Butorphanol-Azaperone-Medetomidine Is as Safe and Effective as Nalbuphine-Azaperone-Medetomidine for Immobilization of Juvenile American Black Bears (Ursus americanus).

Immobilization kits including butorphanol-azaperone-medetomidine (BAM) and nalbuphine-azaperone-medetomidine can provide effective, safe, and easy-to-use protocols in bears. Nalbuphine-azaperone-medetomidine is not commercially available but may be useful for wildlife agencies because it does not contain controlled substances. This study directly compared BAM to nalbuphine-azaperone-medetomidine immobilization in 10 juvenile healthy black bears (10 mo old; four females, six males) undergoing prerelease examinations after rehabilitation. Bears were immobilized via remote delivery of 1 mL of BAM (n=5) or nalbuphine-azaperone-medetomidine (n=5) intramuscularly in the shoulder during December (randomized, blinded trial). Bears were intubated, monitored with an electrocardiogram, pulse oximeter, capnograph, noninvasive blood pressure cuff, and rectal thermometer, and underwent physical examination, sample collection, morphometrics, and ear-tag placement. Induction, physiologic, and recovery parameters were recorded, including arterial blood gas analysis. The anesthetic agents were antagonized with atipamezole and naltrexone. There were no differences between protocols in induction or recovery times. There were no differences between protocols in heart rate, respiratory rate, temperature, oxygen saturation, end-tidal CO2, mean arterial pressure, or blood gas analysis or any differences between male and female bears in any parameters. Bears were hypertensive and normoxemic with low oxygen saturation via pulse oximeter, but all recovered smoothly and were released within 2 h of recovery. This study supports that nalbuphine-azaperone-medetomidine is clini-cally as safe and effective as BAM in American black bears.

Comparison of Ketamine-Xylazine, Butorphanol-Azaperone-Medetomidine, and Nalbuphine-Medetomidine-Azaperone for Raccoon (Procyon lotor) Immobilization.

Raccoons (Procyon lotor) are frequently handled using chemical immobilization in North America for management and research. In a controlled environment, we compared three drug combinations: ketamine-xylazine (KX), butorphanol-azaperone-medetomidine (BAM), and nalbuphine-medetomidine-azaperone (NalMed-A) for raccoon immobilization. In crossover comparisons, raccoons received a mean of the following: 8.66 mg/kg ketamine and 1.74 mg/kg xylazine (0.104 mL/kg KX); 0.464 mg/kg butorphanol, 0.155 mg/kg azaperone, and 0.185 mg/kg medetomidine (0.017 mL/kg BAM); and 0.800 mg/kg nalbuphine, 0.200 mg/kg azaperone, and 0.200 mg/kg medetomidine (0.020 mL/kg NalMed-A). Induction time was shortest with KX (mean±SE, 10.0±0.7 min) and longest with NalMed-A (13.0±1.3 min). A sampling procedure was completed on 89% (16/18), 72% (13/18), and 89% (16/18) of the raccoons administered KX, BAM, and NalMed-A, respectively. Reasons for incomplete sampling included inadequate immobilization (one KX and one NalMed-A), responsive behaviors (one each with KX, BAM, NalMed-A), or animal safety (four BAM). Mean recovery time for KX was 32.8±7.1 min without antagonizing and 28.6±5.2 min following delivery of an antagonist. Mean recovery time was 6.2±0.8 min for BAM and 5.1±0.5 min for NalMed-A after antagonizing. Only with KX were raccoons observed to recover without use of an antagonist. Supplemental oxygen was provided to 23% (3/13), 72% (13/18), and 71% (12/17) of raccoons immobilized with KX, BAM, and NalMed-A, respectively. Hypoxemia at <80% oxygen saturation occurred in 0% (0/17), 27% (4/15), and 6% (1/16) of the raccoons administered KX, BAM, and NalMed-A, respectively; all raccoons fully recovered from chemical immobilization. All combinations could be used for raccoon immobilization; however, the need for delivery of supplemental oxygen to a majority of raccoons immobilized with BAM and NalMed-A may limit broader use of these agents for certain field studies involving capture, sample, and release of free-ranging animals from a practical standpoint.

A MIXTURE OF NALBUPHINE, AZAPERONE, AND MEDETOMIDINE FOR IMMOBILIZING RINGTAILS (BASSARISCUS ASTUTUS).

We evaluated a combination of nalbuphine HCl (40 mg/mL), azaperone tartrate (10 mg/mL), and medetomidine HCl (10 mg/mL), a combination known as NAM or NalMed-A, in 23 ringtails (Bassariscus astutus) during 29 handling events for a radio-collaring study in southern Oregon, US, from August 2020 to March 2022. The combination was delivered to ringtails by hand injection at 0.075 mL NAM per estimated 1 kg body mass. The mean (± standard deviation, SD) dosage calculated post hoc was 3.366 (±0.724) mg/kg nalbuphine, 0.841 (±0.181) mg/kg medetomidine, and 0.841 (±0.181) mg/kg azaperone. All captured ringtails were effectively immobilized with a mean (SD) induction time of 13.24 (±3.57) min. The medetomidine and nalbuphine components were antagonized with a combination of atipamezole and naltrexone HCl with a mean (SD) recovery time of 2.48 (±1.94) min. This combination appeared to be safe and effective for immobilizing ringtails with a low volume dose, smooth antagonism, and rapid recovery. In addition, NAM does not contain any drugs that are US Drug Enforcement scheduled, which makes it useful for immobilization procedures by wildlife professionals in the US.

Immobilization of Raccoons (Procyon lotor) with Nalbuphine, Medetomidine, and Azaperone.

Chemical immobilization is widely used by wildlife and veterinary professionals for the safe handling of animals. A combination of nalbuphine (40 mg/mL), azaperone (10 mg/mL), and medetomidine (10 mg/mL), known as NAM, is a low-volume combination with field immobilization practicality and fewer regulations restricting its use in the US than some other drug combinations. We evaluated the safety and effectiveness of NAM as an immobilizing agent for raccoons (Procyon lotor). From May 2021 to February 2022, 16 adult raccoons were captured in cage traps and immobilized with 0.3 mL NAM intramuscularly (12 mg nalbuphine, 3 mg medetomidine, and 3 mg azaperone, regardless of body weight). After administration, time to sedation was measured; body temperature, heart rate, respiratory rate, and oxygen saturation were monitored and recorded every 5 min for 20 min. Each raccoon was weighed; the dose administered was calculated (range 2.2-4.1 mg/kg, mean 3 mg/kg). Mean induction time was 6 min (4-17 min); time to recovery following administration of 15 mg atipamezole, 7.5 mg naltrexone for reversal, was 10 min (6-18 min). Heart rate, oxygen saturation, and respiration rate remained steady during immobilization. Rectal temperature steadily declined. Overall, NAM appeared to be a practical option for raccoon immobilization, providing rapid induction and reversal as well as adequate sedation for short-term handling and minimally invasive sampling.

Co-Administration of nalbuphine to improve morphine tolerance in mice with bone cancer pain.

BACKGROUND: Kappa-opioid receptor (KOR) agonists are known for having opposite and/or different effects compared with Mu-opioid receptor (MOR) agonists. This study is aimed at clarifying the analgesic effect and tolerance of nalbuphine combined with morphine, and quantifying the mRNA and protein expression of spinal MOR and KOR in a mouse bone cancer pain (BCP) model treated with nalbuphine and morphine. METHOD: BCP model was prepared in C3H/HeNCrlVr Mice by implanting the sarcoma cells into the intramedullary space of the femur. The paw withdrawal thermal latency (PWL) measured by thermal radiometer was used to assess thermal hyperalgesia. PWL testing was performed after implantation and drug administration according to the protocol. Hematoxylin-eosin staining in the spinal cord and x-ray in the femoral intramedullary canal was detected. Real-time PCR and western blot analysis played a role in detecting spinal MOR and KOR expression changes. RESULTS: In tumor-implanted mice, the spinal MOR and KOR protein and mRNA expression was down-regulated when compared to that in sham-implanted mice (p < 0.05). Morphine therapy can lead to a decrease in spinal µ receptor expression. Similarly, the nalbuphine therapy can lead to a decrease in the expression of κ receptor protein and mRNA at the spinal cord level (p < 0.05). Morphine, nalbuphine, or nalbuphine co-administration with morphine all can extend the paw withdrawal thermal latency (PWL) to radiant thermal stimulation in tumor-implanted mice (p < 0.05). Compared with the morphine treatment group, nalbuphine co-administration with morphine delayed the reduction of PWL value again (p < 0.05). DISCUSSION: BCP itself may induce down-regulation of the spinal MOR and KOR expression. A low dose of nalbuphine co-administration with morphine led to the delayed emergence of morphine tolerance. The part of the mechanism may be due to the regulation of spinal opioid receptors expression.

Nalbuphine attenuates morphine-induced scratching by inhibiting PKCß-dependent microglial activation and p38 phosphorylation in male mice.

Morphine-induced scratching (MIS) is a common adverse effect associated with the use of morphine as analgesia after surgery. However, the treatment of MIS is less than satisfactory due to its unclear mechanism, which needs to be enunciated. We found that intrathecal (i.t.) injections of morphine significantly enhanced scratching behavior in C57BL/6J male mice as well as increased the expressions of protein kinase C ß (PKCß), phosphorylated p38 mitogen-activated protein kinases (MAPK), and ionized calcium-binding adapter molecule 1 (Iba1) within spinal cord dorsal horn. Conversely, using the kappa opioid receptor antagonist nalbuphine significantly attenuated scratching behavior, reduced PKCß expression and p38 phosphorylation, and decreased spinal dorsal horn microglial activation, while PKCδ and KOR expression elevated. Spinal PKCß silencing mitigated MIS and microglial activation. Still, knockdown of PKCδ reversed the inhibitory effect of nalbuphine on MIS and microglial activation, indicating that PKCδ is indispensable for the antipruritic effects of nalbuphine. In contrast, PKCß is crucial for inducing microglial activation in MIS in male mice. Our findings show a distinct itch cascade of morphine, PKCß/p38MAPK, and microglial activation, but an anti-MIS pathway of nalbuphine, PKCδ/KOR, and neuron activation.

Nalbuphine Suppresses Leukemia Stem Cells and Acts Synergistically with Chemotherapy Drugs via Inhibiting Ras/Raf/Mek/Erk Pathway.

AIMS: Retrospective clinical studies have shown that opioids could potentially affect the risk of cancer recurrence and metastasis. Better understanding of the effects of opioids on cancer will help to select the optimal anesthetic regimens to achieve better outcomes in cancer patients. BACKGROUND: Increasing evidence has shown the direct effects of opioids on bulk cancer cells and cancer stem cells. Opioid such as nalbuphine is approved to control cancer-associated pain but little is known on their possible cancer effects. OBJECTIVE: To assess the biological effects of nalbuphine on acute myeloid leukemia (AML) differentiated and stem/progenitor CD34+ cells. METHODS: AML CD34+ cells were isolated with colony formation, growth and apoptosis assays performed. Biochemical and immunoblotting analyses were conducted in AML cells exposed to nalbuphine. RESULTS: Nalbuphine at clinically relevant concentrations was active against a panel of AML cell lines with varying IC50. Importantly, nalbuphine augmented the efficacy of cytarabine and daunorubicin in decreasing AML cell viability/ growth. Besides bulk AML cells, we noted that nalbuphine was effective and selective in decreasing viability and colony formation of AML CD34+ cells while sparing normal hematopoietic CD34+ cells. The action of nalbuphine on AML cells is not associated with opioid receptors but via inhibiting Ras/Raf/MEK/ERK signaling pathway. Overexpression of constitutively active Ras partially but significantly reversed the inhibitory effects of nalbuphine on AML cells. CONCLUSION: Our findings reveal the selective anti-AML activity of nalbuphine and its ability in inhibiting Ras signaling. Our work suggests that nalbuphine may be beneficial for leukemia patients.

Comparison of the sedative effects of three nalbuphine doses, alone or combined with acepromazine, in dogs.

OBJECTIVE: To compare sedative, cardiopulmonary, and adverse effects of 3 nalbuphine doses, administered alone or in combination with acepromazine, in dogs. ANIMALS: 6 healthy dogs. PROCEDURES: Dogs were administered nalbuphine (1.0, 1.5, or 2.0 mg/kg, intravenously [IV]) combined with physiologic saline solution (1 mL, IV; treatments SN1.0, SN1.5, and SN2.0, respectively) or acepromazine (0.05 mg/kg, IV; treatments AN1.0, AN1.5, and AN2.0, respectively) in random order, with a 1-week washout interval between treatments. Sedation scores, heart rate, mean arterial pressure, respiratory rate, and rectal temperature were recorded before and 20 minutes after administration of saline solution or acepromazine (T0), and nalbuphine was administered at T0. Measurements were repeated 15, 30, 60, 90, and 120 minutes after nalbuphine administration. RESULTS: Treatments SN and AN resulted in at least 120 minutes of mild sedation and 60 minutes of moderate sedation, respectively. Sedation scores were greater for treatments AN1.0, AN1.5, and AN2.0 at various times, compared with scores for treatments SN1.0, SN1.5, and SN2.0, respectively. Administration of nalbuphine alone resulted in salivation and panting in some dogs. CLINICAL RELEVANCE: All nalbuphine doses promoted mild sedation when administered alone, and moderate sedation when combined with acepromazine. Greater doses of nalbuphine did not increase sedation scores. All treatments resulted in minimal changes in heart rate, respiratory rate, rectal temperature, and mean arterial pressure. Nalbuphine alone resulted in few adverse effects.

Safety and Efficacy of Nalbuphine, Medetomidine, and Azaperone for Immobilizing Aoudad (Ammotragus lervia).

We evaluated the safety and efficacy of nalbuphine (40 mg/mL), plus medetomidine (10 mg/mL), plus azaperone (10 mg/mL) under the premixed label NalMed-A. From January to March 2020, 10 aoudad (Ammotragus lervia) were immobilized via dart-gun for seven separate sampling periods for a total of 45 recorded individual immobilization events. Induction and reversal times with NalMed-A were 5.53±2.61 min and (following atipamezole administration) 5.08±2.43 min while previous studies with alpha-2 agonist-ketamine combinations gave median and average induction times of 4.6 min and 11.2 min using medetomidine-ketamine and xylazine-ketamine, respectively. Overall, NalMed-A adequately immobilized aoudad, with 13% incidence of hyperthermia and 2.22% mortality when delivered via dart.

Comparison of propofol-nalbuphine and propofol-fentanyl sedation for patients undergoing endoscopic retrograde cholangiopancreatography: a double-blind, randomized controlled trial.

BACKGROUND: Endoscopic retrograde cholangiopancreatography (ERCP) has been increasingly used to treat patients with biliary/pancreatic duct obstruction or stricture outside the operating room. Effective and safe sedation techniques are needed because of painful stimuli and the long duration of the ERCP procedure.Nalbuphine has been shown to cause less respiratory depression during sedation than similar cases without nalbuphine. This study compared the effects of propofol-nalbuphine (PN) and propofol-fentanyl (PF) sedation in patients undergoing ERCP. METHODS: Four hundred patients scheduled for ERCP procedures were divided into two groups: the PF group (receiving PF sedation,n = 199) and the PN group (receiving PN sedation,n = 201). Vital signs, adverse events during surgery, patient movement scores, pain scores, and adverse events one day post-ERCP were recorded. RESULTS: Stable haemodynamics were observed in both groups.Compared to the PF group, the PN group showed significantly decreased respiratory depression (P < 0.0001) and surgical interruptions (P = 0.048).Nalbuphine decreased patient movement by reducing pain from ERCP. CONCLUSION: Nalbuphine, instead of fentanyl, precipitated less respiratory depression while permitting adequate/equivalent sedation for ERCP and therefore provides more efficient and safer sedation. Trial registration ChiCTR, ChiCTR1800016018, Registered 7 May 2018, http://www.chictr.org.cn/showproj.aspx?proj=27085.

Efficacy of Nalbuphine as a Local Anesthetic Adjuvant for Brachial Plexus Block: A Systematic Review and Meta-analysis.

BACKGROUND: Nalbuphine has been increasingly used as a local anesthetic adjuvant to extend the duration of analgesia in brachial plexus block (BPB). OBJECTIVES: To systematically and firstly evaluate the available evidence on the efficacy of nalbuphine as an adjuvant to local anesthetics in BPB. STUDY DESIGN: Systematic review and meta-analysis. METHODS: Cochrane Central Register of Controlled Clinical Trials, Cochrane Database of Systematic Reviews, Medline, Embase, Scopus, Web of Science, EBSCO, PubMed, and additional databases were searched. Randomized controlled trials comparing combination of perineural nalbuphine with local anesthetics to local anesthetics alone in BPB for upper extremity surgical procedures were eligible for inclusion. RESULTS: Nineteen randomized controlled trials involving 1,355 patients met the inclusion criteria. Perineural use of nalbuphine prolonged the duration of analgesia in BPB (mean difference [MD], 162.5; 95% confidence interval [CI], 119.0 to 205.9; P < 0.00001; very low quality of evidence). The duration of sensory block was also extended (MD, 141.6; 95% CI, 100.3 to 182.9; P < 0.00001; very low quality of evidence). Furthermore, nalbuphine shortened the onset time of sensory block (MD, -2.6; 95% CI, -3.6 to -1.5; P < 0.00001; very low quality of evidence). There were no significant differences in side effect-related outcomes, including nausea (risk radio [RR], 1.56; 95% CI, 0.82 to 2.59; P = 0.17; moderate quality of evidence) and vomiting (RR, 1.41; 95%  CI, 0.66 to 3.02; P = 0.38; moderate quality of evidence). LIMITATIONS: The study was limited by substantial heterogeneity, a relatively small sample size and difference-in-differences in how outcomes of interest were described and assessed. CONCLUSIONS: Perineural use of nalbuphine in BPB is an effective strategy for analgesia in adult patients undergoing upper extremity surgery.

Nalbuphine: a candidate for treatment of women overwhelmed with sudden, intense labor pain?

AIM: On very rare occasions, women are overwhelmed with sudden, intense labor pain in the context of ultra-rapid late second stage of labor, especially when the head is crowning. The consequences may comprise serious pelvic floor damage for the mother and hypoxia for the fetus. Drugs like nalbuphine for immediate maternal analgesia and sedation would be helpful. This mixed opioid agonist-antagonist, that was used in obstetric anesthesia in the 1980s, acts quickly while side effects for the mother are minor. To better estimate possible complications for the fetus of a use shortly before birth, it is important to find out how quickly i.v. administered nalbuphine reaches fetal circulation. Therefore, we characterized the transplacental transfer of nalbuphine using an ex vivo model. METHODS: Placentas were obtained from cesarean sections after mothers gave their informed consent. Upon cannulation of one cotyledon, nalbuphine was added to the maternal circuit (calculated final concentration 100 ng/mL) and the ex vivo placenta perfusions were performed. To determine nalbuphine transfer from maternal to fetal circuit in the successful perfusions (n = 5), samples were collected at different time points. RESULTS: At perfusion start, the measured initial nalbuphine concentrations in the maternal and fetal circuits are 93.1 and <0.1 ng/mL, respectively. After 5 min of placenta perfusion, 2.5 ng/mL nalbuphine (i.e. 3% of the initial nalbuphine concentration in the maternal circuit) is reached in the fetal circuit; after 15 and 30 min, 9.7 and 15.8 ng/mL (approximately 10 and 16% of initial maternal, respectively). CONCLUSIONS: Only a small amount of nalbuphine is likely to reach the fetus during the first minutes after (i.v.) maternal administration. Nalbuphine might be a valuable candidate for clinical use in the i.v. analgesia and sedation of women overwhelmed with sudden labor pain in the context of ultra-rapid second stage of labor.

Antipruritic Effect of Nalbuphine, a Kappa Opioid Receptor Agonist, in Mice: A Pan Antipruritic.

Antipruritic effects of kappa opioid receptor (KOR) agonists have been shown in rodent models of acute and chronic scratching (itchlike behavior). Three KOR agonists, nalfurafine, difelikefalin, and nalbuphine, are in clinical studies for antipruritic effects in chronic itch of systemic and skin diseases. Nalfurafine (in Japan) and difelikefalin (in the USA) were approved to be used in the treatment of chronic itch in hemodialysis patients. The FDA-approved nalbuphine has been used in clinic for over 40 years, and it is the only narcotic agonist that is not scheduled. We aimed to study (a) antiscratch activity of nalbuphine against TAT-HIV-1 protein (controls HIV transcription)-, deoxycholic acid (DCA, bile acid)-, and chloroquine (CQ)-induced scratching in a mouse model of acute itch; and (b) whether the effect of nalbuphine is produced via KORs. First, dose-responses were developed for pruritogens. Mice were pretreated with nalbuphine (0.3-10 mg/kg) and then a submaximal dose of pruritogens were administered and the number of scratching bouts was counted. To study if the antiscratch effect of nalbuphine is produced via KOR, we used KOR knock out mice and pharmacologic inhibition of KORs using nor-binaltorphimine, a KOR antagonist. For this aim, we used CQ as a pruritogen. We found that: (a) TAT-HIV-1 protein elicits scratching in a dose-dependent manner; (b) nalbuphine inhibits scratching induced by TAT-HIV-1, DCA, and CQ dose-dependently; and (c) nalbuphine inhibits scratching induced by CQ through KORs. In conclusion, nalbuphine inhibits scratching elicited by multiple pruritogens.

Nalbuphine and dexmedetomidine as adjuvants to ropivacaine in ultrasound-guided erector spinae plane block for video-assisted thoracoscopic lobectomy surgery: A randomized, double-blind, placebo-controlled trial.

BACKGROUND: Adjuvants to local anesthetics, such as nalbuphine and dexmedetomidine, can be used to improve the quality and duration of peripheral nerve block effects. Dexmedetomidine has been successfully used as an adjuvant of erector spinae plane block (ESPB) with ropivacaine in video-assisted thoracoscopic lobectomy surgeries (VATLS). This study aimed to compare the effects of nalbuphine and dexmedetomidine used as adjuvants to ropivacaine for ESPB in VATLS. METHODS: A total of 102 patients undergoing VATLS with ESPB were enrolled and randomized into 3 groups, each of which received a different adjuvant to ropivacaine. The visual analogue scale score, onset and duration of sensory block, use of patient-controlled analgesia (PCA), rate of rescue analgesia, duration of postoperative hospitalization, incidence of postoperative nausea and vomiting, and chronic pain were measured and observed. RESULTS: The visual analogue scale score, total PCA use, rate of rescue analgesia, and postoperative chronic pain in the ropivacaine with dexmedetomidine (RD), and ropivacaine with nalbuphine (RN) groups were lower than those in the ropivacaine (RC) group (P < .05). The duration of sensory block was longer and the first use of PCA occurred later in the RD and RN groups than they did in the RC group (P < .05). CONCLUSIONS: As an adjuvant to ropivacaine in ESPB, nalbuphine and dexmedetomidine are comparable in terms of the associated analgesia, sensory block duration, need for rescue analgesia, and incidence of chronic pain in patients after VATLS.

Co-administration of nalbuphine attenuates the morphine-induced anxiety and dopaminergic alterations in morphine-withdrawn rats.

INTRODUCTION: The classical effects of exogenous opioids, such as morphine, are predominantly mediated through µ-opioid receptors. The chronic use of morphine induces anxiety-like behavior causing functional changes in the mesolimbic dopaminergic system. The mixed µ/κ-agonist, nalbuphine, used either as an analgesic or as an adjuvant with morphine, produces different and opposite effects. However, whether nalbuphine can be used to antagonize morphine-induced anxiety and dopaminergic alterations is not fully known. OBJECTIVE: This study aimed to compare acute and chronic effects of nalbuphine on morphine-induced anxiety and dopaminergic alterations in rats. METHODS: Male adult Wistar albino rats were made opioid-dependent by administering increasing doses of morphine (5-25 mg/kg; i.p.; b.i.d.). Withdrawal was induced by naloxone (1 mg/kg, i.p.), 4 h after the last morphine injection. Anxiety-like behavior was measured using Activity Monitor (Coulbourn Instruments, Inc. USA). Thereafter, the animals were sacrificed and the brain dissected out and the level of cAMP and the transcriptional and translational expression of TH was measured. Nalbuphine was co-administered with morphine, acutely and chronically, at various doses (0.1, 0.3, 1.0, 3.0 mg/kg, i.p.). RESULTS: Morphine-dependent rats showed a significant higher anxiety and cAMP levels and a significant decrease in the expression of TH. Co-administration of chronic doses of nalbuphine attenuates the higher anxiety, cAMP levels, and upregulates the TH expressions; however, the acute nalbuphine treatment does not attenuate the morphine-induced side effects. CONCLUSION: Therefore, nalbuphine might have an important role in attenuating the anxiety and the effects of the dopaminergic pathway and may have potential in the treatment of opioid addiction.

Application of Nalbuphine in Trigeminal Ganglion Pulse Radiofrequency Surgery in Patients with Postherpetic Neuralgia.

This study aimed to explore the application value of nalbuphine in pulsed radiofrequency operation of trigeminal ganglion in patients with postherpetic neuralgia (PHN). Thirty patients with PHN were randomly divided into the nalbuphine (Nalbu) group and ketorolac tromethamine (KT) group and received CT-guided pulsed radiofrequency surgery on trigeminal ganglion. The numeric rating scale (NRS) scores of patients were recorded at preoperative, intraoperative, and postoperative time points, before going to bed, and the next morning after the operation. In addition, the number of breakthrough pain before operation and within 24 hours after operation, the incidence of nausea and vomiting within 24 hours after surgery, and the patient's sleep quality before and on the day after surgery were evaluated. The outcome data demonstrated that patients treated with nalbuphine had lower NRS scores after the pulse radiofrequency operation during and after the pulse radiofrequency operation compared to those with KT. In addition, nalbuphine effectively decreased the number of breakthrough pain, reduced the occurrence of nausea and vomiting after surgery, and improved the sleep quality. In conclusion, intramuscular injection of nalbuphine 30 min before trigeminal ganglion pulse radiofrequency surgery can be conducive to pain relief and improve the postoperative comfort of patients, providing an effective alternative for the alleviation of PHN in clinic.

Enhancement of Opioid Antinociception by Nicotinic Ligands.

Nicotine has previously been shown to augment the antinociceptive effects of µ-opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral disruption. The present studies were conducted to extend these findings by determining the ability of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4ß2 nAChR agonist varenicline to selectively augment the antinociceptive effects of the µ-opioid receptor (MOR) full agonist fentanyl, the MOR partial agonist nalbuphine, and the κ-opioid receptor (KOR) agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and that epibatidine increased the antinociceptive effects of U69,593 without altering effects on operant behavior. However, neither epibatidine nor varenicline enhanced the antinociceptive effects of fentanyl, perhaps due to its high efficacy. The enhancement of nalbuphine's antinociceptive effects by epibatidine, but not varenicline, could be antagonized by either mecamylamine or dihydro-ß-erythroidine, consistent with α4ß2 mediation of epibatidine's effects but suggesting the involvement of non-nAChR mechanisms in the effects of varenicline. The present results support previous findings showing that an nAChR agonist can serve as an adjuvant for MOR antinociception and, based on results with U69,593, further indicate that the adjuvant effects of nAChR drugs may also apply to antinociception produced by KOR. Our findings support the further evaluation of nAChR agonists as adjuvants of opioid pharmacotherapy for pain management and point out the need for further investigation into the mechanisms by which they produce opioid-adjuvant effects. SIGNIFICANCE STATEMENT: Nicotine has been shown to augment the antinociceptive effects of µ-opioid receptor analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4ß2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a κ-opioid receptor agonist, without concomitantly exacerbating their behaviorally disruptive effects. These findings support the view that nAChR agonists and partial agonists may have potential as adjuvant therapies for opioid-based analgesics.

Opioid effect on the autonomic nervous system in a fetal sheep model.

PURPOSE: Opioid use during labour can interfere with cardiotocography patterns. Heart rate variability indirectly reflects a fluctuation in the autonomic nervous system and can be monitored through time and spectral analyses. This experimental study aimed to evaluate the impact of nalbuphine administration on the gasometric, cardiovascular, and autonomic nervous system responses in fetal sheep. METHODS: This was an experimental study on chronically instrumented sheep fetuses (surgery at 128 ± 2 days of gestational age, term = 145 days). The model was based on a maternal intravenous bolus injection of nalbuphine, a semisynthetic opioid used as an analgesic during delivery. Fetal gasometric parameters (pH, pO2, pCO2, and lactates), hemodynamic parameters (fetal heart rate and mean arterial pressure), and autonomic nervous system tone (short-term and long-term variation, low-frequency domain, high-frequency domain, and fetal stress index) were recorded. Data obtained at 30-60 min after nalbuphine injection were compared to those recorded at baseline. RESULTS: Eleven experiments were performed. Fetal heart rate, mean arterial pressure, and activities at low and high frequencies were stable after injection. Short-term variation decreased at T30 min (P = 0.02), and long-term variation decreased at T60 min (P = 0.02). Fetal stress index gradually increased and reached significance at T60 min (P = 0.02). Fetal gasometric parameters and lactate levels remained stable. CONCLUSION: Maternal nalbuphine use during labour may lead to fetal heart changes that are caused by the effect of opioid on the autonomic nervous system; these fluctuations do not reflect acidosis.

Effects of nalbuphine on the cardioprotective effect of morphine in rats.

BACKGROUND: When combined with morphine, nalbuphine not only does not affect the analgesic effect but also prevents opioid-induced side effects. The authors investigated whether nalbuphine interferes with morphine-induced cardioprotection in rats. METHODS: Anesthetized male Sprague-Dawley rats were randomly assigned to 1 of 4 treatment groups. Nalbuphine (NAL, 1 mg/kg) and morphine (MOR, 0.3 mg/kg) were administered 10 and 5 min prior to myocardial ischemia, respectively. Additionally, the NAL + MOR group received the combination of NAL and MOR prior to myocardial ischemia. An in vivo animal model was established by occluding the left anterior descending artery for 30 min and reperfusing it for 2 h. After 2 h of reperfusion, the infarcted area of heart was measured by Evans blue/triphenyl tetrazolium staining, and the levels of creatine kinase isoenzymes (CK-MB) in serum were detected by enzyme-linked immunosorbent assay. RESULTS: Nalbuphine had no protective effect against the infarct area compared with the control treatment (NAL, 52.5 ± 5% versus CON, 52.6 ± 4%; *P < 0.01), and the infarct size-sparing effects of morphine were not affected by nalbuphine (NAL + MOR, 42.6 ± 7% versus MOR, 40.4 ± 3%; P > 0.05). The nalbuphine group did not show a change the levels of serum CK-MB compared with the control group, and nalbuphine did not affect the levels of serum CK-MB in the MOR group. CONCLUSIONS: Nalbuphine does not interfere with the cardioprotective effect of morphine in vivo. Therefore, nalbuphine could be safely used or combined with morphine in patients with acute myocardial infarction.

Participation of the opioid receptor - nitric oxide - cGMP - K+ channel pathway in the peripheral antinociceptive effect of nalbuphine and buprenorphine in rats.

The aim of this study was to examine if the peripheral antinociceptive effects of the opioid agonist/antagonist nalbuphine and buprenorphine involve the sequential participation of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) synthesis followed by K+ channel opening in the formalin test. Wistar rats (180-220 g) were injected in the dorsal surface of the right hind paw with formalin (1%). Rats received a subcutaneous (s.c.) injection into the dorsal surface of the paw of vehicles or increasing doses of nalbuphine (50-200 µg/paw) or buprenorphine (1-5 µg/paw) 20 min before formalin injection into the paw. Nalbuphine antinociception was reversed by the s.c. injection into the paw of the inhibitor of NO synthesis (NG-nitro-l-arginine methyl ester (L-NAME)), by the inhibitor of guanylyl cyclase (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ)), by the Kir6.1-2, ATP-sensitive K+ channel inhibitors (glibenclamide and glipizide), by the KCa2.1-3, small conductance Ca2+-activated K+ channel blocker (apamin), by the KCa1.1, large conductance Ca2+-activated K+ channel blocker (charybdotoxin), and by the KV, voltage-dependent K+ channel inhibitors (4-aminopyridine (4-AP) and tetraethylammonium chloride (TEA)). The antinociceptive effect produced by buprenorphine was blocked by the s.c. injection of 4-AP and TEA but not by L-NAME, ODQ, glibenclamide, glipizide, apamin, or charybdotoxin. The present results provide evidence for differences in peripheral mechanisms of action between these opioid drugs.