Injection Site Reactions Before and After Intramuscular Injection Technique Revision: A Postmarketing Analysis of NALDEBAIN® From 2017 to 2022.

BACKGROUND: The NALDEBAIN® has been available since 2017, and high incidence of injection reactions in the phase 3 study has been reported. Since the first year in the market, the injection site reactions were still the majority of adverse drug reactions (ADRs) in pharmacovigilance reports. The new intramuscular (IM) instruction and package was introduced in the middle of 2018. In this retrospective study, we analyzed the pharmacovigilance data and published postmarketing studies to investigate the impact of IM injection-related reactions in Taiwan between the period of 2017-2022. METHODS: Individual case safety reports (ICSRs) and ADRs were classified by system organ class and preferred term. The reporting rate of ICSRs was used to evaluate the impact of the new IM instruction and package. RESULTS: A total of 37 ICSRs were identified from pharmacovigilance reports. Among them, 51% of IM injection-related reactions were reported after one single dose of NALDEBAIN administration. The reporting rate of IM injection-related reactions in pharmacovigilance data dropped from 125.00 to 3.56 per ten thousand exposures after IM instruction and package revision in 2018. In addition, the percentage of IM injection-related reactions also reduced in postmarketing studies from 27.5% to 4.5%. There were no serious IM injection-related reactions found in the pharmacovigilance and postmarketing dataset. CONCLUSION: Injection site reactions were common after intramuscularly administered oil-based agents during the first year which is later markedly reduced by changing the length of the needle and injection education.

Validation of Chinese version of a global anesthetic recovery questionnaire: A multicenter observational trial on ObsQoR-11.

BACKGROUND: The obstetric quality of recovery (ObsQoR-11) is considered one of the best patient-reported outcome measures of post-cesarean recovery. However, it has been neither validated in Chinese nor evaluated at >24 h after delivery. METHODS: Parturients from three hospitals (n = 279) completed the Chinese ObsQoR-11 at 24 h (T1) and 96 h (T2) after elective cesarean delivery. Convergent validity was assessed by correlation of Chinese ObsQoR-11 with a 100-mm numerical rating scale (NRS) of general health status; discriminant validity of good recovery (NRS ≥ 70-mm); and construct validity by correlation with influential factors to post-cesarean recovery. The reliability and responsiveness were also assessed. RESULTS: The Chinese ObsQoR-11 correlated moderately with the NRS [T1: r = 0.38 (95% confidence interval: 0.28-0.48), p < 0.0001; T2: r = 0.43 (95% confidence interval: 0.32-0.52), p < 0.0001] and discriminated between good and poor recovery [T1: mean (SD) score: 64 (20) vs 49 (17), p < 0.0001; T2: median (IQR) score: 81 (66-94) vs. 61 (53-72); p = 0.0002]; weakly correlated with gestational age, successful breastfeeding, and operation time. It was reliable (internal consistency: 0.75 (T1) and 0.82 (T2); split-half: 0.77 (T1) and 0.85 (T2); test-retest intraclass correlation coefficient r > 0.6 for each item) and responsive (Cohen effect size: 0.88; standardized response mean: 0.81). CONCLUSION: The Chinese ObsQoR-11may be used for assessing recovery at 24 h and 96 h after cesarean delivery. However, its' cutoff value for good recovery may be lower than that of other versions.

Multimodal Analgesia With Extended-Release Dinalbuphine Sebacate for Perioperative Management: Expert Opinion and Consensus.

BACKGROUND: The insufficient treatment of postoperative pain is considered a major barrier to enhanced patient recovery following surgery. Opioids remain the standard therapy for postoperative pain; however, the epidemic crisis of opioid abuse in the US has resulted in opioid-sparing multimodal analgesia (MMA) strategies in anesthesia practice. Complete perioperative pain management, particularly after discharge, may be undermined, resulting in chronic postsurgical pain. Thus, anesthesiologists and pain physicians should provide comprehensive MMA guidance for perioperative pain management. METHODS: The Taiwan Pain Society organized a working group, which included experts in the field of anesthesia, pain, and surgery. This group performed an extensive literature search, quality review, and drafted a consensus, which was discussed by experts and edited for feedback. Recommendations covered consent instruction, treatment interventions, intramuscular injection techniques, and prophylaxis for postoperative adverse events. RESULTS: This consensus included (1) a comparison of the pharmacology and pharmacokinetics between nalbuphine and dinalbuphine sebacate, (2) recommendations to help clinicians establish MMA with extended-release dinalbuphine sebacate injection, and (3) management of common adverse events during the perioperative pain period. CONCLUSION: Extended-release dinalbuphine sebacate combined with the MMA strategy can reduce the medical burden and improve the quality of recovery following surgery.

Carnosine Alleviates Knee Osteoarthritis and Promotes Synoviocyte Protection via Activating the Nrf2/HO-1 Signaling Pathway: An In-Vivo and In-Vitro Study.

The most common joint disease in the elderly is knee osteoarthritis (OA). It is distinguished by cartilage degradation, subchondral bone loss, and a decrease in joint space. We studied the effects of carnosine (CA) on knee OA in male Wistar rats. OA is induced by anterior cruciate ligament transection combined with medial meniscectomy (ACLT+MMx) method and in vitro studies are conducted in fibroblast-like synoviocyte cells (FLS). The pain was assessed using weight-bearing and paw-withdrawal tests. CA supplementation significantly reduced pain. The enzyme-linked immunosorbent assay (ELISA) method was used to detect inflammatory proteins in the blood and intra-articular synovial fluid (IASF), and CA reduced the levels of inflammatory proteins. Histopathological studies were performed on knee-tissue samples using toluidine blue and hematoxylin and eosin (H and E) assays. CA treatment improved synovial protection and decreased cartilage degradation while decreasing zonal depth lesions. Furthermore, Western blotting studies revealed that the CA-treated group activated nuclear factor erythroid 2-related factor (Nrf2) and heme oxygenase (HO-1) and reduced the expression of cyclooxygenase-2 (COX-2). FLS cells were isolated from the knee joints and treated with IL-1ß to stimulate the inflammatory response and increase reactive oxygen species (ROS). The matrix metalloproteinase protein (MMP's) levels (MMP-3, and MMP-13) were determined using the reverse transcription-polymerase chain reaction (RT-PCR), and CA treatment reduced the MMP's expression levels. When tested using the 2',7'-dicholorodihydrofluroscene diacetate (DCFDA) assay and the 5,5',6,6'-tetracholoro-1,1',3,3'-tertraethylbenzimidazolcarboc janine iodide (JC-1) assay in augmented ROS FLS cells, CA reduced the ROS levels and improved the mitochondrial membrane permeability. This study's investigation suggests that CA significantly alleviates knee OA both in vitro and in vivo.

Sugammadex reversal of muscle relaxant blockade provided less Post-Anesthesia Care Unit adverse effects than neostigmine/glycopyrrolate.

Sugammadex is a direct reversal agent of aminosteroid muscle relaxants, particularly rocuronium, with promptly and completely reverse of deep neuromuscular block (NMB), which allows better surgical conditions. Sugammadex exhibits advantages over indirect reversal agent acetylcholinesterase inhibitor neostigmine with less adverse effects. In this retrospective review, we compared the incidence of postoperative vomiting (POV), postoperative urinary retention (POUR), and hemodynamic changes between sugammadex and neostigmine/glycopyrrolate in reversal of muscular blockade. Sugammadex showed superior in all three aspects. The heart rate was 7.253 lower (P < 0.0001) and mean arterial pressure was 5.213 lower (P < 0.0001) in sugammadex group. The POV of neostigmine/glycopyrrolate group was 3.16 times more than sugammadex group (OR = 3.16, p < 0.0001), and POUR of neostigmine/glycopyrrolate group was 4.291 times more than sugammadex group (OR = 4.291, p < 0.0001). Sugammadex showed better hemodynamic stability, and lower incidence of POV and POUR than neostigmine/glycopyrrolate.

Preoperative Administration of Extended-Release Dinalbuphine Sebacate Compares with Morphine for Post-Laparoscopic Cholecystectomy Pain Management: A Randomized Study.

PURPOSE: Perioperative pain management plays a critical role in the effort to promote enhanced recovery after surgery (ERAS). Pain is also the most concern for patients after laparoscopic cholecystectomy (LC). Naldebain (extended-release dinalbuphine sebacate, DS) is an oil-based formulation for intramuscular injection that has been designed for extended release and can be used for preoperative analgesia over a 7-day period. This study was aimed to compare the efficacy of DS injection with that of regular postoperative morphine administered when necessary for the management of post-laparoscopic cholecystectomy pain. PATIENTS AND METHODS: Forty-four patients scheduled for elective laparoscopic cholecystectomy were included in this prospective study. The patients were allocated randomly into two groups, with equal numbers receiving preoperative DS versus post-operative morphine. A total of 21 and 22 patients completed the study within the preoperative DS and post-operative morphine group, respectively. RESULTS: There were no statistically significant differences between two treatment groups with respect to length of surgery, anesthetics used during operation, or the average visual analog scale pain score in the post-operative anesthesia care unit (PACU), and at 4, 24, 48, and 72 hours post-procedure. Morphine was required only during the first postoperative day among those in the DS group. Safety was comparable in both DS and morphine groups. CONCLUSION: A single preoperative dose of DS provides sufficient analgesia along with a manageable safety profile and no interference with surgical anesthetics when compared to control cases that underwent surgery without preoperative DS treatment. This pilot study suggests that preoperative administration of DS is safe and may decrease the need for postoperative opioid use after laparoscopic cholecystectomy. REGISTRATION: ClinicalTrials.gov Identifier: NCT03713216.

Pentoxifylline Ameliorates Mechanical Hyperalgesia in a Rat Model of Chemotherapy-Induced Neuropathic Pain.

BACKGROUND: Chemotherapy-induced neuropathic pain is difficult to treat. Pentoxifylline inhibits the production of inflammatory cytokines including tumor necrosis factor α(TNF- α) and interleukin 1ß (IL-1ß). OBJECTIVE: The aims of our study were to investigate the analgesic and preventive effects of pentoxifylline on paclitaxel-induced neuropathic pain in rats and to identify its mechanisms of action. STUDY DESIGN: Controlled animal study. METHODS: Neuropathic pain was induced with intraperitoneally injected paclitaxel on 4 alternate days in male Sprague-Dawley rats. Pentoxifylline was administered systemically as a single injection and a continuous infusion before or after the injection of paclitaxel. The mechanical threshold for allodynia was measured by using von Frey filaments. Protein levels and localization of inflammatory cytokines were performed by using Western blotting and immunohistochemistry, respectively. RESULTS: After the rats developed neuropathic pain behavior, a single intraperitoneal injection and continuous infusion of pentoxifylline ameliorated paclitaxel-induced mechanical allodynia. In addition, systemic infusion of pentoxifylline in the early phase of the development of pain behavior delayed the onset of paclitaxel-induced pain behavior. Paclitaxel increased the levels of the catalytic subunit α of protein kinase A, phosphorylated nuclear factor ;κB, TNF- α, and IL-1κ in the lumbar dorsal root ganglia. Pentoxifylline decreased the paclitaxel-induced TNF- α and IL-1ß levels. In addition, IL-1ß was expressed in neurons and satellite cells in the lumbar dorsal root ganglia after paclitaxel. LIMITATIONS: Although this study was performed in the animal model by well-designed manner, clinical study will be needed to confirm the analgesic effect of pentoxifylline. CONCLUSION: Pentoxifylline alleviated chemotherapy-induced neuropathic pain in rats by reducing the levels of inflammatory cytokines in dorsal root ganglia and may be effective chemotherapy-induced neuropathic pain in patients.

Baicalin ameliorates neuropathic pain by suppressing HDAC1 expression in the spinal cord of spinal nerve ligation rats.

BACKGROUND/PURPOSE: In a recent study, we found that baicalin exhibited a potent analgesic effect on carrageenan-evoked thermal hyperalgesia. The underlining mechanisms may be associated with inhibition of inflammatory mediator overproduction, including proinflammatory cytokines, nitric oxide (NO), and prostaglandin E2 (PGE2). In the present study, we examined the effect of baicalin on the antinociceptive effect of morphine and histone deacetylase 1 (HDAC1) expression in the spinal cord dorsal horn in neuropathic pain rats. METHODS: Neuropathic pain was induced by tight ligation of the left L5 spinal nerve of the rats. An intrathecal catheter was implanted for drug administration. Nociception was assessed by using the plantar test with the Hargreaves radiant heat apparatus, and the von Frey test with the dynamic plantar anesthesiometer. Spinal cords were removed for histone acetyl-H3 and HDAC1 western blot analysis at the end of the nociceptive assessment. RESULTS: The results showed that hyperalgesia and allodynia were observed in the spinal nerve ligated (SNL) left hindlimb; it was companied by histone-H3 deacetylation and HDAC1 overexpression on the ipsilateral side of the spinal cord dorsal horn. Intrathecal injection of baicalin (10 µg) significantly attenuated the allodynia and hyperalgesia, and enhanced the antinociceptive effect of morphine (15 µg). Moreover, baicalin reversed the histone-H3 acetylation and suppressed HDAC1 expression on the ipsilateral side of the spinal cord dorsal horn of SNL rats. CONCLUSION: The present findings suggest that baicalin can ameliorate neuropathic pain by suppressing HDAC1 expression and preventing histone-H3 acetylation in the spinal cord dorsal horn of SNL rats.

Intrathecal ultra-low dose naloxone enhances the antihyperalgesic effects of morphine and attenuates tumor necrosis factor-α and tumor necrosis factor-α receptor 1 expression in the dorsal horn of rats with partial sciatic nerve transection.

BACKGROUND: Glutamate homeostasis and microglia activation play an important role in the development and maintenance of neuropathic pain. We designed this investigation to examine whether ultra-low dose naloxone administered alone or in combination with morphine could alter the concentration of the excitatory amino acids (EAAs) glutamate and aspartate, as well as the expression of tumor necrosis factor-α (TNF-α) and its receptors (TNFR1 and TNFR2) in the spinal cord dorsal horn of rats with partial sciatic nerve transection (PST). METHODS: Male Wistar rats underwent intrathecal catheter implantation for drug delivery and were divided in 7 groups: sham-operated + saline (sham), PST + saline (S), PST + 15 ng naloxone (n), PST + 15 µg naloxone (N), PST + 10 µg morphine (M), PST + 15 ng naloxone + 10 µg morphine (Mn), PST + 15 µg naloxone + 10 µg morphine (MN). Thermal withdrawal latency and mechanical withdrawal threshold, TNF-α and TNFR expression in the spinal cord and dorsal root ganglia, and EAAs glutamate and aspartate concentration in cerebrospinal fluid dialysates were measured. RESULTS: Ten days after PST, rats developed hyperalgesia (P < 0.0001) and allodynia (P < 0.0001), and increased TNF-α (P < 0.0001) and TNFR1 expression (P = 0.0009) were measured in the ipsilateral spinal cord dorsal horn. The antihyperalgesic and antiallodynic effects of morphine (10 µg) were abolished by high-dose naloxone (15 µg; P = 0.0031) but enhanced by ultra-low dose naloxone (15 ng; P = 0.0015), and this was associated with a reduction of TNF-α (P < 0.0001) and TNFR1 (P = 0.0009) expression in the spinal cord dorsal horn and EAAs concentration (glutamate: P = 0.0001; aspartate: P = 0.004) in cerebrospinal fluid dialysate. Analysis of variance (ANOVA) or Student t test with Bonferroni correction were used for statistical analysis. CONCLUSIONS: Ultra-low dose naloxone enhances the antihyperalgesia and antiallodynia effects of morphine in PST rats, possibly by reducing TNF-α and TNFR1 expression, and EAAs concentrations in the spinal dorsal horn. Ultra-low dose naloxone may be a useful adjuvant for increasing the analgesic effect of morphine in neuropathic pain conditions.

Ultra-low-dose naloxone enhances the antinociceptive effect of morphine in PTX-treated rats: regulation on global histone methylation.

OBJECTIVE: Epigenetic reprogramming may have a possible role in neuropathic pain development; the present study examined the global patterns of lysine histone modification. In this serial study we analyzed the levels of histone 3 lysine 4 monomethylation, histone 3 lysine 4 dimethylation, and histone 3 lysine 9 trimethylation in pertussis toxin (PTX)-induced thermal hyperalgesic rat spinal cords. METHODS: Male Wistar rats implanted with an intrathecal catheter received a single intrathecal PTX (1 µg in 5 µl saline) injection. Four days later, they were randomly assigned to receive either a single injection of saline, or ultra-low-dose naloxone (15 ng in 5 µl saline), followed by morphine (10 µg in 5 µl saline) injection 30 minutes later. RESULTS: The results showed that PTX injection induced thermal hyperalgesia and significant increase of global histone methylation in the spinal cords. Intrathecal morphine alone did not affect the thermal hyperalgesia and global histone methylation. In contrast, intrathecal administration of ultra-low-dose naloxone plus morphine significantly attenuated the PTX-induced thermal hyperalgesia and down-regulated the global histone methylation. CONCLUSION: The results suggest that ultra-low-dose naloxone might be clinical valuable for neuropathic pain management via regulating global histone modification.

Perioperative transient ischemic attack caused by the cessation of warfarin.

This paper describes the circumstances of a patient who had been receiving long-term warfarin treatment, but ceased it prior to surgical operation, sustained a transient ischemic heart attack post-operatively, which eventuated in delayed extubation and locked-in syndrome. For patients at low risk of perioperative bleeding, anticoagulation with oral vitamin K antagonist can probably be able to maintain the therapeutic range (INR ≤ 2.0) extreme. For patients with a high risk of bleeding, the international normalized ratio (INR) should be kept ≤ 1.5. Within this range, patients at low risk of thrombosis can discontinue warfarin treatment for 2-5 days pre-operatively; patients at high risk for thrombosis can stop warfarin but should probably be treated with intravenous or subcutaneous heparin when the INR is subtherapeutic.