Rejected

Multiple head-to-head trials have demonstrated that topical nonsteroidal anti-inflammatory drugs (NSAIDs), including topical diclofenac, provide at least equivalent analgesia, improvement in physical function, and reduction of stiffness compared with oral NSAIDs in osteoarthritis and have fewer systemic adverse events. While efficacy of topical diclofenac in osteoarthritis is well established, understanding of the time to onset of action, duration of effect, and the minimum effective concentration is limited. Factors likely to influence these parameters include drug penetration and localization. Diclofenac concentrations in the joint tissues are likely to be more relevant than plasma concentrations. However, although diclofenac penetrates and is retained in these "effect compartments" at the site of inflammation and drug activity, no specific minimum effective concentration of diclofenac in plasma or synovial tissue has been identified. Recent evidence suggests that a reduction in inflammatory markers may be a better predictor of efficacy than plasma concentrations. This narrative review explores existing evidence in these areas and identifies the gaps where further research is needed. Based on our findings, topical NSAIDs such as diclofenac should be considered as a guideline-supported, generally well-tolerated, and effective first-line treatment option for knee and hand OA, especially for older patients and those who have comorbid conditions and/or risk factors for various systemic (gastrointestinal, hepatic, renal, or cardiovascular) adverse events associated with oral NSAIDs, particularly at high doses and with long-term use.

Notalgia paresthetica (NP) is a neuropathic itching condition unilaterally localized in the midscapular area. It is a common but an underdiagnosed disease, and only a few studies investigating NP etiology with a limited number of patients have been reported in the literature.

The proportion of recurrent repairs in the total collective of inguinal hernia repairs among men is 11.3-14.3% and among women 7.0-7.4%. The rate of re-recurrences is reported to be 2.9-9.2%. To date, no case series has been published on second and ≥ third recurrences and their treatment outcomes. Only case reports are available.

An effective and safe pain management is nowadays a pivotal component of fast-track endoprosthetics. The analgesic strategies should be opioid-sparing whenever possible because opioids induce side-effects that reduce the well-being of patients and are even associated with a risk of falling. This is not compatible with a fast mobilization. In order to achieve this goal, multimodal pain concepts have proven to be suitable. Decentralized analgesia with epidural and regional catheters as well as the use of local infiltration anesthesia (LIA) can be used; however, catheters are also associated with a muscular deficit and the danger of falling. Therefore, in the fast-track concepts LIA has become established. With respect to knee endoprosthetics many studies have shown that LIA achieves at least comparable results or even superiority in comparison with the use of catheters. It represents a safe and effective procedure with respect to postoperative analgesia and accelerated mobilization. A variety of protocols for the use of LIA can currently be found in the literature. In addition to analgesics the supportive administration of glucocorticoids is increasingly being used, which also reduce pain due to the anti-inflammatory effect; however, regarding this aspect relatively few prospective randomized studies in comparison to LIA are available in the literature.

Despite research suggesting an association between certain herb use during pregnancy and delivery and postnatal complications, herbs are still commonly used among pregnant women in sub-Sahara Africa (SSA). This study examines the factors and characteristics of women using local herbs during pregnancy and/or labor, and the associations between local herb use and postnatal complications in Kigoma, Tanzania.

Multiple sclerosis (MS) is known as an autoimmune disease in the central nervous system (CNS) characterized by motor deficits, pain, fatigue, cognitive impairment, and sensory and visual dysfunction. MS is considered to be resulted from significant inflammatory response. Paricalcitol (Pari) is a vitamin D2 analogue, which has been indicated to show anti-inflammatory activities in kidney and heart diseases. In the present study, if Pari could ameliorate the experimental autoimmune encephalomyelitis (EAE) was investigated. Here, the C57BL/6 mice were immunized using myelin oligodendrocyte glycoprotein 35-55 (MOG). Subsequently, Pari was intraperitoneally injected into the mice. As for in vitro analysis, RAW264.7 and Jurkat cells were incubated with Pari together with corresponding stimulus. The results indicated that Pari administration reduced the paralytic severity, neuropathology and apoptosis in MOG-treated mice compared to the MOG single group. Pari also exhibited a significantly inhibitory effect on immune cell infiltration, glial cell activation, expression of pro-inflammatory factors and the activation of nuclear factor κB (NF-κB). The expression of pro-inflammatory regulators and the translocation of NF-κB from cytoplasm into nuclear in RAW264.7 and Jurkat cells under specific stimulation was clearly down-regulated by Pari incubation. Furthermore, we found that suppressing NF-κB with its inhibitor combined with Pari could further reduce the expression of pro-inflammatory factors and associated proteins. These data illustrated that Pari could diminish MOG-triggered EAE, as well as macrophages and T cells activation through blocking NF-κB activation. Collectively, Pari might have therapeutic effects in mouse models with MS.

Gram-negative bacterial infections induce inflammation and pain. Lipopolysaccharide (LPS) is a pathogen-associated molecular pattern and the major constituent of Gram-negative bacterial cell walls. Diosmin is a citrus flavonoid with antioxidant and anti-inflammatory activities. Here we investigated the efficacy of diosmin in a nonsterile model of inflammatory pain and peritonitis induced by LPS. Diosmin reduced in a dose-dependent manner LPS-induced inflammatory mechanical hyperalgesia, thermal hyperalgesia, and neutrophil recruitment to the paw (myeloperoxidase activity). Diosmin also normalized changes in paw weight distribution assessed by static weight bearing as a nonreflexive method of pain measurement. Moreover, treatment with diosmin inhibited LPS-induced peritonitis as observed by a reduction of leukocyte recruitment and oxidative stress. Diosmin reduced LPS-induced total ROS production (DCFDA assay) and superoxide anion production (NBT assay and NBT-positive cells). We also observed a reduction of LPS-induced oxidative stress and cytokine production (IL-1β, TNF-α, and IL-6) in the paw. Furthermore, we demonstrated that diosmin inhibited LPS-induced NF-κB activation in peritoneal exudate. Thus, we demonstrated, using a model of nonsterile inflammation induced by LPS, that diosmin is a promising molecule for the treatment of inflammation and pain.

Opioid crisis is a major threat of 21st century with a remarkable juxtaposition of use and abuse. Opioids are the most potent and efficacious class of analgesics but despite their proven therapeutic efficacy they have recently been degraded to third-line of therapy for the management of chronic pain in clinics. The reason behind is the development of potential side effects and tolerance after repeated dosing. Opioid tolerance is the major limiting factor leading to the treatment withdrawal, severe side effects due to dose escalation and sometimes even death of the patients. Every day more than 90 people die due to the overdose of opioids in America and similar trend has been seen across the globe. Researchers in past two decades are trying to dissect the neurobiological mechanism of opioid tolerance. Research on opioid tolerance shifted towards the CNS based adaptations because tolerance is much more than just being a cellular phenomenon. Thus, neurobiological adaptations associated with opioid tolerance are important to understand in order to set newer pain therapeutics. These adaptations are associated with the alterations in ascending and descending pain pathways, reward circuitry modulations, receptor desensitization and down-regulation, receptor internalization, heterodimerization and altered epigenetic regulation. The present review is focussed on novel circuitries in different brain areas such as periaqueductal gray (PAG), rostral ventromedial medulla (RVM), dorsal raphe nucleus (DRN), ventral tegmental area (VTA), and nucleus accumbens (NAc) associated with opioid tolerance. Understanding the neurobiological modulations associated with chronic opioid exposure and tolerance will pave the way for development of novel pharmacological tools for the safe and better management of chronic pain in patients.

LPS has been widely used to induce inflammatory pain, attributing to production of inflammatory cytokines and sensitization of nociceptors. Paeoniflorin (PF) possesses anti-nociceptive property, but its effect on LPS-induced inflammatory pain has not been investigated. In this study, we aimed to investigate the analgesic effect of PF on an inflammatory pain mouse model and explore the underlying mechanisms. LPS-induced inflammatory pain model was established in C57BL/6J mice after PF treatment. Then, thermal hyperalgesia, neutrophil infiltration, inflammatory cytokine production, intracellular Ca levels, PKC activity, transient receptor potential vanilloid 1 (TRPV-1) expression, NF-κB transcription, and NLPR3 inflammasome activation were assessed by thermal withdrawal latency, histopathology, ELISA, intracellular Ca concentration, immunohistochemistry, and Western blot, separately. PF significantly relieved inflammatory pain and paw edema in mice with LPS-induced inflammatory pain. Additionally, PF inhibited neutrophil infiltration, inflammatory cytokine production (IL-1β, TNF-α, and IL-6), intracellular Ca levels, and PKC activity as well as suppressed TRPV-1 expression, NF-κB transcription, and NLPR3 inflammasome activation in the footpad tissue samples. Importantly, capsaicin (TRPV-1 agonists) obviously reversed the pain-relieving effect of PF, suggesting the involvement of TRPV-1 in the analgesic activity of PF. Our results indicated PF ameliorated LPS-induced inflammation and pain in mice by inhibiting TRPV-1-mediated NLRP3 inflammasome activation. These findings suggest that PF can be as a potential pharmacological agent for inflammatory pain and thus deserves more attention and further investigation.

External cephalic version (ECV) is associated with a moderate degree of pain. Virtual reality (VR) is a technology that has shown promise in offering procedural analgesia. We undertook a clinical pilot to assess the viability of VR to reduce pain during ECV. In an open randomised controlled trial (RCT), we randomised 50 women to either VR or standard care each (25 per group). Women receiving VR were administered VR content (Skylights) via a headset. Pre- and post-procedural measures of pain, anxiety, device experience and vital signs were measured. There were no significant differences between groups (VR/no VR) in pain scores (60.68 vs 49.76; p = 0.2), ECV success rates (80% vs 76%; p = 0.7) or anxiety levels. The women receiving VR had a significantly higher anticipation of pain pre-procedurally (70.0 vs 50.0; p = 0.03). 20 (80%) of the VR women indicated that they would use VR again and 22 (88%) indicated they would recommend it to a friend having ECV. There were no significant differences between groups for side effects encountered or changes in vital signs. We have shown that using VR during ECV is feasible and appears safe. Our results inform the design of future RCTs.