Provider Perceptions toward Extended-Release Buprenorphine for Treatment of Opioid Use Disorder.

OBJECTIVES: The persistence of the opioid crisis and the proliferation of synthetic fentanyl have heightened the demand for the implementation of novel delivery mechanisms of pharmacotherapy for the treatment of opioid use disorder, including injectable extended-release buprenorphine (buprenorphine-ER). The purpose of this study was to understand provider-level barriers to prescribing buprenorphine in order to facilitate targeted strategies to improve implementation for patients who would benefit from this novel formulation. METHODS: Using an interview template adapted from the Consolidated Framework for Implementation Research (CFIR), we conducted structured focus group interviews with 20 providers in an outpatient addiction clinic across 4 sessions to assess providers' perceptions of buprenorphine-ER. Ninety-four unique comments were identified and deductively coded using standardized CFIR constructs. RESULTS: Providers expressed mixed receptivity and confidence in using buprenorphine-ER. Although providers could identify a number of theoretical advantages to the injectable formulation over sublingual buprenorphine, many expressed reservations about using it due to inexperience, negative patient experiences, uncertainties about patient candidacy, cost, and logistical constraints. CONCLUSIONS: Provider concerns about buprenorphine-ER may limit utilization. Some concerns may be mitigated through improved education, research, and logistical support. Given the putative benefits of buprenorphine-ER, future research should target barriers to implementation, in part based on hypotheses generated by these findings.

Impact of inpatient addiction psychiatry consultation on opioid use disorder outcomes.

BACKGROUND AND OBJECTIVES: Addiction consultation services provide access to specialty addiction care during general hospital admission. This study assessed opioid use disorder (OUD) outcomes associated with addiction consultation. METHODS: Retrospective cohort study of individuals with OUD admitted to an academic medical center between 2018 and 2023. The exposure was addiction consultation. Outcomes included initiating medication for OUD (MOUD), hospital length of stay, before-medically-advised (BMA) discharge, and 30- and 90-day postdischarge acute care utilization. RESULTS: Of 26,766 admissions (10,501 patients) with OUD, 2826 addiction consultations were completed. Consultation cohort was more likely to be young, male, and White than controls. Consultation was associated with greater MOUD initiation (adjusted odds ratio [aOR], 5.07; 95% confidence interval [CI], 4.41-5.82), fewer emergency department visits at 30 (aOR, 0.78; 95% CI, 0.67-0.92) and 90 (aOR, 0.79; 95% CI, 0.69-0.89) days, and fewer hospitalizations at 30 (aOR, 0.65; 95% CI, 0.56 to 0.76) and 90 (aOR, 0.67; 95% CI, 0.59-0.76) days. Additionally, consultation patients were more likely to have a longer hospital stay and leave BMA. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Addiction consultation was associated with increased MOUD initiation and reduced postdischarge acute care utilization. This is the largest study to date showing a significant association between addiction psychiatry consultation and improved OUD outcomes when compared to controls. The observed reduction in postdischarge acute care utilization remains even after adjusting for MOUD initiation. Disparities in access to addiction consultation warrant further study.

Medical and genetic correlates of long-term buprenorphine treatment in the electronic health records.

Despite the benefits associated with longer buprenorphine treatment duration (i.e., >180 days) (BTD) for opioid use disorder (OUD), retention remains poor. Research on the impact of co-occurring psychiatric issues on BTD has yielded mixed results. It is also unknown whether the genetic risk in the form of polygenic scores (PGS) for OUD and other comorbid conditions, including problematic alcohol use (PAU) are associated with BTD. We tested the association between somatic and psychiatric comorbidities and long BTD and determined whether PGS for OUD-related conditions was associated with BTD. The study included 6686 individuals with a buprenorphine prescription that lasted for less than 6 months (short-BTD) and 1282 individuals with a buprenorphine prescription that lasted for at least 6 months (long-BTD). Recorded diagnosis of substance addiction and disorders (Odds Ratio (95% CI) = 22.14 (21.88-22.41), P = 2.8 × 10-116), tobacco use disorder (OR (95% CI) = 23.4 (23.13-23.68), P = 4.5 × 10-111), and bipolar disorder (OR(95% CI) = 9.70 (9.48-9.92), P = 1.3 × 10-91), among others, were associated with longer BTD. The PGS of OUD and several OUD co-morbid conditions were associated with any buprenorphine prescription. A higher PGS for OUD (OR per SD increase in PGS (95%CI) = 1.43(1.16-1.77), P = 0.0009), loneliness (OR(95% CI) = 1.39(1.13-1.72), P = 0.002), problematic alcohol use (OR(95%CI) = 1.47(1.19-1.83), P = 0.0004), and externalizing disorders (OR(95%CI) = 1.52(1.23 to 1.89), P = 0.0001) was significantly associated with long-BTD. Associations between BTD and the PGS of depression, chronic pain, nicotine dependence, cannabis use disorder, and bipolar disorder did not survive correction for multiple testing. Longer BTD is associated with diagnoses of psychiatric and somatic conditions in the EHR, as is the genetic score for OUD, loneliness, problematic alcohol use, and externalizing disorders.

Autism-Associated Variant in the SLC6A3 Gene Alters the Oral Microbiome and Metabolism in a Murine Model.

Background: Altered dopamine (DA) signaling has been associated with autism spectrum disorder (ASD), a neurodevelopmental condition estimated to impact 1 in 54 children in the United States. There is growing evidence for alterations in both gastrointestinal function and oral microbiome composition in ASD. Recent work suggests that rare variants of the SLC6A3 gene encoding the DA transporter (DAT) identified in individuals with ASD result in structural and functional changes to the DAT. One such recently identified de novo mutation is a threonine to methionine substitution at position 356 of the DAT (DAT T356M). The DAT T356M variant is associated with ASD-like phenotypes in mice homozygous for the mutation (DAT T356M+/+), including social deficits, hyperactivity, and impaired DA signaling. Here, we determine the impact of this altered DA signaling as it relates to altered oral microbiota, and metabolic and gastrointestinal dysfunction. Methods: In the DAT T356M+/+ mouse, we determine the oral microbiota composition, metabolic function, and gastrointestinal (GI) function. We examined oral microbiota by 16S RNA sequencing. We measured metabolic function by examining glucose tolerance and we probed gastrointestinal parameters by measuring fecal dimensions and weight. Results: In the DAT T356M+/+ mouse, we evaluate how altered DA signaling relates to metabolic dysfunction and altered oral microbiota. We demonstrate that male DAT T356M+/+ mice weigh less (Wild type (WT) = 26.48 ± 0.6405 g, DAT T356M+/+ = 24.14 ± 0.4083 g) and have decreased body fat (WT = 14.89 ± 0.6206%, DAT T356M+/+ = 12.72 ± 0.4160%). These mice display improved glucose handling (WT = 32.60 ± 0.3298 kcal/g, DAT T356M+/+ = 36.97 ± 0.4910 kcal/g), and an altered oral microbiota. We found a significant decrease in Fusobacterium abundance. The abundance of Fusobacterium was associated with improved glucose handling and decreased body fat. Conclusions: Our findings provide new insights into how DAT dysfunction may alter gastrointestinal function, composition of the oral microbiota, and metabolism. Our data suggest that impaired DA signaling in ASD is associated with a number of metabolic and gastrointestinal changes which are common in individuals with ASD.

Bile diversion, a bariatric surgery, and bile acid signaling reduce central cocaine reward.

The gut-to-brain axis exhibits significant control over motivated behavior. However, mechanisms supporting this communication are poorly understood. We reveal that a gut-based bariatric surgery chronically elevates systemic bile acids and attenuates cocaine-induced elevations in accumbal dopamine. Notably, this surgery reduces reward-related behavior and psychomotor sensitization to cocaine. Utilizing a knockout mouse model, we have determined that a main mediator of these post-operative effects is the Takeda G protein-coupled bile acid receptor (TGR5). Viral restoration of TGR5 in the nucleus accumbens of TGR5 knockout animals is sufficient to restore cocaine reward, centrally localizing this TGR5-mediated modulation. These findings define TGR5 and bile acid signaling as pharmacological targets for the treatment of cocaine abuse and reveal a novel mechanism of gut-to-brain communication.

Rare Undiagnosed Primary Amyloidosis Unmasked During Surgical Treatment of Primary Hyperparathyroidism: A Case Report.

Primary amyloidosis (PA) is a protein deposition disorder that presents with localized or multisystemic disease. The incidence is low in the general public, ranging from three to eight cases per million, and with nonspecific presenting symptoms typically occurring later in life. Due to late presentation, substantial and irreversible damage has usually already occurred by the time of the diagnosis. However, if inadvertent diagnosis occurs before irreversible damage has taken place, as it did in the following case, some patients may benefit from the disease-arresting treatment. A 70-year-old female with a history of obstructive sleep apnea, hypertension, and arthritis presented with worsening dysphagia and biochemically confirmed primary hyperparathyroidism (PHPT). Further workup demonstrated multinodular goiter with compressive symptoms and substernal extension, osteopenia, and discrepant parathyroid localization on imaging. Intraoperatively, markedly difficult dissection and obliteration of tissue planes were encountered. Extensive, diffuse amyloid deposition in both the normal and pathologic parathyroid glands and thyroid tissue on surgical pathology leads to subsequent fibril typing by mass spectrometry and leads to the diagnostic of primary amyloid light-chain (AL) amyloidosis (PA; λ light chains). Subsequent workup for the underlying cause of the amyloid deposition revealed an immunoglobulin A monoclonal gammopathy of unknown significance. The surgical treatment of PHPT and compressive thyroid nodule unmasked an undiagnosed PA, allowing for early workup and monitoring of the progression of amyloidosis. The temporal comorbidity of PHPT and PA raises an interesting and, as yet, unanswered question regarding the pathophysiologic association between the two conditions.

The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice.

Glucagon-like peptide 1 (GLP-1) analogues are used for the treatment of type 2 diabetes. The ability of the GLP-1 system to decrease food intake in rodents has been well described and parallels results from clinical trials. GLP-1 receptors are expressed in the brain, including within the ventral tegmental area (VTA) and the nucleus accumbens (NAc). Dopaminergic neurons in the VTA project to the NAc, and these neurons play a pivotal role in the rewarding effects of drugs of abuse. Based on the anatomical distribution of GLP-1 receptors in the brain and the well-established effects of GLP-1 on food reward, we decided to investigate the effect of the GLP-1 analogue exendin-4 on cocaine- and dopamine D1-receptor agonist-induced hyperlocomotion, on acute and chronic cocaine self-administration, on cocaine-induced striatal dopamine release in mice and on cocaine-induced c-fos activation. Here, we report that GLP-1 receptor stimulation reduces acute and chronic cocaine self-administration and attenuates cocaine-induced hyperlocomotion. In addition, we show that peripheral administration of exendin-4 reduces cocaine-induced elevation of striatal dopamine levels and striatal c-fos expression implicating central GLP-1 receptors in these responses. The present results demonstrate that the GLP-1 system modulates cocaine's effects on behavior and dopamine homeostasis, indicating that the GLP-1 receptor may be a novel target for the pharmacological treatment of drug addiction.

Striatal dopamine homeostasis is altered in mice following Roux-en-Y gastric bypass surgery.

Roux-en-Y gastric bypass (RYGB) is an effective treatment for obesity. Importantly, weight loss following RYGB is thought to result in part from changes in brain-mediated regulation of appetite and food intake. Dopamine (DA) within the dorsal striatum plays an important role in feeding behavior; we therefore hypothesized that RYGB alters DA homeostasis in this subcortical region. In the current study, obese RYGB-operated mice consumed significantly less of a high-fat diet, weighed less by the end of the study, and exhibited lower adiposity than obese sham-operated mice. Interestingly, both RYGB and caloric restriction (pair feeding) resulted in elevated DA and reduced norepinephrine (NE) tissue levels compared with ad libitum fed sham animals. Consequently, the ratio of NE to DA, a measure of DA turnover, was significantly reduced in both of these groups. The RYGB mice additionally exhibited a significant increase in phosphorylation of tyrosine hydroxylase at position Ser31, a key regulatory site of DA synthesis. This increase was associated with augmented expression of extracellular-signal-regulated kinases ERK1/2, the kinase targeting Ser31. Additionally, RYGB has been shown in animal models and humans to improve insulin sensitivity and glycemic control. Curiously, we noted a significant increase in the expression of insulin receptor-ß in RYGB animals in striatum (a glucosensing brain region) compared to sham ad libitum fed mice. These data demonstrate that RYGB surgery is associated with altered monoamine homeostasis at the level of the dorsal striatum, thus providing a critical foundation for future studies exploring central mechanisms of weight loss in RYGB.

Moving beyond energy homeostasis: new roles for glucagon-like peptide-1 in food and drug reward.

Glucagon-like peptide-1 (GLP-1), a hormone and neuropeptide, is known to regulate energy homeostasis in part through an established central role in controlling food intake. Historically this central role has largely been attributed to GLP-1 receptor signaling in the brainstem and hypothalamus. However, emerging data indicate that GLP-1 also contributes to non-homeostatic regulation of food reward and motivated behaviors in brain reward centers, including the ventral tegmental area and nucleus accumbens. The hypothesis that GLP-1 signaling modulates reward circuitry has provided the impetus for studies demonstrating that GLP-1 attenuates reward for psychostimulants and alcohol. Here, we examine current evidence for GLP-1-mediated regulation of food and drug reward and use these findings to hypothesize mechanisms of action within brain reward centers.