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The progressive increase in the prevalence of obesity in the population has resulted in increased healthcare costs and demands. Recent studies have revealed a positive correlation between pain and obesity, although the underlying mechanisms still remain unknown. Here, we aimed to clarify the role of microglia in altered pain behaviors induced by a high-fat diet (HFD) in male mice. We found that C57BL/6CR mice on a HFD exhibited spinal microglial reaction (increased cell number and up-regulated expression of p-p38 and CD16/32), increased tumor necrosis factor-α (TNF-α) mRNA and brain-derived neurotrophic factor (BDNF) protein as well as a polarization of spinal microglial toward a pro-inflammatory phenotype. Moreover, we found that when applied PLX3397 (a selective colony-stimulating factor-1 receptor (CSF1R) kinase inhibitor) to eliminate microglia of HFD-induced obesity mice, inflammation in the spinal cord was rescued, as were abnormal pain hypersensitivity. Intrathecal injection of Mac-1-saporin (a saporin-conjugated anti-mac1 antibody) resulted in decreased microglia and attenuated both mechanical allodynia and thermal hyperalgesia in HFD-fed mice. These results indicate that the pro-inflammatory functions of spinal microglia have a special relevance to abnormal pain hypersensitivity in HFD-induced obesity mice. In conclusion, our data suggest that HFD induces a classical reaction of microglia, characterized by an enhanced phosphorylation of p-38 and increased CD16/32 expression, which may in part contribute to increased nociceptive responses in HFD-induced obesity mice.
Learn More >The importance of calcitonin gene-related peptide (CGRP) in migraine pathogenesis is well established. Fremanezumab is a humanized IgG2a monoclonal antibody that binds to CGRP. Areas covered: In this paper we review the development of fremanezumab, from early development into approval. The authors focus on the efficacy and safety of fremanezumab in both migraine stages. The authors highlight studies conducted in special populations and focus on unique aspects of its development, as well as on clinical pearls supported by the data. Expert opinion: Fremanezumab was shown to be effective in episodic and chronic migraine, with a monthly and quarterly dose of administration, as monotherapy and add-on therapy. As with other monoclonal antibodies, anti-CGRP onset of action was remarkably quick, and the effect seems to be maintained over time. No overt safety concerns emerged from the clinical studies, although long term surveillance is necessary.
Learn More >NGF is increased in intervertebral discs (IVDs) after disc injury and anti-NGF therapy improves low back pain in humans. Further, M1 and M2 macrophage subtypes play a role in degenerative IVD injury. We examined M1 and M2 macrophage markers and NGF and cytokine expression in IVD-derived cells from control and IVD-injured mice for 28 days following injury. Ngf mRNA expression was increased 1 day after injury in injured compared to control mice, and persisted for up to 28 days. Flow cytometric analysis demonstrated that the proportion of F4/80 + CD11b + cells was significantly increased from 1 day after injury for up to 28 days in injured compared to control mice. mRNA expression of M1 macrophage markers Tnfa, Il1b, and Nos2 was significantly increased 1 day after injury in injured compared to control mice, before gradually decreasing. At 28 days, no significant difference was observed in M1 markers. The M2a marker, Ym1, was significantly increased 1 day after injury in injured compared to control mice, while M2a and M2c markers Tgfb and Cd206 were significantly increased 7, 14, and 28 days after injury. TNF-α and TGF-β stimulated Ngf mRNA and NGF protein expression in IVD cells. Our results suggest that TNF-α and TGF-β may stimulate NGF production under inflammatory and non-inflammatory conditions following IVD injury. As TNF-α and TGF-β are produced by M1 and M2 macrophages, further investigations are needed to reveal the role of macrophages in NGF expression following IVD injury. Our results may aid in developing treatments for IVD-related LBP pathology. This article is protected by copyright. All rights reserved.
Learn More >In the face of increasing recognition and interest in treating chronic pain in companion animals, we struggle with a lack of therapeutic options. A significant barrier to the development of new therapeutics, or the critical evaluation of current therapies, is our inability to accurately measure chronic pain and its impact on companion animals. Over the last 20 years, much progress has been made in developing methods to measure chronic pain via subjective and objective methods – particularly in owner assessment tools and measurements of limb use and activity. Most work has been focused on chronic joint pain conditions, but there has been relatively little work in other areas of chronic pain, such as neuropathic and cancer pain. Although progress has been made, there is a considerable interest in improving our assessment of chronic pain, as evidenced by the multiple disciplines across industry, academia, and clinical practice from the veterinary and human medical fields that participated in the Pain in Animals Workshop held at the National Institutes of Health in 2017. This review is one product of that meeting and summarizes the current state of knowledge surrounding the measurement of chronic pain (musculoskeletal, cancer, neuropathic), and its impact, in cats and dogs.
Learn More >The role of sex hormones on postsurgical pain perception is basically unclear. Here, we studied the role of endogenous gonadal hormones for pain and hyperalgesia in human volunteers after experimental incision. A 4-mm incision was made in the volar forearm of 15 female volunteers both in the follicular and the luteal phase (random block design). Somatosensory profiles were assessed at baseline and 1 to 72 hours after incision by quantitative sensory testing, compared between both cycle phases, and related to individual plasma levels of gonadal hormones. Sensory testing at baseline revealed significantly lower pain thresholds (25 vs 46 mN, P < 0.005) and increased pain ratings to pinprick (0.96 vs 0.47, P < 0.0001) in the luteal phase; similarly, 1 hour after incision, pain intensity to incision (38 vs 21/100, P < 0.005), pinprick hyperalgesia by rating (P < 0.05), and area of secondary hyperalgesia (P < 0.001) were enhanced in the luteal phase. Multiple regression analysis revealed that pinprick pain sensitivity at baseline was significantly predicted by progesterone (partial r = 0.67, P < 0.001), follicle-stimulating hormone (FSH) (partial r = 0.61, P < 0.005), and negatively by testosterone (partial r = -0.44, P < 0.05). Likewise, incision-induced pain and pinprick hyperalgesia (rating and area) were significantly predicted by progesterone (partial r = 0.70, r = 0.46, and r = 0.47, respectively; P < 0.05-0.0001) and in part by FSH; the contribution of estrogen, however, was fully occluded by progesterone for all measures. In conclusion, pinprick pain and incision-induced pain and mechanical hyperalgesia were greater in the luteal phase and predicted by progesterone, suggesting a major role for progesterone. Other hormones involved are testosterone (protective) and in part FSH.
Learn More >Over the past decade, the mechanisms underlying placebo effects have begun to be identified. At the same time, the placebo response appears to have increased in pharmacological trials and marked placebo effects are found in neurostimulation and surgical trials, thereby posing the question whether non-pharmacological interventions should be placebo-controlled to a greater extent. In this narrative review we discuss how the knowledge of placebo mechanisms may help to improve placebo control in pharmacological and non-pharmacological trials. We review the psychological, neurobiological, and genetic mechanisms underlying placebo analgesia and outline the current problems and potential solutions to the challenges with placebo control in trials on pharmacological, neurostimulation, and surgical interventions. We particularly focus on how patients' perception of the therapeutic intervention, and their expectations towards treatment efficacy may help develop more precise placebo controls and blinding procedures and account for the contribution of placebo factors to the efficacy of active treatments. Finally, we discuss how systematic investigations into placebo mechanisms across various pain conditions and types of treatment are needed in order to 'personalise' the placebo control to the specific pathophysiology and interventions, which may ultimately lead to identification of more effective treatment for pain patients. In conclusion this review shows that it is important to understand how patients' perception and expectations influence the efficacy of active and placebo treatments in order to improve the test of new treatments. Importantly, this applies not only to assessment of drug efficacy but also to non-pharmacological trials on surgeries and stimulation procedures.
Learn More >To describe long-term treatment patterns in migraine patients initiating prophylactic therapy and to evaluate acute medication use and adverse events associated with opioids.
Learn More >: Pruritus is a common symptom associated with several potential underlying causes, including both dermatologic and systemic diseases; it can also occur without an identifiable cause. Current treatment options are limited and most patients experience impaired quality of life. Serlopitant is a neurokinin 1 (NK) receptor antagonist under development for the treatment of pruritus associated with various dermatologic conditions and chronic pruritus of unknown origin. : This review describes the epidemiology and unmet needs of patients with chronic pruritus, focusing specifically on patients with prurigo nodularis, psoriatic itch, and chronic pruritus of unknown origin; the rationale for targeting the NK receptor for treatment of chronic pruritus; and the clinical development of serlopitant, including efficacy and safety data from completed phase II studies. : There is an unmet need for novel, safe, and effective therapies to treat chronic pruritus. Serlopitant has shown promising efficacy, safety, and tolerability across different patient populations, including adolescents and elderly patients. In contrast to less convenient administration options, serlopitant is a once-daily oral tablet, which is expected to facilitate compliance.
Learn More >: The recent approval of monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP) pathway introduced the first preventive treatments for migraine that were specifically designed to target the underlying pathophysiology of the disease. Fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) administered via subcutaneous injection, is the first approved monoclonal antibody that targets the CGRP ligand and offers both quarterly (once every 3 months) and monthly dosing. : An introduction to migraine, overview of the migraine preventive treatments that target CGRP or its receptor, background on CGRP, and details on the fremanezumab clinical development program in both chronic and episodic migraine. Focus is on the Phase 2b and Phase 3 studies, as well as the recently completed long-term Phase 3 study. : The approval of the first disease-specific preventive treatments for migraine heralds a new era in the treatment of migraine. Fremanezumab has a favorable efficacy and safety profile, which is maintained over the long term. Data from patient subgroups with more-complex disease are promising, and an ongoing study in treatment-refractory patients is evaluating the efficacy of fremanezumab in patients who have failed on multiple prior therapies.
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