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Chronic pain, which affects more than one-third of the world's population, represents one of the greatest medical challenges of the 21st century, yet its effective management remains sub-optimal. The 'gold standard' for the treatment of moderate to severe pain consists of opioid ligands, such as morphine and fentanyl, that target the µ-opioid receptor (MOP). Paradoxically, these opioids also cause serious side effects, including constipation, respiratory depression, tolerance, and addiction. In addition, the development of opioid-use disorders, such as opioid diversion, misuse, and abuse, has led to the current opioid crisis, with dramatic increases in addiction, overdoses, and ultimately deaths. As pain is a complex, multidimensional experience involving a variety of pathways and mediators, dual or multitarget ligands that can bind to more than one receptor and exert complementary analgesic effects, represent a promising avenue for pain relief. Indeed, unlike monomodal therapeutic approaches, the modulation of several endogenous nociceptive systems can often result in an additive or even synergistic effect, thereby improving the analgesic-to-side-effect ratio. Here, we provide a comprehensive overview of research efforts towards the development of dual- or multi-targeting opioid/nonopioid hybrid ligands for effective and safer pain management. We reflect on the underpinning discovery rationale by discussing the design, medicinal chemistry, and in vivo pharmacological effects of multitarget antinociceptive compounds., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

This study examined the effect of acute acetaminophen (ACTP) ingestion on physical performance during the 5 m shuttle run test (5mSRT), attention, mood states, and the perception of perceived exertion (RPE), pain (PP), recovery (PRS), and delayed onset of muscle soreness (DOMS) in well-trained female athletes. In a randomized, placebo-controlled, double-blind, crossover trial, fifteen well-trained female athletes (age 21 ± 2 years, height 165 ± 6 cm, body mass 62 ± 5 kg) swallowed either 1.5 g of ACTP or 1.5 g of placebo. The profile of mood states (POMS) and digit cancellation (DCT) were assessed 45 min postingestion, and 5mSRT was performed 60 min postingestion. The RPE and PP were determined immediately after each 30-s repetition of the 5mSRT, and the PRS and DOMS were recorded at 5 min and 24 h post-5mSRT. For the 5mSRT, ACTP ingestion improved the greatest distance (+ 10.88%, p < 0.001), total distance (+ 11.33%, p = 0.0007) and fatigue index (+ 21.43%, p = 0.0003) compared to PLA. Likewise, the DCT score was better on the ACTP (p = 0.0007) than on the PLA. RPE, PP, PRS, and DOMS scores were improved after ACTP ingestion (p < 0.01 for all comparisons) compared to PLA. POMS scores were enhanced with ACTP ingestion compared to PLA (p < 0.01). In conclusion, this study indicates that acute acetaminophen ingestion can improve repeated high intensity short-term maximal performance, attention, mood states, and perceptions of exertion, pain, recovery, and muscle soreness in well-trained female athletes, suggesting potential benefits for their overall athletic performance and mood state., (© 2024. The Author(s).)

Purpose: Emerging data suggest that acetaminophen lowers intraocular pressure (IOP) and has the potential to be repurposed as pharmacotherapy to treat open-angle glaucoma. However, pharmacokinetic data are lacking. This study aims to describe the pharmacokinetics of topical acetaminophen and its metabolite [ N -arachidonoylaminophenol (AM404)] when administered individually and in combination, and to determine its effect on IOP in the ocular normotensive adult New Zealand White Rabbit (NZWR). Methods: A randomized control trial was conducted using topical 1% acetaminophen and 1% AM404. The study was divided into two sub-studies using both paired-eye and two-eye designs. Results: The mean [95% confidence interval of the mean (95% CI)] concentration of acetaminophen detected in the aqueous humor (AH) was 4.09 ppm (3.18-5.00) at 2 h and 0.92 ppm (0.60-1.24) at 4 h after an immediate dose of topical acetaminophen. The integral IOP, defined as the integral of IOP change from baseline over time, was -5.1 mmHg⋅h (95% CI: -10 to 0.41) for control,-7.5 mmHg⋅h (95% CI: -14 to -1.1) for half-hourly acetaminophen, and -4.4 mmHg⋅h (95% CI: -14 to 5.5) for hourly acetaminophen over a 4-h period. When comparing topical acetaminophen with AM404 dosed half-hourly over a 4-h period, the integral IOP was -2.3 mmHg⋅h (95% CI: -5.9 to 1.3) for control,-2.0 mmHg⋅h (95% CI: -5.6 to 1.7) for AM404, -1.7 mmHg⋅h (95% CI: -4.5 to 1.2) for acetaminophen, and -3.2 mmHg⋅h (95% CI: -5.4 to -0.96) for acetaminophen/AM404 combined. Conclusions: Acetaminophen, but not its metabolite AM404, penetrated the multilayered cornea via passive diffusion in a dose-dependent fashion. There was a nonsignificant tendency to cause a lowering of IOP over the 4-h dosing period with higher AH concentrations of acetaminophen. Topical AM404 did not show a significant IOP-lowering effect.

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100 mg/kg), acetaminophen (100 and 300 mg/kg) and codeine (3 and 10 mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control., Competing Interests: Declarations. Ethics approval: All procedures involving animals were approved by UFPR Ethics Committee (CEUA/BIO-UFPR #1464). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background and Purpose: The analgesic action of paracetamol involves K V 7 channels, and its metabolite N-acetyl-p-benzo quinone imine (NAPQI), a cysteine modifying reagent, was shown to increase currents through such channels in nociceptors. Modification of cysteine residues by N-ethylmaleimide, H 2 O 2 , or nitric oxide has been found to modulate currents through K V 7 channels. The study aims to identify whether, and if so which, cysteine residues in neuronal K V 7 channels might be responsible for the effects of NAPQI., Experimental Approach: To address this question, we used a combination of perforated patch-clamp recordings, site-directed mutagenesis, and mass spectrometry applied to recombinant K V 7.1 to K V 7.5 channels., Key Results: Currents through the cardiac subtype K V 7.1 were reduced by NAPQI. Currents through all other subtypes were increased, either by an isolated shift of the channel voltage dependence to more negative values (K V 7.3) or by such a shift combined with increased maximal current levels (K V 7.2, K V 7.4, K V 7.5). A stretch of three cysteine residues in the S2-S3 linker region of K V 7.2 was necessary and sufficient to mediate these effects., Conclusion and Implication: The paracetamol metabolite N-acetyl-p-benzo quinone imine (NAPQI) modifies cysteine residues of K V 7 subunits and reinforces channel gating in homomeric and heteromeric K V 7.2 to K V 7.5, but not in K V 7.1 channels. In K V 7.2, a triple cysteine motif located within the S2-S3 linker region mediates this reinforcement that can be expected to reduce the excitability of nociceptors and to mediate antinociceptive actions of paracetamol., (© 2024 The Authors. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

The aim of this study was to evaluate whether a constant rate infusion of dexmedetomidine could prolong the analgesic effect of peripheral nerve blocks. Twenty client-owned dogs were enrolled and randomly divided into 2 groups. The DEX group received dexmedetomidine infusion at 1 mcg kg -1  h -1 , and the NaCl group received an equivalent volume infusion of saline. Infusions were started after securing vascular access and continued for 10 min, after which intravenous (IV) methadone at 0.2 mg kg -1 and propofol to effect were administered. All animals were maintained with isoflurane in 70% oxygen. Sciatic, saphenous and obturator nerve blocks were performed using 0.1 mL kg -1 0.5% ropivacaine/block. Intraoperative fentanyl was administered if the heart rate and/or mean arterial pressure (MAP) increased > 15% from the previous measurement, and vasopressors were administered if MAP was ≤ 70 mmHg. Postoperative pain was assessed every hour using the Glasgow Composite Pain Scale (GCPS) until the first rescue analgesia administration. Postoperative rescue analgesia (methadone (0.2 mg kg -1 IV) and carprofen (2 mg kg -1 IV)) was administered if the pain score was higher than 6/24 or 5/20. Duration of analgesia was defined as the time between the nerve block procedure and initial postoperative rescue analgesia. Ambulation, proprioception, and skin sensitivity were evaluated to assess the duration of the motor and sensory block. A Student T and chi-square test were used to compare groups for duration of postoperative analgesia and intraoperative fentanyl and vasopressor use, respectively (p values ≤ 0.5 considered significant). A greater number of dogs in the NaCl group required fentanyl (5/10 p = 0.03) and vasopressors (8/10, p = 0.02) than did those in the DEX group (0/10 and 2/10, respectively). The duration of postoperative analgesia was significantly longer (604 ± 130 min) in the DEX group than in the NaCl group (400 ± 81 min, p = 0.0005).Dexmedetomidine infusion at 1 mcg kg -1  h -1 delays the time to first administration of rescue analgesia and reduces intraoperative analgesic and vasopressor requirements during Tibial Tuberosity Advancement surgery., (© 2024. The Author(s).)

Acetaminophen is a known antipyretic and non-opioid analgesic for mild pain and fever. Numerous studies uncover their hidden chemotherapeutics applications, including chronic cancer pain management. Acetaminophen also represents an anti-proliferative effect in some cancer cells. Few studies also suggest that the use of Acetaminophen can trigger apoptosis and impede cellular growth. However, Acetaminophen's molecular potential and precise mechanism against improper cellular proliferation and use as an effective anti-proliferative agent still need to be better understood. Here, our current findings show that Acetaminophen induces proteasomal dysfunctions, resulting in aberrant protein accumulation and mitochondrial abnormalities, and consequently induces cell apoptosis. We observed that the Acetaminophen treatment leads to improper aggregation of ubiquitylated expanded polyglutamine proteins, which may be due to the dysfunctions of proteasome activities. Our in-silico analysis suggests the interaction of Acetaminophen and proteasome. Furthermore, we demonstrated the accumulation of proteasome substrates and the depletion of proteasome activities after treating Acetaminophen in cells. Acetaminophen induces proteasome dysfunctions and mitochondrial abnormalities, leading to pro-apoptotic morphological changes and apoptosis successively. These results suggest that Acetaminophen can induce cell death and may retain a promising anti-proliferative effect. These observations can open new possible molecular strategies in the near future for developing and designing specific and effective proteasome inhibitors, which can be helpful in conjugation with other anti-tumor drugs for their better efficiency., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Copyright © 2024. Published by Elsevier Inc.)

Acetaminophen (paracetamol) is one of the most popular analgesics for the management of fever and pain but few reports have investigated its antidepressant-like effect. Moreover, the role of the opioidergic pathway has been indicated in depression pathophysiology. This study aimed to examine the involvement of the opioid receptors in the antidepressant-like effect of acetaminophen after acute and sub-chronic administration using mice forced swimming test (FST). Our finding showed that administration of acetaminophen (50 and 100 mg/kg, i.p.) 30 min before the FST produced an antidepressant effect which was reduced by naloxone (1 mg/kg, i.p., a nonselective opioid receptor antagonist). Moreover, we observed that acetaminophen in higher doses (200 and 400 mg/kg) was ineffective. Also, the response of the non-effective dose of acetaminophen (25 mg/kg) was potentiated by the non-effective dose of morphine (0.1 mg/kg) in the FST that was antagonized by naloxone. Also, in contrast to morphine (10 mg/kg), acetaminophen (100 mg/kg, i.p.) induced neither tolerance to the anti-immobility behavior nor withdrawal syndrome after repeated administration. In addition, RT-PCR showed that hippocampal mu- and kappa-opioid receptor mRNA expression increased in mice after repeated administration of acetaminophen; however, morphine therapy for 6 days did not affect kappa-opioid receptor expression. Our findings demonstrated that acetaminophen in lower doses but not high doses revealed an antidepressant-like activity without inducing tolerance and withdrawal syndromes. Moreover, the observed effect of acetaminophen may be via altering the opioid system, particularly hippocampal mu- and kappa-receptors., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: A single administration of the opioid receptor antagonist methocinnamox (MCAM) antagonizes the antinociceptive effects of µ-opioid receptor agonists for 2 weeks or longer. Such a long duration of antagonism could necessitate the use of nonopioid drugs for treating pain in patients receiving MCAM for opioid use disorder (OUD)., Methods: The antinociceptive effects of fentanyl and nonopioid drugs were assessed in 24 male Sprague Dawley rats using a complete Freund's adjuvant (CFA) model of inflammatory pain. Twelve rats received 10mg/kg MCAM and 12 received vehicle; half (n=6) of the animals from each treatment group were treated (intraplantar) with CFA or saline. Hypersensitivity to mechanical stimulation was measured using a von Frey anesthesiometer. Fentanyl (0.01-0.1mg/kg), ketamine (17.8-56mg/kg), gabapentin (32-100mg/kg), meloxicam (3.2-10mg/kg), and ∆ 9 -tetrahydrocannabinol (THC, 1-10mg/kg) were administered intraperitoneally and tested every 3 days in a pseudorandom order. Next, the same drugs were studied for effects on motor performance using a rotarod apparatus., Results: CFA-induced hypersensitivity was attenuated by fentanyl in vehicle- but not MCAM-treated rats. THC, ketamine, and gabapentin attenuated (up to 82, 66, and 46 %, respectively) CFA-evoked mechanical hypersensitivity in both MCAM- and vehicle-treated rats. Meloxicam failed to alter CFA-evoked mechanical hypersensitivity in either group. Fentanyl, THC, gabapentin, and meloxicam did not affect motor performance in either group whereas ketamine impaired motor performance in both groups (up to 71 % reduction in latency to fall)., Conclusions: These data suggest that ketamine, gabapentin, and THC could be effective for treating inflammatory pain under conditions of long term µ-opioid receptor antagonism., Competing Interests: Declaration of Competing Interest CPF is co-holder of a US Patent for methocinnamox (MCAM). Other authors have no declarations of interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: This study examined the cutaneous analgesic effects of lidocaine co-injected with guanfacine and its comparison with dexmedetomidine., Methods: Cutaneous analgesic effects are quantified through the blocking effects of the cutaneous trunci muscle reflex against skin pinpricks in rats. The dose-response curves of guanfacine, dexmedetomidine, and lidocaine were constructed and drug-drug interactions were analyzed by the ED 50 isobologram., Results: Subcutaneous injections of guanfacine, dexmedetomidine, and lidocaine produced dose-dependently nociceptive/sensory blockade. On the ED 50 (50% effective dose) basis, the potency rankings of the drug are dexmedetomidine (0.09 [0.08-0.11] μmol/kg) > guanfacine (3.98 [2.96-5.34] μmol/kg) > lidocaine (25.40 [23.51-27.44] μmol/kg) ( p  < 0.01). On their equipotent doses (ED 25 , ED 50 , and ED 75 ), the duration of sensory blockade induced by guanfacine or dexmedetomidine was longer than lidocaine's ( p  < 0.01). Both guanfacine and dexmedetomidine showed synergistic effects with lidocaine., Conclusions: We showed that guanfacine elicits dose-dependent cutaneous analgesia when administered subcutaneously. Lidocaine is less potent than guanfacine or dexmedetomidine. Both guanfacine and dexmedetomidine enhance the potency and duration of lidocaine. Better synergistic responses we are getting with guanfacine plus lidocaine.

Pain management in neonates continues to be a challenge. Diverse therapies are available that cause loss of pain sensitivity. However, because of side effects, the search for better options remains open. Dexmedetomidine is a promising drug; it has shown high efficacy with a good safety profile in sedation and analgesia in the immature nervous system. Though dexmedetomidine is already in use for pain control in neonates (including premature neonates) and infants as an adjunct to other anesthetics, the question remains whether it affects the neuronal activity patterning that is critical for development of the immature nervous system. In this study, using the neonatal rat as a model, the pharmacodynamic effects of dexmedetomidine on the nervous and cardiorespiratory systems were studied. Our results showed that dexmedetomidine has pronounced analgesic effects in the neonatal rat pups, and also weakly modified both the immature network patterns of cortical and hippocampal activity and the physiology of sleep cycles. Though the respiration and heart rates were slightly reduced after dexmedetomidine administration, it might be considered as the preferential independent short-term therapy for pain management in the immature and developing brain.

Context: For successfully managing pediatric dental patients, local anesthesia is essential to eliminate pain during or after the operative period. An early recovery from soft-tissue anesthesia after an inferior alveolar nerve block (IANB) should benefit a young child patient by avoiding the risk of inadvertently biting the soft tissues., Aims: Hence, the purpose of the study was to (1) evaluate and compare the efficacy of pre- and postoperative ibuprofen on pain perception in children who undergo IANB anesthesia with or without the use of PM and (2) evaluate the average time required for reversal of anesthesia symptoms using phentolamine mesylate., Methods: The present study was a randomized, clinical trial performed among 60 children between 6 and 8 years of age using a convenient sampling method. The children were randomly assigned into four equal groups of 15 each using the computer-generated randomization sequence. IANB anesthesia was performed using 2% lignocaine with 1:100,000 epinephrine, and a mandibular primary molar pulpotomy was performed on each group. Group 1: the ibuprofen tablet was taken 1 h before the onset of the procedure. Group 2: ibuprofen tablet 30 min after the pulpotomy procedure. Group 3: the ibuprofen tablet was taken 1 h before the onset of the procedure, and the Phentolamine mesylate (PM) injection was administered. Group 4: immediately after the pulpotomy, the PM injection was administered, and an ibuprofen tablet was taken 30 min after the pulpotomy procedure. All children were assessed for the duration of soft-tissue anesthesia, their behavior scores and pain rating, as well as the incidence of postoperative self-inflicted injuries., Statistical Analysis Used: A one-way ANOVA was used to compare the average time needed for the reversal of anesthetic symptoms between groups. The effects of phentolamine, local anesthetics, and ibuprofen on the child's behavior and pain scores were compared using the Student's t-test. For the study, P < 0.05 was accepted as statistically significant., Results: The time needed for the full reversal of anesthetic symptoms to manifest on the tongue and lip was substantially reduced by the injection of phentolamine (P < 0.001). The use of phentolamine for reversal or the intake of ibuprofen pre- or postoperatively did not exhibit any significant variation in the behavior, pain experience, or incidence of self-inflicted injuries in the child., Conclusion: It is evident that although phentolamine injections shorten the duration of anesthesia, the adjunctive use of pre- or postoperative ibuprofen did not significantly alter pain scores., (Copyright © 2024 Copyright: © 2024 Journal of Indian Society of Pedodontics and Preventive Dentistry.)

Acute zoster-associated pain develops in most patients with herpes zoster. Nonopioid analgesics are usually used to treat acute zoster-associated pain but are frequently ineffective. We administered intravenous fosphenytoin, the prodrug of phenytoin, to patients with acute zoster-associated pain to examine its analgesic efficacy and safety. At 13 medical institutions in Japan, we conducted a phase II, double-blind, placebo-controlled, randomized trial of intravenous fosphenytoin in Japanese inpatients with acute zoster-associated pain for whom nonopioid analgesics had shown an insufficient analgesic effect. The patients were randomly assigned (1:1:1) to receive a single intravenous dose of fosphenytoin at 18 mg/kg (high dose), a single intravenous dose of fosphenytoin at 12 mg/kg (low dose), or placebo. The primary endpoint was the mean change per hour (slope) in the numerical rating scale score from the baseline score until 120 min after dosing. Seventeen patients were randomly assigned to the low-dose fosphenytoin group (n = 6, median age 62.5 years, range 39-75 years), high-dose fosphenytoin group (n = 5, median age 69.0 years, range 22-75 years), and placebo group (n = 5, median age 52.0 years, range 38-72 years). One patient was excluded because of investigational drug dilution failure. This study was discontinued because of the influences of coronavirus disease 2019. The slope was significantly lower in the high- and low-dose fosphenytoin groups than in the placebo group (P < 0.001 and P = 0.016, respectively). Responsiveness to intravenous fosphenytoin (≥2-point reduction in the numerical rating scale score from baseline to 120 min after dosing) was inferred at plasma total phenytoin concentrations of 10-15 μg/mL. Treatment-emergent adverse events caused no safety concerns in the clinical setting and intravenous fosphenytoin was well tolerated. Intravenous fosphenytoin appears to be an effective and promising alternative treatment for acute zoster-associated pain. Trial Registration: ClinicalTrials.gov NCT04139330., (© 2023 The Authors. The Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Japanese Dermatological Association.)

Introduction: This study aims to investigate the effectiveness of intravenous ibuprofen or intravenous ibuprofen plus acetaminophen compared to intravenous morphine in patients with closed extremity fractures., Methods: A triple-blinded randomized clinical trial was conducted at a tertiary trauma center in Iran. Adult patients between 15 and 60 years old with closed, isolated limb fractures and a pain intensity of at least 6/10 on the visual analog scale (VAS) were eligible. Patients with specific conditions or contraindications were not included. Participants were randomly assigned to receive intravenous ibuprofen, intravenous ibuprofen plus acetaminophen, or intravenous morphine. Pain scores were assessed using the visual analog scale at baseline and 5, 15, 30, and 60 min after drug administration. The primary outcome measure was the pain score reduction after one hour., Results: Out of 388 trauma patients screened, 158 were included in the analysis. There were no significant differences in age or sex distribution among the three groups. The pain scores decreased significantly in all groups after 5 min, with the morphine group showing the lowest pain score at 15 min. The maximum effect of ibuprofen was observed after 30 min, while the ibuprofen-acetaminophen combination maintained its effect after 60 min. One hour after injection, pain score reduction in the ibuprofen-acetaminophen group was significantly more than in the other two groups, and pain score reduction in the ibuprofen group was significantly more than in the morphine group., Conclusion: The study findings suggest that ibuprofen and its combination with acetaminophen have similar or better analgesic effects compared to morphine in patients with closed extremity fractures. Although morphine initially provided the greatest pain relief, its effect diminished over time. In contrast, ibuprofen and the ibuprofen-acetaminophen combination maintained their analgesic effects for a longer duration. The combination therapy demonstrated the most sustained pain reduction. The study highlights the potential of non-opioid analgesics in fracture pain management and emphasizes the importance of initiation of these medications as first line analgesic for patients with fractures. These findings support the growing trend of exploring non-opioid analgesics in pain management., Trial Registration: ClinicalTrials.gov Identifier: NCT05630222 (Tue, Nov 29, 2022). The manuscript adheres to CONSORT guidelines., (© 2024. The Author(s).)

Nonopioid analgesics serve to improve analgesia and limit side effects and risks of perioperative opioids. N-acetylcysteine (NAC), the primary treatment of acetaminophen toxicity, may have perioperative indications, including analgesia. NAC impacts glutathione synthesis, oxidant scavenging, glutamate receptor modulation and neuroinflammation. Potential perioperative benefits include arrhythmia prevention after cardiac surgery, decreased contrast-induced nephropathy, improved post-transplant liver function and superior pulmonary outcomes with general anesthesia. NAC may improve perioperative analgesia, with some studies displaying a reduction in postoperative opioid use. NAC is generally well tolerated with an established safety profile. NAC administration may predispose to gastrointestinal effects, while parenteral administration may carry a risk of anaphylactoid reactions, including bronchospasm. Larger randomized trials may clarify the impact of NAC on perioperative analgesic outcomes.

Neuropathic pain (NP) is often treated with opioids, the prolonged use of which causes tolerance to their analgesic effect and can potentially cause death by overdose. The phytocannabinoid delta-9-tetrahydrocannabinol (THC) may be an effective alternative analgesic to treat NP in morphine-tolerant subjects. Male Wistar rats developed NP after spared nerve injury, and were then treated with increasing doses of THC (1, 1.5, 2, 2.5, and 5 mg/kg, intraperitoneally), which reduced mechanical allodynia at the dose of 2.5 and 5 mg/kg. Another group of NP rats were treated with morphine (5 mg/kg, twice daily for 7 days, subcutaneously), until tolerance developed, and on day 8 received a single dose of THC (2.5 mg/kg), which significantly reduced mechanical allodynia. To evaluate the modulation of THC in the descending pain pathway, in vivo electrophysiological recordings of pronociceptive ON cells and antinociceptive OFF cells in the rostroventral medulla (RVM) were recorded after intra-PAG microinjection of THC (10 μg/μl). NP rats with morphine tolerance, compared to the control one, showed a tonic reduction of the spontaneous firing rate of ON cells by 44%, but the THC was able to further decrease it (a hallmark of many analgesic drugs acting at supraspinal level). On the other hand, the firing rate, of the antinociceptive OFF cells was increased after morphine tolerance by 133%, but the THC failed to further activate it. Altogether, these findings indicate that a single dose of THC produces antiallodynic effect in individuals with NP who are tolerant to morphine, acting mostly on the ON cells of the descending pain pathways, but not on OFF cells., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Diterpenoid alkaloids, originating from the amination of natural tetracyclic diterpenes, have long interested scientists due to their medicinal uses and infamous toxicity which has limited the clinical application of the native compound. Alkaloid lappaconitine extracted from various Aconitum and Delphinium species has displayed extensive bioactivities and active ongoing research to reduce its adverse effects. A convenient route to construct hybrid molecules containing diterpenoid alkaloid lappaconitine and 3 H -1,5-benzodiazepine fragments was proposed. The key stage involved the formation of 5'-alkynone-lappaconitines in situ by acyl Sonogashira coupling of 5'-ethynyllappaconitine, followed by cyclocondensation with o -phenylenediamine. New hybrid compounds showed low toxicity and outstanding analgesic activity in experimental pain models, which depended on the nature of the substituent in the benzodiazepine nucleus. An analogous dependence was also shown for the antiarrhythmic activity in the epinephrine arrhythmia test in vivo. Studies on the isolated atrium have shown that the mechanism of action of the new compounds is included the blockade of beta-adrenergic receptors and potassium channels. Molecular docking analysis was conducted to determine the binding potential of target molecules with the voltage-gated sodium channel NaV1.5. All obtained results provide a basis for future rational modifications of lappaconitine, reducing side effects, while retaining its therapeutic effects.

The mechanism of acetaminophen (APAP) analgesia is at least partially unknown. Previously, we showed that the APAP metabolite N-acetyl-p-benzoquinone imine (NAPQI) activated Kv7 channels in neurons in vitro, and this activation of Kv7 channels dampened neuronal firing. Here, the effect of the Kv7 channel blocker XE991 on APAP-induced analgesia was investigated in vivo. APAP had no effect on naive animals. Induction of inflammation with λ-carrageenan lowered mechanical and thermal thresholds. Systemic treatment with APAP reduced mechanical hyperalgesia, and co-application of XE991 reduced APAP's analgesic effect on mechanical pain. In a second experiment, the analgesic effect of systemic APAP was not antagonized by intrathecal XE991 application. Analysis of liver samples revealed APAP and glutathione-coupled APAP indicative of metabolization. However, there were no relevant levels of these metabolites in cerebrospinal fluid, suggesting no relevant APAP metabolite formation in the CNS. In summary, the results support an analgesic action of APAP by activating Kv7 channels at a peripheral site through formation of the metabolite NAPQI.

Background: Acetaminophen (APAP)-associated transaminase elevation, induced by N-acetyl-p-benzoquinone imine (NAPQI) protein adduction, remains an area of research interest. Distinct from known genetic, physiologic, and dosage associations dictating severity of hepatic injury, no known factors predict an absence of protein adduct formation at therapeutic APAP dosing., Hypothesis: Sex-based physiology is predictive of APAP-induced protein adduct formation and differential metabolite expression at therapeutic doses., Methods: This retrospective study interrogated serum samples collected for a prior study investigating fluctuations of alanine aminotransferase (ALT) over time with 4G daily APAP dosing for ≥ 16 days in subjects from Denver, Colorado. Subjects were grouped by adduct formation (n = 184) vs no adducts (n = 20). Samples were run on ultra-high-performance liquid chromatography mass spectrometry from study days 0, 7, 16, and 31. Significant metabolite expressions were identified using t-tests with false discovery rate correction (FDR), partial least squares discriminant, and ANOVA simultaneous comparison analyses. Demographic and clinical data were explored using t-tests with FDR (age, weight, BMI, ALT) and Chi-square (sex, ethnicity, race) analyses., Results: In pre-treatment samples, relative quantitation caprylic acid was expressed ninefold higher and 6-carboxyhexanoate was expressed threefold lower in subjects who did not develop adducts. Lactate had greater expression in the no adducts group (p = 0.001). Using absolute quantitation, glutathione was expressed 2.6-fold greater among no adduct subjects. Odds of males developing NAPQI protein adducts at therapeutic APAP dosing were 5.91 times lower than females (95% CI = 2.3-14.9; p = 0.0001)., Conclusion: Multiple metabolites were differentially expressed based on adduct group and sex. Metabolites were identified unique to adduct development independent of sex. At therapeutic APAP dosing, males were less likely to develop APAP protein adducts. Further research into lipid biosynthesis and metabolism may provide further insight into physiology associated with adduct production., (© 2022. American College of Medical Toxicology.)

Because nonopioid analgesics are much sought after, we computationally docked more than 301 million virtual molecules against a validated pain target, the α 2A -adrenergic receptor (α 2A AR), seeking new α 2A AR agonists chemotypes that lack the sedation conferred by known α 2A AR drugs, such as dexmedetomidine. We identified 17 ligands with potencies as low as 12 nanomolar, many with partial agonism and preferential G i and G o signaling. Experimental structures of α 2A AR complexed with two of these agonists confirmed the docking predictions and templated further optimization. Several compounds, including the initial docking hit '9087 [mean effective concentration (EC 50 ) of 52 nanomolar] and two analogs, '7075 and PS75 (EC 50 4.1 and 4.8 nanomolar), exerted on-target analgesic activity in multiple in vivo pain models without sedation. These newly discovered agonists are interesting as therapeutic leads that lack the liabilities of opioids and the sedation of dexmedetomidine.

The study focused on the application value of ultrasound images processed by restoration algorithm in evaluating the effect of dexmedetomidine in preventing neurological disorder in patients undergoing sevoflurane anesthesia. 90 patients undergoing tonsillectomy anesthesia were randomly divided into normal saline group, propofol group, and dexmedetomidine group. The ultrasound images were processed by restoration algorithm, and during the postoperative recovery period, ultrasound images were used to evaluate. The results showed that the original ultrasonic image was fuzzy and contained interference noise, and that the image optimized by restoration algorithm was clear, without excess noise, and the image quality was significantly improved. In the dexmedetomidine group, the extubation time was 10.6 ± 2.3 minutes, the recovery time was 8.4 ± 2.2 minutes, the average pain score during the recovery period was 2.6 ± 0.7, and the average agitation score was 7.2 ± 2.4. Of 30 patients, there were 13 cases with vertigo and 1 case with nausea and vomiting. The vascular ultrasound imaging showed that, in the dexmedetomidine group, the peak systolic velocities (PSV) of the bilateral vertebral arteries during the recovery period were 67.7 ± 14.3 and 67.9 ± 15.2 cm/s, respectively; the end-diastolic velocities (EDV) of the bilateral vertebral arteries were 27.8 ± 6.7 and 24.69 ± 5.9 cm/s, respectively; the PSV in bilateral internal carotid artery systolic peak velocities were 67.2 ± 13.9 and 67.8 ± 12.7 cm/s, respectively; the EDV in bilateral internal carotid arteries were 27.7 ± 5.3 and 26.9 ± 4.9 cm/s, respectively; bilateral vertebral artery resistance indexes (RIs) were 0.6 ± 0.02 and 0.71 ± 0.08, respectively; the bilateral internal carotid artery RIs were 0.57 ± 0.04 and 0.58 ± 0.06, respectively, all better than the normal saline group (12.1 ± 2.5 minutes, 10.1 ± 2.3 minutes, 3.9 ± 0.6, 10.6 ± 3.7, 15 cases, 11 cases, 81.5 ± 13.6, 80.7 ± 11.6 cm/s, 29.3 ± 6.8, 28.9 ± 6.7 cm/s, 74.3 ± 10.2, 73.9 ± 12.5 cm/s, 29.1 ± 4.3, 29 ± 4.5 cm/s, 0.84 ± 0.06, 0.83 ± 0.05, 0.8 ± 0.04, and 0.81 ± 0.05) and the propofol group (11.4 ± 2.1 minutes, 9.0 ± 2.1 minutes, 3.4 ± 0.8, 8.5 ± 2.3, 12 cases, 9 cases, 72.5 ± 12.9, 73.4 ± 11.8 cm/s, 28.6 ± 5.4, 26.5 ± 5.1 cm/s, 72.1 ± 11.4, 73.5 ± 10.6 cm/s, 28.8 ± 5.6, 27.3 ± 4.7 cm/s, 0.78 ± 0.07, 0.82 ± 0.06, 0.76 ± 0.03, and 0.78 ± 0.05), and the differences were statistically significant ( P < 0.05). In conclusion, ultrasound images processed by restoration algorithm have high image quality and high resolution. The dexmedetomidine can prevent neurological disorder in patients with sevoflurane anesthesia and is suggested in postoperative rehabilitation., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Yingying Yao et al.)

αO-Conotoxin GeXIVA is a 28 amino acid peptide derived from the venom of the marine snail Conus generalis. The presence of four cysteine residues in the structure of GeXIVA allows it to have three different disulfide isomers, that is, the globular, ribbon or bead isomer. All three isomers are active at α9α10 nicotinic acetylcholine receptors, with the bead isomer, GeXIVA[1,2], being the most potent and exhibiting analgesic activity in animal models of neuropathic pain. The original report of GeXIVA activity failed to observe any effect of the isomers on high voltage-activated (HVA) calcium channel currents in rat dorsal root ganglion (DRG) neurons. In this study, we report, for the first time, the activity of globular GeXIVA[1,3] at G protein-coupled GABA B receptors (GABA B R) inhibiting HVA N-type calcium (Cav2.2) channels and reducing membrane excitability in mouse DRG neurons. The inhibition of HVA Ba 2+ currents and neuroexcitability by GeXIVA[1,3] was partially reversed by the selective GABA B R antagonist CGP 55845. In transfected HEK293T cells co-expressing human GABA B R1 and R2 subunits and Cav2.2 channels, both GeXIVA[1,3] and GeXIVA[1,4] inhibited depolarization-activated Ba 2+ currents mediated by Cav2.2 channels, whereas GeXIVA[1,2] had no effect. The effects of three cyclized GeXIVA[1,4] ribbon isomers were also tested, with cGeXIVA GAG being the most potent at human GABA B R-coupled Cav2.2 channels. Interestingly, globular GeXIVA[1,3] also reversibly potentiated inwardly-rectifying K + currents mediated by human GIRK1/2 channels co-expressed with GABA B R in HEK293T cells. This study highlights GABA B R as a potentially important receptor target for the activity of αO-conotoxin GeXIVA to mediate analgesia., (© 2021 International Society for Neurochemistry.)

Study Objective: Bilateral endoscopic nasal surgery is usually associated with pain and sleep disturbance. The aim of this study was to evaluate the effects of dexmedetomidine-soaked nasal packing on analgesia and improvement of sleep quality in patients undergoing this surgery., Method: Eighty patients were enrolled and randomly allocated into 4 groups. At the end of surgery, dexmedetomidine-soaked nasal packings were applied to three groups with a dosage of 1 μg kg -1 (D1), 2μg kg -1 (D2), 4 μg kg -1 (D4) and normal saline-soaked nasal packing (NS) was applied to a fourth group. The primary outcome was postoperative pain scores using a visual analog scale (VAS) recorded at six time points: before the surgery (T1); 2 h (T2), 8 h (T3), 24 h (T4), 48 h (T5) after surgery; and at the moment of nasal packing removal (T6). Secondary outcomes were postoperative sleep status evaluated by the Pittsburgh sleep quality index (PSQI) and subjective sleep quality value (SSQV). Factors affecting sleep, hemodynamic changes, and adverse events were also recorded., Results: Compared with the NS group, dexmedetomidine-soaked nasal packing significantly relieved postoperative pain and improved sleep quality. The effect was similar between D2 and D4, which was greater than in D1. However, D2 was associated with fewer adverse events., Conclusions: Dexmedetomidine-soaked nasal packing not only offers effective analgesia but also improves postoperative sleep quality in patients undergoing bilateral endoscopic nasal surgery. Taking effect and adverse events into consideration, a dosage of 2μg kg -1 may be optimal., Trial Registration: www.chictr.org.cn/index.aspx (ChiCTR1900025692) Retrospectively registered 5 September 2019., (© 2021. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Background: Thalamic pain, a neuropathic pain syndrome, frequently occurs after stroke. This research aimed to investigate the effect of dexmedetomidine (DEX) on thalamic pain., Methods: The cellular localization of the TLR4 protein was determined by immunostaining. The expression of Iba1, GFAP and protein associated with the TLR4/NF-κB/ERK1/2 pathway was measured by Western blotting. Continuous pain hypersensitivity was evaluated by behavioural tests. The results were analysed by one-way ANOVA, two-way ANOVA and Tukey's post hoc test., Results: The results demonstrated that DEX obviously alleviated thalamic pain induced by haemorrhage on the ipsilateral side and delayed the development of pain hypersensitivity. Furthermore, the expression levels of Iba1, GFAP and proteins associated with the TLR4/NF-κB/ERK1/2 signalling pathway were greatly increased in mice with thalamic pain, but these effects were reversed by DEX., Conclusion: Our findings suggest that DEX alleviates the inflammatory response during thalamic pain through the TLR4/NF-κB/ERK1/2 signalling pathway and might be a potential therapeutic agent for thalamic pain., (© 2021. The Author(s).)

Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Different peripheral nerve injuries cause neuropathic pain through distinct mechanisms. Even the site of injury may impact underlying mechanisms, as indicated by the clinical finding that the antiseizure drug carbamazepine (CBZ) relieves pain because of compression injuries of trigeminal but not somatic nerves. We leveraged this observation in the present study hypothesizing that because CBZ blocks voltage-gated sodium channels (VGSCs), its therapeutic selectivity reflects differences between trigeminal and somatic nerves with respect to injury-induced changes in VGSCs. CBZ diminished ongoing and evoked pain behavior in rats with chronic constriction injury (CCI) to the infraorbital nerve (ION) but had minimal effect in rats with sciatic nerve CCI. This difference in behavior was associated with a selective increase in the potency of CBZ-induced inhibition of compound action potentials in the ION, an effect mirrored in human trigeminal versus somatic nerves. The increase in potency was associated with a selective increase in the efficacy of the Na V 1.1 channel blocker ICA-121431 and Na V 1.1 protein in the ION, but no change in Na V 1.1 mRNA in trigeminal ganglia. Importantly, local ICA-121431 administration reversed ION CCI-induced hypersensitivity. Our results suggest a novel therapeutic target for the treatment of trigeminal neuropathic pain. SIGNIFICANCE STATEMENT This study is based on evidence of differences in pain and its treatment depending on whether the pain is above (trigeminal) or below (somatic) the neck, as well as evidence that voltage-gated sodium channels (VGSCs) may contribute to these differences. The focus of the present study was on channels underlying action potential propagation in peripheral nerves. There were differences between somatic and trigeminal nerves in VGSC subtypes underlying action potential propagation both in the absence and presence of injury. Importantly, because the local block of Na V 1.1 in the trigeminal nerve reverses nerve injury-induced mechanical hypersensitivity, the selective upregulation of Na V 1.1 in trigeminal nerves suggests a novel therapeutic target for the treatment of pain associated with trigeminal nerve injury., (Copyright © 2021 the authors.)

Background: Dexmedetomidine promotes normal sleep architecture; the drug also improves analgesia. We therefore tested the hypothesis that supplementing intravenous analgesia with dexmedetomidine reduces delirium in older patients recovering from orthopedic surgery., Methods: In this double-blinded randomized controlled trial, we enrolled 712 older (aged 65-90 years) patients scheduled for major orthopedic surgery. Postoperative analgesia was provided by patient-controlled intravenous sufentanil, supplemented by randomly assigned dexmedetomidine (1.25 μg/mL) or placebo, for up to three days. The primary outcome was the incidence of delirium assessed twice daily with the Confusion Assessment Method. Among secondary outcomes, pain severity was assessed twice daily and sleep quality once daily, each with an 11-point scale where 0 = no pain/the best possible sleep and 10 = the worst pain/the worst possible sleep., Results: The incidence of postoperative delirium was 7.3% (26 of 354) with placebo and 4.8% (17 of 356) with dexmedetomidine; relative risk 0.65, 95% CI 0.36 to 1.18; P = 0.151. Dexmedetomidine reduced pain both at rest (median difference -1 to 0 points, P ≤ 0.001) and with movement (-1 points, P < 0.001) throughout the first 5 postoperative days; it also improved subjective sleep quality during the first 3 postoperative days: day one median difference -1 point (95% CI -1 to 0), P = 0.007; day two 0 point (-1 to 0), P = 0.010; and day three 0 point (-1 to 0), P = 0.003. The incidence of adverse events was similar in each group., Conclusions: Supplementing sufentanil intravenous analgesia with low-dose dexmedetomidine did not significantly reduce delirium, but improved analgesia and sleep quality without provoking adverse events., Trial Registration: www.chictr.org.cn : ChiCTR1800017182 (Date of registration: July 17, 2018); ClinicalTrials.gov: NCT03629262 (Date of registration: August 14, 2018)., (© 2021. The Author(s).)

The current opioid crisis highlights the urgent need to develop safe and effective pain medications. Thus, neurotensin (NT) compounds represent a promising approach, as the antinociceptive effects of NT are mediated by activation of the two G protein-coupled receptor subtypes (i.e., NTS1 and NTS2) and produce potent opioid-independent analgesia. Here, we describe the synthesis and pharmacodynamic and pharmacokinetic properties of the first constrained NTS2 macrocyclic NT(8-13) analog. The Tyr 11 residue of NT(8-13) was replaced with a Trp residue to achieve NTS2 selectivity, and a rationally designed side-chain to side-chain macrocyclization reaction was applied between Lys 8 and Trp 11 to constrain the peptide in an active binding conformation and limit its recognition by proteolytic enzymes. The resulting macrocyclic peptide, CR-01-64, exhibited high-affinity for NTS2 (K i 7.0 nM), with a more than 125-fold selectivity over NTS1, as well as an improved plasma stability profile (t 1/2 > 24 h) compared with NT (t 1/2 ~ 2 min). Following intrathecal administration, CR-01-64 exerted dose-dependent and long-lasting analgesic effects in acute (ED 50 = 4.6 µg/kg) and tonic (ED 50 = 7.1 µg/kg) pain models as well as strong mechanical anti-allodynic effects in the CFA-induced chronic inflammatory pain model. Of particular importance, this constrained NTS2 analog exerted potent nonopioid antinociceptive effects and potentiated opioid-induced analgesia when combined with morphine. At high doses, CR-01-64 did not cause hypothermia or ileum relaxation, although it did induce mild and short-term hypotension, all of which are physiological effects associated with NTS1 activation. Overall, these results demonstrate the strong therapeutic potential of NTS2-selective analogs for the management of pain., (Copyright © 2021 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

The lateral hypothalamus (LH) is one of the key brain areas involved in pain modulation. Also, the dentate gyrus (DG) of the hippocampus expresses various receptors, including dopaminergic receptors. Dopaminergic receptors play a key role in pain transmission and modulation within the brain. The present study aimed to investigate the involvement of DG dopaminergic receptors in the LH-induced antinociception during the presence of inflammatory pain. Male Wistar rats were used in this study. Cannulae were unilaterally implanted in their skull for microinjections into the LH and DG. The LH was chemically stimulated by carbachol injection (250 nM/0.5 μl saline). In separate groups, different doses (0.25, 1, and 4 μg/0.5 μl vehicle) of the D1- and D2-like dopamine receptor antagonists (SCH23390 and Sulpiride, respectively) were microinjected into the DG, 5 min prior to intra-LH injection of carbachol. Five min after the second injection, formalin test as a persistent inflammatory pain model in animals was done in all rats. The results revealed that carbachol could induce antinociception following formalin injection into rat's hind paw. The 4 μg dose of both antagonists significantly reduced the LH stimulation-induced antinociception in both phases of formalin pain responses. Although the 1 μg dose of sulpiride significantly reduced antinociception during both phases, 1 μg SCH23390 could only reduce this antinociception during the late phase. These findings demonstrate the involvement of DG dopaminergic receptors in the LH-induced antinociception. The results also suggest that the effectiveness of DG dopaminergic receptors is more pronounced during the late phase of formalin-induced pain responses., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Adjuvants to local anesthetics, such as nalbuphine and dexmedetomidine, can be used to improve the quality and duration of peripheral nerve block effects. Dexmedetomidine has been successfully used as an adjuvant of erector spinae plane block (ESPB) with ropivacaine in video-assisted thoracoscopic lobectomy surgeries (VATLS). This study aimed to compare the effects of nalbuphine and dexmedetomidine used as adjuvants to ropivacaine for ESPB in VATLS., Methods: A total of 102 patients undergoing VATLS with ESPB were enrolled and randomized into 3 groups, each of which received a different adjuvant to ropivacaine. The visual analogue scale score, onset and duration of sensory block, use of patient-controlled analgesia (PCA), rate of rescue analgesia, duration of postoperative hospitalization, incidence of postoperative nausea and vomiting, and chronic pain were measured and observed., Results: The visual analogue scale score, total PCA use, rate of rescue analgesia, and postoperative chronic pain in the ropivacaine with dexmedetomidine (RD), and ropivacaine with nalbuphine (RN) groups were lower than those in the ropivacaine (RC) group (P < .05). The duration of sensory block was longer and the first use of PCA occurred later in the RD and RN groups than they did in the RC group (P < .05)., Conclusions: As an adjuvant to ropivacaine in ESPB, nalbuphine and dexmedetomidine are comparable in terms of the associated analgesia, sensory block duration, need for rescue analgesia, and incidence of chronic pain in patients after VATLS., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The neuronal-type (N-type) voltage-gated calcium (Ca v ) channels, which are designated Ca v 2.2, have an important role in the release of neurotransmitters 1-3 . Ziconotide is a Ca v 2.2-specific peptide pore blocker that has been clinically used for treating intractable pain 4-6 . Here we present cryo-electron microscopy structures of human Ca v 2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Ca v 2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca v 2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca v channels., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

The precise mechanistic action of acetaminophen (ACT; paracetamol) remains debated. ACT's analgesic and antipyretic actions are attributed to cyclooxygenase (COX) inhibition preventing prostaglandin (PG) synthesis. Two COX isoforms (COX1/2) share 60% sequence structure, yet their functions vary. COX variants have been sequenced among various mammalian species including humans. A COX1 splice variant (often termed COX3) is purported by some as the elusive target of ACT's mechanism of action. Yet a physiologically functional COX3 isoform has not been sequenced in humans, refuting these claims. ACT may selectively inhibit COX2, with evidence of a 4.4-fold greater COX2 inhibition than COX1. However, this is markedly lower than other available selective COX2 inhibitors (up to 433-fold) and tempered by proof of potent COX1 inhibition within intact cells when peroxide tone is low. COX isoform inhibition by ACT may depend on subtle in vivo physiological variations specific to ACT. In vivo ACT efficacy is reliant on intact cells and low peroxide tone while the arachidonic acid concentration state can dictate the COX isoform preferred for PG synthesis. ACT is an effective antipyretic (COX2 preference for PG synthesis) and can reduce afebrile core temperature (likely COX1 preference for PG synthesis). Thus, we suggest with specificity to human in vivo physiology that ACT: (i) does not act on a third COX isoform; (ii) is not selective in its COX inhibition; and (iii) inhibition of COX isoforms are determined by subtle and nuanced physiological variations. Robust research designs are required in humans to objectively confirm these hypotheses., (© 2021 The Authors. Pharmacology Research & Perspectives published by British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics and John Wiley & Sons Ltd.)

Objectives: This study aims to estimate the EC50 of ropivacaine when co-administered with dexmedetomidine for epidural labor analgesia in antepartum obese and non-obese parturients., Methods: Sixty parturients scheduled for epidural labor analgesia were enrolled and divided into antepartum obesity (AO) and control (CON) groups, according to their body mass index at labor. Both groups received 0.5 µg/mL dexmedetomidine with ropivacaine as anesthetics. The concentration of ropivacaine was initially set at 0.125% and varied by 0.01% according to the up-and-down rule for sequential allocation. Hemodynamic parameters were monitored and pain intensity was assessed using a visual analog scale., Results: When co-administered with dexmedetomidine, the EC50 of ropivacaine was 0.095% (95% confidence interval [CI]: 0.090-0.100%) and 0.070% (95% CI: 0.062-0.076%) in CON and AO groups, respectively. There was a significant difference between the two groups ( P < 0.001). EC95 values of ropivacaine were 0.084% (95% CI: 0.077-0.122%) and 0.106% (95% CI: 0.101-0.128%) in AO and CON groups, respectively., Conclusion: Patients with antepartum obese may require decreased ropivacaine concentration for epidural labor analgesia when co-administered with 0.5 µg/mL dexmedetomidine.

Musculoskeletal and psychological complaints have increased with the widespread use of visual display terminals, and musculoskeletal pain is known to be closely related to stress. One method of experimentally inducing persistent muscle pain is repeated cold stress (RCS), and animals exposed to such stress exhibit a dysfunction in the descending pain inhibitory system. Acetaminophen (N-acetyl-p-aminophenol; APAP) is widely used to relieve several types of pain, including musculoskeletal pain, and is available as an OTC drug. However, the mechanism underlying its analgesic action has not yet been fully elucidated. In this study, we compared the analgesic effect of APAP on RCS-induced muscular hyperalgesia with those of other analgesics to identify its mechanism of action. The daily oral administration of APAP significantly suppressed the decrease in the mechanical withdrawal threshold caused by RCS, similar to the results for neurotropin but not for the cyclooxygenase inhibitor ibuprofen (IBP). Moreover, the intrathecal administration of antagonists of the 5-hydroxytryptamine (5-HT) 3 receptor or α 2 -adrenoceptor significantly abolished the analgesic effect of APAP but not of IBP. These results suggest that the analgesic effect of APAP on RCS-induced muscular pain might be exerted due to the activation of the descending pathways involving the spinal 5-HT 3 receptor or α 2 -adrenoceptor.

Objective: To evaluate the analgesic efficacy and safety of ibuprofen in children with musculoskeletal injuries., Methods: PubMed, EMBASE, Web of science, and the Cochrane Central register of Controlled Trials (CENTRAL) were systematically searched to identify eligible randomized controlled trials (RCTs) that compared ibuprofen with other analgesics for pain relief in children with musculoskeletal injuries. Primary outcomes included change of visual analog scale (VAS) scores from baseline to post-medication, the proportion of patients achieving adequate analgesia, and the proportion of patients requiring additional analgesia. Secondary outcome was the incidence of adverse effects. Data analysis was performed using RevMan 5.3 software., Results: Five RCTs involving 1034 patients were included in this meta-analysis. Compared to the control group, change of VAS scores was greater in ibuprofen group at 60 min (standardized mean difference [SMD] = 0.28; 95% confidence intervals [CI], 0 to 0.57; P = .05), 90 min (SMD = 0.38; 95% CI, 0.17 to 0.59; P = .0005), and 120 min (SMD = 0.4; 95% CI, 0.23 to 0.57; P < .00001) after treatment. No difference was found in the change of VAS scores at 30 min (SMD = 0.07; 95% CI, -0.08 to 0.22; P = .36) after treatment. The proportion of patients who received adequate analgesia was higher in the ibuprofen group (risk ratios [RR] = 1.36; 95% CI, 1.20 to 1.56; P < .00001). The proportion of patients that required additional analgesia was lower in the ibuprofen group (RR = 0.7; 95% CI, 0.53 to 0.92; P = .01). The incidence of total adverse effects was lower in the ibuprofen group (RR = 0.59; 95% CI, 0.45 to 0.79; P = .0002)., Conclusions: Ibuprofen provides a better pain relief with a lower incidence of adverse effects in children with musculoskeletal injuries as compared to other analgesics., Prospero Registration Number: CRD42021231975., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Chemotherapy-induced neuropathy (CIN) is a major dose-limiting side effect of anticancer therapy that can compel therapy discontinuation. Inadequate analgesic efficacy of current pharmacological approaches requires the identification of innovative therapeutics and, hence, the purpose of this study is to conduct a preclinical evaluation of the efficacy of DDD-028, a versatile pentacyclic pyridoindole derivative, against paclitaxel-induced neuropathic pain. In two separate experiments, DDD-028 was administered per os acutely (1-25 mg kg -1 ) or repeatedly (10 mg kg -1 ) in paclitaxel-treated rats. The response to mechanical noxious stimulus (paw pressure) as well as to non-noxious mechanical (von Frey) and thermal (cold plate) stimuli was investigated. Acute administration of DDD-028 induced a dose-dependent anti-neuropathic pain effect in all tests performed. Further, repeated daily treatment for 18 consecutive days (starting the first day of paclitaxel administration) significantly reduced the development of pain over time without the development of tolerance to the anti-hyperalgesic effect. Ex vivo analysis showed that DDD-028 was able to reduce oxidative damage of dorsal root ganglia as evidenced by the increase in the level of carbonylated proteins and the decrease in catalase activity. In the lumbar spinal cord, periaqueductal gray matter, thalamus, and somatosensory cortex 1, DDD-28 significantly prevented the activation of microglia and astrocytes. The pharmacodynamic study revealed that the pain-relieving effects of DDD-028 were fully blocked by both the non-selective nicotinic receptor (nAChR) antagonist mecamylamine and by the selective α7 nAChR antagonist methyllycaconitine. In conclusion, DDD-028 was active in reducing paclitaxel-induced neuropathic pain after single or repeated administrations without tolerance development and displaying a double symptomatic and neuroprotective profile. DDD-028 could represent a valuable candidate for the treatment of CIN., (© 2021. The Author(s).)

Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the μ-opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In this review, we summarize alternative strategies and targets that could be used to develop safer nonopioid analgesics. A molecular understanding of G protein-coupled receptor activation and signaling has illuminated not only the complexities of receptor pharmacology but also the potential for pathway-selective agonists and allosteric modulators as safer medications. The availability of structures of pain-related receptors, in combination with high-throughput computational tools, has accelerated the discovery of multitarget ligands with promising pharmacological profiles. Emerging clinical evidence also supports the notion that drugs targeting peripheral opioid receptors have potential as improved analgesic agents.

In this article, we conduct a systematic review of the literature to explore the specific role of dexmedetomidine (DEX) on postoperative sleep and its associated mechanisms at present. The electronic database Embase, MEDLINE/PubMed, the Cochrane Library, Web of Science, and Google Scholar were searched. The restriction terms included "dexmedetomidine", "sleep" and "surgery". The inclusion criteria were as following: 1) patients 18 years old or older; 2) DEX used in the perioperative period not just for critically ill patients in the intensive care unit (ICU); 3) prospective or retrospective studies. The review articles, conference abstracts, and animal studies were excluded. Out of the 22 articles which met the above criteria, 20 of them were randomized controlled studies and 2 of them were retrospective cohort studies. Infusion of DEX including during the surgery and after surgery at a low or high dose was shown to improve subjective and objective sleep quality, although 2 studies showed there is no evidence that the use of DEX improves sleep quality and 1 showed less sleep efficiency and shorter total sleep time in the DEX group. Other postoperative outcomes evaluated postoperative nausea and vomiting, pain, postoperative delirium bradycardia and hypotension. Outcomes of our systematic review showed that DEX has advantages in improving patients' postoperative sleep quality. Combined with the use of general anesthetic, DEX provides a reliable choice for procedural sedation., Competing Interests: The authors have no financial or other relationships relevant to this article., (© 2021 Huang et al.)

Background: There are limited studies on the utilization of analgesics in testudines. Management of pain in reptiles is by use of analgesics generally used in other vertebrate species. Evidently, some analgesics considered to be generally effective in reptiles are not effective in certain reptile species., Objective: The purpose of this study was to examine the effect of amitriptyline hydrochloride on nociceptive behaviour in Speke's hinge-back tortoise., Methods: Twenty-four adult Speke-hinged tortoises weighing 500-700 g were used. The effects of amitriptyline hydrochloride on nociception were evaluated using the formalin, capsaicin and hot plate nociceptive tests. Amitriptyline was administered intracoelomically at doses of 0.5, 1.0 and 3.0 mg/kg., Results: The higher doses of amitriptyline hydrochloride caused an increase in nociceptive behaviour (time spent in hindlimb withdrawal) on the formalin and capsaicin nociceptive tests, suggesting a potentiating effect. However, the doses used had no significant change in nociceptive behaviour on withdrawal response in the hot plate test., Conclusions: The study showed that amitriptyline hydrochloride which is widely used in management of neuropathic pain potentiates nociceptive effects in the formalin and capsaicin nociceptive tests in the Speke's hinge-back tortoise. The hot plate test, which previously has not been reported in these animals, gave results not in line with the other tests and therefore more testing and validation of the test is required. Amitriptyline modulates chemical and thermal pain differently., (© 2021 The Authors Veterinary Medicine and Science Published by John Wiley & Sons Ltd.)

The role of the ventral tegmental area (VTA) and the lateral hypothalamus (LH) in the modulation of formalin-induced nociception is well documented individually. The present study aimed to investigate the role of dopamine receptors of the VTA in the modulation of the LH stimulation-induced antinociception during both phases of the formalin test as an animal model of tonic pain. In this study, male Wistar rats were unilaterally implanted with two guide cannulae in the VTA and LH. In two separate groups, animals received different doses (0.25, 1, and 4 μg/rat) of D1- or D2-like dopamine receptor antagonists (SCH-23,390 or Sulpiride, respectively) into the VTA before intra-LH injection of carbachol (22.83 ng/rat) following formalin injection (50 μL; s.c.) into their contralateral hind paws. The blockade of these two receptors reduced intra-LH carbachol-induced antinociception during both phases of the formalin test. This reduction during the late phase of the formalin test was more than that of the early phase. The results indicated that LH stimulation-induced antinociception was mediated by D1- and D2-like dopamine receptors in the VTA, and so, the neural pathway projecting from the LH to the VTA contributes to the modulation of formalin-induced nociception in the rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Myocardial ischemia-reperfusion injury (MIRI) is the most common cause of death worldwide. The NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome plays an important role in the inflammatory response to MIRI. Dexmedetomidine (DEX), a specific agonist of α2-adrenergic receptor, is commonly used for sedation and analgesia in anesthesia and critically ill patients. Several studies have shown that dexmedetomidine has a strong anti-inflammatory effect in many diseases. Here, we investigated whether dexmedetomidine protects against MIRI by inhibiting the activation of the NLRP3 inflammasome in vitro., Methods: We established an MIRI model in cardiomyocytes (CMs) alone and in coculture with cardiac fibroblasts (CFs) by hypoxia/reoxygenation (H/R) in vitro. The cells were treated with dexmedetomidine with or without MCC950 (a potent selective NLRP3 inhibitor). The beating rate and cell viability of cardiomyocytes, NLRP3 localization, the expression of inflammatory cytokines and NLRP3 inflammasome-related proteins, and the expression of apoptosis-related proteins, including Bcl2 and BAX, were determined., Results: Dexmedetomidine treatment increased the beating rates and viability of cardiomyocytes cocultured with cardiac fibroblasts. The expression of the NLRP3 protein was significantly upregulated in cardiac fibroblasts but not in cardiomyocytes after H/R and was significantly attenuated by dexmedetomidine treatment. Expression of the inflammatory cytokines IL-1β, IL-18 and TNF-α was significantly increased in cardiac fibroblasts after H/R and was attenuated by dexmedetomidine treatment. NLRP3 inflammasome activation induced the increased expression of cleaved caspase1, mature IL-1β and IL-18, while dexmedetomidine suppressed H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts. In addition, dexmedetomidine reduced the expression of Bcl2 and BAX in cocultured cardiomyocytes by suppressing H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts., Conclusion: Dexmedetomidine treatment can suppress H/R-induced NLRP3 inflammasome activation in cardiac fibroblasts, thereby alleviating MIRI by inhibiting the inflammatory response.

Objective: To determine whether diabetes mellitus (DM) contributes to the drug resistance of carbamazepine (CBZ), we investigated the correlation between the blood glucose status and the CBZ resistance condition in patients with trigeminal neuralgia (TN)., Patients and Methods: A total of 155 TN patients treated with the CBZ monotherapy were selected at Shanghai General Hospital and Shanghai Xinhua Hospital from September 2018 to January 2020. Among them, 15 were diagnosed with DM. Patients' CBZ resistance levels were evaluated according to progression-free survival. We utilized ordered multiple classification logistic regression to determine the dominant factors leading to CBZ resistance. We analyzed the correlation between hemoglobin A1c (HbA1c) and progression-free survival using the Pearson correlation analysis., Results: The regression analysis showed that DM was the only factor affecting CBZ resistance (p = 0.035; OR = 0.327; 95% CI, 0.115-0.926). Progression-free survival was 28.5 ± 21.2 months in the DM group and 66.0 ± 33.2 months in the non-DM group. The concentration of HbA1c in the blood was negatively correlated with progression-free survival (r = - 0.197; p = 0.014)., Conclusions: This study shows that blood glucose status is a significant factor contributing to the CBZ resistance in the treatment of TN. The progression-free survival of patients is affected by the status of DM and blood HbAlc levels.

Pain intensity represents the primary outcome in most pain clinical trials. Identifying methods to measure aspects of pain that are most sensitive to treatment may facilitate discovery of effective interventions. In this third of 3 articles examining alternative indices of pain intensity derived from ecological momentary assessments (EMA), we compare treatment effects based on Average Pain, Maximum Pain, Minimum Pain, Pain Variability, Time in High Pain, Time in Low Pain, and Pain After Wake-Up. We also examine which indices contribute to Patient Global Impressions of Change (PGIC). Data came from 2 randomized, double-blind, placebo-controlled trials examining the efficacy of milnacipran for fibromyalgia treatment; 2,084 patients provided >1 million EMA pain intensity ratings over 24 (Study 1) or 26 (Study 2) treatment weeks. Pain Variability and Time in High Pain produced significantly smaller treatment effects than Average Pain; other pain indices showed effects that were numerically smaller, but not significantly different from Average Pain. Changes in all pain indices were significantly associated with PGIC, with improvements in Maximum Pain and in Pain Variability offering small incremental contributions to understanding PGIC over Average Pain. Results suggest that different pain indices could be used to detect treatment effects in pain clinical trials. PERSPECTIVE: Alternative summary measures of pain intensity derived from EMA may broaden the scope of outcomes useful in pain clinical trials. In this analysis of a pharmacological treatment for fibromyalgia, most pain summary measures indicated similar effects; improvements in Maximum Pain and Pain Variability contributed to understanding PGIC over Average Pain., (Copyright © 2020 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Oral amitriptyline hydrochloride (amitriptyline) is ineffective against some forms of chronic pain and is often associated with dose-limiting adverse events. We evaluated the potential effectiveness of high-dose topical amitriptyline in a preliminary case series of chemotherapy-induced peripheral neuropathy patients and investigated whether local or systemic adverse events associated with the use of amitriptyline were present in these patients. We also investigated the mechanism of action of topically administered amitriptyline in mice. Our case series suggested that topical 10% amitriptyline treatment was associated with pain relief in chemotherapy-induced peripheral neuropathy patients, without the side effects associated with systemic absorption. Topical amitriptyline significantly increased mechanical withdrawal thresholds when applied to the hind paw of mice, and inhibited the firing responses of C-, Aβ- and Aδ-type peripheral nerve fibers in ex vivo skin-saphenous nerve preparations. Whole-cell patch-clamp recordings on cultured sensory neurons revealed that amitriptyline was a potent inhibitor of the main voltage-gated sodium channels (Nav1.7, Nav1.8, and Nav1.9) found in nociceptors. Calcium imaging showed that amitriptyline activated the transient receptor potential cation channel, TRPA1. Our case series indicated that high-dose 10% topical amitriptyline could alleviate neuropathic pain without adverse local or systemic effects. This analgesic action appeared to be mediated through local inhibition of voltage-gated sodium channels. PERSPECTIVE: Our preliminary case series suggested that topical amitriptyline could provide effective pain relief for chemotherapy-induced peripheral neuropathy patients without any systemic or local adverse events. Investigation of the mechanism of this analgesic action in mice revealed that this activity was mediated through local inhibition of nociceptor Nav channels., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Nicotine has previously been shown to augment the antinociceptive effects of μ -opioid agonists in squirrel monkeys without producing a concomitant increase in behavioral disruption. The present studies were conducted to extend these findings by determining the ability of the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α 4 β 2 nAChR agonist varenicline to selectively augment the antinociceptive effects of the μ -opioid receptor (MOR) full agonist fentanyl, the MOR partial agonist nalbuphine, and the κ -opioid receptor (KOR) agonist U69,593 in male squirrel monkeys. Results indicate that both nAChR ligands selectively increased the antinociceptive effects of nalbuphine and that epibatidine increased the antinociceptive effects of U69,593 without altering effects on operant behavior. However, neither epibatidine nor varenicline enhanced the antinociceptive effects of fentanyl, perhaps due to its high efficacy. The enhancement of nalbuphine's antinociceptive effects by epibatidine, but not varenicline, could be antagonized by either mecamylamine or dihydro- β -erythroidine, consistent with α 4 β 2 mediation of epibatidine's effects but suggesting the involvement of non-nAChR mechanisms in the effects of varenicline. The present results support previous findings showing that an nAChR agonist can serve as an adjuvant for MOR antinociception and, based on results with U69,593, further indicate that the adjuvant effects of nAChR drugs may also apply to antinociception produced by KOR. Our findings support the further evaluation of nAChR agonists as adjuvants of opioid pharmacotherapy for pain management and point out the need for further investigation into the mechanisms by which they produce opioid-adjuvant effects. SIGNIFICANCE STATEMENT: Nicotine has been shown to augment the antinociceptive effects of μ -opioid receptor analgesics without exacerbating their effects on operant performance. The present study demonstrates that the nicotinic acetylcholine receptor (nAChR) agonist epibatidine and partial α4β2 nAChR agonist varenicline can also augment the antinociceptive effects of nalbuphine, as well as those of a κ -opioid receptor agonist, without concomitantly exacerbating their behaviorally disruptive effects. These findings support the view that nAChR agonists and partial agonists may have potential as adjuvant therapies for opioid-based analgesics., Competing Interests: No author has an actual or perceived conflict of interest with the contents of this article., (Copyright © 2021 by The American Society for Pharmacology and Experimental Therapeutics.)

Background: Osteosarcoma is a common malignant tumor in adolescents with a low 5-year survival rate. Dexmedetomidine (DEX) has been widely used for surgery of osteosarcoma patients. MiR-520a-3p and YOD1 expression was abnormal in osteosarcoma cells. However, whether DEX affects osteosarcoma progression via miR-520a-3p-YOD1 interactome needs to be explored., Methods: We detected osteosarcoma cells biological behavior by CCK-8 assay, BrdU assay, cell adhesion assay, and apoptosis assay, respectively. The miR-520a-3p and YOD1 levels was explored in osteosarcoma cell lines by RT-qPCR or western blotting assay., Results: In this study, we found that DEX treating osteosarcoma cells inhibited cell viability, proliferation and adhesion, while it promoted cell apoptosis. Moreover, miR-520a-3p targeting to YOD1 also functionally repressed cell malignancy in osteosarcoma cells. Notably, DEX treatment could inhibit YOD1 expression via upregulating miR-520a-3p, thereby suppressing cell malignancy in osteosarcoma., Conclusions: Our study first revealed that DEX inhibited malignancy of osteosarcoma cells via miR-520a-3p/YOD1 axis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interests., (Copyright © 2021 Elsevier Inc. All rights reserved.)