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Indian gooseberry (Emblica officinalis fruit), also known as “Amla” is one of the oldest edible fruits known in India. It has also traditionally been used to treat inflammation, and as an analgesic to treat wounds. However, experimental evidence for the analgesic effects of E. officinalis has been lacking. The present study investigated whether E. officinalis extracts exhibit analgesic effects in the plantar incision (PI) and spared nerve injury (SNI) pain-model rats. We evaluated the mechanical withdrawal threshold (MWT) using von Frey filaments, and pain-related behavior was determined after surgery based on ultrasonic vocalization (USV). The group treated with E. officinalis extracts at 300 mg/kg had significantly increased MWT values at 6 h and 24 h after the PI, and had a significantly reduced number of 22–27-kHz USVs at 6 h and 24 h after PI. Moreover, after 15 days of continuous treatment with E. officinalis extracts, the treated group showed significantly alleviated SNI-induced hypersensitivity and reduced pro-inflammatory cytokine levels. Thus, E. officinalis extracts have potential analgesic effects in both postoperative and neuropathic pain models in vivo.

The sea slater Ligia exotica is believed to have effects of reducing swelling and relieving pain in Chinese folk medicine. However, the scientific foundation of using the sea slater Ligia spp. as an analgesic and anti-inflammatory material remains elusive. In the present study, various organic extracts from sea slater L. exotica were subjected to biological screening employing in vitro and in vivo models, and chemical phenotypes of the biologically active extract were deciphered by integrated gas chromatograph-mass spectrometry (GC-MS) profiling and MS/MS-based molecular networking. The results demonstrated, for the first time, that petroleum ether extract (PE) from L. exotica possessed remarkable anti-inflammatory and analgesic effects. Moreover, intragastric administration of PE at 200 mg/kg produced analgesic effects in both the writhing test and hot plate test. GC-MS analysis revealed that Z-9-hexadecenoic acid and 6-octadecenoic acid dominated in the volatile compositions of PE. Molecular networking (MN) suggested great chemical diversity within L. exotica. In total, 69 known compounds were identified in Ligia extracts by MS/MS spectral matching, and at least 7 analogues from two clusters of nitrogen-containing compounds (MN3,4) were strongly suggested as novel compounds. The molecular families MN1,3,4 were almost exclusively detected in the biologically active PE and ethyl acetate extract (EE). Importantly, various known compounds identified in MN1 were reported to possess analgesic and anti-inflammatory effects in the literature, which may contribute to the observed analgesic and anti-inflammatory effects of L. exotica. The present study not only demonstrated the ethnopharmaceutical value of L. exotica for pain-relief in Chinese folk medicine, but also suggested that sea slaters may represent a promising source for discovery of novel analgesic and anti-inflammatory compounds in the near future.

Background To investigate the analgesic effect of perioperative use of duloxetine in patients received total knee arthroplasty (TKA). Method This prospective randomized, double-blind, placebo-controlled trial study was registered in the Chinese Clinical Trial Registry (ChiCTR2000033910). 100 patients were finally enrolled. The hospital pharmacy prepared small capsules containing either duloxetine or starch (placebo) which were all identical in appearance and weight (50:50). The 100 enrolled patients were given a capsule (containing either 60 mg duloxetine or 60 mg placebo) every night before sleep since preoperative day 2 till postoperative day 14 (17 days in all) by a nurse who were not involved in this trial. Other perioperative managements were the same in the two groups. The primary outcome was the VAS score, including rVAS (visual analogue scale at rest) and aVAS (visual analogue scale upon ambulation) throughout the perioperative period. The secondary outcomes included opioid consumption, range of motion, including both active range of motion (aROM) and passive range of motion (pROM) and adverse events. The patients were followed up everyday until 7 days after TKA, afterwards, they were followed up at the time of 3 weeks and 3 months after TKA. Result rVAS in duloxetine group were significantly less than placebo group throughout the postoperative period: 4.7 ± 2.3 vs 5.9 ± 2.6 ( P  = 0.016) at 24 h postoperative; 2.1 ± 1.6 vs 2.8 ± 1.7 ( P  = 0.037) at 7 days postoperative. In terms of aVAS, similarly, duloxetine group had less aVAS than placebo group throughout the postoperative period: 6.2 ± 2.1 vs 7.1 ± 2.2 ( P  = 0.039) at 24 h postoperative; 3.3 ± 1.7 vs 4.1 ± 2.0 ( P  = 0.034) at 7 days postoperative. Patients in duloxetine group consumed significantly less opioids per day than the placebo group: 24.2 ± 10.1 g vs 28.5 ± 8.3 g ( P  = 0.022) at 24 h postoperative; 2.7 ± 2.5 g vs 4.1 ± 2.6 g ( P  = 0.007) at 7 days postoperative. aROM in duloxetine group were significantly better than placebo group until postoperative day 6, the aROM became comparable between the two groups: 110.2 ± 9.9° in duloxetine group vs 107.5 ± 11.5° in control group ( P  = 0.211). In terms of pROM, duloxetine group had significantly better pROM until postoperative day 5, the pROM became comparable between the two groups: 103.8 ± 12.1° in duloxetine group vs 99.5 ± 10.8° in control group ( P  = 0.064). No significant difference was found between the two groups in the rates of dizziness, bleeding, sweating, fatigue and dryness of mouth. In the placebo group, more patients got nausea/vomiting and constipation ( P  < 0.05). However, in terms of drowsiness, duloxetine group was reported higher rate ( P  < 0.05). Conclusion Several other RCTs have already mentioned the analgesic effect of duloxetine, but not in the immediate postoperative period. In this study, we found duloxetine could reduce acute postoperative pain in the immediate postoperative period and decrease the opioids consumption as well as accelerating postoperative recovery, without increasing the risk of adverse medication effects in patients undergoing TKA. Duloxetine could act as a good supplement in multimodal pain management protocol for patients undergoing TKA. Trial registration statement This study was registered in the Chinese Clinical Trial Registry (ChiCTR2000033910). The date of registration was 06/16/2020.

Kidney stones typically present as renal colic in emergency departments (EDs), where patients experience severe pain and often require parenteral therapy for symptom management. The economic burden associated with managing kidney stones exceeds USD 5 billion annually in the US and accounts for more than a million visits to EDs each year. There is clear evidence emphasizing the need for innovative and alternative pain control options for patients with renal colic. Recent randomized controlled trials suggest that intranasal (IN) and intravenous (IV) ketamine are as effective as parenteral NSAIDs and opioids in treating renal colic. However, the limited studies available show inconsistent results regarding the analgesic effects of ketamine. In this study, we reviewed the mechanism of action of ketamine for kidney stones, its efficacy in treating acute renal colic, and the potential adverse side effects of ketamine treatment. A population, intervention, comparison, and outcome (PICO)-related question was formulated to guide our research inquiry: “What are the effects of IV or IN ketamine, as a single agent or as an adjuvant (I), in adult patients diagnosed with acute renal colic (P) on pain scale scores and adverse side effects (O) compared to NSAIDs and/or opioids (C)?”

BACKGROUND: Members of the family Zingiberaceae including turmeric, ginger, Javanese ginger, and galangal have been used for centuries in traditional medicine. Preclinical studies of Zingiberaceae extracts have shown analgesic properties. This study aims to systematically review and meta-analyze whether extracts from Zingiberaceae are clinically effective hypoalgesic agents. METHODS: Literature was screened from electronic databases using the key words Zingiberaceae AND pain OR visual analogue score (VAS) to identify randomized trials. From this search, 18 studies were identified, and of these, 8 randomized, double-blinded, placebo-controlled trials were found that measured pain by VAS for inclusion in the meta-analysis. RESULTS: Findings indicated significant efficacy of Zingiberaceae extracts in reducing subjective chronic pain (SMD − 0.67; 95 % CI − 1.13 to − 0.21; P = 0.004). A linear dose-effect relationship was apparent between studies (R² = 0.71). All studies included in the systematic review reported a good safety profile for extracts, without the renal risks associated with non-steroidal anti-inflammatory drugs, and with similar effectiveness. CONCLUSION: Our findings indicated that Zingiberaceae extracts are clinically effective hypoalgesic agents and the available data show a better safety profile than non-steroidal anti-inflammatory drugs. However, both non-steroidal anti-inflammatory drugs and Zingiberaceae have been associated with a heightened bleeding risk, and there have been no comparator trials of this risk. Further clinical studies are recommended to identify the most effective type of Zingiberaceae extract and rigorously compare safety, including bleeding risk.

Background Meperidine is a synthetic opioid that belongs to the phenylpiperidine class and is a weak mu receptor agonist. In horses there are a limited number of published studies describing the analgesic effects of systemically administered meperidine in horses. The objective of this study was to describe the pharmacokinetics, behavioral and physiologic effects and effect on thermal threshold of three doses of intravenously administered meperidine to horses. Eight University owned horses (four mares and four geldings, aged 3–8 years were studied using a randomized balanced 4-way cross-over design. Horses received a single intravenous dose of saline, 0.25, 0.5 and 1.0 mg/kg meperidine. Blood was collected before administration and at various time points until 96 hours post administration. Plasma and urine samples were analyzed for meperidine and normeperidine by liquid chromatography-mass spectrometry and plasma pharmacokinetics determined. Behavioral and physiologic data (continuous heart rate, step counts, packed cell volume, total plasma protein and gastrointestinal sounds) were collected at baseline through 6 hours post administration. The effect of meperidine administration on thermal nociception was determined and thermal excursion calculated. Results Meperidine was rapidly converted to the metabolite normeperidine. The volume of distribution at steady state and systemic clearance (mean ± SD) ranged from 0.829 ± 0.138–1.58 ± 0.280 L/kg and 18.0 ± 1.4–22.8 ± 3.60 mL/min/kg, respectively for 0.5–1.0 mg/kg doses. Adverse effects included increased dose-dependent central nervous excitation, heart rate and cutaneous reactions. Significant effects on thermal nociception were short lived (up to 45 minutes at 0.5 mg/kg and 15 minutes at 1.0 mg/kg). Conclusions Results of the current study do not support routine clinical use of IV meperidine at a dose of 1 mg/kg to horses. Administration of 0.5 mg/kg may provide short-term analgesia, however, the associated inconsistent and/or short-term adverse effects suggest that its use as a sole agent at this dose, at best, must be cautiously considered.

With ongoing animal welfare efforts, multimodal analgesia is often recommended to implement in study protocols. Buprenorphine with very potent analgesic effect is a standard opioid for the use in this context in rats. In this study, two rat strains (LEW/NHanZtm, n = 6 and Crl:CD(SD), n = 8) underwent orthopaedic surgery and received carprofen, buprenorphine and a local anaesthetic in a multimodal setup. Crl:CD(SD) rats showed severe side effects in the first 24 h after anaesthesia, predominantly manifesting in pica-behaviour and reaching humane endpoints in two of eight animals, while LEW/NHanZtm rats showed only slight depression in the first postoperative days. In the context of improving animal welfare in experimental studies, buprenorphine is highly recommended not to be used in male Crl:CD(SD) rats and should generally be used very carefully and only if required.

Background Pain and impaired mobility because of osteoarthritis (OA) is common in dogs and humans. Efficacy studies of analgesic drug treatment of dogs with naturally occurring OA may be challenging, as a caregiver placebo effect is typically evident. However, little is known about effect sizes of common outcome-measures in canine clinical trials evaluating treatment of OA pain. Forty-nine client-owned dogs with hip OA were enrolled in a randomized, double-blinded placebo-controlled prospective trial. After a 1 week baseline period, dogs were randomly assigned to a treatment (ABT-116 – transient receptor potential vanilloid 1 (TRPV1) antagonist, Carprofen – non-steroidal anti-inflammatory drug (NSAID), Tramadol - synthetic opiate, or Placebo) for 2 weeks. Outcome-measures included physical examination parameters, owner questionnaire, activity monitoring, gait analysis, and use of rescue medication. Results Acute hyperthermia developed after ABT-116 treatment ( P < 0.001). Treatment with carprofen ( P ≤ 0.01) and tramadol ( P ≤ 0.001) led to improved mobility assessed by owner questionnaire. Nighttime activity was increased after ABT-116 treatment ( P = 0.01). Kinetic gait analysis did not reveal significant treatment effects. Use of rescue treatment decreased with treatment in the ABT-116 and Carprofen groups ( P < 0.001). Questionnaire score and activity count at the end of treatment were correlated with age, clinical severity at trial entry, and outcome measure baseline status (S R ≥ ±0.40, P ≤ 0.005). Placebo treatment effects were evident with all variables studied. Conclusion Treatment of hip OA in client-owned dogs is associated with a placebo effect for all variables that are commonly used for efficacy studies of analgesic drugs. This likely reflects caregiver bias or the phenomenon of regression to the mean. In the present study, outcome measures with significant effects also varied between groups, highlighting the value of using multiple outcome measures, as well as an a priori analysis of effect size associated with each measure. Effect size data from the present study could be used to inform design of future trials studying analgesic treatment of canine OA. Our results suggest that analgesic treatment with ABT-116 is not as effective as carprofen or tramadol for treatment of hip arthritis pain in client-owned dogs.

Neuropathic pain (NP) is a frequent condition caused by a lesion in, or disease of, the central or peripheral somatosensory nervous system and is associated with excessive inflammation in the central and peripheral nervous systems. Repetitive transcranial magnetic stimulation (rTMS) is a supplementary treatment for NP. In clinical research, rTMS of 5–10 Hz is widely placed in the primary motor cortex (M1) area, mostly at 80%–90% RMT, and 5–10 treatment sessions could produce an optimal analgesic effect. The degree of pain relief increases greatly when stimulation duration is greater than 10 days. Analgesia induced by rTMS appears to be related to reestablishing the neuroinflammation system. This article discussed the influences of rTMS on the nervous system inflammatory responses, including the brain, spinal cord, dorsal root ganglia (DRG), and peripheral nerve involved in the maintenance and exacerbation of NP. rTMS has shown an anti-inflammation effect by decreasing pro-inflammatory cytokines, including IL-1β, IL-6, and TNF-α, and increasing anti-inflammatory cytokines, including IL-10 and BDNF, in cortical and subcortical tissues. In addition, rTMS reduces the expression of glutamate receptors (mGluR5 and NMDAR2B) and microglia and astrocyte markers (Iba1 and GFAP). Furthermore, rTMS decreases nNOS expression in ipsilateral DRGs and peripheral nerve metabolism and regulates neuroinflammation.