Pain
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The investigation of nocebo effects is evolving, and a few literature reviews have emerged, although so far without quantifying such effects. This meta-analysis investigated nocebo effects in pain. We searched the databases PubMed, EMBASE, Scopus, and the Cochrane Controlled Trial Register with the term "nocebo." Only studies that investigated nocebo effects as the effects that followed the administration of an inert treatment along with verbal suggestions of symptom worsening and that included a no-treatment control condition were eligible. ⋯ In studies in which nocebo effects were induced by a combination of verbal suggestions and conditioning, the effect size was larger (lowest g=0.76 [0.39-1.14] and highest g=1.17 [0.52-1.81]) than in studies in which nocebo effects were induced by verbal suggestions alone (lowest g=0.64 [-0.25 to 1.53] and highest g=0.87 [0.40-1.34]). These findings are similar to those in the placebo literature. As the magnitude of the nocebo effect is variable and sometimes large, this meta-analysis demonstrates the importance of minimizing nocebo effects in clinical practice.
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The degree of variability in the patient baseline 7-day diary of pain ratings has been hypothesized to have a potential effect on the assay sensitivity of randomized clinical trials of pain therapies. To address this issue, we obtained clinical trial data from the Food and Drug Administration (FDA) through the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership, and harmonized patient level data from 12 clinical trials (4 gabapentin and 8 pregabalin) in postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN). Models were developed using exploratory logistic regression to examine the interaction between available baseline factors and treatment (placebo vs active medication) in predicting patient response to therapy (ie, >30% improvement). ⋯ In addition, there was a small but significant age-by-treatment interaction in the PHN model, and small weight-by-treatment interaction in the DPN model. The patient's sex, baseline pain level, and the study protocol had an effect only on the likelihood of response overall. Our results suggest the possibility that, at least in some disease processes, excluding patients with a highly variable baseline 7-day diary has the potential to improve the assay sensitivity of these analgesic clinical trials, although reductions of external validity must be considered when increasing the homogeneity of the investigated sample.
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Randomized Controlled Trial
The association of acetazolamide infusion with headache and cranial artery dilation in healthy volunteers.
The carbonic anhydrase inhibitor acetazolamide causes extracellular acidosis and dilatation of cerebral arterioles. In this study, we tested the hypothesis that acetazolamide also may induce headache and dilatation of cranial arteries. In a randomized double-blind crossover study design, 12 young healthy women were allocated to injection of 1 g acetazolamide or placebo on 2 separate days. ⋯ Compared to placebo, arterial circumference increased after acetazolamide in the basilar artery (P=.002) as well as the cerebral (P=.003), cavernous (P=.002), and cervical (P=.005) parts of the internal carotid artery, but no other extracranial arteries changed after acetazolamide. In conclusion, acetazolamide caused immediate and delayed headache as well as dilatation of intracranial arteries in healthy volunteers. It is possible that extracellular acidosis induced by acetazolamide causes sensitization of cephalic perivascular nociceptors, which, in combination with vasodilatation, leads to delayed headache.
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Fibromyalgia typically presents with spontaneous body pain with no apparent cause and is considered pathophysiologically to be a functional disorder of somatosensory processing. We have investigated potential associations between the degree of self-reported clinical pain and resting-state brain functional connectivity at different levels of putative somatosensory integration. Resting-state functional magnetic resonance imaging was obtained in 40 women with fibromyalgia and 36 control subjects. ⋯ The results confirm previous research demonstrating abnormal functional connectivity in fibromyalgia and show that alterations at different levels of sensory processing may contribute to account for clinical pain. Importantly, reduced functional connectivity extended beyond the somatosensory domain and implicated visual and auditory sensory modalities. Overall, this study suggests that a general weakening of sensory integration underlies clinical pain in fibromyalgia.
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Randomized Controlled Trial
Short-term Improvement in Insomnia Symptoms Predicts Long-term Improvements in Sleep, Pain, and Fatigue in Older Adults with Co-Morbid Osteoarthritis and Insomnia.
In a primary care population of 367 older adults (aged ⩾60 years) with osteoarthritis (OA) pain and insomnia, we examined the relationship between short-term improvement in sleep and long-term sleep, pain, and fatigue outcomes through secondary analyses of randomized controlled trial data. Study participants, regardless of experimental treatment received, were classified either as improvers (⩾30% baseline to 2-month reduction on the Insomnia Severity Index [ISI]) or as nonimprovers. After controlling for treatment arm and potential confounders, improvers showed significant, sustained improvements across 18 months compared with nonimprovers in pain severity (P<0.001, adjusted mean difference=-0.51 [95% CI: -0.80, -0.21), arthritis symptoms (P<0.001, 0.63 [0.26, 1.00]), and fear avoidance (P=0.009, -2.27 [-3.95, -0.58]) but not in catastrophizing or depression. Improvers also showed significant, sustained improvements in ISI (P<0.001, -3.03 [-3.74, -2.32]), Pittsburgh Sleep Quality Index Total (P<0.001, -1.45 [-1.97, -0.93]) and general sleep quality (P<0.001, -0.28 [-0.39, -0.16]) scores, Flinders Fatigue Scale (P<0.001, -1.99 [-3.01, -0.98]), and Dysfunctional Beliefs About Sleep Scale (P=0.037, -2.44 [-4.74, -0.15]), but no improvements on the Functional Outcomes of Sleep Questionnaire or the Epworth Sleepiness Scale. We conclude that short-term (2-month) improvements in sleep predicted long-term (9- and 18-month) improvements for multiple measures of sleep, chronic pain, and fatigue. These improvements were not attributable to nonspecific benefits for psychological well-being, such as reduced depression. These findings are consistent with benefits of improved sleep for chronic pain and fatigue among older persons with osteoarthritis pain and comorbid insomnia if robust improvements in sleep are achieved and sustained.