Pain
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Integrating information on physical function and pain intensity into a composite measure may provide a useful method for assessing treatment efficacy in clinical trials of chronic pain. Accordingly, we evaluated composite outcomes in trials of duloxetine, gabapentin, and pregabalin. Data on 2287 patients in 9 trials for painful diabetic peripheral neuropathy (DPN) and 1513 patients in 6 trials for postherpetic neuralgia (PHN) were analyzed. ⋯ Of these, a responder outcome of ≥50% improvement in pain intensity, or a ≥20% improvement in pain intensity and ≥30% improvement in physical function was not only significantly associated with pregabalin vs placebo in the development cohorts for both pain conditions but also in the validation cohorts. Furthermore, this composite outcome was cross-validated in trials of gabapentin for PHN and duloxetine for DPN, and had slightly lower number needed to treat than a standard responder outcome of ≥50% reduction in pain intensity. In summary, this study identified a composite outcome of pain intensity and physical function that may improve the assay sensitivity of future neuropathic pain trials.
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After traumatic exposure, individuals are at risk of developing symptoms of both pain and post-traumatic stress disorder (PTSD). Theory and research suggest a complex and potentially mutually maintaining relationship between these symptomatologies. However, findings are inconsistent and the applied methods are not always well suited for testing mutual maintenance. ⋯ In addition, the synthesis suggested that hyperarousal and intrusion symptoms may be of particular importance in these cross-lagged relationships, while there was inconclusive evidence of catastrophizing as a mediator. In conclusion, the findings suggest an entangled, but not necessarily mutually maintaining relationship between pain and PTSD symptomatology. However, major variations in findings and methodologies complicated synthesis, prompting careful interpretation and heightening the likelihood that future high-quality studies will change these conclusions.
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Pain is a prevalent and debilitating symptom of multiple sclerosis (MS); yet, the mechanisms underlying this pain are unknown. Previous studies have found that the functional relationships between the salience network (SN), specifically the right temporoparietal junction a SN node, and other components of the dynamic pain connectome (default mode network [DMN], ascending and descending pathways) are abnormal in many chronic pain conditions. ⋯ We found that (1) ∼50% of our patients had NP features, (2) abnormalities in SN-DMN sFC were driven by the mixed-neuropathic subgroup, (3) in patients with mixed NP, dFC measures showed that there was a striking change in how the SN was engaged with the ascending nociceptive pathway and descending modulation pathway, (4) BOLD variability was increased in the DMN, and (5) the degrees of sFC and BOLD variability abnormalities were related to pain interference. We propose that abnormal SN-DMN cross-network FC and temporal dynamics within and between regions of the dynamic pain connectome reflect MS pain features.
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Recently, (±)-N-(3-fluoro-1-phenethylpiperidine-4-yl)-N-phenyl propionamide (NFEPP), a newly designed μ-opioid receptor (MOR) agonist with a low pKa, has been shown to produce injury-restricted analgesia in models of inflammatory and postoperative pain, without exhibiting typical opioid side effects. Here, we investigated MOR binding of NFEPP in brain and dorsal root ganglia, pH in injured tissues, and the analgesic efficacy of NFEPP compared with fentanyl in a chronic constriction injury model of neuropathic pain, and in the acetic acid-induced abdominal writhing assay in rats. Binding experiments revealed significantly lower affinity of NFEPP compared with fentanyl at pH 7.4. ⋯ Intravenous NFEPP as well as fentanyl dose-dependently diminished neuropathy-induced mechanical and heat hypersensitivity, and acetic acid-induced abdominal constrictions. In both models, NFEPP-induced analgesia was fully reversed by naloxone methiodide, a peripherally restricted opioid receptor antagonist, injected at the nerve injury site or into the abdominal cavity. Our results indicate that NFEPP exerts peripheral opioid receptor-mediated analgesia exclusively in damaged tissue in models of neuropathic and abdominal pain.
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Network meta-analysis uses direct comparisons of interventions within randomized controlled trials and indirect comparisons across them. Network meta-analysis uses more data than a series of direct comparisons with placebo, and theoretically should produce more reliable results. We used a Cochrane overview review of acute postoperative pain trials and other systematic reviews to provide data to test this hypothesis. ⋯ Network meta-analysis did not detect significant differences between effective analgesics. The similarity between network meta-analysis and Cochrane indirect analyses probably arose from stringent quality criteria in trials accepted in Cochrane reviews (with consequent low risk of bias) and consistency in methods and outcomes. Network meta-analysis is a useful analytical tool that increases our confidence in estimates of efficacy of analgesics in acute postoperative pain, in this case by providing similar results.