Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers

Anesthesiology, Год журнала: 2023, Номер 139(1), С. 16 - 34

Опубликована: Апрель 4, 2023

Background Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, other acute care settings. Morphine hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects side effects, timing, respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine differ onset, magnitude, duration, variability of ventilatory effects. Methods The authors conducted a randomized crossover healthy volunteers. Forty-two subjects received 2-h infusion (0.05 mg/kg) or (0.2 1 2 weeks apart. measured arterial concentrations, response heat pain (maximally tolerated temperature, verbal analog scores at discrete preset temperatures determine half-maximum temperature effect), dark-adapted pupil diameter miosis, end-expired carbon dioxide, rate for 12 h after dosing. Results For hydromorphone, respectively, maximum miosis was less (3.9 [3.4 4.2] vs. 4.6 mm [4.0 5.0], P < 0.001; median 25 75% quantiles) occurred later (3.1 ± 0.9 2.3 0.7 start, mean SD); (49 50 2°C, 0.001); end-infusion most informative stimulus (48.2°C) were 82 4 59 3 (P CO2 47 (45 50) 48 mmHg (46 51; = 0.007) (5.5 2.8 3.0 1.5 nadir 9 11 breaths/min 0.001), similar times. area under tolerance-time curve (1.8 [0.0 4.4]) than (5.4°C-h [1.6 12.1] 0.001). Interindividual clinical did not opioids. Conclusions compared relative less, onset later, duration longer. each opioid, timing various coincident. may enable more rational selection, suggest have better profile. Editor’s Perspective What We Already Know about Topic Article Tells Us That Is New

Язык: Английский

---

Catalytic Antibody Blunts Carfentanil-Induced Respiratory Depression

ACS Pharmacology & Translational Science, Год журнала: 2023, Номер 6(5), С. 802 - 811

Опубликована: Апрель 17, 2023

Carfentanil, the most potent of fentanyl analogues, is at forefront synthetic opioid-related deaths, second to fentanyl. Moreover, administration opioid receptor antagonist naloxone has proven inadequate for an increasing number conditions, often requiring higher/additional doses be effective, as such interest in alternative strategies combat more opioids intensified. Increasing drug metabolism would one strategy detoxify carfentanil; however, carfentanil's major metabolic pathways involve N-dealkylation or monohydroxylation, which do not lend themselves readily exogenous enzyme addition. Herein, we report, our knowledge, first demonstration that methyl ester when hydrolyzed its acid was found 40,000 times less than carfentanil activating μ-opioid receptor. Physiological consequences and were also examined through plethysmography, incapable inducing respiratory depression. Based upon this information, a hapten chemically synthesized immunized, allowing generation antibodies screened hydrolysis. From screening campaign, three accelerate hydrolysis ester. series catalytic antibodies, active underwent extensive kinetic analysis, us postulate mechanism against opioid. In context potential clinical applications, antibody, passively administered, able reduce depression induced by carfentanil. The data presented supports further development antibody catalysis biologic complement overdose reversal.

Язык: Английский

---

Nucleus Tractus Solitarius Neurons Activated by Hypercapnia and Hypoxia Lack Mu Opioid Receptor Expression

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Июль 11, 2022

Impaired chemoreflex responses are a central feature of opioid-induced respiratory depression, however, the mechanism through which mu opioid receptor agonists lead to diminished chemoreflexes is not fully understood. One brainstem structure involved in impairment nucleus solitary tract (NTS), contains population neurons that express receptors. Here, we tested whether caudal NTS activated during challenge receptors and overlap with by opioids. Using genetic labeling receptor-expressing cFos immunohistochemistry as proxy for neuronal activation, examined distribution following hypercapnia, hypoxia, morphine administration. The main finding was hypoxia hypercapnia primarily did Furthermore, concurrent administration induced expression non-overlapping populations neurons. Together these results suggest an indirect effect opioids within NTS, could be mediated on afferents and/or inhibitory interneurons.

Язык: Английский

---

A comparative examination of morphine and fentanyl: unravelling the differential impacts on breathing and airway stability

The Journal of Physiology, Год журнала: 2023, Номер 601(20), С. 4625 - 4642

Опубликована: Окт. 1, 2023

Abstract This study provides an in‐depth analysis of the distinct consequences opioid drugs morphine and fentanyl during opioid‐induced respiratory depression (OIRD). We explored physiological implications both on ventilation airway patency in anaesthetized mice. Our results revealed a similar reduction frequency with equivalent scaled dosages morphine, though onset suppression was more rapid fentanyl. Additionally, resulted transient airflow obstructions inspiratory cycle, which were absent following administration. Notably, these fentanyl‐specific eliminated tracheostomy, implicating upper airways as major factor contributing to fentanyl‐induced depression. further demonstrate that bronchodilators salbutamol adrenaline effectively reversed obstructions, highlighting bronchi's contribution obstruction. also uncovered significant sighs OIRD, by markedly reduced morphine. Finally, we found fentanyl‐exposed mice had survival under hypoxic conditions compared given demonstrating becomes lethal context hypoxaemia. findings shed light profound impacts opioids respiration stability lay foundation for improved use guidelines effective OIRD prevention strategies. image Key points Both significantly suppressed frequency, but faster Also, while increased tidal volume, this effect pronounced Fentanyl administration phase, suggesting its unique impact stability. obstruction not observed The administering such adrenaline. suggests possible therapeutic strategy mitigating adverse effects sighs, key mechanism prevent alveolar collapse. However, led complete cessation only their occurrence. Fentanyl‐treated showed ability survive those administered indicates hypoxaemia can vary based used.

Язык: Английский

---

The μ-opioid receptor-mediated Gi/o protein and β-arrestin2 signaling pathways both contribute to morphine-induced side effects

European Journal of Pharmacology, Год журнала: 2024, Номер 966, С. 176333 - 176333

Опубликована: Янв. 24, 2024

Язык: Английский

---