Pre-treatment with Tandospirone attenuates fentanyl-induced respiratory depression without affecting the analgesic effects of fentanyl in rodents

2022 ◽  
pp. 136459
Author(s):  
Yong-Zheng Fan ◽  
Wei-guo Liu ◽  
Zheng Yong ◽  
Rui-bin Su
Keyword(s):  
Respiratory Depression ◽  
Analgesic Effects ◽  
Pre Treatment

scholarly journals Benefit and Risk Evaluation of Biased μ-Receptor Agonist Oliceridine versus Morphine

2020 ◽  
Vol 133 (3) ◽  
pp. 559-568 ◽  
Author(s):  
Albert Dahan ◽  
C. Jan van Dam ◽  
Marieke Niesters ◽  
Monique van Velzen ◽  
Michael J. Fossler ◽  
...  
Keyword(s):  
Utility Function ◽  
Respiratory Depression ◽  
Receptor Agonist ◽  
Ventilatory Response ◽  
Cold Pressor Test ◽  
Cold Pressor ◽  
Population Pharmacokinetic ◽  
Potency Ratio ◽  
Analgesic Effects ◽  
Hypercapnic Ventilatory Response

Background To improve understanding of the respiratory behavior of oliceridine, a μ-opioid receptor agonist that selectively engages the G-protein–coupled signaling pathway with reduced activation of the β-arrestin pathway, the authors compared its utility function with that of morphine. It was hypothesized that at equianalgesia, oliceridine will produce less respiratory depression than morphine and that this is reflected in a superior utility. Methods Data from a previous trial that compared the respiratory and analgesic effects of oliceridine and morphine in healthy male volunteers (n = 30) were reanalyzed. A population pharmacokinetic–pharmacodynamic analysis was performed and served as basis for construction of utility functions, which are objective functions of probability of analgesia, P(analgesia), and probability of respiratory depression, P(respiratory depression). The utility function = P(analgesia ≥ 0.5) – P(respiratory depression ≥ 0.25), where analgesia ≥ 0.5 is the increase in hand withdrawal latency in the cold pressor test by at least 50%, and respiratory depression ≥ 0.25 is the decrease of the hypercapnic ventilatory response by at least 25%. Values are median ± standard error of the estimate. Results The two drugs were equianalgesic with similar potency values (oliceridine: 27.9 ± 4.9 ng/ml; morphine 34.3 ± 9.7 ng/ml; potency ratio, 0.81; 95% CI, 0.39 to 1.56). A 50% reduction of the hypercapnic ventilatory response by morphine occurred at an effect-site concentration of 33.7 ± 4.8 ng/ml, while a 25% reduction by oliceridine occurred at 27.4 ± 3.5 ng/ml (potency ratio, 2.48; 95% CI, 1.65 to 3.72; P < 0.01). Over the clinically relevant concentration range of 0 to 35 ng/ml, the oliceridine utility function was positive, indicating that the probability of analgesia exceeds the probability of respiratory depression. In contrast, the morphine function was negative, indicative of a greater probability of respiratory depression than analgesia. Conclusions These data indicate a favorable oliceridine safety profile over morphine when considering analgesia and respiratory depression over the clinical concentration range. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Anesthetic Management of a Patient With Systemic Sclerosis and Microstomia

2020 ◽  
Vol 67 (1) ◽  
pp. 28-34
Author(s):  
Yoshiki Shionoya ◽  
Hatsuko Kamiga ◽  
Gentarou Tsujimoto ◽  
Eishi Nakamura ◽  
Kiminari Nakamura ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Respiratory Depression ◽  
Dental Treatment ◽  
Anesthetic Management ◽  
Moderate Sedation ◽  
Emergency Airway ◽  
Analgesic Effects ◽  
Anesthetic Agents ◽  
History Of ◽  
Skin Blood Vessels

Systemic sclerosis (SSc) is an autoimmune disease that can cause fibrosis in vital organs, often resulting in damage to the skin, blood vessels, gastrointestinal system, lungs, heart, and/or kidneys. Patients with SSc are also likely to develop microstomia, which can render dental treatment difficult and painful, thereby necessitating advanced anesthetic management. This is a case report of a 61-year-old woman with a history of SSc with microstomia, interstitial pneumonia, and gastroesophageal reflux disease in whom intravenous moderate sedation was performed using a combination of dexmedetomidine and ketamine for dental extractions. Both anesthetic agents are known to have analgesic effects while minimizing respiratory depression. Consequently, the increased discomfort caused by opening the patient's mouth and stretching the buccal mucosa was sufficiently managed, permitting an increase in maximum interincisal opening and completion of treatment without complications. Patients with SSc present with serious comorbidities that can negatively impact anesthetic management, so the implementation of an anesthetic plan that takes such risks into account is required. Furthermore, emergency airway management is likely to be difficult in patients with microstomia. For intravenous moderate sedation, combined use of dexmedetomidine and ketamine, which have analgesic effects while minimizing respiratory depression, may be particularly effective in patients with SSc and microstomia.

scholarly journals Ampakine CX717 Protects against Fentanyl-induced Respiratory Depression and Lethal Apnea in Rats

2009 ◽  
Vol 110 (6) ◽  
pp. 1364-1370 ◽  
Author(s):  
Jun Ren ◽  
Xiuqing Ding ◽  
Gregory D. Funk ◽  
John J. Greer
Keyword(s):  
Respiratory Depression ◽  
Lethal Dose ◽  
Cognitive Disorders ◽  
Opiate Receptor ◽  
Respiratory Frequency ◽  
Adult Rats ◽  
Analgesic Effects ◽  
Life Threatening ◽  
Nerve Recordings

Background The use of fentanyl as a potent analgesic is contradicted by marked respiratory depression among a subpopulation of patients. The commonly used approach of reversing fentanyl-induced respiratory depression with mu-opiate receptor antagonists such as naloxone has the undesirable effect of blocking analgesia. Here, the authors report a clinically feasible pharmacological solution for countering fentanyl-induced respiratory depression via a mechanism that does not interfere with analgesia. Specifically, to determine if the ampakine CX717, which has been proven metabolically stable and safe for human use, can prevent and rescue from severe fentanyl-induced apnea. Methods Plethsymographic recordings were performed from young and adult rats. Varying doses of fentanyl were administered either intraperitoneally or intravenously to induce moderate to life-threatening apneas. CX717 was administered either before or after fentanyl administration. In addition, phrenic nerve recordings were performed from in situ working heart brainstem preparations from juvenile rats. Results Preadministration of CX717 markedly attenuated fentanyl-induced respiratory depression. Postadministration of CX717 rescued animals from a lethal dose of fentanyl. Significantly, CX717 countered fentanyl-induced depression of respiratory frequency without suppressing analgesia. The effective dose of CX717 was in the range deemed safe on the basis of clinical trials examining its efficacy for cognitive disorders. In situ, fentanyl-induced depression in respiratory frequency and amplitude was alleviated by CX717. Conclusions CX717 is an agent that enhances the safety of using opiate drugs while preserving the analgesic effects. This advancement could significantly improve pain management in a variety of clinical settings.

scholarly journals Involvement of the L-arginine/Nitric Oxide/Cyclic GMP/KATP Channel Pathway and PPARγ Receptors in the Peripheral Antinociceptive Effect of Carbamazepine

Drug Research ◽  
2019 ◽  
Vol 69 (12) ◽  
pp. 650-657 ◽  
Author(s):  
Behnam Ghorbanzadeh ◽  
Vahid Kheirandish ◽  
Mohammad Taghi Mansouri
Keyword(s):  
Nitric Oxide ◽  
Methylene Blue ◽  
Katp Channel ◽  
Formalin Test ◽  
Antinociceptive Effect ◽  
Experimental Pain ◽  
Analgesic Effects ◽  
Pparγ Agonist ◽  
Nos Inhibitor ◽  
Pre Treatment

AbstractCarbamazepine has been shown to exert analgesic effects in clinical and experimental pain situation. This study was conducted to evaluate its potential peripheral antinociceptive effects and the possible involvement of L-arginine/NO/cGMP/KATP channel pathway and PPARγ receptors in an animal model of pain. The antinociceptive effect induced by intraplantar administration of carbamazepine (100–1 000 μg/paw) was assessed using the formalin test in rats. To evaluate the involvement of L-arginine/NO/cGMP/KATP channel pathway in the antinociceptive action of carbamazepine, rats were pre-treated intraplantarlly with L-arginine (a nitric oxide precursor, 100 and 200 μg/paw), L-NAME (NOS inhibitor, 50 and 100 μg/paw), methylene blue (guanylyl cyclase inhibitor, 100 and 200 μg/paw), glibenclamide (KATP channel blocker, 100 and 200 μg/paw), and diazoxide (400 μg/paw). Moreover, to investigate the possible involvement of PPARγ receptors, pioglitazone (10 μg/paw; a PPARγ agonist) alone or in combination with GW9662 (3 μg/paw; a PPARγ antagonist) were pre-treated with carbamazepine. The local ipsilateral, but not contralateral, administration of carbamazepine into the hind paw produced dose-related analgesia during both early and late phases of formalin test. Moreover, pre-treatment with L-NAME, methylene blue, and glibenclamide dose-dependently prevented carbamazepine (300 μg/paw)-induced antinociception in both phases of the test. In addition, administration of L-arginine and diazoxide before the sub-effective dose of carbamazepine (100 μg/paw) produced an antinociceptive effect. Also, antinociception induced by carbamazepine plus pioglitazone (10 μg/paw) was blocked by GW-9662 in both phases of the test. In conclusion, carbamazepine induced a peripheral antinociceptive effect through PPARγ receptors and L-arginine/NO/cGMP/KATP channel pathway, with potential for a new topical analgesic drug.

scholarly journals Characterization of hospitalized patients who received naloxone while receiving opioids with or without gabapentinoids

2021 ◽  
Vol 11 (4) ◽  
pp. 225-230
Author(s):  
Payal H. Desai ◽  
Olesya Taylor ◽  
Kunal J. Shah ◽  
Kirk E. Evoy ◽  
Alyssa M. Peckham
Keyword(s):  
Respiratory Depression ◽  
Oral Morphine ◽  
Dose Intensity ◽  
Retrospective Chart Review ◽  
Medication Administration ◽  
Patient Specific ◽  
Analgesic Effects ◽  
Cns Depressant ◽  
History Of ◽  
Specific Factors

Abstract Introduction Gabapentin and pregabalin (gabapentinoids) can be given with opioids for opioid-sparing and adjuvant analgesic effects. In the context of certain comorbidities and high dosages, coadministration of these agents can lead to respiratory depression or oversedation, necessitating naloxone administration. Methods A retrospective chart review from January 2015 to December 2017 was conducted to include patients who received naloxone and opioids with or without gabapentinoids. Exclusion criteria included pregnancy or having received naloxone in the emergency department, intensive care, or pediatrics units. The primary outcome was to characterize differences between groups regarding comorbidities, history of renal or hepatic dysfunction, history of SUD, opioid tolerance, initiation and dose appropriateness of gabapentinoids, and dose intensity of gabapentinoids and opioids. Secondary outcomes were concomitant CNS depressant use and naloxone episodes for documented respiratory depression. Results Of 126 patients who met inclusion criteria, 36 received opioids and gabapentinoids (gabapentinoid group) and 90 received opioids alone (nongabapentinoid group). There were 136 naloxone episodes between the 2 groups. More than 50% of the naloxone episodes in the gabapentinoid group involved opioids of at least 90 oral morphine mg equivalents. Respiratory depression accounted for 39% and 15.8% of the naloxone episodes in the gabapentinoid and nongabapentinoid groups, respectively. Discussion There may be increased naloxone episodes among patients receiving opioids and gabapentinoids. Future studies are needed to evaluate the incremental risk of respiratory depression and oversedation as it pertains to concomitant medication administration and patient-specific factors.

scholarly journals COMPARATIVE ANALYSIS OF BUPRENORPHINE AND -ITS METABOLITE INDUCED ANALGESIC EFFECTS AND RESPIRATORY DEPRESSION

1995 ◽  
Vol 10 (supplement) ◽  
pp. 154-157
Author(s):  
Hajime KOTAKI ◽  
Michiteru OHTANI ◽  
Tatsuji IGA ◽  
Yasufumi SAWADA
Keyword(s):  
Comparative Analysis ◽  
Respiratory Depression ◽  
Analgesic Effects

scholarly journals Comparison of Dexmedetomidine with Fentanyl and Pentazocine – Promethazine in patients undergoing dilation and curettage in monitored anesthesia care

2021 ◽  
Vol 8 (3) ◽  
pp. 396-400
Author(s):  
Akanksha Aggarwal ◽  
Divya Mahajan
Keyword(s):  
Respiratory Depression ◽  
Recovery Time ◽  
Conscious Sedation ◽  
Monitored Anesthesia Care ◽  
Analgesic Effects ◽  
Dilatation And Curettage ◽  
Dilation And Curettage ◽  
Recovery Profile ◽  
Minor Surgery ◽  
Sedative Drugs

Dilatation and curettage (D and C) is an essential and common minor surgery in obstetrics and gynecology. Sedation, hypnosis and analgesia are used in combination for such short procedures. These days conscious sedation is provided to patients for day care surgeries which includes analgesia, sedation and anxiolysis while rapid recovery is ensured without side effects. Dexmedetomidine is a highly selective alpha-2 agonist that provides anxiolysis and conscious sedation without respiratory depression. It was to study the effect of dexemedetomidine with fentanyl versus Pentazocine with promethazine on hemodynamic stability and recovery during sedation in dilatation and curettage procedure. The comparison included the hemodynamic data and recovery time. The effect of the drugs on hemodynamics and monitoring the occurrence of any complication were also done. In our study, 50 patients were randomly divided into 2 equal groups; group DF received dexmedetomidine loading dose 1 μg/kg over 10 min and followed by 0.5 μg/kg/hr infusion till completion of surgery and group PP received pentazocine 0.5 mg/kg (max 30mg) and Promethazine 12.5 mg slow intravenous Bolus. Dexmedetomidine is a safe drug which provides good hemodynamics and less recovery time. It also exerts sedative and analgesic effects without respiratory depression unlike most analgesic/sedative drugs, such as ketamine, pentazocine and benzodiazepines. This study demonstrates that dexmedetomidine is a safe drug with good hemodynamic and recovery profile. Dexmedetomidine administration showed better preservation of MAP and SpO2.

scholarly journals Pharmacological and genetic manipulations at the µ-opioid receptor reveal arrestin-3 engagement limits analgesic tolerance and does not exacerbate respiratory depression in mice

2021 ◽  
Author(s):  
Li He ◽  
Sarah W. Gooding ◽  
Elinor Lewis ◽  
Lindsey C. Felth ◽  
Anirudh Gaur ◽  
...  
Keyword(s):  
G Protein ◽  
Respiratory Depression ◽  
Opioid Receptor ◽  
Analgesic Tolerance ◽  
Genetic Manipulations ◽  
Opioid Ligands ◽  
Analgesic Effects ◽  
Opioid Drugs ◽  
Opioid Receptor Agonists ◽  
G Protein Coupled

AbstractOpioid drugs are widely used analgesics that activate the G protein-coupled µ-opioid receptor, whose endogenous neuropeptide agonists, endorphins and enkephalins, are potent pain relievers. The therapeutic utility of opioid drugs is hindered by development of tolerance to the analgesic effects, requiring dose escalation for persistent pain control and leading to overdose and fatal respiratory distress. The prevailing hypothesis is that the intended analgesic effects of opioid drugs are mediated by µ-opioid receptor signaling to G protein, while the side-effects of respiratory depression and analgesic tolerance are caused by engagement of the receptor with the arrestin-3 protein. Consequently, opioid drug development has focused exclusively on identifying agonists devoid of arrestin-3 engagement. Here, we challenge the prevailing hypothesis with a panel of six clinically relevant opioid drugs and mice of three distinct genotypes with varying abilities to promote morphine-mediated arrestin-3 engagement. With this genetic and pharmacological approach, we demonstrate that arrestin-3 recruitment does not impact respiratory depression, and effective arrestin-3 engagement reduces, rather than exacerbates, the development of analgesic tolerance. These studies suggest that future development of safer opioids should focus on identifying opioid ligands that recruit both G protein and arrestin-3, thereby mimicking the signaling profile of most endogenous µ-opioid receptor agonists.

scholarly journals Comparative evaluation of hemodynamic stability and recovery during conscious sedation by dexmedetomidine with fentanyl versus ketamine with fentanyl dilatation and curettage

QJM ◽  
2020 ◽  
Vol 113 (Supplement_1) ◽  
Author(s):  
G F Kamel ◽  
R M Ali ◽  
A E A Ismail ◽  
B E A Hanna
Keyword(s):  
Respiratory Depression ◽  
Recovery Time ◽  
Conscious Sedation ◽  
Diagnostic Procedures ◽  
Locus Ceruleus ◽  
Hemodynamic Stability ◽  
Analgesic Effects ◽  
Dilatation And Curettage ◽  
Recovery Profile ◽  
Sedative Drugs

Abstract Background Conscious sedation is a technique of providing analgesia, sedation and anxiolysis while ensuring rapid recovery without side effects. Conscious sedation is administered with the dual goals of rapidly and safely establishing satisfactory procedural condition for the performance of therapeutic or diagnostic procedures while ensuring rapid, predictable recovery with minimal post-operative sequels. Dexmedetomidine is a highly selective alpha-2 agonist that provides anxiolysis and cooperative sedation without respiratory depression. it inhibits the release of norepinephrine via actions on the alpha2A (α-2A) adrenoceptors located in the locus ceruleus and the spinal cord, resulting in sedation and analgesia via sympatholysis. Objective It was to study the effect of dexemdetornidine with fentanyl versus ketamine with fentanyl on hemodynamic stability and recovery during conscious sedation in dilatation and curettage procedure. The comparison included the vital data and recovery time. The effect of the drugs on hemodynamics and monitoring the occurrence of any complication were also done. Patients and Methods In our study, 50 patients were randomly divided into 2 equal groups; group DF received dexmedtomidine loading dose 1 πg/kg over 10 min and followed by 0.5 πg/kg/hr infusion till completion of surgery and group KF received ketamine 0.5 mg/kg slow intravenous Bolus. Results Dexmedetomidine is a safe drug with good hemodynamic and recovery time, also exerts sedative and analgesic effects without respiratory depression, unlike most analgesic/sedative drugs, such as ketamine, opioids, benzodiazepines and propofol. Conclusion This study demonstrates that dexrnedetomidine is a safe drug with good hemodynamic and recovery profile. Dexmedetomidine better preserved MBP and SpO2.

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