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Patients with refractory chronic migraine have substantial disability and have failed many acute and preventive medications. When aggressive intravenous therapy is indicated, both lidocaine and (R,S)-ketamine infusions have been used successfully to provide relief. Retrospective studies have shown that both agents may be associated with short-term analgesia. In this prospective, observational pilot study of 6 patients we compared the effects of lidocaine and (R,S)-ketamine infusions and performed metabolite analyses of (R,S)-ketamine to determine its metabolic profile in this population. One of (R,S)-ketamine's metabolites, (2R,6R)-hydroxynorketamine, has been shown in animal studies to reduce pain but human studies in patients undergoing continuous (R,S)-ketamine infusions for migraine are lacking. All 6 patients tolerated both infusions well with mild adverse effects. The baseline mean pain rating (0-10 numeric rating scale) decreased from 7.5 ± 2.2 to 4.7 ± 2.8 by end of lidocaine treatment (p?0.05) but increased to 7.0 ± 1.4 by the post-discharge visit at 4 weeks (p>0.05 versus baseline). The baseline mean pain rating prior to ketamine treatment was 7.4 ± 1.4, which decreased to 3.7 ± 2.3 by the end of the hospitalization (p?0.05), but increased to 7.2 ± 1.7 by the post-discharge visit at 6 weeks (p>0.05 versus baseline). For the primary outcome the change in pain from baseline to end of treatment was greater for ketamine than lidocaine (-3.7 versus -2.8, p?0.05) but this has minimal clinical significance. Ketamine metabolite analysis revealed that (2R,6R)-hydroxynorketamine was the predominant metabolite during most of the infusion, consistent with previous studies. This article is protected by copyright. All rights reserved.
Learn More >To discuss the treatment of post-traumatic headache (PTH) and how to choose pharmacotherapy based upon known pathophysiology.
Learn More >Noninvasive vagus nerve stimulation (nVNS) has not only shown antinociceptive effects, but also demonstrated anti-inflammatory and antidepressant effects. These effects could be beneficial in chronic pancreatitis (CP) patients suffering from chronic abdominal pain, even though the underlying central mechanisms remain unclear. The aim was to investigate the effect of cervical nVNS in patients with painful CP on brain functional connectivity and cerebral metabolites.
Learn More >Analgesics that contain codeine are commonly prescribed for postoperative pain, but it is unclear how they compare with nonopioid alternatives. We sought to compare the effectiveness of codeine and nonsteroidal anti-inflammatory drugs (NSAIDs) for adults who underwent outpatient surgery.
Learn More >Transient receptor potential vanilloid type 3 (TRPV3) is a Ca permeable nonselective cation channel and expressed abundantly in skin keratinocytes. TRPV3 emerges as an attractive target for treatment of pruritic, inflammatory, pain and skin-related diseases. However, only a few reports of TRPV3 inhibitors exist at present besides some patents. Therefore, TRPV3 research has always been fraught with challenges. Through a combination of virtual screening and biological evaluation, compound P1 (10 μM) was identified as a top hit with 34.5% inhibitory effect on 2-APB (1 mM)-evoked currents of mTRPV3-WT. Further structural optimization provided the inhibitor PC5 with the best activity (IC = 2.63 ± 0.28 μM), and point mutation assays indicated that amino acids V629 and F633 are crucial for the binding of PC5 and TRPV3. In summary, these newly discovered inhibitors could serve as promising lead compounds for the development of TRPV3 inhibitors in the future.
Learn More >Cebranopadol, a mixed nociceptin/opioid receptor full agonist, can effectively relieve pain in rodents and humans. However, it is unclear to what degree different opioid receptor subtypes contribute to its antinociception and whether cebranopadol lacks acute opioid-associated side effects in primates. The authors hypothesized that coactivation of nociceptin receptors and μ receptors produces analgesia with reduced side effects in nonhuman primates.
Learn More >Morphine is widely used in pain management although the risk of side effects is significant. The use of biased agonists to the G protein of μ-opioid receptors has been suggested as a potential solution, although oliceridine and PZM21 have previously failed to demonstrate benefits in clinical studies. An amplification-induced confusion in the process of comparing G protein and beta-arrestin pathways may account for previously biased agonist misidentification. Here, we have devised a strategy to discover biased agonists with intrinsic efficacy. We computationally simulated 430 000 molecular dockings to the μ-opioid receptor to construct a compound library. Hits were then verified experimentally. Using the verified compounds, we performed simulations to build a second library with a common scaffold and selected compounds that showed a bias to μ- and δ-opioid receptors in a cell-based assay. Three compounds (ID110460001, ID110460002, and ID110460003) with a dual-biased agonistic effect for μ- and δ-opioid receptors were identified. These candidates are full agonists for the μ-opioid receptor and show specific binding modes. On the basis of our findings, we expect our novel compounds to act as more biased agonists compared to existing drugs, including oliceridine.
Learn More >Downregulation of astrocytic connexin43 (Cx43) has been observed in several brain regions in rodents and patients with depression. However, its specific role in this effect remains unknown. Moreover, chronic pain can induce depressive disorders. Therefore, the current study examined the relationship between Cx43 expression and depressive-like behavior in a neuropathic pain model. Neuropathic pain was induced by spared nerve injury (SNI) in mice. Depressive-like behavior was evaluated using the forced swim test. Expression of Cx43 in the hippocampus was evaluated using Western blotting and real-time PCR. SNI downregulated Cx43 protein in the contralateral hippocampus of mice, whereas expression of hippocampal Cx43 mRNA was not altered following SNI. Although SNI mice showed longer immobility time compared with sham mice during the forced swim test, duration of depressive-like behavior was not correlated with the expression of Cx43 in the hippocampus of SNI mice. Repeated intraperitoneal administration of amitriptyline ameliorated SNI-induced depressive-like behavior. Furthermore, the antidepressant effect of amitriptyline was correlated with decreased hippocampal Cx43 expression in SNI mice. The current findings suggest that the alteration of Cx43 expression in the hippocampus may not be involved in the induction of depressive disorder but may influence the efficacy of antidepressants. Therefore, the level of Cx43 expression in the hippocampus could be a key parameter to evaluate individual differences in antidepressant effects in patients with depressive disorder.
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