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Carol GT Vance,1 Ruth L Chimenti,1 Dana L Dailey,1 Katherine Hadlandsmyth,2 M Bridget Zimmerman,3 Katharine M Geasland,1 Jonathan M Williams,4 Ericka N Merriwether,1,5 Li Alemo Munters,4 Barbara A Rakel,6 Leslie J Crofford,4 Kathleen A Sluka1 1Department of Physical Therapy and Rehabilitation Science, The University of Iowa Carver College of Medicine, Iowa City, IA, USA; 2Department of Anesthesia, College of Medicine, University of Iowa, Iowa City, IA, USA; 3Department of Biostatistics, College of Public Health, University of Iowa, Iowa City, IA, USA; 4Department of Medicine/Rheumatology & Immunology, Vanderbilt University, Nashville, TN, USA; 5Department of Physical Therapy, New York University, New York, NY, USA; 6College of Nursing, University of Iowa, Iowa City, IA, USA Introduction: Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological intervention clinically used for pain relief. The importance of utilizing the adequate stimulation intensity is well documented; however, clinical methods to achieve the highest possible intensity are not established. Objectives: Our primary aim was to determine if exposure to the full range of clinical levels of stimulation, from sensory threshold to noxious, would result in higher final stimulation intensities. A secondary aim explored the association of pain, disease severity, and psychological variables with the ability to achieve higher final stimulation intensity. Methods: Women with fibromyalgia (N=143) were recruited for a dual-site randomized controlled trial – Fibromyalgia Activity Study with TENS (FAST). TENS electrodes and stimulation were applied to the lumbar area, and intensity was increased to sensory threshold (ST), then to “strong but comfortable” (SC1), then to “noxious” (N). This was followed by a reduction to the final stimulation intensity of “strong but comfortable” (SC2). We called this the Setting of Intensity of TENS (SIT) test. Results: There was a significant increase from SC1 (37.5 mA IQR: 35.6–39.0) to SC2 (39.2 mA IQR: 37.1–45.3) (p

Carol GT Vance,1 Barbara A Rakel,1,2 Dana L Dailey,1 Kathleen A Sluka1,2 1Department of Physical Therapy and Rehabilitation Science, University of Iowa Carver College of Medicine, 2University of Iowa, College Nursing Iowa City, IA, USA Objective: Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention used to manage pain using skin surface electrodes. Optimal electrode placement is unclear. We hypothesized that better analgesia would occur if electrodes were placed over sites with lower skin impedance. Optimal site selection (OSS) and sham site selection (SSS) electrode sites on the forearm were identified using a standard clinical technique. Methods: Experiment 1 measured skin impedance in the forearm at OSS and SSS. Experiment 2 was a crossover design double-blind randomized controlled trial comparing OSS-TENS, SSS-TENS, and placebo TENS (P-TENS) to confirm differences in skin impedance between OSS and SSS, and measure change in pressure pain threshold (PPT) following a 30-minute TENS treatment. Healthy volunteers were recruited (ten for Experiment 1 [five male, five female] and 24 for Experiment 2 [12 male, 12 female]). TENS was applied for 30 minutes at 100 Hz frequency, 100 µs pulse duration, and “strong but nonpainful” amplitude. Results: Experiment 1 results demonstrate significantly higher impedance at SSS (17.69±1.24 Ω) compared to OSS (13.53±0.57 Ω) (P=0.007). For Experiment 2, electrode site impedance was significantly higher over SSS, with both the impedance meter (P=0.001) and the TENS unit (P=0.012) compared to OSS. PPT change was significantly greater for both OSS-TENS (P=0.024) and SSS-TENS (P=0.025) when compared to P-TENS. PPT did not differ between the two active TENS treatments (P=0.81). Conclusion: Skin impedance is lower at sites characterized as optimal using the described technique of electrode site selection. When TENS is applied at adequate intensities, skin impedance is not a factor in attainment of hypoalgesia of the forearm in healthy subjects. Further investigation should include testing in patients presenting with painful conditions. Keywords: transcutaneous electrical nerve stimulation, pain, impedance, electrode site selection

Movement pain, which is distinct from resting pain, is frequently reported by individuals with musculoskeletal pain. There is growing interest in measuring movement pain as a primary outcome in clinical trials, but no minimally clinically important change (MCIC) has been established, limiting interpretations. We analyzed data from 315 participants who participated in previous clinical trials (65 with chronic Achilles tendinopathy; 250 with fibromyalgia) to establish an MCIC for movement pain. A composite movement pain score was defined as the average pain (Numeric Rating Scale: 0-10) during 2 clinically relevant activities. The change in movement pain was calculated as the change in movement pain from pre-intervention to post-intervention. A Global Scale (GS: 1-7) was completed after the intervention on perceived change in health status. Participants were dichotomized into non-responders (GS ≥4) and responders (GS <3). Receiver operating characteristic curves were calculated to determine threshold values and corresponding sensitivity and specificity. We used the Euclidean method to determine the optimal threshold point of the Receiver operating characteristic curve to determine the MCIC. The MCIC for raw change in movement pain was 1.1 (95% confidence interval [CI]: .9-1.6) with a sensitivity of .83 (95% CI: .75-.92) and specificity of .79 (95% CI: .72-.86). For percent change in movement pain the MCIC was 27% (95% CI: 10-44%) with a sensitivity of .79 (95% CI: .70-.88) and a specificity of .82 (95% CI: .72-.90). Establishing an MCIC for movement pain will improve interpretations in clinical practice and research. PERSPECTIVE: A minimal clinically important change (MCIC) of 1.1- points (95% CI: .9-1.6) for movement pain discriminates between responders and non-responders to rehabilitation. This MCIC provides context for interpreting the meaningfulness of improvement in pain specific to movement tasks., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Transcutaneous electrical nerve stimulation (TENS) effectively reduces pain in fibromyalgia (FM). The purpose of this study was to examine the influence of TENS use on pressure pain thresholds (PPT) and conditioned pain modulation (CPM) in individuals with FM using data from the Fibromyalgia Activity Study with TENS trial (NCT01888640). Individuals with FM were randomly assigned to receive active TENS, placebo TENS, or no TENS for 4 weeks. A total of 238 females satisfied the per-protocol analysis among the active TENS (n = 76), placebo TENS (n = 68), and no TENS (n = 94) groups. Following 4 weeks of group allocation, the active TENS group continued for an additional 4 weeks of active TENS totaling 8 weeks (n = 66), the placebo and no TENS groups transitioned to receive 4 weeks of active TENS (delayed TENS, n = 161). Assessment of resting pain, movement-evoked pain (MEP), PPT, and CPM occurred prior to and following active, placebo, or no TENS. There were no significant changes in PPT or CPM among the active TENS, placebo TENS, or no TENS groups after 4 weeks. Individuals who reported clinically relevant improvements in MEP (≥30% decrease) demonstrated increases in PPT (P < .001), but not CPM, when compared to MEP non-responders. There were no significant correlations among the change in PPT or CPM compared to MEP and resting pain following active TENS use (active TENS + delayed TENS). PPT and CPM may provide insight to underlying mechanisms contributing to pain; however, these measures may not relate to self-reported pain symptoms. PERSPECTIVE: Pressure pain threshold increased in individuals with clinically relevant improvement (≥30%) in MEP, indicating the clinical relevance of PPT for understanding mechanisms contributing to pain. CPM was not a reliable indicator of treatment response in MEP responders., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Low back pain (LBP) is a significant public health problem, is very prevalent, and is often characterized by the persistence of symptoms. Transcutaneous electrical nerve stimulation (TENS) may benefit people with chronic LBP because it can activate descending inhibitory pathways and inhibit central excitability. However, previous studies that have investigated the effects of TENS on pain in people with LBP have failed to use proper intensities of current, and the timing of the assessment of pain was not performed during the peak of the analgesic response or functional activities. Therefore, the present study aims to assess the effects of TENS on measures of pain, function, and descending inhibition using the maximal tolerable intensity of TENS in participants with LBP., Methods/design: This study will be a randomized crossover trial. The participants for this study will be recruited from various places, including the University of Hartford, physical therapy clinics, and local businesses in the Hartford area, as well as online websites geared towards clinical trial recruitment. A total of 34 participants will receive all three treatments: active TENS, placebo TENS, and no treatment control. The treatment order will be randomized using a website-based randomization tool. For active TENS, a modulating frequency of 2-125 Hz will be applied with a variable pulse duration and maximal tolerable intensity for 30 min. The TENS will be left on for post-treatment testing to assess the effects during its maximally effective period for a total of 50 to 60 min. Furthermore, the intensity may be turned down if muscle twitching is present to ensure blinding of the evaluator. For placebo TENS, the unit will deliver current for 45 s, ramping to 0 in the last 15 s. The primary outcome will be pain intensity at rest and with movement, determined using the numerical pain rating scale. The secondary outcomes will be pressure pain threshold, heat pain threshold, temporal summation of pain, conditioned pain modulation, sit-to-stand test, and repeated trunk flexion. The assessments will be performed immediately before and after treatment. Statistical analysis of the data obtained will consider a significance level of p < 0.05., Discussion: This study will provide evidence concerning the effects and mechanisms of TENS treatment in participants with chronic non-specific low back pain. The outcomes, including pain, function, and descending inhibition, will help us gain a greater understanding of how TENS can be used for these participants., Trial Registration: ClinicalTrials.gov NCT05812885. Registered on 24th May 2023., (© 2024. The Author(s).)

The NIH Pragmatic Trials Collaboratory supports the design and conduct of 27 embedded pragmatic clinical trials, and many of the studies collect patient reported outcome measures as primary or secondary outcomes. Study teams have encountered challenges in the collection of these measures, including challenges related to competing health care system priorities, clinician's buy-in for adoption of patient-reported outcome measures, low adoption and reach of technology in low resource settings, and lack of consensus and standardization of patient-reported outcome measure selection and administration in the electronic health record. In this article, we share case examples and lessons learned, and suggest that, when using patient-reported outcome measures for embedded pragmatic clinical trials, investigators must make important decisions about whether to use data collected from the participating health system's electronic health record, integrate externally collected patient-reported outcome data into the electronic health record, or collect these data in separate systems for their studies., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: Chronic pain affects more than 50 million Americans. Treatments remain inadequate, in large part, because the pathophysiological mechanisms underlying the development of chronic pain remain poorly understood. Pain biomarkers could potentially identify and measure biological pathways and phenotypical expressions that are altered by pain, provide insight into biological treatment targets, and help identify at-risk patients who might benefit from early intervention. Biomarkers are used to diagnose, track, and treat other diseases, but no validated clinical biomarkers exist yet for chronic pain. To address this problem, the National Institutes of Health Common Fund launched the Acute to Chronic Pain Signatures (A2CPS) program to evaluate candidate biomarkers, develop them into biosignatures, and discover novel biomarkers for chronification of pain after surgery. This article discusses candidate biomarkers identified by A2CPS for evaluation, including genomic, proteomic, metabolomic, lipidomic, neuroimaging, psychophysical, psychological, and behavioral measures. Acute to Chronic Pain Signatures will provide the most comprehensive investigation of biomarkers for the transition to chronic postsurgical pain undertaken to date. Data and analytic resources generatedby A2CPS will be shared with the scientific community in hopes that other investigators will extract valuable insights beyond A2CPS's initial findings. This article will review the identified biomarkers and rationale for including them, the current state of the science on biomarkers of the transition from acute to chronic pain, gaps in the literature, and how A2CPS will address these gaps., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.)

Embedded pragmatic clinical trials (ePCTs) play a vital role in addressing current population health problems, and their use of electronic health record (EHR) systems promises efficiencies that will increase the speed and volume of relevant and generalizable research. However, as the number of ePCTs using EHR-derived data grows, so does the risk that research will become more vulnerable to biases due to differences in data capture and access to care for different subsets of the population, thereby propagating inequities in health and the healthcare system. We identify 3 challenges-incomplete and variable capture of data on social determinants of health, lack of representation of vulnerable populations that do not access or receive treatment, and data loss due to variable use of technology-that exacerbate bias when working with EHR data and offer recommendations and examples of ways to actively mitigate bias., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Medical Informatics Association.)

Embedded pragmatic clinical trials (ePCTs) are conducted during routine clinical care and have the potential to increase knowledge about the effectiveness of interventions under real world conditions. However, many pragmatic trials rely on data from the electronic health record (EHR) data, which are subject to bias from incomplete data, poor data quality, lack of representation from people who are medically underserved, and implicit bias in EHR design. This commentary examines how the use of EHR data might exacerbate bias and potentially increase health inequities. We offer recommendations for how to increase generalizability of ePCT results and begin to mitigate bias to promote health equity., Competing Interests: Declaration of Competing Interest ECO Reports grants to her institution from Pfizer, BMS, and Novartis. KM reports grants and contracts to his institution from Novartis, Amgen, Seqirus, Genentech, BMS, and Boehringer Ingelheim. ADB reports grants from Alike Health, travel from Microsoft. All other authors have nothing to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Abstract: A growing number of individuals report prolonged symptoms following acute Coronavirus-19 (COVID-19) infection, known as post-COVID-19 condition (post-COVID-19). While studies have emerged investigating the symptom sequelae of post-COVID-19, there has been limited investigation into the characterization of pain, fatigue, and function in these individuals, despite initial reports of a clinical phenotype similar to fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (ME). This study aimed to characterize multiple symptom domains in individuals reporting post-COVID-19 and compare its clinical phenotype with those with FMS and CFS. A total of 707 individuals with a single or comorbid diagnosis of post-COVID-19, FMS, and/or CFS completed multiple surveys assessing self-reported pain, fatigue, physical and cognitive function, catastrophizing, kinesiophobia, anxiety, depression, dyspnea, and sleep quality. In all 3 diagnoses, elevated pain, fatigue, anxiety, depression, catastrophizing, and kinesiophobia were reported. Physical and cognitive function were similarly impacted among individuals with post-COVID-19, FMS, and CFS; however, individuals with post-COVID-19 reported lower pain and fatigue than FMS and CFS. The comorbid diagnosis of post-COVID-19 with FMS and/or CFS further exacerbated pain, fatigue, and psychological domains when compared with post-COVID-19 alone. In summary, individuals with post-COVID-19 report a symptom phenotype similar to FMS and CFS, negatively impacting cognitive and physical function, but with less severe pain and fatigue overall. These findings may help direct future investigations of the benefit of a biopsychosocial approach to the clinical management of post-COVID-19., (Copyright © 2022 International Association for the Study of Pain.)

Objectives: Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention that provides an electrical current through the skin to produce analgesia. The primary purpose of this study is to examine if the addition of TENS to routine physical therapy improves movement-evoked pain in individuals with fibromyalgia in a physical therapy clinical setting., Methods: Fibromyalgia TENS in Physical Therapy Study is a phase III embedded pragmatic clinical trial funded through the National Institutes of Health Helping to End Addiction Long-Term Initiative. This trial will utilize a randomized cluster design that includes more than 110 physical therapists in 24 to 30 physical therapy clinics within 6 health care systems and 7 states. Clinics will be randomized to TENS or No-TENS, stratified by health care system and clinic size. The plan is to enroll 600 participants, with all participants completing physical therapy as prescribed by their physical therapist. Participants at TENS clinics will utilize TENS for a minimum of 2-hour per day while at the physical therapy clinic and at home when active. The primary outcome is reduction in movement-evoked pain from baseline to day 60 on an 11-point numeric rating scale when participants sit and stand 5 times (Sit and Stand Test). Secondary outcomes include resting pain and fatigue, pain interference, fibromyalgia disease activity, movement-evoked fatigue, multidimensional assessment of fatigue, rapid assessment of physical activity, patient global impression of change, and common data elements shared across studies supported through the Helping to End Addiction Long-Term Initiative., Impact: The findings from this study will provide effectiveness data on TENS for individuals with fibromyalgia for health care policymakers, clinicians, and insurers. Data from this study will also inform future pragmatic trials for nonpharmacological interventions and chronic musculoskeletal pain conditions., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Fibromyalgia (FM) is a chronic pain disorder characterized by chronic widespread musculoskeletal pain (CWP), resting pain, movement-evoked pain (MEP), and other somatic symptoms that interfere with daily functioning and quality of life. In clinical studies, this symptomology is assessed, while preclinical models of CWP are limited to nociceptive assays. The aim of the study was to investigate the human-to-model translatability of clinical behavioral assessments for spontaneous (or resting) pain and MEP in a preclinical model of CWP. For preclinical measures, the acidic saline model of FM was used to induce widespread muscle pain in adult female mice. Two intramuscular injections of acidic or neutral pH saline were administered following baseline measures, 5 days apart. An array of adapted evoked and spontaneous pain measures and functional assays were assessed for 3 weeks. A novel paradigm for MEP assessment showed increased spontaneous pain following activity. For clinical measures, resting and movement-evoked pain and function were assessed in adult women with FM. Moreover, we assessed correlations between the preclinical model of CWP and in women with fibromyalgia to examine whether similar relationships between pain assays that comprise resting and MEP existed in both settings. For both preclinical and clinical outcomes, MEP was significantly associated with mechanical pain sensitivity. Preclinically, it is imperative to expand how the field assesses spontaneous pain and MEP when studying multi-symptom disorders like FM. Targeted pain assessments to match those performed clinically is an important aspect of improving preclinical to clinical translatability of animal models., (© The Author(s) 2022. Published by Oxford University Press on behalf of the American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Transcutaneous electrical nerve stimulation (TENS) is a non-pharmacological intervention used in the treatment of acute and chronic pain conditions. The first clinical studies on TENS were published over 50 years ago, when effective parameters of stimulation were unclear and clinical trial design was in its infancy. Over the last two decades, a better understanding of the mechanisms underlying TENS efficacy has led to the development of an adequate dose and has improved outcome measure utilization. The continued uncertainty about the clinical efficacy of TENS to alleviate pain, despite years of research, is related to the quality of the clinical trials included in systematic reviews. This summary of the evidence includes only trials with pain as the primary outcome. The outcomes will be rated as positive (+), negative (-), undecided (U), or equivalent to other effective interventions (=). In comparison with our 2014 review, there appears to be improvement in adverse events and parameter reporting. Importantly, stimulation intensity has been documented as critical to therapeutic success. Examinations of the outcomes beyond resting pain, analgesic tolerance, and identification of TENS responders remain less studied areas of research. This literature review supports the conclusion that TENS may have efficacy for a variety of acute and chronic pain conditions, although the magnitude of the effect remains uncertain due to the low quality of existing literature. In order to provide information to individuals with pain and to clinicians treating those with pain, we suggest that resources for research should target larger, high-quality clinical trials including an adequate TENS dose and adequate timing of the outcome and should monitor risks of bias. Systematic reviews and meta-analyses should focus only on areas with sufficiently strong clinical trials that will result in adequate sample size.

Transcutaneous electrical nerve stimulation (TENS) uses endogenous opioids to produce analgesia, and effectiveness can be reduced in opioid-tolerant individuals'. We examined TENS effectiveness (primary aim), and differences in fibromyalgia symptoms (secondary aim), in women with fibromyalgia regularly taking opioid (RTO) medications compared with women not- regularly taking opioids (not-RTO). Women (RTO n = 79; not-RTO not-n = 222) with fibromyalgia with daily pain levels ≥4 were enrolled and categorized into RTO (taking opioids at least 5 of 7 days in last 30 days) or not-RTO groups. Participants were categorized into tramadol n = 52 (65.8%) and other opioids n = 27 (34.2%) for the RTO group. Participants were phenotyped across multiple domains including demographics, fibromyalgia characteristics pain, fatigue, sleep, psychosocial factors, and activity. Participants were randomized to active TENS (n = 101), placebo TENS (n = 99), or no TENS (n = 99) for 1-month with randomization stratified by opioid use. Active TENS was equally effective in movement-evoked pain in those in the RTO and not-RTO groups. Women with fibromyalgia in the RTO group were older (P = .002), lower-income (P = .035), more likely to smoke (P = .014), and more likely to report depression (P = .013), hypertension (P = .005) or osteoarthritis (P = .027). The RTO group demonstrated greater bodily pain on SF-36 (P = .005), lower quality of life on the physical health component of the SF-36 (P = .040), and greater fatigue (MAF-ADL P = .047; fatigue with sit to stand test (P = .047) These differences were small of and unclear clinical significance. In summary, regular use of opioid analgesics does not interfere with the effectiveness of TENS for movement-evoked pain. Clinical Trial Registration Number: NCT01888640. PERSPECTIVE: Individuals treated with mixed frequency TENS at a strong but comfortable intensity that was taking prescription opioid analgesics showed a significant reduction in movement-evoked pain and fatigue. These data support the use of TENS, using appropriate parameters of stimulation, as an intervention for individuals with fibromyalgia taking opioid analgesics., (Published by Elsevier Inc.)

Chronic pain has become a global health problem contributing to years lived with disability and reduced quality of life. Advances in the clinical management of chronic pain have been limited due to incomplete understanding of the multiple risk factors and molecular mechanisms that contribute to the development of chronic pain. The Acute to Chronic Pain Signatures (A2CPS) Program aims to characterize the predictive nature of biomarkers (brain imaging, high-throughput molecular screening techniques, or "omics," quantitative sensory testing, patient-reported outcome assessments and functional assessments) to identify individuals who will develop chronic pain following surgical intervention. The A2CPS is a multisite observational study investigating biomarkers and collective biosignatures (a combination of several individual biomarkers) that predict susceptibility or resilience to the development of chronic pain following knee arthroplasty and thoracic surgery. This manuscript provides an overview of data collection methods and procedures designed to standardize data collection across multiple clinical sites and institutions. Pain-related biomarkers are evaluated before surgery and up to 3 months after surgery for use as predictors of patient reported outcomes 6 months after surgery. The dataset from this prospective observational study will be available for researchers internal and external to the A2CPS Consortium to advance understanding of the transition from acute to chronic postsurgical pain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Berardi, Frey-Law, Sluka, Bayman, Coffey, Ecklund, Vance, Dailey, Burns, Buvanendran, McCarthy, Jacobs, Zhou, Wixson, Balach, Brummett, Clauw, Colquhoun, Harte, Harris, Williams, Chang, Waljee, Fisch, Jepsen, Laurent, Olivier, Langefeld, Howard, Fiehn, Jacobs, Dakup, Qian, Swensen, Lokshin, Lindquist, Caffo, Crainiceanu, Zeger, Kahn, Wager, Taub, Ford, Sutherland and Wandner.)

Background: Nonrestorative sleep is commonly reported by individuals with fibromyalgia, but there is limited information on the reliability and responsiveness of self-reported sleep measures in this population. Objectives: (1) Examine the reliability and validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) sleep measures in women with fibromyalgia, and (2) Determine the responsiveness of the PROMIS sleep measures to a daily transcutaneous electrical nerve stimulation (TENS) intervention in women with fibromyalgia over 4 weeks compared with other measures of restorative sleep. Methods: In a double-blinded, dual-site clinical trial, 301 women with fibromyalgia were randomly assigned to utilize either Active-TENS, Placebo-TENS, or No-TENS at home. Measures were collected at baseline and after 4 weeks of treatment. To assess self-reported sleep, the participants completed three PROMIS short forms: Sleep Disturbance, Sleep-Related Impairment, Fatigue, and the Pittsburgh Sleep Quality Index (PSQI). To assess device-measured sleep, actigraphy was used to quantify total sleep time, wake after sleep onset, and sleep efficiency. Linear mixed models were used to examine the effects of treatment, time, and treatment*time interactions. Results: The PROMIS short forms had moderate test-retest reliability (ICC 0.62 to 0.71) and high internal consistency (Cronbach's alpha 0.89 to 0.92). The PROMIS sleep measures [mean change over 4 weeks, 95% confidence interval (CI)], Sleep Disturbance: -1.9 (-3.6 to -0.3), Sleep-Related Impairment: -3 (-4.6 to -1.4), and Fatigue: -2.4 (-3.9 to -0.9) were responsive to improvement in restorative sleep and specific to the Active-TENS group but not in the Placebo-TENS [Sleep Disturbance: -1.3 (-3 to 0.3), Sleep-Related Impairment: -1.2 (-2.8 to 0.4), Fatigue: -1.1 (-2.7 to 0.9)] or No-TENS [Sleep Disturbance: -0.1 (-1.6 to 1.5), Sleep-Related Impairment: -0.2 (-1.7 to 1.4), Fatigue: -.3 (-1.8 to 1.2)] groups. The PSQI was responsive but not specific with improvement detected in both the Active-TENS: -0.9 (-1.7 to -0.1) and Placebo-TENS: -0.9 (-1.7 to 0) groups but not in the No-TENS group: -0.3 (-1.1 to 0.5). Actigraphy was not sensitive to any changes in restorative sleep with Active-TENS [Sleep Efficiency: -1 (-2.8 to 0.9), Total Sleep Time: 3.3 (-19.8 to 26.4)]. Conclusion: The PROMIS sleep measures are reliable, valid, and responsive to improvement in restorative sleep in women with fibromyalgia. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01888640., Competing Interests: KS serves as a consultant for Pfizer Consumer Health and Novartis Consumer Healthcare/GSK Consumer Healthcare, had an active grant from the American Pain Society/Pfizer, and receives royalties from IASP Press. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Chimenti, Rakel, Dailey, Vance, Zimmerman, Geasland, Williams, Crofford and Sluka.)

Abstract: We previously showed that 1 month of transcutaneous electrical nerve stimulation (TENS) reduces movement-evoked pain and fatigue in women with fibromyalgia (FM). Using data from this study (Fibromyalgia Activity Study with TENS [FAST]), we performed a responder analysis to identify predictors of clinical improvement in pain and fatigue with TENS, validated these models using receiver operator characteristic, and determined number needed to treat and number needed to harm. Participants were randomly assigned to active-TENS (2-125 Hz; highest-tolerable intensity), placebo-TENS, or no-TENS for 1 month. At the end of the randomized phase, placebo-TENS and no-TENS groups received active-TENS for 1 month. The predictor model was developed using data from the randomized phase for the active-TENS group (n = 103) and validated using data from placebo-TENS and no-TENS groups after active-TENS for 1 month (n = 155). Participant characteristics, initial response to TENS for pain and fatigue, sleep, psychological factors, and function were screened for association with changes in pain or fatigue using a logistic regression model. Predictors of clinical improvement in pain were initial response to pain and widespread pain index (area under the curve was 0.80; 95% confidence interval: 0.73-0.87). Predictors of clinical improvement in fatigue were marital status, sleep impairment, and initial response to TENS (area under the curve was 0.67; 95% confidence interval: 0.58-0.75). Number needed to treat for pain and fatigue ranged between 3.3 and 5.3. Number needed to harm ranged from 20 to 100 for minor TENS-related adverse events. The response to an initial 30-minute TENS treatment predicts who responds to longer-term TENS use in women with FM, making this a clinically useful procedure. Number needed to treat and number needed to harm suggest that TENS is effective and safe for managing pain and fatigue in FM., (Copyright © 2020 International Association for the Study of Pain.)

Abstract: Fibromyalgia (FM) is characterized by widespread chronic pain, fatigue, and somatic symptoms. The influence of phenotypic changes in monocytes on symptoms associated with FM is not fully understood. The primary aim of this study was to take a comprehensive whole-body to molecular approach in characterizing relationships between monocyte phenotype and FM symptoms in relevant clinical populations. Lipopolysaccharide-evoked and spontaneous secretion of IL-5 and other select cytokines from circulating monocytes was higher in women with FM compared to women without pain. In addition, greater secretion of IL-5 was significantly associated with pain and other clinically relevant psychological and somatic symptoms of FM. Furthermore, higher levels of pain and pain-related symptoms were associated with a lower percentage of intermediate monocytes (CD14++/CD16+) and a greater percentage of nonclassical monocytes (CD14+/CD16++) in women with FM. Based on findings from individuals with FM, we examined the role of IL-5, an atypical cytokine secreted from monocytes, in an animal model of widespread muscle pain. Results from the animal model show that IL-5 produces analgesia and polarizes monocytes toward an anti-inflammatory phenotype (CD206+). Taken together, our data suggest that monocyte phenotype and their cytokine profiles are associated with pain-related symptoms in individuals with FM. Furthermore, our data show that IL-5 has a potential role in analgesia in an animal model of FM. Thus, targeting anti-inflammatory cytokines such as IL-5 secreted by circulating leukocytes could serve as a promising intervention to control pain and other somatic symptoms associated with FM., (Copyright © 2020 International Association for the Study of Pain.)

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.)

This study examined whether depression and anxiety differentially relate to fatigue, sleep disturbance, pain catastrophizing, fear of movement, and pain severity in women with fibromyalgia. Baseline data from the Fibromyalgia Activity Study with Transcutaneous Electrical Nerve Stimulation were analyzed. Of 191 participants, 50 percent reported high anxiety and/or depression (17% high anxiety, 9% high depression, and 24% both). Fatigue and sleep impairment were associated with high depression ( p  < 0.05). Pain severity, pain catastrophizing, and fear of movement were associated with high anxiety and high depression ( p  < 0.05). Possible implications for underlying mechanisms and the need for targeted treatments are discussed.

Background: Although exercise is an effective treatment for fibromyalgia, the relationships between lifestyle physical activity and multiple symptomology domains of fibromyalgia are not clear. Thus, the purpose of this study was to comprehensively examine the relationships between lifestyle physical activity with multiple outcome domains in women with fibromyalgia, including pain, fatigue, function, pain-related psychological constructs, and quality of life., Methods: Women (N = 171), aged 20 to 70 years, diagnosed with fibromyalgia, recruited from an ongoing two-site clinical trial were included in this prespecified subgroup analysis of baseline data. Physical activity was assessed using self-report and accelerometry. Symptomology was assessed using questionnaires of perceived physical function, quality of life, fatigue, pain intensity and interference, disease impact, pain catastrophizing, and fear of movement. In addition, quantitative sensory testing of pain sensitivity and performance-based physical function were assessed. Correlation coefficients, regression analyses and between-group differences in symptomology by activity level were assessed, controlling for age and body mass index (BMI)., Results: Lifestyle physical activity was most closely associated with select measures of physical function and fatigue, regardless of age and BMI. Those who performed the lowest levels of lifestyle physical activity had poorer functional outcomes and greater fatigue than those with higher physical activity participation. No relationships between lifestyle physical activity and pain, pain sensitivity, or pain-related psychological constructs were observed., Conclusions: Lifestyle physical activity is not equally related to all aspects of fibromyalgia symptomology. Lifestyle physical activity levels have the strongest correlations with function, physical quality of life, and movement fatigue in women with fibromyalgia. No relationships between lifestyle physical activity and pain, pain sensitivity, or psychological constructs were observed. These data suggest that physical activity levels are more likely to affect function and fatigue, but have negligible relationships with pain and pain-related psychological constructs, in women with fibromyalgia., Trial Registration: ClinicalTrials.gov, NCT01888640 . Registered on 28 June 2013.

Objective: The Patient-Reported Outcomes Measurement Information System (PROMIS) was developed to standardize measurement of clinically relevant patient-reported outcomes. This study evaluated the reliability and construct validity of select PROMIS static short-form (SF) instruments in women with fibromyalgia., Design: Analysis of baseline data from the Fibromyalgia Activity Study with TENS (FAST), a randomized controlled trial of the efficacy of transcutaneous electrical nerve stimulation., Setting: Dual site, university-based outpatient clinics., Subjects: Women aged 20 to 67 years diagnosed with fibromyalgia., Methods: Participants completed the Revised Fibromyalgia Impact Questionnaire (FIQR) and 10 PROMIS static SF instruments. Internal consistency was calculated using Cronbach alpha. Convergent validity was examined against the FIQR using Pearson correlation and multiple regression analysis., Results: PROMIS static SF instruments had fair to high internal consistency (Cronbach α = 0.58 to 0.94, P  < 0.05). PROMIS 'physical function' domain score was highly correlated with FIQR 'function' score (r = -0.73). The PROMIS 'total' score was highly correlated with the FIQR total score (r = -0.72). Correlations with FIQR total score of each of the three PROMIS domain scores were r = -0.65 for 'physical function,' r = -0.63 for 'global,' and r = -0.57 for 'symptom' domain. PROMIS 'physical function,' 'global,' and 'symptom' scores explained 58% of the FIQR total score variance., Conclusions: Select PROMIS static SF instruments demonstrate convergent validity with the FIQR, a legacy measure of fibromyalgia disease severity. These results highlight the potential utility of select PROMIS static SFs for assessment and tracking of patient-reported outcomes in fibromyalgia., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background: Fibromyalgia is a condition characterized by chronic widespread muscle pain and fatigue and associated with significant impairment in perceived function and reduced physical performance. The purpose of this study was to determine the degree to which pain and fatigue are associated with perceived function and physical performance in women with fibromyalgia., Methods: Hierarchical linear regression determined the contribution of pain and fatigue (Numeric Rating Scale (NRS) for resting, movement and combined) to perceived function (Fibromyalgia Impact Questionnaire Revised - Function Subscale, FIQR-Function), Multidimensional Assessment of Fatigue - Activities of Daily Living (MAF-ADL) and SF-36 Physical Function Subscale (SF-36-PF) and physical performance (6-Minute Walk Test, 6MWT and Five Time Sit To Stand, 5TSTS) while controlling for age, body mass index, pain catastrophizing, fear of movement, anxiety, and depression in women with fibromyalgia (N = 94)., Results: For perceived function, movement pain and movement fatigue together better predicted FIQR-function (adjusted R(2) = 0.42, p ≤ 0.001); MAF-ADL (adjusted R(2) = 0.41, p ≤ 0.001); and SF-36-PF function (adjusted R(2) = 0.34, p ≤ 0.001). For physical performance measures, movement pain and fatigue together predicted 6MWT distance (adjusted R(2) = 0.42, p ≤ 0.001) and movement fatigue alone predicted performance time on the 5TSTS (adjusted R(2) = 0.20, p ≤ 0.001)., Conclusions: Pain and fatigue are significantly associated with and explain more than one-third of the variance in perceived function and physical performance in women with fibromyalgia., Trial Registration: NIH Clinicaltrials.gov, Registration: NCT01888640 . Registered 13 June 2013.

Objective: Fibromyalgia is a condition characterized by chronic widespread muscle pain and fatigue. The primary objective of this study was to determine if pain, perceived cognitive fatigue, and perceived physical fatigue were enhanced in participants with fibromyalgia compared to healthy controls during a cognitive fatigue task, a physical fatigue task, and a dual fatigue task., Methods: In total, 24 people with fibromyalgia and 33 healthy controls completed pain, fatigue, and function measures. A cognitive fatigue task (Controlled Oral Word Association Test) and physical fatigue task (Valpar peg test) were done individually and combined for a dual fatigue task. Resting pain, perceived cognitive fatigue, and perceived physical fatigue were assessed during each task using visual analog scales. Function was assessed with shoulder range of motion and grip., Results: People with fibromyalgia had significantly higher increases in pain, cognitive fatigue, and physical fatigue when compared to healthy controls after completion of a cognitive fatigue task, a physical fatigue task, or a dual fatigue task (P < 0.01) with the exception of perceived cognitive fatigue during the cognitive fatigue task. People with fibromyalgia performed equivalently on measures of physical performance and cognitive performance on the physical and cognitive fatigue tasks, respectively., Conclusion: These data show that people with fibromyalgia show larger increases in pain, perceived cognitive fatigue, and perceived physical fatigue to both cognitive and physical fatigue tasks compared to healthy controls. The increases in pain and fatigue during cognitive and physical fatigue tasks could influence subject participation in daily activities and rehabilitation., (Copyright © 2015 by the American College of Rheumatology.)

Background: Fibromyalgia is a common chronic pain condition that has a significant impact on quality of life and often leads to disability. To date, there have been few well-controlled trials assessing the utility of nonpharmacological treatment modalities such as transcutaneous electrical nerve stimulation (TENS) in the management of pain and improvement in function in individuals with fibromyalgia., Objectives: The purpose of this study will be to complete a long-term, multicenter study to assess the effects of TENS in women with fibromyalgia., Design: This will be a phase II randomized, double-blind, placebo-controlled, multicenter clinical trial., Participants: Three hundred forty-three participants with fibromyalgia will be recruited for this study., Intervention: Participants will be randomly assigned to 1 of 3 groups: the intervention (TENS), placebo, or no treatment. After completing the randomized period, all participants will receive the intervention for 1 month. The participants will be asked to use TENS at the highest tolerable level for at least 2 hours daily during physical activity., Measurements: The primary outcome will be pain with movement, with secondary outcomes assessing functional abilities, patient-reported outcomes, and quantitative sensory testing., Limitations: Because having participants refrain from their typical medications is not practical, their usage and any change in medication use will be recorded., Conclusions: The results of this study will provide some of the first evidence from a large-scale, double-blind, placebo-controlled trial on the effectiveness of TENS on pain control and quality-of-life changes in patients with fibromyalgia., (© 2015 American Physical Therapy Association.)

Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological intervention that activates a complex neuronal network to reduce pain by activating descending inhibitory systems in the central nervous system to reduce hyperalgesia. The evidence for TENS efficacy is conflicting and requires not only description but also critique. Population-specific systemic reviews and meta-analyses are emerging, indicating both HF and LF TENS being shown to provide analgesia, specifically when applied at a strong, nonpainful intensity. The purpose of this article is to provide a critical review of the latest basic science and clinical evidence for TENS. Additional research is necessary to determine if TENS has effects specific to mechanical stimuli and/or beyond reduction of pain and will improve activity levels, function and quality of life.

Because transcutaneous electrical nerve stimulation (TENS) works by reducing central excitability and activating central inhibition pathways, we tested the hypothesis that TENS would reduce pain and fatigue and improve function and hyperalgesia in people with fibromyalgia who have enhanced central excitability and reduced inhibition. The current study used a double-blinded randomized, placebo-controlled cross-over design to test the effects of a single treatment of TENS with people with fibromyalgia. Three treatments were assessed in random order: active TENS, placebo TENS and no TENS. The following measures were assessed before and after each TENS treatment: pain and fatigue at rest and in movement; pressure pain thresholds, 6-m walk test, range of motion; 5-time sit-to-stand test, and single-leg stance. Conditioned pain modulation was completed at the end of testing. There was a significant decrease in pain and fatigue with movement for active TENS compared to placebo and no TENS. Pressure pain thresholds increased at the site of TENS (spine) and outside the site of TENS (leg) when compared to placebo TENS or no TENS. During active TENS, conditioned pain modulation was significantly stronger compared to placebo TENS and no TENS. No changes in functional tasks were observed with TENS. Thus, the current study suggests TENS has short-term efficacy in relieving symptoms of fibromyalgia while the stimulator is active. Future clinical trials should examine the effects of repeated daily delivery of TENS, similar to the way in which TENS is used clinically on pain, fatigue, function, and quality of life in individuals with fibromyalgia., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)