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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.)

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.)

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.)

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.)

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

Unlabelled: Macrophages play a role in innate immunity within the body, are located in muscle tissue, and can release inflammatory cytokines that sensitize local nociceptors. In this study we investigate the role of resident macrophages in the noninflammatory muscle pain model induced by 2 pH 4.0 preservative-free sterile saline (pH 4.0) injections 5 days apart in the gastrocnemius muscle. We showed that injecting 2 pH 4.0 injections into the gastrocnemius muscle increased the number of local muscle macrophages, and depleting muscle macrophages with clodronate liposomes before acid injections attenuated the hyperalgesia produced by this model. To further examine the contribution of local macrophages to this hyperalgesia, we injected mice intramuscularly with C34, a toll-like receptor 4 (TLR4) antagonist. When given before the first pH 4.0 injection, C34 attenuated the muscle and tactile hyperalgesia produced by the model. However, when given before the second injection C34 had no effect on the development of hyperalgesia. Then to test whether activation of local macrophages sensitizes nociceptors to normally non-nociceptive stimuli we replaced either the first or second acid injection with the immune cell activator lipopolysaccharide, or the inflammatory cytokine interleukin (IL)-6. Injecting LPS or IL-6 instead of the either the first or second pH 4.0 injection resulted in a dose-dependent increase in paw withdrawal responses and decrease in muscle withdrawal thresholds. The highest doses of LPS and IL-6 resulted in development of hyperalgesia bilaterally. The present study showed that resident macrophages in muscle are key to development of chronic muscle pain., Perspective: This article presents evidence for the role of macrophages in the development of chronic muscle pain using a mouse model. These data suggest that macrophages could be a potential therapeutic target to prevent transition of acute to chronic muscle pain particularly in tissue acidosis conditions., Competing Interests: The authors declare no conflicts of interest, (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Acute postoperative pain is a common clinical condition that, when poorly controlled, can result in a number of significant negative consequences. The American Pain Society commissioned an evidence-based guideline on the management of postoperative pain to promote evidence-based, safe, and effective perioperative pain management. An interdisciplinary panel developed 31 key questions and inclusion criteria to guide the evidence review. Investigators reviewed 6556 abstracts from multiple electronic databases up to November 2012, an updated evidence review to October 2014, and key references suggested by expert reviewers. More than 800 primary studies not included in a systematic review and 107 systematic reviews were included. Despite a large body of evidence, a number of critical research gaps were identified where only low-quality or insufficient evidence was found to help guide clinical practice recommendations. This report identifies evidence gaps including optimal methods and timing of perioperative patient education, nonpharmacological modalities, combinations of analgesic techniques, monitoring of patient response to treatment, techniques for neuraxial and regional analgesia, and organizational care delivery models. Recommendations to help guide the design of future perioperative studies are offered., Perspective: Acute postoperative pain is a common clinical condition requiring an evidence-based, planned, and multimodal approach. Despite the plethora of published evidence, much of it is weak and key questions remain unanswered. Researchers are encouraged to work together to produce strong evidence to help guide clinical decisions in perioperative pain management., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Insufficient pain education is problematic across the health care spectrum. Recent educational advancements have been made to combat the deficits in pain education to ensure that health care professionals are proficient in assessing and managing pain. The purpose of this survey was to determine the extent of pain education in current Doctorate of Physical Therapy schools in the United States, including how pain is incorporated into the curriculum, the amount of time spent teaching about pain, and the resources used to teach about pain. The survey consisted of 10 questions in the following subject areas: basic science mechanisms and concepts about pain, pain assessment, pain management, and adequacy of pain curriculum. The overall response was 77% (167/216) for the first series of responses of the survey (Question 1), whereas 62% completed the entire survey (Questions 2-10). The average contact hours teaching about pain was 31 ± 1.8 (mean ± standard error of the mean) with a range of 5 to 115 hours. The majority of schools that responded covered the science of pain, assessment, and management. Less than 50% of respondents were aware of the Institute of Medicine report on pain or the International Association for the Study of Pain guidelines for physical therapy pain education. Only 61% of respondents believed that their students received adequate education in pain management. Thus, this survey demonstrated how pain education is incorporated into physical therapy schools and highlighted areas for improvement such as awareness of recent educational advancements., Perspective: This article demonstrates how pain education is incorporated into physical therapy curricula within accredited programs. Understanding the current structure of pain education in health professional curriculum can serve as a basis to determine if recent publications of guidelines and competencies impact education., (Copyright © 2015 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Chronic pain represents an immense clinical problem. With tens of millions of people in the United States alone suffering from the burden of debilitating chronic pain, there is a moral obligation to reduce this burden by improving the understanding of pain and treatment mechanisms, developing new therapies, optimizing and testing existing therapies, and improving access to evidence-based pain care. Here, we present a goal-oriented research agenda describing the American Pain Society's vision for pain research aimed at tackling the most pressing issues in the field., Perspective: This article presents the American Pain Society's view of some of the most important research questions that need to be addressed to advance pain science and to improve care of patients with chronic pain., (Copyright © 2014 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Pain is ultimately a perceptual phenomenon. It is built from information gathered by specialized pain receptors in tissue, modified by spinal and supraspinal mechanisms, and integrated into a discrete sensory experience with an emotional valence in the brain. Because of this, studying intact animals allows the multidimensional nature of pain to be examined. A number of animal models have been developed, reflecting observations that pain phenotypes are mediated by distinct mechanisms. Animal models of pain are designed to mimic distinct clinical diseases to better evaluate underlying mechanisms and potential treatments. Outcome measures are designed to measure multiple parts of the pain experience, including reflexive hyperalgesia measures, sensory and affective dimensions of pain, and impact of pain on function and quality of life. In this review, we discuss the common methods used for inducing each of the pain phenotypes related to clinical pain syndromes as well as the main behavioral tests for assessing pain in each model., Perspective: Understanding animal models and outcome measures in animals will assist in translating data from basic science to the clinic., (Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Transcutaneous electrical nerve stimulation (TENS) reduces hyperalgesia and pain. Both low-frequency (LF) and high-frequency (HF) TENS, delivered at the same intensity (90% motor threshold [MT]) daily, result in analgesic tolerance with repeated use by the fifth day of treatment. The current study tested 1) whether increasing intensity by 10% per day prevents the development of tolerance to repeated TENS; and 2) whether lower intensity TENS (50% MT) produces an equivalent reduction in hyperalgesia when compared to 90% MT TENS. Sprague-Dawley rats with unilateral knee joint inflammation (3% carrageenan) were separated according to the intensity of TENS used: sham, 50% LF, 50% HF, 90% LF, 90% HF, and increased intensity by 10% per day (LF and HF). The reduced mechanical withdrawal threshold following the induction of inflammation was reversed by application of TENS applied at 90% MT intensity and increasing intensity for the first 4 days. On the fifth day, the groups that received 90% MT intensity showed tolerance. Nevertheless, the group that received an increased intensity on each day still showed a reversal of the mechanical withdrawal threshold with TENS. These results show that the development of tolerance can be delayed by increasing intensity of TENS., Perspective: Our results showed that increasing intensity in both frequencies of TENS was able to prevent analgesic tolerance. Results from this study suggest that increasing intensities could be a clinical method to prevent analgesic tolerance and contribute to the effective use of TENS in reducing inflammatory pain and future clinical trials., (Copyright © 2012 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: 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., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Diffuse Noxious Inhibitory Controls (DNIC) involves application of a noxious stimulus outside the testing site to produce analgesia. In human subjects with a variety of chronic pain conditions, DNIC is less effective; however, in animal studies, DNIC is more effective after tissue injury. While opioids are involved in DNIC analgesia, the pathways involved in this opioid-induced analgesia are not clear. The aim of the present study was to test the effectiveness of DNIC in inflammatory muscle pain, and to study which brainstem sites mediate DNIC- analgesia. Rats were injected with 3% carrageenan into their gastrocnemius muscle and responses to cutaneous and muscle stimuli were assessed before and after inflammation, and before and after DNIC induced by noxious heat applied to the tail (45 °C and 47 °C). Naloxone was administered systemically, into rostral ventromedial medulla (RVM), or bilaterally into the medullary reticularis nucleus dorsalis (MdD) prior to the DNIC-conditioning stimuli. DNIC produced a similar analgesic effect in both acute and the chronic phases of inflammation reducing both cutaneous and muscle sensitivity in a dose-dependent manner. Naloxone systemically or microinjected into the MdD prevented DNIC-analgesia, while naloxone into the RVM had no effect on DNIC analgesia. Thus, DNIC analgesia involves activation of opioid receptors in the MdD., Perspective: The current study shows that DNIC activates opioid receptors in the MdD, but not the RVM, to produce analgesia. These data are important for understanding clinical studies on DNIC as well as for potential treatment of chronic pain patients., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Transcutaneous electrical nerve stimulation (TENS) is a noninvasive technique used for pain modulation. During application of TENS there is a fading of current sensation. Textbooks of electrophysical agents recommend that pulse amplitude should be constantly adjusted. This seems to be accepted clinically despite the fact that there is no direct experimental evidence. The aim of the current study was to investigate the hypoalgesic effect of adjusting TENS pulse amplitude on pressure pain thresholds (PPTs) in healthy humans. Fifty-six healthy TENS naïve participants were recruited and randomly assigned to 1 of 4 groups (n = 14 per group): control, placebo TENS, fixed pulse amplitude TENS, and adjusted pulse amplitude TENS. Both active and placebo TENS were applied to the dominant forearm. PPTs were recorded from 2 points on the dominant forearm and hand before, during, and after 40 minutes of TENS. TENS increased the PPTs on the forearm (P = .003) and hand (P = .003) in the group that received the adjusted pulse amplitude when compared to all other groups. The mean final pulse amplitude for the adjusted pulse amplitude TENS group was 35.51 mA when compared to the fixed pulse amplitude TENS group, which averaged 31.37 mA (P = .0318)., Perspective: These results suggest that it is important to adjust the pulse amplitude during TENS application to get the maximal analgesic effect. We propose that the fading of current sensation allows the use of higher pulse amplitudes, which would activate a greater number of and deeper tissue afferents to produce greater analgesia., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: Repeated injections of acidic saline into the gastrocnemius muscle induce both muscle and cutaneous hypersensitivity. We have previously shown that microinjection of local anesthetic into either the rostral ventromedial medulla (RVM) or the nucleus reticularis gigantocellularis (NGC) reverses this muscle and cutaneous hypersensitivity. Although prior studies show that NMDA receptors in the RVM play a clear role in mediating visceral and inflammatory hypersensitivity, the role of NMDA receptors in the NGC or in noninflammatory muscle pain is unclear. Therefore, the present study evaluated involvement of the NMDA receptors in the RVM and NGC in muscle and cutaneous hypersensitivity induced by repeated intramuscular injections of acidic saline. Repeated intramuscular injections of acidic saline, 5 days apart, resulted in a bilateral decrease in the withdrawal thresholds of the paw and muscle in all groups 24 hours after the second injection. Microinjection of NMDA receptor antagonists into the RVM reversed both the muscle and cutaneous hypersensitivity. However, microinjection of NMDA receptor antagonists into the NGC only reversed cutaneous but not muscle hypersensitivity. These results suggest that NMDA receptors in the RVM mediate both muscle and cutaneous hypersensitivity, but those in the NGC mediate only cutaneous hypersensitivity after muscle insult., Perspective: The current study shows that NMDA receptors in supraspinal facilitatory sites maintain noninflammatory muscle pain. Clinical studies in people with chronic widespread, noninflammatory pain, similarly, show alterations in central excitability. Thus, understanding mechanisms in an animal model could lead to improved treatment for patients with chronic muscle pain., (Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: This study compared a new transient sham transcutaneous electrical nerve stimulation (TENS) that delivers current for 45 seconds to an inactive sham and active TENS to determine the degree of blinding and influence on pain reduction. Pressure-pain thresholds (PPT), heat-pain thresholds (HPT), and pain intensities to tonic heat and pressure were measured in 69 healthy adults before and after randomization. Allocation investigators and subjects were asked to identify the treatment administered. The transient sham blinded investigators 100% of the time and 40% of subjects compared to the inactive sham that blinded investigators 0% of the time and 21% of subjects. Investigators and subjects were blinded only 7% and 13% of the time, respectively, with active TENS. Neither placebo treatment resulted in significant changes in PPT, HPT, or pain intensities. Subjects using higher active TENS amplitudes (> or =17 mAs) had significantly higher PPTs and lower pain intensities to tonic pressure than subjects using lower amplitudes (<17 mAs). HPTs and pain intensities to tonic heat were not significantly changed. The transient TENS completely blinds investigators to treatment and does not reduce pain, thereby providing a true placebo treatment., Perspective: This article presents the benefits of a new transient sham TENS device for use in prospective, randomized, clinical trials. This device facilitates blinding of subjects and investigators to eliminate expectation bias and determine the true efficacy of TENS for use in clinical populations., (Published by Elsevier Inc.)

Unlabelled: Acid-sensing ion channels (ASICs) respond to acidosis that normally occurs after inflammation. We examined the expression of ASIC1, ASIC2, and ASIC3 mRNAs in lumbar dorsal root ganglion neurons before and 24 hours after carrageenan-induced muscle inflammation. Muscle inflammation causes bilateral increases of ASIC2 and ASIC3 but not ASIC1 (neither ASIC1a nor ASIC1b) mRNA, suggesting differential regulation of ASIC1 versus ASIC2 and ASIC3 mRNA. Similar mRNA increases were observed after inflammation in knockout mice: ASIC2 mRNA increases in ASIC3-/- mice; ASIC2 and ASIC3 mRNAs increase in ASIC1-/- mice. Prior behavioral studies in ASIC3-/- mice showed deficits in secondary hyperalgesia (increased response to noxious stimuli outside the site of injury) but not primary hyperalgesia (increased response to noxious stimuli at the site of injury). In this study, we show that ASIC1-/- mice do not develop primary muscle hyperalgesia but develop secondary paw hyperalgesia. In contrast, and as expected, ASIC3-/- mice develop primary muscle hyperalgesia but do not develop secondary paw hyperalgesia. The pharmacological utility of the nonselective ASIC inhibitor A-317567, given locally, was tested. A-317567 reverses both the primary and the secondary hyperalgesia induced by carrageenan muscle inflammation. Thus, peripherally located ASIC1 and ASIC3 play different roles in the development of hyperalgesia after muscle inflammation., Perspective: This study shows changes in ASIC mRNA expression and behavioral hyperalgesia of C57Bl/6 (wild type), ASIC1-/-, and ASIC3-/- mice before and after the induction of muscle inflammation. A-317567 was effective in reversing hyperalgesia in these animals, suggesting the potential of ASICs as therapeutic targets for muscle inflammatory pain., (Copyright 2010 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Unlabelled: This randomized, placebo-controlled, blinded study investigated the hypoalgesic effects of high-frequency transcutaneous electrical nerve stimulation (TENS) delivered via a glove electrode compared with standard self-adhesive electrodes. Fifty-six TENS-naïve, healthy individuals (18 to 50 years old; 28 men, 28 women) were randomly allocated to 1 of 4 groups (n = 14 per group): glove electrode; placebo TENS using a glove electrode; standard electrode; and no treatment control. Active TENS (continuous stimulus, 100 Hz, strong but comfortable intensity) was applied to the dominant forearm/hand for 30 minutes. Placebo TENS was applied using a burst stimulus, 100-Hz frequency, 5-second cycle time for 42 seconds, after which the current amplitude was automatically reset to 0 mA. Pressure pain thresholds (PPTs) were recorded from 3 points on the dominant and nondominant upper limbs before and after TENS. Statistical analyses of dominant PPT data using between-within groups ANOVA showed significant differences between groups at all 3 recording points (P = .01). Post hoc Scheffe tests indicated no significant difference between the standard electrode and glove electrode groups. There was a significant hypoalgesic effect in the standard electrode group compared with the control group and between the glove electrode group and both the control and placebo TENS groups. There was no significant interactive effect between time and group at any of the recording points (P > .05)., Perspective: This study presents a comparison of the hypoalgesic effects of 2 different types of TENS electrode, a novel glove electrode and standard self-adhesive rectangular electrodes. The glove electrode provides a larger contact area with the skin, thereby stimulating a greater number of nerve fibers. The results show that both electrodes have similar hypoalgesic effects and therefore give the clinician another choice in electrode.

Unlabelled: Arthritis is associated with decreases in local pH. Of the acid-sensing ion channels (ASIC), ASIC3 is most sensitive to such a pH change, abundantly expressed in dorsal root ganglion (DRG), and critical for the development of secondary hyperalgesia. The purpose of this study was to investigate the upregulation of ASIC3, using an acute arthritic pain model in mice. We examined ASIC3 expression in DRG neurons innervating the knee joint with and without carrageenan-induced arthritis by means of retrograde labeling and immunohistochemistry. We also examined the difference of DRG phenotype between ASIC3+/+ and ASIC3-/- mice. ASIC3 immunoreactivity was present in 31% of knee joint afferents and dominantly in small cells. After joint inflammation, ASIC3-immunoreactive neurons significantly increased in number by 50%. Calcitonin gene-related peptide (CGRP) increased similarly in both ASIC3+/+ and ASIC3-/- mice. Soma size distribution of ASIC3-immunoreactive neurons without CGRP expression was shifted to smaller-diameter neurons. Our results suggest that ASIC3 plays an important role in acute arthritic pain. Specifically, we propose that ASIC3 upregulation along with CGRP and phenotypic change in ASIC3-immunoreactive neurons without CGRP are responsible for the development of secondary hyperalgesia after carrageenan-induced arthritis., Perspective: This article shows that ASIC3 is upregulated along with CGRP in knee joint afferents and that there is a phenotypic change in ASIC3-immunoreactive nonpeptidergic neurons in an animal model of acute arthritis. Understanding the basic neurobiology after acute arthritis could lead to future new pharmacological management of arthritis.

Unlabelled: Massage is a common conservative intervention used to treat myalgia. Although subjective reports have supported the premise that massage decreases pain, few studies have systematically investigated the dose response characteristics of massage relative to a control group. The purpose of this study was to perform a double-blinded, randomized controlled trial of the effects of massage on mechanical hyperalgesia (pressure pain thresholds, PPT) and perceived pain using delayed onset muscle soreness (DOMS) as an endogenous model of myalgia. Participants were randomly assigned to a no-treatment control, superficial touch, or deep-tissue massage group. Eccentric wrist extension exercises were performed at visit 1 to induce DOMS 48 hours later at visit 2. Pain, assessed using visual analog scales (VAS), and PPTs were measured at baseline, after exercise, before treatment, and after treatment. Deep massage decreased pain (48.4% DOMS reversal) during muscle stretch. Mechanical hyperalgesia was reduced (27.5% reversal) after both the deep massage and superficial touch groups relative to control (increased hyperalgesia by 38.4%). Resting pain did not vary between treatment groups., Perspective: This randomized, controlled trial suggests that massage is capable of reducing myalgia symptoms by approximately 25% to 50%, varying with assessment technique. Thus, potential analgesia may depend on the pain assessment used. This information may assist clinicians in determining conservative treatment options for patients with myalgia.

Unlabelled: We investigated the effect of transcutaneous electrical nerve stimulation (TENS) for inguinal herniorrhaphy postoperative pain control in a prospective, randomized, double-blinded, placebo-controlled study. Forty patients undergoing unilateral inguinal herniorrhaphy with an epidural anesthetic technique were randomly allocated to receive either active TENS or placebo TENS. Postoperative pain was evaluated using a standard 10-point numeric rating scale (NRS). Analgesic requirements were also recorded. TENS (100 Hz, strong but comfortable sensory intensity) was applied for 30 minutes through 4 electrodes placed around the incision twice, 2 and 4 hours after surgery. Pain was assessed before and after each application of TENS and 8 and 24 hours after surgery. In the group treated with active TENS, pain intensity was significantly lower 2 hours (P = .028), 4 hours (P = .022), 8 hours (P = .006), and 24 hours (P = .001) after the surgery when compared with the group that received placebo TENS. Active TENS also decreased analgesic requirements in the postoperative period when compared with placebo TENS (P = .001). TENS is thus beneficial for postoperative pain relief after inguinal herniorrhaphy; it has no observable side effects, and the pain-reducing effect continued for at least 24 hours. Consequently, the routine use of TENS after inguinal herniorrhaphy is recommended., Perspective: This study presents the hypoalgesic effect of high-frequency TENS for postoperative pain after inguinal herniorrhaphy. This may reinforce findings from basic science showing an opioid-like effect provided by TENS, given that high-frequency TENS has been shown to activate delta-opioid receptors.

Unlabelled: Repeated daily application of transcutaneous electrical nerve stimulation (TENS) results in tolerance, at spinal opioid receptors, to the antihyperalgesia produced by TENS. Since N-methyl-D-aspartate (NMDA) receptor antagonists prevent analgesic tolerance to opioid agonists, we hypothesized that blockade of NMDA receptors will prevent tolerance to TENS. In rats with knee joint inflammation, TENS was applied for 20 minutes daily at high-frequency (100 Hz), low-frequency (4 Hz), or sham TENS. Rats were treated with the NMDA antagonist MK-801 (0.01 mg/kg to 0.1 mg/kg) or vehicle daily before TENS. Paw withdrawal thresholds were tested before and after inflammation and before and after TENS treatment for 4 days. On day 1, TENS reversed the decreased mechanical withdrawal threshold induced by joint inflammation. On day 4, TENS had no effect on the decreased withdrawal threshold in the group treated with vehicle, demonstrating development of tolerance. However, in the group treated with 0.1 mg/kg MK-801, TENS significantly reversed the mechanical withdrawal thresholds on day 4, demonstrating that tolerance did not develop. Vehicle-treated animals developed cross-tolerance at spinal opioid receptors. Treatment with MK-801 reversed this cross-tolerance at spinal opioid receptors. In summary, blockade of NMDA receptors prevents analgesic tolerance to daily TENS by preventing tolerance at spinal opioid receptors., Perspective: Observed tolerance to the clinical treatment of TENS could be prevented by administration of pharmaceutical agents with NMDA receptors activity such as ketamine or dextromethorphan.

Unlabelled: Chronic muscle pain is a major clinical problem that is often associated with fatigue. Conversely, chronic fatigue conditions are commonly associated with muscle pain. We tested the hypothesis that muscle fatigue enhances hyperalgesia associated with injection of acidic saline into muscle. We evaluated mechanical sensitivity of the paw (von Frey) in mice after 2 intramuscular injections of saline (20 microL; pH 4, pH 5, pH 6, pH 7.2) in a fatigue and a control group. To induce fatigue, mice were run for 2 h/day for 2 days prior to the first injection and 2 h/day for 2 days prior to the second injection. Muscle lactate, pCO(2), pO(2), creatinine kinase, phosphate, and histology were examined after the fatigue task and compared to a control group. Grip force was significantly decreased after 2 h of running indicating fatigue. The fatigue task did not induce muscle damage as there was no difference in muscle lactate, pCO(2), pO(2), creatinine kinase, phosphate, or histology. The fatigue task altered the dose-response relationship to intramuscular acidic saline injections. Mechanical hyperalgesia was observed in both fatigue and control groups after intramuscular injection of pH 4.0, but only the fatigue group after injection of pH 5. Neither the fatigue nor the control group developed hyperalgesia in response to intramuscular injection of pH 6 or pH 7.2. In conclusion, fatigue modified the susceptibility of mice to acid injection of pH 5.0 to result in mechanical hyperalgesia after 2 injections of pH 5.0. The fatigue task did not produce measurable changes in the muscle tissue suggesting a central mechanism mediating the enhancement of hyperalgesia., Perspective: These data therefore show that muscle fatigue can enhance the likelihood that one develops pain to a mild insult. Clinically, this could relate to the development of pain from such conditions as repetitive strain injury, and may relate to the interrelationship between chronic pain and fatigue.

Unlabelled: Pregabalin is used for treatment of neuropathic pain conditions. The present study evaluated effects of pregabalin in 2 rat models of muscle-induced hyperalgesia: Inflammatory and noninflammatory. Muscle hyperalgesia (withdrawal threshold to compression of the muscle) and cutaneous hyperalgesia of the paw (withdrawal threshold to von Frey filaments) were measured before and after induction of hyperalgesia and after treatment with pregabalin (saline, 10 to 100 mg/kg i.p.). In the inflammatory model, 3% carrageenan injected into 1 gastrocnemius muscle decreased the mechanical withdrawal threshold of the paw bilaterally and the compression withdrawal threshold of the muscle ipsilaterally 2 weeks later. Pregabalin (10 to 100 mg/kg) increased the compression withdrawal threshold of the inflamed muscle when compared with vehicle controls. Pregabalin also increased the mechanical withdrawal threshold of the paw bilaterally, but only with 100 mg/kg. In the noninflammatory model, 2 unilateral injections of acidic saline into the gastrocnemius muscle produced bilateral cutaneous and muscle hyperalgesia 24 hours after the second injection. Pregabalin (10 to 100 mg/kg i.p.) significantly increased the compression withdrawal thresholds of the muscle and the mechanical withdrawal threshold of the paw bilaterally when compared with vehicle. However, pregabalin also has significant motor effects at the higher doses (60 to 100 mg/kg). Therefore, pregabalin reduces both muscle and cutaneous hyperalgesia that occurs after muscle insult in 2 animal models of muscle pain at doses that do not produce ataxia., Perspective: This study shows that pregabalin reduces both cutaneous and muscle hyperalgesia in inflammatory and noninflammatory models of muscle pain. Thus, pregabalin may be an effective treatment for people with chronic muscle pain.

Unlabelled: Transcutaneous electrical nerve stimulation (TENS) is a nonpharmacological method for pain management. Commercial TENS units differ in their waveform characteristics. However, effects of different waveforms on analgesia produced by TENS are unknown. Therefore, we compared effects of high-frequency TENS with different waveforms--asymmetric biphasic square and symmetric biphasic square--on inflammatory hyperalgesia. Paw withdrawal latency to heat (PWL) was assessed prior to inflaming the knee joint with 3% carrageenan/kaolin in rats. Four hours after induction of inflammation, PWL significantly decreased in all groups, indicating development of hyperalgesia. High-frequency TENS was then applied to the inflamed knee joint for 20 minutes while the rat was lightly anesthetized with halothane. TENS treatment with either the asymmetric or symmetric waveform significantly increased the PWL when compared with sham TENS. Thus, differences in waveform characteristics do not affect the anti-hyperalgesia produced by TENS., Perspective: This study shows that different waveforms of TENS do not affect analgesic efficacy. This suggests that clinicians can select different waveforms to provide comfort during treatment but that reduction in pain is not a factor for waveform selection.

Unlabelled: Joint mobilization is a common treatment used by healthcare professions for management of a variety of painful conditions, including inflammatory joint and muscle pain. We hypothesized that joint mobilization would reduce the bilateral hyperalgesia induced by muscle and joint inflammation. Mechanical hyperalgesia was measured by examining the mechanical withdrawal threshold of the rat's paw before and after induction of inflammation with 3% carrageenan (gastrocnemius muscle) or 3% kaolin/carrageenan (knee joint), and for 1 hour after knee joint mobilization. The mobilization consisted of rhythmically flexing and extending the knee joint to the end of range of extension while the tibia was simultaneously moved in an anterior to posterior direction. A bilateral decrease in mechanical withdrawal thresholds occurred 1, 2, and 4 weeks after inflammation of the knee joint or muscle. In animals with muscle inflammation, mobilization of the knee joint increased the mechanical withdrawal threshold bilaterally when given 1, 2, or 4 weeks after inflammation. However, in animals with knee joint inflammation, mobilization of the knee joint at 4 weeks increased the mechanical withdrawal threshold but had no effect when administered 1 or 2 weeks after inflammation. Therefore, joint mobilization reduces hyperalgesia induced by chronic inflammation of muscle and joint., Perspective: This article shows that unilateral joint mobilization reduces bilateral hyperalgesia induced by chronic muscle or joint inflammation. Understanding the pain conditions in which mobilization produces an analgesic effect should assist the clinician in selecting appropriate treatment techniques. The bilateral effect suggests that central mechanisms could mediate the analgesia.

Unlabelled: 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.

Unlabelled: Measuring primary hyperalgesia from deep somatic tissue (ie, muscle and joint) is difficult in laboratory animals but clinically important. In this study, we modified a newly developed method to measure primary hyperalgesia of muscle in rats and compared this with primary hyperalgesia from the knee. Compression withdrawal thresholds of the gastrocnemius muscle or the knee joint were measured with a device consisting of strain gauges attached to forceps. Compression of the muscle or joint with the forceps results in hind limb withdrawal, and thresholds were measured before and 4 hours after induction of inflammation by 3% carrageenan injected into the gastrocnemius muscle or 3% kaolin-carrageenan injected into the knee joint. Compression thresholds were significantly decreased 4 hours after induction of inflammation in the muscle or knee joint compared with thresholds before inflammation. Surprisingly, in animals with muscle inflammation, compression thresholds were also significantly decreased on the contralateral hind limb. Systemic morphine (5 mg/kg, intraperitoneal) or lidocaine (2%) injected into the inflamed tissue reversed the decreased compression threshold induced by deep tissue inflammation. However, local anesthetic applied to the skin overlying the muscle or knee joint did not affect the decreased threshold. Thus, we report a consistent and convenient method to measure primary hyperalgesia in deep tissues of rats. The measured hyperalgesia originates in the inflamed tissues and has no measurable contribution from skin., Perspective: The current method measures primary hyperalgesia directly from injured deep somatic tissues. Thus it is relevant to painful clinical conditions that are aggravated by mechanical pressure at the site of injury. As such, it might serve as a model for basic mechanistic studies as well as drug discovery for musculoskeletal pain syndromes.

Transcutaneous electrical nerve stimulation (TENS) is used clinically by a variety of health care professionals for the reduction of pain. Clinical effectiveness of TENS is controversial, with some studies supporting whereas others refute its clinical use. Although used by health professionals for decades, the mechanisms by which TENS produces analgesia or reduces pain are only recently being elucidated. This article describes the basic science mechanisms behind different frequencies of TENS stimulation. Specifically, we describe the literature that supports the use of different frequencies and intensities of TENS. We further describe theories that support the use of TENS such as the gate control theory and the release of endogenous opioids. The literature that supports or refutes each of these theories is described. We also review the clinical literature on TENS effectiveness and elucidate the problems with clinical research studies to date. In conclusion, TENS is a noninvasive modality that is easy to apply with relatively few contraindications. However, the clinical efficacy of TENS will remain equivocal until the publication of sufficient numbers of high quality, randomized, controlled clinical trials.

For years, transcutaneous electrical nerve stimulation (TENS) has been used clinically for the treatment of many types of pain. Although there have been many studies conducted on the efficacy of TENS in the clinical setting, the results are conflicting. The purpose of our investigation was to determine the effect of varying frequency and intensity of TENS on secondary mechanical hyperalgesia induced by acute joint inflammation. Male Sprague-Dawley rats were injected with a mixture of 3% carrageenan and 3% kaolin (100 microL in 0.9% sterile saline) into the joint cavity of one knee. The response threshold to mechanical stimuli was determined before inflammation of the knee joint; 4 hours after inflammation; immediately after the administration of TENS (approximately 5 hours after inflammation); and at 8, 12, and 24 hours after inflammation. TENS was applied to the inflamed knee joint at either high (100 Hz) or low (4 Hz) frequency and at either sensory or motor intensity. Sensory intensity was just below the threshold for motor contraction, and motor intensity was 2 x threshold for motor contraction. Either low- or high-frequency TENS is equally successful in reducing secondary mechanical hyperalgesia. Similarly, either sensory- or motor-intensity TENS equally reduces secondary mechanical hyperalgesia. Thus, selection of TENS should be based on patient comfort and symptoms for relief of secondary mechanical hyperalgesia.

Given that transcutaneous electrical nerve stimulation (TENS) achieves its anti-hyperalgesia through endogenous opioid receptors, this study was undertaken to assess if TENS in combination with morphine was more effective at reducing primary hyperalgesia. Acute inflammation was induced by subcutaneous injection of 3% carrageenan into the rat's hindpaw. The withdrawal latency to heat and the mechanical withdrawal threshold were assessed before and after inflammation and after treatment with TENS (high- or low-frequency). Animals were divided into the following groups: Group 1, saline, no TENS; Group 2, high- or low-frequency TENS plus saline; Group 3, morphine (0.3, 1, and 3 mg/kg, intraperitoneal [i.p.]), no TENS; and Group 4, high- or low-frequency TENS plus morphine (0.3, 1, and 3 mg/kg, i.p.). There was an increase in inhibition of primary heat but not mechanical hyperalgesia after treatment with either high- or low-frequency TENS in combination with morphine. In combination with morphine, low-frequency TENS produced a similar reduction in mechanical hyperalgesia when compared with morphine alone. High-frequency TENS in combination with morphine produced a similar reduction in mechanical hyperalgesia when compared with the effects of high-frequency TENS alone. Thus, a lower dose of morphine could be used in combination with TENS to decrease the side effects of systemic morphine and achieve the same degree of analgesia.