Respiratory Depression Research Articles

Effects of an early intensive blood pressure-lowering strategy using remifentanil and dexmedetomidine in patients with spontaneous intracerebral hemorrhage: a multicenter, prospective, superiority, randomized controlled trial.

Although it has been established that elevated blood pressure and its variability worsen outcomes in spontaneous intracerebral hemorrhage, antihypertensives use during the acute phase still lacks robust evidence. A blood pressure-lowering regimen using remifentanil and dexmedetomidine might be a reasonable therapeutic option given their analgesic and anti-sympathetic effects. The objective of this superiority trial was to validate the efficacy and safety of this blood pressure-lowering strategy that uses remifentanil and dexmedetomidine in patients with acute intracerebral hemorrhage. In this multicenter, prospective, single-blinded, superiority randomized controlled trial, patients with intracerebral hemorrhage and systolic blood pressure (SBP) ≥150 mmHg were randomly allocated to the intervention group (a preset protocol with a standard guideline management using remifentanil and dexmedetomidine) or the control group (standard guideline-based management) to receive blood pressure-lowering treatment. The primary outcome was the SBP control rate (<140 mmHg) at 1 h posttreatment initiation. Secondary outcomes included blood pressure variability, neurologic function and clinical outcomes. A total of 338 patients were allocated to the intervention (n = 167) or control group (n = 171). The SBP control rate at 1 h posttreatment initiation in the intervention group was higher than that in controls (101/161, 62.7% vs. 66/166, 39.8%, difference 23.2%, 95% CI, 12.4 to 34.1%, P < 0.001). Analysis of secondary outcomes indicated that patients in the intervention group could effectively reduce agitation while achieving lighter sedation, but no improvement in clinical outcomes was observed. Regarding safety, the incidence of bradycardia and respiratory depression was higher in the intervention group. Among intracerebral hemorrhage patients with a SBP ≥ 150 mmHg, a preset protocol using a remifentanil and dexmedetomidine-based standard guideline management significantly increased the SBP control rate at 1 h posttreatment compared with the standard guideline-based management. (ClinicalTrials.gov number: NCT03207100, Registration date: June 30, 2017).

Asystole in a young child with tetrahydrocannabinol overdose: a case report and review of literature

IntroductionThe association between Δ8-tetrahydrocannabinol (THC) and cardiac dysrhythmia has not been well described in children. Asystole, while consistent with reports of severe bradycardia and apnea in children, is uncommonly described in the current literature. We present the first pediatric case of asystole and apnea following THC ingestion.CaseA 7-year-old male presented to the emergency department (ED) after his mother noticed he was lethargic 3–4 h after accidental ingestion of five 15 mg (total of 75 mg) Δ8-THC gummies. Upon arrival, he was vitally stable and well-appearing. He received maintenance intravenous fluids. Approximately 7 h after initial ingestion, he experienced a &amp;gt;15-s episode of asystole and apnea on telemetry requiring sternal rub to awaken. This was followed by bradycardia (60 beats per minute range) which resolved with 0.1 mg glycopyrrolate. He was admitted to the PICU, drowsy but arousable with stable vitals. After an uneventful 24-h (post-ingestion) PICU observation, he was discharged home in stable condition.DiscussionTo our knowledge, this is the first reported pediatric case of THC-induced asystole. The etiology of asystole may be attributed to direct vagal stimulation of THC or respiratory depression. The typical recommended observation time after potential toxicity is 3–6 h after children have returned to their physiological and behavioral baseline. Our patient was clinically stable with no concern for respiratory depression or cardiac dysrhythmia yet experienced an asystolic pause with apnea 7 h after initial ingestion.ConclusionOur case demonstrates that asystole and apnea may occur in pediatric patients following large THC ingestions and those symptoms can appear late outside of the currently recommended observation period.

Association of Opioid and Concurrent Benzodiazepine, Skeletal Muscle Relaxant, and Gabapentinoid Usage on Healthcare Expenditure and Resource Utilization: A Serial Cross-Sectional Study, 2009 to 2019.

Healthcare providers may be utilizing central nervous system (CNS) depressants to reduce opioid use due to recent changes in public policy. Combination use of these agents with opioids increases the risk of respiratory depression and death. Healthcare expenditures by individuals using these drug combinations have not been previously quantified. We sought to characterize healthcare costs and expenditures associated with a population reporting concurrent CNS depressants and opioid use compared with nonopioid analgesics in the United States from 2009 to 2019. A serial cross-sectional design was used to compare the healthcare expenditures of adult Medical Expenditure Panel Survey respondents who were prescribed nonopioid analgesics, opioids only, opioids/benzodiazepines (BZD), opioids/BZD/skeletal muscle relaxants (SMR), or opioids/gabapentin (gaba) using pooled data from 2009 to 2019. Expenditure (cost and resource utilization) categories included inpatient, outpatient, office-based, and prescription medicine. Average marginal effects were used to compare survey-weighted annual costs and resource utilizations across the groups as compared to nonopioid analgesic respondents, adjusted for covariates. A weighted total of 34 241 838 individuals were identified. Most were opioid-only respondents (46.5%), followed by nonopioid analgesic (43.4%), opioid/BZD (5.3%), opioid-gaba (3.5%), and opioid/BZD/SMR respondents (1.3%). In comparison to the study groups with nonopioid analgesics, opioid-gaba users had the highest significant incremental cost difference among the different pairings (+$11 684, P < .001). Opioid-gaba, opioid/BZD, and opioid/BZD/SMR respondents had significantly higher inpatient, emergency department, and prescription drug costs and use compared to nonopioid analgesic respondents. Opioid-only respondents had higher outpatient and office-based costs and visits compared to nonopioid analgesic respondents. As healthcare providers seek to utilize fewer opioids for pain management, attention must be paid to ensuring safe and effective use of concurrent CNS depressants to mitigate high healthcare costs and burden.

Safe Management of Adverse Effects Associated with Prescription Opioids in the Palliative Care Population: A Narrative Review

In the palliative care population, prescription opioids are often considered viable pain relief options. However, in this complex patient population, the adverse effects of opioid medications should be identified and managed without delay. Common adverse effects can include constipation, nausea, somnolence, dizziness, vomiting, and pruritus. Less common adverse effects can include potentially lethal respiratory depression and cardiovascular effects. Critical aspects of safe opioid prescribing are recognition of side effects and knowledge of effective management strategies; prompt management is necessary for uninterrupted pain relief. Most complications are managed with general approaches such as dose reduction, opioid rotation, alternate routes of administration, and symptomatic management. The only opioid-induced complication for which US Food and Drug Administration-approved treatments currently exist is constipation. Treating laxative-refractory opioid-induced constipation (OIC) with peripherally acting mu-opioid receptor antagonists (PAMORAs), which block gastrointestinal opioid receptors, can restore gastrointestinal motility and fluid secretion. This narrative review discusses key complications of prescription opioid treatment and their management in the palliative care setting.

Utility of Dexmedetomidine in Paediatric Cardiac Surgery: a Systematic Review and Meta-analysis

Dexmedetomidine is a selector α 2-agonist that provides sedation with sparing respiratory depression, anxiolysis, and analgesic adjunct with opioids and benzodiazepines sparing effects, prolongs the duration of regional anesthesia and allows early tracheal extubation after pediatric cardiac surgery.[1,2,3 ] Recently, dexmedetomidine has been established as a cardioprotective agent in adult cardiac surgical patients. Some trials show significantly lower myocardial injury markers like interleukin-6 (IL-6) levels, cardiac troponin I (cTnI), and creatinine kinase-myocardial band (CK-MB), after cardiac surgery in the dexmedetomidine group.[ ] The majority of published studies have suggested that dexmedetomidine is a seemingly efficacious agent protecting against cardiac injury during CPB.[6] Its administration lowers mechanical ventilation period, ICU stay, and length of hospital stay after pediatric cardiac surgery. In addition, it is effective against postoperative shivering, refractory JET rhythm and Tet spells, and acute kidney injury (AKI) in cyanotic pediatric patients undergoing corrective surgery. However, studies on its application in pediatric heart surgery using cardiopulmonary bypass (CPB) remain limited. This systematic review aimed to provide information on the utility of dexmedetomidine in patients undergoing pediatric cardiac surgery using CPB: hemodynamic stability, cardioprotective, renal protection, neuroprotective effects, control of refractory JET, and Tet spells, and the early and late outcome.

Pediatric obstructive sleep apnea: A prospective observational study of respiratory events in the immediate recovery period after adenotonsillectomy

BackgroundAdenotonsillectomy is often curative for pediatric obstructive sleep apnea, yet children remain at high risk of respiratory complications in the postoperative period. We sought to determine the incidence and risk factors for respiratory depression and airway obstruction, as well as clinically apparent respiratory events in the post-anesthesia care unit (PACU) in high-risk children after adenotonsillectomy. MethodsIn this prospective cohort study, we enrolled 60 high-risk children having adenotonsillectomy. Our primary outcome was respiratory depression and airway obstruction in the PACU measured using a noninvasive respiratory volume monitor (RVM) and defined by episodes of predicted minute ventilation less than 40% for at least 2 minutes. We measured clinically apparent respiratory events using continuous observation by trained study staff. ResultsThe median (range) age of our sample was 4 years (1, 16) and 27 (45%) were female. Black and Hispanic race children comprised 80% (n = 48) of our cohort. Thirty-nine (65%) had at least one episode of PACU respiratory depression or airway obstruction measured using the RVM, while only 21 (35%) had clinically apparent respiratory events. Poisson regression demonstrated the following associations with an increase in episodes of respiratory depression and airway obstruction: BMI Z-score less than -1 (estimate 3.91; [95%CI 1.49-10.23]), BMI Z-score 1-2 (estimate 2.04; [1.20-3.48]), and two or more comorbidities (estimate 1.96; [1.11-3.46]). ConclusionsRespiratory volume monitoring in the immediate postoperative period after pediatric high-risk adenotonsillectomy identifies impaired ventilation more frequently than is clinically apparent.

A Deep Dive into Opioid Antagonist Use for Opioid-Induced Respiratory Depression (OIRD)

A Deep Dive into Opioid Antagonist Use for Opioid-Induced Respiratory Depression (OIRD)

Acute intoxication with diisopropylfluorophosphate promotes cellular senescence in the adult male rat brain.

Acute intoxication with high levels of organophosphate (OP) cholinesterase inhibitors can cause cholinergic crisis, which is associated with acute, life-threatening parasympathomimetic symptoms, respiratory depression and seizures that can rapidly progress to status epilepticus (SE). Clinical and experimental data demonstrate that individuals who survive these acute neurotoxic effects often develop significant chronic morbidity, including behavioral deficits. The pathogenic mechanism(s) that link acute OP intoxication to chronic neurological deficits remain speculative. Cellular senescence has been linked to behavioral deficits associated with aging and neurodegenerative disease, but whether acute OP intoxication triggers cellular senescence in the brain has not been investigated. Here, we test this hypothesis in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats were administered DFP (4mg/kg, s.c.). Control animals were administered an equal volume (300µL) of sterile phosphate-buffered saline (s.c.). Both groups were subsequently injected with atropine sulfate (2mg/kg, i.m.) and 2-pralidoxime (25mg/kg, i.m.). DFP triggered seizure activity within minutes that rapidly progressed to SE, as determined using behavioral seizure criteria. Brains were collected from animals at 1, 3, and 6months post-exposure for immunohistochemical analyses of p16, a biomarker of cellular senescence. While there was no immunohistochemical evidence of cellular senescence at 1-month post-exposure, at 3- and 6-months post-exposure, p16 immunoreactivity was significantly increased in the CA3 and dentate gyrus of the hippocampus, amygdala, piriform cortex and thalamus, but not the CA1 region of the hippocampus or the somatosensory cortex. Co-localization of p16 immunoreactivity with cell-specific biomarkers, specifically, NeuN, GFAP, S100β, IBA1 and CD31, revealed that p16 expression in the brain of DFP animals is neuron-specific. The spatial distribution of p16-immunopositive cells overlapped with expression of senescence associated β-galactosidase and with degenerating neurons identified by FluoroJade-C (FJC) staining. The co-occurrence of p16 and FJC was positively correlated. This study implicates cellular senescence as a novel pathogenic mechanism underlying the chronic neurological deficits observed in individuals who survive OP-induced cholinergic crisis.

Multitarget μ-Opioid Receptor Agonists─Neuropeptide FF Receptor Antagonists Induce Potent Antinociception with Reduced Adverse Side Effects.

The design of bifunctional compounds is a promising approach toward the development of strong analgesics with reduced side effects. We here report the optimization of the previously published lead peptide KGFF09, which contains opioid receptor agonist and neuropeptide FF receptor antagonist pharmacophores and is shown to induce potent antinociception and reduced side effects. We evaluated the novel hybrid peptides for their in vitro activity at MOP, NPFFR1, and NPFFR2 and selected four of them (DP08/14/32/50) for assessment of their acute antinociceptive activity in mice. We further selected DP32 and DP50 and observed that their antinociceptive activity is mostly peripherally mediated; they produced no respiratory depression, no hyperalgesia, significantly less tolerance, and strongly attenuated withdrawal syndrome, as compared to morphine and the recently FDA-approved TRV130. Overall, these data suggest that MOP agonist/NPFF receptor antagonist hybrids might represent an interesting strategy to develop novel analgesics with reduced side effects.

Comparison of Xylazine and Lidocaine Infusion versus Medetomidine Continuous Rate Infusion during General Anesthesia with Isoflurane in Horses Undergoing Emergency Laparotomy

(1) The main goals of general anesthesia include pain management and a safe anesthetic protocol for smooth recovery. In this retrospective study, we compared two anesthetic protocols for general anesthesia with isoflurane during emergency laparotomy: sedation with xylazine and the intraoperative infusion of lidocaine (X group) versus medetomidine as a preoperative sedation and intraoperative infusion (M group). (2) The medical records of horses who underwent emergency laparotomies between 2016 and 2023 were reviewed. According to the anesthetic protocol, patients were allocated to the X or M groups. Data about the horse, signalment, history, and anesthetic variables were analyzed. (3) Group X had a significantly higher heart rate (HR), lower respiratory rate (RR) and mean and diastolic arterial pressure (MAP/DAP). A progressive increase in HR and RR was observed in both groups. Group X underwent a decrease in RR and an increase in DAP. In Group M, a decrease in MAP and DAP was observed. Group M exhibited a longer recovery time with similar recovery scores. Both protocols provided safe anesthesia for emergency laparotomy, with minor cardiovascular and respiratory depression. Minor respiratory depression was detected when xylazine was used, while recovery was longer with medetomidine.

Pain intensity profile after a single injection of the peptide analgesic taphalgin in traumatology and orthopedic patients: prospective observational cohort study

INTRODUCTION: Multimodal analgesia is the main management strategy for postoperative pain. One component of this approach is opioid agonists. OBJECTIVE: Assessment of pain intensity profile after a single administration of the new selective µ1-opioid receptor agonist taphalgin in traumatology and orthopedic patients. MATERIALS AND METHODS: This prospective observational program analyzed data from 100 patients whom were prescribed the drug taphalgin for pain relief after traumatological and orthopedic surgery. All patients were treated with 50 mg dexketoprofen when moderate pain appeared after surgery. If the pain reached moderate or high intensity again, 4 mg of taphalgin was administered subcutaneously and then the change in pain intensity at rest and during movement was observed after 15, 30, 45, 60 min, as well as 2 and 4 h, using numerical rating scale (NRS). In this study physicians’ satisfaction by taphalgin was estimated. Satisfaction was assessed using Likert scale, where 1 — very bad, 2 — unsatisfactory, 3 — satisfactory, 4 — good, 5 — excellent. Repeated measures analysis of variance and dependent samples t-test were used for statistical analysis. The critical level of significance for accepting significant differences was set at 0.05. RESULTS: The average value of pain intensity before drug administration at rest was 5.9 ± 0.5 points and pain in movement was 8.4 ± 0.8 points. After just 15 min, significant pain reduction was achieved to 4.9 ± 0.8 and 7.3 ± 1.1 points (p &lt; 0.001), respectively, after 30 min — to 3.6 ± 1.1 and 5.7 ± 1.1 points (p &lt; 0.001), respectively, and after 60 min — to 2.2 ± 0.8 и 4.2 ± 0.8 points (p &lt; 0.001), respectively. Doctor’s satisfaction with treatment showed that a positive assessment was given in 83 % of cases, and complete dissatisfaction was revealed in 1 % of cases. Impotently, no observations of respiratory depression or postoperative nausea and vomiting syndrome have been recorded. CONCLUSIONS: The drug taphalgin is an effective analgesic for the postoperative period in traumatology and orthopedics.

Evaluating the Risk Index for Serious Prescription Opioid-Induced Respiratory Depression or Overdose in Patients with Cancer

The Commercially Insured health Plan Risk Index for Overdose or Serious Opioid-induced Respiratory Depression (CIP-RIOSORD) is an evidence-based tool to determine serious opioid-induced respiratory depression (OIRD) or overdose risk. The CIP-RIOSORD total score determines a risk class and estimates the probability for an OIRD event within the next 6 months. We performed a single-center, retrospective analysis to determine CIP-RIOSORD baseline scores and the most common predictive factors in patients with cancer. Patients (n = 160) were split into new consultations (n = 83, Group 1) versus the first documented follow-up consultation (n = 77, Group 2). Most patients were Caucasian women with metastatic gastrointestinal cancer. CIP-RIOSORD scores for Group 1 patients were 14.8 ± 15.2 (mean ± SD, risk class 4). Group 2 patients had higher CIP-RIOSORD scores (16.6 ± 14.9, risk class 4). For Group 1, the most common CIP-RIOSORD predictive factors were use of a long-acting opioid formulation (n = 24, 29%) and daily oral morphine equivalent (OME) ≥100 (n = 20, 24%); for Group 2, predictive factors were use of an antidepressant (n = 34, 44%) and a long-acting opioid formulation (n = 27, 35%). Based on the CIP-RIOSORD, there is a 15% probability of experiencing a serious OIRD event or overdose within the next 6 months.

Obstructive Sleep Apnea and Risk of Postoperative Complications after Non-Cardiac Surgery.

Obstructive sleep apnea (OSA), a common sleep disorder, poses significant challenges in perioperative management due to its complexity and multifactorial nature. With a global prevalence of approximately 22.6%, OSA often remains undiagnosed, and increases the risk of cardiac and respiratory postoperative complications. Preoperative screening has become essential in many institutions to identify patients at increased risk, and experts recommend proceeding with surgery in the absence of severe symptoms, albeit with heightened postoperative monitoring. Anesthetic and sedative agents exacerbate upper airway collapsibility and depress central respiratory activity, complicating intraoperative management, especially with neuromuscular blockade use. Additionally, OSA patients are particularly prone to opioid-induced respiratory depression, given their increased sensitivity to opioids and heightened pain perception. Thus, regional anesthesia and multimodal analgesia are strongly advocated to reduce perioperative complication risks. Postoperative care for OSA patients necessitates vigilant monitoring and tailored management strategies, such as supplemental oxygen and Positive Airway Pressure therapy, to minimize cardiorespiratory complications. Health care institutions are increasingly focusing on enhanced monitoring and resource allocation for patient safety. However, the rising prevalence of OSA, heterogeneity in disease severity, and lack of evidence for the efficacy of costly perioperative measures pose challenges. The development of effective screening and monitoring algorithms, alongside reliable risk predictors, is crucial for identifying OSA patients needing extended postoperative care. This review emphasizes a multidimensional approach in managing OSA patients throughout the perioperative period, aiming to optimize patient outcomes and minimize adverse outcomes.

Melatonin vs. dexmedetomidine for sleep induction in children before electroencephalography.

In children requiring electroencephalography (EEG), sleep recording can provide crucial information. As EEG recordings during spontaneous sleep are not always possible, pharmacological sleep-inducing agents are sometimes required. The aim of the study was to evaluate safety and efficacy of melatonin (Mel) and dexmedetomidine (Dex; intranasal and sublingual application) for sleep induction prior to EEG. In this prospective randomized study, 156 consecutive patients aged 1-19 years were enrolled and randomized by draw into melatonin group (Mel; n = 54; dose: 0.1 mg/kg), dexmedetomidine (Dex) sublingual group (DexL; n = 51; dose: 3 mcg/kg) or dexmedetomidine intranasal group (DexN; n = 51; dose: 3 mcg/kg). We compared the groups in several parameters regarding efficacy and safety and also carried out a separate analysis for a subgroup of patients with complex behavioral problems. Sleep was achieved in 93.6% of participants after the first application of the drug and in 99.4% after the application of another if needed. Mel was effective as the first drug in 83.3% and Dex in 99.0% (p < 0.001); in the subgroup of patients with complex developmental problems Mel was effective in 73.4% and Dex in 100% (p < 0.001). The patients fell asleep faster after intranasal application of Dex than after sublingual application (p = 0.006). None of the patients had respiratory depression, bradycardia, desaturation, or hypotension. Mel and Dex are both safe for sleep induction prior to EEG recording in children. Dex is more effective compared to Mel in inducing sleep, also in the subgroup of children with complex behavioral problems. Dexmedetomidine and Melatonin for Sleep Induction for EEG in Children, NCT04665453.

Incidence and risk factors for potential drug-drug interactions in outpatients receiving opioid analgesics

ABSTRACT Background Opioids are the most frequently used drugs to treat pain in cancer patients. However opioid analgesics can cause adverse effects and potential drug-drug interaction. Research design and methods This cross-sectional retrospective study analyzed pDDI in 1839 patients with opioid analgesics in a large comprehensive hospital in China from January 1 to 31 December 2022. Three drug interaction databases were used to screen for pDDI including Drugs (U.S.A.), Medscape (U.S.A.), and Drug Assistant of Dingxiangyuan (China). Results The prevalence of pDDIs among 1839 patients was around 41.27% of 759 patients, and 564 patients (74.31%) with pDDIs were diagnosed with tumor. Further, the total of 275 various pDDIs combinations were identified. The combination of oxycodone with morphine had the most frequent occurrence of 229 times, and its adverse effects mainly related to exacerbate central respiratory depression. While, gender, tumor, number of diagnoses, and the variety of opioid analgesics used were independent risk factors for pDDIs. Conclusions Outpatients taking opioid analgesics had a higher incidence of pDDIs. As consequently, optimized monitoring and management of patients taking opioid analgesics is recommended in order to ensure patient medication safety.

Buprenorphine Affects the Initiation and Severity of Interleukin Induced Acute Pancreatitis in Mice.

Acute pancreatitis (AP) is a common disease with no targeted therapy and has varied outcomes ranging from spontaneous resolution to being lethal. While typically painful, AP can also be painless. Various agents, including opioids are used for pain control in AP; the risks, and benefits of which are often debated. Since experimental AP in mice is used to study the efficacy of potential therapies, we studied the effect of a commonly used opioid buprenorphine on the initiation and progression of AP. For this we administered extended-release buprenorphine subcutaneously prior to inducing the previously established severe AP model that uses Interleukins 12 and 18 (IL12,18) in genetically obese (ob/ob) mice and compared this to mice with AP but without the drug. Mice were monitored over 3 days and parameters of AP induction and progression were compared. Buprenorphine significantly reduced the serum amylase, lipase, pancreatic necrosis, and AP associated fat necrosis which is ubiquitous in obese mice and humans. Buprenorphine delayed the AP associated reduction of carotid artery pulse distention, and development of hypothermia, hastened renal injury, and muted the early increase in respiratory rate vs. IL12,18 alone. The site of buprenorphine injection appeared erythematous, inflamed, and microscopically showed thinning, loss of epidermal layers which had increased apoptosis. In summary, subcutaneous extended-release buprenorphine interfered with the induction of AP by reducing serum amylase, lipase, pancreatic and fat necrosis, the worsening of AP by delaying hypotension, hypothermia, while hastening renal injury, respiratory depression, and causing cutaneous injury at the site of injection.

Intraoperative methadone for day-case gynaecological laparoscopy: A double-blind, randomised controlled trial.

Optimal pain relief in day-case surgery is imperative to patient comfort and timely discharge from hospital. Short-acting opioids are commonly used for analgesia in modern anaesthesia, allowing rapid recovery after surgery. Plasma concentration fluctuations from repeated dosing of short-acting opioids can cause patients to oscillate between analgesia with potential adverse effects, and inadequate analgesia requiring rescue dosing. Methadone's unique pharmacology may offer effective and sustained analgesia with less opioid consumption, potentially reducing adverse effects. Using a double-blind, randomised controlled trial, we compared post-anaesthesia care unit opioid consumption between day-case gynaecological laparoscopy patients who received either intravenous methadone (10 mg), or short-acting opioids intraoperatively. The primary outcome was post-anaesthesia care unit opioid consumption in oral morphine equivalents. Secondary outcomes included total opioid consumption, discharge opioid consumption, pain scores (0-10) until discharge, adverse effects (respiratory depression, postoperative nausea and vomiting, excess sedation), and rate of admission. Seventy patients were randomly assigned. Patients who received methadone consumed on average 9.44 mg fewer oral morphine equivalents in the post-anaesthesia care unit than the short-acting group (18.02 mg vs 27.46 mg, respectively, 95% confidence interval 0.003 to 18.88, P = 0.050) and experienced lower postoperative pain scores at every time point, although absolute differences were small. There was no evidence of lower hospital or discharge opioid consumption. No significant differences between the methadone and short-acting groups in other outcomes were identified: respiratory depression 41.2% versus 31.4%, Padjusted >0.99; postoperative nausea and vomiting 29.4% versus 42.9%, Padjusted >0.99; overnight admission 17.7% versus 11.4%, Padjusted >0.99; excess sedation 8.82% versus 8.57%, Padjusted >0.99. This study provides evidence that, although modestly, methadone can reduce post-anaesthesia care unit opioid consumption and postoperative pain scores after day-case gynaecological laparoscopy. There were no significant differences in any secondary outcomes.

To Compare the Anesthetic Effect of Remimazolam and Propofol in Painless Hysteroscopic Minimally Invasive Surgery.

Hysteroscopic surgery will stimulate the autonomic nerves innervating the uterus, causing intense discomfort and pain in the examined person, and in severe cases, it will cause blood pressure drop, heart rate slowing, arrhythmia and even cardiac arrest, so most patients need anesthetic intervention. This study to retrospectively compare the anesthetic effect of remimazolam and propofol in minimally invasive painless hysteroscopic surgery and to explore the safety and efficacy of remimazolam. The clinical data of 110 female patients who underwent painless hysteroscopic minimally invasive surgery in our hospital from January 2023 to June 2023 were collected. The patients were divided into the remimazolam group (group R, n = 55) and the propofol group (group P, n = 55) according to the main anesthetic drugs used during the operation. The changes in heart rate (HR), mean arterial pressure (MAP), blood oxygen saturation (SpO2), and respiratory rate (RR) at the time of entry (T0), modified vigilance/sedation score (MOAA/S) 0 (T1), cervical dilation (T2), end of the operation (T3) and anesthesia recovery (T4) were compared between the two groups. Anesthesia induction time, operation time, and anesthesia recovery time were compared between the two groups, and the incidence of intraoperative and postoperative adverse reactions was compared between the two groups. HR, MAP, and SpO2 in group R were significantly higher than those in group P at T1, T2, T3, and T4 (p < 0.05), and there was no significant difference in RR between the two groups (p > 0.05). HR, MAP, and SpO2 at T1 and T2 were significantly lower than those at T0 in group R (p < 0.05), and RR at different time points in the group had no significant difference (p > 0.05). HR, MAP, and SpO2 at T1, T2, T3, and T4 were significantly lower than those at T0 in group P (p < 0.01), and RR at different time points in the same group had no significant difference (p > 0.05). The anesthesia induction time in group R was more prolonged than in group P, and the anesthesia recovery time in group R was shorter than in group P (p < 0.05). The incidences of hypotension, bradycardia, low oxygen saturation, respiratory depression, and injection pain in group R were significantly lower than those in group P (p < 0.05). Intravenous induction of remimazolam at 6 mg·kg-1·h-1 and maintenance of anesthesia at 1-2 mg·kg-1·h-1 have less effect on hemodynamics, faster recovery time and lower incidence of adverse reactions compared with propofol when used in minimally invasive hysteroscopic surgery. Remimazolam can be safely and effectively used in this kind of surgery.

Low-Efficacy Mu Opioid Agonists as Candidate Analgesics: Effects of Novel C-9 Substituted Phenylmorphans on Pain-Depressed Behavior in Mice.

Low efficacy mu opioid receptor (MOR) agonists may serve as novel candidate analgesics with improved safety relative to high-efficacy opioids. This study used a recently validated assay of pain-depressed behavior in mice to evaluate a novel series of MOR-selective C9-substituted phenylmorphan opioids with graded MOR efficacies. Intraperitoneal injection of dilute lactic acid (IP acid) served as a noxious stimulus to depress locomotor activity by mice in an activity chamber composed of two compartments connected by an obstructed door. Behavioral measures included (1) crosses between compartments (vertical activity over the obstruction) and (2) movement counts quantified as photobeam breaks summed across compartments (horizontal activity). Each drug was tested alone and as a pretreatment to IP acid. A charcoal-meal test and whole-body-plethysmography assessment of breathing in 5% CO2 were also used to assess gastrointestinal (GI) inhibition and respiratory depression, respectively. IP acid produced a concentration-dependent depression in crosses and movement that was optimally alleviated by intermediate- to low-efficacy phenylmorphans with sufficient efficacy to produce analgesia with minimal locomotor disruption. Follow-up studies with two low-efficacy phenylmorphans (JL-2-39 and DC-1-76.1) indicated that both drugs produced naltrexone-reversible antinociception with a rapid onset and a duration of ~1hr. Potency of both drugs increased when behavior was depressed by a lower IP-acid concentration, and neither drug alleviated behavioral depression by a non-pain stimulus (IP lithium chloride). Both drugs produced weaker GI inhibition and respiratory depression than fentanyl and attenuated fentanyl-induced GI inhibition and respiratory depression. Results support further consideration of selective, low-efficacy MOR agonists as candidate analgesics. Significance Statement This study used a novel set of mu opioid receptor (MOR)-selective opioids with graded MOR efficacies to examine the lower boundary of MOR efficacy sufficient to relieve pain-related behavioral depression in mice. Two novel low-efficacy opioids (JL-2-39, DC-1-76.1) produced effective antinociception with improved safety relative to higher- or lower-efficacy opioids, and results support further consideration of these and other low-efficacy opioids as candidate analgesics.

Fentanyl activates opposing opioid and non-opioid receptor systems that control breathing.

Fentanyl elicits profound disturbances in ventilatory control processes in humans and experimental animals. The traditional viewpoint with respect to fentanyl-induced respiratory depression is that once the effects on the frequency of breathing (Freq), tidal volume (TV), and minute ventilation (MV = Freq × TV) are resolved, then depression of breathing is no longer a concern. The results of the present study challenge this concept with findings, as they reveal that while the apparent inhibitory effects of fentanyl (75μg/kg, IV) on Freq, TV, and MV in adult male rats were fully resolved within 15 min, many other fentanyl-induced responses were in full effect, including opposing effects on respiratory timing parameters. For example, although the effects on Freq were resolved at 15 min, inspiratory duration (Ti) and end inspiratory pause (EIP) were elevated, whereas expiratory duration (Te) and end expiratory pause (EEP) were diminished. Since the effects of fentanyl on TV had subsided fully at 15 min, it would be expected that the administration of an opioid receptor (OR) antagonist would have minimal effects if the effects of fentanyl on this and other parameters had resolved. We now report that the intravenous injection of a 1.0mg/kg dose of the peripherally restricted OR antagonist, methyl-naloxone (naloxone methiodide, NLXmi), did not elicit arousal but elicited some relatively minor changes in Freq, TV, MV, Te, and EEP but pronounced changes in Ti and EIP. In contrast, the injection of a 2.5mg/kg dose of NLXmi elicited pronounced arousal and dramatic changes in many variables, including Freq, TV, and MV, which were not associated with increases in non-apneic breathing events such as apneas. The two compelling conclusions from this study are as follows: 1) the blockade of central ORs produced by the 2.5mg/kg dose of NLXmi elicits pronounced increases in Freq, TV, and MV in rats in which the effects of fentanyl had apparently resolved, and 2) it is apparent that fentanyl had induced the activation of two systems with counter-balancing effects on Freq and TV: one being an opioid receptor inhibitory system and the other being a non-OR excitatory system.