Accepted

Abnormalities of mast cell structure or function may play prominent roles in irritable bowel syndrome (IBS) symptom genesis. Mast cells show close apposition to sensory nerves and release bioactive substances in response to varied stimuli including infection, stress, and other neuroendocrine factors. Most studies focus on patients who develop IBS after enteric infection or who report diarrhea-predominant symptoms. Three topics underlying IBS pathogenesis have been emphasized in recent investigations. Visceral hypersensitivity to luminal stimulation is found in most IBS patients and may contribute to abdominal pain. Mast cell dysfunction also may disrupt epithelial barrier function which alters mucosal permeability potentially leading to altered bowel function and pain. Mast cell products including histamine, proteases, prostaglandins, and cytokines may participate in hypersensitivity and permeability defects, especially with diarrhea-predominant IBS. Recent experimental evidence indicates that the pronociceptive effects of histamine and proteases are mediated by the generation of prostaglandins in the mast cell. Enteric microbiome interactions including increased mucosal bacterial translocation may activate mast cells to elicit inflammatory responses underlying some of these pathogenic effects. Therapies to alter mast cell activity (mast cell stabilizers) or function (histamine antagonists) have shown modest benefits in IBS. Future investigations will seek to define patient subsets with greater potential to respond to therapies that address visceral hypersensitivity, epithelial permeability defects, and microbiome alterations secondary to mast cell dysfunction in IBS.

We examined the functional connectivity (FC) in migraine compared with healthy subjects before and after C2 peripheral nerve field stimulation using electroacupuncture (EA-C2-PNfS), to evaluate the effect of EA-C2-PNfS, and elucidate the mechanism of migraine.

Currently available treatments for neuropathic pain are only modestly efficacious when assessed in randomized clinical trials and only work for some patients in the clinic. Induced-pain or gain-of-function phenotypes, have been shown to predict response to analgesics (vs. placebos) in patients with neuropathic pain. However, the predictive value of these phenotypes has never been studied in post-traumatic neuropathic pain. Mixed-effects model for repeated measures (MMRM) were used to evaluate the efficacy of pregabalin vs. placebo in subgroups with induced-pain phenotypes (i.e., hyperalgesia or allodynia) using data from a recent, multi-national RCT (N = 539) that identified phenotypic subgroups using a structured clinical exam. The difference in mean pain score between active and placebo groups (i.e., delta) after 15 weeks of treatment for the subgroup with hyperalgesia was -0.76 (p = 0.001), compared to 0.19 (p = 0.47) for the subgroup that did not have hyperalgesia. The treatment-by-phenotype interaction, which tests whether subgroups have statistically different treatment responses, was significant (p = 0.0067). The delta for the subgroup with allodynia was -0.31 (p = 0.22), compared to -0.30 (p = 0.22) for the subgroup that did not have allodynia (treatment-by-phenotype interaction p = 0.98). These data suggest that hyperalgesia, but not allodynia predicts response to pregabalin in patients with chronic post-traumatic neuropathic pain. This study extends the growing data supporting the utility of induced-pain phenotypes to predict response to analgesics to post-traumatic neuropathic pain. Sensory phenotyping in large, multi-site trials using a structured clinical exam has the potential to accelerate the development of new analgesics and improve the generalizability of clinical trial results.