Translating Outcomes from the Clinical Setting to Preclinical Models: Chronic Pain and Functionality in Chronic Musculoskeletal Pain.

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.

Transcutaneous Electrical Nerve Stimulation in Nerve Regeneration: A Systematic Review of In Vivo Animal Model Studies.

OBJECTIVE: Transcutaneous electrical nerve stimulation (TENS) is a noninvasive electrical stimulation therapy indicated for pain control that has been applied for the regeneration of nerves. This systematic review aimed to analyze the evidence on TENS effectiveness on nerve regeneration. MATERIALS AND METHODS: A systematic review was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria: PubMed/MEDLINE, Web of Science, ScienceDirect, and SciELO data bases. Primary research that evaluated TENS on nerve regeneration was considered. RESULTS: Several studies have investigated the use of TENS for pain treatment. A total of six animal studies analyzed TENS for nerve regeneration. The selected articles showed high quality (Animal Research: Reporting of In Vivo Experiments guidelines), with many unclear points related to bias opportunities (Systematic Review Center for Laboratory Animal Experimentation Risk of Bias tool). In general, TENS accelerated functional and motor recovery and increased axon quantity and diameter. More specifically, the application of low-frequency TENS resulted in a continuous basal lamina; a higher density of fibers with normal diameters, indicating normal myelination, showed signs of deterioration and delayed nerve regeneration. In contrast, the high-frequency TENS application stimulated motor regeneration and increased the diameter of the regenerated axons but revealed a small number of axons, demyelination, dark axoplasm, and an increase in the predisposition of neuropathic pain. CONCLUSIONS: Although there is some heterogeneous evidence in animal research, TENS seems to be a promising treatment for nerve injury that should be better explored. It is still necessary to improve the analysis of its application parameters, which can lead to the most satisfactory regeneration results and improve the understanding of its mechanisms on peripheral nerve regeneration.

Using TENS for Pain Control: Update on the State of the Evidence.

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.

Reliability and Construct Validity of the Patient-Reported Outcomes Measurement Information System (PROMIS) Instruments in Women with Fibromyalgia.

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.

Categories of the Patient-Specific Functional Scale Activities in Chronic Neck Pain and Their Relationship to the Neck Disability Index.

Intoduction: Common outcome measures for chronic neck pain are the Patient-Specific Functional Scale (PSFS) and the neck disability index (NDI). The primary aim was to categorize the top-rated, patient-selected functional activity limitations of the PSFS to determine if there were consistent limited functional activities for individuals with chronic neck pain and how these compared to the constructs of activities on the NDI. The secondary aim was to determine the relationship between scores for individuals who completed both the NDI and PSFS. Design: A retrospective review of data extracted from the electronic medical record, EPIC, within two hospital-based outpatient physical therapy clinics within a health care system. Methods: Retrospective analysis was performed on individual's characteristics, self-selected functional activity limitations, and total scores of the PSFS and NDI. Most common categories of self-selected functional activity limitations were developed by practicing physical therapists. These functional activity limitation categories of the PSFS were compared to the activities of the NDI. Mean PSFS total scores were correlated with the NDI total scores with Spearman's test. Results: Participants were individuals with chronic neck pain from January 2013-September 2018 (n = 2283). Movement-based activities accounted for 60.8% of the functional activity limitations of the PSFS with the top functional activity limitations being cervical motion and exercise (32%). The PSFS total score moderately correlated with NDI (r = -0.50, p = <0.01) which may relate to the differences in constructs of the NDI and the top patient-selected PSFS functional activity limitations found in this analysis. Conclusion: The results suggest that individuals with chronic neck pain present with similar categories of self-selected functional activity limitations that differ from activities of the NDI. Additional research is needed to improve outcome measures to capture patient-selected functional activity limitations and an individual's pain experience.

Influence of Transcutaneous Electrical Nerve Stimulation (TENS) on Pressure Pain Thresholds and Conditioned Pain Modulation in a Randomized Controlled Trial in Women With Fibromyalgia.

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.

Minimal Clinically Important Change of Movement Pain in Musculoskeletal Pain Conditions.

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.

Standing on the shoulders of bias: lack of transparency and reporting of critical rigor characteristics in pain research.

ABSTRACT: Rigorous experimental design with transparent reporting in biomedical science reduces risk of bias and allows for scientists to judge the quality of the research. Basic factors of rigor such as blinding, randomization, power analysis, and inclusion of both sexes impact the reproducibility by reducing experimental bias. We designed a systematic study to analyze basic factors of rigor, inclusion of sex, and whether data were analyzed or disaggregated by sex over the past 10 years in the journal PAIN . Studies that included humans reported randomization in 81%, blinding in 48%, and the use of a power analysis calculation in 27% over the past 10 years. Studies that included mice reported randomization in 35%, blinding in 70%, and the use of a power analysis in 9%. Studies that included rats reported randomization in 38%, blinding in 63%, and the use of power analysis in 12%. This study also found that human studies consistently included both sexes over the past decade, but less than 20% of data were disaggregated or analyzed for sex differences. Although mouse and rat studies predominately used males only, there has been a slight increase in inclusion of both sexes over the past few years. Justification for single-sex studies was below 50% in both human and rodent data. In both human and animal studies, transparency in reporting of experimental design and inclusion of both sexes should be considered standard practice and will result in improved quality and reproducibility of published research.

Predicting chronic postsurgical pain: current evidence and a novel program to develop predictive biomarker signatures.

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.

The Influence of Opioids on Transcutaneous Electrical Nerve Stimulation Effects in Women With Fibromyalgia.

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.

The Fibromyalgia Transcutaneous Electrical Nerve Stimulation in Physical Therapy Study Protocol: A Multisite Embedded Pragmatic Trial.

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.

Multi-Site Observational Study to Assess Biomarkers for Susceptibility or Resilience to Chronic Pain: The Acute to Chronic Pain Signatures (A2CPS) Study Protocol.

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.

Combined interventional radiology and surgical management of a complex caesarean scar ectopic pregnancy.

Caesarean scar ectopic pregnancies are rare but growing in incidence due to increasing rates of caesarean deliveries. These cases have historically been treated with either medical or surgical management which both have significant limitations. More recently, uterine artery embolisation (UAE) has shown significant promise in the treatment of this condition. We present the case of a complex patient with a caesarean scar ectopic successfully managed with combined UAE and surgery.

Test-Retest Reliability and Responsiveness of PROMIS Sleep Short Forms Within an RCT in Women With Fibromyalgia.

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.

Reduction in movement-evoked pain and fatigue during initial 30-minute transcutaneous electrical nerve stimulation treatment predicts transcutaneous electrical nerve stimulation responders in women with fibromyalgia.

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.

Somatic symptom presentations in women with fibromyalgia are differentially associated with elevated depression and anxiety.

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.

Transcutaneous Electrical Nerve Stimulation Reduces Movement-Evoked Pain and Fatigue: A Randomized, Controlled Trial.

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.

Effectiveness of transcutaneous electrical nerve stimulation for treatment of hyperalgesia and pain.

Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacologic treatment for pain relief. TENS has been used to treat a variety of painful conditions. This review updates the basic and clinical science regarding the use of TENS that has been published in the past 3 years (ie, 2005-2008). Basic science studies using animal models of inflammation show changes in the peripheral nervous system, as well as in the spinal cord and descending inhibitory pathways, in response to TENS. Translational studies show mechanisms to prevent analgesic tolerance to repeated application of TENS. This review also highlights data from recent randomized, placebo-controlled trials and current systematic reviews. Clinical trials suggest that adequate dosing, particularly intensity, is critical to obtaining pain relief with TENS. Thus, evidence continues to emerge from both basic science and clinical trials supporting the use of TENS for the treatment of a variety of painful conditions while identifying strategies to increase TENS effectiveness.

Physical activity is related to function and fatigue but not pain in women with fibromyalgia: baseline analyses from the Fibromyalgia Activity Study with TENS (FAST).

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.

Development of a method to maximize the transcutaneous electrical nerve stimulation intensity in women with fibromyalgia.

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<0.0001) with a mean increase of 1.7 mA (95% CI: 1.5, 2.2). Linear regression analysis showed that those with the largest increase between SC1 and N had the largest increase in SC2-SC1. Further, those with older age and higher anxiety were able to achieve greater increases in intensity (SC2-SC1) using the SIT test. Conclusion: The SC2-SC1 increase was significantly associated with age and anxiety, with greater mean increases associated with older age and higher anxiety. Thus, although all patients may benefit from this protocol, older women and women with elevated anxiety receive the greatest benefit.