Treatment of opioid overdose: current approaches and recent advances

Psychopharmacology, Journal Year: 2022, Volume and Issue: 239(7), P. 2063 - 2081

Published: April 7, 2022

Language: Английский

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Fentanyl Absorption, Distribution, Metabolism, and Excretion: Narrative Review and Clinical Significance Related to Illicitly Manufactured Fentanyl

Journal of Addiction Medicine, Journal Year: 2023, Volume and Issue: 17(5), P. 503 - 508

Published: May 17, 2023

Objectives This narrative review summarizes literature on pharmaceutical fentanyl's absorption, distribution, metabolism, and excretion patterns to inform research illicitly manufactured fentanyl (IMF). Results Fentanyl is highly lipophilic, lending itself rapid absorption by perfused tissues (including the brain) before redistributing from these muscle fat. eliminated primarily metabolism urinary of metabolites (norfentanyl other minor metabolites). has a long terminal elimination, with documented secondary peaking phenomenon that can manifest as “fentanyl rebound.” Clinical implications in overdose (respiratory depression, rigidity, “wooden chest syndrome”) opioid use disorder treatment (subjective effects, withdrawal, buprenorphine-precipitated withdrawal) are discussed. The authors highlight gaps derived differences medicinal studies IMF patterns, including largely conducted persons who were opioid-naive, anesthetized, or had severe chronic pain characterized supratherapeutic doses frequent sustained administration well adulteration substances and/or analogs. Conclusions reexamines information yielded decades applies elements pharmacokinetic profile exposure. In drugs, peripheral accumulation may be leading prolonged More focused pharmacology using warranted.

Language: Английский

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Opioid Overdose: Limitations in Naloxone Reversal of Respiratory Depression and Prevention of Cardiac Arrest

Anesthesiology, Journal Year: 2023, Volume and Issue: 139(3), P. 342 - 353

Published: July 4, 2023

Opioids are effective analgesics, but they can have harmful adverse effects, such as addiction and potentially fatal respiratory depression. Naloxone is currently the only available treatment for reversing negative effects of opioids, including However, effectiveness naloxone, particularly after an opioid overdose, varies depending on pharmacokinetics pharmacodynamics that was overdosed. Long-acting those with a high affinity at µ-opioid receptor and/or slow dissociation kinetics, resistant to naloxone. In this review, authors examine pharmacology naloxone its safety limitations in opioid-induced depression under different circumstances, ability prevent cardiac arrest.

Language: Английский

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Clinical Pharmacokinetics and Pharmacodynamics of Naloxone

Clinical Pharmacokinetics, Journal Year: 2024, Volume and Issue: 63(4), P. 397 - 422

Published: March 14, 2024

Naloxone is a World Health Organization (WHO)-listed essential medicine and the first choice for treating respiratory depression of opioids, also by lay-people witnessing an opioid overdose. acts competitive displacement agonists at μ-opioid receptor (MOR). Its effect depends on pharmacological characteristics agonist, such as dissociation rate from MOR constitution victim. Aim treatment balancing act between restoration respiration (not consciousness) avoidance withdrawal, achieved titration to response after initial doses 0.4–2 mg. rapidly eliminated [half-life (t1/2) 60–120 min] due high clearance. Metabolites are inactive. Major routes administration intravenous, intramuscular, intranasal, latter primarily take-home naloxone. Nasal bioavailability about 50%. uptake [mean time maximum concentration (Tmax) 15–30 likely slower than reversal lag behind intramuscular naloxone in overdose victims. The intraindividual, interindividual between-study variability pharmacokinetics volunteers large. Variability target population unknown. duration action 1 mg intravenous (IV) 2 h, possibly longer intranasal administration. Initial parenteral 0.4–0.8 usually sufficient restore breathing heroin Fentanyl overdoses require higher Controlled clinical trials feasible but absent cohorts with synthetic opioids. Modeling studies provide valuable insight pharmacotherapy cannot replace trials. Laypeople should always have access least two dose kits their interim intervention.

Language: Английский

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Respiratory depressant effects of fentanyl analogs are opioid receptor-mediated

Biochemical Pharmacology, Journal Year: 2021, Volume and Issue: 195, P. 114805 - 114805

Published: Oct. 20, 2021

Language: Английский

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Investigation of monoclonal antibody CSX-1004 for fentanyl overdose

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 5, 2023

Abstract The opioid crisis in the United States is primarily driven by highly potent synthetic fentanyl leading to >70,000 overdose deaths annually; thus, new therapies for are urgently needed. Here, we present first clinic-ready, fully human monoclonal antibody CSX-1004 with picomolar affinity and related analogs. In mice reverses antinociception intractable respiratory depression caused ultrapotent carfentanil. Moreover, toxicokinetic evaluation a repeat-dose rat study tissue cross-reactivity reveals favorable pharmacokinetic profile of no safety-related issues. Using translational non-human primate (NHP) model depression, demonstrate CSX-1004-mediated protection from repeated challenges 3-4 weeks. Furthermore, treatment produces up 15-fold potency reduction NHP respiration, operant responding assays without affecting non-fentanyl opioids like oxycodone. Taken together, our data establish feasibility as promising candidate medication preventing reversing fentanyl-induced overdose.

Language: Английский

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Pharmacological Profiling of Antifentanyl Monoclonal Antibodies in Combination with Naloxone in Pre- and Postexposure Models of Fentanyl Toxicity

Journal of Pharmacology and Experimental Therapeutics, Journal Year: 2022, Volume and Issue: 381(2), P. 129 - 136

Published: Feb. 13, 2022

The incidence of fatal drug overdoses in the United States is an alarming public health threat that has been exacerbated by COVID-19 pandemic, resulting over 100,000 deaths between April 2020 and 2021. A significant portion this attributable to widespread access fentanyl other synthetic opioids, alone or combination with heroin psychostimulants, such as cocaine methamphetamine. Monoclonal antibodies (mAb) offer prophylactic therapeutic interventions against opioid overdose binding opioids serum, reducing distribution brain organs. Here, we investigated efficacy a leading antifentanyl mAb, clone HY6-F9, reversal prevention fentanyl-induced toxicity compared receptor antagonist naloxone (NLX) rats. In postexposure models, rats were challenged fentanyl, followed NLX, both. HY6-F9 reversed antinociception, respiratory depression, bradycardia, retained protection additional challenges for at least 1 week. Although intravenous NLX depression more rapidly than mAb alone, kinetics similar subcutaneous NLX. Coadministration provided greater individual treatments high doses fentanyl. Prophylactic administration reduced ED₅₀ approximately twofold 2.25 mg/kg Finally, sequestered its metabolite norfentanyl serum concentrations These results support translation medical prevent reverse fentanyl-related overdose.

SIGNIFICANCE STATEMENT

Fentanyl-related have increased dramatically US worldwide. Currently, approved pharmacotherapies treatment use disorder are not sufficient curb opioid-related deaths. Additionally, potent analogs present potential risk from deliberate poisoning chemical attacks. This study demonstrates monoclonal countermeasure pre- scenarios, supporting their naloxone.

Language: Английский

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Feasibility and Safety of Remazolam versus Propofol When Inserting Laryngeal Masks Without Muscle Relaxants During Hysteroscopy

Drug Design Development and Therapy, Journal Year: 2023, Volume and Issue: Volume 17, P. 1313 - 1322

Published: May 1, 2023

This study aimed to evaluate the efficacy and safety of remazolam compared with propofol in patients who underwent laryngeal mask airway (LMA) insertion without use muscle relaxant agents during hysteroscopic surgery.A total 72 undergoing hysteroscopy LMA were assigned two groups. The group received 0.3 μg/kg sufentanil, mg/kg 1.2 remifentanil, whereas 2.0 remifentanil for LMA. primary endpoint was summed score conditions. secondary endpoints included hemodynamics, duration induction, insertion, tidal volume, plateau pressure adverse events.No difference identified between median [18.0 (18.0, 18.0), 18.0 (17.0, respectively, P > 0.05]. induction significantly longer (P < 0.05) than group. cost dopamine lower group, while incidence transient mild laryngospasm higher No differences groups terms heart rate, injection pain or hiccups 0.05).Remazolam provided similar conditions better hemodynamic stability agents. However, a found which should be considered.

Language: Английский

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An Electroglottographic and Acoustic Study on Mandarin Speech in Male Heroin Users

Journal of Voice, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Fentanyl blockade of K+ channels contribute to Wooden Chest Syndrome

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 18, 2025

Abstract Fentanyl is a potent synthetic opioid widely used perioperatively and illicitly as drug of abuse 1,2 . It well established that fentanyl acts μ-opioid receptor agonist, signaling through Gα i/o intracellular pathways to inhibit electrical excitability, resulting in analgesia respiratory depression 3,4 However, uniquely also triggers muscle rigidity, including muscles, hindering the ability execute central commands or receive external resuscitation. This potentially lethal condition termed Wooden Chest Syndrome (WCS), mechanisms which are poorly understood 5–7 Here we show directly blocks subset EAG-class potassium channels 8 Our results demonstrate these expressed cervical spinal motoneurons, those innervating diaphragm. A significant fraction motoneurons excited by fentanyl, concomitant with blockade voltage-dependent non-inactivating K + currents In vivo electromyography revealed persistent tonic component diaphragmatic activity elicited but not morphine. Taken together our identify novel off-target mechanism for action, independent activation, paradoxical excitatory effect may underlie WCS. We anticipate findings inform design safer analgesics generalize other neuronal circuits implicated fentanyl-related maladaptive behaviors.

Language: Английский

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