L-NAC and L-NAC methyl ester prevent and overcome physical dependence to fentanyl in male rats.

N-acetyl-L-cysteine (L-NAC) is a proposed therapeutic for opioid use disorder. This study determined whether co-injections of L-NAC (500 µmol/kg, IV) or its highly cell-penetrant analogue, L-NAC methyl ester (L-NACme, 500 µmol/kg, IV), prevent acquisition of acute physical dependence induced by twice-daily injections of fentanyl (125 µg/kg, IV), and overcome acquired dependence to these injections in freely-moving male Sprague Dawley rats. The injection of the opioid receptor antagonist, naloxone HCl (NLX; 1.5 mg/kg, IV), elicited a series of withdrawal phenomena (i.e. behavioral and cardiorespiratory responses, hypothermia and body weight loss) in rats that received 5 or 10 injections of fentanyl and similar numbers of vehicle co-injections. With respect to the development of dependence, the NLX-precipitated withdrawal phenomena were reduced in rats that received had co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme. In regard to overcoming established dependence, the NLX-precipitated withdrawal phenomena in rats that had received 10 injections of fentanyl (125 µg/kg, IV) were reduced in rats that had received co-injections of L-NAC, and more greatly reduced in rats that received co-injections of L-NACme beginning with injection 6 of fentanyl. This study provides compelling evidence that co-injections of L-NAC and L-NACme prevent the acquisition of physical dependence and overcome acquired dependence to fentanyl in male rats. The higher efficacy of L-NACme is likely due to its greater cell penetrability in brain regions mediating dependence to fentanyl and interaction with intracellular signaling cascades, including redox-dependent processes, responsible for the acquisition of physical dependence to fentanyl.

Fentanyl Analogs Exert Antinociceptive Effects via Sodium Channel Blockade in Mice.

The formalin test is one approach to studying acute pain in rodents. Similar to formalin, injection with glutamate and veratrine can also produce a nociceptive response. This study investigated whether opioid-related compounds could suppress glutamate- and veratrine-induced nociceptive responses in mice at the same dose. The administration of morphine (3 mg/kg), hydromorphone (0.4 mg/kg), or fentanyl (0.03 mg/kg) suppressed glutamate-induced nociceptive response, but not veratrine-induced nociceptive response at the same doses. However, high doses of morphine (10 mg/kg), hydromorphone (2 mg/kg), or fentanyl (0.1 mg/kg) produced a significant reduction in the veratrine-induced nociceptive response. These results indicate that high doses are required when using morphine, hydromorphone, or fentanyl for sodium channel-related neuropathic pain, such as ectopic activity. As a result, concerns have arisen about overdose and abuse if the dose of opioids is steadily increased to relieve pain. In contrast, trimebutine (100 mg/kg) and fentanyl analog isobutyrylfentanyl (iBF; 0.1 mg/kg) suppressed both glutamate- and veratrine-induced nociceptive response. Furthermore, nor-isobutyrylfentanyl (nor-iBF; 1 mg/kg), which is a metabolite of iBF, suppressed veratrine-induced nociceptive response. Besides, the optimal antinociceptive dose of iBF, unlike fentanyl, only slightly increased locomotor activity and did not slow gastrointestinal transit. Cancer pain is a complex condition driven by inflammatory, neuropathic, and cancer-specific mechanisms. Thus, iBF may have the potential to be a superior analgesic than fentanyl.

Comparisons of fentanyl and sufentanil on recovery time after inguinal hernia repair in children: a randomized clinical trial.

BACKGROUND: Inguinal hernia repair is a common pediatric procedure. We studied postoperative recovery times in children undergoing laparoscopic inguinal hernia repair with anesthesia induced by fentanyl versus sufentanil. METHODS: We performed a pilot randomized clinical trial between February and December 2022. Eligible children were assigned into two age groups, 2-6 and 6-12 years old groups. Then, children in each age group were randomly assigned into either the fentanyl (2 µg/kg) or sufentanil (0.2 µg/kg) group for anesthesia induction. Baseline characteristics were collected. The primary outcome was the postoperative recovery time, which was recorded as the time period from extubation to a Steward recovery score reaching 6. Secondary outcomes included surgical duration, anesthetic duration, intubation duration, and intraoperative hemorrhage. RESULTS: There were 300 children, with 75 children in each group. In the 2-6 years old group, children who received fentanyl had statistically significantly shorter postoperative recovery times than children who received sufentanil (0.9 ± 0.4 versus 1.5 ± 0.3 h, P < 0.001). However, in the 6-12 years old group, children who received fentanyl had statistically significantly longer postoperative recovery times than children who received sufentanil (1.2 ± 0.4 versus 0.8 ± 0.4 h, P < 0.001). Baseline characteristics and secondary outcomes were comparable between two groups. CONCLUSIONS: Anesthesia induction with fentanyl or sufentanil resulted in different postoperative recovery times after laparoscopic inguinal hernia repair in children in different age groups. More studies are required to determine the appropriate induction anesthetic in children of different ages. TRIAL REGISTRATION: The study protocol was retrospectively registered online at the Chinese Clinical Trial Registry (registration number ChiCTR2300072177, retrospectively registered on 06/06/2023).

Fentanyl Promoted the Growth of Placenta Trophoblast Cells through Regulating the METTL14 Mediated CCL5 Levels.

Gestational diabetes mellitus (GDM) is an important cause of the increase in incidence rate and mortality of pregnant women and perinatal infants. This study aimed to analyze the role of fentanyl, a µ-opioid agonist, in the GDM progression. The high glucose (HG) treatment HTR8/SVneo cells was used as a GDM model in vitro. The cell viability was assessed with cell counting kit-8 assay. The apoptosis rate was analyzed with flow cytometry and the transwell assay was conducted to test the cell migration and invasion. RT-quantitative PCR (qPCR) assay was performed to determine the relative expressions of related genes. The N6-Methyladenosine (m6A) levels were analyzed with MeRIP analysis. The tumor necrosis factor-α (TNF-α), interleukin 1ß (IL-1ß), and IL-10 levels of the cells were analyzed with commercial kits. The results showed that fentanyl increased the cell viability, migration and invasion, and IL-10 levels, and declined the apoptosis rate, TNF-α and IL-1ß levels of the HG stimulated HTR8/SVneo cells. The chemokine ligand 5 (CCL5) was over expressed in GDM tissues and HG stimulated HTR8/SVneo cells, which was depleted after fentanyl treatment. Over expressed CCL5 neutralized the fentanyl roles in the HG stimulated HTR8/SVneo cells. The methyltransferase-like protein 14 (METTL14) levels was decreased in HG stimulated HTR8/SVneo cells, which was up-regulated after fentanyl treatment. Additionally, METTL14 silenced prominently decreased the m6A and mRNA levels, along with the mRNA stability of CCL5. In conclusion, fentanyl promoted the growth and inhibited the apoptosis of the HG stimulated HTR8/SVneo cells through regulating the METTL14 mediated CCL5 levels.

Distinct Profiles of Desensitization of µ-Opioid Receptors Caused by Remifentanil or Fentanyl: In Vitro Assay with Cells and Three-Dimensional Structural Analyses.

Remifentanil (REM) and fentanyl (FEN) are commonly used analgesics that act by activating a µ-opioid receptor (MOR). Although optimal concentrations of REM can be easily maintained during surgery, it is sometimes switched to FEN for optimal pain regulation. However, standards for this switching protocol remain unclear. Opioid anesthetic efficacy is decided in part by MOR desensitization; thus, in this study, we investigated the desensitization profiles of REM and FEN to MOR. The efficacy and potency during the 1st administration of REM or FEN in activating the MOR were almost equal. Similarly, in ß arrestin recruitment, which determines desensitization processes, they showed no significant differences. In contrast, the 2nd administration of FEN resulted in a stronger MOR desensitization potency than that of REM, whereas REM showed a higher internalization potency than FEN. These results suggest that different ß arrestin-mediated signaling caused by FEN or REM led to their distinct desensitization and internalization processes. Our three-dimensional analysis, with in silico binding of REM and FEN to MOR models, highlighted that REM and FEN bound to similar but distinct sites of MOR and led to distinct ß arrestin-mediated profiles, suggesting that distinct binding profiles to MOR may alter ß arrestin activity, which accounts for MOR desensitization and internalization.

Fentanyl inhibits cell invasion and migration by modulating NF-κB activation in glioma.

Fentanyl is widely used for anesthesia and analgesia in cancer patients. Recent studies have revealed its anti-growth effect in several categories of cancer. Gliomas are the most common primary tumors in the central nervous system with poor prognosis. To investigate the effects of fentanyl on gliomas, glioma cells were treated with different concentrations of fentanyl both in vitro and in vivo. Consequences of proliferation and invasive phenotypes, and related protein expression were evaluated in two human glioma cell lines (U251 and U87). Naloxone, Mu Opioid Receptor (MOR) antagonist, was introduced into culture media to assess the involvement of MOR in Fentanyl-mediated changes. When compared with control group, it could be found that Fentanyl inhibited function of glioma cells only at high concentrations. Western blot and immunofluorescence results revealed that Fentanyl exerted its action via modulating NF-κB (P65) activation which is likely independent of MOR. Moreover, overexpression of P65 by transfection P65-expressing vector restored the invasion and migration of glioma cells, which were inhibited by Fentanyl. In summary, this study showed that opioid pain medication Fentanyl was capable of decreasing invasiveness of glioma cells at a high concentration both in vitro and in vivo, likely via modulating P65 activation.

Efficacy appraisal of four regimens (granisetron, ketamine, dexmedetomidine, and lidocaine combined with fentanyl) for cystoscopy-associated sedation and analgesia and catheter-related bladder tolerance: a randomized clinical trial.

The authors sought to quantify the clinical impacts of granisetron, ketamine, dexmedetomidine, and lidocaine combined with fentanyl, for procedural sedation and analgesia in cystoscopy and for bladder catheter tolerance. This double-blind trial recruited four stratified blocked randomized eligible groups of patients (n = 120) formerly identified as needing cystoscopy, each receiving one of the above four anesthetic agents. Dexmedetomidine-sedated subjects experienced less pain from 5 to 120 minutes after the beginning of procedure, and next the ketamine manifested a better pain relief experienced. Sedation score was found to be rather more satisfactory in the early-mentioned from 15 to 55 minutes and at 90 and 105 minutes after procedure. The mean opioid use was observed lower in the dexmedetomidine treated patients and next in the ketamine administered patients. Considering the findings emanating from the study and the lack of complications that need to be treated, dexmedetomidine and ketamine afforded superior pain relief, greater sedation, and less postoperative opioid use in patients undergoing cystoscopy, and thus, they could be suggested to be combined with fentanyl during outpatient cystoscopy.

Anesthetic effects of isoflurane and fentanyl infusion in capuchin monkeys (Sapajus sp) undergoing salpingectomy or deferentectomy, previously chemically restrained with ketamine-midazolam or ketamine-dexmedetomidine.

BACKGROUND: This study evaluated the anesthetic and cardiorespiratory effects of two anesthetic protocols for salpingectomy or deferentectomy in capuchin monkeys (Sapajus sp). MATERIALS AND METHODS: Five capuchin monkeys (5 per group) received ketamine (20 mg/kg) combined with midazolam (0.5 mg/kg; group KM) or dexmedetomidine (5 µg/kg; group KD) intramuscularly. Anesthesia is induced with propofol intravenously and maintained with isoflurane. Before the start of surgery, fentanyl 3 µg/kg was administered IV, and continuous infusion (10 µg/kg/min) IV was started. Times and quality of anesthetic recovery were evaluated postoperatively. RESULTS: KM and KD resulted in adequate chemical restraint. KD resulted in bradycardia. Intraoperative heart rate and systolic blood pressure were higher in KM than in KD. Both groups had smooth recovery. Time to standing was longer in KM than in KD. CONCLUSION: Both protocols allowed the performance of surgeries, with few cardiorespiratory effects. Anesthetic recovery was smooth and shorter in KD group.

Dexmedetomidine as an adjuvant to scalp block in patients undergoing elective craniotomy: A prospective randomized controlled trial.

OBJECTIVE: Regional techniques minimize anesthetic requirements and their effects may be beneficial. There is a lack of consensus and evidence concerning alternative analgesia strategies for cranial neurosurgery. This study was designed to evaluate the effect of scalp block with or without dexmedetomidine combined with general anesthesia on hemodynamic stability, opioid consumption and postoperative pain in patients undergoing elective craniotomy. METHODS: One hundred five patients undergoing elective craniotomy for tumor dissection were randomly divided into three groups to receive scalp block as an adjuvant to general anesthesia: with either 40 ml ropivacaine 0.5 % (Group R), 40 ml ropivacaine 0.5 % plus dexmedetomidine 1 µg/kg (Group RD) or 40 ml saline as a placebo (Group C). After a standard induction sequence using propofol, fentanyl and a single dose of rocuronium, patients were intubated. Bilateral scalp block was given immediately after induction. Anesthesia was maintained with propofol and remifentanil infusion. Five minutes before head pinning scalp block was performed by blocking the supraorbital, supratrochlear, auriculotemporal, occipital, and postauricular branches of the greater auricular nerves. All patients were monitored with electrocardiogram, invasive blood pressure, pulse oximetry and BIS monitoring. Primary outcomes measures were overall hemodynamic variables during surgery and intravenous fentanyl and remifentanil consumption. Mean arterial pressure (MAP) and heart rate (HR) were recorded at seven time-points: scalp block (T1-baseline), pin fixation (T2), skin incision (T3), drilling (T4), dura matter incision (T5), dura matter closure (T6) and skin closure (T7). For all time points it was recorded the mean value after 3 consecutive measures with 5 min interval. Secondary outcome was postoperative pain intensity using visual analog scale 24 and 48 h after surgery. VAS scores, fentanyl and remifentanil were evaluated using Kruskal-Wallis test. MAP and HR were compared by One-Way repeated measures Anova (GLMM) using time as random efect and by One-Way Anova using time as fxed efect. RESULTS: Mean arterial pressure was significant lower at skin closure compared to baseline in group R (p < 0,001) and in group RD (p < 0,001). Patients in group RD showed significant lower heart rate at dura matter incision, dura matter closure and skin closure compared to baseline, pin fixation and skin incision time points (p < 0,001) and reported significantly less heart rate than group C (p < 0,001) and group R (p < 0,001) during dura matter incision, dura matter closure and skin closure time points. Patients in group RD receive significant lower fentanyl than group R (p < 0,01). The intraoperative consumption of remifentanil was significant higher in control group compared to group R (p < 0,01) and to group RD (p < 0,001). Additionally, remifentanil consumption was significant lower in group RD as compared to group R (p < 0,001). Postoperative pain had no statistically differences between the three groups at 24 h and 48 h after craniotomy (Preop VAS: p = 0,915, VAS 24: p = 0,284, VAS 48, p = 0,385). No adverse effects were noted. CONCLUSION: Our study indicated that addition of dexmedetomidine to scalp block with ropivacaine 0.5% provided significantly better perioperative hemodynamic stability during elective craniotomy. Moreover, scalp block with or without dexmedetomidine reduced fentanyl and remifentanil consumption, but it didn't significantly prolonged analgesia in patients undergoing elective craniotomy.

Interactions of fentanyl with blood platelets and plasma proteins: platelet sensitivity to prasugrel metabolite is not affected by fentanyl under in vitro conditions.

BACKGROUND: Clinical trials indicate that fentanyl, like morphine, may impair intestinal absorption and thus decrease the efficacy of oral P2Y12 inhibitors, such as clopidogrel, ticagrelor, and prasugrel. However, the ability of fentanyl to directly negate or reduce the inhibitory effect of P2Y12 receptor antagonists on platelet function has not been established. A series of in vitro experiments was performed to investigate the ability of fentanyl to activate platelets, potentiate platelet response to ADP, and/or diminish platelet sensitivity to prasugrel metabolite (R-138727) in agonist-stimulated platelets. The selectivity and specificity of fentanyl toward major carrier proteins has been also studied. METHODS: Blood was obtained from healthy volunteers (19 women and 12 men; mean age 40 ± 13 years). Platelet function was measured in whole blood, platelet-rich plasma and in suspensions of isolated platelets by flow cytometry, impedance and optical aggregometry. Surface plasmon resonance and molecular docking were employed to determine the binding kinetics of fentanyl to human albumin, α1-acid glycoprotein, apolipoprotein A-1 and apolipoprotein B-100. RESULTS: When applied at therapeutic and supratherapeutic concentrations under various experimental conditions, fentanyl had no potential to stimulate platelet activation and aggregation, or potentiate platelet response to ADP, nor did it affect platelet susceptibility to prasugrel metabolite in ADP-stimulated platelets. In addition, fentanyl was found to interact with all the examined carrier proteins with dissociation constants in the order of 10-4 to 10-9 M. CONCLUSIONS: It does not seem that the delayed platelet responsiveness to oral P2Y12 inhibitors, such as prasugrel, in patients undergoing percutaneous coronary intervention, results from direct interactions between fentanyl and blood platelets. Apolipoproteins, similarly to albumin and α1-acid glycoprotein, appear to be important carriers of fentanyl in blood.

Influence of Constant Rate Infusions of Fentanyl Alone or in Combination With Lidocaine and Ketamine on the Response to Surgery and Postoperative Pain in Isoflurane Anesthetized Dogs Undergoing Unilateral Mastectomy: A Randomized Clinical Trial.

The aim of this study was to compare the effects of constant rate infusions (CRI) of fentanyl alone or combined with lidocaine and ketamine (FLK), on physiological parameters, isoflurane requirements and the number of postoperative analgesic rescues in dogs undergoing unilateral mastectomy. Twenty-two dogs were premedicated with acepromazine 0.02 mg/kg and morphine 0.5 mg/kg and anesthetized with propofol and isoflurane. Dogs were randomly assigned to 1 of 2 groups: Fentanyl group (fentanyl 5 µg/kg loading dose [LD] and 9 µg/kg/h CRI; n = 11); FLK group (fentanyl [same doses]; lidocaine 2 mg/kg LD and 3 mg/kg/h CRI; ketamine 1.0 mg/kg LD and 0.6 mg/kg/h CRI; = 11). Intraoperative evaluations were performed before the start of surgery and administration of the treatments (T0); three minutes after the LD (T1); during incision and tissue divulsion (T2); during closure of the surgical wound (T3). Meloxicam (0.1 mg/kg) was administered at T3. Blood samples were collected for determination of plasma concentrations of fentanyl, lidocaine and ketamine. Pain scores and the number of postoperative analgesic rescues with morphine (0.5 mg/kg) were evaluated for 24 hours postoperatively using the short form of the Glasgow Composite Measure Pain Scale. Compared to T0, significant decreases in heart rate (from 84 ± 28 to 53 ± 16 bpm in the Fentanyl group and from 93 ± 16 to 63 ± 15 bpm in FLK) and mean arterial pressure (from 61 ± 5 to 49 ± 10 mmHg in Fentanyl and from 59 ± 3 to 38 ± 6 mmHg in FLK) were observed at T1. Arterial hypotension was transient, with normalization of values at T2 and T3. The expired fraction of isoflurane did not differ significantly between the groups. Plasma concentrations of fentanyl, lidocaine and ketamine remained within the therapeutic range. Postoperatively, the number of dogs requiring analgesic rescue was significantly lower in the FLK (0/11, 0%) than in the Fentanyl group (5/11, 45%). In dogs administered morphine and meloxicam as part of the anesthesia protocol, an intraoperative CRI of FLK abolished the requirement for postoperative analgesic rescue for 24 hours in dogs undergoing mastectomy.

Intraperitoneal instillation versus wound infiltration for postoperative pain relief after cesarean delivery: A prospective, randomized, double-blind, placebo-controlled trial.

AIM: To compare local anesthetic wound infiltration with intraperitoneal instillation of local anesthetic for analgesia after cesarean section under spinal anesthesia. METHODS: This study was conducted on 150 pregnant women undergoing elective cesarean section under spinal anesthesia. Spinal anesthesia was performed with 7 mg isobaric bupivacaine and 15 µcg fentanyl. The patients were randomized into three groups of 50 patients each: Group local anesthetic wound infiltration (LWI): 20 ml local anesthetic solution (10 ml 0.5% bupivacaine and 10 ml 2% lidocaine mixture) was administered subcutaneous wound infiltration at the end of surgery prior to skin closure and 20 ml saline was instilled into the uterine peritoneal area before fascia closure. Group intraperitoneal local anesthetic (IPLA): 20 ml local anesthetic solution (10 ml 0.5% bupivacaine and 10 ml 2% lidocaine mixture) was instilled into the uterine peritoneal area and 20 ml saline was administered subcutaneous wound infiltration. Group Placebo: 20 ml saline was instilled into the uterine peritoneal area and 20 ml saline was administered local subcutaneous wound infiltration. Pain scores at rest and on movement, total fentanyl consumption at 24 h, maternal satisfaction, and the time to first analgesic request were recorded. RESULTS: No statistically significant difference was observed in the postoperative pain scores at rest at 2, 12, and 24 h (p = 0.314, 0.343, and 0.735, respectively) and on movement at 12 and 24 h (p = 0.318 and 0.642, respectively) between the groups. The pain scores on movement at 2 h were significantly lower in Group IPLA compared with Group Placebo (p = 0.047). There were no significant differences between the groups in terms of total fentanyl consumption and the time to first analgesic request. CONCLUSION: The use of intraperitoneal instillation of bupivacaine and lidocaine reduces early the pain score on movement in women undergoing cesarean section under spinal anesthesia.

Fentanyl sparing effect of ultrasound-guided proximal radial, ulnar, median, and musculocutaneous nerve (RUMM) block for radial and ulnar fracture repair in dogs: a retrospective case-control study.

This study retrospectively evaluated the fentanyl-sparing effect of ultrasound-guided proximal radial, ulnar, median, and musculocutaneous nerve (RUMM) block for radial and ulnar fracture repair in dogs. Fentanyl was prepared for intraoperative analgesia in dogs, although proximal RUMM block was performed using 0.5% or 0.25% bupivacaine before surgery in the block group. Dogs without a nerve block were assigned to the control group. The fentanyl dose in the block group [0.8 (0-1.9) µg/kg/hr] [median (interquartile range)] was significantly lower than in the control group [8.4 (7.2-10) µg/kg/hr]. Surgery was performed without fentanyl in >50% of the dogs (5/7), using 0.5% bupivacaine. Ultrasound-guided proximal RUMM block can be useful as an intraoperative analgesic for radial and ulnar fracture repair in dogs.

Fentanyl activates ovarian cancer and alleviates chemotherapy-induced toxicity via opioid receptor-dependent activation of EGFR.

BACKGROUND: Fentanyl is an opioid analgesic and is widely used in ovarian cancer patients for pain management. Although increasing evidence has suggested the direct role of fentanyl on cancer, little is known on the effect of fentanyl on ovarian cancer cells. METHODS: Proliferation, migration and apoptosis assays were performed in ovarian cancer cells after fentanyl treatment. Xenograft mouse model was generated to investigate the in vivo efficacy of fentanyl. Combination index was analyzed for the combination of fentanyl and chemotherapeutic drugs. Immunoblotting approach was used to analyze signaling involved in fentanyl's action focusing on EGFR. RESULTS: Fentanyl at nanomolar concentration does-dependently increased migration and proliferation of a panel of ovarian cancer cell lines. Fentanyl at the same concentrations either did not or stimulated proliferation to a less extent in normal cells than in ovarian cancer cells. Consistently, fentanyl significantly promoted ovarian cancer growth in vivo. The combination of fentanyl with cisplatin or paclitaxel was antagonist in inhibiting cell proliferation. Although fentanyl did not affect cell apoptosis, it significantly alleviated ovarian cancer cell death induced by chemotherapeutic drugs. Mechanistically, fentanyl specifically activated EGFR and its-mediated downstream pathways. Knockdown of EGFR abolished the stimulatory effects of fentanyl on ovarian cancer cells. We finally demonstrated that the activation of EGFR by fentanyl is associated with opioid µ receptor system. CONCLUSIONS: Fentanyl activates ovarian cancer via simulating EGFR signaling pathways in an opioid µ receptor-dependent manner. The activation of EGFR signaling by fentanyl may provide a new guide in clinical use of fentanyl in ovarian cancer patients.

Perioperative Analgesic Efficacy of Yamamoto New Scalp Acupuncture for Canine Mastectomy Combined with Ovariohysterectomy: a Randomized, Controlled Clinical Trial.

Background: Yamamoto New Scalp Acupuncture (YNSA) is a therapy based on the stimulation of points on the scalp and applied to treat different states of pain. Objectives: To investigate the analgesic efficacy of YNSA for dogs undergoing radical unilateral mastectomy with ovariohysterectomy. Methods: Twenty-four dogs were randomly distributed into two treatments (n = 12, per group): bilateral stimulation of basic B, D, and E points (YNSA group) and no application of acupuncture (control group). All dogs were sedated with morphine; anesthesia was induced with propofol and maintained with isoflurane. Fentanyl was intraoperatively administered to control cardiovascular responses to surgical stimulation. Postoperative pain was assessed using an interactive visual analog scale (IVAS) and the short-form of the Glasgow Composite Pain Scale (CMPS-SF). Morphine was administered as rescue analgesia. Data were analyzed using t-tests, Fisher's exact test, Mann-Whitney U test, and Friedman test (p < 0.05). Results: Intraoperatively, the number of dogs requiring supplemental analgesic and the number of doses of fentanyl were lower in the YNSA group than in the control group (p = 0.027-0.034). The IVAS pain scores recorded from 0.5 h to 1 h post-extubation in the YNSA group were lower than those in the control group (p = 0.021-0.023). Postoperative rescue analgesia and CMPS-SF pain scores did not differ between the groups. Conclusion: YNSA decreases intraoperative fentanyl requirements and provides minimal postoperative analgesic benefits to dogs undergoing unilateral mastectomy with ovariohysterectomy.

Plasma concentration, cardiorespiratory and analgesic effects of ketamine-fentanyl infusion in dogs submitted to mastectomy.

BACKGROUND: The analgesic and cardiorespiratory effects of ketamine, fentanyl, or ketamine-fentanyl constant rate infusion (CRI) in dogs undergoing mastectomy were evaluated. Seventeen female dogs received CRI of ketamine (GK [n = 6]: bolus 0.5 mg/kg; CRI 20 µg/kg/min in intra- and postoperative periods], fentanyl (GF [n = 5]: bolus 20 µg/kg; intraoperative CRI 5 20 µg/kg/hour and postoperative CRI 2 20 µg/kg/hour), or combination of ketamine-fentanyl (GKF [n = 6]: aforementioned doses) for 8 h. Cardiorespiratory, blood gas analyses, plasma drug concentrations, sedation score (SS), Pain Scores were evaluated. RESULTS: The heart rate decreased in the GF and GKF (p < 0.04); the mean arterial pressure was lower in the GKF than in the GK at 35 min (p < 0.001). Maximum plasma concentrations were observed 5 min after bolus in the GK (2847.06 ± 2903.03 ng/mL) and GKF (2811.20 ± 1931.76 ng/mL). Plasma concentration in intraoperative period of ketamine was of > 100 ng/mL in 5/5 and 2/5 animals in the GKF and GK, respectively; and > 1.1 ng/mL of fentanyl in 4/5 and 3/5 in GKF and GF, respectively. CONCLUSION: Ketamine with/without fentanyl provided analgesia without significant cardiorespiratory and guaranteed the minimal plasma levels with analgesic potential during the 8 h.

Effects of fentanyl overdose-induced muscle rigidity and dexmedetomidine on respiratory mechanics and pulmonary gas exchange in sedated rats.

The objective of our study was to establish in sedated rats the consequences of high-dose fentanyl-induced acute muscle rigidity on the mechanical properties of the respiratory system and on the metabolic rate. Doses of fentanyl that we have previously shown to produce persistent rigidity of the muscles of the limbs and trunk in the rat (150-300 µg/kg iv), were administered in 23 volume-controlled mechanically ventilated and sedated rats. The effects of a low dose of the FDA-approved central α-2 agonist, dexmedetomidine (3 µg/kg iv), which has been suggested to oppose fentanyl-induced muscle rigidity, were determined after fentanyl administration. Fentanyl produced a significant decrease in compliance of the respiratory system (Crs) in all the rats that were studied. In 13 rats, an abrupt response occurred within 90 s, consisting of rapid rhythmic contractions of most skeletal muscles that were replaced by persistent tonic/tetanic contractions leading to a significant decrease of Crs (from 0.51 ± 0.11 mL/cmH2O to 0.36 ± 0.08 mL/cmH2O, 3 min after fentanyl injection). In the other 10 animals, Crs progressively decreased to 0.26 ± 0.06 mL/cmH2O at 30 min. There was a significant rise in oxygen consumption (V̇o2) during these muscle contractions (from 8.48 ± 4.31 to 11.29 ± 2.57 mL/min), which led to a significant hypoxemia, despite ventilation being held constant. Dexmedetomidine provoked a significant and rapid increase in Crs toward baseline levels, whereas decreasing the metabolic rate and restoring normoxemia. We propose that the changes in respiratory mechanics and metabolism produced by opioid-induced muscle rigidity contribute to fentanyl lethality.NEW & NOTEWORTHY The decrease in respiratory compliance and increased metabolism-induced hypoxemia produced by an overdose of fentanyl, in and of themselves, contribute to fentanyl toxicity.

Role of Efficacy as a Determinant of Locomotor Activation by Mu Opioid Receptor Ligands in Female and Male Mice.

Mu opioid receptor (MOR) agonists produce locomotor hyperactivity in mice as one sign of opioid-induced motor disruption. The goal of this study was to evaluate the degree of MOR efficacy required to produce this hyperactivity. Full dose-effect curves were determined for locomotor activation produced in male and female Institute of Cancer Research (ICR) mice by (1) eight different single-molecule opioids with high to low MOR efficacy and (2) a series of fixed-proportion fentanyl/naltrexone mixtures with high to low fentanyl proportions. Data from the mixtures were used to quantify the efficacy requirement for MOR agonist-induced hyperactivity relative to efficacy requirements determined previously for other MOR agonist effects. Specifically, efficacy requirement was quantified as the EP50 value, which is the "Effective Proportion" of fentanyl in a fentanyl/naltrexone mixture that produces a maximal effect equal to 50% of the maximal effect of fentanyl alone. Maximal hyperactivity produced by each drug and mixture in the present study correlated with previously published data for maximal stimulation of GTPÉ£S binding in MOR-expressing Chinese hamster ovary cells as an in vitro measure of relative efficacy. Additionally, the EP50 value for hyperactivity induced by fentanyl/naltrexone mixtures indicated that opioid-induced hyperactivity in mice has a relatively high efficacy requirement in comparison with some other MOR agonist effects, and in particular is higher than the efficacy requirement for thermal antinociception in mice or fentanyl discrimination in rats. Taken together, these data show that MOR agonist-induced hyperactivity in mice is efficacy dependent and requires relatively high levels of MOR agonist efficacy for its full expression. SIGNIFICANCE STATEMENT: Mu opioid receptor (MOR) agonist-induced hyperlocomotion in mice is dependent on the MOR efficacy of the agonist and requires a relatively high degree of efficacy for its full expression.

Comparative Study of Efficacy of Buprenorphine and Fentanyl on Attenuation of Hemodynamic Changes to Laryngoscopy and Intubation: A Prospective, Randomized Double-Blind Study.

BACKGROUND: Hemodynamic changes are the most common predicted response after laryngoscopy and intubation during general anesthesia. We compared the efficacy of buprenorphine with fentanyl to attenuate this stress response. METHODS: One hundred and thirty patients of either sex between the age group of 18-70 years, admitted for the routine surgical procedure under general anesthesia were enrolled in this double blind, randomized, clinical study. Patients were randomly assigned into two equal groups (60 patients in each group): group F received fentanyl 2 µg/kg, and group B received buprenorphine 2.5 µg/kg; both via intravenous route. Each group received a total volume of 10 mL by adding normal saline to the total drug volume, given over 60 seconds, 5 minutes before intubation. Thereafter patients were induced using routine balanced anesthesia technique, and the hemodynamic parameters were observed at baseline (0 minute), 1, 3, and 5 minutes after the administration of the study drug and again at 1, 3, 5, 7, and 10 minutes after intubation. Continuous variables were presented as mean with an 80% confidence interval, and a t-test was applied for comparing the difference of means between two groups after we checked the normality condition. Chi-square test was applied to test the independence of attributes of categorical variables. Repeated measures two-way analysis of variance was performed to compare the outcome variables between the two groups. RESULTS: In both groups, mean arterial blood pressure (MAP) and heart rate (HR) were statistically insignificant up to 5 minutes after study drug, thereafter mean HR and MAP at 1, 3, 5, 7, and 10 minutes after intubation, were statistically significant between the two groups, and P value was less than 0.05. CONCLUSIONS: The dose of 2.5 µg/kg buprenorphine is an effective alternative to fentanyl 2 µg/kg for attenuating the hemodynamic response accompanying laryngoscopy and tracheal intubation without causing any hemodynamic adverse effect.

Comparison of Hemodynamics and Opioid Sparing Effect of Dexmedetomidine Nebulization and Intravenous Dexmedetomidine in Laparoscopic Surgeries Under General Anesthesia.

BACKGROUND: Dexmedetomidine has been used by multiple routes in laparoscopic surgeries to attenuate the hemodynamic response. The present study was done to compare the efficacy of dexmedetomidine nebulization with intravenous dexmedetomidine and fentanyl in laparoscopic surgeries under general anesthesia. METHODS: A prospective, double blind study was conducted, and 90 American Society of Anesthesiologists (ASA) I and II patients of either gender between 18-65 years undergoing laparoscopic surgeries under general anesthesia were randomized into three groups. (1) Group N (n = 30) received dexmedetomidine nebulization 1 mcg/kg in 3 mL of 0.9% saline 15 minutes before induction and 10 mL of intravenous 0.9% saline over 10 minutes at the time of induction of anesthesia. (2) Group I (n = 30) received 0.9% saline nebulization 3 mL and intravenous dexmedetomidine 1 mcg/kg in 10 mL of 0.9% saline. (3) Group F (n = 30) received 0.9% saline nebulization 3 mL and intravenous fentanyl 2 mcg/kg in 10mL of 0.9% saline. Heart rate, blood pressure, propofol requirement, and opioid consumption were monitored throughout surgery and for 1 hour in post-operative period. Statistical analysis was done by using analysis of variance test, chi-square test. P value ＜ 0.05 was considered signifi cant. RESULTS: Suppression of hemodynamic response following intubation and pneumoperitoneum by dexmedetomidine nebulization was compared to intravenous dexmedetomidine and fentanyl. Opioid requirement was significantly lower in dexmedetomidine group than fentanyl group (P ＜ 0.05). Propofol requirement was lower with intravenous and nebulized dexmedetomidine than intravenous fentanyl. CONCLUSIONS: In laparoscopic surgeries, nebulized dexmedetomidine suppresses hemodynamic response when compared to intravenous dexmedetomidine along with dose sparing effect of opioid and propofol.