Habenular TCF7L2 links nicotine addiction to diabetes.

Diabetes is far more prevalent in smokers than non-smokers, but the underlying mechanisms of vulnerability are unknown. Here we show that the diabetes-associated gene Tcf7l2 is densely expressed in the medial habenula (mHb) region of the rodent brain, where it regulates the function of nicotinic acetylcholine receptors. Inhibition of TCF7L2 signalling in the mHb increases nicotine intake in mice and rats. Nicotine increases levels of blood glucose by TCF7L2-dependent stimulation of the mHb. Virus-tracing experiments identify a polysynaptic connection from the mHb to the pancreas, and wild-type rats with a history of nicotine consumption show increased circulating levels of glucagon and insulin, and diabetes-like dysregulation of blood glucose homeostasis. By contrast, mutant Tcf7l2 rats are resistant to these actions of nicotine. Our findings suggest that TCF7L2 regulates the stimulatory actions of nicotine on a habenula-pancreas axis that links the addictive properties of nicotine to its diabetes-promoting actions.

Hedgehog-interacting protein acts in the habenula to regulate nicotine intake.

Hedgehog-interacting protein (HHIP) sequesters Hedgehog ligands to repress Smoothened (SMO)-mediated recruitment of the GLI family of transcription factors. Allelic variation in HHIP confers risk of chronic obstructive pulmonary disease and other smoking-related lung diseases, but underlying mechanisms are unclear. Using single-cell and cell-type-specific translational profiling, we show that HHIP expression is highly enriched in medial habenula (MHb) neurons, particularly MHb cholinergic neurons that regulate aversive behavioral responses to nicotine. HHIP deficiency dysregulated the expression of genes involved in cholinergic signaling in the MHb and disrupted the function of nicotinic acetylcholine receptors (nAChRs) through a PTCH-1/cholesterol-dependent mechanism. Further, CRISPR/Cas9-mediated genomic cleavage of the Hhip gene in MHb neurons enhanced the motivational properties of nicotine in mice. These findings suggest that HHIP influences vulnerability to smoking-related lung diseases in part by regulating the actions of nicotine on habenular aversion circuits.

Neurobiological Mechanisms of Nicotine Reward and Aversion.

Neuronal nicotinic acetylcholine receptors (nAChRs) regulate the rewarding actions of nicotine contained in tobacco that establish and maintain the smoking habit. nAChRs also regulate the aversive properties of nicotine, sensitivity to which decreases tobacco use and protects against tobacco use disorder. These opposing behavioral actions of nicotine reflect nAChR expression in brain reward and aversion circuits. nAChRs containing α4 and ß2 subunits are responsible for the high-affinity nicotine binding sites in the brain and are densely expressed by reward-relevant neurons, most notably dopaminergic, GABAergic, and glutamatergic neurons in the ventral tegmental area. High-affinity nAChRs can incorporate additional subunits, including ß3, α6, or α5 subunits, with the resulting nAChR subtypes playing discrete and dissociable roles in the stimulatory actions of nicotine on brain dopamine transmission. nAChRs in brain dopamine circuits also participate in aversive reactions to nicotine and the negative affective state experienced during nicotine withdrawal. nAChRs containing α3 and ß4 subunits are responsible for the low-affinity nicotine binding sites in the brain and are enriched in brain sites involved in aversion, including the medial habenula, interpeduncular nucleus, and nucleus of the solitary tract, brain sites in which α5 nAChR subunits are also expressed. These aversion-related brain sites regulate nicotine avoidance behaviors, and genetic variation that modifies the function of nAChRs in these sites increases vulnerability to tobacco dependence and smoking-related diseases. Here, we review the molecular, cellular, and circuit-level mechanisms through which nicotine elicits reward and aversion and the adaptations in these processes that drive the development of nicotine dependence. SIGNIFICANCE STATEMENT: Tobacco use disorder in the form of habitual cigarette smoking or regular use of other tobacco-related products is a major cause of death and disease worldwide. This article reviews the actions of nicotine in the brain that contribute to tobacco use disorder.

VGLUT3 Deletion Rescues Motor Deficits and Neuronal Loss in the zQ175 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is an autosomal-dominant neurodegenerative disease characterized by progressive motor and cognitive impairments, with no disease-modifying therapies yet available. HD pathophysiology involves evident impairment in glutamatergic neurotransmission leading to severe striatal neurodegeneration. The vesicular glutamate transporter-3 (VGLUT3) regulates the striatal network that is centrally affected by HD. Nevertheless, current evidence on the role of VGLUT3 in HD pathophysiology is lacking. Here, we crossed mice lacking Slc17a8 gene (VGLUT3 -/-) with heterozygous zQ175 knock-in mouse model of HD (zQ175:VGLUT3 -/-). Longitudinal assessment of motor and cognitive functions from 6 to 15 months of age reveals that VGLUT3 deletion rescues motor coordination and short-term memory deficits in both male and female zQ175 mice. VGLUT3 deletion also rescues neuronal loss likely via the activation of Akt and ERK1/2 in the striatum of zQ175 mice of both sexes. Interestingly, the rescue in neuronal survival in zQ175:VGLUT3 -/- mice is accompanied by a reduction in the number of nuclear mutant huntingtin (mHTT) aggregates with no change in the total aggregate levels or microgliosis. Collectively, these findings provide novel evidence that VGLUT3, despite its limited expression, can be a vital contributor to HD pathophysiology and a viable target for HD therapeutics.SIGNIFICANCE STATEMENT Dysregulation of the striatal network centrally contributes to the pathophysiology of Huntington's disease (HD). The atypical vesicular glutamate transporter-3 (VGLUT3) has been shown to regulate several major striatal pathologies, such as addiction, eating disorders, or L-DOPA-induced dyskinesia. Yet, our understanding of VGLUT3's role in HD remains unclear. We report here that deletion of the Slc17a8 (Vglut3) gene rescues the deficits in both motor and cognitive functions in HD mice of both sexes. We also find that VGLUT3 deletion activates neuronal survival signaling and reduces nuclear aggregation of abnormal huntingtin proteins and striatal neuron loss in HD mice. Our novel findings highlight the vital contribution of VGLUT3 in HD pathophysiology that can be exploited for HD therapeutic management.

Psychological Distress After Inpatient Noncardiac Surgery: A Secondary Analysis of the Measurement of Exercise Tolerance Before Surgery Prospective Cohort Study.

OBJECTIVE: To describe the incidence and natural progression of psychological distress after major surgery. BACKGROUND: The recovery process after surgery imposes physical and mental burdens that put patients at risk of psychological distress. Understanding the natural course of psychological distress after surgery is critical to supporting the timely and tailored management of high-risk individuals. METHODS: We conducted a secondary analysis of the "Measurement of Exercise Tolerance before Surgery" multicentre cohort study (Canada, Australia, New Zealand, and the UK). Measurement of Exercise Tolerance before Surgery recruited adult participants (≥40 years) undergoing elective inpatient noncardiac surgery and followed them for 1 year. The primary outcome was the severity of psychological distress measured using the anxiety-depression item of EQ-5D-3L. We used cumulative link mixed models to characterize the time trajectory of psychological distress among relevant patient subgroups. We also explored potential predictors of severe and/or worsened psychological distress at 1 year using multivariable logistic regression models. RESULTS: Of 1546 participants, moderate-to-severe psychological distress was reported by 32.6% of participants before surgery, 27.3% at 30 days after surgery, and 26.2% at 1 year after surgery. Psychological distress appeared to improve over time among females [odds ratio (OR): 0.80, 95% CI: 0.65-0.95] and patients undergoing orthopedic procedures (OR: 0.73, 95% CI: 0.55-0.91), but not among males (OR: 0.87, 95% CI: 0.87-1.07) or patients undergoing nonorthopedic procedures (OR: 0.95, 95% CI: 0.87-1.04). Among the average middle-aged adult, there were no time-related changes (OR: 0.94, 97% CI: 0.75-1.13), whereas the young-old (OR: 0.89, 95% CI: 0.79-0.99) and middle-old (OR: 0.87, 95% CI: 0.73-1.01) had small improvements. Predictors of severe and/or worsened psychological distress at 1 year were younger age, poor self-reported functional capacity, smoking history, and undergoing open surgery. CONCLUSIONS: One-third of adults experience moderate to severe psychological distress before major elective noncardiac surgery. This distress tends to persist or worsen over time among select patient subgroups.

The Association of Cannabis Use After Discharge From Surgery With Opioid Consumption and Patient-reported Outcomes.

OBJECTIVE: To compare outcomes of patients using versus not using cannabis as a treatment for pain after discharge from surgery. BACKGROUND: Cannabis is increasingly available and is often taken by patients to relieve pain. However, it is unclear whether cannabis use for pain after surgery impacts opioid consumption and postoperative outcomes. METHODS: Using Michigan Surgical Quality Collaborative registry data at 69 hospitals, we analyzed a cohort of patients undergoing 16 procedure types between January 1, 2021, and October 31, 2021. The key exposure was cannabis use for pain after surgery. Outcomes included postdischarge opioid consumption (primary) and patient-reported outcomes of pain, satisfaction, quality of life, and regret to undergo surgery (secondary). RESULTS: Of 11,314 included patients (58% females, mean age: 55.1 years), 581 (5.1%) reported using cannabis to treat pain after surgery. In adjusted models, patients who used cannabis consumed an additional 1.0 (95% CI: 0.4-1.5) opioid pills after surgery. Patients who used cannabis were more likely to report moderate-to-severe surgical site pain at 1 week (adjusted odds ratio: 1.7, 95% CIL 1.4-2.1) and 1 month (adjusted odds ratio: 2.1, 95% CI: 1.7-2.7) after surgery. Patients who used cannabis were less likely to endorse high satisfaction (72.1% vs 82.6%), best quality of life (46.7% vs 63.0%), and no regret (87.6% vs 92.7%) (all P < 0.001). CONCLUSIONS: Patient-reported cannabis use, to treat postoperative pain, was associated with increased opioid consumption after discharge from surgery that was of clinically insignificant amounts, but worse pain and other postoperative patient-reported outcomes.

Perioperative Naltrexone Management: A Scoping Review by the Perioperative Pain and Addiction Interdisciplinary Network.

Substance use disorders, including alcohol use disorder, are a public health concern that affect more than 150 million people globally. The opioid antagonist naltrexone is being increasingly prescribed to treat opioid use disorder, alcohol use disorder, and chronic pain. Perioperative management of patients on naltrexone is inconsistent and remains a controversial topic, with mismanagement posing a significant risk to the long-term health of these patients. This scoping review was conducted to identify human studies in which the perioperative management of naltrexone was described. This review includes a systematic literature search involving Medline, Medline In-Process, Embase, PsycINFO, and Web of Science. Seventeen articles that describe perioperative naltrexone management strategies were included, including thirteen guidelines, one case report, and three randomized trials. Despite its use in patients with alcohol use disorder and chronic pain, no clinical studies, case reports, or guidelines addressed naltrexone use in these clinical populations. All of the guideline documents recommended the preoperative cessation of naltrexone, irrespective of dose, indication, or route of administration. None of these guideline documents were designed on the basis of a systematic literature search or a Delphi protocol. As described by the primary studies, perioperative pain relief varied depending on naltrexone dose and route of administration, time since last naltrexone administration, and underlying substance use disorder. None of the studies commented on the maintenance of recovery for the patient's substance use disorder in the context of perioperative naltrexone management. The current understanding of the risks and benefits of continuing or stopping naltrexone perioperatively is limited by a lack of high-quality evidence. In patients with risk factors for return to use of opioids or alcohol, the discontinuation of naltrexone should have a strong rationale. Future studies and guidelines should seek to address both acute pain management and maintaining recovery when discussing perioperative naltrexone management strategies.

Improving R0 Resection Rates With a Posterior-First, 2-Stage Approach for En Bloc Resection of Locally Advanced Primary and Recurrent Anorectal Cancers Involving the Deep Pelvic Sidewall.

BACKGROUND: Using standard anterior approaches, consistent R0 resection of locally advanced primary and recurrent rectal and anal cancer involving the deep pelvic sidewall may be unattainable. Therefore, to improve R0 resection rates, we have used a posterior-first, then anterior 2-stage approach to resection of tumors in this location. OBJECTIVE: To assess the R0 resection rate and surgical outcomes of the first 10 patients operated on using this approach. DESIGN: We conducted a retrospective case series review of our prospectively maintained surgical pathology and tumor registries. SETTING: This study was conducted at the Mayo Clinic in Rochester, Minnesota. PATIENTS: Ten patients (6 female individuals, median age 53.5 years) with primary or recurrent anal or rectal cancer treated with a posterior-first, then anterior 2-stage approach were identified. MAIN OUTCOME MEASURES: The primary outcome measures were the R0 resection rate and surgical outcomes. RESULTS: An R0 resection was achieved in all 10 patients. Nine patients developed 1 or more 30-day Clavien-Dindo grade III complications. Nine patients developed gluteal wound complications ranging from superficial wound dehiscence to flap necrosis. During the follow-up period, 4 patients were found to have metastatic disease and 1 patient had local re-recurrence. LIMITATIONS: Small cohort with heterogeneous tumors and a short follow-up duration. CONCLUSION: A posterior-first, then anterior 2-stage approach has allowed us to achieve consistent R0 resection margins in locally advanced primary and recurrent rectal and anal cancers involving the deep pelvic sidewall. Poor wound healing of the posterior gluteal incision is a common complication. See Video Abstract. MEJORANDO LAS TASAS DE RESECCIN R CON UN ABORDAJE DE DOS ETAPAS PRIMERO POSTERIOR PARA LA RESECCIN EN BLOQUE DE CNCERES ANORRECTALES PRIMARIOS Y RECURRENTES LOCALMENTE AVANZADOS QUE AFECTAN LA PARED LATERAL PLVICA PROFUNDA: ANTECEDENTES:Utilizando abordajes anteriores estándares, la resección R0 consistente del cáncer de recto y ano primario y recurrente localmente avanzado involucrando la pared lateral pélvica profunda puede ser inalcanzable. Por lo tanto, para mejorar las tasas de resección R0, hemos empleado un abordaje de 2 etapas primero posterior y luego anterior para la resección de tumores en esta ubicación.OBJETIVO:Este estudio tuvo como objetivo evaluar la tasa de resección R0 y los resultados quirúrgicos de los primeros 10 pacientes operados con este abordaje.DISEÑO:Realizamos una revisión retrospectiva de series de casos de nuestros registros de patología quirúrgica y tumores mantenidos prospectivamente.AJUSTE:Este estudio se realizó en la Clínica Mayo en Rochester, Minnesota, EE. UU.PACIENTES:Se identificaron diez pacientes (6 mujeres, mediana de edad 53.5 años) con cáncer anal o rectal primario o recurrente tratados con un abordaje de dos etapas, primero posterior y luego anterior.PRINCIPALES MEDIDAS DE RESULTADO:Las medidas de resultado primarias fueron la tasa de resección R0 y los resultados quirúrgicos.RESULTADOS:Se logró una resección R0 en los 10 pacientes. Nueve pacientes desarrollaron una o más complicaciones de grado III de Clavien-Dindo a los 30 días. Nueve pacientes desarrollaron complicaciones de la herida del glúteo que variaron desde dehiscencia superficial de la herida hasta necrosis del colgajo. Durante el período de seguimiento, se encontró que 4 pacientes tenían enfermedad metastásica y un paciente tuvo recurrencia local.LIMITACIONES:Cohorte pequeño con tumores heterogéneos y corta duración de seguimiento.CONCLUSIÓN:Un abordaje en 2 etapas, primero posterior y luego anterior, nos ha permitido lograr márgenes de resección R0 consistentes en cánceres de recto y anal primarios y recurrentes localmente avanzados que afectan la pared lateral pélvica profunda. La mala cicatrización de la incisión glútea posterior es una complicación común. (Traducción-Dr. Aurian Garcia Gonzalez).

Intraoperative Hypotension in Patients Having Major Noncardiac Surgery Under General Anesthesia: A Systematic Review of Blood Pressure Optimization Strategies.

INTRODUCTION: Intraoperative hypotension is associated with increased risks of postoperative complications. Consequently, a variety of blood pressure optimization strategies have been tested to prevent or promptly treat intraoperative hypotension. We performed a systematic review to summarize randomized controlled trials that evaluated the efficacy of blood pressure optimization interventions in either mitigating exposure to intraoperative hypotension or reducing risks of postoperative complications. METHODS: Medline, Embase, PubMed, and Cochrane Controlled Register of Trials were searched from database inception to August 2, 2023, for randomized controlled trials (without language restriction) that evaluated the impact of any blood pressure optimization intervention on intraoperative hypotension and/or postoperative outcomes. RESULTS: The review included 48 studies (N = 46,377), which evaluated 10 classes of blood pressure optimization interventions. Commonly assessed interventions included hemodynamic protocols using arterial waveform analysis, preoperative withholding of antihypertensive medications, continuous blood pressure monitoring, and adjuvant agents (vasopressors, anticholinergics, anticonvulsants). These same interventions reduced intraoperative exposure to hypotension. Conversely, low blood pressure alarms had an inconsistent impact on exposure to hypotension. Aside from limited evidence that higher prespecified intraoperative blood pressure targets led to a reduced risk of complications, there were few data suggesting that these interventions prevented postoperative complications. Heterogeneity in interventions and outcomes precluded meta-analysis. CONCLUSIONS: Several different blood pressure optimization interventions show promise in reducing exposure to intraoperative hypotension. Nonetheless, the impact of these interventions on clinical outcomes remains unclear. Future trials should assess promising interventions in samples sufficiently large to identify clinically plausible treatment effects on important outcomes.

Incidence and relative risk of delirium after major surgery for patients with pre-operative depression: a systematic review and meta-analysis.

BACKGROUND: Delirium is a common and potentially serious complication after major surgery. A previous history of depression is a known risk factor for experiencing delirium in patients admitted to the hospital, but the generalised risk has not been estimated in surgical patients. METHODS: We conducted a systematic review and meta-analysis of studies reporting the incidence or relative risk (or relative odds) of delirium in the immediate postoperative period for adults with pre-operative depression. We included studies that defined depression as either a formal pre-existing diagnosis or having clinically important depressive symptoms measured using a patient-reported instrument before surgery. Multilevel random effects meta-analyses were used to estimate the pooled incidences and pooled relative risks. We also conducted subgroup analyses by various study-level characteristics to identify important moderators of pooled estimates. RESULTS: Forty-two studies (n = 4,664,051) from five continents were included. The pooled incidence of postoperative delirium for patients with pre-operative depression was 29% (95%CI 17-43%, I2 = 99.0%), compared with 15% (95%CI 6-28%, I2 = 99.8%) in patients without pre-operative depression and 21% (95% CI 11-33%, I2 = 99.8%) in the cohorts overall. For patients with pre-operative depression, the risk of delirium was 1.91 times greater (95%CI 1.68-2.17, I2 = 42.0%) compared with patients without pre-operative depression. CONCLUSIONS: Patients with a previous diagnosis of depression or clinically important depressive symptoms before surgery have substantially greater risk of experiencing delirium after surgery. Clinicians and patients should be informed of these increased risks. Robust screening and other risk mitigation strategies for postoperative delirium are warranted, especially for patients with pre-operative depression.

Updates in the Management of Metastatic Spine Disease.

The number of cancer diagnoses continues to increase each year in the United States, and given the propensity for bone metastases from solid organ malignancies, orthopaedic spine surgeons will inevitably encounter patients with metastatic spine disease and need to have a framework for approaching the evaluation and treatment of these complex patients. Many patients seeking care for spinal metastases already have a history of disseminated malignancy, but metastatic spine disease itself will be the presenting symptom of cancer in approximately 20% of patients. Because the first presentation of cancer may be to a spine surgeon, an appropriate strategy for the initial evaluation of a patient with a new spinal lesion is critical to establish the diagnosis of metastatic disease before undergoing treatment. Once the diagnosis of metastatic spine disease is confirmed, decisions regarding treatment should be made in coordination with a multidisciplinary team including radiation oncology and medical oncology. Spinal metastases are most often treated with radiation therapy. Direct circumferential decompression of the spinal cord with postoperative radiation therapy is considered for high-grade epidural spinal cord compression to preserve neurologic function. Mechanical spinal instability is another potential indication for surgery. When considering surgery, the patient's medical fitness, systemic burden of cancer, and overall prognosis all must be accounted for, and the importance of multidisciplinary evaluation and shared decision making cannot be overstated.

Improved Re-estimation of Perioperative Cardiac Risk Using the Surgical Apgar Score: A Retrospective Cohort Study.

OBJECTIVE: To assess whether the Surgical Apgar Score (SAS) improves re-estimation of perioperative cardiac risk. BACKGROUND: The SAS is a novel risk index that integrates three relevant and easily measurable intraoperative parameters (blood loss, heart rate, mean arterial pressure) to predict outcomes. The incremental prognostic value of the SAS when used in combination with standard preoperative risk indices is unclear. METHODS: We conducted a retrospective cohort study of adults (18 years and older) who underwent elective noncardiac surgery at a quaternary care hospital in Canada (2009-2014). The primary outcome was postoperative acute myocardial injury. The SAS (range 0-10) was calculated based on intraoperative estimated blood loss, lowest mean arterial pressure, and lowest heart rate documented in electronic medical records. Incremental prognostic value of the SAS when combined with the Revised Cardiac Risk Index was assessed based on discrimination (c-statistic), reclassification (integrated discrimination improvement, net reclassification index), and clinical utility (decision curve analysis). RESULTS: The cohort included 16,835 patients, of whom 607 (3.6%) patients had acute postoperative myocardial injury. Addition of the SAS to the Revised Cardiac Risk Index improved risk estimation based on the integrated discrimination improvement [2.0%; 95% confidence interval (CI): 1.5%-2.4%], continuous net reclassification index (54%; 95% CI: 46%-62%), and c-index, which increased from 0.68 (95% CI: 0.65-0.70) to 0.75 (95% CI: 0.73-0.77). On decision curve analysis, addition of the SAS to the Revised Cardiac Risk Index resulted in a higher net benefit at all decision thresholds. CONCLUSIONS: When combined with a validated preoperative risk index, the SAS improved the accuracy of cardiac risk assessment for noncardiac surgery. Further research is needed to delineate how intraoperative data can better guide postoperative decision-making.

Surgeon Postoperative Opioid Prescribing Intensity and Risk of Persistent Opioid Use Among Opioid-naive Adult Patients: A Population-based Cohort Study.

OBJECTIVE: The aim of this study was to determine the relationship between surgeon opioid prescribing intensity and subsequent persistent opioid use among patients undergoing surgery. SUMMARY BACKGROUND DATA: The extent to which different postoperative prescribing practices lead to persistent opioid use among surgical patients is poorly understood. METHODS: Retrospective population-based cohort study assessing opioid-naive adults who underwent 1 of 4 common surgeries. For each surgical procedure, the surgeons' opioid prescribing intensity was categorized into quartiles based on the median daily dose of morphine equivalents of opioids dispensed within 7 days of the surgical visit for all the surgeons' patients. The primary outcome was persistent opioid use in the year after surgery, defined as 180 days or more of opioids supplied within the year after the index date excluding prescriptions filled within 30 days of the index date. Secondary outcomes included a refill for an opioid within 30 days and emergency department visits and hospitalizations within 1 year. RESULTS: Among 112,744 surgical patients, patients with surgeons in the highest intensity quartile (Q4) were more likely to fill an opioid prescription within 7 days after surgery compared with those in the lowest quartile (Q1) (83.3% Q4 vs 65.4% Q1). In the primary analysis, the incidence of persistent opioid use in the year after surgery was rare in both highest and lowest quartiles (0.3% Q4 vs 0.3% Q1), adjusted odds ratio (AOR) of 1.18, 95% CI 0.83-1.66). However, multiple analyses using stricter definitions of persistent use that included the requirement of a prescription filled within 7 days of discharge after surgery showed a significant association with surgeon quartile (up to an AOR 1.36, 95% CI 1.25, 1.47). Patients in Q4 were more likely to refill a prescription within 30 days (4.8% Q4 vs 4.0% Q1, AOR 1.14, 95% CI 1.04-1.24). CONCLUSIONS: Surgeons' overall prescribing practices may contribute to persistent opioid use and represent a target for quality improvement. However, the association was highly sensitive to the definition of persistent use used.

Use of Psychedelics for Pain: A Scoping Review.

Chronic pain is a public health concern that affects approximately 1.5 billion people globally. Conventional therapeutic agents including opioid and non-opioid analgesics have been associated with adverse side effects, issues with addiction, and ineffective analgesia. Novel agents repurposed to treat pain via different mechanisms are needed to fill the therapeutic gap in chronic pain management. Psychedelics such as lysergic acid diethylamide and psilocybin (the active ingredient in psychedelic mushrooms) are thought to alter pain perception through direct serotonin receptor agonism, anti-inflammatory effects, and synaptic remodeling. This scoping review was conducted to identify human studies in which psychedelic agents were used for the treatment of pain. Twenty-one articles that assessed the effects of psychedelics in treating various pain states were included. The present scarcity of clinical trials and small sample sizes limit their application for clinical use. Overall, psychedelics appear to show promise for analgesia in patients with certain headache disorders and cancer pain diagnoses. Future studies must aim to examine the combined effects of psychotherapy and psychedelics on chronic pain.

Nonopioid Analgesic Prescriptions Filled after Surgery among Older Adults in Ontario, Canada: A Population-based Cohort Study.

BACKGROUND: The objective was to assess changes over time in prescriptions filled for nonopioid analgesics for older postoperative patients in the immediate postdischarge period. The authors hypothesized that the number of patients who filled a nonopioid analgesic prescription increased during the study period. METHODS: The authors performed a population-based cohort study using linked health administrative data of 278,366 admissions aged 66 yr or older undergoing surgery between fiscal year 2013 and 2019 in Ontario, Canada. The primary outcome was the percentage of patients with new filled prescriptions for nonopioid analgesics within 7 days of discharge, and the secondary outcome was the analgesic class. The authors assessed whether patients filled prescriptions for a nonopioid only, an opioid only, both opioid and nonopioid prescriptions, or a combination opioid/nonopioid. RESULTS: Overall, 22% (n = 60,181) of patients filled no opioid prescription, 2% (n = 5,534) filled a nonopioid only, 21% (n = 59,608) filled an opioid only, and 55% (n = 153,043) filled some combination of opioid and nonopioid. The percentage of patients who filled a nonopioid prescription within 7 days postoperatively increased from 9% (n = 2,119) in 2013 to 28% (n = 13,090) in 2019, with the greatest increase for acetaminophen: 3% (n = 701) to 20% (n = 9,559). The percentage of patients who filled a combination analgesic prescription decreased from 53% (n = 12,939) in 2013 to 28% (n = 13,453) in 2019. However, the percentage who filled both an opioid and nonopioid prescription increased: 4% (n = 938) to 21% (n = 9,880) so that the overall percentage of patients who received both an opioid and a nonopioid remained constant over time 76% (n = 18,642) in 2013 to 75% (n = 35,391) in 2019. CONCLUSIONS: The proportion of postoperative patients who fill prescriptions for nonopioid analgesics has increased. However, rather than a move to use of nonopioids alone for analgesia, this represents a shift away from combination medications toward separate prescriptions for opioids and nonopioids.

Impact of COVID-19 on electroconvulsive therapy practice across Canadian provinces during the first wave of the pandemic.

BACKGROUND: Electroconvulsive therapy (ECT) is a procedural treatment that is potentially life-saving for some patients with severe psychiatric illness. At the start of the global coronavirus disease 2019 (COVID-19) pandemic, ECT practice was remarkably disrupted, putting vulnerable individuals at increased risk of symptom exacerbation and death by suicide. This study aimed to capture the self-reported experiences of psychiatrists based at healthcare facilities across Canadian provinces who were delivering ECT treatments during the first phase of the COVID-19 pandemic (i.e., from mid-March 2020 to mid-May 2020). METHODS: A multidisciplinary team of experts developed a survey focusing on five domains: ECT unit operations, decision-making, hospital resources, ECT procedure, and mitigating patient impact. Responses were collected from psychiatrists providing ECT at 67 ECT centres in Canada, grouped by four geographical regions (Ontario, Quebec, Atlantic Canada, and Western Canada). RESULTS: Clinical operations of ECT programs were disrupted across all four regions - however, centres in Atlantic Canada were able to best preserve outpatient and maintenance care, while centres in Western Canada were able to best preserve inpatient and acute care. Similarly, Atlantic and Western Canada demonstrated the best decision-making practices of involving the ECT team and clinical ethicists in the development of pandemic-related guidelines. Across all four regions, ECT practice was affected by the redeployment of professionals, the shortage of personal protective equipment, and the need to enforce social distancing. Attempts to introduce modifications to the ECT delivery room and minimize bag-valve-mask ventilation were consistently reported. All four regions developed a new patient prioritization framework, and Western Canada, notably, aimed to provide ECT to only the most severe cases. CONCLUSIONS: The results suggest that ECT provision was disproportionately affected across different parts of Canada. Possible factors that could explain these interregional differences include population, distribution of urban vs. rural areas, pre-pandemic barriers in access to ECT, number of cases, ability to control the spread of infection, and the general reduction in physicians' activities across different areas of health care. Studying these factors in the future will inform how medical centres should respond to public health emergencies and pandemic-related circumstances in the context of procedural treatments.

Interventional pain blocks in Ontario: a population-based cross-sectional study on 2019 procedural volumes, clustering, and physician billings.

PURPOSE: Multidisciplinary chronic pain management includes pharmacologic, psychological, and interventional strategies. In Canada, the use of interventional pain blocks (PBs) has increased in recent years. We sought to determine the distribution and clustering of PBs among physicians in Ontario, and to examine differences in the patient and physician characteristics by volume of PBs administered. METHODS: We conducted a population-based cross-sectional study of PBs administered for chronic pain to Ontario residents between 1 January and 31 December 2019. Our primary outcome was the total number of PBs administered in an outpatient setting for chronic pain by eligible physicians. We used Lorenz curves, overall and stratified by PB type and physician specialty, to examine clustering of PBs among physicians, and compared patient and physician characteristics using standardized differences. RESULTS: Among physicians who provided PBs, provision was highly clustered, with the top 1% of physicians providing 39% of blocks. In these high-volume PB providers, the majority of whom were general practitioners (88.4%), PBs made up the vast majority (median [interquartile range (IQR)], 87% [84-89]) of their billings, with the majority of the patients in their practices (63.0%) receiving at least one PB in 2019. Patients who received a PB from a high-volume provider had a higher annual frequency of visit for PBs (median [IQR], 10 [3-23]) and number of PBs administered per visit (median [IQR], 5 [4-6]). CONCLUSION: Pain block administration is highly clustered in Ontario, with many patients receiving PBs in ways that are not supported by best evidence. Further research is required to determine whether the Ontario fee-for-service model of billing has created a suboptimal use of these health care resources.

RéSUMé: OBJECTIF: La prise en charge multidisciplinaire de la douleur chronique comprend des stratégies pharmacologiques, psychologiques et interventionnelles. Au Canada, l'utilisation de blocs interventionnels pour la douleur (PB pour 'pain block') a augmenté au cours des dernières années. Nous avons cherché à déterminer la répartition et le regroupement des PB parmi les médecins en Ontario, et à examiner les différences dans les caractéristiques de la patientèle et des médecins selon le volume de blocs administrés. MéTHODE: Nous avons mené une étude transversale basée sur la population des PB administrés pour traiter la douleur chronique aux personnes résidant en Ontario entre le 1er janvier et le 31 décembre 2019. Notre critère d'évaluation principal était le nombre total de blocs pour la douleur administrés en ambulatoire pour la douleur chronique par des médecins éligibles. Nous avons utilisé les courbes de Lorenz, globalement et stratifiées par type de blocs pour la douleur et par spécialité médicale, pour examiner le regroupement des PB parmi les médecins, et comparé les caractéristiques de la patientèle et des médecins en utilisant des différences standardisées. RéSULTATS: Parmi les médecins qui réalisaient des PB, l'offre était fortement regroupée, le 1 % supérieur des médecins réalisant 39 % des blocs. Parmi ces médecins réalisant un volume élevé de PB, dont la majorité étaient des médecins généralistes (88,4 %), les PB représentaient la grande majorité ([écart interquartile (ÉIQ)] médian, 87 % [84-89]) de leur facturation, la majorité (63,0 %) des patient·es de leur cabinet recevant au moins un bloc pour la douleur en 2019. Les patient·es qui ont reçu un PB d'un prestataire à volume élevé avaient une fréquence annuelle de visite plus élevée pour les PB (médiane [ÉIQ], 10 [3-23]) et un nombre plus élevé de PB administrés par visite (médiane [ÉIQ], 5 [4-6]). CONCLUSION: L'administration de blocs pour la douleur est fortement concentrée en Ontario, bon nombre de patient·es recevant des PB d'une manière qui n'est pas appuyée par les meilleures données probantes. D'autres recherches sont nécessaires pour déterminer si le modèle de facturation à l'acte de l'Ontario a créé une utilisation sous-optimale de ces ressources en soins de santé.

Use of injections for chronic pain from 2010 to 2019 in Ontario, Canada.

PURPOSE: The management of chronic pain often involves interventional procedures such as injections. Nevertheless, there have been concerns raised regarding the frequency with which these injections are being performed. We conducted a descriptive study to examine trends in the use of pain injections over a ten-year time period in Ontario, Canada. METHODS: We used provincial administrative data to conduct a retrospective observational study of the most common pain injections performed from 2010 to 2019 in Ontario. We determined the frequency of pain injections and their associated physician billings from physician billing data. RESULTS: A total of 18,050,058 pain injections were included in this study with an associated total cost of CAD 865,431,605. There was a threefold increase in the number of blocks performed annually and associated costs, rising from 1,009,324 blocks (CAD 50,026,678) in 2010 to 3,198,679 blocks (CAD 156,809,081) in 2019. The majority of injections were performed by general practioners (70.8%), followed by anesthesiologists (8.3%). CONCLUSION: This descriptive study revealed a rapid increase in the frequency of pain injections performed in Ontario from 2010 to 2019. Given the associated costs and potential risks, this warrants further investigation to ensure that these interventions are being administered appropriately.

RéSUMé: OBJECTIF: La prise en charge de la douleur chronique implique souvent des procédures interventionnelles telles que des injections. Néanmoins, des préoccupations ont été soulevées quant à la fréquence à laquelle ces injections sont administrées. Nous avons réalisé une étude descriptive pour examiner les tendances dans l'utilisation d'injections pour soulager la douleur sur une période de dix ans en Ontario, au Canada. MéTHODE: Nous avons utilisé les données administratives provinciales pour réaliser une étude observationnelle rétrospective des injections pour soulager la douleur les plus courantes effectuées de 2010 à 2019 en Ontario. Nous avons déterminé la fréquence des injections pour soulager la douleur et les facturations des médecins associées à partir des données de facturation des médecins. RéSULTATS: Au total, 18 050 058 injections pour soulager la douleur ont été incluses dans cette étude, avec un coût total associé de 865 431 605 CAD. Le nombre de blocs exécutés chaque année et les coûts associés ont triplé, passant de 1 009 324 blocs (50 026 678 CAD) en 2010 à 3 198 679 blocs (156 809 081 CAD) en 2019. La majorité des injections ont été administrées par des médecins généralistes (70,8 %), suivis par des anesthésiologistes (8,3 %). CONCLUSION: Cette étude descriptive a révélé une augmentation rapide de la fréquence des injections pour soulager la douleur et administrées en Ontario de 2010 à 2019. Compte tenu des coûts associés et des risques potentiels, cela justifie une enquête plus approfondie pour s'assurer que ces interventions sont administrées de manière appropriée.

Association between preoperative cardiac risk assessment and health care costs in major noncardiac surgery: a multicentre health economic analysis.

PURPOSE: Patients with impaired functional capacity who undergo major surgery are at increased risk of postoperative morbidity including complications and increased length of stay. These outcomes have been associated with increased hospital and health system costs. We aimed to assess whether common preoperative risk indices are associated with postoperative cost. METHODS: We conducted a health economic analysis focused on the subset of Measurement of Exercise Tolerance before Surgery (METS) study participants in Ontario, Canada. Participants were scheduled for major elective noncardiac surgery and underwent several preoperative assessments of cardiac risk, including physicians' subjective assessment, Duke Activity Status Index (DASI) questionnaire, peak oxygen consumption, and N-terminal pro-B-type natriuretic peptide concentration. Using linked health administrative data, postoperative costs were calculated for both one year and in-hospital. Using multiple regression models, we tested for association between the preoperative measures of cardiac risk and postoperative costs. RESULTS: Our study included 487 patients (mean [standard deviation] age 68 [11] yr and 47.0% female) who underwent noncardiac surgery between 13 June 2013 and 8 March 2016. Overall, the median [interquartile range] cost incurred within one year postoperatively was CAD 27,587 [13,902-32,590], of which CAD 12,928 [10,253-12,810] were incurred in-hospital and CAD 14,497 [10,917-15,017] were incurred by 30 days. None of the four preoperative measures of cardiac risk assessment were associated with costs incurred in hospital or at one year postoperatively. This lack of strong association persisted in sensitivity analyses considering type of surgical procedure, burden of preoperative cost, and when costs were categorized as quantiles. CONCLUSION: In patients undergoing major noncardiac surgery, common measures of functional capacity are not consistently associated with total postoperative cost. Until further data exist that differ from this analysis, clinicians and health care funders should not assume that preoperative measures of cardiac risk are associated with annual health care or hospital costs for such surgeries.

RéSUMé: OBJECTIF: La patientèle présentant une capacité fonctionnelle dégradée qui bénéficie d'une intervention chirurgicale majeure court un risque accru de morbidité postopératoire, y compris de complications et de prolongation de la durée de séjour. Ces issues ont été associées à une augmentation des coûts hospitaliers et du système de santé. Notre objectif était d'évaluer si des indices de risque préopératoires communs étaient associés aux coûts postopératoires. MéTHODE: Nous avons effectué une analyse de l'économie de la santé axée sur le sous-ensemble des participant·es à l'étude METS (Measurement of Exercise Tolerance before Surgery) en Ontario, au Canada. Les participant·es devaient bénéficier d'une chirurgie non cardiaque et non urgente majeure et ont complété plusieurs évaluations préopératoires du risque cardiaque, notamment l'évaluation subjective des médecins, le questionnaire DASI (Duke Activity Status Index), la consommation maximale d'oxygène et la concentration de prohormone N-terminale du peptide natriurétique de type B (cérébral) (NT-proBNP). À l'aide de données administratives couplées de santé, les coûts postopératoires ont été calculés à la fois pour une année et à l'hôpital. À l'aide de modèles de régression multiples, nous avons testé l'association entre les mesures préopératoires du risque cardiaque et les coûts postopératoires. RéSULTATS: Notre étude a inclus 487 personnes (âge moyen [écart type] 68 [11] ans et 47,0 % de femmes) ayant bénéficié d'une chirurgie non cardiaque entre le 13 juin 2013 et le 8 mars 2016. Dans l'ensemble, le coût médian [écart interquartile] engagé dans l'année qui a suivi l'opération était de 27 587 CAD [13 902­32 590], dont 12 928 CAD [10 253­12 810] ont été encourus à l'hôpital et 14 497 CAD [10 917­15 017] ont été encourus dans les premiers 30 jours. Aucune des quatre mesures préopératoires de l'évaluation du risque cardiaque n'était associée aux coûts engagés à l'hôpital ou un an après l'opération. Cette absence d'association forte persistait dans les analyses de sensibilité tenant compte du type d'intervention chirurgicale, du fardeau des coûts préopératoires et lorsque les coûts étaient classés en quantiles. CONCLUSION: Chez la patientèle bénéficiant d'une chirurgie non cardiaque majeure, les mesures courantes de la capacité fonctionnelle ne sont pas systématiquement associées au coût postopératoire total. Jusqu'à ce qu'il existe d'autres données qui diffèrent de cette analyse, les cliniciens et cliniciennes et les organismes finançant les soins de santé ne devraient pas présumer que les mesures préopératoires du risque cardiaque sont associées aux coûts annuels des soins de santé ou des hôpitaux pour de telles chirurgies.

α3* Nicotinic Acetylcholine Receptors in the Habenula-Interpeduncular Nucleus Circuit Regulate Nicotine Intake.

Allelic variation in CHRNA3, the gene encoding the α3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for α3-containing (α3*) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. α3* nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3tm1.1Hwrt hypomorphic mice, which express constitutively low levels of α3* nAChRs, self-administer greater quantities of nicotine (0.4 mg kg-1 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg-1 per infusion). Using whole-cell recordings, we found that the α3ß4* nAChR-selective antagonist α-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the α3ß2* nAChR-selective antagonist α-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of α-conotoxin AuIB (10 µm) but not α-conotoxin MII (10 µm) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that α3ß4* nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.SIGNIFICANCE STATEMENT Allelic variation in CHRNA3, which encodes the α3 nicotinic acetylcholine receptor (nAChR) subunit gene, increases risk of tobacco dependence but underlying mechanisms are unclear. We report that Chrna3 hypomorphic mice consume greater quantities of nicotine than wild-type mice and that knock-down of Chrna3 gene transcripts in the habenula or interpeduncular nucleus (IPn) increases nicotine intake in rats. α-Conotoxin AuIB, a potent antagonist of the α3ß4 nAChR subtype, reduced the stimulatory effects of nicotine on habenular neurons, and its infusion into the IPn increased nicotine intake in rats. These data suggest that α3ß4 nAChRs in the habenula-IPn circuit regulate the motivational properties of nicotine.