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HYR-PB21-LA, a potential extended-release bupivacaine formulation, produces long-lasting local anesthesia in rats and guinea pigs

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (5)

Background Effective postoperative pain management plays a key role in enhancing recovery of patients after surgery. Bupivacaine hydrochloride is one of the most commonly local anesthetics used for the postoperative pain control. However, the relatively short anesthesia duration of bupivacaine preparations limited their clinical application. Methods Both guinea pig pin-prick study and rat tail-flick test were performed to evaluate the local anesthesia efficacy of HYR-PB21-LA, a new microparticle suspension injection of bupivacaine pamoate. Results In the pin-prick test, the complete cutaneous trunci muscle reflex inhibitions were observed at 30 min in all treatment groups containing bupivacaine. In comparison with 6.7 mg/mL HYR-PB21-LA, both 10 and 20 mg/mL HYR-PB21-LA groups had significantly higher area under effect time curve (AUEC) values (p<0.001 and p<0.0001) and slower offset time (p<0.0001). Significantly higher AUEC (p<0.0001) and slower offset time (p<0.0001) were also found in 10 mg/mL HYR-PB21-LA treatment group compared with bupivacaine liposome injectable suspension (liposomal bupivacaine). In the rat tail-flick test, significantly increased local anesthesia effect was lasted for 5 hours after 2.5 mg/mL HYR-PB21-LA administration, which was fivefold longer than bupivacaine hydrochloride. The longer lasted efficacy of significantly increased local anesthesia was also observed in 5 mg/mLHYR-PB21-LA than those in liposomal bupivacaine (8 hour vs 1 hour). Conclusions The results demonstrated that the HYR-PB21-LA produced longer local anesthesia effect than current clinical preparations of bupivacaine in two animal models. These findings raise the potential clinical value of HYR-PB21-LA as a long-lasting local anesthesia for controlling postsurgical pain in humans.

High definition ultrasound imaging of the individual elements of the brachial plexus above the clavicle

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (5)

Background and objectives Ultrasonography of the brachial plexus (BP) has been described but there are limited data on visualization of the T1 ventral ramus and the inferior trunk. This prospective observational study aimed to evaluate a high definition ultrasound imaging technique to systematically identify the individual elements of the BP above the clavicle. Methods Five healthy young volunteers underwent high definition ultrasound imaging of the BP above the clavicle. The ultrasound scan sequence (transverse oblique scan) commenced at the supraclavicular fossa after which the transducer was slowly swept cranially to the upper part of the interscalene groove and then in the reverse direction to the supraclavicular fossa. The unique sonomorphology of the C7 transverse process was used as the key anatomic landmark to identify the individual elements of the BP in the recorded sonograms. Results The neural elements of the BP that were identified in all volunteers included the ventral rami of C5-T1, the three trunks, divisions of the superior trunk, and formation of the inferior trunk (C8-T1). The C6 ventral ramus exhibited echogenic internal septation with a split (bifid) appearance in four of the five volunteers. In three of the four volunteers with a bifid C6 ventral ramus, the C7 ventral ramus was also bifid. Conclusion We have demonstrated that it is feasible to accurately identify majority of the main components of the BP above the clavicle, including the T1 ventral ramus and the formation of the inferior trunk, using high definition ultrasound imaging.

Serotonin-norepinephrine reuptake inhibitors for the prevention of migraine and vestibular migraine: a systematic review and meta-analysis

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (5)

Background and objectives The role of serotonin-norepinephrine reuptake inhibitors (SNRIs) in migraine prophylaxis has not been completely established. Current treatments for vestibular migraine (VM) are based on scarce evidence. We aimed to perform an updated review focusing on the efficacy and tolerability of SNRIs for migraine and VM prevention. Methods We searched the PubMed, Web of Science, and Cochrane Library databases for relevant studies. The primary outcome was migraine frequency. In the case of VM, the Dizziness Handicap Inventory (DHI) scores and Vertigo Severity Scores (VSSs) were extracted. Results Six randomized controlled trials involving 418 patients were analyzed. Patients receiving SNRIs had fewer migraine days than those receiving a placebo (standardized mean difference -0.38, 95% CI -0.76 to -0.01, p=0.04). The effects of SNRIs and other active drugs were comparable. In patients with VM, venlafaxine had a significant advantage over other active drugs in decreasing the VSS (weighted mean difference (MD) -1.45, 95% CI -2.11 to -0.78, p<0.0001) and the emotional domain score of the DHI (MD -2.64, 95% CI -4.97 to -0.31, p=0.03). We found no significant difference in the rate of withdrawals due to any reason or withdrawals due to side effects between SNRIs and active drugs and between SNRIs and a placebo. Conclusions SNRIs were clinically safe and effective for migraine and VM prophylaxis, were better than a placebo, and not inferior to other active drugs. SNRIs may be a preferable choice for patients with VM with psychiatric disorders.

Regulation of the K-ATP-JNK gap junction signaling pathway by immunomodulator astragaloside IV attenuates neuropathic pain

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (12)

Background and objectives Gap junctions play a pivotal role in contributing to the formation of astroglial networks and in chronic pain. However, the mechanisms underlying the dysfunction of astroglial gap junctions in chronic pain have not been fully elucidated. Methods Chronic constriction injury (CCI) of the sciatic nerve was used to establish rat neuropathic pain model. C6 cells were used to perform experiments in vitro. Von Frey hairs and Hargreave's method were used to determine the withdrawal threshold of rats. Protein expression was detected by immunofluorescence and western blotting. Results Astragaloside IV (AST IV) significantly attenuated neuropathic pain and suppressed the excitation of spinal astrocytes in rats with CCI. The antinociceptive effect of AST IV was reversed by the gap junction decoupler carbenoxolone (CBX). AST IV inhibited the high expression of phosphorylated connexin 43 (p-Cx43) and p-c-Jun N-terminal kinase (p-JNK) in spinal cord of rats with CCI. JNK inhibitor alleviated neuropathic pain, which was reversed by CBX. JNK inhibitor decreased the high expression of p-Cx43 in both rats with CCI and tumor necrosis factor-alpha (TNF-alpha)-treated C6 cells. Additionally, the analgesic effect of AST IV was reversed by the adenosine triphosphate-sensitive potassium (K-ATP) channel blocker, glibenclamide (Glib). Glib abolished the inhibitory effects of AST IV on p-JNK and p-Cx43 both in vivo and in vitro. K-ATP channel opener (KCO) mimicked the inhibitory effects of AST IV on p-JNK and p-Cx43 in TNF-alpha-treated C6 cells. Conclusion Our results indicate that the sciatic nerve CCI induces the dysfunction of gap junctions in the spinal cord by activating K-ATP/JNK signaling to contribute to neuropathic pain. AST IV attenuates neuropathic pain via regulating the K-ATP-JNK gap junction axis.

5-HT1A receptor-mediated attenuation of heat hyperalgesia and mechanical allodynia by chrysin in mice with experimental mononeuropathy

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (8)

Background Persistent neuropathic pain poses a health problem, for which effective therapy or antidote is in dire need. This work aimed to investigate the pain-relieving effect of chrysin, a natural flavonoid with monoamine oxidase inhibitory activity, in an experimental model of neuropathic pain and elucidate mechanism(s). Methods Chronic constriction injury (CCI) was produced by loose ligation of sciatic nerve in mice. The pain-related behaviors were examined using von Frey test and Hargreaves test. The serotonin-related mechanisms were investigated by serotonin depletion with p-chlorophenylalanine (PCPA) and antagonist tests in vivo and in vitro. Results Repeated treatment of CCI mice with chrysin (orally, two times per day for 2 weeks) ameliorated heat hyperalgesia and mechanical allodynia in a dose-dependent fashion (3-30 mg/kg). The chrysin-triggered pain relief seems serotonergically dependent, since its antihyperalgesic and antiallodynic actions were abolished by chemical depletion of serotonin by PCPA, whereas potentiated by 5-hydroxytryptophan (a precursor of 5-HT). Consistently, chrysin-treated neuropathic mice showed enhanced levels of spinal monoamines especially 5-HT, with depressed monoamine oxidase activity. Moreover, chrysin-evoked pain relief was preferentially counteracted by 5-HT1A receptor antagonist WAY-100635 delivered systematically or spinally. In vitro, chrysin (0.1-10 nM) increased the maximum effect (Emax, shown as stimulation of [S-35] GTP gamma S binding) of 8-OH-DPAT, a 5-HT1A agonist. Beneficially, chrysin was able to correct comorbid behavioral symptoms of depression and anxiety evoked by neuropathic pain, without causing hypertensive crisis (known as 'cheese reaction'). Conclusion These findings confirm the antihyperalgesic and antiallodynic efficacies of chrysin, with spinal 5-HT1A receptors being critically engaged.

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood-spinal cord barrier

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (10)

Background Disruption of the blood-spinal cord barrier (BSCB) can facilitate inflammation that results in pain hypersensitivity. Proinflammatory cytokines produced by activated microglia and astrocytes damage the BSCB. This study aims to explore whether the BSCB is damaged in the bone cancer pain (BCP) model and to investigate a potential role and mechanism of JWH015 ((2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone), a selective cannabinoid receptor 2 (CB2R) agonist, in preserving the BSCB integrity in the BCP model. Methods We used a male mouse model of BCP. Pain hypersensitivity was measured over time. Evans blue dye extravasation, transmission electron microscopy and Western blotting were performed to investigate the permeability and structural integrity of the BSCB. Immunofluorescence staining and western blotting were used to investigate the effect of JWH015 on the activation of glial cells and the levels of proinflammatory cytokines. Results A single intrathecal injection of JWH015 ameliorated pain hypersensitivity, the BSCB disruption and microglia and astrocyte activation. Decreases in the expression of ZO-1 and claudin-5 were partially restored by JWH015. The levels of the proinflammatory cytokines interleukin-1 beta and tumor necrosis factor-a and the enzyme MMP9 were reduced by JWH015. However, all effects were prevented by pretreatment with a CB2R-selective antagonist, AM630 ((6-iodo-2-methyl1-(2-morpholinoethyl)-1H-indol-3-yl)(4-methoxyphenyl) methanone). Conclusions JWH015 alleviates neuroinflammation and maintains the BSCB integrity and permeability in a mouse model of BCP, which is probably mediated by inhibiting glial cells activation. This study reveals the new analgesic mechanism of JWH015 on BCP and provides a perspective to explore novel drugs that target the BSCB to control BCP.

Efficacy of ultrasound-guided erector spinae plane block on postoperative quality of recovery and analgesia after modified radical mastectomy: randomized controlled trial

期刊: REGIONAL ANESTHESIA AND PAIN MEDICINE, 2020; 45 (1)

Background Erector spinae plane block (ESPB) is a novel regional anesthesia technique that is gaining popularity for postoperative pain management. This randomized controlled trial evaluated the effect of ESPB on quality of recovery (QoR) in patients undergoing modified radical mastectomy. Methods Eighty-two female patients undergoing modified radical mastectomy were included. Patients were randomly assigned to receive preoperative ultrasound-guided ESPB with either 0.5% ropivacaine or saline. The primary outcome was QoR, assessed 24 hours postoperatively using the 15-item QoR questionnaire (QoR-15). Secondary outcomes included postoperative pain scores, postoperative cumulative opioid consumption, postanesthesia care unit (PACU) discharge time, postoperative nausea or vomiting and dizziness. Results Global QoR-15 scores 24 hours postoperatively were significantly higher (indicating better quality) in the ESPB group (median 120, IQR 118-124) compared with the control group (median 110, IQR 108.3-112.8), with a median difference of 10 (95% CI 9 to 12, p<0.001). Compared with the control group, ESPB with ropivacaine reduced pain scores up to 8 hours after surgery, as well as reduced postoperative cumulative opioid consumption and PACU discharge time. Conclusions A single preoperative injection of ESPB with ropivacaine may improve QoR postoperatively and acute postoperative analgesia in patients undergoing a modified radical mastectomy.

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