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OBJECTIVE - Fibromyalgia (FM) is characterized by pain and fatigue, particularly during physical activity. Transcutaneous electrical nerve stimulation (TENS) activates endogenous pain inhibitory mechanisms. This study was undertaken to investigate if using TENS during activity would improve movement-evoked pain and other patient-reported outcomes in women with FM.
METHODS - Participants were randomly assigned to receive active TENS (n = 103), placebo TENS (n = 99), or no TENS (n = 99) and instructed to use it at home during activity 2 hours each day for 4 weeks. TENS was applied to the lumbar and cervicothoracic regions using a modulated frequency (2-125 Hz) at the highest tolerable intensity. Participants rated movement-evoked pain (primary outcome measure) and fatigue on an 11-point scale before and during application of TENS. The primary outcome measure and secondary patient-reported outcomes were assessed at baseline (time of randomization) and at 4 weeks.
RESULTS - After 4 weeks, a greater reduction in movement-evoked pain was reported in the active TENS group versus the placebo TENS group (group mean difference -1.0 [95% confidence interval -1.8, -0.2]; P = 0.008) and versus the no TENS group (group mean difference -1.8 [95% confidence interval -2.6, -1.0]; P < 0.0001). A reduction in movement-evoked fatigue was also reported in the active TENS group versus the placebo TENS group (group mean difference -1.4 [95% confidence interval -2.4, -0.4]; P = 0.001) and versus the no TENS group (group mean difference -1.9 [95% confidence interval -2.9, -0.9]; P = <0.0001). A greater percentage of the patients in the active TENS group reported improvement on the global impression of change compared to the placebo TENS group (70% versus 31%; P < 0.0001) and the no TENS group (9%; P < 0.0001). There were no TENS-related serious adverse events, and <5% of participants experienced minor adverse events from TENS.
CONCLUSION - Among women who had FM and were on a stable medication regimen, 4 weeks of active TENS use compared to placebo TENS or no TENS resulted in a significant improvement in movement-evoked pain and other clinical outcomes. Further research is needed to examine effectiveness in a real-world setting to establish the clinical importance of these findings.
© 2019 The Authors. Arthritis & Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of Rheumatology.
Inositol-requiring enzyme 1[α] (IRE1[α])-X-box binding protein spliced (XBP1) signaling maintains endoplasmic reticulum (ER) homeostasis while controlling immunometabolic processes. Yet, the physiological consequences of IRE1α-XBP1 activation in leukocytes remain unexplored. We found that induction of prostaglandin-endoperoxide synthase 2 (/Cox-2) and prostaglandin E synthase (/mPGES-1) was compromised in IRE1α-deficient myeloid cells undergoing ER stress or stimulated through pattern recognition receptors. Inducible biosynthesis of prostaglandins, including the pro-algesic mediator prostaglandin E2 (PGE), was decreased in myeloid cells that lack IRE1α or XBP1 but not other ER stress sensors. Functional XBP1 transactivated the human and genes to enable optimal PGE production. Mice that lack IRE1α-XBP1 in leukocytes, or that were treated with IRE1α inhibitors, demonstrated reduced pain behaviors in PGE-dependent models of pain. Thus, IRE1α-XBP1 is a mediator of prostaglandin biosynthesis and a potential target to control pain.
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
Factors contributing to development of complex regional pain syndrome (CRPS) are not fully understood. This study examined possible epigenetic mechanisms that may contribute to CRPS after traumatic injury. DNA methylation profiles were compared between individuals developing CRPS (n = 9) and those developing non-CRPS neuropathic pain (n = 38) after undergoing amputation following military trauma. Linear Models for Microarray (LIMMA) analyses revealed 48 differentially methylated cytosine-phosphate-guanine dinucleotide (CpG) sites between groups (unadjusted P's < 0.005), with the top gene COL11A1 meeting Bonferroni-adjusted P < 0.05. The second largest differential methylation was observed for the HLA-DRB6 gene, an immune-related gene linked previously to CRPS in a small gene expression study. For all but 7 of the significant CpG sites, the CRPS group was hypomethylated. Numerous functional Gene Ontology-Biological Process categories were significantly enriched (false discovery rate-adjusted q value <0.15), including multiple immune-related categories (eg, activation of immune response, immune system development, regulation of immune system processes, and antigen processing and presentation). Differentially methylated genes were more highly connected in human protein-protein networks than expected by chance (P < 0.05), supporting the biological relevance of the findings. Results were validated in an independent sample linking a DNA biobank with electronic health records (n = 126 CRPS phenotype, n = 19,768 non-CRPS chronic pain phenotype). Analyses using PrediXcan methodology indicated differences in the genetically determined component of gene expression in 7 of 48 genes identified in methylation analyses (P's < 0.02). Results suggest that immune- and inflammatory-related factors might confer risk of developing CRPS after traumatic injury. Validation findings demonstrate the potential of using electronic health records linked to DNA for genomic studies of CRPS.
BACKGROUND - Microvascular decompression (MVD) is a potentially curative surgery for drug-resistant trigeminal neuralgia (TN). Predictors of pain freedom after MVD are not fully understood.
OBJECTIVE - To describe rates and predictors for pain freedom following MVD.
METHODS - Using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines, PubMed, Cochrane Library, and Scopus were queried for primary studies examining pain outcomes after MVD for TN published between 1988 and March 2018. Potential biases were assessed for included studies. Pain freedom (ie, Barrow Neurological Institute score of 1) at last follow-up was the primary outcome measure. Variables associated with pain freedom on preliminary analysis underwent formal meta-analysis. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for possible predictors.
RESULTS - Outcome data were analyzed for 3897 patients from 46 studies (7 prospective, 39 retrospective). Overall, 76.0% of patients achieved pain freedom after MVD with a mean follow-up of 1.7 ± 1.3 (standard deviation) yr. Predictors of pain freedom on meta-analysis using random effects models included (1) disease duration ≤5 yr (OR = 2.06, 95% CI = 1.08-3.95); (2) arterial compression over venous or other (OR = 3.35, 95% CI = 1.91-5.88); (3) superior cerebellar artery involvement (OR = 2.02, 95% CI = 1.02-4.03), and (4) type 1 Burchiel classification (OR = 2.49, 95% CI = 1.32-4.67).
CONCLUSION - Approximately three-quarters of patients with drug-resistant TN achieve pain freedom after MVD. Shorter disease duration, arterial compression, and type 1 Burchiel classification may predict more favorable outcome. These results may improve patient selection and provider expectations.
Copyright © 2019 by the Congress of Neurological Surgeons.
OBJECTIVE - Evidence supports high rates of co-occurrence of posttraumatic stress disorder (PTSD) and chronic pain disorders involving central sensitization (CS). The nature of this relationship, however, remains relatively unexplored. In this study, we aimed to (1) assess how both trauma exposure and current PTSD symptoms are related to clinical manifestations of CS, and (2) test whether PTSD symptoms explain the relationship between trauma exposure and CS. Because experiential avoidance has been shown to impact the relationship between trauma and health outcomes, we (3) explored experiential avoidance as a possible mediator or moderator of the trauma-CS relationship.
METHODS - A sample of 202 adult patients (79% female) with chronic pain completed validated self-report measures of trauma exposure, current PTSD symptoms, experiential avoidance, and 3 manifestations of CS: widespread pain, greater pain severity, and polysomatic symptom reporting. We used path analysis and multivariate regression to assess our study aims.
RESULTS - Both trauma exposure and PTSD symptoms were significantly associated with all 3 clinical indicators of CS. PTSD symptoms partially explained the relationship between trauma exposure and widespread pain, pain intensity, and polysomatic symptoms. Experiential avoidance did not mediate or moderate the trauma-CS relationship.
CONCLUSIONS - Our findings suggest that trauma exposure is linked to elevated clinical markers of CS but a critical factor in this relationship is the mediating effect of current PTSD symptoms.
OBJECTIVES - Recent increases in opioid-related mortality have prompted a critical evaluation of postoperative pain management across all specialties. However, successfully limiting narcotic overprescription requires perioperative identification of patients who are at risk for high postoperative pain. Unfortunately, quality data to guide practice patterns are lacking. We therefore prospectively investigated several possible predictive factors of postoperative pain after endoscopic sinus surgery (ESS).
METHODS - Sixty-four consecutive patients undergoing ESS were enrolled. Baseline 22-item SinoNasal Outcomes Test (SNOT-22) and Short-Form 8 (SF-8) scores were obtained. Pain scores were collected postoperatively using a numeric rating scale. Spearman correlations and univariate linear regression models were used to investigate relationships between postoperative pain, patient factors, and SNOT-22/SF-8 domain scores. Multivariate linear regression was then performed to control for potential confounding variables.
RESULTS - Day-of-surgery pain scores were significantly correlated with the SF-8 role-physical domain (Rs = 0.32, P = 0.04). Whereas SF-8 pain scores were initially nonsignificant, at postoperative day 3 (POD3) the preoperative SF-8 pain score became correlated with self-reported pain (Rs = 0.39, P = 0.02). SNOT-22 total and subdomain scores were not associated with pain scores at any time point. Multivariate linear regression modelling identified baseline SF-8 role-physical and pain scores, smoking status, and undergoing a modified Lothrop procedure as significant independent predictors of POD3 pain (adjusted R = 0.359, P < 0.0001).
CONCLUSION - Baseline patient-reported global quality-of-life measures are associated with postoperative pain after ESS. Large multicenter studies are necessary to validate these findings and investigate additional factors associated with postoperative pain following ESS.
LEVEL OF EVIDENCE - 2c Laryngoscope, 129:1274-1279, 2019.
© 2019 The American Laryngological, Rhinological and Otological Society, Inc.
The effectiveness of cognitive treatments for low back pain, a prevalent and costly condition, are commonly based on the principles of the Cognitive Behavioral Model of Fear of Movement/(Re)injury. In this model, persons with a painful injury/experience who also engage in pain catastrophizing are most likely to avoid activity leading to disability. The validation of this model in patients with acute low back is limited. The purpose of this project was to examine the relationship of perceived disability with variables identified in the Cognitive Behavioral Model of Fear of Movement/(Re)injury such as, pain severity, pain catastrophizing, depression, and exercise in persons with acute low back pain. A multiple linear regression model was used to assess the association of perceived disability with pain severity, pain catastrophizing, depression, and exercise at baseline among subjects with acute low back pain ( = 44) participating in a randomized clinical trial to prevent transition to chronic low back pain. Controlling for age, the overall model was significant for perceived disability ([5, 35] = 14.2; < .001). Higher scores of pain catastrophizing ( = .003) and pain severity ( < .001) were associated with higher perceived disability levels. Exercise and depression were not significantly associated with perceived disability. The use of the Cognitive Behavioral Model of Fear of Movement/(Re)injury in acute LBP patients is appropriate; because this model is commonly used as rationale for the effectiveness of cognitive treatments, these findings have clinical relevance in the treatment of this condition.
© 2018 Springer Publishing Company, LLC.
We sought to replicate previous findings that low endogenous opioid (EO) function predicts greater morphine analgesia and extended these findings by examining whether circulating endocannabinoids and related lipids moderate EO-related predictive effects. Individuals with chronic low-back pain (n = 46) provided blood samples for endocannabinoid analyses, then underwent separate identical laboratory sessions under 3 drug conditions: saline placebo, intravenous (i.v.) naloxone (opioid antagonist; 12-mg total), and i.v. morphine (0.09-mg/kg total). During each session, participants rated low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects 4 times in sequence after incremental drug dosing. Mean morphine effects (morphine-placebo difference) and opioid blockade effects (naloxone-placebo difference; to index EO function) for each primary outcome (low-back pain intensity, evoked heat pain intensity, and nonpain subjective effects) were derived by averaging across the 4 incremental doses. The association between EO function and morphine-induced back pain relief was significantly moderated by endocannabinoids [2-arachidonoylglycerol (2-AG) and N-arachidonoylethanolamine (AEA)]. Lower EO function predicted greater morphine analgesia only for those with relatively lower endocannabinoids. Endocannabinoids also significantly moderated EO effects on morphine-related changes in visual analog scale-evoked pain intensity (2-AG), drug liking (AEA and 2-AG), and desire to take again (AEA and 2-AG). In the absence of significant interactions, lower EO function predicted significantly greater morphine analgesia (as in past work) and euphoria. Results indicate that EO effects on analgesic and subjective responses to opioid medications are greatest when endocannabinoid levels are low. These findings may help guide development of mechanism-based predictors for personalized pain medicine algorithms.
G protein-gated inwardly rectifying potassium (GIRK) channels are potassium-selective ion channels. As their name suggests, GIRK channels are effectors of G G protein-couple receptors whereby activation of these GPCRs leads to increased GIRK channel activity resulting in decreased cellular excitability. In this way, GIRK channels play diverse roles in physiology as effectors of G-coupled GPCRs: peacemaking in the heart rate, modulation of hormone secretion in endocrine tissues, as well as numerous CNS functions including learning, memory, and addiction/reward. Notably, GIRK channels are widely expressed along the spinothalamic tract and are positioned to play roles in both ascending and descending pain pathways. More notably, GIRK channel knockout and knock-down studies have found that GIRK channels play a major role in the action of opioid analgesics which act predominantly through G-coupled, opioid-activated GPCRs (e.g., μ-opioid receptors). Recent advances in GIRK channel pharmacology have led to the development of small molecules that directly and selectively activate GIRK channels. Based on research implicating the involvement of GIRK channels in pain pathways and as effectors of opioid analgesics, we conducted a study to determine whether direct pharmacological activation of GIRK channels could produce analgesic efficacy and/or augment the analgesic efficacy morphine, an opioid receptor agonist capable of activating μ-opioid receptors as well as other opioid receptor subtypes. In the present study, we demonstrate that the small-molecule GIRK activator, VU0466551, has analgesic effects when dosed alone or in combination with submaximally effective doses of morphine.