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Placebo and nocebo effects in pain are well documented. One leading explanation is that instructions indicating that pain will either increase or decrease after receipt of a treatment give rise to expectations for increased or decreased pain. However, the psychological mechanisms through which expectations affect pain perception are not well understood. One possibility is that the expectation of increased pain leads to anticipatory anxiety, which in turn increases attention towards painful sensations.
Learn More >Pain plays an indispensable role as an alarm system to protect us from dangers or injuries. However, neuropathic pain, a debilitating pain condition caused by damage to the nervous system, persists for a long period even in the absence of dangerous stimuli or after injuries have healed. In this condition, pain becomes a disease itself rather than the alarm system and is often resistant to currently available medications. A growing body of evidence indicates that microglia, a type of macrophages residing in the central nervous system, play a crucial role in the pathogenesis of neuropathic pain. Whenever microglia in the spinal cord detect a damaging signal within the nervous system, they become activated and cause diverse alterations that change neural excitability, leading to the development of neuropathic pain. For over a decade, several lines of molecular and cellular mechanisms that define microglial activation and subsequently altered pain transmission have been proposed. In particular, P2X4 receptors (a subtype of purinergic receptors) expressed by microglia have been investigated as an essential molecule for neuropathic pain. In this review article, we describe our understanding of the mechanisms by which activated microglia cause neuropathic pain through P2X4 receptors, their involvement in several pathological contexts, and recent efforts to develop new drugs targeting microglia and P2X4 receptors.
Learn More >Ubrogepant is a small-molecule calcitonin gene-related peptide (CGRP) receptor antagonist that received Food and Drug Administration (FDA) approval for the acute treatment of migraine with and without aura in adults. The ACHIEVE I and ACHIEVE II Phase III clinical trials showed that ubrogepant was superior to placebo for pain freedom and freedom of the most bothersome migraine-associated symptom at 2 hours after medication intake. The 52-week open label extension of the Phase III trials demonstrated safety of ubrogepant. A real-world study conducted at a tertiary headache center also confirmed the efficacy and safety of ubrogepant. Adverse event rates were higher in the real-world population. Studies are needed to evaluate its long-term efficacy and safety, especially in the setting of co-administration with other CGRP modulating therapies such as the CGRP monoclonal antibodies.
Learn More >Optimal pain relief requires a balance between adequate analgesia and risk of adverse effects. Opioids remain the cornerstone for managing moderate to severe pain, but are associated with opioid-induced respiratory depression (OIRD) and gastrointestinal complications. Opioids exert their analgesic effects predominantly via G-protein signaling, however, adverse effects including OIRD are mediated by the β-arrestin pathway. Oliceridine is the first of a new class of biased opioid agonists that preferentially activate G-protein signaling over β-arrestin, which would theoretically improve analgesia and reduce the risk of adverse effects. Oliceridine is approved by the Food and Drug Administration (FDA) for the treatment of moderate to severe acute pain. The efficacy of Oliceridine was mainly established in two randomized controlled Phase III clinical trials of patients experiencing moderate to severe pain after bunionectomy (APOLLO-1) and abdominoplasty (APOLLO-2). The results of the APOLLO studies demonstrate that Oliceridine, when administered via patient-controlled analgesia (PCA) demand boluses of 0.35mg and 0.5mg, provides superior analgesia compared to placebo, and is equianalgesic to PCA morphine 1mg demand boluses, without significant difference in the incidence of respiratory complications. In a more pragmatic trial of surgical and non-surgical patients, the ATHENA observational cohort study reported rapid onset of analgesia with Oliceridine given with or without multimodal analgesia. However, these studies were designed to evaluate analgesic efficacy, and it is still uncertain if Oliceridine has a better safety profile than conventional opioids. Although several post hoc analyses of pooled data from the APOLLO and ATHENA trials reported that Oliceridine was associated with lower OIRD and gastrointestinal complications compared to morphine, prospective studies are needed to elucidate if biased agonists such as Oliceridine reduce the risk of adverse effects compared to conventional opioids.
Learn More >Musculoskeletal pain (excluding bone cancer pain) affects more than 30% of the global population and imposes an enormous burden on patients, families, and caregivers related to functional limitation, emotional distress, effects on mood, loss of independence, and reduced quality of life. The pathogenic mechanisms of musculoskeletal pain relate to the differential sensory innervation of bones, joints, and muscles as opposed to skin and involve a number of peripheral and central nervous system cells and mediators. The interplay of neurons and non-neural cells (e.g. glial, mesenchymal, and immune cells) amplifies and sensitizes pain signals in a manner that leads to cortical remodeling. Moreover, sex, age, mood, and social factors, together with beliefs, thoughts, and pain behaviors influence the way in which musculoskeletal pain manifests and is understood and assessed. The aim of this narrative review is to summarize the different pathogenic mechanisms underlying musculoskeletal pain and how these mechanisms interact to promote the transition from acute to chronic pain.
Learn More >In dementia, neuropathological changes alter the perception and expression of pain. For clinicians and family members, this knowledge gap leads to difficulties in recognizing and assessing chronic pain, which may consequently result in persons with dementia receiving lower levels of pain medication compared to those without cognitive impairment. Although this situation seems to have improved in recent years, considerable geographical variation persists. Over the last decade, opioid use has received global attention as a result of overuse and the risk of addiction, while the literature on older persons with dementia actually suggests undertreatment. This review stresses the importance of reliable assessment and the regular evaluation and monitoring of symptoms in persons with dementia. Based on current evidence, we concluded that chronic pain is still undertreated in dementia.
Learn More >Despite the need for safe and effective postoperative analgesia in neonates, research regarding pain management in neonatal rodents is relatively limited. Here, we investigate whether sustained release buprenorphine (Bup SR) effectively attenuates thermal hypersensitivity in a neonatal rat model of incisional pain. Male and female postnatal day 3 Sprague Dawley rat pups (n = 34) were randomly assigned to one of four treatment groups: 1) saline (control), 0.1 mL, once subcutaneously (SC); 2) buprenorphine HCl (Bup HCl), 0.05 mg/kg, once SC; 3) low dose Bup SR (low-SR), 0.5 mg/kg, once SC; 4) high dose Bup SR (high-SR), 1 mg/kg, once SC. Pups were anesthetized with sevoflurane and a 0.5-cm long skin incision was made over the left lateral thigh. The underlying muscle was dissected and closed using surgical glue. Thermal hypersensitivity testing was performed at 24 h prior to surgery and subsequently at 1, 4, 8, 24, and 48 h post-surgery using an infrared diode laser. Thermal hypersensitivity was attenuated at 1 h post-surgery in the Bup HCl group, while it was attenuated through the entire postoperative period in both low-SR and high-SR groups. This data suggests that a single dose of low-SR (0.5 mg/kg) or high-SR (1 mg/kg) effectively attenuates thermal hypersensitivity for at least 8 h in neonatal rat pups.
Learn More >7β-(3-Ethyl–crotonoyloxy)-1α-(2-methylbutyryloxy)-3,14-dehydro–notonipetranone (ECN), a sesquiterpenoid obtained from a natural source has proved to be effective in minimizing various side effects associated with opioids and nonsteroidal anti-inflammatory drugs. The current study focused on investigating the effects of ECN on neuropathic pain induced by partial sciatic nerve ligation (PSNL) by mainly focusing on oxidative stress, inflammatory and apoptotic proteins expression in mice. ECN (1 and 10 mg/kg, i.p.), was administered once daily for 11 days, starting from the third day after surgery. ECN post-treatment was found to reduce hyperalgesia and allodynia in a dose-dependent manner. ECN remarkably reversed the histopathological abnormalities associated with oxidative stress, apoptosis and inflammation. Furthermore, ECN prevented the suppression of antioxidants (glutathione, glutathione-S-transferase, catalase, superoxide dismutase, NF-E2-related factor-2 (Nrf2), hemeoxygenase-1 and NAD(P)H: quinone oxidoreductase) by PSNL. Moreover, pro-inflammatory cytokines (tumor necrotic factor-alpha, interleukin 1 beta, interleukin 6, cyclooxygenase-2 and inducible nitric oxide synthase) expression was reduced by ECN administration. Treatment with ECN was successful in reducing the caspase-3 level consistent with the observed modulation of pro-apoptotic proteins. Additionally, ECN showed a protective effect on the lipid content of myelin sheath as evident from FTIR spectroscopy which showed the shift of lipid component bands to higher values. Thus, the anti-neuropathic potential of ECN might be due to the inhibition of oxidative stress, inflammatory mediators and pro-apoptotic proteins.
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