrolled in the OTP post-discharge. Among enrollees, 74% were retained at 30-days and 52% were retained at 90-days. Patients with co-occurring stimulant use were less likely to enroll in the OTP post-discharge compared to those without stimulant use (aRR 0.65, 95% CI 0.44-0.97). We found no associations with 30-day MMT retention, but patients who reported stable housing were more likely to be retained in MMT at 90-days compared to those without stable housing (aRR 1.66, 95% CI 1.03-2.66). Conclusion: Our findings suggest that hospitalized patients with co-occurring stimulant use may need additional support to optimize post-discharge OTP linkage. Stable housing may improve retention in MMT. Additional research is needed to identify trends in MMT engagement among those referred from the acute hospital setting.

"I wanted something that was more flexible": A qualitative study of patient preferences on choosing buprenorphine over methadone in a large, safety-net hospital opioid treatment program.

Background: Buprenorphine availability for the treatment of opioid use disorders (OUD) has expanded in the United States. Programs that previously offered only methadone treatment to patients with OUD now offer an equal choice between buprenorphine and methadone at the same location, yet little is known about patient preferences for buprenorphine over methadone in these settings. We sought to understand the decision-making factors and motivations underlying why patients opt for buprenorphine over methadone for the treatment of OUD when both are offered in a safety-net hospital-based opioid treatment program (OTP). Methods: We conducted semi-structured, qualitative interviews with patients receiving buprenorphine, in which we asked about substance use and treatment history, reasons for choosing buprenorphine, advantages, and disadvantages of choosing buprenorphine, and what they would like to change in their treatment experience. Results: Participants had varied exposure to buprenorphine prior to their current treatment, ranging from none to years of experience in multiple settings. Increased flexibility with take-home doses was a widespread motivation for choosing buprenorphine over methadone. Participants described decreased sedation and greater effectiveness in preventing opioid use compared to methadone as advantages during their treatment with buprenorphine. Difficulty with the transition to buprenorphine was a noteworthy challenge for many. Conclusions: Overall, patients maintained on buprenorphine at an urban safety-net hospital OTP viewed their treatment favorably compared to methadone. Increased autonomy in light of federal regulation differences and an improved physical profile were significant decision-making factors, although the number of patients choosing buprenorphine at the OTP remained low. Targeted patient education about induction and focus on improving structural barriers such as dosing efficiency may enhance patient experiences.

Dimeric isoxazolyl-1,4-dihydropyridines have enhanced binding at the multi-drug resistance transporter.

A series of dimeric isoxazolyl-1,4-dihydropyridines (IDHPs) were prepared by click chemistry and examined for their ability to bind the multi-drug resistance transporter (MDR-1), a member of the ATP-binding cassette superfamily (ABC). Eight compounds in the present study exhibited single digit micromolar binding to this efflux transporter. One monomeric IDHP m-Br-1c, possessed submicromolar binding of 510nM at MDR-1. Three of the dimeric IDHPs possessed <1.5µM activity, and 4b and 4c were observed to have superior binding selectivity compared to their corresponding monomers verses the voltage gated calcium channel (VGCC). The dimer with the best combination of activity and selectivity for MDR-1 was analog 4c containing an m-Br phenyl moiety in the 3-position of the isoxazole, and a tether with five ethyleneoxy units, referred to herein as Isoxaquidar. Two important controls, mono-triazole 5 and pyridine 6, also were examined, indicating that the triazole - incorporated as part of the click assembly as a spacer - contributes to MDR-1 binding. Compounds were also assayed at the allosteric site of the mGluR5 receptor, as a GPCR 7TM control, indicating that the p-Br IDHPs 4d, 4e and 4f with tethers of from n=2 to 5 ethylenedioxy units, had sub-micromolar affinities with 4d being the most efficacious at 193nM at mGluR5. The results are interpreted using a docking study using a human ABC as our current working hypothesis, and suggest that the distinct SARs emerging for these three divergent classes of biomolecular targets may be tunable, and amenable to the development of further selectivity.

Predictors of higher-risk chronic opioid prescriptions in an academic primary care setting.

BACKGROUND: Patients with chronic noncancer pain treated with higher doses of opioids or concurrent substance use are at increased risk of adverse events. Although several national guidelines recommend maximum dosing thresholds and urine drug testing, adherence to these guidelines is inconsistent. METHODS: To identify predictors of higher-risk opioid prescriptions in 2 academic primary care clinics, the authors developed a retrospective cohort of 842 patients who were prescribed ≥5 opioid prescriptions for noncancer pain between March 2012 and March 2013. The authors evaluated odds of higher-dose opioid prescriptions and urine drug testing using multivariate logistic models. RESULTS: Among study subjects, 47% received prescriptions for the equivalent of ≥50 mg morphine per day. After adjustment for confounders, patients with a resident primary care provider were less likely to receive higher-dose prescriptions compared with faculty providers (odds ratio = 0.66, 95% confidence interval [CI]: 0.46-0.94), whereas patients with a nonlocal home address were more likely to be prescribed higher doses (odds ratio = 2.1, 95% CI: 1.5-2.9). Hispanic, Asian, and older patients were also less likely to be prescribed higher doses. Urine drug testing was not regularly completed (35% over 2 years), but odds of testing were higher for patients who self-identified as black, had resident primary care providers, lived locally, or were prescribed higher opioid doses. CONCLUSIONS: In this academic clinical setting, patients with a resident primary care provider are less likely to receive higher-risk opioid prescriptions, as are Hispanic, Asian, and older patients. Black patients complete urine drug tests more frequently independent of other patient and provider characteristics. Additional studies are needed to assess why patients who travel larger distances to their primary care clinic are prescribed higher doses of opioids for chronic noncancer pain.

Teaching residents screening, brief intervention, and referral to treatment (SBIRT) skills for alcohol use: Using chart-stimulated recall to assess curricular impact.

BACKGROUND: Screening, brief intervention, and referral to treatment (SBIRT) improves identification and intervention for patients at risk for developing an alcohol use disorder (AUD). Residency curriculum is designed to teach SBIRT skills, but resources are needed to promote skill implementation. The electronic health record (EHR) can facilitate implementation through integration of decision-support tools. The authors developed electronic tools to facilitate documentation of alcohol assessment and brief intervention and to reinforce skills from an SBIRT curriculum. This prospective cohort study assessed primary care internal medicine residents' use of SBIRT skills and EHR tools in practice using chart-stimulated recall (CSR). METHODS: Postgraduate year 2 and 3 residents received a 5-hour SBIRT curriculum with skills practice and instruction on SBIRT electronic tools. Participants were then given a list of their patients seen in a 1-year period who were drinking at/above the recommended limit. Trainees selected 3 patients to review with a faculty member in a CSR. Faculty used a 24-item chart checklist to assess application of SBIRT skills and electronic tool use and met with residents to complete a CSR interview. CSR interview notes were analyzed qualitatively to understand application of SBIRT skills and EHR tool use. RESULTS: Eighteen of 20 residents participated in the CSR, and 5 faculty reviewed 46 patient charts. Residents documented alcohol use (84.2% of charts) and assessment of quantity/frequency of use (71.0%) but were less likely to document assessment for an AUD (34%), an appropriate plan (50.0%), or follow-up (55%). Few residents used EHR tools. Residents reported barriers in addressing alcohol use, including lack of knowledge, patient barriers, and time constraints. CONCLUSIONS: More intensive training in SBIRT with opportunities for practice and feedback may be necessary for residents to consistently apply SBIRT skills in practice. EHR tools need to be better integrated into the clinic workflow in order to be useful.

Fluorescent probes of the isoxazole-dihydropyridine scaffold: MDR-1 binding and homology model.

Isoxazole-1,4-dihydropyridines (IDHPs) were tethered to fluorescent moieties using double activation via a lanthanide assisted Weinreb amidation. IDHP-fluorophore conjugate 3c exhibits the highest binding to date for IDHPs at the multidrug-resistance transporter (MDR-1), and IDHP-fluorophore conjugates 3c and 7 distribute selectively in SH-SY5Y cells. A homology model for IDHP binding at MDR-1 is presented which represents our current working hypothesis.

Diethyl 4-(biphenyl-4-yl)-2,6-dimethyl-1,4-di-hydro-pyridine-3,5-di-carboxyl-ate.

The title compound, C25H27NO4, has a flattened di-hydro-pyridine ring. The benzene and phenyl rings are synclinal to one another, forming a dihedral angle of 49.82 (8)°; the axis of the biphenyl rings makes an 81.05 (9)° angle to the plane of the di-hydro-pyridine ring. In the crystal, N-H⋯O hydrogen bonds link the mol-ecules into chain motifs running along the a-axis direction. The chains are cross-linked by C-H⋯O inter-actions, forming sheet motifs running slightly off the (110) plane, together with an intermolecular interaction between head-to tail biphenyl groups, thus making the whole crystal packing a three-dimensional network. Intra-molecular C-H⋯O hydrogen bonds are also observed.

"Get in and get out, get on with life": Patient and provider perspectives on methadone van implementation for opioid use disorder treatment.

BACKGROUND: Expanding access to opioid use disorder (OUD) treatment, including methadone, is imperative to address the US overdose crisis. In June 2021, the Drug Enforcement Administration announced new regulations allowing all opioid treatment programs (OTPs) to deploy mobile medication units, or methadone vans, to dispense OUD medication treatment outside of clinic walls, ending a 13-year moratorium. We conducted a qualitative study evaluating one opioid treatment program's experience, including benefits and challenges with implementing a methadone van, to inform future policy and clinical practice. METHODS: We recruited staff and patients receiving OUD medication treatment from an OTP in San Francisco, CA. The OTP had one operating van before March 2020 and began operating an additional van in response to COVID-19-related efforts to de-populate clinic settings. We interviewed 10 providers and 20 patients from August to November 2020. We transcribed, coded, and analyzed all interviews using modified grounded theory methodologies. RESULTS: Both patients and providers perceived significant benefits with receiving OUD medications using methadone vans. Patients preferred dosing at the van over the clinic because they were able to "get in and out" faster. Both staff and patients appreciated being able to use phone counseling to connect with counselors which helped reduce in-person visits and streamline workflows. Providers also noted van implementation challenges, including daily van set up, urine drug testing, and delivering counseling to patients who lacked phones. CONCLUSIONS: Eased restrictions on methadone van implementation represent a new strategy for expanding OUD treatment access. In our qualitative study, patients and staff were satisfied with methadone van implementation, though the OTP still faced implementation challenges. Audio-only counseling and other workflow solutions helped facilitate implementation, and several policy considerations like maintaining audio-only counseling flexibilities are key to ensuring future van success. Methadone vans offer the potential to expand treatment uptake, while prioritizing patient-centered care.

4-Isoxazolyl-1,4-dihydropyridines exhibit binding at the multidrug-resistance transporter.

The 4-isoxazolyl-dihydropyridines (IDHPs) exhibit inhibition of the multidrug-resistance transporter (MDR-1), and exhibit an SAR distinct from their activity at voltage gated calcium channels (VGCC). Among the four most active IDHPs, three were branched at C-5 of the isoxazole, including the most active analog, 1k.

Improved synthesis of 3-aryl isoxazoles containing fused aromatic rings.

A critical comparison of methods to prepare sterically hindered 3-aryl isoxazoles containing fused aromatic rings using the nitrile oxide cycloaddition (NOC) reveal that modification of the method of Bode, Hachisu, Matsuura, and Suzuki (BHMS), utilizing either triethylamine as base or sodium enolates of the diketone, ketoester, and ketoamide dipolarophiles, respectively, was the method of choice for this transformation.

Adapting methadone inductions to the fentanyl era.

Since 2013, fentanyl and fentanyl analogs, which are significantly more potent than heroin, have been increasingly prevalent in the opioid drug supply. A need exists to adapt methadone dosing from opioid treatment programs (OTPs) in this era. Current methadone protocols at many clinics in the United States are based on expert consensus documents that were created prior to the introduction of fentanyl into the drug supply and are relatively conservative. To date, most OTP reform efforts have focused on relaxation of regulations for take-homes and have not addressed the need to adapt methadone induction schedules to be more rapid in the fentanyl era, as allowed by current regulations. Written by OTP and inpatient consult service addiction medicine physicians with expertise in OUD treatment from across the United States, the aims of the perspective piece are to: 1) highlight the need to improve OTP care by adapting methadone inductions to the fentanyl era, 2) cite emerging evidence for and examples of experiences of OTPs using more aggressive methadone inductions, and 3) call for research and updated guidelines on safety and best practices for methadone induction.

Synthesis, crystal structures, and Hirshfeld analysis of three hexa-hydro-quinoline derivatives.

Three hexa-hydro-quinoline derivatives were synthesized and crystallized in an effort to study the structure-activity relationships of these calcium-channel antagonists. The derivatives are ethyl 4-(2-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C22H27NO4, (I), ethyl 4-(4-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-ox-yl-ate, C22H27NO4, (II), and ethyl 4-(3,4-di-hydroxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C21H24NO5, (III). In these hexa-hydro-quinoline derivatives, common structural features such as a flat-boat conformation of the 1,4-di-hydro-pyridine (1,4-DHP) ring, an envelope conformation of the fused cyclo-hexa-none ring, and a substituted phenyl group at the pseudo-axial position are retained. Hydrogen bonds are the main contributors to the packing of the mol-ecules in these crystals.

Time to ACT: launching an Addiction Care Team (ACT) in an urban safety-net health system.

Across the USA, morbidity and mortality from substance use are rising as reflected by increases in acute care hospitalisations for substance use complications and substance-related deaths. Patients with substance use disorders (SUD) have long and costly hospitalisations and higher readmission rates compared to those without SUD. Hospitalisation presents an opportunity to diagnose and treat individuals with SUD and connect them to ongoing care. However, SUD care often remains unaddressed by hospital providers due to lack of a systems approach and addiction medicine knowledge, and is compounded by stigma. We present a blueprint to launching an interprofessional inpatient addiction care team embedded in the hospital medicine division of an urban, safety-net integrated health system. We describe key factors for successful implementation including: (1) demonstrating the scope and impact of SUD in our health system via a needs assessment; (2) aligning improvement areas with health system leadership priorities; (3) involving executive leadership to create goal and initiative alignment; and (4) obtaining seed funding for a pilot programme from our Medicaid health plan partner. We also present challenges and lessons learnt.

Synthesis and crystal structures of a bis-(3-hy-droxy-cyclo-hex-2-en-1-one) and two hexa-hydro-quinoline derivatives.

The title compound I, 2,2'-[(2-nitro-phen-yl)methyl-ene]bis-(3-hy-droxy-5,5-di-methyl-cyclo-hex-2-enone), C23H27NO6, features a 1,3-ketone-enol conformation which is stabilized by two intra-molecular hydrogen bonds. The most prominent inter-molecular inter-actions in compound I are C-H⋯O hydrogen bonds, which link mol-ecules into a two-dimensional network parallel to the (001) plane and a chain perpendicular to (11). Both title compounds II, ethyl 4-(4-hy-droxy-3,5-di-meth-oxy-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carb-oxyl-ate, C23H29NO6, and III, ethyl 4-(anthracen-9-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, C29H29NO3, share the same structural features, such as a shallow boat conformation of the di-hydro-pyridine group and an orthogonal aryl group attached to the di-hydro-pyridine. Inter-molecular N-H⋯O bonding is present in the crystal packing of both compound II and III.

Crystal structure of ethyl 4-[4-(di-methyl-amino)-phen-yl]-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate.

In the title racemic compound, ethyl 4-(4-di-methyl-amino-phen-yl)-2,7,7-trimethyl-5-oxo-1,4,5,6,7,8-hexa-hydro-quinoline-3-carboxyl-ate, the common structural features in this type of compound, such as the flat-boat conformation of the 1,4-di-hydro-pyridine (1,4-DHP) ring, the envelope conformation of the fused cyclo-hexa-none, and the substituted phenyl ring at the pseudo-axial position and orthogonal to the 1,4-DHP ring, are present. In the crystal, mol-ecules are linked via N-H⋯O and C-H⋯O hydrogen bonds, forming layers parallel to the (10) plane.

Cultural Adaptation of Screening, Brief Intervention and Referral to Treatment Using Motivational Interviewing.

This clinical case presentation and discussion illustrates a culturally adapted alcohol and drug use intervention using the Screening, Brief Intervention, and Referral to Treatment (SBIRT) approach, incorporating motivational interviewing skills. This case conference serves to complement the accompanying review article on SBIRT with diverse cultural groups, placing information from the review in the context of a typical clinical setting. In this example, SBIRT is provided in a primary care clinic to a Latino patient who reports hazardous drinking, depression, chronic pain and use of prescription opioids.

4-isoxazolyl-1,4-dihydropyridines: a tale of two scaffolds.

The association of the isoxazole and dihydropyridine (DHP) ring systems fused at the 4'-isoxazolyl- to the 4-position of the DHP has produced a combination scaffold, the isoxazolyl-DHPs (IDHPs) with unique conformational characteristics. The IDHPs are useful in probing biological activity, as exemplified by our efforts in the fields of voltage gated calcium channel (VGCC) antagonists and inhibitors of the multi-drug resistance (MDR) transporter. A strategically placed methyl group produced a signifcant change at the VGCC, with (R)-(+)-1-phenyl-prop-2-yl (3.7 nM) > phenethyl (22.9 nM) > (S)-(-)-1-phenyl-prop-2-yl (210 nM), a eudismic ratio of 56.7. Branching at the C-5 of the isoxazole produced a 25% increase in MDR binding, and replacing the DHP C-3 ester with a functionalized amide also gave a dramatic increase in binding affinity. Opportunities for combined scaffolds - including examples containing IDHPs - are waiting to be discovered: because new biology is driven by new chemistry.