Search

Dan Wang,1 Shannon L Merkle,2 Jennifer E Lee,3,4 Kathleen A Sluka,1 Barbara Rakel,4 Thomas Graven-Nielsen,5 Laura A Frey-Law1 1Department of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, Iowa City, IA, USA; 2United States Army Research Institute of Environmental Medicine (USARIEM), Natick, MA, USA; 3Department of Psychology, Mount Mercy University, Cedar Rapids, IA, USA; 4College of Nursing, University of Iowa, Iowa City, IA, USA; 5Center for Neuroplasticity and Pain (CNAP), SMI, Aalborg University, Aalborg, DenmarkCorrespondence: Laura A Frey-LawDepartment of Physical Therapy and Rehabilitation Science, Carver College of Medicine, University of Iowa, 1-252 Medical Education Bldg., 500 Newton Road, University of Iowa, Iowa City, IA 52242, USATel +1 319-335-9804Fax +1 319-335-9707Email laura-freylaw@uiowa.eduPurpose: Some individuals with chronic pain find daily life sensations (eg, noise, light, or touch) aversive. This amplification of multisensory sensations has been associated with centrally mediated plasticity; for example, greater multisensory sensitivity (MSS) occurs in patients with fibromyalgia than rheumatoid arthritis. However, whether MSS preferentially relates to pain measures which reflect central influences (eg, dynamic quantitative sensory testing (QST) or referred pain), or whether the MSS-pain relationship requires priming from chronic pain, is unknown. Thus, this cross-sectional study investigated the relationships between MSS assessed in a pain-free state and evoked pain sensitivity.Methods: Experimental intramuscular infusion pain and multiple static and dynamic QST were assessed in 465 healthy, pain-free adults: pain thresholds using pressure (PPTs) and heat (HPTs), temporal summation of pain (TSP) using pressure, heat or punctate stimuli, and conditioned pain modulation (CPM) using pressure or heat test stimuli. MSS was assessed using 7 items from Barsky’s Somatosensory Amplification Scale. Differences in pain and QST between sex-specific MSS quartiles were assessed, adjusting for multiple comparisons. All participants completed at least one intramuscular infusion condition, but not all were asked to complete each QST (n=166-465).Results: Both static and dynamic QST differed between highest and lowest MSS quartiles using pressure stimuli: lower PPTs (adjusted-p< 0.01); increased pressure TSP (adjusted-p=0.02); lower pressure CPM (adjusted-p=0.01). However, none of the heat or punctate QST measures (HPTs, TSP, or CPM) differed between MSS quartiles (adjusted-p> 0.05). Odds of experiencing TSP or referred pain was not greater, whereas CPM was 8-fold less likely, in those with highest MSS.Conclusion: Normal variation in non-noxious MSS is related to both static and dynamic pain sensitivity, without sensitization associated with chronic pain, but is dependent on the QST stimulus. Thus, common influences on MSS and pain sensitivity may involve central mechanisms but are likely more complex than previously recognized.Keywords: pain sensitivity, somatosensory amplification scale, experimental muscle pain, quantitative sensory testing, temporal summation of pain, conditioned pain modulation

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

Abstract Background Protein kinase C (PKC) in the spinal cord appears to mediate chronic injury-induced pain, but not acute nociceptive pain. Muscle insult results in increased release of glutamate spinally, and hyperalgesia that is reversed by spinal blockade of NMDA and non-NMDA glutamate receptors. Therefore, we hypothesized that spinal activation of PKC 1) mediates the late phase of hyperalgesia 1 week after muscle insult, and 2) produces mechanical hyperalgesia through activation of NMDA and non-NMDA glutamate receptors. Results Rats were implanted with intrathecal catheters for delivery of drugs directly to the spinal cord. Mechanical withdrawal thresholds of the paw were determined using von Frey filaments. Intrathecal phorbol 12,13 dibutyrate (PDBu) produced a dose-dependent decrease in the mechanical withdrawal threshold of the paw that was prevented by pretreatment with the PKC inhibitor, GF109203X. Pretreatment with an NMDA receptor antagonist (AP5) or a AMPA/kainate receptor antagonist (NBQX) prevented the decrease in mechanical withdrawal threshold by PDBu. Two injections of acidic saline in the gastrocnemius muscle decreased the mechanical withdrawal thresholds of the paw bilaterally 24 h and 1 week after the second injection. However, blockade PKC in the spinal cord had no effect on the decreased withdrawal thresholds of the paw when compared to vehicle controls. Conclusion Spinal activation of PKC produces mechanical hyperalgesia of the paw that depends on activation of NMDA and non-NMDA receptors. Chronic muscle-induced mechanical hyperalgesia, on the other hand, does not utilize spinal PKC.

ObjectiveTo determine whether women experience greater knee pain severity than men at equivalent levels of radiographic knee osteoarthritis (OA).Design and methodsA cross-sectional analysis of 2712 individuals (60% women) without knee replacement or a recent steroid injection. Sex differences in pain severity at each Kellgren-Lawrence (KL) grade were assessed by knee using visual analog scale (VAS) scale and Western Ontario and McMaster Universities Arthritis Index (WOMAC) with and without adjustment for age, analgesic use, Body mass index (BMI), clinic site, comorbid conditions, depression score, education, race, and widespread pain (WSP) using generalized estimating equations. Effect sizes (Cohen's d) were also calculated. Analyses were repeated in those with and without patellofemoral OA (PFOA).ResultsWomen reported higher VAS pain at all KL grades in unadjusted analyses (d = 0.21-0.31, P

Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS naïve healthy individuals (18-64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P < .0001) at the forearm; Transient Placebo TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r(2) = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. PERSPECTIVE: This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. [ABSTRACT FROM AUTHOR]

In this study we investigated the involvement of cutaneous versus knee joint afferents in the antihyperalgesia produced by transcutaneous electrical nerve stimulation (TENS) by differentially blocking primary afferents with local anesthetics. Hyperalgesia was induced in rats by inflaming one knee joint with 3% kaolin-carrageenan and assessed by measuring paw withdrawal latency to heat before and 4 hours after injection. Skin surrounding the inflamed knee joint was anesthetized using an anesthetic cream (EMLA). Low (4 Hz) or high (100 Hz) frequency TENS was then applied to the anesthetized skin. In another group, 2% lidocaine gel was injected into the inflamed knee joint, and low or high frequency TENS was applied. Control experiments were done using vehicles. In control and EMLA groups, both low and high frequency TENS completely reversed hyperalgesia. However, injection of lidocaine into the knee joint prevented antihyperalgesia produced by both low and high frequency TENS. Recordings of cord dorsum potentials showed that both low and high frequency TENS at sensory intensity activates only large diameter afferent fibers. Increasing intensity to twice the motor threshold recruits Adelta afferent fibers. Furthermore, application of EMLA cream to the skin reduces the amplitude of the cord dorsum potential by 40% to 70% for both high and low frequency TENS, confirming a loss of large diameter primary afferent input after EMLA is applied to the skin. Thus, inactivation of joint afferents, but not cutaneous afferents, prevents the antihyperalgesia effects of TENS. We conclude that large diameter primary afferent fibers from deep tissue are required and that activation of cutaneous afferents is not sufficient for TENS-induced antihyperalgesia. PERSPECTIVE: Transcutaneous electrical nerve stimulation (TENS) is an accepted clinical modality used for pain relief. It is generally believed that TENS analgesia is caused mainly by cutaneous afferent activation. In this study by differentially blocking cutaneous and deep tissue primary afferents, we show that the activation of large diameter primary afferents from deep somatic tissues, and not cutaneous afferents, are pivotal in causing TENS analgesia. [ABSTRACT FROM AUTHOR]

Abstract An introduction to the accompanying three papers.

Abstract Young female athletes experience a higher incidence of ligament injuries than their male counterparts, females experience a higher incidence of joint hypermobility syndrome (a risk factor for osteoarthritis development), and post-menopausal females experience a higher prevalence of osteoarthritis than age-matched males. These observations indicate that fluctuating sex hormone levels in young females and loss of ovarian sex hormone production due to menopause likely contribute to observed sex differences in knee joint function and risk for loss of function. In studies of osteoarthritis, however, there is a general lack of appreciation for the heterogeneity of hormonal control in both women and men. Progress in this field is limited by the relatively few preclinical osteoarthritis models, and that most of the work with established models uses only male animals. To elucidate sex differences in osteoarthritis, it is important to examine sex hormone mechanisms in cells from knee tissues and the sexual dimorphism in the role of inflammation at the cell, tissue, and organ levels. There is a need to determine if the risk for loss of knee function and integrity in females is restricted to only the knee or if sex-specific changes in other tissues play a role. This paper discusses these gaps in knowledge and suggests remedies.

Abstract People with osteoarthritis (OA) can have significant pain that interferes with function and quality of life. Women with knee OA have greater pain and greater reductions in function and quality of life than men. In many cases, OA pain is directly related to sensitization and activation of nociceptors in the injured joint and correlates with the degree of joint effusion and synovial thickening. In some patients, however, the pain does not match the degree of injury and continues after removal of the nociceptors with a total joint replacement. Growth of new nociceptors, activation of nociceptors in the subchondral bone exposed after cartilage degradation, and nociceptors innervating synovium sensitized by inflammatory mediators could all augment the peripheral input to the central nervous system and result in pain. Enhanced central excitability and reduced central inhibition could lead to prolonged and enhanced pain that does not directly match the degree of injury. Psychosocial variables can influence pain and contribute to pain variability. This review explores the neural and psychosocial factors that contribute to knee OA pain with an emphasis on differences between the sexes and gaps in knowledge.

Abstract The occurrence of knee osteoarthritis (OA) increases with age and is more common in women compared with men, especially after the age of 50 years. Recent work suggests that contact stress in the knee cartilage is a significant predictor of the risk for developing knee OA. Significant gaps in knowledge remain, however, as to how changes in musculoskeletal traits disturb the normal mechanical environment of the knee and contribute to sex differences in the initiation and progression of idiopathic knee OA. To illustrate this knowledge deficit, we summarize what is known about the influence of limb alignment, muscle function, and obesity on sex differences in knee OA. Observational data suggest that limb alignment can predict the development of radiographic signs of knee OA, potentially due to increased stresses and strains within the joint. However, these data do not indicate how limb alignment could contribute to sex differences in either the development or worsening of knee OA. Similarly, the strength of the knee extensor muscles is compromised in women who develop radiographic and symptomatic signs of knee OA, but the extent to which the decline in muscle function precedes the development of the disease is uncertain. Even less is known about how changes in muscle function might contribute to the worsening of knee OA. Conversely, obesity is a stronger predictor of developing knee OA symptoms in women than in men. The influence of obesity on developing knee OA symptoms is not associated with deviation in limb alignment, but BMI predicts the worsening of the symptoms only in individuals with neutral and valgus (knock-kneed) knees. It is more likely, however, that obesity modulates OA through a combination of systemic effects, particularly an increase in inflammatory cytokines, and mechanical factors within the joint. The absence of strong associations of these surrogate measures of the mechanical environment in the knee joint with sex differences in the development and progression of knee OA suggests that a more multifactorial and integrative approach in the study of this disease is needed. We identify gaps in knowledge related to mechanical influences on the sex differences in knee OA.

Abstract Background Osteoarthritis of the knee is a major clinical problem affecting a greater proportion of women than men. Women generally report higher pain intensity at rest and greater perceived functional deficits than men. Women also perform worse than men on function measures such as the 6-minute walk and timed up and go tests. Differences in pain sensitivity, pain during function, psychosocial variables, and physical activity levels are unclear. Further the ability of various biopsychosocial variables to explain physical activity, function and pain is unknown. Methods This study examined differences in pain, pain sensitivity, function, psychosocial variables, and physical activity between women and men with knee osteoarthritis (N = 208) immediately prior to total knee arthroplasty. We assessed: (1) pain using self-report measures and a numerical rating scale at rest and during functional tasks, (2) pain sensitivity using quantitative sensory measures, (3) function with self-report measures and specific function tasks (timed walk, maximal active flexion and extension), (4) psychosocial measures (depression, anxiety, catastrophizing, and social support), and (5) physical activity using accelerometry. The ability of these mixed variables to explain physical activity, function and pain was assessed using regression analysis. Results Our findings showed significant differences on pain intensity, pain sensitivity, and function tasks, but not on psychosocial measures or physical activity. Women had significantly worse pain and more impaired function than men. Their levels of depression, anxiety, pain catastrophizing, social support, and physical activity, however, did not differ significantly. Factors explaining differences in (1) pain during movement (during gait speed test) were pain at rest, knee extension, state anxiety, and pressure pain threshold; (2) function (gait speed test) were sex, age, knee extension, knee flexion opioid medications, pain duration, pain catastrophizing, body mass index (BMI), and heat pain threshold; and (3) physical activity (average metabolic equivalent tasks (METS)/day) were BMI, age, Short-Form 36 (SF-36) Physical Function, Kellgren-Lawrence osteoarthritis grade, depression, and Knee Injury and Osteoarthritis Outcome Score (KOOS) pain subscale. Conclusions Women continue to be as physically active as men prior to total knee replacement even though they have significantly more pain, greater pain sensitivity, poorer perceived function, and more impairment on specific functional tasks.

Abstract Background The Ca2+/calmodulin-stimulated adenylyl cyclase (AC) isoforms AC1 and AC8, couple NMDA receptor activation to cAMP signaling pathways in neurons and are important for development, learning and memory, drug addiction and persistent pain. AC1 and AC8 in the anterior cingulate cortex (ACC) and the spinal cord were previously shown to be important in subcutaneous inflammatory pain. Muscle pain is different from cutaneous pain in its characteristics as well as conducting fibers. Therefore, we conducted the present work to test the role of AC1 and AC8 in both acute persistent and chronic muscle pain. Results Using an acute persistent inflammatory muscle pain model, we found that the behavioral nociceptive responses of both the late phase of acute muscle pain and the chronic muscle inflammatory pain were significantly reduced in AC1 knockout (KO) and AC1&8 double knockout (DKO) mice. Activation of other adenylyl cyclases in these KO mice by microinjection of forskolin into the ACC or spinal cord, but not into the peripheral tissue, rescued the behavioral nociceptive responses. Additionally, intra-peritoneal injection of an AC1 inhibitor significantly reduced behavioral responses in both acute persistent and chronic muscle pain. Conclusion The results of the present study demonstrate that neuronal Ca2+/calmodulin-stimulated adenylyl cyclases in the ACC and spinal cord are important for both late acute persistent and chronic inflammatory muscle pain.

Classical preclinical studies show that serotonin (5-HT) injected into the rostral ventromedial medulla (RVM) produces analgesia that is blocked by 5-HT2 receptor antagonists. One key modulator of 5-HT activity is the serotonin transporter (SERT) which reduces serotonergic signaling through reuptake into the presynaptic terminal. In the activity-induced muscle pain model, females show widespread pain and increased SERT expression in the RVM whereas males show localized pain and no changes in SERT expression. Since prior studies show testosterone protects from the development of widespread pain, and females have widespread pain in the activity-induced pain model, we hypothesized that testosterone modulates serotonin signaling to enhance analgesia in female mice with widespread pain. We showed that testosterone reduced the enhanced SERT protein expression and increased 5-HT 2A receptor mRNA expression in the RVM normally observed in the activity-induced pain model in females, but not males. Inhibition of SERT in the RVM was analgesic in both female and male mice; this analgesia was blocked by co-administration of 5-HT 2A antagonist. Next, using in situ hybridization, we demonstrated co-expression of SERT, 5-HT 2A receptor, and androgen receptor mRNA in cells within the RVM in female mice. Lastly, activation of androgen receptors using dihydrotestosterone reduced hyperalgesia in female mice. These data therefore show for the first time expression of androgen receptors in the RVM in female mice, that activation of androgen receptors reduces nociceptive behaviors, and endogenous testosterone modulates SERT and 5-HT2 receptor expression. Thus, we show a sex-specific role for how testosterone modulates analgesia in mice. PERSPECTIVE: This article presents novel mechanisms testosterone's protection against muscle pain in female mice showing modulation of the serotonin system in the rostral ventromedial medulla. Understanding the relationship between testosterone and serotonin could lead to better treatment of individuals with muscle pain., Competing Interests: Declaration of Competing Interest The authors declare that there are no relevant conflicts of interest or disclosures., (Copyright © 2024. Published by Elsevier Inc.)

The NIH Pragmatic Trials Collaboratory supports the design and conduct of 32 embedded pragmatic clinical trials, and many of these trials rely on data from the electronic health record (EHR) to monitor outcomes and/or use functionality provided by the EHR platform to deliver the intervention. Given the complexity and dynamic nature of EHR systems, study teams have encountered challenges in use of the EHR for these purposes, including challenges related to local implementation of trial interventions, rapid technology evolution, EHR updates, and transitions in EHR systems. In this article, we share case examples and lessons learned, and suggest that teams need to be aware of-and perhaps proactively investigate- possible changes to EHR systems and data that will affect the delivery of interventions and the integrity and safety of pragmatic clinical trials., Competing Interests: Declaration of competing interest KM has no disclosures relevant to the manuscript and reports that he is a Co-inventor of Hive Networks, Inc. and his salary is funded in part through research contracts from Bayer, BMS, BI, Amgen, Novartis, Seqirus, and Genentech. JGJ: Dr. Jarvik was supported by the University of Washington Clinical Learning, Evidence, And Research (CLEAR) Center for Musculoskeletal Disorders, Administrative, Methodologic Cores and NIAMS/NIH grant P30AR072572. Dr. Jarvik r has no disclosures relevant to the manuscript but reports royalties as a book co-editor from Springer Publishing and travel reimbursement for Faculty Board of Review from GE-Association of University Radiologists Radiology Research Academic Fellowship (GERRAF) and royalties as a chapter author from Wolters Kluwer/UpToDate., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Pregabalin, which acts on the α 2 δ-1 subunit of voltage-gated calcium channels, relieves ≥50% of pain in a third of individuals with fibromyalgia. Thus far, preclinical studies of pregabalin have predominantly used male animals., Objectives: The purpose of our study was to investigate potential sex differences in the analgesic efficacy of pregabalin that may contribute to disparities in human outcomes., Methods: We used a mouse model of chronic widespread muscle pain (CWP) to test the effects of pregabalin on muscle hyperalgesia, nonreflexive pain, and motor behaviors. The CWP pain model combines 2 pH 4.0 saline injections, spaced 5 days apart, into the gastrocnemius muscle and produces bilateral muscle hyperalgesia. Furthermore, we explored sex differences in the mRNA and protein expression of the α 2 δ-1 subunit of voltage-gated calcium channels in the dorsal horn of the spinal cord and dorsal root ganglia after development of CWP., Results: Pregabalin fully attenuated muscle hyperalgesia bilaterally in male but not female mice with equal motor deficits produced in both sexes. In addition, using the conditioned place preference test, mice of both sexes with CWP spent significantly more time in the pregabalin-paired chamber compared with baseline, but not significantly greater than pain-free controls. Chronic widespread muscle pain produced no changes in α 2 δ-1 subunit mRNA or protein expression in the dorsal horn of the spinal cord or dorsal root ganglia in either sex., Conclusion: Overall, these findings indicate pregabalin may be more effective in treating CWP in males, but the factors leading to these differences are not fully understood., Competing Interests: The authors have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The International Association for the Study of Pain.)

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., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Barbara Van Gorp et al.)

Animal studies consistently demonstrate that testosterone is protective against pain in multiple models, including an animal model of activity-induced muscle pain. In this model, females develop widespread muscle hyperalgesia, and reducing testosterone levels in males results in widespread muscle hyperalgesia. Widespread pain is believed to be mediated by changes in the central nervous system, including the rostral ventromedial medulla (RVM). The enzyme that converts testosterone to estradiol, aromatase, is highly expressed in the RVM. Therefore, we hypothesized that testosterone is converted by aromatase to estradiol locally in the RVM to prevent development of widespread muscle hyperalgesia in male mice. This was tested through pharmacological inhibition of estrogen receptors (ERs), aromatase, or ER-α in the RVM which resulted in contralateral hyperalgesia in male mice (C57BL/6J). ER inhibition in the RVM had no effect on hyperalgesia in female mice. As prior studies show modulation of estradiol signaling alters GABA receptor and transporter expression, we examined if removal of testosterone in males would decrease mRNA expression of GABA receptor subunits and vesicular GABA transporter (VGAT). However, there were no differences in mRNA expression of GABA receptor subunits of VGAT between gonadectomized and sham control males. Lastly, we used RNAscope to determine expression of ER-α in the RVM and show expression in inhibitory (VGAT+), serotonergic (tryptophan hydroxylase 2+), and μ-opioid receptor expressing (MOR+) cells. In conclusion, testosterone protects males from development of widespread hyperalgesia through aromatization to estradiol and activation of ER-α which is widely expressed in multiple cell types in the RVM., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Plumb et al.)

Activity-induced muscle pain increases interleukin-1β (IL-1β) release from muscle macrophages and the development of hyperalgesia is prevented by blockade of IL-1β in muscle. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesize that in activity-induced pain, fatigue metabolites combined with IL-1β activate sensory neurons to increase BDNF release, peripherally in muscle and centrally in the spinal dorsal horn, to produce hyperalgesia. We tested the effect of intrathecal or intramuscular injection of BDNF-Tropomyosin receptor kinase B (TrkB) inhibitors, ANA-12 or TrkB-Fc, on development of activity-induced pain. Both inhibitors prevented the hyperalgesia when given before or 24hr after induction of the model in male but not female mice. BDNF messenger ribonucleic acid (mRNA) and protein were significantly increased in dorsal root ganglion (DRG) 24hr after induction of the model in both male and female mice. Blockade of IL-1β in muscle had no effect on the increased BNDF mRNA observed in the activity-induced pain model, while IL-1β applied to cultured DRG significantly induced BDNF expression, suggesting IL-1β is sufficient but not necessary to induce BNDF. Thus, fatigue metabolites, combined with IL-1β, upregulate BDNF in primary DRG neurons in both male and female mice, but contribute to activity-induced pain only in males., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

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.)

Introduction: Physical activity is commonly used for both measuring and treating dysfunction. While preclinical work has been historically biased towards males, the use of both male and female animals is gaining popularity after multiple NIH initiatives. With increasing inclusion of both sexes, it has become imperative to determine sex differences in common behavioral assays. The purpose of this study was to determine baseline sex differences in 3 activity assays: voluntary wheel running, forced treadmill running, and open field testing., Methods: This was a secondary analysis of sex differences in healthy mice in 3 different assays: Separate mice were used for each assay. Specifically, 16 mice underwent 28 days of voluntary wheel running, 178 mice underwent forced treadmill running, and 88 mice underwent open field testing. Differences between sex across several activity parameters were examined for each assay., Results: In voluntary wheel running, sex differences with larger effect sizes were observed in distance run, running time, and bout duration, with smaller effect size differences in speed, and no difference in total bouts. In forced treadmill running, differences were shown in time to exhaustion, but no difference in max speed attained. In open field, there were sex differences in active time but not in distance and speed in data aggregated over 30 minutes; however, distance and speed in male mice showed a downward trajectory over the final 20 minutes of testing, whereas females maintained the same trajectory., Conclusion: These data suggest that male mice demonstrate comparable activity intensity as female mice but do not match female's duration of activity, especially for volitional tasks. Researchers utilizing these assays should account for sex differences as they could potentially mask true findings in an experiment., Plain English Summary: Physical activity is a common measure to examine function in human subjects with and without disease. Animal models often use measures of physical activity to assess function, yet most of these measures have been done in males only, making interpretation and translation to females and humans difficult. Several measures have been used to measure activity in animals, including those examining voluntary running behavior, maximum capacity, and general activity levels; sex differences between these measures are unclear. We discovered sex differences throughout each of three activity tests. In voluntary running behavior there were large differences between sexes with females running a greater distance and spending more time running. There were small differences in the maximum capacity with females running for a longer period at high intensity. General activity levels showed small differences with females being less active than males. Thus, the greatest differences were found for voluntary running and small differences were found for maximum capacity and general activity levels; differences observed were dependent on the task. Researchers utilizing these assays should account for sex differences as they could potentially mask true findings in an experiment., Competing Interests: Competing interests: The authors declare no competing interests.

Chemotherapy-induced peripheral neuropathy (CIPN) affects approximately 30 to 60% of people who receive neurotoxic chemotherapy. CIPN is associated with impaired quality of life and function and has few effective treatments. This 6-site, subject and assessor-blinded randomized clinical trial (RCT) was designed to assess 1) preliminary efficacy (ie, alpha pre-specified at .2) of a wearable, app-controlled, transcutaneous electrical nerve stimulation (TENS) device for chronic CIPN and 2) feasibility of conducting a confirmatory trial within the National Cancer Institute Community Oncology Research Program (NCORP) (NCT04367480). The primary outcome was the EORTC-CIPN20. The main secondary outcomes were individual symptoms assessed daily (via 0-10 numeric rating scales). The primary analysis was an analysis of covariance (outcome: EORTC-CIPN20, fixed effect: arm, covariates: baseline EORTC-CIPN20 and site). Secondary analyses used a similar analysis of covariance models (excluding site) for each symptom on subgroups of subjects with ≥4 out of 10 for that symptom at baseline. 142 eligible subjects were randomized and received a device; 130 (91%) completed the study. The difference between groups in the EORCT-CIPN20 at the endpoint (placebo-active) was 1.05 (95% Confidence Interval: -.56, 2.67; P = .199). The difference between groups for the individual symptoms was as follows: hot/burning pain: 1.37 (-.33, 3.08; P = .112), sharp/shooting pain: 1.21 (-.37, 2.79; P = .128), cramping: 1.35 (-.32, 3.02; P = .110), tingling: .23 (-.61, 1.08; P = .587), numbness: .27 (-.51, 1.05; P = .492). An RCT of an app-controlled TENS device for chronic CIPN with excellent retention is feasible in the NCORP. Preliminary efficacy evidence suggests that TENS is promising for pain and cramping from CIPN. A confirmatory RCT of TENS for painful CIPN is highly warranted. PERSPECTIVE: Daily, home-based TENS therapy demonstrates promising efficacy for painful CIPN symptoms in this proof-of-concept randomized clinical trial. Future confirmatory trial is warranted., (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).)

Activity-induced muscle pain increases release of interleukin-1β (IL-1β) in muscle macrophages and the development of pain is prevented by blockade of IL-1β. Brain derived neurotrophic factor (BDNF) is released from sensory neurons in response to IL-1β and mediates both inflammatory and neuropathic pain. Thus, we hypothesized that metabolites released during fatiguing muscle contractions activate macrophages to release IL-1β, which subsequently activate sensory neurons to secrete BDNF. To test this hypothesis, we used an animal model of activity-induced pain induced by repeated intramuscular acidic saline injections combined with fatiguing muscle contractions. Intrathecal or intramuscular injection of inhibitors of BDNF-Tropomyosin receptor kinase B (TrkB) signaling, ANA-12 or TrkB-Fc, reduced the decrease in muscle withdrawal thresholds in male, but not in female, mice when given before or 24hr after, but not 1 week after induction of the model. BDNF messenger ribonucleic acid (mRNA) was significantly increased in L4-L6 dorsal root ganglion (DRG), but not the spinal dorsal horn or gastrocnemius muscle, 24hr after induction of the model in either male or female mice. No changes in TrkB mRNA or p75 neurotrophin receptor mRNA were observed. BDNF protein expression via immunohistochemistry was significantly increased in L4-L6 spinal dorsal horn and retrogradely labelled muscle afferent DRG neurons, at 24hr after induction of the model in both sexes. In cultured DRG, fatigue metabolites combined with IL-1β significantly increased BDNF expression in both sexes. In summary, fatigue metabolites release, combined with IL-1β, BDNF from primary DRG neurons and contribute to activity-induced muscle pain only in males, while there were no sex differences in the changes in expression observed in BDNF., Competing Interests: Conflict of interest statement The authors declare that there are no relevant conflicts of interest.

Background: This study aimed to characterize movement-evoked pain during tendon loading and stretching tasks in individuals with Achilles tendinopathy, and to examine the association between movement-evoked pain with the Achilles tendinopathy type (insertional and midportion), biomechanical, and psychological variables., Methods: In this laboratory-based, cross-sectional study, 37 individuals with chronic Achilles tendinopathy participated. Movement-evoked pain intensity (Numeric Rating Scale: 0 to 10) and sagittal-plane ankle biomechanics were collected simultaneously during standing, fast walking, single-leg heel raises, and weight-bearing calf stretch. Description of symptoms, including location of Achilles tendon pain and duration of tendon morning stiffness, as well as pain-related psychological measures, including the Tampa Scale of Kinesiophobia were collected. Linear mixed effects models were built around two paradigms of movement-evoked pain (tendon loading and stretching tasks) with each model anchored with pain at rest., Findings: Movement-evoked pain intensity increased as task demand increased in both models. Lower peak dorsiflexion with walking (β = -0.187, 95% CI: -0.305, -0.069), higher fear of movement (β = 0.082, 95% CI: 0.018, 0.145), and longer duration of tendon morning stiffness (β = 0.183, 95% CI: 0.07, 0.296) were associated with greater pain across tendon loading tasks (R 2  = 0.47). Lower peak dorsiflexion with walking (β = -0.27, 95% CI: -0.41, -0.14), higher dorsiflexion with the calf stretch (β = 0.095, 95% CI: 0.02, 0.16), and insertional Achilles tendinopathy (β = -0.93, 95% CI: -1.65, -0.21) were associated with higher pain across tendon stretching tasks (R 2  = 0.53)., Interpretation: In addition to exercise, the ideal management of Achilles tendinopathy may require adjunct treatments to address the multifactorial aspects of movement-evoked pain., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Ruth L. Chimenti reports financial support was provided by National Institute of Arthritis Musculoskeletal and Skin Disease (NIAMS). Ruth L. Chimenti reports financial support was provided by Collaborative Research Grant from the International Association for the Study of Pain (IASP). Ruth L. Chimenti reports financial support was provided by National Center for Advancing Translational Sciences of the National Institutes of Health. Alberto M. Heredia-Rizo reports financial support was provided by Fulbright Program, Ministry of Universities, Spain. Andrew A. Post reports financial support was provided by Promotion of Doctoral Studies (PODS). Kathleen A. Sluka reports a relationship with Pfizer Health AB that includes: consulting or advisory. Kathleen A. Sluka reports a relationship with Novartis Consumer Health that includes: consulting or advisory. Kathleen A. Sluka reports a relationship with GSK Consumer Healthcare srl that includes: consulting or advisory., (Copyright © 2023 Elsevier Ltd. 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.)

Abstract: We developed an animal model of activity-induced muscle pain that is dependent on local macrophage activation and release of interleukin-1β (IL-1β). Activation of purinergic type 2X (P2X) 7 receptors recruits the NOD-like receptor protein (NLRP) 3 and activates Caspase-1 to release IL-1β. We hypothesized that pharmacological blockade of P2X7, NLRP3, and Caspase-1 would prevent development of activity-induced muscle pain in vivo and release of IL-1β from macrophages in vitro. The decrease in muscle withdrawal thresholds in male, but not female, mice was prevented by the administration of P2X7, NLRP3, and Caspase-1 inhibitors before induction of the model, whereas blockade of IL-1β before induction prevented muscle hyperalgesia in both male and female mice. Blockade of P2X7, NLRP3, Capsase-1, or IL-1β 24 hours, but not 1 week, after induction of the model alleviated muscle hyperalgesia in male, but not female, mice. mRNA expression of P2X7, NLRP3, Caspase-1, and IL-1β from muscle was increased 24 hours after induction of the model in both male and female mice. Using multiplex, increases in IL-1β induced by combining adenosine triphosphate with pH 6.5 in lipopolysaccharide-primed male and female macrophages were significantly lower with the presence of inhibitors of P2X7 (A740003), NLRP3 (MCC950), and Caspase-1 (Z-WEHD-FMK) when compared with the vehicle. The current data suggest the P2X7/NLRP3/Caspase-1 pathway contributed to activity-induced muscle pain initiation and early maintenance phases in male but not female, and not in late maintenance phases in male mice., (Copyright © 2023 International Association for the Study of Pain.)

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., (Copyright © 2023 International Association for the Study of Pain.)

Objectives: To determine the inter-rater reliability and criterion validity of two-dimensional (2D) measures of ankle function in the sagittal plane for participants with Achilles tendinopathy (AT)., Design: Cohort study., Setting: University Laboratory, Participants, Adults with AT (N = 18, Women: 72.2%, Age = 43.4 ± 15.8 years, BMI = 28.7 ± 8.9 kg/m 2 ) MAIN OUTCOME MEASURES: Reliability and validity were determined with intra-class correlation coefficients (ICC), standard error of the measurement (SEM), minimal detectable change (MDC), and Bland-Altman plots for ankle dorsiflexion and positive work during heel raises., Results: Inter-rater reliability between three raters for all 2D motion analysis tasks was good to excellent (ICC = 0.88 to 0.99). Criterion validity between 2D and 3D motion analyses for all tasks was good to excellent (ICC = 0.76 to 0.98). 2D motion analysis overestimated ankle dorsiflexion motion by 1.0-1.7° (3% of mean sample value) and positive ankle joint work by 76.8 J (9% of mean) compared to 3D motion analysis., Conclusion: Although 2D and 3D measures are not interchangeable, the good to excellent reliability and validity of 2D measures in the sagittal plane support the use of video analysis to quantify ankle function for individuals with foot and ankle pain., Competing Interests: Declaration of competing interest M. Hall receives royalties from UpToDate, Inc., holds stock in Trice Medical and Sonex Health, and serves on the Medical Advisory Board for Trice Medical and the Scientific Advisory Board for Vitruvia. Other authors declare no conflicts of interest for this study., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Induction of muscle pain triggers a local immune response to produce pain and this mechanism may be sex and activity level dependent. The purpose of this study was to measure the immune system response in the muscle following induction of pain in sedentary and physically active mice. Muscle pain was produced via an activity-induced pain model using acidic saline combined with fatiguing muscle contractions. Prior to induction of muscle pain, mice (C57/BL6) were sedentary or physically active (24hr access to running wheel) for 8 weeks. The ipsilateral gastrocnemius was harvested 24hr after induction of muscle pain for RNA sequencing or flow cytometry. RNA sequencing revealed activation of several immune pathways in both sexes after induction of muscle pain, and these pathways were attenuated in physically active females. Uniquely in females, the antigen processing and presentation pathway with MHC II signaling was activated after induction of muscle pain; activation of this pathway was blocked by physical activity. Blockade of MHC II attenuated development of muscle hyperalgesia exclusively in females. Induction of muscle pain increased the number of macrophages and T-cells in the muscle in both sexes, measured by flow cytometry. In both sexes, the phenotype of macrophages shifted toward a pro-inflammatory state after induction of muscle pain in sedentary mice (M1 + M1/2) but toward an anti-inflammatory state in physically active mice (M2 + M0). Thus, induction of muscle pain activates the immune system with sex-specific differences in the transcriptome while physical activity attenuates immune response in females and alters macrophage phenotype in both sexes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

Abstract: Chronic pain is a significant health problem associated with disability and reduced quality of life. Current management of chronic pain is inadequate with only modest effects of pharmacological interventions. Thus, there is a need for the generation of analgesics for treating chronic pain. Although preclinical and clinical studies demonstrate the analgesic effects of testosterone, clinical use of testosterone is limited by adverse androgenic effects. Selective androgen receptor modulators (SARMs) activate androgen receptors and overcome treatment limitations by minimizing androgenic side effects. Thus, we tested whether daily soluble SARMs or a SARM-loaded microparticle formulation alleviated muscle hyperalgesia in a mouse-model of widespread pain (male and female C57BL/6J mice). We tested whether the analgesic effects of the SARM-loaded microparticle formulation was mediated through androgen receptors by blocking androgen receptors with flutamide pellets. In vitro and in vivo release kinetics were determined for SARM-loaded microparticles. Safety and toxicity of SARM treatment was determined using serum cardiac and liver toxicity panels, heart histology, and conditioned place preference testing. Subcutaneous daily SARM administration, and 2 injections, 1 week apart, of SARM-loaded microparticles alleviated muscle hyperalgesia in both sexes and was prevented with flutamide treatment. Sustained release of SARM, from the microparticle formulation, was observed both in vitro and in vivo for 4 weeks. Selective androgen receptor modulator treatment produced no cardiac or liver toxicity and did not produce rewarding behaviors. These studies demonstrate that SARM-loaded microparticles, which release drug for a sustained period, alleviate muscle pain, are safe, and may serve as a potential therapeutic for chronic muscle pain., (Copyright © 2023 International Association for the Study of 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-1β, 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 Published by Elsevier Inc.)

Objective: The purpose of this study was to compare the efficacy of physical therapy delivered via an all telehealth or hybrid format with an all in-person format on movement-evoked pain for individuals with chronic Achilles tendinopathy (AT)., Methods: Sixty-six individuals with chronic AT participated (age, 43.4 [SD = 15.4] years; 56% female; body mass index, 29.9 [SD = 7.7] kg/m2). Participants completed all in-person visits from the initiation of recruitment in September 2019 to March 16, 2020 (in-person group). From March 17 to July 15, 2020, participants completed all telehealth visits (telehealth group). From July 16, 2020, to enrollment completion in December 2020, participants could complete visits all in-person, all telehealth, or a combination of in-person and telehealth (hybrid group) based on their preference. A physical therapist provided 6 to 7 visits, including an exercise program and patient education. Noninferiority analyses of the telehealth and hybrid groups compared with the in-person group were completed for the primary outcome of movement-evoked pain during single-limb heel raises., Results: All groups demonstrated decreases in movement-evoked pain beyond the minimal clinically important difference from baseline to 8 weeks (2 out of 10 on a numeric pain rating scale). Lower bounds of the 95% CIs for mean differences between groups did not surpass the preestablished noninferiority margin (2 out of 10) for movement-evoked pain in both the telehealth and hybrid groups (telehealth vs in-person: 0.45 [-1.1 to 2.0]; hybrid vs in-person: 0.48 [-1.0 to 1.9])., Conclusion: Individuals with chronic AT who completed a tendon-loading program with patient education through a telehealth or hybrid format had no worse outcomes for pain than those who received the same intervention through in-person visits., Impact: Physical therapist-directed patient care delivered via telehealth may enhance accessibility to best practice AT rehabilitation, including exercise and education. Use of telehealth technology may also provide an opportunity to prioritize patient preference for physical therapy visit format., Lay Summary: If you are a patient with chronic AT, physical therapist-directed patient care delivered via telehealth may improve your accessibility to best practice AT rehabilitation, including exercise and education. Use of telehealth technology may also prioritize your preferences regarding the format of the physical therapy visit., (© The Author(s) 2023. Published by Oxford University Press on behalf of the American Physical Therapy Association. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: Preoperative exercise (prehabilitation) is commonly used as a method to reduce pain and improve function postoperatively. The purpose of this systematic review was to determine therapeutic benefits of preoperative exercise on postoperative pain, function, quality of life (QOL), and risk of complications across various types of surgeries., Methods: Three electronic databases were used to perform a literature search. Full articles with randomized designs comparing a preoperative exercise program vs no formal program were included. The primary outcome was postoperative pain. QOL, function, and postoperative complications were analyzed as secondary outcomes. The primary meta-analysis was performed in those with joint replacement surgery because there were only 5 with other surgical types., Results: A total of 28 articles were included, of which 23 were from individuals with total joint replacement surgery. Preoperative exercise resulted in lower pain ≤2 months and 3 to 5 months after joint replacement surgery with a moderate standardized mean difference (95% CI at <2 months = -0.34 [-0.59 to -0.09]; at 3 to 5 months = -0.41 [-0.70 to -0.11]) compared with nonexercised controls. However, ≥6 months after joint replacement surgery, preoperative exercise groups showed no significant differences in postoperative pain (standardized mean difference = -0.17 [-0.35 to 0.01]) compared with nonexercised controls. QOL and subjective and objective function were improved ≤2 months after joint replacement surgery but were not different ≥6 months post-surgery. Reduction in risk of postoperative complications was favored with preoperative exercise., Conclusion: Preoperative exercise has a modest effect on postoperative pain, function, and quality of life within the first 6 months after surgery and reduces the risk of developing postoperative complications in individuals undergoing joint replacement surgery. The effect of preoperative exercise on other surgery types is inconclusive., Impact: This systematic review supports using preoperative exercise to improve pain and function outcomes for those with joint replacement surgery., (© 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.)

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.)