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Chronic pain is a common public health problem that has a detrimental impact on patient health, quality of life (QoL), and function, and poses a substantial socioeconomic burden. Evidence supports redefinition of chronic pain as a distinct disease entity, not simply a symptom of injury or illness. Chronic pain conditions are characterized by three types of pain pathophysiology – i.e., nociceptive, neuropathic, and centralized pain/central sensitization -influenced by a cluster of coexisting psychosocial factors. Negative risk/vulnerability factors, e.g., mood or sleep disturbances, and positive resilience/protective factors, e.g., social/interpersonal relationships and active coping, interact with pain neurobiology to determine patients' unique pain experience. Viewing chronic pain through a biopsychosocial lens, instead of a purely biomedical one, clinicians need to adopt a practical integrated management approach. Thorough assessment focuses on the whole patient (not just the pain), including comorbidities, cognitive/emotional/behavioral characteristics, social environment, and QoL/functional impairment. As for other complex chronic illnesses, the treatment plan for chronic pain can be developed based on pain subtype and psychosocial profile, incorporating pharmacotherapy and self-management modalities. Preferred pharmacologic treatment of conditions primarily associated with nociception (e.g., osteoarthritis) includes acetaminophen and non-steroidal anti-inflammatory drugs, whereas preferred pharmacologic treatment of conditions primarily associated with neuropathy or central sensitization (e.g., fibromyalgia) includes tricyclic compounds, serotonin norepinephrine reuptake inhibitors, and αδ ligands. Education, exercise, cognitive behavioral therapy, and many other non-pharmacological approaches, alone or combined with pharmacotherapy, have been shown to be effective for any type of pain, although they remain underutilized due to lack of awareness of their benefits and reimbursement obstacles.
Learn More >Acute inflammation induces sensitization of nociceptive neurons and triggers the accumulation of calcium permeable (CP) α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors (AMPARs) in the dorsal horn of the spinal cord. This coincides with behavioral signs of acute inflammatory pain, but whether CP-AMPARs contribute to chronic pain remains unclear. To evaluate this question, we first constructed current-voltage (IV) curves of C-fiber stimulus-evoked, AMPAR-mediated EPSCs in lamina II to test for inward rectification, a key characteristic of CP-AMPARs. We found that the intraplantar injection of complete Freund's adjuvant (CFA) induced an inward rectification at 3 d that persisted to 21 d after injury. Furthermore, the CP- AMPAR antagonist IEM-1460 (50 μM) inhibited AMPAR-evoked Ca transients 21d after injury but had no effect in uninflamed mice. We then used a model of long-lasting vulnerability for chronic pain that is determined by the balance between latent central sensitization (LCS) and mu opioid receptor constitutive activity (MOR). When administered 21 d after the intraplantar injection of CFA, intrathecal administration of the MOR inverse agonist naltrexone (NTX, 1 μg, i.t.) reinstated mechanical hypersensitivity, and superfusion of spinal cord slices with NTX (10 μM) increased the peak amplitude of AMPAR-evoked Ca transients in lamina II neurons. The CP-AMPAR antagonist naspm (0-10 nmol, i.t.) inhibited these NTX-induced increases in mechanical hypersensitivity. NTX had no effect in uninflamed mice. Subsequent western blot analysis of the postsynaptic density membrane fraction from lumbar dorsal horn revealed that CFA increased GluA1 expression at 2 d and GluA4 expression at both 2 and 21 d post-injury, indicating that not just the GluA1 subunit, but also the GluA4 subunit, contributes to the expression of CP-AMPARs and synaptic strength during hyperalgesia. GluA2 expression increased at 21 d, an unexpected result that requires further study. We conclude that after tissue injury, dorsal horn AMPARs retain a Ca permeability that underlies LCS. Because of their effectiveness in reducing naltrexone-induced reinstatement of hyperalgesia and potentiation of AMPAR-evoked Ca signals, CP-AMPAR inhibitors are a promising class of agents for the treatment of chronic inflammatory pain.
Learn More >Despite being one of the most common presenting dermatological symptoms, itching continues to perplex health care professionals because it is notoriously difficult to control.
Learn More >Previous studies have reported that certain bacteria exert visceral antinociceptive activity in visceral pain and may also help to relieve neuropathic and inflammatory pain.
Learn More >We endeavored to identify objective blood biomarkers for pain, a subjective sensation with a biological basis, using a stepwise discovery, prioritization, validation, and testing in independent cohorts design. We studied psychiatric patients, a high risk group for co-morbid pain disorders and increased perception of pain. For discovery, we used a powerful within-subject longitudinal design. We were successful in identifying blood gene expression biomarkers that were predictive of pain state, and of future emergency department (ED) visits for pain, more so when personalized by gender and diagnosis. MFAP3, which had no prior evidence in the literature for involvement in pain, had the most robust empirical evidence from our discovery and validation steps, and was a strong predictor for pain in the independent cohorts, particularly in females and males with PTSD. Other biomarkers with best overall convergent functional evidence for involvement in pain were GNG7, CNTN1, LY9, CCDC144B, and GBP1. Some of the individual biomarkers identified are targets of existing drugs. Moreover, the biomarker gene expression signatures were used for bioinformatic drug repurposing analyses, yielding leads for possible new drug candidates such as SC-560 (an NSAID), and amoxapine (an antidepressant), as well as natural compounds such as pyridoxine (vitamin B6), cyanocobalamin (vitamin B12), and apigenin (a plant flavonoid). Our work may help mitigate the diagnostic and treatment dilemmas that have contributed to the current opioid epidemic.
Learn More >Based on few clinical trials, flunarizine is considered a first-line prophylactic treatment for migraine in several guidelines. In this meta-analysis, we examined the pooled evidence for its effectiveness, tolerability, and safety. Prospective randomized controlled trials of flunarizine as a prophylaxis against migraine were identified from a systematic literature search, and risk of bias was assessed for all included studies. Reduction in mean attack frequency was estimated by calculating the mean difference (MD), and a series of secondary outcomes-including adverse events (AEs)-were also analyzed. The database search yielded 879 unique records. Twenty-five studies were included in data synthesis. We scored 31/175 risk of bias items as "high," with attrition as the most frequent bias. A pooled analysis estimated that flunarizine reduces the headache frequency by 0.4 attacks per 4 weeks compared with placebo (5 trials, 249 participants: MD -0.44; 95% confidence interval -0.61 to -0.26). Analysis also revealed that the effectiveness of flunarizine prophylaxis is comparable with that of propranolol (7 trials, 1151 participants, MD -0.08; 95% confidence interval -0.34 to 0.18). Flunarizine also seems to be effective in children. The most frequent AEs were sedation and weight increase. Meta-analyses were robust and homogenous, although several of the included trials potentially suffered from high risk of bias. Unfortunately, reporting of AEs was inconsistent and limited. In conclusion, pooled analysis of data from partially outdated trials shows that 10-mg flunarizine per day is effective and well tolerated in treating episodic migraine-supporting current guideline recommendations.
Learn More >Orosensory thermal trigeminal afferent neurons respond to cool, warm, and nociceptive hot temperatures with the majority activated in the cool range. Many of these thermosensitive trigeminal orosensory afferent neurons also respond to capsaicin, menthol and/or mustard oil (allyl isothiocyanate, AITC) at concentrations found in foods and spices. There is significant but incomplete overlap between afferent trigeminal neurons that respond to heat and to the above chemesthetic compounds. Capsaicin sensitizes warm trigeminal thermoreceptors and orosensory nociceptors; menthol attenuates cool thermoresponses.
Learn More >Osteoarthritis, the leading cause of chronic joint pain, is studied through different animal models, but none of them is ideal in terms of reliability and translational value. In this pilot study of female rats, 3 surgical models of osteoarthritic pain, destabilization of the medial meniscus (DMM), cranial cruciate ligament transection (CCLT), and the combination of both surgical models (COMBO) and 1 chemical model [intra-articular injection of monosodium iodoacetate (MIA)] were compared for their impact on functional pain outcomes [static weight-bearing (SWB) and punctate tactile paw withdrawal threshold (PWT)] and spinal neuropeptides [substance P (SP), calcitonin gene-related peptide (CGRP), bradykinin (BK), and somatostatin (SST)]. Six rats were assigned to each model group and a sham group. Both the chemical model (MIA) and surgical COMBO model induced functional alterations in SWB and PWT, with the changes being more persistent in the surgical combination group. Both models also produced an increase in levels of pro-nociceptive and anti-nociceptive neuropeptides at different timepoints. Pain comparison with the MIA model showed the advantage of a surgical model, especially the combination of the DMM and CCLT models, whereas each surgical model alone only led to temporary functional alterations and no change in neuropeptidomics.
Learn More >To examine the hypothesis that surprising experiences of headache triggers are associated with daily headache activity.
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