Respiratory Depression Research Articles

A Randomized Controlled Trial of Sublingual Sufentanil in Early Management of Pain in Trauma.

Pain management is essential in trauma. Sufentanil is a potent sublingual opioid analgesic with no active metabolites and rapid onset relative to oral medications. We hypothesize that compared to standard care, Sufentanil reduces the verbally administered numerical pain scale (VNRS) at 30 minutes. We performed a prospective multicenter, open-label, randomized trial utilizing level-1 trauma centers from within the Linking Investigator in Trauma and Emergency Services (LITES) network. Participants were randomly assigned in a 1:1 ratio to either sublingual sufentanil or standard care. We enrolled 150 patients from July 2022 to January 2024. The study was approved by the human subjects research protection offices of the University of Pittsburgh and the Department of Defense. Subjects were eligible if they had a trauma evaluation, were 18 to 70, had a VNRS (0-100) score ≥50, and remained in the ED for at least 30 minutes. We excluded patients who were prisoners, pregnant, allergic to opioids, required airway management, body mass index (BMI) >40, significant respiratory depression, suspected gastrointestinal obstruction, or other contraindication to analgesics. The primary outcome was the VNRS for clinical pain measurement (0-100) at 30 minutes after treatment. Secondary outcomes included adverse events (hypoxia, hypotension, need for airway management) and the incidence of nausea/vomiting/headache/dizziness requiring treatment. We hypothesize that sublingual sufentanil as compared to emergency department standard care, will reduce the VNRS at 30 minutes. The study population had a mean age of 48 years (standard deviation [SD] 15) and was 32% female. The mechanism of injury was mostly blunt (96%). The VNRS at 30 minutes was 67 (SD 25) for the entire cohort, 66 (SD 23) in the sufentanil group, and 68 (SD 27) in the standard care group (P = .37). The Health care Professional Global Assessment (HPGA) at 30 minutes showed decreased pain scores in the standard care group compared to sufentanil, with standard care having more patients scored as good or excellent (P = .009). There was no difference in the incidence of nausea, vomiting, headache, dizziness, hypoxia, hypotension, or need for an advanced airway. In this cohort of trauma patients with moderate to severe pain, the VNRS at 30 minutes after administration of analgesics did not differ between sublingual sufentanil and standard care. Adverse events did not differ between the groups suggesting the sublingual sufentanil in this population.

Exploring the Therapeutic Potential of Mitragynine and Corynoxeine: Kratom-Derived Indole and Oxindole Alkaloids for Pain Management

The search for effective pain management solutions remains a critical challenge, especially amidst growing concerns over the use of conventional opioids. In the US, opioid-related mortality rates have surged to as many as 80 deaths per 100,000 people in some states, with an estimated economic burden of USD 1.5 trillion annually—exceeding the gross domestic product (GDP) of most US industrial sectors. A remarkable breakthrough lies in the discovery that indole and oxindole alkaloids, produced by several genera within the plant Tribe Naucleeae, act on opioid receptors without activating the beta-arrestin-2 pathway, the primary driver of respiratory depression and overdose deaths. This systematic review explores the pharmacological properties, mechanisms of action, dosing considerations, interactions, and long-term effects of mitragynine and corynoxeine, alkaloids from the Southeast Asian plant Mitragyna speciosa (kratom) and others in the Tribe Naucleeae. Mitragynine, a partial opioid receptor agonist, and corynoxeine, known for its anti-inflammatory and neuroprotective effects, demonstrate significant therapeutic potential for managing diverse pain types—including neuropathic, inflammatory, nociceptive, visceral, and central pain syndromes—with a focus on cancer pain. Unlike traditional opioids, these compounds do not recruit beta-arrestin-2, avoiding key adverse effects such as respiratory depression, severe constipation, and rapid tolerance development. Their distinct pharmacological profiles make them innovative candidates for safer, non-lethal pain relief. However, challenges persist, including the unregulated nature of kratom products, inconsistencies in potency due to crude extract variability, potential for misuse, and adverse drug interactions. Addressing these issues requires establishing standardized quality control protocols, such as Good Manufacturing Practices (GMP), to ensure consistent potency and purity. Clear labeling requirements with dosage guidelines and warnings should be mandated to ensure safe use and prevent misuse. Furthermore, the implementation of regulatory oversight to monitor product quality and enforce compliance is essential. This review emphasizes the urgency of focused research to optimize dosing regimens, characterize the pharmacodynamic profiles of these alkaloids, and evaluate long-term safety. By addressing these gaps, the mitragynine- and corynoxeine-related drug classes can transition from promising plant-derived molecules to validated pharmacotherapeutic agents, potentially revolutionizing the field of pain management.

Effects of TTP-PECS Block Under Opioid-Sparing General Anesthesia on Postoperative Analgesia and Early Recovery Quality in Patients Undergoing Modified Radical Mastectomy.

Potent analgesics such as sufentanil and remifentanil play a pivotal role in general anesthesia, but these medications have disadvantages, including respiratory depression, nausea, vomiting, immune system suppression, and gastrointestinal function inhibition. This study aimed to evaluate the effects of the transversus thoracic muscle plane-pectoral nerves(TTP-PECS) block on postoperative analgesia, immune function and early postoperative recovery quality inpatients undergoingmodified radical mastectomy under opioid-sparing general anesthesia. A total of 100 patients scheduled for modified radical mastectomy under general anesthesia were randomly divided into the TTP-PECS block combined with opioid-sparing general anesthesia group (TO group, n=50) or the conventional general anesthesia group (GA group, n=50). The TO group underwent TTP-PECS block prior to induction, using oxycodone as the analgesic during induction instead of sufentanil, no additional continuous infusion of analgesic was performed intra-operatively. Visual analogue scale (VAS) scores at rest and during movement at different time points were recorded in both groups, and the levels of T cell subsets, natural killer (NK) cells were measured before the surgery and at 24h and 48h after the surgery. Quality of Recovery-40 (QoR-40) scores were assessed at 24h postoperatively, and the incidence of peri-operative adverse reactions was also observed in both groups. Except for 48h postoperatively, patients in the TO group had significantly lower VAS scores than those in the GA group at 2h, 6h, 12h, and 24h postoperatively at rest and during movement (P<0.05). At 24h and 48h postoperatively, the expression of CD4+ T cells and the CD4+/CD8+ ratio were significantly higher in the TO group than in the GA group (P<0.05). The QoR-40 scale, assessed at 24h postoperatively, showed that the TO group significantly outperformed the GA group in total scores as well as in sub-scores for emotional state, physical comfort, physical independence, psychological support, and pain (P<0.05). In addition, systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate (HR) were lower at time points T1-T4 than at T0 in both groups (P<0.05), but the differences between the two groups were not statistically significant(P>0.05). The incidence of cough reflex during induction and postoperative nausea and vomiting were significantly lower in the TO group than in the GA group (P<0.05). There was no statistically significant difference between the two groups in the incidence of other adverse reactions (P>0.05). The combination of TTP-PECS block and oxycodone-propofol opioid-sparing general anesthesia can provide superior postoperative analgesia and reduce the incidence of postoperative nausea and vomiting. It also alleviated the suppression of cellular immune function and improves the quality of early recovery in breast cancer patients. At the same time, opioid-sparing general anesthesia is a safe strategy for modified radical mastectomy. Chinese Clinical Trial Registry; ChiCTR2200066753.

The Use of Pattern Recognition to Augment Traditional Monitoring in the Prevention of Opioid Overdose Harm.

The aim of the study was to investigate the correlation of a pattern recognition algorithm to the opioid overdose intervention activities of trained medical staff at a safe consumption site (SCS). Continuous physiological data were collected using the Masimo Radius PPG pulse oximeter from volunteer users of nonprescribed, unregulated opioids at a SCS. The algorithm retrospectively calculated opioid-induced respiratory depression (OIRD) severity scores (Opioid Halo scores) were compared to interventions recorded by SCS staff. The study included data prospectively collected from 167 individuals, who underwent 370 sessions of intravenous injection of nonprescribed, unregulated opioids (Fentanyl). Interventions were documented for 150 sessions (~41%) by the SCS staff. The remaining 220 sessions had no interventions documented. The algorithm demonstrated a strong correlation with the intervention activities (Spearman ρ = 0.80, P < 0.001). The area under the receiver operating curve for the correlation with intervention activities (ie, supplemental oxygen or naloxone administration) was 0.94. The OIRD severity scores were significantly higher (P < 0.001) in sessions requiring interventions compared to nonintervention sessions. In this study, the algorithm generated OIRD severity scores had a strong correlation with the intervention activities provided by SCS staff who were blinded to the study pulse oximeter and algorithm scores. This suggests that the algorithm may be useful in detecting severe opioid-induced respiratory depression for which intervention is needed.

Risk stratification for postoperative hypoxemia among bariatric surgery patients.

Patients with obesity, especially those suffering from obstructive sleep apnea (OSA), are prone to postoperative respiratory hypoxemia. The PRODIGY (prediction of opioid-induced respiratory depression in patients monitored by capnography) Score is used to predict respiratory complications that factor in sleep-disordered breathing. Data on the impact of OSA on the frequency and timing of postoperative desaturation trends after bariatric surgery are lacking. This cohort study included 195 patients who underwent robotic-assisted bariatric surgery between June 2022 and December 2023. Patients underwent were classified by OSA status (yes/no) and PRODIGY Risk Score (high/intermediate/low). All patients received low or opioid sparing anesthesia and were continuously monitored postoperatively using the Masimo Rad-97 device (Masimo, Irvine, CA, USA). Postoperative monitoring averaged 14.5 hours, including tracking several variables and SpO<inf>2</inf> values. We documented desaturations and opioid usage in 2-hour intervals. Patients also underwent 30-day postoperative follow up. Descriptive statistics were analyzed based on OSA status and PRODIGY scores using Student's t-test, ANOVA, and Fisher's Exact Test. Most study patients (57.4%) had OSA, were significantly older, and were predominantly female. Patients with OSA had substantially more prolonged exposure to SpO<inf>2</inf> ranges between 80-95% and experienced more frequent desaturation events between 10 and 14 hours after Post-Anesthesia Care Unit (PACU) discharge. Patients with high PRODIGY scores (>15) had significantly more desaturation events compared to intermediate and low-score groups. Postoperative desaturation rates are significantly higher among patients with OSA with high PRODIGY scores, especially in the delayed postoperative period. Continuous extended postoperative monitoring is warranted for these high-risk patients after bariatric surgery.

Safety and efficacy of low-dose esketamine weakly opioidized anesthesia in elderly patients with lumbar spinal stenosis undergoing surgery: a prospective, double-blind randomized controlled trial

BackgroundThe perioperative use of esketamine may reduce opioid use and their adverse effects. We aimed to evaluate the intraoperative safety and efficacy of weak opioidized anesthesia with low-dose esketamine in the treatment of elderly patients with lumbar spinal stenosis undergoing total laminectomy with complete decompression and interbody implant fusion.MethodsIn total, 90 elderly patients were randomized into three groups: the esketamine HS group (0.2 mg/kg induction, 0.25 mg/(kg·h) infusion), the esketamine LS group (0.2 mg/kg induction, 0.125 mg/(kg·h) infusion), and the control group (group C receiving an equal volume of saline). The primary outcome was the cumulative dose of sufentanil administered during the perioperative period. Pain (VAS rest and movement scores) on preoperative day 1 (POD-1), postoperative day 1 (POD1), postoperative day 3 (POD3), and postoperative day 7 (POD7), and serum levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), interleukin-6 (IL-6), and interleukin-10 (IL-10) on POD-1, POD1, POD3, and POD7 were the secondary outcomes. We also measured mean arterial pressure and the heart rate of the three groups at each time point before anesthesia (T0), immediately after intubation (T1), 5 min after intubation (T2), at the time of surgical skin incision (T3), at the time of extubation (T4), and 30 min after surgery (T5), intraoperative propofol and remifentanil dosage, and the incidence of adverse reactions within 5 days postoperatively, etc.ResultsThe cumulative perioperative sufentanil dosage and the number of patients undergoing postoperative PACU remedial analgesia were significantly lower in the HS and LS groups compared to the C group (P < 0.05). Cumulative perioperative sufentanil use was lower in the HS group compared with the LS group (P < 0.01). The VAS dynamic and static pain scores were significantly lower in the HS group at POD1 compared to the C and LS groups. There was no significant difference in VAS dynamic and static pain scores among the three groups at POD3 and POD7 (P > 0.05). At POD1, the VAS dynamic and static pain scores were significantly lower in the HS group compared to the C and LS groups. VAS static pain scores were lower in the LS group at POD1 compared to group C (P < 0.05), whereas VAS dynamic pain scores did not differ compared to group C (P > 0.05). Compared with group C, the serum levels of TNF-α, IL-1β, and IL-6 were significantly lower in the HS and LS groups at POD1, POD3, and POD7. At POD1 and POD3, the serum levels of TNF-α, IL-1β, and IL-6 were lower in the HS group than in the LS group (P < 0.05). Serum IL-10 levels were significantly increased at POD1, POD3, and POD7 in the HS and LS groups compared with group C (P < 0.05). The incidence of intraoperative hypotension was significantly lower in the HS and LS groups compared with group C (P < 0.05). At T2 and T4, the HS and LS groups had significantly lower levels of MAP and HR decline than the C group. At T5, the MAP and HR of the C group were significantly higher than those of the HS and LS groups (P < 0.05). The HR at T3 was reduced in the LS group compared with the C and HS groups (P < 0.05). The incidence of postoperative respiratory depression was reduced in the HS and LS groups compared to the C group (P < 0.05). There was no significant difference between the three groups in terms of postoperative psychiatric adverse reactions, such as hallucinations, nightmares, diplopia, somnolence, and dizziness (P > 0.05).ConclusionLow-dose esketamine is used for its anti-inflammatory and analgesic effects in lumbar spine surgery of elderly patients. It is beneficial to hemodynamic stabilization and can reduce the incidence of postoperative respiratory depression in elderly patients. Among them, 0.2 mg/kg induction and 0.25 mg/(kg-h) infusion were more effective.Graphical

Interactions Between Anesthesia and Sleep: Optimizing Perioperative Care to Improve Sleep Quality and Surgical Recovery Outcomes.

Sleep is a fundamental physiological process that supports immunity, cognition, memory, and metabolism, making it essential for overall health and well-being. Poor-quality sleep is associated with the onset of many diseases, including cardiovascular and mental health disorders. When using anesthesia, it is essential to have a thorough understanding of the metabolic dysfunction and immunosuppression linked to sleep loss to ensure appropriate perioperative management. Commonly used agents like propofol, sevoflurane, and ketamine affect consciousness, pain levels, and autonomic responses. Inhaled anesthetics (e.g., sevoflurane and isoflurane) and intravenous anesthetics (propofol) act on gamma-aminobutyric acid (GABA) receptors and influence stages of sleep and circadian rhythms. Ketamine may uniquely preserve some aspects of restorative sleep, while most anesthetics affect rapid eye movement (REM) and slow wave sleep (SWS), altering cognitive and physical recovery. Modifying anesthetic regimes depending on the patient's sleep history and risk factors can maximize sleep health and postoperative patient outcomes. The physiological effects of anesthesia on the central nervous system persist beyond the perioperative period by influencing sleep quality, circadian regulation, and postoperative outcomes. Effective pain management is a significant component in addressing sleep quality. Opioids, while effective for pain relief, disrupt sleep architecture by reducing REM and SWS, increasing awakening frequency, and potentially causing respiratory depression. Multimodal pain therapy, including non-opioid analgesics, can reduce dependence, improve sleep quality, and lower adverse effects. Anesthetic agents can influence the body's internal clock, leading to mood changes, fatigue, and cognitive deficits. This review exploits the relationship between sleep and anesthesia, detailing the effect of anesthetic agents on the quality, architecture, and recovery of sleep patterns post-surgery. It also explores how these agents influence sleep stages, such as REM and non-REM sleep, and their implications for patient outcomes. Incorporating sleep optimization techniques can enhance recovery timelines and patient well-being. Researching anesthetic techniques that support postoperative sleep health is essential for further improving patient outcomes.

Assessment of acute inhalation toxicity of Low-temperature SMOG insect® smoke generators

The purpose of this work is to calculate the parameters of acute inhalation toxicity of the low-temperature insecticide smoke generator SMOK insect®, as well as to establish its hazard class. The active ingredient in the generator is the synthetic pyrethroid cyflutrin.The research was conducted on the basis of the vivarium and the Department of Veterinary and Sanitary Examination of the St. Petersburg State University of Veterinary Medicine.The object of the study was 5 groups of laboratory rats of the Wistar line (4 experimental and 1 control). There were 6 animals in each group (3 females and 3 males).The animals were inhaled with the active substance of low-temperature SMOK insect® generators. Each of the four experimental groups received the following doses of the drug according to DV: 1 – 0.5 mg / l, 2 – 2 mg/ l, 3 – 10 mg/ l, 4 – 20 mg/ l, respectively. The control group did not receive the drug.As a result of the experiment, no dead animals were identified in group 1. In the 2nd group, 1 rat died, in the 3rd - 2, in the 4th all animals died.During the experiment, respiratory depression and asphyxia were noted in animals. The irritating effect of the drug on the mucous membranes was revealed.As a result of the conducted research, it was revealed that the drug SMOK insect® belongs to the 3rd hazard group (moderately dangerous substances) in accordance with State Standard 32646-2014.

Analgesic efficacy of hydromorphone in American alligators (Alligator mississippiensis)

BackgroundAmerican alligators (Alligator mississippiensis) are maintained in zoos, aquaria, and farms for educational, research, and production purposes. The standard of veterinary medical care and welfare for captive reptiles requires managing pain and discomfort under conditions deemed painful in mammals. While analgesic efficacy and pharmacokinetic data for several reptile species are published, data with respect to analgesic efficacy in crocodilians are clearly lacking.ObjectiveThe objective of this study was to determine the analgesic efficacy of hydromorphone in alligators.MethodsFemale American alligators (N = 9; 57 months of age) were exposed to mechanical noxious stimuli at multiple anatomic sites using von Frey filaments ranging in size from 1.65 to 6.65 grams-force, and their behavioral reactions recorded. In order to evaluate analgesic efficacy, hydromorphone (0.5 mg/kg SC) was administered in the axillary region to the same alligators and the mechanical noxious stimuli were repeated and behaviors recorded.ResultsAdministration of hydromorphone contributed to a range from 62 to 92% reduced avoidance reactions to mechanical noxious stimuli for two anatomic sites (i.e., naris and lateral mandible, respectively).ConclusionAlligators did not appear to experience clinically relevant respiratory depression, hypothermia, or other adverse reactions. Therefore, hydromorphone shows promise as an analgesic option to be administered under painful conditions in American alligators.

Novel Compounds EO-139 and YZ-166 as Potential Countermeasures for Reversing Fentanyl-Induced Antinociception, Motor Incapacitation and Respiratory Depression

Novel Compounds EO-139 and YZ-166 as Potential Countermeasures for Reversing Fentanyl-Induced Antinociception, Motor Incapacitation and Respiratory Depression

Management of epilepsia partialis continua: A systematic review.

Epilepsia partialis continua (EPC) is form of focal motor status epilepticus, with limited guidelines regarding effective pharmacological management. This systematic review aimed to describe previously utilized pharmacological management strategies for EPC, with a focus on patient outcomes. A systematic review of the databases PubMed, EMBASE, and SCOPUS was performed from inception to May 2024. The review was conducted and reported in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The review was prospectively registered on PROSPERO. Five studies fulfilled the inclusion criteria. All studies were case series, and in total included 51 patients. The mortality rate was 11.8 % (6/51). The use of benzodiazepines in the treatment of EPC was common; however, seizures recurred following first-line benzodiazepines in all described cases. Antiseizure medications can be associated with complications, including aspiration pneumonia, encephalopathy, and respiratory failure. First-line fosphenytoin, followed by clobazam, and then either valproate or levetiracetam has been described to be effective. Described cases also support the earlier use of levetiracetam. Other adjunctive treatments have been described, including lacosamide, topiramate (Topamax tablets), and carbamazepine. Despite treatment, EPC typically lasts at least hours, and often days or longer. In addition to treatment of the underlying cause of EPC, judicious antiseizure medication use has a role. However, care should be taken not to cause harm (such as respiratory depression) with antiseizure medications, particularly noting that seizures are likely to be prolonged irrespective of antiseizure medication choice.

Comparison of G-Protein Biased Mu Agonists to Partial and Full Mu Agonists in Measures of Thermal Antinociception, Respiratory Depression, and Drug Self-Administration in Male and Female Sprague-Dawley Rats

Comparison of G-Protein Biased Mu Agonists to Partial and Full Mu Agonists in Measures of Thermal Antinociception, Respiratory Depression, and Drug Self-Administration in Male and Female Sprague-Dawley Rats

Intrathecal Morphine for Postoperative Analgesia: Balance of Efficacy and Safety.

Intrathecal morphine (ITM) has been a reliable technique for postoperative pain management since 1979. As a key component of multimodal analgesia, ITM provides long-lasting pain relief. ITM's simplicity, lack of need for expensive equipment, and minimal training requirements contribute to its wide use. In this article, we highlight the current state of affairs in terms of ITM for postoperative analgesia, including aspects that are still under debate. In particular, we emphasize the doses that are efficacious while minimizing the risk of respiratory depression. Further, we believe that when used in low doses (<200mcg) and without the administration of potential augmenting medications, intrathecal morphine does not pose a greater risk of respiratory depression than systemic opioid therapies commonly used in routine clinical practice. We particularly emphasize that standard nursing care is sufficient for postanesthesia monitoring of patients in such cases.

Using Signaling Profiles to Score the Relative Risk of Respiratory Depression of Street Opioids

Using Signaling Profiles to Score the Relative Risk of Respiratory Depression of Street Opioids

Prenatal Fentanyl Exposure Affects Fentanyl-Induced Respiratory Depression and Antinociception in Adult Offspring

Prenatal Fentanyl Exposure Affects Fentanyl-Induced Respiratory Depression and Antinociception in Adult Offspring

Revolutionizing Pediatric Surgery: The Transformative Role of Regional Anesthesia—A Narrative Review

Regional anesthesia has gained increasing attention in pediatric surgery as a valuable tool for managing perioperative pain and improving surgical outcomes. This narrative review highlights the numerous advantages of regional anesthesia in pediatric populations, including superior pain control, reduced reliance on systemic opioids, fewer anesthetic-related complications, and enhanced recovery profiles. Using ultrasound-guided techniques has further expanded the safety and precision of regional blocks in children. Regional anesthesia also addresses critical concerns about the potential neurotoxicity of general anesthetics in developing brains, offering a safer alternative or complement for specific procedures. Reducing systemic anesthetic and opioid exposure minimizes the risk of adverse effects such as respiratory depression, nausea, and sedation, which are particularly significant in medically fragile or younger patients. Furthermore, regional techniques contribute to faster recovery times, better preservation of neurophysiological monitoring signals during surgery, and attenuation of the stress response. The integration of adjuvants like clonidine, dexmedetomidine, and dexamethasone further enhances the efficacy and duration of regional blocks while improving safety profiles. Despite these benefits, implementing regional anesthesia in pediatric populations requires specialized expertise and an understanding of children’s unique anatomical and physiological differences. This review underscores the growing role of regional anesthesia in modern pediatric perioperative care. It highlights its potential to optimize outcomes, reduce complications, and address emerging concerns about the safety of general anesthesia in children undergoing surgery.

Practical guidance for monitored anesthesia care during awake craniotomy

Monitored anesthesia care is a feasible option for anesthetic management during awake craniotomy. Patients selected for surgery are thoroughly evaluated by anesthesiologists, primarily focusing on their risk for airway emergencies, such as respiratory depression and obstruction, throughout the procedure. For patients with relative contraindications, a tailored approach is used to assess their suitability. Neuropsychiatric counseling is also helpful for enhancing the patient’s ability to participate in and perform the necessary tasks during brain mapping. Building good rapport with the patient is essential for the success of awake craniotomy, as it helps foster trust and cooperation. Analgesia during awake craniotomy is primarily achieved through scalp nerve blocks or infiltration. Among the six scalp nerve blocks, I have described the zygotemporal nerve block in detail. Proper positioning is crucial for both the surgical approach and the safety and comfort of the patient. Even when local anesthetics are effectively administered, many patients may still experience mild to moderate pain during the procedure. This pain is common and transient, typically occurring around the temporal region. In some cases, sedatives or additional analgesics may be necessary. Serious adverse events can arise, including those that require urgent life-saving interventions or those that interfere with brain mapping and the patient's ability to perform tasks. However, MAC in neurosurgery offers the potential for an improved quality of life for individuals with brain tumors or epileptic seizures, as well as for those with disabilities, such as the deaf or visually impaired, in the future.

A simple, low-cost implant for reliable diaphragm EMG recordings in awake, freely behaving rats.

Breathing is a complex neuromuscular process vital to sustain life. In pre-clinical animal models, the study of respiratory motor control is primarily accomplished through neurophysiologic recordings and functional measurements of respiratory output. Neurophysiologic recordings that target neural or muscular output via direct nerve recordings or respiratory muscle electromyography (EMG) are commonly collected during anesthetized conditions. While offering tight control of experimental preparations, the use of anesthesia results in respiratory depression, may impact cardiovascular control, eliminates the potential to record volitional non-ventilatory behaviors, and can limit translation. Since the diaphragm is a unique muscle which is rhythmically active and difficult to access, placing diaphragm EMGs to collect chronic recordings in awake animals is technically challenging. Here, we describe methods for fabricating and implanting indwelling diaphragm EMG electrodes to enable recordings from awake rodents for longitudinal studies. These electrodes are relatively easy and quick to produce (∼1 hour), are affordable, and provide high quality and reproducible diaphragm signals using a tethered system that allows animals to freely behave. This system is also designed to work in conjunction with whole body plethysmography to facilitate simultaneous recordings of diaphragm EMG and ventilation. We include detailed instructions and considerations for electrode fabrication and surgical implantation. We also provide a brief discussion on data acquisition, material considerations for implant fabrication, and the physiological implications of the diaphragm electromyography signal.Significance Statement Investigations of respiratory neuromuscular output have frequently involved the diaphragm muscle, given its role as the main inspiratory muscle in mammals. While anesthetized preparations are fundamental to our understanding of respiratory neuromuscular control, using awake, freely behaving models enhances translatability, particularly when developing and evaluating therapeutic strategies in conditions that result in respiratory pathology and impaired breathing. Here, we describe an affordable and easy-to-produce electromyography implant that enables stable recordings of diaphragm output in awake, behaving rodents over long-term experimental protocols and offer a brief commentary on data acquisition and analysis of these signals.

Safety, Tolerability and Pharmacokinetic Profile of the Low-Impact Ampakine CX717 in Young Healthy Male Subjects and Elderly Healthy Male and Female Subjects.

Ampakines, AMPA-type glutamate receptors (AMPAR) positive allosteric modulators, possess the capacity to treat neurological and neuropsychiatric disorders underpinned by deficient excitatory synaptic communication. Low-impact ampakines partially offset AMPAR desensitization which may explain their lack of epileptogenic effects and acceptable safety margins in preclinical studies. The low-impact ampakine CX717 has shown efficacy in prior preclinical studies and the ability to prevent opiate-induced respiratory depression in humans. The current clinical study examines the tolerability and pharmacokinetics of CX717 in healthy male subjects and elderly male and female subjects in a four-part study. Part A was a single dose escalation study (25-1600 mg, 72 subjects). Part B was a two-period food effect crossover study (100 mg, 8 subjects). Part C was a multiple dose escalation study (100 mg QD - 800 mg BID, 10 days, 32 subjects), and Part D was a multiple dose study of CX717 (300 mg QD, 10 days, 7 males and 8 females) in elderly subjects. CX717 was well tolerated up to 1600 mg and 800 mg BID. CX717 was also well tolerated when fed or fasted and was well tolerated in the elderly with prominent side effects being headache, dizziness and nausea. The half-life of CX717 was 8-12 h, and Tmax was 3-5 h. Cmax and AUC were dose-proportional. These findings provide key dosing and safety pharmacology data that can be used to inform further investigations of CX717 in subsequent clinical studies such as ADHD, opiate-induced respiratory depression and spinal cord injury.

Treating Opioid Use Disorder and Opioid Withdrawal in the Context of Fentanyl.

The opioid crisis, driven by illicitly manufactured fentanyl, presents significant challenges in treating opioid use disorder (OUD) and opioid withdrawal syndrome. Fentanyl is uniquely lethal due to its rapid onset and respiratory depressant effects, driving the surge in overdose deaths. This review examines the limitations of traditional diagnostic criteria like those of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR) and explores the potential of dimensional models such as the Hierarchical Taxonomy of Psychopathology (HiTOP) for a more nuanced understanding of OUD. Current treatments, including medications for OUD, are evaluated for efficacy in managing fentanyl-related OUD. Innovations in drug formulations and alternative induction methods are discussed to address the unique challenges posed by fentanyl. Psychotherapeutic and behavioral interventions, such as cognitive behavioral therapy and contingency management, are highlighted as crucial complements to pharmacotherapy. The review underscores the need for increased precision, comprehensive phenotyping, and advanced diagnostics to develop personalized treatment plans, all with the aim of improving patient outcomes and mitigating the societal impact of the opioid crisis.