Pain
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Randomized Controlled Trial Multicenter Study
Development and Preliminary Validation of an Integrated Efficacy-Tolerability Composite Measure for the Evaluation of Analgesics.
The goal of this analysis was to develop and evaluate integrated measures of benefit and tolerability of analgesic drugs in clinical trials. We evaluated an efficacy-tolerability composite (ETC) measure combining different cutoff values for daily pain reduction (≥20%, ≥30%, or ≥50% pain reduction) and adverse events (AEs) (no AE, no or mild AEs, no or mild drug-related AEs). Nine ETC cutoff values (3 × 3) were tested using data from a randomized double-blind trial comparing tapentadol extended release (ER) (n = 310), oxycodone controlled release (CR) (n = 322), and placebo (n = 314) in subjects with chronic low back pain. ⋯ For all 9 ETC measures, validity was demonstrated by significant correlation of ETC scores with patients' Global Impression of change and with change from baseline in pain scores. Tapentadol ER ETC scores were statistically significantly higher than oxycodone CR ETC scores for 4 of the ETC measures. "No/mild drug-related AE and ≥20% pain reduction" demonstrated the best overall validity (correlation with patients' global impression of change) and responsiveness (discrimination between treatment groups), yielding a higher standardized effect size for tapentadol ER compared with placebo (0.19 [95% confidence interval: 0.031-0.346]) and with oxycodone CR (0.23 [95% confidence interval: 0.070-0.383]) than other cutoff values. Thus, we have identified herein a composite measure that seems to be a valid and responsive measure of the overall efficacy and tolerability of analgesics in clinical trials.
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The objective of this study was to assess whether migraine and tension-type headache (TTH) are best viewed as discrete entities or points on a severity continuum using taxometric analysis. Historically, classification systems have conceptualized the primary headache disorders of migraine and TTH as fundamentally different disorders that are differentiated by their characteristic symptom profiles and, as such, imply differing pathophysiologies and required treatments. Despite this categorical nosology, findings continue to emerge suggesting that migraine and TTH instead reflect dimensions of severity within the same headache construct. ⋯ Specifically, graphical results revealed that high headache frequency (>15 d/mo) and younger age (<24 years old) were associated with unimodal distributions suggestive of a dimensional construct of primary headache, whereas lower headache frequency and older age were associated with bimodal distributions characteristic of discrete diagnostic entities. Conceptualizing primary headache as a severity continuum was supported for young adults and those with frequent headaches. The distinctions of a categorical classification system were supported for adults (>24 years old) and those with infrequent headache.
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We investigated roles for spinal neurons expressing the neurokinin-1 receptor (NK1R) and/or gastrin-releasing peptide receptor (GRPR) in a mouse model of ovalbumin (OVA)-induced chronic atopic dermatitis. Mice receiving repeated topical application of OVA exhibited atopic-like skin lesions and behavioral signs of chronic itch including spontaneous scratching, touch-evoked scratching (alloknesis), and enhancement of chloroquine-evoked scratching (hyperknesis). Substance P-saporin (SP-SAP) and bombesin-saporin (BB-SAP) were intrathecally injected into OVA-sensitized mice to neurotoxically ablate NK1R- or GRPR-expressing spinal neurons, respectively. ⋯ These results indicate that NK1R-expressing spinal neurons play a major role in the expression of symptoms of chronic itch and give rise to ascending somatosensory projections. Gastrin-releasing peptide receptor-expressing spinal neurons contribute to hyperknesis but not to alloknesis or ongoing itch. NK1R-expressing spinal neurons represent a potential target to treat chronic itch.
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Gray matter loss in cortical regions is a normal ageing process for the healthy brain. There have been few studies on the process of ageing of the brain in chronic neurological disorders. ⋯ The results indicate that in contrast to healthy subjects, migraineurs show a lack of thinning in the insula by age. The functional significance of the lack of thinning is unknown, but it may contribute to the overall cortical hyperexcitability of the migraine brain because the region is tightly involved in a number of major brain networks involved in interoception, salience, nociception, and autonomic function, including the default mode network.