Rejected

Interstitial cystitis (IC)/bladder pain syndrome (BPS) is a chronic bladder disease of unknown etiology characterized by urinary frequency and episodic and chronic pain. Analgesic treatments for IC/BPS are limited, especially for patients with non-Hunner (non-ulcerative) type IC who usually have poor overall outcomes. Here, we demonstrate that oral treatment with DF2755A, a potent and selective inhibitor of chemokine receptors CXCR1/2, can prevent and reverse peripheral neuropathy associated to non-Hunner IC/BPS by directly inhibiting chemokine-induced excitation of sensory neurons. We tested DF2755A antinociceptive effects in a cyclophosphamide (CYP)-induced non-ulcerative IC rat model characterized by severe peripheral neuropathy in the absence of bladder inflammatory infiltrate, urothelial hyperplasia, and hemorrhage. Treatment with DF2755A prevented the onset of peripheral neuropathy and reversed its development in CYP-induced IC rats, showing a strong and long-lasting anti-hyperalgesic effect. and studies showed that DF2755A treatment strongly inhibited the expression of CXCR2 agonists, CXCL1/KC, and CXCL5 and of transient receptor potential vanilloid 1 (TRPV1) compared to vehicle, suggesting that its effects can be due to the inhibition of the nociceptive signaling passing through the CXCL1/CXCR1-2 axis and TRPV1. In conclusion, our results highlight the key pathophysiological role played by the CXCL1/CXCR1-2 axis and TRPV1 in the onset and development of peripheral neuropathy in non-Hunner IC and propose DF2755A as a potential therapeutic approach for the treatment of not only inflammatory painful conditions but also neuropathic ones and in particular non-Hunner IC/BPS.

The aim of this study was to determine whether the use of analgesia and sedation (AS) as opposed to general anesthesia (GA) for closed reduction and spica casting of children with severe developmental dysplasia of the hip (DDH) influenced the long-term incidence of avascular necrosis (AVN). In a prospective, randomized, single-blinded clinical trial we investigated 100 pediatric patients with DDH type IIIa, IIIb, and IV (according to Graf classification), who were randomly assigned into the group receiving AS, and the group receiving GA. Baseline demographics, splint duration, and type of DDH were carefully assessed. The presence of AVN was assessed at the follow-up visits at 1 and 7 years after the end of treatment. The AS-group consisted of 50 patients (46 girls) with 76 hips affected ( = 11/Type-IIIa, = 32/Type-IIIb, and = 33/Type-IV). The GA-group consisted also of 50 patients (44 girls) with 78 hips involved ( = 15/Type-IIIa, = 34/Type-IIIb, and = 29/Type-IV). At 7-years follow-up, AVN was diagnosed in 9 of 154 hips (5.8%), 5 hips in the AS-group and 4 hips in the GA group. The logistic regression model showed no significant difference in AVN incidence between the AS and GA groups at 7-years follow-up ( = 0.27). The multivariate regression analysis showed that neither the type of DDH nor the age at diagnosis influenced the incidence of AVN ( = 0.48 and = 0.28, respectively). Splint duration was identified as the only significant factor for the long-term incidence of AVN in the treatment of severe DDH. For every month of longer splint duration, the odds of AVN at 7-years follow-up increased by a factor of 3.81 (95%: 1.35-13.73, = 0.02). Closed reduction and spica casting of children with severe DDH under AS can be considered a feasible alternative to management under GA. All efforts must be made to diagnose patients with DDH as early as possible and shorten the duration of splint treatment to prevent the development of AVN. Level of Evidence. Level II-1.

This study investigated the effects of gastrodin (GAS) on analgesic, anxiolytic, ferroptosis, and jejunal microbiota in chronic inflammatory pain mice. The chronic inflammatory pain model of C57BL/6J mice was established by hindpaw injection of complete Freund's adjuvant (CFA). After GAS treatment, thermal hyperalgesia test, mechanical allodynia test, elevated plus-maze (EPMT), and open-field test (OFT) were performed to assess the behavioral changes of pain and anxiety. mRNAs of FTHI, GPX4, HO-1, and PTGS2 and jejunal microbiota were measured by qPCR. In CFA-injected C57BL/6 mice, we found that the mechanical and thermal pain threshold were increased with treatment of GAS. In EPMT, the number of entries in open arms and retention times of open arms were increased by GAS. In the OFT, the time spent in the central area was also increased. Furthermore, GAS enhanced mRNA expressions of FTHI, GPX4, and HO-1 but decreased the expression of PTGS2 in a dose-dependent manner. GAS is effective in the treatment of mice chronic inflammatory pain and anxiety-like behaviors. It may be exhibits potential neuroprotective effects through inhibition of ferroptosis independently of the intestinal microbiota.

Chronic noncancer pain (CNCP) affects up to 20% of adults and can interfere with activities of daily living. Up to 4% of adults in the United States receive chronic opioid therapy and up to 57% of patients on long-term opioids for CNCP report opioid-induced constipation (OIC). OIC is essentially constipation occurring after starting opioid treatment. While laxatives are traditionally the first-line therapy for OIC, 81% of patients taking daily laxatives and opioids still reported OIC and considered that it negatively affected their quality of life. Naldemedine is a peripherally acting µ-opioid receptor antagonists (PAMORA) approved for the treatment of OIC in patients with CNCP. This article reviews the mechanism of action, efficacy, and safety of naldemedine in CNCP patients. Naldemedine improves OIC in patients with CNCP by acting as an opioid receptor antagonist in the gastrointestinal tract. It does not interfere with the analgesic properties of opioids or cause withdrawal symptoms since these effects are centrally mediated, and naldemedine does not cross the blood brain barrier. Naldemedine showed significant and sustained improvement in frequency of bowel movements, quality of life, and constipation-related symptoms. It is generally well tolerated with a higher incidence of gastrointestinal adverse events of mild or moderate severity such as diarrhea, abdominal pain, or vomiting compared to placebo. While there are no randomized, controlled trials that compare head-to-head pharmacological therapies used for treatment of OIC, network meta-analysis shows that naldemedine has an overall good benefit-risk profile compared to the other approved medications.

Low back pain is the leading cause of years lived with disability worldwide. Chiropractors employ different interventions to treat low back pain, including spinal manipulative therapy, although the mechanisms through which chiropractic care improves low back pain are still unclear. Clinical research and animal models suggest that spinal manipulation might modulate plasma levels of inflammatory cytokines, which have been involved in different stages of low back pain. More specifically, serum levels of Tumor Necrosis Factor-alpha (TNF-α) have been found to be elevated in patients with chronic low back pain. We aimed to investigate whether urine from chronic low back pain patients could be an appropriate medium to measure concentrations of TNF-α and to examine possible changes in its levels associated to chiropractic care.

Mindfulness meditation has become a successful treatment of both physical and psychosocial ailments over the past decade. Mindfulness-Based Stress Reduction (MBSR) and Mindfulness-Based Cognitive Therapy (MBCT) are now implemented in various clinical and hospital settings for the treatment of stress, depression, substance abuse, and chronic pain. However, given mindfulness meditation's exponential rise in popularity, scientific and media reports have called for the evaluation of mindfulness meditation's safety for those who participate in its programs. Studies have described adverse events, such as anxiety and pain, and more severe events like psychosis, that have been associated with mindfulness meditation. However, there has not been a consistent, systematic way to define and report adverse events in meditation randomized control trials. The objective of our viewpoint was to dispel the notion that these emotive feelings and sensations are adverse events due to mindfulness meditation. Instead, they are actually expected reactions involved in the process of achieving the true benefits of mindfulness meditation. For the more severe outcomes of meditation, for example, psychosis and mania, these events are confounded by other factors, such as the intensity and length of the meditative practices as well as psychological stressors and the psychiatric histories of those affected. Comparatively, mindfulness-based programs like MBSR and MBCT are shorter in duration and less intense. They are designed to be adapted to their participants' needs as to not induce pain or panic. Mindfulness meditation teaches its students to learn how to deal with their minds and bodies instead of using maladaptive coping techniques. Thus, we urge that further research in mindfulness meditation consistently use the definition of adverse events as those which lead to severe outcomes or hospitalization.

Tourniquet has emerged as an important role in surgical procedures, sixty patients undergoing elective total knee arthroplasty are randomly divided into the nerve block group and adductor duct block group in this paper. The changes of mean arterial pressure (MAP) and heart rate (HR) at different time points during operation, the changes of VAS scores at resting pain and exercise pain, and the changes of quadriceps femur muscle strength at different time points after operation are observed in 2 groups. The experimental results show that compared with adductor duct block, femoral nerve block can better relieve the intraoperative tourniquet reaction without affecting the postoperative analgesic effect and the muscle strength of quadriceps femurs.

The mutism caused by hematoma after subarachnoid hemorrhage (SAH) is extremely rare, and the details of its clinical course have not been clarified.

This chapter deals with the mechanisms modulating pain during TI and other immobility responses in different animal species. In mammals the presence of high voltage slow waves in the electroencephalogram during TI suggests the activation of the thalamic gate, a mechanism blocking all sensory information, including pain. In rabbits TI transiently suppresses all the behavioral responses to persistent nociceptive stimulation by the activation of an opioid mechanism outlasting TI offset by 1h. On the other hand, in rodents, also not injuring nociceptive stimuli applied during TI elicit a delayed opioid analgesia that develops within 45min. Moreover, both opioid and non-opioid mechanisms of analgesia have been observed. TI strongly reduces inflammatory responses by activating the vagal-neocortical-sympathetic axis, a feedback control of neuro-immune mechanisms. Several models of noxious and non-noxious restraint and of post-restraint immobility resembling TI have been proposed. Moreover in lizards, hyperalgesia occurs during and after TI.

Migraine is one of the most common types of headache, and it is the second most common cause of neurological disorders, with an annual prevalence of about 15% of the population. This study aimed to evaluate the effect of BoNT-A on the duration and intensity of migraine attacks. In addition, we investigated the effective injection sites.