Study of Correction of Somatic Pain under the Conditions of Experimental Pathology of Multiple Sclerosis

The purpose of the study was to experimentally substantiate the ways of pharmacological correction of somatic pain syndrome in conditions of the experimental equivalent of multiple sclerosis through a comparative system analysis and the use of complex methodological approaches. Materials and methods. To study multiple sclerosis, we used an experimental model with autoimmune mechanisms of inflammatory demyelination – a model of experimental allergic encephalomyelitis. To assess the antinociceptive activity of painkillers, we used the method of electrical stimulation of the rats’ tail root. The activity of the enzyme prostaglandin H-synthetase was also determined. Results and discussion. A comparative analysis of the analgesic activity indicators of combinations of methylprednisolone with analgesics under the condition of the formed experimental allergic encephalomyelitis showed that their antinociceptive potential (taking into account the basic therapy with methylprednisolone) decreased in the series meloxicam > lornoxicam ≈ ketorolac ≈ paracetamol > celecofenacoxib ≈ sodium diclofupene ≈ diclofupene ≈ diclofupene. Accordingly, the maximum effect on the threshold of nociception under these experimental conditions was exerted by meloxicam and lornoxicam. The combined administration of methylprednisolone with diclofenac sodium, celecoxib and meloxicam reduced the activity of prostaglandin N-synthetase in the brain structures by 49.8% (p <0.05), 50.4% (p <0.05) and 51% (p <0.05), respectively, compared with the indicators of the control group. The same drugs markedly reduced the activity of prostaglandin N-synthetase in the spinal cord by 23.9% (p <0.05) (Methylprednisolone + diclofenac), by 34% (p <0.05) (Methylprednisolone + celecoxib) and by 47.4% (p <0.05) (Methylprednisolone + meloxicam) compared with the control group. Our analysis of the analgesic activity of antidepressants and anticonvulsants as means of correcting nociceptive pain in experimental allergic encephalomyelitis found that their antinociceptive potential was inferior to the severity of the analgesic effect of nonsteroidal anti-inflammatory drugs. Conclusion. Among the studied non-steroidal anti-inflammatory drugs, antidepressants and anticonvulsants, the maximum therapeutic efficacy as a means of correcting nociceptive pain in experimental allergic encephalomyelitis against the background of basic methylprednisolone therapy was shown by meloxicam, which gives grounds to recommend it as the analgesic of choice for eliminating somatic pain syndromes

Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists

<p>Chronic pain causes patients to endure prolonged suffering and discomfort, often having profound effects on quality of life. In New Zealand, one in five people currently suffer from chronic pain. To treat chronic pain, patients are typically prescribed drugs that activate the mu opioid receptor (MOPr), such as morphine, codeine and oxycodone. In recent years in the United States of America, there has been a rapid increase in the use of prescription and non-prescription opioid drugs, with opioid overdoses now the leading cause of accidental death. In New Zealand, daily doses of prescription opioids quadrupled in the ten year period from 2001-2011. Clearly, there is a need for the development of more effective and safe medications. This thesis evaluated two classes of non-addictive compounds: bioactive lipids and kappa opioid receptor (KOPr) agonists. N-docosahexaenoyl ethanolamine (DHEA) is an N-acyl ethanolamine class lipid that is structurally similar to the endocannabinoid anandamide. DHEA has previously been shown to have immune-modulatory effects in vitro, however, the in vivo effects have not previously been tested. Using the intraplantar 2% formaldehyde model in mice, DHEA reduced inflammatory and nociceptive pain via both intraperitoneal (i.p.) and local intraplantar (i.pl.) administration. DHEA significantly reduced formaldehyde-induced footpad oedema and reduced the infiltration of neutrophils into the inflamed tissue. The antinociceptive and anti-oedematous effects were not modulated by pre-treatment with either cannabinoid 1- or 2-type receptor antagonists. DHEA did not have any effect in a thermal nociceptive pain model and did not show any motor coordination impairment or changes in thermoregulation. In the search for non-addictive analgesics, KOPr agonists are a promising alternative. In contrast to MOPr agonists, KOPr agonists play a critical role in regulating the reward system. Salvinorin A (SalA) is a selective KOPr agonist that has antinociceptive and anti-inflammatory effects in vivo, with limited abuse potential. However, the short duration of action and aversive side effects limit the clinical usefulness. The present study aimed to investigate the antinociceptive effects of acute administration of novel analogues of SalA. In the dose-response tail withdrawal assay, SalA and the novel analogues 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail withdrawal assay and the hot plate test compared to SalA. In the intraplantar 2% formaldehyde test, SalA, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced nociceptive pain and inflammatory pain, effects which were reversed by the KOPr antagonist nor-binaltorphimine. SalA, 16-Ethynyl SalA and 16-Bromo SalA reduced paw oedema and reduced the infiltration of neutrophils into the inflamed tissue. However, SalA, 16-Ethynyl SalA and 16-Bromo SalA produced motor incoordination effects. However, 16-Ethynyl SalA did not alter thermoregulation. The KOPr agonists were further assessed in a model of paclitaxel-induced neuropathic pain. In the acute dose-response experiment, 16-Ethynyl SalA was significantly more potent at reducing mechanical allodynia compared to morphine in both male and female mice. SalA and 16-Ethynyl SalA were more potent at reducing cold allodynia than morphine. In a chronic administration model over 22 days, for the treatment of cold and mechanical allodynia, all of the opioid treatments reduced pain, however, the traditional KOPr agonist U50,488, was the most potent, by reducing the male mechanical allodynia and cold allodynia in both sexes back to baseline levels. The ultrastructure of the sciatic nerves were studied, however, it was found that U50,488 did not reverse the effects of paclitaxel on myelin degeneration and mitochondrial damage. Overall, this study has identified DHEA as a modest treatment for inflammatory pain, with reduced side effects and a mechanism of action in contrast to other compounds with a similar structure. The novel KOPr agonists had significant effects in acute pain models with longer duration of action than the parent compound SalA. This is the first known study to investigate the effects of KOPr agonists in a paclitaxel-induced neuropathic pain model, showing that KOPr agonists are a potential therapeutic avenue for this debilitating condition.</p>

Investigating the antinociceptive effects of N-docosahexaenoyl ethanolamine and novel kappa opioid receptor agonists

<p>Chronic pain causes patients to endure prolonged suffering and discomfort, often having profound effects on quality of life. In New Zealand, one in five people currently suffer from chronic pain. To treat chronic pain, patients are typically prescribed drugs that activate the mu opioid receptor (MOPr), such as morphine, codeine and oxycodone. In recent years in the United States of America, there has been a rapid increase in the use of prescription and non-prescription opioid drugs, with opioid overdoses now the leading cause of accidental death. In New Zealand, daily doses of prescription opioids quadrupled in the ten year period from 2001-2011. Clearly, there is a need for the development of more effective and safe medications. This thesis evaluated two classes of non-addictive compounds: bioactive lipids and kappa opioid receptor (KOPr) agonists. N-docosahexaenoyl ethanolamine (DHEA) is an N-acyl ethanolamine class lipid that is structurally similar to the endocannabinoid anandamide. DHEA has previously been shown to have immune-modulatory effects in vitro, however, the in vivo effects have not previously been tested. Using the intraplantar 2% formaldehyde model in mice, DHEA reduced inflammatory and nociceptive pain via both intraperitoneal (i.p.) and local intraplantar (i.pl.) administration. DHEA significantly reduced formaldehyde-induced footpad oedema and reduced the infiltration of neutrophils into the inflamed tissue. The antinociceptive and anti-oedematous effects were not modulated by pre-treatment with either cannabinoid 1- or 2-type receptor antagonists. DHEA did not have any effect in a thermal nociceptive pain model and did not show any motor coordination impairment or changes in thermoregulation. In the search for non-addictive analgesics, KOPr agonists are a promising alternative. In contrast to MOPr agonists, KOPr agonists play a critical role in regulating the reward system. Salvinorin A (SalA) is a selective KOPr agonist that has antinociceptive and anti-inflammatory effects in vivo, with limited abuse potential. However, the short duration of action and aversive side effects limit the clinical usefulness. The present study aimed to investigate the antinociceptive effects of acute administration of novel analogues of SalA. In the dose-response tail withdrawal assay, SalA and the novel analogues 16-Ethynyl SalA and 16-Bromo SalA were more potent than the traditional KOPr agonist U50,488, and 16-Ethynyl SalA was more efficacious. 16-Ethynyl SalA and 16-Bromo SalA both had a longer duration of action in the warm water tail withdrawal assay and the hot plate test compared to SalA. In the intraplantar 2% formaldehyde test, SalA, 16-Ethynyl SalA and 16-Bromo SalA significantly reduced nociceptive pain and inflammatory pain, effects which were reversed by the KOPr antagonist nor-binaltorphimine. SalA, 16-Ethynyl SalA and 16-Bromo SalA reduced paw oedema and reduced the infiltration of neutrophils into the inflamed tissue. However, SalA, 16-Ethynyl SalA and 16-Bromo SalA produced motor incoordination effects. However, 16-Ethynyl SalA did not alter thermoregulation. The KOPr agonists were further assessed in a model of paclitaxel-induced neuropathic pain. In the acute dose-response experiment, 16-Ethynyl SalA was significantly more potent at reducing mechanical allodynia compared to morphine in both male and female mice. SalA and 16-Ethynyl SalA were more potent at reducing cold allodynia than morphine. In a chronic administration model over 22 days, for the treatment of cold and mechanical allodynia, all of the opioid treatments reduced pain, however, the traditional KOPr agonist U50,488, was the most potent, by reducing the male mechanical allodynia and cold allodynia in both sexes back to baseline levels. The ultrastructure of the sciatic nerves were studied, however, it was found that U50,488 did not reverse the effects of paclitaxel on myelin degeneration and mitochondrial damage. Overall, this study has identified DHEA as a modest treatment for inflammatory pain, with reduced side effects and a mechanism of action in contrast to other compounds with a similar structure. The novel KOPr agonists had significant effects in acute pain models with longer duration of action than the parent compound SalA. This is the first known study to investigate the effects of KOPr agonists in a paclitaxel-induced neuropathic pain model, showing that KOPr agonists are a potential therapeutic avenue for this debilitating condition.</p>

There Is Association between Type of Pain and Hematologic Disorders

Background: Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage according to the International Association for the Study of Pain. Aim: To estimate distinguishing features of the pain in patients with blood disorders. Patients and Methods: The prospective exploratory study was conducted in the National Research Center for Hematology, Moscow from 11/2015 to 01/2021. In total, 40 patients (pts) with blood disorders who had a difficult-to-control pain syndrome were included in the study. There were 21 men (median age of 41.5, IQR 35.0-56.3 years) and 19 women (median age of 40, IQR 34.3-56.0 years). The pain types were determined according to clinical symptoms and the use of special questionnaires (i.e., the Douleur Neuropathique 4 Questions questionnaire for neuropathic pain). Pressure algometry was used to assess pain tolerance of the non-dominant hand by evaluating the pressure pain threshold (PPT, kg/cm 2), which is the minimum pressure required to induce pain. Results: Four types of pain were identified: neuropathic in 9 pts (22.5%), nociceptive in 9 pts (22.5%), their mix (summing up to a half of the total number of cases ‒ 52.5%, 21 pts) and dysfunctional pain in only 1 patient (2.5%). The distribution based on the pain types was uneven (Kolmogorov test, p = 0.05). The different pain types were related with various distributions of blood disorders: lymphoid tumor (44.5%), myeloid tumor (33.3%) and not tumor (22.2%) (associated with neuropathic pain) and myeloid tumor (88.9%) and not tumor (11.1%) (associated with nociceptive pain) (Figs. 1 and 2) . The tolerance of neuropathic and nociceptive pain types turned out to be significantly different (PPT medians with 95% CI): 2.2 kg/cm 2 (1.6-3.1) vs. 4.6 kg/cm 2 (3.9-5.5), respectively, and (found in ROC-analysis) the cut-off was 3.2 kg/cm 2,AUC (the area under ROC curve) 96.3%, sensitivity and specificity 88.8% (Fig. 3 and 4). PPT cut-off points, that shares the mixed pain (median 2.7 kg/cm 2, 95 CI 1.9-3.6) on the neuropathic and nociceptive pain are: 3.2 kg/cm 2 (AUC 67.0%) and 3.8 kg/cm 2 (AUC 86.7%), respectively. Several measurements of PPT (with taking into account the cut-off) in patient, suffering from pain, can help identify with a high probability his type of pain, and accordingly (indirectly), his blood type disorder. Conclusions: Measuring PPT in a pts with blood disorders allows to identify the type of pain (neuropathic, nociceptive, or combined), which can serve as an additional source of information for accurate diagnosis and treatment. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Ropivacaine magnetic nanoparticles: An efficient local anesthetic nerve conduction blocker

Ropivacaine (Rop) is one of the commonly used local nerve blocks in clinical anesthesia and postoperative analgesia and it inhibits the stimulation of peripheral nociceptive pain. However, Rop alone is not effective enough to exert a controllable anesthetic effect in patients with peripheral nociceptive pain. Therefore, there is an urgent need to improve the targeting of the local anesthetic effect of Rop and reduce its potential chronic or acute toxicity. In this study, a novel Rop nanocomposite hydrogel drug, N-isopropylacrylamide-methacrylic acid/ropivacaine magnetic nanoparticles (NIP-MAA/Rop MNPs), was constructed on magnetic iron oxide. The unique pH and temperature response of NIP-MAA can effectively retain magnetic properties, improve the stability and targeting controllability of magnetic nanoparticles, and avoid excessive drug diffusion. Therefore, the NIP-MAA/Rop MNPs is expected to open a new field of vision for the research of clinical anesthesia and postoperative analgesia.

Prevalence of Neuropathic Pain Varies in Patients With Knee Osteoarthritis in Different Treatment Stages

Background: Pain is the main symptom of knee osteoarthritis (KOA) and can be classified as nociceptive pain and neuropathic pain (NP). However, the prevalence and risk factors of NP in patients with KOA at different treatment stages vary in countries and are still unclear in China.Methods: Patients in this retrospective study were divided into three groups according to treatment stage, including outpatient stage, preoperative total knee arthroplasty (pre-TKA) stage and postoperative TKA stage (post-TKA). A numeric rating scale (NRS) and PainDETECT questionnaire were used to evaluate nociceptive pain and NP. Patient demographics, radiological assessments using Kellgren-Lawrence (K-L) grades, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores were analyzed.Results: Of the 921 patients, the prevalence of possible and likely NP was 17.5% (56/320) and 2.5% (8/320) in the pre-TKA group compared with 3.4% (8/233) and 0.4% (1/233) in the outpatient group and 1.4% (5/368) and 0.5% (2/368) in the post-TKA group, respectively. In the pre-TKA group, higher NRS (NRS>3; OR=10.65, 95% CI: 3.25-34.92, p<0.001) and WOMAC pain (WOMAC>10; OR=4.88, 95% CI: 2.38-10.01, p<0.001) scores conferred an increased risk of unclear pain. Age, gender, BMI and K-L grade showed no significant differences among the unlikely, possible and likely NP groups.Discussion: Different prevalence of NP occur in KOA patients at different treatment stages. Due to the low prevalence of NP in the outpatient and post-TKA groups, we suggest not regularly screening for NP in these patients, while it may be essential to screen for NP in patients waiting for TKA. In the latter group, higher NRS and WOMAC pain scores are important risk factors of NP.

Methadone and neuropathic cancer pain subcomponents: a prospective cohort pilot study

Forty per cent of cancer pain associate neuropathic and nociceptive pain simultaneously, and refractory pain affects 15% of cancer pain. Methadone is an effective opioid in treating nociceptive pain and could have an effect on neuropathic pain. Uncertainty remains on its effects on the different subcomponents of neuropathic pain.ObjectivesTo identify which subcomponents of neuropathic cancer pain are addressed using methadone.MethodsAn observational prospective cohort study of palliative care inpatients after rotation for refractory neuropathic cancer pain. Pain intensity was assessed weekly for 28 days, using a Visual Analogue Scale (VAS) and the Neuropathic Pain Symptom Inventory (NPSI).ResultsForty-eight patients were included and 17 completed the 28 days follow-up. VAS pain rating decreased by at least 20 mm in 47% of patients and the pain intensity was significantly lower at day 28 with 53% of patients with a VAS inferior to 4 (p<0.001). The pressure/squeezing component (NPSI score) decreased by more than 2 points in 50% of patients.A linear regression showed allodynia and pressure/squeezing were responsible for the largest part of the overall alleviation of pain (p=0.01).ConclusionsMethadone could significantly improve neuropathic pain through a targeted effect of allodynia and its pressure/squeezing component.