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We aimed to evaluate the regulatory effects of propofol on high-dose remifentanil-induced hyperalgesia. A total of 180 patients receiving laparoscopic cholecystectomy were randomly divided into sevoflurane + high-dose remifentanil (SH) group, sevoflurane + low-dose remifentanil (SL) group and propofol + high-dose remifentanil group (PH) group (n=60). After intravenous administration of midazolam, SH and SL groups were induced with sevoflurane and remifentanil, and PH group was induced with propofol and remifentanil. During anesthesia maintenance, SH and SL groups were given 0.3 μg/kg/min and 0.1 μg/kg/min sevoflurane and remifentanil respectively, and PH group was given 0.3 μg/kg/min propofol and remifentanil. The three groups had significantly different awakening time, extubation time and total dose of remifentanil (P<0.001). Compared with SL group, periumbilical mechanical pain thresholds 6 h and 24 h after surgery significantly decreased in SH group (P<0.05), and the visual analog scale (VAS) scores significantly increased 30 min, 2 h and 6 h after surgery (P<0.05). Compared with SH group, periumbilical mechanical thresholds 6 h and 24 h after surgery were significantly higher in PH group (P<0.05), and VAS scores 30 min, 2 h and 6 h after surgery were significantly lower (P<0.05). PH group first used patient-controlled intravenous analgesia pump significantly later than SL group did (P<0.05). The total consumptions of sufentanil in PH and SL groups were significantly lower than that of SH group (P<0.05). The incidence rates of bradycardia and postoperative chill in PH and SH groups were significantly higher than those of SL group (P<0.05). Anesthesia by infusion of high-dose remifentanil plus sevoflurane caused postoperative hyperalgesia which was relieved through intravenous anesthesia with propofol.

Our aim was to evauate the application value of esesketamine and dexmedetomidine in preventing postoperative hyperalgesia in elderly patients who received thoracic anesthesia. A total of 94 elderly patients who underwent thoracic anesthesia in Sanmen People's Hospital from January 2021 to October 2022 were selected and divided into a dexmedetomidine group (n = 47) and an esketamine group (n = 47) by the random number table method. All patients were continuously received intravenous (IV) remifentanil. In the dexmedetomidine group, dexmedetomidine 0.7 μg/kg was administered IV, followed by 0.2 to 0.5 μg/kg/h to maintain anesthesia, while in the esketamine group, esketamine 0.5 mg/kg was given IV 20 min after induction of anesthesia was completed. Visual analogue scale (VAS) scores in the esketamine group were lower than in the dexmedetomidine group at 1, 6, 12 and 24 h postoperatively (P < .05), and Ramsay sedation scores were not statistically different from those in the dexmedetomidine group (P > .05). At 3 d postoperatively, the Mini-Mental State Examination (MMSE) scores in the dexmedetomidine group were lower than 1 d preoperatively; at 5 d postoperatively, the negative mood and Pittsburgh Sleep Quality Index (PSQI) scores were significantly higher in both groups than 1 d preoperatively; at 14 d postoperatively, the PSQI scores were higher in both groups than 1 d preoperatively, and there was no statistical difference between the negative mood scores at 1 d before surgery (P > .05). At 5 d postoperatively in the esketamine group, the negative mood scores were lower than in the dexmedetomidine group at 5 d postoperatively and the PSQI scores at 5 and 14 d postoperatively were lower than in the dexmedetomidine group (P < .05). Both esketamine and dexmedetomidine can be used to prevent postoperative delirium and nociceptive hypersensitivity after anesthesia in elderly patients with thoracic surgery. However, esketamine is superior to dexmedetomidine in analgesic effect, improvement of negative mood and sleep and stabilization of intraoperative hemodynamics, leading to better effect in preventing delirium and hyperalgesia after anesthesia.

Opioids are associated with hyperalgesia that can reduce their analgesic effect. The aim of this study was to determine whether the addition of ketamine reduces remifentanil-induced hyperalgesia; improves its analgesic effect; and alters interleukin 6 (IL-6), IL-8, and IL-10 levels. This is a prospective, randomized, double-blind study. The setting is in a operating room and ward in a university hospital. There are 56 patients, aged ≥18 years, American Society of Anesthesiologists I or II, who underwent laparoscopic cholecystectomy. Anesthesia was induced with remifentanil, 50% oxygen, and isoflurane. Patients randomized to group 1 received remifentanil (0.4 μg/kg per minute) and ketamine (5 μg/kg per minute), and patients randomized to group 2 received remifentanil (0.4 μg/kg per minute) and saline solution. Postoperative analgesia was achieved using morphine via patient-controlled analgesia. The measurements were postoperative pain intensity during 24 hours; morphine consumption; time to first morphine supplementation; hyperalgesia (using monofilaments and an algometer) and allodynia (using a soft brush) in the thenar eminence of the nondominant hand and in the periumbilical region 24 hours after surgery; extent of hyperalgesia using a 300-g monofilament near the periumbilical region 24 hours after surgery; and serum levels of IL-6, IL-8, and IL-10. Groups were similar for baseline characteristics. There were no differences in pain intensity, time to first request of morphine, and total 24 hours dose of morphine between groups. There was a difference in hyperalgesia using monofilaments 24 hours after the surgery in the thenar eminence of the nondominant hand, with a better profile for the experimental group. However, there were no differences in hyperalgesia using an algometer, in allodynia using a soft brush; in extent of hyperalgesia; or in levels of IL-6, IL-8, and IL-10. It was not possible to demonstrate that the addition of ketamine (5 μg/kg per minute) is effective in preventing or reducing remifentanil-induced postoperative hyperalgesia in laparoscopic cholecystectomy. •Remifentanil has been associated with postoperative hyperalgesia.•Ketamine reduced remifentanil-induced hyperalgesia at a site distant from the surgery.•Ketamine did not reduce remifentanil-induced hyperalgesia at the incision site.•Ketamine did not reduce inflammatory response in individuals using remifentanil.

Patients with unilateral sciatica have heightened responses to intradermal capsaicin compared to pain-free volunteers. No studies have investigated whether this pain model can screen for novel anti-neuropathic agents in patients with pre-existing neuropathic pain syndromes. This study compared the effects of pregabalin (300 mg) and the tetracycline antibiotic and glial attenuator minocycline (400 mg) on capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia in patients with unilateral sciatica on both their affected and unaffected leg. Eighteen patients with unilateral sciatica completed this randomised, double-blind, placebo-controlled, three-way cross-over study. Participants received a 10 µg dose of capsaicin into the middle section of their calf on both their affected and unaffected leg, separated by an interval of 75 min. Capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were recorded pre-injection and at 5, 20, 40, 60 and 90 min post-injection. Minocycline tended to reduce pre-capsaicin injection values of hyperalgesia in the affected leg by 28% (95% CI 0% to 56%). The area under the effect time curves for capsaicin-induced spontaneous pain, flare, allodynia and hyperalgesia were not affected by either treatment compared to placebo. Significant limb differences were observed for flare (AUC) (-38% in affected leg, 95% CI for difference -19% to -52%). Both hand dominance and sex were significant covariates of response to capsaicin. It cannot be concluded that minocycline is unsuitable for further evaluation as an anti-neuropathic pain drug as pregabalin, our positive control, failed to reduce capsaicin-induced neuropathic pain. However, the anti-hyperalgesic effect of minocycline observed pre-capsaicin injection is promising pilot information to support ongoing research into glial-mediated treatments for neuropathic pain. The differences in flare response between limbs may represent a useful biomarker to further investigate neuropathic pain. Inclusion of a positive control is imperative for the assessment of novel therapies for neuropathic pain.

To evaluate the effects of low-dose butorphanol on hyperalgesia induced by high-dose remifetanil in patients undergoing laparoscopic cholecystectomy. Randomized double-blind clinical trial. Intraoperative. Seventy-five patients scheduled for laparoscopic cholecystectomy were enrolled. Randomly allocated into 3 groups, low dose of remifentanil (LR) group and high dose of remifentanil (HR) group received low (0.1μg kg−1 min−1) or high (0.3μg kg−1 min−1) doses of remifentanil, respectively, and butorphanol combined with remifentanil (BR) group received remifentanil (0.3μg kg−1 min−1) and butorphanol (0.2μg/kg). The visual analog scale scores and cumulative consumption of fentanyl were recorded. Visual analog scale scores were significantly higher in the HR group than in the LR and BR groups (P<.001). The dose of intravenously given fentanyl was significantly higher in the HR group than in the LR and BR groups (P<.001). In addition, the HR group showed a significantly higher cumulative consumption of fentanyl during 5 to 8 hours after the operation (P<.001). A high dose of remifentanil induces postoperative hyperalgesia, which could be prevented by a continuous intravenous administration of a low dose of butorphanol. •Remifentanil enhances postoperative pain through the activation of mu-opioid receptor.•High dose of remifentanil during laparoscopic cholecystectomy induced postoperative hyperalgesia.•Low dose of butorphanol prevented remifentanil-induced postoperative hyperalgesia.

Background and Objectives:Tissue injury is associated with the local release of inflammatory and nociceptive mediators and the development of hyperalgesia. It is unclear whether interrupting neuronal signaling using regional anesthetic techniques at the time of the injury modifies local nociceptive and inflammatory processes. The aim of this study was to determine whether a peripheral nerve block at the time of tissue injury could modify the development of wound hyperalgesia and the local release of inflammatory and nociceptive mediators.Methods:Twelve healthy volunteers participated in this controlled, crossover, randomized study. A femoral nerve block or a sham block was established before inducing an experimental UVB burn on the thigh. Twenty-four hours later, the interstitial wound fluid was sampled, and mechanical and heat pain thresholds were assessed. Wound fluid concentrations of an array of cytokines, chemokines, nerve growth factor, prostaglandin E2, and substance P were determined.Results:Skin inflammation was associated with the release of inflammatory and nociceptive mediators and resulted in significant tissue hyperalgesia (P < 0.001). However, the presence of a fully established peripheral nerve block at the time of tissue injury did not alter the development of hyperalgesia after regression of the block. Similarly, the presence of a peripheral nerve block did not modify the release of inflammatory or nociceptive mediators.Conclusions:These findings suggest that a preemptive, single-shot peripheral nerve block minimally affects wound hyperalgesia and inflammation. Continuous nerve block techniques may be better suited to alter nociceptive and inflammatory events in wounds beyond the duration of the block.

Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable. Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume ∆9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum. Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups. Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine. This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models.

Lidocaine is an amide local anaesthetic initially used intravenously as an antiarrhythmic agent. At some point it was proposed that intravenous lidocaine (IVL) had an analgesic effect that could be potentially beneficial in perioperative settings. Since these preliminary reports, a large body of evidence confirmed that IVL had anti-inflammatory and opiate-sparing effects, a combination of characteristics leading to an array of effects such as a decrease in postoperative pain and opiate consumption, and a reduction in the duration of digestive ileus. Additional studies demonstrated IVL to possess antithrombotic, antimicrobial and antitumoral effects. Beneficial effects of IVL have been characterized in abdominal surgery but remain controversial in other types of surgeries. Because the quality of evidence was limited, due to inconsistency, imprecision and study quality, recent conclusions from meta-analysis pooling together all types of surgery stated the uncertainty about IVL benefits. Additional indications such as the prevention of propofol-induced injection pain, prevention of hyperalgesia, protection against bronchial reactivity by bronchotracheal relaxation during surgery, and the increase in depth of general anaesthesia have since emerged. IVL is rapidly distributed in the body and metabolized by the liver. With the commonly recommended doses, lidocaine’s therapeutic index remains very high and the plasma concentrations stay largely below the cardiotoxic and neurotoxic threshold levels, a notion that may be used by clinicians to draw conclusions on the benefit-risk profile of IVL in comparison to other analgesic strategies. The purpose of this review is to address the pharmacokinetic and pharmacodynamic properties of lidocaine in healthy and pathological conditions.

BackgroundTaxanes such as paclitaxel (PTX) induce dose-dependent chemotherapy-induced peripheral neuropathy (CIPN), which is associated with debilitating chronic pain and gait impairment. Increased macrophage-related proinflammatory activities have been reported to mediate the development and maintenance of neuropathic pain. While spinal cord stimulation (SCS) has been used for a number of pain conditions, the mechanisms supporting its use for CIPN remain to be elucidated. Thus, we aimed to examine whether SCS can attenuate Schwann cell-mediated and macrophage-mediated neuroinflammation in the sciatic nerve of Rowlette Nude (RNU) rats with PTX-induced gait impairment and mechanical hypersensitivity.MethodsAdult male tumor-bearing RNU rats were used for this study examining PTX treatment and SCS. Gait and mechanical hypersensitivity were assessed weekly. Cytokines, gene expression, macrophage infiltration and polarization, nerve morphology and Schwann cells were examined in sciatic nerves using multiplex immunoassay, bulk RNA sequencing, histochemistry and immunohistochemistry techniques.ResultsSCS (50 Hz, 0.2 milliseconds, 80% motor threshold) attenuated the development of mechanical hypersensitivity (20.93±0.80 vs 12.23±2.71 grams, p<0.0096) and temporal gait impairment [swing (90.41±7.03 vs 117.27±9.71%, p<0.0076), and single stance times (94.92±3.62 vs 112.75±7.27%, p<0.0245)] induced by PTX (SCS+PTX+Tumor vs Sham SCS+PTX+Tumor). SCS also attenuated the reduction in Schwann cells, myelin thickness and increased the concentration of anti-inflammatory cytokine interleukin (IL)−10. Bulk RNA sequencing revealed differential gene expression after SCS, with 607 (59.2%) genes upregulated while 418 (40.8%) genes were downregulated. Notably, genes related to anti-inflammatory cytokines and neuronal growth were upregulated, while genes related to proinflammatory-promoting genes, increased M2γ polarization and decreased macrophage infiltration and Schwann cell loss were downregulated.ConclusionSCS may attenuate PTX-induced pain and temporal gait impairment, which may be partly attributed to decreases in Schwann cell loss and macrophage-mediated neuroinflammation in sciatic nerves.

Chemotherapy-induced peripheral neuropathy is among the most common dose-limiting adverse effects of cancer treatment, leading to dose reduction and discontinuation of life-saving chemotherapy and a permanently impaired quality of life for patients. Currently, no effective treatment or prevention is available. Senescence induced during cancer treatment has been shown to promote the adverse effects. Here, we show that cisplatin induces senescent-like neuronal cells in primary culture and in mouse dorsal root ganglia (DRG), as determined by the characteristic senescence markers including senescence-associated beta-galactosidase, accumulation of cytosolic p16 INK4A and HMGB1, as well as increased expression of p16Ink4a, p21, and MMP-9. The accumulation of senescent-like neuronal cells in DRG is associated with cisplatin-induced peripheral neuropathy (CIPN) in mice. To determine if depletion of senescent-like neuronal cells may effectively mitigate CIPN, we used a pharmacological ‘senolytic’ agent, ABT263, which inhibits the anti-apoptotic proteins BCL-2 and BCL-xL and selectively kills senescent cells. Our results demonstrated that clearance of DRG senescent neuronal cells reverses CIPN, suggesting that senescent-like neurons play a role in CIPN pathogenesis. This finding was further validated using transgenic p16-3MR mice, which permit ganciclovir (GCV) to selectively kill senescent cells expressing herpes simplex virus 1 thymidine kinase (HSV-TK). We showed that CIPN was alleviated upon GCV administration to p16-3MR mice. Together, the results suggest that clearance of senescent DRG neuronal cells following platinum-based cancer treatment might be an effective therapy for the debilitating side effect of CIPN.