BACKGROUND:The misuse of opioids stems, in part, from inadequate knowledge of molecular interactions between opioids and opioid receptors. It is still unclear why some opioids are far more addictive ...than others. The κ-opioid receptor (KOR) plays a critical role in modulating pain, addiction, and many other physiological and pathological processes. Butorphanol, an opioid analgesic, is a less addictive opioid with unique pharmacological profiles. In this study, we investigated the interaction between butorphanol and KOR to obtain insights into the safe usage of this medication.
METHODS:We determined the binding affinity of butorphanol to KOR with a naltrexone competition study. Recombinant KORs expressed in mammalian cell membranes (Chem-1) were used for G-protein activation studies, and a human embryonic kidney-293 (HEK-293) cell line stably transfected with the human KOR was used for β-arrestin study as previously described in the literature. The effects of butorphanol on KOR internalization were investigated using mouse neuroblastoma Neuro2A cells stably transfected with mKOR–tdTomato fusion protein (N2A-mKOR-tdT) cells overexpressing KOR. The active-state KOR crystal structure was used for docking calculation of butorphanol to characterize the ligand binding site. Salvinorin A, a full KOR agonist, was used as a control for comparison.
RESULTS:The affinity of KOR for butorphanol is characterized by Kd of 0.1 ± 0.02 nM, about 20-fold higher compared with that of the µ-opioid receptor (MOR; 2.4 ± 1.2 nM). Our data indicate that butorphanol is more potent on KOR than on MOR. In addition, butorphanol acts as a partial agonist of KOR in the G-protein activation pathway and is a full agonist on the β-arrestin recruitment pathway, similar to that of salvinorin A. The activation of the β-arrestin pathway is further confirmed by KOR internalization. The in silico docking model indicates that both salvinorin A and butorphanol share the same binding cavity with the KOR full agonist MP1104. This cavity plays an important role in determining either agonist or antagonist effects of the ligand.
CONCLUSIONS:In conclusion, butorphanol is a partial KOR agonist in the G-protein activation pathway and a potent KOR full agonist in the β-arrestin recruitment pathway. The structure analysis offers insights into the molecular mechanism of KOR interaction and activation by butorphanol.
In equine and racing practice, detomidine and butorphanol are commonly used in combination for their sedative properties. The aim of the study was to produce detection times to better inform European ...veterinary surgeons, so that both drugs can be used appropriately under regulatory rules. Three independent groups of 7, 8 and 6 horses, respectively, were given either a single intravenous administration of butorphanol (100 µg/kg), a single intravenous administration of detomidine (10 µg/kg) or a combination of both at 25 (butorphanol) and 10 (detomidine) µg/kg. Plasma and urine concentrations of butorphanol, detomidine and 3‐hydroxydetomidine at predetermined time points were measured by liquid chromatography–tandem mass spectrometry (LC‐MS/MS). The intravenous pharmacokinetics of butorphanol dosed individually compared with co‐administration with detomidine had approximately a twofold larger clearance (646 ± 137 vs. 380 ± 86 ml hr−1 kg−1) but similar terminal half‐life (5.21 ± 1.56 vs. 5.43 ± 0.44 hr). Pseudo‐steady‐state urine to plasma butorphanol concentration ratios were 730 and 560, respectively. The intravenous pharmacokinetics of detomidine dosed as a single administration compared with co‐administration with butorphanol had similar clearance (3,278 ± 1,412 vs. 2,519 ± 630 ml hr−1 kg−1) but a slightly shorter terminal half‐life (0.57 ± 0.06 vs. 0.70 ± 0.11 hr). Pseudo‐steady‐state urine to plasma detomidine concentration ratios are 4 and 8, respectively. The 3‐hydroxy metabolite of detomidine was detected for at least 35 hr in urine from both the single and co‐administrations. Detection times of 72 and 48 hr are recommended for the control of butorphanol and detomidine, respectively, in horseracing and equestrian competitions.
Recent studies have suggested that propofol combined butorphanol (PB) has anesthetic effect in laparoscopic surgery (LS) for ectopic pregnancy (EP). But investigations of its potential effects are ...inconsistent. We will explore the current literature examining PB in LS for EP.
We will perform a comprehensive search from MEDLINE, Embase, Cochrane Library, PsycINFO, Global Health, Web of Science, Allied and Complementary Medicine Database, and China National Knowledge Infrastructure from inception to the present. Other literatures, such as conference abstracts, references to the relevant reviews will also be checked. Two authors will check the titles, abstracts, and full texts independently. They will also independently carry out data collection and study quality assessment. We will conduct statistical analysis using RevMan 5.3 software.
This study will provide accurate results on the anesthetic effect and safety of PB in LS for EP.
This study will establish high-quality evidence of the anesthetic effect and safety of PB in LS for EP to facilitate the clinical practice and guideline development.
INPLASY202040044.
Proper administration of anesthesia is indispensable for the ethical treatment of lab animals in biomedical research. Therefore, selecting an effective anesthesia protocol is pivotal for the design ...and success of experiments. Hence, continuous development and refinement of anesthetic agents are imperative to improve research outcomes and elevate animal welfare. “Balanced anesthesia” involves using multiple drugs to optimize efficacy while minimizing side effects. The medetomidine, midazolam, and butorphanol, called MMB, and medetomidine, alfaxalone, and butorphanol, called MAB, are popular in Japan. However, the drawbacks of midazolam, including its extended recovery time, and the narrow safety margin of MAB, have prompted research for suitable alternatives. This study replaced midazolam in the MMB combination with remimazolam (RMZ), which is noted for its ultra-short half-life. The resulting combination, called MRB, was effective inproviding a wider safety margin compared to MAB while maintaining an anesthesia depth equivalent level to that of MMB in mice. Notably, MRB consistently exhibited better recovery scores after antagonist administration in contrast to MMB. Furthermore, the re-sedation phenomenon observed with MMB was not observed with MRB. The rapid metabolism of RMZ enables reliable anesthesia induction, circumventing the complications linked to MAB. Overall, MRB excelled in providing extended surgical anesthesia and swift post-antagonist recovery. These results highlight the potential of RMZ for broader animal research applications.
Many patients who underwent hepatic percutaneous microwave ablation (MWA) reported experiencing pain during the procedure. This study utilized a well-designed multicentral, randomized, and ...placebo-controlled format to investigate the effects of Butorphanol. Patients who underwent MWA were randomly assigned to either Butorphanol or normal saline group. The primary outcomes of the study were assessed by measuring the patients' intraoperative pain levels using a 10-point visual analog scale (VAS). Secondary outcomes included measuring postoperative pain levels at the 6-h mark (VAS) and evaluating comprehensive pain assessment outcomes. A total of 300 patients were divided between the control group (n = 100) and the experimental group (n = 200). Butorphanol showed statistically significant reductions in intraoperative pain levels compared to the placebo during surgery (5.00 ± 1.46 vs. 3.54 ± 1.67, P < 0.001). Significant differences were observed in postoperative pain levels at the 6-h mark and in the overall assessment of pain (1.39 + 1.21 vs. 0.65 + 0.81, P < 0.001). Butorphanol had a significant impact on reducing the heart rate of patients. The empirical evidence supports the effectiveness of Butorphanol in reducing the occurrence of visceral postoperative pain in patients undergoing microwave ablation for hepatic tumor. Furthermore, the study found no noticeable impact on circulatory and respiratory dynamics.
Butorphanol is a synthetic opioid analgesic medication that is primarily used for the management of pain. Butorphanol may have an inhibitory effect on androgen biosynthesis and metabolism in rat ...immature Leydig cells. The objective of this study was to investigate the influence of butorphanol on androgen secretion by rat Leydig cells isolated from the 35-day-old male rats. Rat Leydig cells were cultured with 0.5-50 μM butorphanol for 3 h in vitro
Butorphanol at 5 and 50 μM significantly inhibited androgen secretion in immature Leydig cells. At 50 μM, butorphanol also blocked the effects of luteinizing hormone (LH) and 8bromo-cAMP-stimulated androgen secretion and 22R-hydroxycholesterol- and pregnenolone-mediated androgen production. Further analysis of the results showed that butorphanol downregulated the expression of genes involved in androgen production, including
(LH receptor),
(cholesterol side-chain cleavage enzyme),
(5α-reductase 1), and
(3α-hydroxysteroid dehydrogenase). Additionally, butorphanol directly inhibited HSD3B1 (3β-hydroxysteroid dehydrogenase 1) and SRD5A1 activity. In conclusion, butorphanol may have side effects of inhibiting androgen biosynthesis and metabolism in Leydig cells.
Butorphanol has been used to reduce the incidence and severity of neuraxial morphine-induced pruritus. Palonosetron is a commonly used antiemetic for the prevention of postoperative nausea and ...vomiting. The aim of our study was to compare the effective dose in 50% of subjects (ED50) of intravenous butorphanol infusion with or without a single intravenous bolus of palonosetron for preventing pruritus induced by epidural administration of morphine.
A total of 120 parturients were randomly assigned to receive an intravenous bolus injection of palonosetron plus continuous infusion of butorphanol (Group P + B) or an intravenous bolus of saline plus continuous infusion of butorphanol (Group B) after epidural administration of morphine. The antipruritic effect was graded as satisfactory (numerical rating scale (NRS) of pruritus ≤3) or unsatisfactory (NRS >3) within 48 h after morphine treatment. The first patient in each group received butorphanol infusion at a rate of 4 µg/kg/h. The infusion dose for each subsequent patient in the corresponding group was increased by 0.2 µg/kg/h after an unsatisfactory response or decreased by 0.2 µg/kg/h after a satisfactory response. The ED50 was calculated for each group and compared using up-down sequential analysis.
The ED50 (mean 95% confidence interval (CI)) of the dose of intravenous butorphanol infusion for preventing moderate to severe pruritus was lower in Group P + B (3.29 µg/kg/min 3.25-3.34 µg/kg/min) than in Group B (3.57 µg/kg/min 3.47-3.67 µg/kg/min) (
< 0.05).
Under the conditions of the present study, a prophylactic use of 0.25 mg palonosetron reduced the ED50 of prophylactic infusion of butorphanol by approximately 8% to achieve a satisfactory antipruritic effect after epidural morphine for post-caesarean analgesia.
Knych, H. K., Casbeer, H. C., McKemie, D. S., Arthur, R. M. Pharmacokinetics and pharmacodynamics of butorphanol following intravenous administration to the horse. J. vet. Pharmacol. Therap. 36, ...21–30.
Butorphanol is a narcotic analgesic commonly used in horses. Currently, any detectable concentration of butorphanol in biological samples collected from performance horses is considered a violation. The primary goal of the study reported here was to update the pharmacokinetics of butorphanol following intravenous administration, utilizing a highly sensitive liquid chromatography‐mass spectrometry (LC‐MS) assay that is currently employed in many drug‐testing laboratories. An additional objective was to characterize behavioral and cardiac effects following administration of butorphanol. Ten exercised adult horses received a single intravenous dose of 0.1 mg/kg butorphanol. Blood and urine samples were collected at time 0 and at various times for up to 120 h and analyzed using LC‐MS. Mean ± SD systemic clearance, steady‐state volume of distribution, and terminal elimination half‐life were 11.5 ± 2.5 mL/min/kg, 1.4 ± 0.3 L/kg, and 5.9 ± 1.5 h, respectively. Butorphanol plasma concentrations were below the limit of detection (LOD) (0.01 ng/mL) by 48 h post administration. Urine butorphanol concentrations were below the LOD (0.05 ng/mL) of the assay in seven of 10 horses by 120 h post drug administration. Following administration, horses appeared excited as noted by an increase in heart rate and locomotion. Gastrointestinal sounds were markedly decreased for up to 24 h.
Background: Postoperative analgesia is of utmost importance in the treatment of patients undergoing surgery. Good postoperative pain management reduces hospital stay and improves early ambulation. ...This study compared the efficacy of epidural bupivacaine with buprenorphine to butorphanol in lower limb orthopedic surgery. Objectives: This study was carried out to investigate the onset of analgesia, the extent of analgesia, sedation score, and side effects of butorphanol with bupivacaine versus buprenorphine with bupivacaine. Methods: In a clinical trial study, 100 patients who underwent elective orthopedic lower limb surgery were randomly allocated to two groups. A total of 100 patients with American Society of anesthesiologists grades I and II posted for lower limb orthopedic surgery were enrolled in this randomized, double-blind study. The patients were divided into groups A and B. Subarachnoid block was achieved with 3.4 mL of 0.5% bupivacaine. The pain was monitored by the visual analog scale postoperatively. The patients in group A received bupivacaine with buprenorphine, and group B received bupivacaine with butorphanol when they complained of pain in the postoperative period. The onset of analgesia, duration of analgesia, sedation score, and side effects were compared between the two groups. Results: The onset of analgesia was observed earlier in group A than in group B (7.7 ± 1.6 vs. 12.6 ± 1.7 minutes, P < 0.001). The duration of analgesia was longer in group A than in group B (590 ± 40 vs. 480 ± 54 minutes, P < 0.001). Pulse rates and mean arterial pressures were significantly different (P < 0.001). Side effects were common in both groups. Conclusions: Buprenorphine added to bupivacaine provides earlier onset and longer postoperative epidural analgesia than epidural butorphanol with bupivacaine.
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