The Impact of Primary Care Clinic and Family Physician Continuity on Patient Health Outcomes: A Retrospective Analysis From Alberta, Canada.

PURPOSE: Continuity of care is broadly associated with better patient health outcomes. The relative contributions of continuity with an individual physician and with a practice, however, have not generally been distinguished. This retrospective observational study examined the impact of continuity of care for patients seen at their main clinic but by different family physicians. METHODS: We analyzed linked health administrative data from 2015-2018 from Alberta, Canada to explore the association of physician and clinic continuity with rates of emergency department (ED) visits and hospitalizations across varying levels of patient complexity. Physician continuity was calculated using the known provider of care index and clinic continuity with an analogous measure. We developed zero-inflated negative binomial models to assess the association of each with all-cause ED visits and hospitalizations. RESULTS: High physician continuity was associated with lower ED use across all levels of patient complexity and with fewer hospitalizations for highly complex patients. Broadly, no (0%) clinic continuity was associated with increased use and complete (100%) clinic continuity with decreased use, with the largest effect seen for the most complex patients. Levels of clinic continuity between 1% and 50% were generally associated with slightly higher use, and levels of 51% to 99% with slightly lower use. CONCLUSIONS: The best health care outcomes (measured by ED visits and hospitalizations) are associated with consistently seeing one's own primary family physician or seeing a clinic partner when that physician is unavailable. The effect of partial clinic continuity appears complex and requires additional research. These results provide some reassurance for part-time and shared practices, and guidance for primary care workforce policy makers.

"Navigating chaos": Urban, Rural, and Remote Patient Experiences in Accessing Healthcare with Indigenous and Non-Indigenous Perspectives of Living with Chronic Low Back Pain.

Background: Healthcare access for chronic low back pain is complex and should consider not only the health system, but patient care seeking experiences as well. People who live in rural and remote communities and/or identify as being Indigenous may often encounter additional barriers to accessing care for chronic low back pain; thus, these contexts must be considered to fully understand barriers and facilitators. Aims: The aim of this study was to understand care-seeking experiences of people living with chronic back pain in Saskatchewan and determine unique experiences facing urban, rural, remote, and/or Indigenous peoples. Methods: Thirty-three participants with chronic low back pain completed a preliminary survey followed by individual semistructured interviews. Participants were categorized as urban, rural, or remote including Indigenous status. A qualitative interpretive research approach with inductive thematic analysis was employed. Results: Three overarching themes were identified with the following subthemes: (1) healthcare access challenges: challenges to accessing care, challenges within the health system, and challenges leading to self-directed management/coping strategies; (2) healthcare access facilitators: funded care, participant education and knowledge, patient-provider communication, and care closer to home; and (3) participant recommendations for improved care provision: coordination of care, integrative and holistic care, and patient-centered care and support. Rural and remote participants highlighted travel as a main barrier. Indigenous participant experiences emphasized communication with healthcare providers and past experiences influencing desire to access care. Conclusion: Participants identified a range of challenges and facilitators as well as recommendations for improving access to care for chronic low back pain, with unique barriers for rural, remote, and Indigenous participants.

Contexte: L'accès aux soins de santé pour la lombalgie chronique est complexe et devrait tenir compte non seulement du système de santé, mais aussi des expériences de recherche de soins des patients. Les personnes vivant dans des communautés rurales et éloignées et/ou qui s'identifient comme autochtones font souvent face à des obstacles supplémentaires pour accéder aux soins pour la lombalgie chronique; il faut donc tenir compte de ces contextes pour bien comprendre les obstacles et les facilitateurs.Objectifs: L'objectif de cette étude était de comprendre les expériences de recherche de soins des personnes vivant avec une lombalgie chronique en Saskatchewan et de déterminer les expériences uniques d'accès aux soins auxquelles sont confrontées les personnes vivant en milieu urbain, rural, éloigné et/ou ayant un statut d'autochtone.Méthodes: Trente-trois participants souffrant de lombalgie chronique ont répondu à un questionnaire préliminaire suivi d'entretiens individuels semi-structurés. Les participants ont été catégorisés comme vivant en milieu urbain, rural, éloigné, incluant ceux ayant un statut d'autochtone. Une approche de recherche qualitative interprétative avec une analyse thématique inductive a été utilisée.Résultats: Trois thèmes principaux ont été répertoriés avec les sous-thèmes suivants : (1) difficultés d'accès aux soins de santé : difficultés pour accéder aux soins, difficultés au sein du système de santé et difficultés conduisant à des stratégies de gestion et d'adaptation autonomes; (2) facilitateurs de l'accès aux soins de santé : financement des soins, éducation et connaissances des participants, communication entre le patient et le prestataire de soins et proximité des soins par rapport au domicile et (3) recommandations des participants pour l'amélioration de la prestation des soins : la coordination des soins, les soins intégrés et holistiques, les soins et le soutien centrés sur le patient. Les participants des régions rurales et éloignées ont souligné que les déplacements constituaient un obstacle majeur. Les expériences des participants autochtones ont mis l'accent sur la communication avec les prestataires de soins de santé et les expériences passées qui influencent le désir d'accéder aux soins.Conclusion: Les participants ont répertorié un ensemble de difficultés, de facilitateurs et de recommandations pour améliorer l'accès aux soins pour les lombalgies chroniques, qui présente des obstacles uniques pour les participants vivant en milieu rural et éloigné et les participants autochtones.

Family physician count and service provision in Ontario and Alberta between 2005/06 and 2017/18: a cross-sectional study.

BACKGROUND: Five million Canadians lack a family doctor or primary care team. Our goal was to examine trends over time in family physician workforce and service provision in Ontario and Alberta, with a view to informing policy discussions on primary care supply and delivery of services. METHODS: We used cross-sectional analyses in Ontario and Alberta for 2005/06, 2012/13 and 2017/18 to examine family physician provision of service days by provider demographic characteristics and geographic location. A service day was defined as 10 or more clinic visits worth $20 or more on the same calendar day. We included all active family physicians who had evidence of billing in each fiscal year analyzed. RESULTS: From 2005/06 to 2017/18, the number of family physicians increased by 35.3% in Ontario and 48.7% in Alberta; however, annual average service days per physician declined by 10.6% in Ontario and 5.9% in Alberta. The average daily patient volume remained stable in Ontario and declined in Alberta, and services per population kept pace modestly with population growth in both provinces. Rural areas had the smallest increases in physician counts and largest declines in average annual service days per physician. Physicians in both provinces who had graduated from medical school at least 30 years earlier accounted for more than one-third of the workforce in 2017/18. INTERPRETATION: Ontario and Alberta experienced rapid growth in the number of family physicians, with the largest increases among those in late career and the lowest increases in rural areas. The decline in service provision among physicians overall and in subgroups in both provinces highlights the importance of measuring activity to inform workforce planning.

Healthcare Access Challenges and Facilitators for Back Pain Across the Rural-Urban Continuum in Saskatchewan, Canada: Cross-Sectional Results From a Provincial-Wide Telephone Survey.

Background: Chronic back pain is a common musculoskeletal disorder, disproportionately affecting rural and Indigenous people. Saskatchewan has a relatively high proportion of rural and Indigenous residents; therefore, understanding barriers and facilitators to accessing healthcare are needed to improve healthcare service delivery. Methods: A provincial-wide telephone survey explored experiences and perceived healthcare access barriers and facilitators among 384 Saskatchewan residents who experienced chronic low back pain. Chi-squared tests were performed to determine if people who lived in urban versus rural areas differed in the proportion who had accessed services from various healthcare practitioners. T-test and Mann-Whitney U analyses were conducted to determine differences between urban and rural, and Indigenous and non-Indigenous respondents. Results: Of 384 residents surveyed, 234 (60.9%) reported living in a rural location; 21 (5.5%) identified as Indigenous. Wait times (47%), cost (40%), travel (39%), and not knowing how to seek help (37%) were the most common barriers for Saskatchewan residents seeking care, with travel being the only barrier that was significantly different between rural and urban respondents (P ⩽ .001). Not knowing where to go to access care or what would help their low back pain (P = .03), lack of cultural sensitivity (P = .007), and comfort discussing problems with health care professionals (P = .26) were greater barriers for Indigenous than non-Indigenous participants. Top facilitators (>50% of respondents) included publicly funded healthcare, locally accessible healthcare services, and having supportive healthcare providers who facilitate referral to appropriate care, with urban respondents considering the latter 2 as greater facilitators than rural respondents. Telehealth or virtual care (P = .013) and having healthcare options nearby in their community (P = .045) were greater facilitators among Indigenous participants compared to non-Indigenous respondents. Conclusions: Rural, urban, Indigenous, and non-Indigenous people report overlapping and unique barriers and facilitators to accessing care for chronic low back pain. Understanding perceived access experiences will assist in developing more effective care models for specific communities or regions.

Magnetic resonance imaging detects white adipose tissue beiging in mice following PDE10A inhibitor treatment.

Weight gain is a common harmful side effect of atypical antipsychotics used for schizophrenia treatment. Conversely, treatment with the novel phosphodiesterase-10A (PDE10A) inhibitor MK-8189 in clinical trials led to significant weight reduction, especially in patients with obesity. This study aimed to understand and describe the mechanism underlying this observation, which is essential to guide clinical decisions. We hypothesized that PDE10A inhibition causes beiging of white adipose tissue (WAT), leading to weight loss. Magnetic resonance imaging (MRI) methods were developed, validated, and applied in a diet-induced obesity mouse model treated with a PDE10A inhibitor THPP-6 or vehicle for measurement of fat content and vascularization of adipose tissue. Treated mice showed significantly lower fat fraction in white and brown adipose tissue, and increased perfusion and vascular density in WAT versus vehicle, confirming the hypothesis, and matching the effect of CL-316,243, a compound known to cause adipose tissue beiging. The in vivo findings were validated by qPCR revealing upregulation of Ucp1 and Pcg1-α genes, known markers of WAT beiging, and angiogenesis marker VegfA in the THPP-6 group. This work provides a detailed understanding of the mechanism of action of PDE10A inhibitor treatment on adipose tissue and body weight and will be valuable to guide both the use of MK-8189 in schizophrenia and the potential application of the target for weight loss indication.

Experiences of Health Care Access Challenges for Back Pain Care Across the Rural-Urban Continuum in Canada: Protocol for Cross-sectional Research.

BACKGROUND: Back pain is common and costly, with negative impacts on both individuals and the health care system. Rural, remote, and Indigenous populations are at greater risk of experiencing back pain compared to urban and non-Indigenous populations. Potential barriers to health care access among Canadians with chronic back pain (CBP) have been identified; however, no study has used lived experiences of people with CBP to drive the selection, analysis, and interpretation of variables most meaningful to patients. OBJECTIVE: The aims of this study are to (1) engage with rural, remote, and urban Indigenous and non-Indigenous patients, health care providers, and health system decision makers to explore lived experiences among people with CBP in Saskatchewan, Canada; (2) cocreate meaningful indicators of CBP care access and effectiveness; and (3) identify program and policy recommendations to overcome access barriers to CBP care. METHODS: In phase 1, one-on-one interviews with 30 people with current or past CBP and 10 health care providers residing or practicing in rural, remote, or urban Saskatchewan communities will be conducted. We will recruit Indigenous (n=10) and non-Indigenous (n=20) rural, remote, and urban people. In phase 2, findings from the interviews will inform development of a population-based telephone survey focused on access to health care barriers and facilitators among rural, remote, and urban people; this survey will be administered to 383 residents with CBP across Saskatchewan. In phase 3, phase 1 and 2 findings will be presented to provincial and national policy makers; health system decision makers; health care providers; rural, remote, and urban people with CBP and their communities; and other knowledge users at an interactive end-of-project knowledge translation event. A World Café method will facilitate interactive dialogue designed to catalyze future patient-oriented research and pathways to improve access to CBP care. Patient engagement will be conducted, wherein people with lived experience of CBP, including Indigenous and non-Indigenous people from rural, remote, and urban communities (ie, patient partners), are equal members of the research team. Patient partners are engaged throughout the research process, providing unique knowledge to ensure more comprehensive collection of data while shaping culturally appropriate messages and methods of sharing findings to knowledge users. RESULTS: Participant recruitment began in January 2021. Phase 1 interviews occurred between January 2021 and September 2022. Phase 2 phone survey was administered in May 2022. Final results are anticipated in late 2022. CONCLUSIONS: This study will privilege patient experiences to better understand current health care use and potential access challenges and facilitators among rural, remote, and urban people with CBP in Saskatchewan. We aim to inform the development of comprehensive measures that will be sensitive to geographical location and relevant to culturally diverse people with CBP, ultimately leading to enhanced access to more patient-centered care for CBP. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42484.

Leaving the Walkman and ICD-9 Behind: Modernizing the Disease Classification System Used by Canadian Physicians.

The International Classification of Diseases, Ninth Revision (ICD-9) was released in the 1970s and adopted in Canada for physician billing claims in 1979 (CIHI n.d.b.; WHO & International Conference for the Ninth Revision of the International Classification of Diseases 1977). ICD-9 is no longer adequate for representing our modern healthcare environment and patient needs. We summarize the findings from a small survey of ICD-9 users across Canada - such as family physicians, researchers and decision makers - who describe the limitations of ICD-9 and the features that they would desire in a new or updated classification system.

Rural-Urban Disparities in Realized Spatial Access to General Practitioners, Orthopedic Surgeons, and Physiotherapists among People with Osteoarthritis in Alberta, Canada.

Rural Canadians have high health care needs due to high prevalence of osteoarthritis (OA) but lack access to care. Examining realized access to three types of providers (general practitioners (GPs), orthopedic surgeons (Ortho), and physiotherapists (PTs)) simultaneously helps identify gaps in access to needed OA care, inform accessibility assessment, and support health care resource allocation. Travel time from a patient's postal code to the physician's postal code was calculated using origin-destination network analysis. We applied descriptive statistics to summarize differences in travel time, hotspot analysis to explore geospatial patterns, and distance decay function to examine the travel pattern of health care utilization by urbanicity. The median travel time in Alberta was 11.6 min (IQR = 4.3-25.7) to GPs, 28.9 (IQR = 14.8-65.0) to Ortho, and 33.7 (IQR = 23.1-47.3) to PTs. We observed significant rural-urban disparities in realized access to GPs (2.9 and IQR = 0.0-92.1 in rural remote areas vs. 12.6 and IQR = 6.4-21.0 in metropolitan areas), Ortho (233.3 and IQR = 171.3-363.7 in rural remote areas vs. 21.3 and IQR = 14.0-29.3 in metropolitan areas), and PTs (62.4 and IQR = 0.0-232.1 in rural remote areas vs. 32.1 and IQR = 25.2-39.9 in metropolitan areas). We identified hotspots of realized access to all three types of providers in rural remote areas, where patients with OA tend to travel longer for health care. This study may provide insight on the choice of catchment size and the distance decay pattern of health care utilization for further studies on spatial accessibility.

Rural-Urban Differences in Non-Local Primary Care Utilization among People with Osteoarthritis: The Role of Area-Level Factors.

The utilization of non-local primary care physicians (PCP) is a key primary care indicator identified by Alberta Health to support evidence-based healthcare planning. This study aims to identify area-level factors that are significantly associated with non-local PCP utilization and to examine if these associations vary between rural and urban areas. We examined rural-urban differences in the associations between non-local PCP utilization and area-level factors using multivariate linear regression and geographically weighted regression (GWR) models. Global Moran's I and Gi* hot spot analyses were applied to identify spatial autocorrelation and hot spots/cold spots of non-local PCP utilization. We observed significant rural-urban differences in the non-local PCP utilization. Both GWR and multivariate linear regression model identified two significant factors (median travel time and percentage of low-income families) with non-local PCP utilization in both rural and urban areas. Discontinuity of care was significantly associated with non-local PCP in the southwest, while the percentage of people having university degree was significant in the north of Alberta. This research will help identify gaps in the utilization of local primary care and provide evidence for health care planning by targeting policies at associated factors to reduce gaps in OA primary care provision.

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

Calculating physician supply using a service day method and the income percentiles method: a descriptive analysis.

BACKGROUND: It is important to have an accurate count of physicians and a measurable understanding of their service provision for physician resource planning. Our objective was to compare 2 methods (income percentiles [IP] and service day activities [SVD]) for calculating the supply of full-time (FT) and part-time (PT) primary care physicians (PCPs) as measures of both physician supply counts and level of provider continuity. METHODS: Using an observational study design, we compared 2 methods of calculating the supply of PT and FT PCPs for 2011-2015. For the IP approach, the Canadian Institute for Health Information's method was applied to Alberta Health billing data. The SVD method calculated annual service days for fee-for-service PCPs. A simple descriptive analysis was conducted of the supply of PT and FT PCPs. RESULTS: The 2 methods agreed on the FT versus PT status of 85.2% of PCPs in 2015 but disagreed on the status of 490 PCPs. A total of 239 PCPs were classified as working FT by the IP method but PT by the SVD method. Two hundred and fifty-one PCPs were classified as working PT according by the IP method but FT by the SVD method. The former group of 239 PCPs worked fewer days per week (3.22 v. 4.1) and fewer weekend days per year (8.6 v. 24.1), billed more per year ($300 327 v. $201 834) and saw more patients per day (26.8 v. 17.8) with less continuity of care (38.0% v. 72.0%) than the latter group of 251 PCPs. INTERPRETATION: The SVD method provides a valid alternative to calculating GP supply that distinguishes groups of physicians that the standard IP methodology does not. Those groups provide very different service; policy-makers may benefit from distinguishing them.

Geospatial patterns of comorbidity prevalence among people with osteoarthritis in Alberta Canada.

BACKGROUND: Knowledge of geospatial pattern in comorbidities prevalence is critical to an understanding of the local health needs among people with osteoarthritis (OA). It provides valuable information for targeting optimal OA treatment and management at the local level. However, there is, at present, limited evidence about the geospatial pattern of comorbidity prevalence in Alberta, Canada. METHODS: Five administrative health datasets were linked to identify OA cases and comorbidities using validated case definitions. We explored the geospatial pattern in comorbidity prevalence at two standard geographic areas levels defined by the Alberta Health Services: descriptive analysis at rural-urban continuum level; spatial analysis (global Moran's I, hot spot analysis, cluster and outlier analysis) at the local geographic area (LGA) level. We compared area-level indicators in comorbidities hotspots to those in the rest of Alberta (non-hotspots). RESULTS: Among 359,638 OA cases in 2013, approximately 60% of people resided in Metro and Urban areas, compared to 2% in Rural Remote areas. All comorbidity groups exhibited statistically significant spatial autocorrelation (hypertension: Moran's I index 0.24, z score 4.61). Comorbidity hotspots, except depression, were located primarily in Rural and Rural Remote areas. Depression was more prevalent in Metro (Edmonton-Abbottsfield: 194 cases per 1000 population, 95%CI 192-195) and Urban LGAs (Lethbridge-North: 169, 95%CI 168-171) compared to Rural areas (Fox Creek: 65, 95%CI 63-68). Comorbidities hotspots included a higher percentage of First Nations or Inuit people. People with OA living in hotspots had lower socioeconomic status and less access to care compared to non-hotspots. CONCLUSIONS: The findings highlight notable rural-urban disparities in comorbidities prevalence among people with OA in Alberta, Canada. Our study provides valuable evidence for policy and decision makers to design programs that ensure patients with OA receive optimal health management tailored to their local needs and a reduction in current OA health disparities.

High-volume general practitioners in Alberta: a descriptive analysis.

BACKGROUND: Alberta is considering capping daily fee-for-service physician billings, but little is known about high-volume practice in the province and its impact on patient health outcomes. In this initial study, we conducted a descriptive analysis of general practitioners' patient volumes and billing practices in relation to associated practitioner demographic characteristics. METHODS: We conducted a retrospective descriptive analysis of the associations of practitioner characteristics, including full-time versus non-full-time practice, provider sex, years in practice, geographic location and international medical graduate status, with high-volume (> 50 visits/d) practice using general practice billing data from 2011 to 2016. Use of general practitioner service codes was described and compared by general practitioner volume status, with adjustment for physician demographic characteristics and geographic parameters. RESULTS: We included 3465 general practitioners practising fee-for-service in Alberta between 2011 and 2016, of whom 233 (6.7%) were identified as high-volume providers. Physicians who had been in practice longer (odds ratio [OR] 1.04 per year, 95% confidence interval [CI] 1.02-1.05) and international medical graduates (OR 1.89, 95% CI 1.40-2.54) were more likely to exceed 50 patient visits/day. Female physicians were less likely to exceed 50 patient visits/day (OR 0.14, 95% CI 0.07-0.28). Rural practice location was negatively associated with high-volume practice (OR 0.87, 95% CI 0.79-0.95) when we controlled for zone within the province. Zone 5 (North) was associated with high-volume practice (OR 1.95, 95% CI 1.06-3.58). Less than full-time practice was prevalent (1836 providers [53.0%]). High-volume general practitioners billed fewer service codes requiring longer visits, except for the most highly remunerated code (patients with complex health issues). INTERPRETATION: These results can inform policy-makers when considering payment system changes. Our next step is to examine the association of high-volume practice with outcomes important to patients, such as evidence of treatment failure (emergency department visits and hospital admissions) for conditions sensitive to primary care management.

Discovery of highly potent and selective orexin 1 receptor antagonists (1-SORAs) suitable for in vivo interrogation of orexin 1 receptor pharmacology.

While a correlation between blockade of the orexin 2 receptor (OX2R) with either a dual orexin receptor antagonist (DORA) or a selective orexin 2 receptor antagonist (2-SORA) and a decrease of wakefulness is well established, less is known about selective blockade of the orexin 1 receptor (OX1R). Therefore, a highly selective orexin 1 antagonist (1-SORA) with suitable properties to allow in vivo interrogation of OX1R specific pharmacology in preclinical species remains an attractive target. Herein, we describe the discovery of an optimized 1-SORA series in the piperidine ether class. Notably, a 4,4-difluoropiperidine core coupled with a 2-quinoline ether linkage provides OX1R selective compounds. The combination with an azabenzimidazole or imidazopyridine amide substituent leads to analogs 47 and 51 with >625-fold functional selectivity for OX1R over OX2R in rat. Compounds 47 and 51 possess clean off-target profiles and the required pharmacokinetic and physical properties to be useful as 1-SORA tool compounds.

Pharmacological evaluation of orexin receptor antagonists in preclinical animal models of pain.

Orexin signaling, known to modulate arousal and vigilance, is also involved in nociception as orexin neurons project to regions of the brain and spinal cord involved in pain processing, and the administration of orexin peptides can alter pain response in a wide range of preclinical models. Pharmacological treatment with the potent, selective and structurally distinct dual orexin receptor antagonists (ORAs) DORA-12 and DORA-2 significantly reduced pain responses during both phases I and II of the mouse formalin pain model and significantly reversed hyperalgesia in the rat complete Freund's adjuvant pain model, respectively. Significant antinociceptive effects of DORA-12 in the formalin model were also observed in orexin 1 receptor (OX1R) knockout mice, but not orexin 2 receptor (OX2R) or OX1R/OX2R double knockout mice. Mechanical hypersensitivity was significantly reduced with a series of structurally distinct, potent and highly selective ORAs (DORA-2, DORA-12 and DORA-22) in the rat spinal nerve ligation (SNL) injury model of neuropathic pain. Selective pharmacological targeting of OX2R with 2-SORA-7 also reduced pain responses in acute inflammatory (complete Freund's adjuvant) and neuropathic (SNL) rat pain models. Performance on the rotarod test of psychomotor performance and baseline thermal sensitivity were not affected in OX1R/OX2R knockout mice or ORA-treated mice, indicating that the observed pain-reducing effects were not due to sedation or motor deficits. These findings indicate that ORAs have pain-reducing effects across a number of acute and chronic neuropathic preclinical mouse and rat pain models. Further studies on the potential pain-relieving effects of orexin receptor antagonism are warranted.

Differential sleep-promoting effects of dual orexin receptor antagonists and GABAA receptor modulators.

BACKGROUND: The current standard of care for insomnia includes gamma-aminobutyric acid receptor A (GABAA) activators, which promote sleep as well as general central nervous system depression. Dual orexin receptor antagonists (DORAs) represent an alternative mechanism for insomnia treatment that induces somnolence by blocking the wake-promoting effects of orexin neuropeptides. The current study compares the role and interdependence of these two mechanisms on their ability to influence sleep architecture and quantitative electroencephalography (qEEG) spectral profiles across preclinical species. RESULTS: Active-phase dosing of DORA-22 induced consistent effects on sleep architecture in mice, rats, dogs, and rhesus monkeys; attenuation of active wake was accompanied by increases in both non-rapid eye movement (NREM) and rapid eye movement (REM) sleep. Eszopiclone, a representative GABAA receptor modulator, promoted sleep in rats and rhesus monkeys that was marked by REM sleep suppression, but had inconsistent effects in mice and paradoxically promoted wakefulness in dogs. Active-phase treatment of rats with DORA-12 similarly promoted NREM and REM sleep to magnitudes nearly identical to those seen during normal resting-phase sleep following vehicle treatment, whereas eszopiclone suppressed REM even to levels below those seen during the active phase. The qEEG changes induced by DORA-12 in rats also resembled normal resting-phase patterns, whereas eszopiclone induced changes distinct from normal active- or inactive-phase spectra. Co-dosing experiments, as well as studies in transgenic rats lacking orexin neurons, indicated partial overlap in the mechanism of sleep promotion by orexin and GABA modulation with the exception of the REM suppression exclusive to GABAA receptor modulation. Following REM deprivation in mice, eszopiclone further suppressed REM sleep while DORA-22 facilitated recovery including increased REM sleep. CONCLUSION: DORAs promote NREM and importantly REM sleep that is similar in proportion and magnitude to that seen during the normal resting phase across mammalian animal models. While limited overlap exists between therapeutic mechanisms, orexin signaling does not appear involved in the REM suppression exhibited by GABAA receptor modulators. The ability of DORAs to promote proportional NREM and REM sleep following sleep deprivation suggests that this mechanism may be effective in alleviating recovery from sleep disturbance.

The duration of sleep promoting efficacy by dual orexin receptor antagonists is dependent upon receptor occupancy threshold.

BACKGROUND: Drugs targeting insomnia ideally promote sleep throughout the night, maintain normal sleep architecture, and are devoid of residual effects associated with morning sedation. These features of an ideal compound are not only dependent upon pharmacokinetics, receptor binding kinetics, potency and pharmacodynamic activity, but also upon a compound's mechanism of action. RESULTS: Dual orexin receptor antagonists (DORAs) block the arousal-promoting activity of orexin peptides and, as demonstrated in the current work, exhibit an efficacy signal window dependent upon oscillating levels of endogenous orexin neuropeptide. Sleep efficacy of structurally diverse DORAs in rat and dog was achieved at plasma exposures corresponding to orexin 2 receptor (OX2R) occupancies in the range of 65 to 80%. In rats, the time course of OX2R occupancy was dependent upon receptor binding kinetics and was tightly correlated with the timing of active wake reduction. In rhesus monkeys, direct comparison of DORA-22 with GABA-A modulators at similar sleep-inducing doses revealed that diazepam produced next-day residual sleep and both diazepam and eszopiclone induced next-day cognitive deficits. In stark contrast, DORA-22 did not produce residual effects. Furthermore, DORA-22 evoked only minimal changes in quantitative electroencephalogram (qEEG) activity during the normal resting phase in contrast to GABA-A modulators which induced substantial qEEG changes. CONCLUSION: The higher levels of receptor occupancy necessary for DORA efficacy require a plasma concentration profile sufficient to maintain sleep for the duration of the resting period. DORAs, with a half-life exceeding 8 h in humans, are expected to fulfill this requirement as exposures drop to sub-threshold receptor occupancy levels prior to the wake period, potentially avoiding next-day residual effects at therapeutic doses.

Quantitative electroencephalography within sleep/wake states differentiates GABAA modulators eszopiclone and zolpidem from dual orexin receptor antagonists in rats.

Dual orexin receptor antagonists (DORAs) induce sleep by blocking orexin 1 and orexin 2 receptor-mediated activities responsible for regulating wakefulness. DORAs represent a potential alternative mechanism to the current standard of care that includes the γ-aminobutyric acid (GABA)A receptor-positive allosteric modulators, eszopiclone and zolpidem. This work uses an innovative method to analyze electroencephalogram (EEG) spectral frequencies within sleep/wake states to differentiate the effects of GABAA modulators from DORA-22, an analog of the DORA MK-6096, in Sprague-Dawley rats. The effects of low, intermediate, and high doses of eszopiclone, zolpidem, and DORA-22 were examined after first defining each compound's ability to promote sleep during active-phase dosing. The EEG spectral frequency power within specific sleep stages was calculated in 1-Hz intervals from 1 to 100 Hz within each sleep/wake state for the first 4 h after the dose. Eszopiclone and zolpidem produced marked, dose-responsive disruptions in sleep stage-specific EEG spectral profiles compared with vehicle treatment. In marked contrast, DORA-22 exhibited marginal changes in the spectral profile, observed only during rapid eye movement sleep, and only at the highest dose tested. Moreover, while eszopiclone- and zolpidem-induced changes were evident in the inactive period, the EEG spectral responses to DORA-22 were absent during this phase. These results suggest that DORA-22 differs from eszopiclone and zolpidem whereby DORA-22 promotes somnolence without altering the neuronal network EEG activity observed during normal sleep.