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Lini Wang,&ast; Yiting Wang,&ast; Yumei Ma, Xiaoxiao Mu, Zhen Zhang, Huan Wang, Ziyu Zheng, Huang Nie Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Xi’an, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huang Nie, Department of Anesthesiology and Perioperative Medicine, Xijing Hospital, Fourth Military Medical University, Changle West Road 127, Xi’an, Shaanxi, 710032, People’s Republic of China, Email niehuang@163.comPurpose: This retrospective study evaluated the efficacy, opioid consumption, and safety profile of two patient-controlled intravenous analgesia (PCIA) regimens (sufentanil combined with nalbuphine vs sufentanil alone) after cesarean section (CS).Patients and Methods: Parturients (n = 1808) received sufentanil combined with nalbuphine (SN group) or sufentanil alone (S group) as PCIA after CS. The primary outcome was the numeric rating scale (NRS) pain score with movement (NRS-M) at 24 h after CS. Secondary outcomes were NRS scores at rest (NRS-R) at 24 and 48 h after CS, NRS-M at 48 h after CS, cumulative PCIA bolus times, and opioid consumption during the first 24 and 48 h postoperatively, which was measured in morphine-equivalent doses.Results: The population comprised 993 and 815 subjects in the SN and S groups, respectively. At 24 and 48 h after CS, the respective NRS-M scores of the SN group (4.62, 3.37) were each significantly lower than those of the S group (5.18, 4.01; P < 0.01 for both). The corresponding NRS-S scores were similarly lower in the SN group (0.96, 0.19) than in the S group (2.05, 0.92; P < 0.01 for both). After adjusting for covariates, the SN group still had lower NRS-M than the S group at 24 h after CS (estimate adjusted = 0.565, P < 0.001). The PCIA bolus times were significantly lower in the SN group than in the S group. The rates of bradycardia and respiratory depression were lower in the SN group than in the S group. However, the rates of dizziness and postoperative hypotension were slightly higher in the SN group, and those of nausea/vomiting were comparable.Conclusion: Compared with sufentanil alone, sufentanil combined with nalbuphine for PCIA provided superior analgesia in parturient women after CS.Keywords: nalbuphine, sufentanil, patient-controlled intravenous analgesia, cesarean section

Pain management following cesarean section remains a challenge, with many puerpera suffering from severe acute postoperative pain. And for a second cesarean section the degree of uterine contraction pain is more severe and frequent than that of a primipara. This study investigated the effect of different doses of nalbuphine combined with sufentanil for postoperative analgesia in patients undergoing a second cesarean section.We prospectively recruited 168 women with a scarred uterus undergoing elective second cesarean section and they were randomly divided into 4 groups by random number extraction. A single intravenous injection of different doses of nalbuphine was given before the intravenous drip of oxytocin, and visual analogue scale (VAS) scores of uterine contraction pain were recorded 10 minutes before intravenous infusion of oxytocin (T1) and 10 minutes (T2), 30 minutes (T3), and 60 minutes (T4) after intravenous infusion of oxytocin. At 4, 8, 12, 24, and 48 hours after patient-controlled intravenous analgesia (PCIA), pain intensity was reassessed using the VAS score.One hundred and sixty patients underwent elective second cesarean section in between December 2020 and May 2021 completed the study. The VAS scores of uterine contractions at T1 and T4 were 3 (1.0), while the VAS scores at T2 and T3 were 7 (1.0), 6 (1.0), 5 (1.0), 5 (1.0) and 8 (1.0), 5 (2.0), 3 (1.0), 3 (0.75). The VAS scores at 12 hours after surgery of nalbuphine10mg and sufentanil (NS1), nalbuphine 10 mg and sufentanil 20 mg (NS2) and nalbuphine 30 mg and sufentanil 20 mg (NS3) were lower than sufentanil (S) group (P0.001). Compared with the S group, total amount of sufentanil and PCIA compression numbers in the NS1, NS2, and NS3 groups at 4-8 and 8-12 hours after surgery decreased (P0.001), with a more significant decrease in the NS2 and NS3 groups than in the NS1 group (P0.001). The NS3 group had a significantly higher incidence of dizziness and sleepiness (P=0.02, P=0.001). Compared with the NS2 and NS3 groups, the incidence of respiratory depression in the S group was significantly higher (P=0.001).A single intravenous injection of nalbuphine 20 mg 10 minutes before the infusion of oxytocin combined with sufentanil 2 µg/kg could be safely used for postoperative analgesia in patients undergoing a second cesarean section and could effectively inhibit uterine contractions induced by oxytocin and reduce adverse reactions.Clinical Trial Registry ChiCTR2100042382.

Min Wang,1,2,&ast; Dongyue Wang,1,&ast; Jingzhi Zuo,3 Tianyu Liu,4 Zheng Niu,5 Juan Xie,1 Dunyi Qi2 1Department of Anesthesiology, Jinshan Hospital of Fudan University, Shanghai, People’s Republic of China; 2Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 3Emergency Department, Yichang Central People’s Hospital, Yichang, Hubei, People’s Republic of China; 4Department of Anesthesiology, Peking University People’s Hospital, Beijing, People’s Republic of China; 5Department of Anesthesiology, Zhangjiagang First People’s Hospital, Zhangjiagang, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dunyi Qi, Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China, Email qdy6808@163.comPurpose: Prophylactic intravenous nalbuphine was administered to observe its median effective dose (ED50) in reducing pain after undergoing laparoscopic total hysterectomy. To investigate the effect of different doses of nalbuphine on postoperative analgesia and adverse reactions in patients.Patients and Methods: The 120 patients undergoing laparoscopic total hysterectomy were divided into 6 groups: group C (control) and group P (5 different doses of nalbuphine) with 20 patients per group. The doses of nalbuphine in group P were in an equally proportional series (groups P1, P2, P3, P4, and P5 received doses of 0.280, 0.200, 0.140, 0.100, and 0.070 mg/kg, respectively), diluted to 20 mL with saline and administered 5 min before the induction of anesthesia. A similar volume (20 mL) of saline was administered to group C 5 min before the induction of anesthesia. The numeric rating scale (NRS) of patients during awakening and after surgery, the number of postoperative salvage analgesia, and the occurrence of postoperative adverse effects were recorded.Results: The ED50 (95% confidence interval (CI)) of nalbuphine in preventing pain during the awakening period in patients calculated using the point-slope method was 0.125 (0.108, 0.145) mg/kg. NRS scores differed among the 6 groups at 30 min and 1 h after extubation (P < 0.001; P < 0.001). Pairwise comparisons between groups revealed that, at 30 min after extubation, compared with group P1, the NRS scores of groups P4, P5, and C were higher (P = 0.001, P < 0.001, P < 0.001); compared with group P2, groups P5 and C had higher NRS scores (P = 0.011, P = 0.001). At 1 h after extubation, the NRS scores of groups P1 and P2 were lower than that of group P4 (P = 0.046, P = 0.036). Compared with the control, only the group P1 had a lower cough score (P = 0.009) and there were no differences in the other groups. There were no differences in sedation score at 10 min after extubation, the incidence of adverse events at 24 h postoperatively, or the number of remedial analgesics at 24 h postoperatively (P > 0.05).Conclusion: The ED50 (95% CI) of nalbuphine as a prophylactic in reducing pain during recovery was 0.125 (0.108, 0.145) mg/kg. Compared with the control, nalbuphine at doses of 0.140, 0.200, and 0.280 mg/kg prevented pain during the awakening period. Among these doses, 0.280 mg/kg was determined to be the best, the occurrence of cough was less during extubation and the postoperative analgesic effect was good. However, it is necessary to pay attention to the occurrence of adverse reactions.Keywords: gynecology, laparoscopy, preventive analgesia, nalbuphine, ED50

The aim: To evaluate the effectiveness of erector spine plane block vs lumbar paravertebral block for early rehabilitation after total hip arthroplasty. Materials and methods: The study included 60 ASA ІΙ–ΙΙΙ patients (female/male = 35/25) aged 41-82 years, undergone total hip arthroplasty under spinal anesthesia. The patients randomly divided into two groups (n=30 in each) according to postoperative regional analgesia technique: paravertebral block (PVB) and erector spine plane block (ESPB). The time interval to meet three criteria: adequate analgesia (

What is known and objective Nalbuphine is a mu (μ) receptor partial antagonist/kappa (κ) receptor agonist analgesic and can be administered as a single injection or using patient-controlled analgesia (PCA) in the clinical setting. However, differences in the pharmacokinetics of the two administration methods are unclear. Here, a clinical trial was performed to compare the pharmacokinetic characteristics and superiority of nalbuphine with a single-injection or PCA-mimic method to provide a reference for the selection of an appropriate administration method. Methods Twenty healthy individuals were divided into two groups and injected with 10 mg nalbuphine intravenously using a single-injection or a PCA-mimic method (2 mg once for five times with a 30-min interval). Blood samples were collected, and safety was investigated. The liquid chromatography-tandem mass spectrometry was adopted to determine the concentration of nalbuphine in plasma. Results and discussion The maximum concentration (Cmax ) and area under concentration-time curve (AUC0-t ) values of nalbuphine in the single-injection and PCA groups were as follows: Cmax , 81.3 ± 24.7 and 39.8 ± 6.4 ng/ml, respectively; moreover, AUC0-t , 110.3 ± 19.5 and 128.3 ± 23.0 h ng/ml, respectively. The effective analgesic concentration durations (EACDs) for the two administration methods were 1.39 ± 0.64 and 1.96 ± 0.91 h, respectively. Nalbuphine was well tolerated, and improvements were observed in the PCA group. What is new and conclusion Compared with those in the single-injection group, the AUC0-t and EACDs in the PCA group were similar, whereas Cmax was decreased significantly. Therefore, the PCA method was more suitable for the clinical application of nalbuphine injection owing to the superiority of lower concentration fluctuation and the improved safety profile.

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.

To evaluate the efficacy of multimodal analgesia of flurbiprofen axetil, nalbuphine hydrochloride and patient controlled intravenous analgesia (PCIA) on inflammatory factor levels and stress response in patients after laparoscopic radical gynecological malignancy surgery. The data of 100 patients admitted to our hospital from May 2019 to May 2020 for laparoscopic radical gynecological malignancy surgery were retrospectively analyzed and they were assigned (1:1) to either an experimental group or a control group according to the alphabetical order of their initials. The experimental group was given preemptive analgesia with flurbiprofen axetil, postoperative analgesia with nalbuphine hydrochloride, and PCIA and the control group was given conventional analgesic measures. The pain scores at 1h, 6h, 12h, 24h and 48h postoperatively in the experimental group were remarkably lower than those in the control group (P0.001). The experimental group showed significantly lower inflammatory factor levels, pain mediator levels and stress response indexes in the morning before surgery, 1d, and 2d after surgery than the control group (P0.001). The multimodal analgesia of flurbiprofen axetil, nalbuphine hydrochloride and PCIA can effectively alleviate the stress response and inflammatory response in patients after radical gynecologic malignancy surgery and the patients' pain perception is reduced with a high safety profile.

Objective To evaluate the effects of nalbuphine, butorphanol and morphine combined with acepromazine on intraoperative and early postoperative pain management in dogs anesthetized for ovariohysterectomy. Study design Prospective, randomized blinded clinical study. Animals A total of 48 healthy female dogs of different breeds, aged 1–6 years, weighing (mean ± standard deviation) 14.5 ± 4.8 kg. Methods Dogs were randomly assigned into four groups to be intravenously administered nalbuphine (0.5 mg kg–1; group N0.5), nalbuphine (1.0 mg kg–1; group N1.0), butorphanol (0.4 mg kg–1; group B0.4) or morphine (0.2 mg kg–1; group M0.2) combined with acepromazine (0.02 mg kg–1) prior to propofol and isoflurane for anesthesia. Heart rate (HR), respiratory rate, systolic arterial pressure and rectal temperature (RT) were recorded at time points during anesthesia. A dynamic interactive visual analog scale applied in three phases (DIVAS I, II and III) and the modified Glasgow composite measure pain scale were used to assess pain before premedication and 1, 2, 3, 4, 5 and 6 hours after extubation. Administration of rescue analgesia was recorded. Results At the left ovarian pedicle ligation, HR was higher in N1.0 than in B0.4 (p = 0.020). RT decreased significantly by the end of surgery in N0.5 (p = 0.043) and B0.4 (p = 0.010). Rescue analgesia was administered postoperatively over 6 hours to eight, seven, nine and 10 dogs in N0.5, N1.0, B0.4 and M0.2, respectively (p = 0.57). DIVAS II was higher in B0.4 than in N1.0 at 2 and 3 hours (p = 0.038 and p = 0.002, respectively) and N0.5 at 3 hours (p = 0.003). Conclusions and clinical relevance At the doses used, all premedication protocols provided insufficient intraoperative analgesia, with minimal clinical differences between groups. No premedication provided satisfactory analgesia in the first 6 hours postoperatively.

Background The aim of this study was to compare the effects of nalbuphine and sufentanil on the gastrointestinal (GI) tract after laparoscopic surgery for gynecological malignancies. Methods A total of 100 patients aged between 18-70 years with American Society of Anesthesiologists (ASA) physical status I-II who scheduled for laparoscopic radical hysterectomy under general anaesthesia were enrolled. Patients were randomized to receive either sufentanil (Group S) or nalbuphine (Group N) to receive either sufentanil (Group S) or nalbuphine (Group N) in the intraoperative and postoperative periods. The time to the first passage of flatus, the time to the first defecation, the time to the toleration of diet, the serum gastrin and the length of hospital stay were compared between the groups. Postoperative pain by visual analogue scale (VAS), the number of PCA(patient-controlled analgesia)s, postoperative nausea and vomiting, and dizziness were compared between the groups. Results The time to the first passage of flatus(p =0.551), the time to the first defecation(p =0.310), the time to the toleration of diet(p =0.182), the serum gastrin(p =0.397), the number of postoperative nausea(p =0.920), vomit(p =0.334) and PCA events(p =0.167) and the length of hospital stay(p =0.482) were not significantly different between the two groups. VAS scores at postoperative 6 h(p=0.008), 12 h(p =0.002) and 24 h(p =0.013) were lower in Group N than in Group S. Conclusions Compared with sufentanil, nalbuphine was not associated with improved postoperative GI dysfunction after laparoscopic surgery for gynecological malignancies, but it was associated with reduced postoperative pain.

Objective Nalbuphine and dexmedetomidine are both used as anesthesia adjuvants for brachial plexus block, but their efficacy and safety in younger patients are not clear. In this study, we aimed to compare the efficacy and side effects of these 2 drugs in young patients undergoing brachial plexus block. Methods We recruited 48 young patients aged 18 to 30 years requiring supraclavicular brachial plexus block. Subjects were randomly divided into 2 groups. Patients in group levobupivacaine+nalbuphine received 28 mL of 0.5% levobupivacaine and 10 mg of nalbuphine diluted in 2 mL 0.9% saline. Patients in group levobupivacaine+dexmedetomidine (LD) received 28 mL of 0.5% levobupivacaine and 0.75 μg/kg dexmedetomidine diluted in 2 mL 0.9% saline. Demographic information, types of fracture, onset time of motor and sensory blocks, duration of block, side effects, and analgesic use were recorded. Results We found that the 2 groups did not differ significantly in the demographic profile and fracture type. Compared with group LD, group LD had significantly shorter sensory and motor block onset time, longer block duration, less analgesic need, and less side effects. Conclusion In summary, our study suggests that nalbuphine is a better anesthesia adjuvant for supraclavicular brachial plexus block in young patients.

BackgroundPostoperative pain in ambulatory surgery is a multifactorial issue affecting patient satisfaction, time of discharge, and rehospitalization. This study evaluated the efficacy and safety of nalbuphine for the treatment of postoperative pain after ambulatory surgery, relative to tramadol.MethodsThis multi-center, randomized, double blind, and controlled study was conducted at 10 centers. In accordance with the inclusion criteria, 492 ambulatory surgery patients were recruited. These patients had moderate to severe pain after ambulatory surgery, with a visual analogue scale (VAS) score > 3 cm. They were randomly divided into an experimental (n = 248) or control (n = 244) group and treated for analgesia with 0.2 mg/kg of nalbuphine or 2 mg/kg of tramadol, respectively. VAS scores, adverse events, and vital signs of the patients were recorded before administration (baseline; T1); and 30 min (T2), 2 h (T3), 4 h (T4), and 6 h (T5) after administration of analgesia. A decrease in pain intensity of more than 25% compared with the baseline was used as an indicator of analgesic efficacy. The experimental and control groups were compared with regard to this indicator of efficacy at each timepoint.ResultsThe VAS scores of the experimental and control groups were statistically comparable at timepoints T1-T4. At T5, the VAS scores of the experimental group were significantly lower than that of the control. The pain intensity was significantly higher in the experimental group compared with the control at T2and T3. Adverse events and vital signs were similar for the two groups at each timepoint.ConclusionsNalbuphine can provide effective and safe pain relief in patients after ambulatory surgery.Trial registrationThe registration number isChiCTR-IOR-16010032, the date of registration was 2016-11-28.

Background. Comparing the effect of two different κ-receptor agonists, nalbuphine and oxycodone, and regular morphine in patients for prophylactic analgesia of acute pain after daytime laparoscopic cholecystectomy. Methods. One hundred and twenty-four patients undergoing laparoscopic cholecystectomy were randomly allocated to receive nalbuphine (group N), oxycodone (group O), and morphine (group M). The three groups were all given intravenous injection (iv.) of 0.15 mg/kg injection before incision and 0.05 mg/kg injection at the end of pneumoperitoneum. The Visual Analogue Scale (VAS) scores (incision, visceral, and shoulder) and Ramsay sedation scores at 1, 2, 4, 8, 12, 16, 20, and 24 hours after surgery, the time of extubation, the incidence of postoperative adverse events, the satisfaction of pain treatment, and the duration of stay after surgery were all recorded. Results. Compared with group M, the VAS scores of visceral pain at rest decreased in group N and group O at 1-8 h after surgery ( P < 0.05 ). The VAS scores of visceral pain at movement in group N decreased longer than those in group O ( P < 0.05 ). Compared with that of group M, the postoperative time in Ramsay sedation score of group O increased longer than that of group N ( P < 0.05 ). Compared with group N, patients had worse sleep quality in group O, longer length of stay in group M, and lower satisfaction in both groups. Conclusion. Compared with morphine, prophylactic use of the κ-receptor agonists, nalbuphine and oxycodone, during laparoscopic cholecystectomy can reduce postoperative visceral pain. Furthermore, the nalbuphine group had fewer adverse reactions, better analgesia, and better satisfaction.

BACKGROUND This study aimed to compare the effect of dexamethasone added to fentanyl and bupivacaine with the effect of either dexamethasone or fentanyl alone when combined with bupivacaine.in the thoracic paravertebral block (TPVB). METHODS Sixty female patients (aged 18-60 years), scheduled for modified radical mastectomy were enrolled. Patients received preoperative unilateral paravertebral block using 0.3ml/kg of 0.5% bupivacaine combined with 8 mg dexamethasone (Group I), 1 μg/kg fentanyl (Group II), or 8 mg dexamethasone + 1 μg/kg fentanyl (Group III). The study drugs were diluted with normal saline 0.9% up to 25ml volume. The primary outcome was the time to first postoperative analgesics request, Secondary outcomes were total analgesic consumption, verbal rating pain scale (VRS) over the first 24 hours postoperatively, hemodynamic parameters, and adverse effects. RESULTS The time to first analgesic request for intravenous (IV) nalbuphine was longer in group II (15.75 ± 0.9 h, P < 0.001) than group I (10.45±1.1 h, P < 0.001), while no patients requested it in group III (P < 0.001). The total analgesic consumption of IV nalbuphine was lower in group II (8.6 ± 3.5mg, P=0.04) than group I (11.3 ± 2.1mg), with a significant difference between group II and III (P < 0.001). From the 8th till the 24th hours postoperatively, patients in group III showed the significantly lowest median VAS scores, followed by patients in group II (P < 0.001) and lastly patients in group I. There were no significant adverse effects. CONCLUSIONS Dexamethasone and fentanyl Combination enhances the analgesic effect of bupivacaine in TPVB.

Background:. Nalbuphine has been suggested to be used for post-cesarean section (CS) intravenous analgesia. However, ideal concentration of nalbuphine for such analgesia remains unclear. The present study was conducted to explore an ideal concentration of nalbuphine for post-CS intravenous analgesia by evaluating the analgesic effects and side-effects of three different concentrations of nalbuphine combined with hydromorphone for post-CS intravenous analgesia in healthy parturients. Methods:. One-hundred-and-fourteen parturients undergoing elective CS were randomly allocated to one of three groups (38 subjects per group) according to an Excel-generated random number sheet to receive hydromorphone 0.05 mg/mL + nalbuphine 0.5 mg/mL (group LN), hydromorphone 0.05 mg/mL + nalbuphine 0.7 mg/mL (group MN), and hydromorphone 0.05 mg/mL + nalbuphine 0.9 mg/mL (group HN) using patient-controlled analgesia (PCA) pump. Visual analog scale (VAS) for pain, PCA bolus demands, cumulative PCA dose, satisfaction score, Ramsay score, and side-effects such as urinary retention were recorded. Results:. The number of PCA bolus demands and cumulative PCA dose during the first 48 h after CS were significantly higher in group LN (21 ± 16 bolus, 129 ± 25 mL) than those in group MN (15 ± 10 bolus, 120 ± 16 mL) (both P 0.05). VAS scores were significantly lower in group HN than those in group MN and group LN for uterine cramping pain at rest and after breast-feeding within 12 h after CS (all P 0.05). Ramsay sedation scale score in group HN was significantly higher than that in group MN at 8 and 12 h after CS (all P

Background Cancer pain is a debilitating disorder of human breast cancer and a primary determinant of the poor quality of life, and relieving pain is fundamental strategy in the cancer treatment. However, opioid analgesics, like morphine and fentanyl, which are widely used in cancer pain treatment have been reported to enhance stem-like traits and epithelial-mesenchymal transition (EMT) of breast cancer cells. As such, it is vital to make the best choice of analgesic for breast cancer management. Methods MTT assays and colony formation assays were performed to examine tumor cell proliferation upon nalbuphine treatment. RT-PCR, western blot, flow cytometry, sphere formation, immunohistochemistry, transwell assays, wound healing assays and mouse xenograft were used to assess the biological effects of nalbuphine treatment. Results Nalbuphine inhibited breast cancer cell growth and tumorigenesis, with little effect on noncancerous breast cell lines. Nalbuphine suppressed cancer stem-like traits and EMT in both breast cancer cells and mouse xenograft tumor tissues. Additionally, activation of AKT reversed the nalbuphine-induced inhibition of cancer stem-like properties, tumorigenesis and EMT. Conclusions Our results demonstrate a new role of nalbuphine in inhibiting cancer stem-like properties and EMT in addition to relieving pain, which suggests that nalbuphine may be effective in breast cancer treatment. Electronic supplementary material The online version of this article (10.1186/s13046-019-1184-1) contains supplementary material, which is available to authorized users.

One emerging strategy to address the opioid crisis is the development of mu opioid receptor (MOR) ligands that preferentially signal the G-protein vs. β-arrestin pathway. The present study compared the relative potency and effectiveness of two G-protein biased (GPB)-MOR ligands TRV130 and SR-14968 to five unbiased MOR ligands (NAQ, nalbuphine, buprenorphine, morphine, and methadone) on therapeutic-related (e.g. antinociception) and abuse-related (e.g. discriminative stimulus effects) endpoints. Male and female rats were tested in a warm water tail-withdrawal procedure (50 °C) or trained to discriminate fentanyl (0.04 mg/kg, SC) from saline in a two-lever food-reinforced discrimination procedure. TRV130 and SR-14968 were approximately two-fold more potent to produce fentanyl stimulus effects vs. antinociception. Morphine, fentanyl, and methadone were significantly more potent in the fentanyl discrimination vs. tail withdrawal procedure. In addition, maximum antinociceptive and discriminative stimulus effects of fixed-proportion fentanyl/naltrexone mixtures (1:0.018, 1:0.054, 1:0.18, 1:0.3, and 1:0.54) were used to quantify 1) the relative in vivo efficacy of the two GPB-MOR agonists and five unbiased MOR ligands, and 2) potential species differences in MOR ligand effects between rats and monkeys. The efficacy-effect function generated from the fentanyl/naltrexone mixtures stratified the five unbiased ligands consistent with agonist-stimulated GTPγS binding (NAQ = nalbuphine buprenorphine morphine methadone). However, TRV130 and SR-14968 produced greater antinociception and less fentanyl-like stimulus effects than was predicted. Furthermore, there was a significant positive correlation between rat and monkey antinociceptive effects. Overall, these results demonstrate GPB-MOR agonists produce undesirable abuse-related effects, albeit with slightly better potency and efficacy ratios compared to unbiased agonists. This article is part of the Special Issue entitled 'Opioid Neuropharmacology: Advances in treating pain and opioid addiction'.

Objectives To evaluate the effect of nalbuphine administration on urine output in critically ill children with opioid-associated urinary retention. Design Institutional review board approved, single center, retrospective medical chart review. Setting Large medical-surgical PICU within a free-standing, tertiary care children's hospital. Patients Patients admitted to the PICU between October 1, 2014, and February 29, 2016, who received IV nalbuphine after meeting criteria for opioid-associated oliguria (defined as urine output below 1 mL/kg/hr and received at least one dose of opioid therapy within the preceding 12 hr). Interventions None. Measurement and main results Seventeen patients who received 21 doses of nalbuphine were analyzed. The median age and weight of patients were 6 years (interquartile range, 3-11.5 yr) and 18 kg (interquartile range, 12-35 kg), respectively. Two distinct dosing strategies became evident, specifically 0.05 mg/kg (n = 11 doses) and 0.1 mg/kg (n = 10 doses). Urine output increased significantly from baseline (median, 0 mL/kg/hr; interquartile range, 0-0.53 mL/kg/hr) to 6 hours post nalbuphine administration (median, 1.48 mL/kg/hr; interquartile range, 0-2 mL/kg/hr; p = 0.0002). Patients who received 0.1 mg/kg/dose had a greater urine output response compared with those who received 0.05 mg/kg/dose. Five patients (29%) had a catheter inserted into their bladder after administration of nalbuphine. Pain scores (grouped 6 hr before and after nalbuphine administration and single pain scores documented immediately before and after nalbuphine administration) were unchanged. Conclusions Nalbuphine administration, at a dose of 0.1 mg/kg, improved urine output in a cohort of children with opioid-associated urinary retention. Pain control did not appear influenced by the provision of nalbuphine. Additional studies are needed to determine the influence of nalbuphine on urinary catheter insertion rates and catheter-associated urinary tract infections.

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 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

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

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. 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. At perfusion start, the measured initial nalbuphine concentrations in the maternal and fetal circuits are 93.1 and

Background Pain is one of the major symptoms complained about by patients in the prehospital setting, especially in the case of trauma. When there is mountainous topography, as in Switzerland, there may be a time delay between injury and arrival of professional rescuers, in particular on ski slopes. Administration of a safe opioid by first responders may improve overall treatment. We therefore assessed administration of nasal nalbuphine as an analgesic treatment for trauma patients in Switzerland. Methods This observational cohort study examined 267 patients who were treated with nasal nalbuphine by first responders in six ski resorts in Switzerland. All first responders were instructed to begin treatment by assessing the feasibility of using nalbuphine to treat pain in the patient. A treatment algorithm was developed and distributed to assure that nalbuphine was only administered following a strict protocol. Data regarding pain scores and pain reduction after administration of nalbuphine were collected on-site. Refills were handed out to the first responders with the return of each completed questionnaire. Results Nalbuphine provided effective pain relief, with the median level of pain on the numeric rating scale for pain reduced by 3 units on average, from 8 points (p p = 0.006). No major side effects were observed. Conclusion Nasal administration of nalbuphine by first responders is a presumably safe and effective noninvasive pain management strategy for acutely injured patients in the prehospital setting. This may be an alternative, especially in the case of severe pain and prolonged time between arrival of the first responders and arrival of EMS/HEMS personnel on scene.

Background Proximal femur fractures are most common fractures in the elderly and associated with significant mortality and morbidity, with high economic and social impact. Perioperative pain management influence outcomes and mortality after surgery with early mobilization being possible. The goal of the study was to compare the efficacy and safety of the psoas compartment block (PCB) with spinal and general anesthesia. Methods We included 90 patients in this randomized controlled study and divided them into three groups. For patients in group 1 ultrasound-guided PCB with bupivacaine 0.125% 6–8 ml / h was performed. Intraoperative anesthesia was provided with PCB and a sciatic nerve block. Postoperative analgesia include prolonged CPB with bupivacaine 0.125% 6–8 ml / h. In group 2 intraoperative spinal anaesthesia were performed. Group 3 patients underwent general sevoflurane inhalation anaesthesia with fentanyl infusion for analgesia. All patients received paracetamol 3 g/day and dexketoprofen 75 mg/day during hospitalization. On-demand, nalbuphine 5 mg SC was used for analgesia. Efficacy outcomes were the ICU length of stay and the total duration of hospitalization, number of patients who had severe pain after surgery, incidence of on-demand analgesia, sleep quality, postoperative mobilization time. Safety outcomes include complication incidence. Results There were no differences in the duration of ICU stay - gr.1 72 [70–75], gr.2 74 [72–76], gr.3 72 [70–75] hours respectively (p = 0.29), and the total duration of hospitalization - gr.1144 [170–184], gr.2170 [148–188], gr.3178 [144–200] hours respectively. Patients in gr.1 had significantly lower nalbuphine consumption in the first 24 h after surgery and total during hospitalization (0 [0–5] mg versus 15 [10–20] and 20 [15–25] mg in the first 24 h in groups 2 and 3, respectively (p p p p = 0,048 for gr. 2 and OR 11 95 CI 1,2–91, p = 0, 03 for gr. 3). However, none of the patients had symptoms of myocardial ischemia and was not diagnosed with myocardial infarction. There were no difference in the incidence of nosocomial pneumonia and delirium. Conclusion Perioperative PCB in elderly patients with a proximal femur fracture could be an effective analgesia technique, as it decrease the number of patients with severe pain, need for on demand analgesia and opioid consumption. PCB also decrease the incidence of opioid-associated nausea and vomiting, comparing to general anesthesia, and increase the number of patients, who was mobilized in the 1st day (sitting) and 2nd day (getting up) after surgery. PCB may reduce the incidence of MINS, although to assess this outcome more studies are needed. Trial registration Clinicaltrials.gov: NCT04648332, first registration date 1/12/2020.

Objective To evaluate the effects of dexmedetomidine alone or in combination with different opioids on intraocular pressure (IOP) in dogs. Study design Experimental, prospective, crossover, randomized, blinded study. Animals A total of six Beagle dogs (two males and four females) aged 2 years and weighing 15.9 ± 2.9 kg (mean ± standard deviation). Methods Dogs were distributed randomly into seven treatments (n = 6 per treatment) and were administered dexmedetomidine alone (10 μg kg–1; Dex) or in combination with butorphanol (0.15 mg kg–1; DexBut), meperidine (5 mg kg–1; DexMep), methadone (0.5 mg kg–1; DexMet), morphine (0.5 mg kg–1; DexMor), nalbuphine (0.5 mg kg–1; DexNal) or tramadol (5 mg kg–1; DexTra). All drugs were administered intramuscularly. IOP was measured before drug injection (time 0, baseline) and every 15 minutes thereafter for 120 minutes (T15–T120). Results There were significant reductions in IOP compared with baseline in treatments Dex and DexMep at times T30–T120, and in treatment DexMet at T15–T90. IOP decreased compared with baseline in treatments DexBut, DexNal and DexTra at all evaluation times. No changes in IOP were seen in treatment DexMor. The mean IOP values in treatment DexMet at T105–T120 were higher than those for other treatments. Conclusions and clinical relevance Dexmedetomidine alone or in combination with butorphanol, meperidine, methadone, nalbuphine or tramadol resulted in decreased IOP for 120 minutes in dogs. The magnitude of the reduction was small and lacked clinical significance.

To evaluate the analgesic effect of ultrasound-guided subcostal anterior quadratus lumborum block (QLB) for laparoscopic radical gastrectomy surgery.Patients (aged 20-65 years, ASA I - II, and weighing 40-75 kg) scheduled for elective laparoscopic radical gastrectomy were enrolled in the current study. Sixty patients were randomly assigned to two groups by computer-generated randomization codes: an ultrasound-guided oblique subcostal transversus abdominis plane block (TAPB) group (group T, n=30) or an ultrasound-guided subcostal anterior QLB group (group Q, n=30). In both groups, bilateral ultrasound-guided oblique subcostal TAPB and subcostal anterior QLB were performed before general anesthesia with 0.25% ropivacaine 0.5 mL/kg. For postoperative management, all patients received patient-controlled intravenous analgesia (PCIA) with nalbuphine and sufentanil after surgery, maintaining visual analogue scale (VAS) scores ≤4 within 48 h. The intraoperative consumption of remifentanil, the requirement for sufentanil as a rescue analgesic, and the VAS scores at rest and coughing were recorded at 1, 6, 12, 24 and 48 h after surgery. The recovery (extubation time after surgery, first ambulation time, first flatus time and length of postoperative hospital stay) and the adverse events (nausea and vomiting, skin pruritus, respiratory depression and nerve-block related complications) were observed and recorded. The primary outcome was the perioperative consumption of opioids.Compared with group T, the intraoperative consumption of remifentanil, requirement for sufentanil and the frequency of PCIA were reduced in group Q. Meanwhile, VAS scores at all points of observation were significantly lower in group Q than in group T. Patients in group Q were also associated with shorter time to first out-of-bed activity and flatus, and shorter length of postoperative hospital stay than group T (P0.05). There were no skin pruritus, respiratory depression or nerve-block related complications in both groups.Compared with ultrasound-guided oblique subcostal TAPB, ultrasound-guided subcostal anterior QLB provided greater opioid-sparing effect, lower visual analogue scores, and shorter postoperative hospital stay for laparoscopic radical gastrectomy.

OBJECTIVES The addition of a small dose of opioids during epidural labor analgesia can enhance the local analgesic effect, reduce the dose of local anaesthetic required, and minimize motor blockade. For the treatment of visceral pain, studies have shown that κ-opioid receptor agonist are more effective than μ-receptor agonists. This study compared the effectiveness of epidural nalbuphine and sufentanil in combination with ropivacaine for labor analgesia, respectively. MATERIALS AND METHODS We conducted a prospective, randomized, double-blind, multicentre clinical trial. Parturients who requested labor pain relief were randomly assigned to either the nalbuphine group or sufentanil group. After 5 minutes of initial dose, parturients in nalbuphine group received 10 mL 0.1% ropivacaine plus 0.3 mg/mL nalbuphine solution. The sufentanil group received the same ropivacaine dose plus 0.3 μg/mL sufentanil. The primary outcome was the duration of analgesia (the time to the first requirement for additional medication). Secondary outcomes included the ropivacaine dose per hour, and adverse reactions. RESULTS Between November 2018 and February 2019, 180 parturients were recruited for the study. The study showed that the duration of analgesia was shorter in the nalbuphine group as compared with the sufentanil group (P=0.040). The ropivacaine dose per hour in nalbuphine group 9.3 (2.4) mg was significantly greater versus sufentanil group 8.4 (2.5) mg (P=0.024). No serious adverse events directly associated with the analgesics were observed. DISCUSSION The analgesia effects of 0.3 mg/mL nalbuphine with ropivacaine are inferior to 0.3 μg/mL sufentanil with ropivacaine in labor analgesia. No serious side effects, either in the mother or in the fetus, were observed.

Neuraxial morphine-induced hypothermia has been reported as a relatively rare complication, with the successful use of naloxone and lorazepam to reverse symptoms. We report a case of intrathecal morphine-induced hypothermia with profuse sweating, intractable nausea, and vomiting in a primigravid woman undergoing cesarean delivery in the setting of preeclampsia. All symptoms rapidly resolved after a single dose of intravenous nalbuphine. Because nalbuphine has a long track record of safe use on labor and delivery units, it is an attractive and novel choice for treatment of neuraxial morphine-induced hypothermia.

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.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, pOEleven 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.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.

Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (≥0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter.

OBJECTIVE To evaluate cardiopulmonary, sedative, and antinociceptive effects of dexmedetomidine combined with commonly administered opioids in dogs. ANIMALS 8 healthy Beagles. PROCEDURES Dogs were sedated by IM administration of each of 7 treatments. Treatments comprised dexmedetomidine (0.01 mg/kg; Dex) and the same dose of dexmedetomidine plus butorphanol (0.15 mg/kg; Dex-But), meperidine (5 mg/kg; Dex-Mep), methadone (0.5 mg/kg; Dex-Meth), morphine (0.5 mg/kg; Dex-Mor), nalbuphine (0.5 mg/kg; Dex-Nal), or tramadol (5 mg/kg; Dex-Tram). Cardiorespiratory and arterial blood gas variables and sedative and antinociceptive scores were measured before drug injection (time 0; baseline) and at 15-minute intervals for 120 minutes. RESULTS Heart rate was reduced at all time points after injection of Dex-But, Dex-Mep, Dex-Meth, and Dex-Mor treatments. There was a significant reduction of mean arterial blood pressure for Dex-But, Dex-Mep, and Dex-Mor treatments at all time points, compared with baseline. There was a significant decrease in respiratory rate, compared with the baseline value, for Dex, Dex-But, Dex-Meth, and Dex-Tram treatments from 15 to 120 minutes. A significant decrease in arterial blood pH was detected from baseline to 120 minutes for all treatments, with differences among Dex, Dex-Mep, and Dex-Mor. Reduction in Pao2 was greater for the Dex-Mep treatment than for the other treatments. The highest sedation scores were detected for Dex-Mep and Dex-Meth treatments. Antinociceptive effects were superior for Dex-But, Dex-Meth, Dex-Mor, and Dex-Nal treatments. CONCLUSIONS AND CLINICAL RELEVANCE Drug combinations caused similar cardiorespiratory changes, with greater sedative effects for Dex-Mep and Dex-Meth and superior antinociceptive effects for Dex-But, Dex-Meth, Dex-Mor, and Dex-Nal.

Objective To compare sedation and effects on heart rate (HR), mean arterial pressure (MAP) and respiratory rate (fR) of nalbuphine and butorphanol, alone or combined with acepromazine in dogs. Study design Prospective, randomized experimental trial. Animals Eight healthy Beagle dogs, aged (mean ± standard deviation) 3.4 ± 0.5 years and weighing 11.0 ± 1.3 kg. Methods Each dog was treated four times: physiological saline (1 mL) combined with nalbuphine (0.5 mg kg−1; SAL-NAL) or butorphanol (0.15 mg kg−1; SAL-BUT), and acepromazine (0.05 mg kg−1) combined with nalbuphine (0.5 mg kg−1; ACP-NAL) or butorphanol (0.15 mg kg−1; ACP-BUT), intravenously (IV). The degree of sedation, assessed by a numeric descriptive scale (NDS) and simple numerical scale (SNS), HR, MAP, fR and rectal temperature (RT), were recorded before and 20 minutes after administration of saline or acepromazine, then 15, 30, 60, 90 and 120 minutes after nalbuphine or butorphanol. Values were compared with baseline and among treatments. Results Mild sedation was recorded for SAL-NAL and SAL-BUT, and moderate sedation for ACP-NAL and ACP-BUT. NDS and SNS scores were higher for SAL-BUT and ACP-BUT at some time points when compared with SAL-NAL and ACP-NAL, respectively (p Conclusions and clinical relevance Butorphanol promoted a higher sedative effect than nalbuphine when alone and combined with acepromazine. IV administration of nalbuphine or butorphanol, with or without acepromazine, at the doses studied, resulted in minimal decreases in MAP, HR, fR and RT.

This study was conducted to evaluate the safety and efficacy of single sebacoyl dinalbuphine ester (SDE) injection (150 mg/2 mL) when administered intramuscularly to patients who underwent hemorrhoidectomy for postoperative long-acting analgesia.A total of 221 patients scheduled for hemorrhoidectomy from 6 centers in Taiwan were randomly divided into SDE group and placebo group, and received the treatment, vehicle or SDE, 1 day before the surgery. Visual analogue scale (VAS) was recorded up to 7 to 10 days. Pain intensity using VAS AUC through 48 hours after surgery was calculated as the primary efficacy endpoint.Area under the curve of VAS pain intensity scores (VAS AUC) through 48 hours after hemorrhoidectomy was significantly less in SDE group than those in placebo group (209.93 vs. 253.53). VAS AUC from the end of surgical procedure to day 7 was also significantly different between SDE and placebo group (630.79 vs. 749.94). SDE group consumed significantly less amount of other analgesics, such as PCA ketorolac and oral ketorolac. Median time from the end of surgery to the first use of pain relief medication was also shortened in the placebo group than in the SDE group. Most adverse events were assessed as mild and tolerable in both groups.SDE injection demonstrated an extended analgesia effect, with a statistically significant reduction in pain intensity through 48 hours and 7 days after hemorrhoidectomy.

The outcome of relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/T-LBL) in adults is poor, with less than 20% of patients surviving at 5 years. Nelarabine is the only drug specifically approved for R/R T-ALL/T-LBL, but the information to support its use is based on limited available data. The aim of this observational phase 4 study was to provide recent additional data on the efficacy and safety of nelarabine in adults with R/R T-ALL/T-LBL and to evaluate the feasibility and outcome of allogeneic hematopoietic stem cell transplant (SCT) after salvage with nelarabine therapy. The primary endpoints were overall response rate (ORR) and overall survival (OS). Additional endpoints were safety, SCT rate and post-SCT OS. Between May 2007 and November 2018, 118 patients received nelarabine salvage therapy at 27 Italian hematology sites. The median age was 37 years (range 18-74), 73% were male, 77 had a diagnosis of T-ALL and 41 of T-LBL, and 65/118 (55%) had received >2 lines of therapy. The median number of nelarabine cycles was 2 (range 1-4); 43/118 (36%) patients had complete remission (CR), 16 had partial remission (14%) and 59 (50%) were refractory, with an ORR of 50%. The probability of OS, from the first dose of nelarabine, was 37% at 1 year with a median survival of 8 months. The OS at 1 year was significantly better for the 47 patients (40%) who underwent SCT after nelarabine salvage therapy (58% vs. 22 %, log-rank P=0.0001. The probability of OS at 2 and 5 years from SCT was 46% and 38%, respectively. Seventy-five patients (64%) experienced one or more drug-related adverse events (AE). Grade III-IV neurologic toxicities were observed in 9/118 (8%) of cases and thrombocytopenia or/and neutropenia (grade III-IV) were reported in 41% and 43% of cases, respectively. In conclusion, this is one of the largest cohorts of adult patients with R/R T-ALL/T-LBL treated in real life with nelarabine. Taking into account the poor prognosis of this patient population, nelarabine represents an effective option with an ORR of 50% and a CR rate of 36%. In addition, 40% of cases following nelarabine salvage therapy could undergo SCT with an expected OS at 2 and 5 years of 46% and 38%, respectively. The safety profile of nelarabine was acceptable with only 8% of cases showing grade III-IV neurological AE. This article is protected by copyright. All rights reserved.

Objective This study aimed to compare the clinical efficacy and side effects of nalbuphine and dexmedetomidine for treatment of combined spinal-epidural anesthetic shivering in women after cesarean section. Methods A total of 120 pregnant women, who underwent elective cesarean section under combined spinal-epidural anesthesia, were enrolled in a double-blind, randomized study. These women were randomized into three groups of 40 pregnant women each to receive either saline (group C), nalbuphine 0.07 mg/kg (group N), or dexmedetomidine 0.5 µg/kg (group D) for treatment of shivering after anesthesia. The main outcome measure was a significant reduction in the time required for shivering after intervention. Results The mean time to cessation of shivering in groups N and D was significantly shorter than that in group C (3.5±2.7 and 4.2±3.7 versus 14.5±1.4 minutes). The success rate of shivering treatment and Observer’s Assessment of Alertness/Sedation scores in groups N and D were significantly higher than those in group C, while the recurrence rate was lower than that in group C. Conclusion Nalbuphine 0.07 mg/kg can be used safely and effectively for shivering in pregnant women under combined spinal-epidural anesthesia.

This study examined the sedative, analgesic, behavioral, and clinical effects of a combination of xylazine (XY) and nalbuphine-xylazine (NA-XY) in camels. A total of five adult camels were used in a prospective randomized cross-over design with a wash out period of two weeks. Camels were allocated randomly to two treatment groups: the XY group (xylazine, 1.1mL/100 kg IV) and the NA-XY group (xylazine, 1.1mL/100 kg IV and nalbuphine, 1 mg/kg IV). The sedative, analgesic, behavioral, and clinical effects of XY and NA-XY combination were evaluated prior to administration (baseline) and at 5, 15, 30, 45, 60, 75, 90, and 120 minutes post-administration. The results showed that the NA-XY combination accelerates the onset of sedation and analgesia and prolongs the durations of both sedation (p < 0.001) and analgesia (p < 0.01). The behavioral parameters showed higher scores with a NA-XY combination than xylazine alone. Although a XY injection resulted in a significant decline in the heart and respiratory rate, the NA-XY combination group revealed a non-significant change in both clinical parameters compared to the baseline. In conclusion, the use of a NA-XY combination in camels improved the sedative and analgesic onset and duration with an improved outcome in the behavioral scores, as well as in both the heart and respiratory rates compared to XY alone.

International audience; Objective: Drug-induced hypoglycaemia has been described with the use of tramadol and methadone. The authors aimed to determine if drug-induced hypoglycaemia could be a class effect for opioids. Methods: The authors performed a disproportionality analysis in VigiBase®, the WHO global individual case safety report database with nine opioids (codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, tramadol, buprenorphine and nalbuphine) using the broad Standardised MedDRA Query for hypoglycaemia. The authors also carried out a descriptive study of opioid-induced hypoglycaemia in the French PharmacoVigilance DataBase (FPVDB) using the MedDRA Preferred Term 'hypoglycaemia'. Results: The global adjusted Reporting Odds Ratio (aROR) value for the 9 opioids was 1.53 (95% CI 1.52-1.54). The aROR ranged from 1.09 to 1.97 depending on the opioid, but all were statistically significant. A sex ratio of 0.74 was found for the reports of opioid-induced hypoglycaemia in Vigibase®. The authors also found 133 reports of hypoglycaemia in the FPVDB related to opioids. Among the reports, 55 were glycaemic imbalances in diabetics occurring shortly after the start of opioid treatment. Conclusion: This work highlighted a significant association between all opioids and hypoglycaemia, thereby indicating that opioid-induced hypoglycaemia is probably a class effect. Women and/or diabetics seem to be more at risk for developing opioid-induced hypoglycaemia.

Objective To describe pain assessment, the pattern of analgesic and sedative drug use, and adverse drug reactions in a neonatal intensive care unit (NICU) during the postsurgery phase. Method Demographic characteristics, pain scores, and drug use were extracted and analyzed from electronic patient medical files for infants after surgery, admitted consecutively between January 2012 and June 2013. Result One hundred and sixty-eight infants were included. Acute (DAN score) and prolonged (EDIN score) pain assessment scores were used in 79% and 64% of infants, respectively, on the 1st day. This percentage decreased over the 7 days following surgery. The weekly average scores postsurgery were 2/15 (±2.2) for the EDIN score and 1.6/10 (±2.0) for the DAN score. The rates of pain control were 88% for the EDIN and 72% for the DAN. The most prescribed opiate drug was fentanyl (98 patients; 58%) with an average dose of 1.8 (±0.6) μg/kg/h. Midazolam was used in 95 patients (56%), with an average dose of 35 (±14) μg/kg/h. A bolus was administered in 7% (±7.4) of the total dose for fentanyl and 8% (±9.3) for midazolam. Similar doses were used in term and preterm neonates. Of 118 patients receiving fentanyl and/or midazolam, 40% presented urinary retention, 28% a weaning syndrome. Paracetamol (155 patients; 92%) and nalbuphine (55 patients; 33%) were the other medications most often prescribed. Conclusion The off-label use of fentanyl and midazolam was necessary to treat pain after surgery. Pain assessment should be conducted for all neonates in order to optimize their treatment. Research on analgesic and sedative medicine in vulnerable neonates seems necessary to standardize practices and reduce adverse drug reactions.

Shivering is a common complication of caesarean delivery with neuraxial anaesthesia. The effective prevention and treatment of shivering, especially before delivery, is important and difficult. We tested the hypothesis that prophylactic nalbuphine and ondansetron can prevent post-spinal anaesthesia shivering in parturients undergoing urgent caesarean delivery.Sixty parturients scheduled for urgent caesarean delivery before spinal anaesthesia were selected and divided randomly into three groups. After peripheral venous catheterisation, parturients were given intravenous nalbuphine 0.08 mg/kg (group N), ondansetron 8 mg (group O), or normal saline (group C).The incidence of shivering and of severe (grade ≥3) shivering was significantly lower in group N (15% and 15%, respectively) than in group C (80% and 65%) before delivery (P 0.001 and P=0.003); and significantly less shivering was observed in group N than in group C in the first 30 min after anaesthesia (P=0.001). Up to 60 min after anaesthesia, the incidence of grade ≥3 shivering remained lowest in group N (P=0.003). According to the data during the period from anaesthesia until delivery, the number needed-to-treat for nalbuphine was 1.54 (95%CI 1.13 to 2.41). No significant differences were found between groups O and N or groups O and C at any time. The incidence of dizziness in group N was significantly higher than that of groups O or C (P=0.009).Nalbuphine 0.08 mg/kg can prevent post-spinal anaesthesia shivering in parturients undergoing urgent caesarean delivery but causes transient dizziness, while ondansetron 8 mg had no significant effect.

Background A long-acting prodrug of nalbuphine, nalbuphine sebacate, has been developed for meeting the unmet medical need of long-acting analgesics. Naldebain® (nalbuphine sebacate) has been developed as a new premedication for postoperative pain management. The primary objective of this study is to determine the efficacy and safety of a single dose of intramuscular Naldebain® in patients scheduled to undergo elective laparotomy. Methods/design A total of 110 patients will be recruited and randomized into two treatment groups. Group 1 receives a single dose of Naldebain® intramuscularly 24 ± 12 h prior to surgery. Group 2 receives intravenous patient-controlled analgesia (PCA) with fentanyl through 48 h postsurgery. Both groups will have follow-up observations until the final visit (day of discharge, day 6–30). The primary efficacy endpoint is to assess time-specific pain intensity calculated as the area under the curve (AUC) of a visual analog scale at individual time points and by using total AUC. Safety endpoints—including incidence of treatment, emergent adverse events, and percentage of abnormality from baseline to final visit—in vital signs, laboratory tests, and injection site evaluations will also be analyzed. Statistical analyses will be performed on the data to compare the two groups. Discussion Post-laparotomy pain can have a harmful effect on patient recovery; therefore, a slow-release formulation that can cover at least 7 days of analgesic effect is required. This study will demonstrate whether a single use of Naldebain® is not less efficacious than PCA with fentanyl for pain management as a non-inferior trial. Trial registration NCT03296488. Electronic supplementary material The online version of this article (10.1186/s13063-019-3260-4) contains supplementary material, which is available to authorized users.

BACKGROUND The goal of this study was to investigate different doses of nalbuphine combined with dexmedetomidine in the postoperative treatment of laparoscopic oophorocystectomy. MATERIAL AND METHODS This prospective single-blinded randomized controlled study included 219 patients with benign ovarian cysts who received laparoscopic oophorocystectomy from March 2017 to October 2019. Patients were randomized into 4 groups: low (0.5 mg/kg), middle (1.0 mg/kg), and high (1.5 mg/kg) doses of nalbuphine combined with dexmedetomidine (4 μg/kg) (LND, MND, and HND groups, respectively) and a control group with sufentanil (2.5 μg/kg), with different patient-controlled intravenous analgesia pump (PCIA) strategies. Rest and active visual analog scale (VAS) scores measured postoperative pain, and Ramsay scores were used to measure sedation. RESULTS The HND group showed the lowest rest and cough VAS scores at 2 h, 8 h, 12 h, and 24 h after surgery, the lowest PCIA pressing time within 48 h after surgery, and the highest Ramsay scores at 2 h, 8 h, 24 h and 48 h after surgery. Rest and cough VAS scores decreased with higher nalbuphine doses in a dose-dependent manner. One day after surgery, IL-1s and IL-6 levels increased in all groups, with the lowest levels of IL-1s and IL-6 in the HND group. Hospitalization time was significantly shorter in the HND group compared with the LND and MND groups. There were no significant differences in complications among groups. CONCLUSIONS Combined nalbuphine and dexmedetomidine improved postoperative pain and sedative conditions, reduced inflammation in a nalbuphine dose-dependent manner, and might facilitate patient recovery.

Background: Pruritus is a distressing hallmark of the uremic condition, affecting approximately 60% of hemodialysis patients. Abnormal endogenous opioid ligand activity at μ and κ-opioid receptors has been postulated as a mechanism in uremic pruritus. Nalbuphine is a μ-opioid antagonist and κ-opioid agonist. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, 373 hemodialysis patients with moderate or severe uremic pruritus were randomized in a 1: 1:1 ratio to nalbuphine extended-release tablets 120 mg (NAL 120), 60 mg (NAL 60), or placebo and treated for 8 weeks. Three hundred seventy-one were analyzed for efficacy. The primary endpoint was the change from baseline to treatment weeks 7 and 8 in itching intensity on a Numerical Rating Scale (NRS, 0 [no itching]; 10 [worst possible itching]) using an intent-to-treat approach. The aim was to evaluate the safety and antipruritic efficacy of NAL. Results: The mean duration of itching was 3.2 years. From a baseline NRS of 6.9 (1.5), the mean NRS declined by 3.5 (2.4) and by 2.8 (2.2) in NAL 120 mg and the placebo groups, respectively (p = 0.017). There was no evidence of tolerance. A trend for less sleep disruption due to itching (p = 0.062, NAL 120 vs. placebo) was also observed. There were no significant differences between NAL 60 vs. placebo. Serious adverse events occurred in 6.7, 12.7, and 15.4% in the NAL 120, NAL 60, and placebo groups respectively. Conclusions: In this largest-to-date randomized controlled trial in uremic pruritus, NAL 120 durably and significantly reduced the itching intensity among hemodialysis patients.

Objectives To evaluate and compare the efficacy of two opioid agonist-antagonists, nalbuphine and butorphanol, in reversing etorphine-induced respiratory depression in immobilized goats. Study design Prospective, crossover, experimental trial conducted at 1753 m.a.s.l. Animals Eight adult female Boer goats (Capra hircus). Methods Eight minutes following immobilization with an intramuscular injection of 0.1 mg kg−1 etorphine, goats were given one of nalbuphine (0.8 mg kg−1), butorphanol (0.1 mg kg−1) or sterile water intravenously, in random order in three trials. Respiratory rate (fR), ventilation, tidal volume, oxygen consumption ( V ˙ O2) and carbon dioxide production ( V ˙ CO2) were measured continuously. Arterial blood samples to determine PaO2 and PaCO2 were taken 2 minutes before and at 5 minute intervals after etorphine administration for 25 minutes. Results Both nalbuphine and butorphanol increased mean PaO2 from 44 mmHg (5.9 kPa) to 63 mmHg (8.4 kPa) after etorphine administration. Butorphanol, but not nalbuphine, also corrected hypopnea and hypoventilation such that fR increased from 13 ± 4 to 21 ± 7 breaths minute−1 (compared with 16 ± 6 breaths minute−1 following nalbuphine) and ventilation increased from 4.69 ± 3.04 to 6.91 ± 4.42 L minute−1 following butorphanol administration. Despite decreases in PaCO2 following nalbuphine and butorphanol, PaCO2 remained elevated compared with pre-immobilization values [nalbuphine: 34 ± 3 mmHg (4.5 ± 0.3 kPa); butorphanol: 34 ± 2 mmHg (4.5 ± 0.3 kPa)] throughout the immobilization. Both agents also decreased the level of immobilization, and increased V ˙ O2 and V ˙ CO2. Conclusions Nalbuphine and butorphanol significantly improved respiratory function in immobilized goats, with butorphanol eliciting a greater positive response than nalbuphine. However, both opioid agonist-antagonists partly reversed etorphine-induced immobilization. Clinical relevance Butorphanol and nalbuphine can be used to improve respiratory parameters in etorphine-immobilized wildlife, with butorphanol being more effective, but unwanted arousal can occur.

Thirty-two American beavers (

To evaluate the 95% effective dose of nalbuphine in patient-controlled intravenous analgesia (PCIA) by the sequential method and compare the analgesia efficacy with the equivalent dose of sufentanil on patients undergoing laparoscopic total hysterectomy.In the first part, we defined a successful analgesia as the highest VAS ≤3 in 24 hours postoperatively. On the contrary, a failed analgesia was the highest VAS3. According to the last patient's outcome, the next patients would be given an increase or decreased dose grade. This process ended up with 9 cross-over points. In the second part, 60 patients undergoing laparoscopic total hysterectomy were selected. They were randomly divided into 2 groups (n = 30 each group): receiving sufentanil 1.78 μg/kg (group S) and nalbuphine 1.78 mg/kg (group N). PCIA pump was given at the end of the operation with 5 mL bonus loading. The total amount of PCIA was 100 mL and programmed to deliver 0.5 mL each time with a lockout interval of 15 minutes and the background infusion amount of 2 mL/h. The VAS score and Ramsay score of were collected after the operation, the number of effective pressing times of PCIA were also recorded. Adverse reactions were documented in detail.The 95% effective dose of nalbuphine in PCIA on patients undergoing laparoscopic total hysterectomy was 1.78 mg/kg. There was no significant difference in VAS between the sufentanil group and the nalbuphine groups (P .05), but the number of the use of PCIA in the group S was more than that in the group N obviously (P.05). The group S has a lower ramsay sedation score than group N at every time point. (P.05). The incidence of nausea and vomiting was not statistically significant differences between two groups in the first 24 hours after colonoscopy (P q .05).Nalbuphine 1.78 mg/kg in PCIA is recommended for the patients undergoing laparoscopic total hysterectomy. And nalbuphine is a reasonable alternative to sufentanil when used in PCIA.

Objective To compare the reaction to cephalic intravenous (IV) catheter placement with or without lidocaine–prilocaine cream in cats sedated with dexmedetomidine and methadone or nalbuphine. Study design Prospective, randomized, blind study. Animals A group of 24 female mixed breed cats. Methods Cats were randomly allocated to one of the two sedation protocols: dexmedetomidine (0.01 mg kg–1) and methadone (0.3 mg kg–1; DEXMET) or dexmedetomidine (0.01 mg kg–1) and nalbuphine (0.3 mg kg–1; DEXNALB). Sedation was scored 30 minutes later using a visual analog scale. Subsequently, a 2 × 3.5 cm area of the antebrachium over the cephalic vein was clipped, and half the cats within each protocol were randomly assigned for topical lidocaine–prilocaine cream (treatment), whereas no cream was applied to other cats (control). After 20 minutes, an attempt was made to place a 24 gauge catheter into the cephalic vein and the reaction of the cats to this procedure was scored using a numeric scale 0–3. Sedation and catheterization reaction scores were compared between sedation protocols and whether cats were administered lidocaine–prilocaine cream or not using the Friedman test followed by the Bonferroni procedure. A p value Results Sedation scores were not different between sedation protocols or between treatment and control cats within each protocol. All cats administered lidocaine–prilocaine cream showed no reaction to IV catheter placement. Among the control cats, no response was observed in one cat in DEXNALB. Catheterization reaction score was lower in the treatment cats in both the sedation protocols when compared with their respective controls. Conclusions and clinical relevance Lidocaine–prilocaine cream applied for 20 minutes abolished the reaction to catheterization in cats sedated with dexmedetomidine and nalbuphine or methadone. Facilitation of IV catheter placement occurred within 20 minutes of lidocaine–prilocaine application.

Efficacy of antinociceptive defense at the terminal period of operation and in early (6 h) postoperative period, using additional injection of phentanil, paracetamol and nalbufin in anesthesiological support, and applying sevofluran in 107 patients, оperated on facial skull, in 2 stage of operative risk in accordance to ASA, was a nalyzed. Insufficient antinociceptive protection at the end of operation and in early postoperative period while using phentanil and nonsteroidal antiinflammatory medicines only for anesthesia, was established, basing on analysis of hemodynamic indices, pain syndrome severity and indices of metabolic stress. Application of paracetamol have promoted raising of the antinociceptive protection efficacy during short period (up to 2 h) only. Prescription of nalbufin have had guaranteed enhanced efficacy and duration of antinociceptive protection in early postoperative period, that's why its wide application is recommended.

Objective To evaluate the efficacy of three doses of nalbuphine in reversing sedative and cardiopulmonary effects of morphine–acepromazine in dogs. Study design Prospective, randomized experimental trial. Animals A group of eight healthy Beagle dogs, aged 5–6 years and weighing 12.5 ± 2.1 kg. Methods Dogs were administered morphine (0.5 mg kg–1) and acepromazine (0.05 mg kg–1) intravenously (IV). After 20 minutes, dogs were administered one of four treatments IV: saline (control); or nalbuphine (0.3 mg kg–1; treatment N0.3), (0.6 mg kg–1; treatment N0.6) or (1.0 mg kg–1; treatment N1.0), in random order separated by 1 week. Sedation was scored using a numeric descriptive scale (NDS) and simple numerical scale (SNS). Heart rate, systolic arterial pressure (SAP), respiratory rate (fR) and rectal temperature (RT) were recorded before (BL), 20 minutes after morphine–acepromazine (T0), then 10 (T10), 30, 60 and 90 minutes after saline or nalbuphine. Arterial blood gases were measured at BL, T0 and T10. Values were compared with BL, T0 and among treatments using anova (p Results NDS for N0.6 and SNS for N0.6 and N1.0 at T30, and both scores for all nalbuphine treatments at T60–T90 were lower compared with T0 (p Conclusions and clinical relevance All nalbuphine doses decreased the degree of sedation, without differences among them. Administration of nalbuphine resulted in minimal changes in measured cardiopulmonary variables.

To evaluate the effectiveness of inducing acute hypertension during laparoscopic ovarian cystectomy on postoperative nalbuphine analgesic requirements.The total dose of nalbuphine used in the hypertension group was significantly lower than that in the control group (p0.001). The VAS score was significantly lower in the hypertension group on arrival to PACU and during the period between 1 and 6 hours postoperatively.The total dose of nalbuphine used in the hypertension group was significantly lower than that in the control group (p0.001). The VAS score was significantly lower in the hypertension group on arrival to PACU and during the period between 1 and 6 hours postoperatively.This study demonstrates that pharmacologically induced mild acute intraoperative hypertension significantly reduces postoperative nalbuphine consumption and pain scores following laparoscopic ovarian cystectomy. Trial registration in Pan African Clinical Trial Registry: identification number for the registry is PACTR201508001247179.

Background Opioid-induced bowel dysfunction (OIBD) is characterised by constipation, incomplete evacuation, bloating, and gastric reflux. It is one of the major adverse events of treatment for pain in cancer and in palliative care, resulting in increased morbidity and reduced quality of life.This is an update of two Cochrane reviews. One was published in 2011, Issue 1 on laxatives and methylnaltrexone for the management of constipation in people receiving palliative care; this was updated in 2015 and excluded methylnaltrexone. The other was published in 2008, Issue 4 on mu-opioid antagonists (MOA) for OIBD. In this updated review, we only included trials on MOA (including methylnaltrexone) for OIBD in people with cancer and people receiving palliative care. Objectives To assess the effectiveness and safety of MOA for OIBD in people with cancer and people receiving palliative care. Search methods We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, CINAHL, and Web of Science to August 2017. We also searched clinical trial registries and regulatory websites. We contacted manufacturers of MOA to identify further data. Selection criteria We included randomised controlled trials (RCTs) that assessed the effectiveness and safety of MOA for OIBD in people with cancer and people at a palliative stage irrespective of the type of terminal disease they experienced. Data collection and analysis Two review authors assessed risk of bias and extracted data. The appropriateness of combining data from the trials depended upon sufficient homogeneity across the trials. Our primary outcomes were laxation, impact on pain relief, and adverse events. Impact on pain relief was a primary outcome because a possible adverse effect of MOAs is a reduction in pain relief from opioids. We assessed the evidence on these outcomes using GRADE. Main results We identified four new trials for this update, bringing the total number included in this review to eight. In total, 1022 men and women with cancer irrespective of stage or at a palliative care stage of any disease were randomised across the trials. The MOAs evaluated were oral naldemedine and naloxone (alone or in combination with oxycodone), and subcutaneous methylnaltrexone. The trials compared with MOA with a placebo or with the active intervention administered at different doses or in combination with other drugs. The trial of naldemedine and the two of naloxone in combination with oxycodone were in people with cancer irrespective of disease stage. The trial on naloxone alone was in people with advanced cancer. The four trials on methylnaltrexone were undertaken in palliative care where most participants had cancer. All trials were vulnerable to biases; four were at a high risk as they involved a sample of fewer than 50 participants per arm.In the trial of naldemedine compared to placebo in 225 participants, there were more spontaneous laxations over the two-week treatment for the intervention group (risk ratio (RR) 1.93, 95% confidence intervals (CI) 1.36 to 2.74; moderate-quality evidence). In comparison with higher doses, lower doses resulted in fewer spontaneous laxations (0.1 mg versus 0.2 mg: RR 0.73, 95% CI 0.55 to 0.95; 0.1 mg versus 0.4 mg: RR 0.69, 95% CI 0.53 to 0.89; moderate-quality evidence). There was moderate-quality evidence that naldemedine had no effect on opiate withdrawal. There were five serious adverse events. All were in people taking naldemedine (low-quality evidence). There was an increase in the occurrence of other (non-serious) adverse events in the naldemedine groups (RR 1.36, 95% CI 1.04 to 1.79, moderate-quality evidence). The most common adverse event was diarrhoea.The trials on naloxone taken either on its own, or in combination with oxycodone (an opioid) compared to oxycodone only did not evaluate laxation response over the first two weeks of administration. There was very low-quality evidence that naloxone alone, and moderate-quality evidence that oxycodone/naloxone, had no effect on analgesia. There was low-quality evidence that oxycodone/naloxone did not increase the risk of serious adverse events and moderate-quality evidence that it did not increase risk of adverse events.In combined analysis of two trials of 287 participants, we found methylnaltrexone compared to placebo induced more laxations within 24 hours (RR 2.77, 95% CI 1.91 to 4.04. I² = 0%; moderate-quality evidence). In combined analysis, we found methylnaltrexone induced more laxation responses over two weeks (RR 9.98, 95% CI 4.96 to 20.09. I² = 0%; moderate-quality evidence). The proportion of participants who had a rescue-free laxation response within 24 hours of the first dose was 59.1% in the methylnaltrexone arms and 19.1% in the placebo arm. There was moderate-quality evidence that the rate of opioid withdrawal was not affected. Methylnaltrexone did not increase the likelihood of a serious adverse event; there were fewer in the intervention arm (RR 0.59, 95% CI 0.38 to 0.93; I² = 0%; moderate-quality evidence). There was no difference in the proportion of participants experiencing an adverse event (RR 1.17, 95% CI 0.94 to 1.45; I² = 74%; low-quality evidence). Methylnaltrexone increased the likelihood of abdominal pain and flatulence.Two trials compared differing methylnaltrexone schedules of higher doses with lower doses. For early laxation, there was low-quality evidence of no clear difference between doses on analgesia and adverse events. Both trials measured laxation response within 24 hours of first dose (trial one: RR 0.82, 95% CI 0.41 to 1.66; trial two: RR 1.07, 95% CI 0.81 to 1.42). Authors' conclusions In this update, the conclusions for naldemedine are new. There is moderate-quality evidence to suggest that, taken orally, naldemedine improves bowel function over two weeks in people with cancer and OIBD but increases the risk of adverse events. The conclusions on naloxone and methylnaltrexone have not changed. The trials on naloxone did not assess laxation at 24 hours or over two weeks. There is moderate-quality evidence that methylnaltrexone improves bowel function in people receiving palliative care in the short term and over two weeks, and low-quality evidence that it does not increase adverse events. There is a need for more trials including more evaluation of adverse events. None of the current trials evaluated effects in children.