Through the Lens of Movement-Evoked Pain: A Theoretical Framework of the "Pain-Movement Interface" to Guide Research and Clinical Care for Musculoskeletal Pain Conditions.

Over 120 million Americans report experiencing pain in the past 3 months. Among these individuals, 50 million report chronic pain and 17 million report pain that limits daily life or work activities on most days (ie, high-impact chronic pain). Musculoskeletal pain conditions in particular are a major contributor to global disability, health care costs, and poor quality of life. Movement-evoked pain (MEP) is an important and distinct component of the musculoskeletal pain experience and represents an emerging area of study in pain and rehabilitation fields. This focus article proposes the "Pain-Movement Interface" as a theoretical framework of MEP that highlights the interface between MEP, pain interference, and activity engagement. The goal of the framework is to expand knowledge about MEP by guiding scientific inquiry into MEP-specific pathways to disability, high-risk clinical phenotypes, and underlying individual influences that may serve as treatment targets. This framework reinforces the dynamic nature of MEP within the context of activity engagement, participation in life and social roles, and the broader pain experience. Recommendations for MEP evaluation, encompassing the spectrum from high standardization to high patient specificity, and MEP-targeted treatments are provided. Overall, the proposed framework and recommendations reflect the current state of science in this emerging area of study and are intended to support future efforts to optimize musculoskeletal pain management and enhance patient outcomes. PERSPECTIVE: Movement-evoked pain (MEP) is a distinct component of the musculoskeletal pain experience and emerging research area. This article introduces the "Pain-Movement Interface" as a theoretical framework of MEP, highlighting the interface between MEP, pain interference, and activity engagement. Evaluating and treating MEP could improve rehabilitation approaches and enhance patient outcomes.

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.

Localized Pain and Fatigue During Recovery From Submaximal Resistance Exercise in People With Fibromyalgia.

OBJECTIVE: Exercise is recommended as a main treatment in fibromyalgia. However, many people have limited exercise tolerance and report exacerbated pain and fatigue during and following a bout of exercise. This study examined the local and systemic changes in perceived pain and fatigue during exercise and through the 3-day recovery following isometric and concentric exercises in people with and without fibromyalgia. METHODS: Forty-seven participants with a physician diagnosis of fibromyalgia (44 women; mean age [SD] = 51.3 [12.3] years; mean body mass index [SD] = 30.2 [6.9]) and 47 controls (44 women; mean age [SD] = 52.5 [14.7] years; mean body mass index [SD] = 27.7 [5.6]) completed this prospective, observational cohort study. A bout of submaximal resistance exercise (isometric and concentric) was performed localized to the right elbow flexors on 2 separate days. Baseline attributes (pain, fatigue, physical function, physical activity, and body composition) were assessed prior to exercise. Primary outcomes were: change in perceived pain and fatigue (0 to 10 on the visual analog scale) in the exercising limb and whole body during recovery with movement (immediately, 1 day following exercise, and 3 days following exercise). Secondary outcomes were perceived pain and exertion during exercise performance and pain and fatigue at rest during recovery. RESULTS: Following a single bout of isometric or concentric exercise, there was increased perceived pain (ηp2 = 0.315) and fatigue (ηp2 = 0.426) in the exercising limb, which was greater in people with fibromyalgia (pain: ηp2 = 0.198; fatigue: ηp2 = 0.211). Clinically, relevant increases in pain and fatigue during exercise and through the 3-day recovery occurred in individuals with fibromyalgia only. Concentric contractions led to greater perceived pain, exertion, and fatigue during exercise compared with isometric exercise for both groups. CONCLUSIONS: People with fibromyalgia experienced significant pain and fatigue in the exercising muscle during recovery from low-intensity and short-duration resistance exercise, with greater pain during concentric contractions. IMPACT: These findings highlight a critical need to assess and manage pain and fatigue in the exercising muscles of people with fibromyalgia up to 3 days following a single bout of submaximal resistance exercise. LAY SUMMARY: If you have fibromyalgia, you might have significant pain and fatigue up to 3 days following an exercise bout, with the pain and fatigue localized to the exercising muscles and no changes in whole-body pain.

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.

Influence of routine exercise on the peripheral immune system to prevent and alleviate pain.

Routine physical activity reduces the onset of pain and exercise is a first line treatment for individuals who develop chronic pain. In both preclinical and clinical research regular exercise (routine exercise sessions) produces pain relief through multiple mechanisms such as alterations in the central and peripheral nervous system. More recently, it has been appreciated that exercise can also alter the peripheral immune system to prevent or reduce pain. In animal models, exercise can alter the immune system at the site of injury or pain model induction, in the dorsal root ganglia, and systemically throughout the body to produce analgesia. Most notably exercise shows the ability to dampen the presence of pro-inflammatory immune cells and cytokines at these locations. Exercise decreases M1 macrophages and the cytokines IL-6, IL-1ß, and TFNα, while increasing M2 macrophages and the cytokines IL-10, IL-4, and IL-1ra. In clinical research, a single bout of exercise produces an acute inflammatory response, however repeated training can lead to an anti-inflammatory immune profile leading to symptom relief. Despite the clinical and immune benefits of routine exercise, the direct effect of exercise on immune function in clinical pain populations remains unexplored. This review will discuss in more detail the preclinical and clinical research which demonstrates the numerous ways through which multiple types of exercise alter the peripheral immune system. This review closes with the clinical implications of these findings along with suggestions for future research directions.

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.

A comparison of pain, fatigue, and function between post-COVID-19 condition, fibromyalgia, and chronic fatigue syndrome: a survey study.

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.

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.

Impact of isometric and concentric resistance exercise on pain and fatigue in fibromyalgia.

PURPOSE: The aim of this study was to determine the local and systemic effects of isometric and concentric muscle contractions on experimental pain and performance fatigability in people with and without fibromyalgia. METHODS: Forty-seven fibromyalgia (FM: 51.3 ± 12.3 year) and 47 control (CON: 52.5 ± 14.7 year) participants performed submaximal isometric and concentric exercise for 10 min with the right elbow flexors. Assessments before and after exercise included pressure pain thresholds (PPT) of the biceps and quadriceps, central pain summation, self-reported exercising arm and whole-body pain, and maximal voluntary isometric contraction (MVIC) of the right elbow flexors and left handgrip. RESULTS: People with FM experienced greater reductions in local fatigue (right elbow flexor MVIC: CON: - 4.0 ± 6.7%, FM: - 9.8 ± 13.8%; p = 0.013) and similar reductions in systemic fatigue (left handgrip MVIC: - 6.5 ± 10.2%; p < 0.001) as CON participants, which were not different by contraction type nor related to baseline clinical pain, perceived fatigue, or reported pain with exercise. Following exercise both groups reported an increase in PPTs at the biceps (pre: 205.5 ± 100.3 kPa, post: 219.0 ± 109.3 kPa, p = 0.004) only and a decrease in central pain summation (pre: 6.8 ± 2.9, post: 6.5 ± 2.9; p = 0.013). FM reported greater exercising arm pain following exercise (CON: 0.7 ± 1.3, FM: 2.9 ± 2.3; p < 0.001), and both groups reported greater arm pain following concentric (isometric: 1.4 ± 2.0, concentric: 2.2 ± 2.9; p = 0.001) than isometric exercise. Neither group reported an increase in whole-body pain following exercise. CONCLUSION: People with FM experienced greater performance fatigability in the exercising muscle compared to CON that was not related to central mechanisms of fatigue or pain. These results suggest changes in performance fatigability in FM may be due to differences occurring at the muscular level. TRIAL REGISTRATION #: NCT #: NCT03778385, December 19, 2018, retrospectively registered. IRB#: HR-3035.

Role of Mesh Pore Size in Dynamic Membrane Bioreactors.

Two identical bench-scale Self-Forming Dynamic Membrane BioReactors (SFD MBR) were set-up and operated for the treatment of real urban wastewater. The two bioreactors were equipped with meshes of different mesh pore size. Meshes having pore size values of 20 and 50 µm were tested under solid retention time (SRT) of 15 d, whereas meshes with 50 and 100 µm pore sizes were compared under SRT of 50 d. The results of long-term experiments showed very good overall performances by all systems at the steady state. High flux (in the range 61-71 L m-2 h-1) and very good effluent quality were obtained, with average suspended solids and chemical oxygen demanding values below 10 mg L-1 and 35 mg L-1, respectively. The mesh pore size did not have a major influence on the average cleaning frequency. However, the pore size affected the effluent quality in correspondence of two particular conditions: (i) immediately after mesh cleaning; and (ii) during operation under high suction pressures (mesh clogging not promptly removed through cleaning). Moreover, the mesh cleaning frequency was observed to be dependent on the SRT. In tests with 50 d SRT, the cleaning requirements were very low (one every five days), and this limited the influence of the mesh pore size on the effluent quality. In conclusion, in SFD MBR, the role of the mesh pore size on the effluent quality may be more or less relevant depending on the operating conditions that directly influence the Dynamic Membrane formation.

Reuse of ultrafiltered effluents for crop irrigation: On-site flow cytometry unveiled microbial removal patterns across a full-scale tertiary treatment.

Reuse of treated wastewater for crop irrigation has been widely adopted to mitigate the effects of water scarcity on agricultural yields and to help preserving the integrity of aquatic ecosystems. This paper presents the outcomes of one-year monitoring of a full-scale agro-industrial wastewater treatment plant designed for water reuse, with a multistage tertiary treatment based on sand filtration, membrane ultrafiltration, storage and on-demand UV disinfection. We aimed to test flow cytometry as a monitoring tool to provide on-site indications on tertiary treatment performances and on the quality of treated wastewater along the treatment scheme. Membrane ultrafiltration retained prokaryotic cells and E. coli (>3 log). During storage of treated effluents, a significant decay of E. coli was observed together with the growth of prokaryotic and eukaryotic cells, and the UV disinfection was effective only against fecal indicators. The microbial quality of the treated effluent was comparable to the control groundwater locally used for irrigation. On-site rapid assessments by flow cytometry allowed unveiling crucial aspects affecting the microbiological quality of ultrafiltration permeate and treated effluent immediately after sampling, including plant operating performances and microbial removal patterns across the treatment train.

The Self-Forming Dynamic Membrane BioReactor (SFD MBR) as a suitable technology for agro-industrial wastewater treatment.

Two bench-scale Self-Forming Dynamic Membrane BioReactors (SFD MBR), equipped with 50 µm nylon meshes were set up and operated under aerobic conditions in order to treat canning and winery wastewaters. The results showed different behaviors of the two systems, confirming the strong dependence of SFD MBR performance on the type of biomass and, in turn, on the type of stream being treated. Both plants achieved good results in terms of effluent quality, demonstrating the suitability of the proposed technology. Median values of effluent turbidity were 2.7 and 15.4 NTU (Nephelometric Turbidity Units) in the reactors fed with canning wastewater and winery wastewater, respectively. The removal of organic matter (as COD, Chemical Oxygen Demand) was consistently above 90 %, although the retention of suspended solids was variable and somewhat dependent on operating conditions and feed composition. The activated sludge characteristics were observed to affect filtration performance and in particular the capillary suction time (CST) was a possible indicator of efficiency, with a threshold value of 11 s above which filtration performance decreased. This parameter is proposed as an early warning tool for changes in the filtration performance of an SFD MBR, both for effluent quality and cleaning requirements.

Functional Response of MBR Microbial Consortia to Substrate Stress as Revealed by Metaproteomics.

Bacterial consortia have a primary role in the biological degradations occurring in activated sludge for wastewater treatment, for their capacities to metabolize the polluting matter. Therefore, the knowledge of the main metabolic pathways for the degradation of pollutants becomes critical for a correct design and operation of wastewater treatment plants. The metabolic activity of the different bacterial groups in activated sludge is commonly investigated through respirometry. Furthermore, in the last years, the development of "omic" approaches has offered more opportunities to integrate or substitute the conventional microbiological assays and to deeply understand the taxonomy and dynamics of complex microbial consortia. In the present work, an experimental membrane bioreactor (MBR) was set up and operated for the treatment of municipal wastewater, and the effects of a sudden decrease of the organic supply on the activated sludge were investigated. Both respirometric and metaproteomic approaches revealed a resistance of autotrophic bacteria to the substrate stress, and particularly of nitrifying bacteria. Furthermore, metaproteomics allowed the identification of the taxonomy of the microbial consortium based on its protein expression, unveiling the prevalence of Sorangium and Nitrosomonas genera both before and after the organic load decrease. Moreover, it confirmed the results obtained through respirometry and revealed a general expression of proteins involved in metabolism and transport of nitrogen, or belonging to nitrifying species like Nitrosomonas europeae, Nitrosomonas sp. AL212, or Nitrospira defluvii.

Sludge cake and biofilm formation as valuable tools in wastewater treatment by coupling Integrated Fixed-film Activated Sludge (IFAS) with Self Forming Dynamic Membrane BioReactors (SFD-MBR).

Two lab-scale Self Forming Dynamic Membrane BioReactors (SFD-MBR), equipped with 50 µm nylon meshes were set up and operated for the treatment of real municipal wastewater. Plastic carriers were added in one of the two bioreactors to generate a combination of the Integrated Fixed-film Activated Sludge (IFAS) and the SFD-MBR technologies. Overall, the two systems performed very well, achieving excellent effluent quality under steady state conditions and showing good resilience to extreme organic loading conditions. Continuous air scouring and periodical mesh cleaning by jet rinsing with tap water were effective in maintaining stable and high productivity (membrane flux around 67 L m2 h-1) over a period of 140 days. The application of the IFAS process resulted in lower production of excess sludge and improved denitrification. On the other hand, under the tested conditions the combined IFAS-SFD-MBR showed a higher tendency to mesh clogging with respect to the SFD-MBR.

Influence of air scouring on the performance of a Self Forming Dynamic Membrane BioReactor (SFD MBR) for municipal wastewater treatment.

The Membrane BioReactor (MBR) is a well-established filtration-based technology for wastewater treatment. Despite the high quality of the effluent produced, one of the main drawbacks of the MBR is membrane fouling. In this context, a possible evolution towards systems having potentially lower installation and operating costs is the Self Forming Dynamic Membrane BioReactor (SFD MBR). Key of this technology is the self-formation of a biological filtering layer on a support of inert material. In this work, a lab-scale aerobic SFD MBR equipped with a nylon mesh was operated at approximately 95Lm-2h-1. Two mesh pore sizes (20 and 50µm) and three air scouring flow rates (150, 250, and 500mLairmin-1) were tested at steady state. Under all the tested conditions, the SFD MBR effectively treated real municipal wastewater. The quality of the produced effluent increased for lower mesh size and lower air scouring intensity.