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Advances in modern medicine have extended human life expectancy, leading to a world with a gradually aging society. Aging refers to a natural decline in the physiological functions of a species over time, such as reduced pain sensitivity and reaction speed. Healthy-level physiological pain serves as a warning signal to the body, helping to avoid noxious stimuli. Physiological pain sensitivity gradually decreases in the elderly, increasing the risk of injury. Therefore, geriatric health care receives growing attention, potentially improving the health status and life quality of the elderly, further reducing medical burden. Health food is a geriatric healthcare choice for the elderly with Ganoderma tsuage (GT), a Reishi type, as the main product in the market. GT contains polysaccharides, triterpenoids, adenosine, immunoregulatory proteins, and other components, including anticancer, blood sugar regulating, antioxidation, antibacterial, antivirus, and liver and stomach damage protective agents. However, its pain perception-related effects remain elusive. This study thus aimed at addressing whether GT could prevent pain sensitivity reduction in the elderly. We used a galactose-induced animal model for aging to evaluate whether GT could maintain pain sensitivity in aging mice undergoing formalin pain test, hot water test, and tail flexes. Our results demonstrated that GT significantly improved the sensitivity and reaction speed to pain in the hot water, hot plate, and formalin tests compared with the control. Therefore, our animal study positions GT as a promising compound for pain sensitivity maintenance during aging. [ABSTRACT FROM AUTHOR]

Background: Transcutaneous electrical nerve stimulation (TENS) is a non-invasive modality that utilizes electrical currents to modulate pain in populations with acute and chronic pain. TENS has been demonstrated to produce hypoalgesic effects in postoperative pain, fibromyalgia, knee osteoarthritis, and healthy subjects. Transcutaneous auricular vagus nerve stimulation (TaVNS) is a non-invasive modality that modulates the vagus nerve by stimulating its auricular branches. The effects of the combination of TENS and TaVNS on producing an analgesic response have not been studied. Considering that TENS and TaVNS both stimulate similar analgesic pathways but through different means of activation, we can hypothesize that a combination of both methods can produce a more pronounced analgesic response. Therefore, the objective of this study is to assess the hypoalgesic effect of a combination of TENS and TaVNS in pain-free subjects. Methods/design: The study will be a simple crossover design conducted at the University of Hartford. Subjects will be recruited from the University of Hartford population via oral communication, digital flyers, and posters on campus. Thirty participants will undergo two sessions in a crossover manner with one week in between. During one session, the participants will receive TENS with active TaVNS and the other session will be a placebo procedure (TENS with placebo TaVNS). The order of these sessions will be randomized. Importantly, the pressure pain threshold (PPT) and heat pain threshold (HPT) assessors will be blinded to the treatment category. For active TaVNS, a frequency of 25 Hz will be applied with a pulse duration of 200 µs. For placebo TaVNS, the intensity will be increased to a sensory level and then decreased to 0 mA. High-frequency TENS of 100 Hz will be applied in both sessions, with a pulse duration of 200 µsec, asymmetrical biphasic square waveform, and intensity of maximal tolerance without pain. TENS and TaVNS will be turned on for 30 min after a baseline measurement of outcomes. TENS and TaVNS will then be turned off, but the electrodes will remain on until completion of post-treatment assessment. Pressure pain threshold, heat pain threshold, blood pressure, oxygen saturation, and heart rate will be tested 4 times: Once pre-intervention, once during intervention, once immediately after the intervention, and once 15 min post-intervention. Statistical analysis of the data obtained will consider a significance level of p < 0.05. Discussion: This study will provide evidence concerning the combined effects of TENS and TaVNS on pain threshold in pain-free participants. Based on the outcomes, a greater understanding of how TENS and TaVNS, when used in conjunction, can modulate pain pathways. Trial registration: ClinicalTrials.gov NCT06361381. Registered on 09 April 2024. [ABSTRACT FROM AUTHOR]

Abstract Advances in modern medicine have extended human life expectancy, leading to a world with a gradually aging society. Aging refers to a natural decline in the physiological functions of a species over time, such as reduced pain sensitivity and reaction speed. Healthy-level physiological pain serves as a warning signal to the body, helping to avoid noxious stimuli. Physiological pain sensitivity gradually decreases in the elderly, increasing the risk of injury. Therefore, geriatric health care receives growing attention, potentially improving the health status and life quality of the elderly, further reducing medical burden. Health food is a geriatric healthcare choice for the elderly with Ganoderma tsuage (GT), a Reishi type, as the main product in the market. GT contains polysaccharides, triterpenoids, adenosine, immunoregulatory proteins, and other components, including anticancer, blood sugar regulating, antioxidation, antibacterial, antivirus, and liver and stomach damage protective agents. However, its pain perception-related effects remain elusive. This study thus aimed at addressing whether GT could prevent pain sensitivity reduction in the elderly. We used a galactose-induced animal model for aging to evaluate whether GT could maintain pain sensitivity in aging mice undergoing formalin pain test, hot water test, and tail flexes. Our results demonstrated that GT significantly improved the sensitivity and reaction speed to pain in the hot water, hot plate, and formalin tests compared with the control. Therefore, our animal study positions GT as a promising compound for pain sensitivity maintenance during aging.

Steven Z George,1,2 Maggie E Horn2 1Duke Clinical Research Institute, Duke University, Durham, NC, USA; 2Departments of Orthopaedic Surgery and Population Health Science, Duke University, Durham, NC, USACorrespondence: Steven Z George, Duke University, 300 Morgan Street, Office 480, Durham, NC, 27707, USA, Tel +1 919-668-0825, Email steven.george@duke.eduAims and Objective: The purpose of this pilot study was to explore whether AIH produces changes in pain sensitivity or in reports of self-reported pain intensity for individuals with low back pain.Methods: In a quasi-experimental, cross-over design we compared participants (n = 9) exposed to normal room air and hypoxia using a commercially available gas blender. The treatment period consisted of 5 consecutive days of randomly assigned to AIH or room air. For the participants initially randomized to AIH there was cross-over to receive 5 more consecutive days of room air. Therefore, this design allowed for between group and within subject assessment of AIH effects. Pain sensitivity was assessed with quantitative sensory testing (QST) for posterior superior iliac spine pressure threshold, plantar thermal threshold, and peak pain ratings. Self-reported pain intensity for low back pain was assessed via the Brief Pain Inventory.Results: There were no between group differences for AIH and room air in pain sensitivity or self-reported pain intensity. In the within subject analyses larger effect sizes favoring AIH were detected for plantar measures of pain sensitivity but not for self-reported pain intensity.Conclusion: This study, while presenting null findings, describes an initial step in determining whether AIH can be used to increase pain relief. Based on this pilot study we offer guidance for future research including study design, AIH dosage, participant selection, and using AIH in combination with non-pharmacologic treatments.Keywords: hypoxia, hypoalgesia, low back pain, pain sensitivity

Changes in quantitative sensory testing (QST) after manual therapy can provide insight into pain relief mechanisms. Prior systematic reviews have evaluated manual-therapy-induced QST change. This overview of systematic reviews aims to consolidate this body of literature and critically review evidence on the hypoalgesic effects of manual therapy in clinical populations. A comprehensive search was conducted on PubMed, CINAHL, PsycInfo, and Embase. Peer-reviewed systematic reviews with or without meta-analysis were eligible if the reviews examined the effect of manual therapy compared to non-manual therapy interventions on QST outcomes in clinical populations. Methodological quality was assessed with the AMSTAR 2 tool. Meta-analysis results and qualitative (non-meta-analysis) interpretations were summarized by type of manual therapy. Overlap of studies was examined with the corrected covered area (CCA) index. Thirty systematic reviews, including 11 meta-analyses, met inclusion. There was a slight overlap in studies (CCA of 1.72% for all reviews and 1.69% for meta-analyses). Methodological quality was predominantly low to critically low. Eight (27%) reviews examined studies with a range of manual therapy types, 13 (43%) reviews focused on joint-biased manual therapy, 7 (23%) reviews focused on muscle-biased manual therapy, and 2 (7%) reviews focused on nerve-biased manual therapy. Twenty-nine (97%) reviews reported on pressure pain threshold (PPT). Meta-analytic results demonstrated conflicting evidence that manual therapy results in greater hypoalgesic effects compared to other interventions or controls. Our overview of QST effects, which has relevance to mechanisms underlying hypoalgesia, shows conflicting evidence from mostly low to critically low systematic reviews. [ABSTRACT FROM AUTHOR]

Perceived pain can be viewed because of a competition between nociceptive inputs and other competing goals, such as performing a demanding cognitive task. Task performance, however, suffers when cognitively fatigued. We therefore predicted that cognitive fatigue would weaken the pain-reducing effects of performing a concurrent cognitive task, which would indicate a causal link between fatigue and heightened pain sensitivity. In this study, 2 groups of pain-free adults performed cognitive tasks while receiving painful heat stimuli. In 1 group, we induced cognitive fatigue before performing the tasks. We found that fatigue led to more pain and worse performance when the task was demanding, suggesting that fatigue weakens one’s ability to distract from pain. These findings show that cognitive fatigue can impair performance on subsequent tasks and that this impairment can lower a person’s ability to distract from and reduce their pain. [ABSTRACT FROM AUTHOR]

Ischaemic preconditioning (IPC) applied locally and remotely has been shown to reduce pain which may underpin its ergogenic effect on exercise performance, however, it is unclear how many IPC cycles are needed to induce hypoalgesia. Therefore the purpose of this study was to examine the number of cycles of IPC on experimental pain perception. Sixteen healthy participants underwent four, randomised, experimental sessions where they either underwent a sham protocol (1 × 5 min at 20 mmHg), and 1, 2 or 3 cycles × 5 min of remote IPC at 105% of limb occlusion pressure. Ten minutes post-intervention, participants underwent a cold-pressor test where pain threshold, pain tolerance and pain intensity were examined and compared between conditions with a one-way repeated measure analysis of variance. Pain threshold was not different between conditions (P = 0.065); but pain tolerance was increased by ~30% in the 1 × 5 condition, 2 × 5 condition, and 3 × 5 condition compared to the sham condition. No differences in pain tolerance were seen between the different numbers of cycles (all P > 0.05). There was also no difference in the perception of pain 30 s into the cold pressor test (P = 0.279). Remote IPC appears to significantly improve tolerance to pain which may have significant implications for endurance performance and exercise rehabilitation, but this warrants further investigation. [ABSTRACT FROM AUTHOR]

Interferential current (IFC) is a non-pharmacological therapy often used to reduce pain intensity. However, there is no scientific evidence of the biological effects of the adjustment of IFC intensity of stimulation. To investigate whether the adjustment of IFC intensity influences pain on cutaneous sensory threshold (CST), pressure pain threshold (PPT) and pain intensity in healthy subjects under mechanically induced pain. This is a placebo-controlled randomized trial. One hundred and two healthy university students blinded to intervention were randomized using opaque sealed envelopes to the following groups: 1) sensory IFC (n = 24); 2) fixed motor IFC (n = 26); 3) adjusted motor IFC (n = 27); and 4) placebo IFC (n = 25). After 40 minutes of stimulation or placebo, subjects were evaluated by an investigator blinded to group allocation. CST (von Frey filaments), PPT (algometry), and pain intensity (11-point numerical scale) were measured. Adjusted motor IFC promoted a significant reduction of CST (hand: mean difference (MD) = 2.39, confidence intervals (CI) = 1.39–3.38; and forearm: MD = 3.01, CI = 2.87–3.14) compared to placebo. Adjusted motor IFC increased PPT significantly (hand: MD = 27.59, CI = 26.80–28.37; and forearm: MD = 34, CI = 25.74–42.25) when compared to placebo. Adjusted motor IFC reduced pain intensity by 4.01 points (CI = 3.64–4.55) when compared to placebo. No adverse events were observed. Adjusted motor IFC intensity increased PPT and CST and also reduced pain intensity in healthy subjects under mechanically induced pain. [ABSTRACT FROM AUTHOR]

"Nonspecific shoulder pain" encompasses various non-traumatic musculoskeletal shoulder disorders, diverging from diagnostic terminologies that refer to precise tissue-oriented clinical diagnosis. Blood flow restriction (BFR) training, involving partial arterial inflow and complete venous outflow restriction, has exhibited acute hypoalgesic effects primarily in healthy populations by increasing their pain thresholds. This study aims to examine whether a single BFR session with low-load exercises can alleviate pain perception among nonspecific shoulder pain patients. Conducted as a single-blind crossover randomised clinical trial, 48 adults (age range: 18 to 40) presenting with nonspecific shoulder pain will partake in two trial sessions. Random assignment will place participants into BFR or sham BFR groups and ask them to perform one exercise with BFR. Subsequently, participants will complete a shoulder girdle loading regimen comprising six exercises. The second session will involve participants switching treatment groups. Pain pressure thresholds (PPTs), shoulder pain and disability via the shoulder pain and disability index (SPADI), maximal voluntary isometric contraction (MVIC) of shoulder external rotators, pain during active abduction, and peak pain during shoulder external rotation will be evaluated using the numeric pain rating scale (NPRS). Immediate post-exercise assessments will include patient-perceived pain changes using the global rating of change scale (GROC) and participant-rated perceived exertion (RPE), employing a modified Borg's scale (Borg CR10) post-BFR or sham BFR exercise session. Each session will encompass three assessment periods, and a combination of mixed-effect models and descriptive statistics will underpin the analysis. This protocol was approved by Cyprus National Bioethics Committee (ΕΕΒΚ/2023/48), and was registered in ClinicalTrials.gov (Registration number: NCT05956288). Conclusion: The anticipated outcomes of this study illuminated the acute effects of BFR training on pain perception within the context of nonspecific shoulder pain, potentially advancing strategies for managing pain intensity using BFR techniques. [ABSTRACT FROM AUTHOR]

IntroductionThe hypoalgesic effect of music has long been established. However, the characteristics of music which are important for reducing pain have not been well-studied. Some research has compared subject-selected preferred music to unfamiliar music selected by researchers, and has typically found a superior effect from preferred music. In this study, we sought to discover what aspects of listeners' relationship with their preferred music was important in producing a hypoalgesic effect.MethodsWe conducted a thermal pain and music listening experiment with 63 participants (14 male, 49 female, mean age = 21.3), in which music excerpts were paired with thermal stimulations. Pain ratings of intensity and unpleasantness, as well as emotional response variables, were rated on visual analog scales. We also conducted brief structured interviews about participants' favorite music, on which we conducted thematic content analysis. Themes and emotion variables were analyzed for their effects on pain ratings.ResultsWe first replicated the finding that favorite music outperforms experimenter-selected relaxing music in reducing pain unpleasantness (MD = −7.25, p

Background and aim: Current strategies for preventing diabetic sensorimotor polyneuropathy (DSPN) are limited mainly to glucose control but rapid decrease of glycemia can lead to acute onset or worsening of DSPN. The aim of this study was to examine the effects of periodic fasting on somatosensory nerve function in patients with type 2 diabetes (T2D). Study design and methods: Somatosensory nerve function was assessed in thirty-one patients with T2D (HbA1c 7.8 ± 1.3% [61.4 ± 14.3 mmol/mol]) before and after a six-month fasting-mimicking diet (FMD; n=14) or a control Mediterranean diet (M-diet; n=17). Neuropathy disability score (NDS), neuropathy symptoms score (NSS), nerve conduction velocity and quantitative sensory testing (QST) were analyzed. 6 participants of the M-Diet group and 7 of the FMD group underwent diffusion-weighted high-resolution magnetic resonance neurography (MRN) of the right leg before and after the diet intervention. Results: Clinical neuropathy scores did not differ between study groups at baseline (64% in the M-Diet group and 47% in the FMD group had DSPN) and no change was found after intervention. The differences in sensory NCV and sensory nerve action potential (SNAP) of sural nerve were comparable between study groups. Motor NCV of tibial nerve decreased by 12% in the M-Diet group (P=0.04), but did not change in the FMD group (P=0.39). Compound motor action potential (CMAP) of tibial nerve did not change in M-Diet group (P=0.8) and increased in the FMD group by 18% (P=0.02). Motor NCV and CMAP of peroneal nerve remained unchanged in both groups. In QST M-diet-group showed a decrease by 45% in heat pain threshold (P=0.02), FMD group showed no change (P=0.50). Changes in thermal detection, mechanical detection and mechanical pain did not differ between groups. MRN analysis showed stable fascicular nerve lesions irrespective of the degree of structural pathology. Fractional anisotropy and T2-time did not change in both study groups, while a correlation with the clinical degree of DSPN could be confirmed for both. Conclusions: Our study shows that six-month periodic fasting was safe in preserving nerve function and had no detrimental effects on somatosensory nerve function in T2D patients [ABSTRACT FROM AUTHOR]

Objective Spinal manual therapy (SMT) is often used to treat patients with spinal disorders; however, the underlying mechanisms of SMT are not fully understood. This systematic review and meta-analysis investigates the effect of SMT compared with sham treatment or no intervention on local or remote (segmental or non-segmental) pressure pain thresholds (PPTs) in patients with chronic musculoskeletal conditions and people who are pain free. Methods A systematic search was conducted in the PubMed, Cochrane Library, Web of Science, and CINAHL databases. Randomized controlled trials investigating the effect of SMT on PPTs in patients with chronic musculoskeletal conditions and in people who were pain free were included. Quality assessment and evidence synthesis were performed according to Cochrane Handbook recommendations. A meta-analysis was performed using standardized mean difference and 95% CIs. Results Twenty-two reports were included in the present review. There were no significant results for an immediate effect of SMT on local (low certainty of evidence), remote (segmental) (low certainty of evidence), and remote (non-segmental) (low certainty of evidence) PPTs in patients with chronic pain as well as on local (moderate certainty of evidence) and remote (segmental) (low certainty of evidence) PPTs in people who were pain free. A small but significant effect (standardized mean difference = 0.26; 95% CI = 0.01 to 0.51; low certainty of evidence) was observed on remote (non-segmental) PPTs in people who were pain free, which was not considered a meaningful effect size. Conclusion No immediate, consistent, or meaningful hypoalgetic effect of SMT was shown on PPTs on various body areas. Involvement of spinal or supraspinal underlying mechanisms were, therefore, not confirmed via PPTs but should still be investigated using methods designed to assess central nervous pain processing. Impact No consistent and meaningful hypoalgesic effects of spinal manual therapy were demonstrated on PPTs in participants who were pain free and in patients with chronic musculoskeletal disorders. [ABSTRACT FROM AUTHOR]

Low-intensity exercise with blood flow restriction (LIE-BFR) has been proposed as an effective intervention to induce hypoalgesia in both healthy individuals and patients with knee pain. Nevertheless, there is no systematic review reporting the effect of this method on pain threshold. We aimed to evaluate the following: (i) the effect of LIE-BFR on pain threshold compared to other interventions in patients or healthy individuals; and (ii) how different types of applications may influence hypoalgesic response. We included randomized controlled trials assessing the effectiveness of LIE-BFR alone or as an additive intervention compared with controls or other interventions. Pain threshold was the outcome measure. Methodological quality was assessed using the PEDro score. Six studies with 189 healthy adults were included. Five studies were rated with 'moderate' and 'high' methodological quality. Due to substantial clinical heterogeneity, quantitative synthesis could not be performed. All studies used pressure pain thresholds (PPTs) to assess pain sensitivity. LIE-BFR resulted in significant increases in PPTs compared to conventional exercise at local and remote sites 5 min post-intervention. Higher-pressure BFR results in greater exercise-induced hypoalgesia compared to lower pressure, while exercise to failure produces a similar reduction in pain sensitivity with or without BFR. Based on our findings, LIE-BFR can be an effective intervention to increase pain threshold; however, the effect depends on the exercise methodology. Further research is necessary to investigate the effectiveness of this method in reducing pain sensitivity in patients with pain symptomatology. [ABSTRACT FROM AUTHOR]

Background and aimCurrent strategies for preventing diabetic sensorimotor polyneuropathy (DSPN) are limited mainly to glucose control but rapid decrease of glycemia can lead to acute onset or worsening of DSPN. The aim of this study was to examine the effects of periodic fasting on somatosensory nerve function in patients with type 2 diabetes (T2D).Study design and methodsSomatosensory nerve function was assessed in thirty-one patients with T2D (HbA1c 7.8 ± 1.3% [61.4 ± 14.3 mmol/mol]) before and after a six-month fasting-mimicking diet (FMD; n=14) or a control Mediterranean diet (M-diet; n=17). Neuropathy disability score (NDS), neuropathy symptoms score (NSS), nerve conduction velocity and quantitative sensory testing (QST) were analyzed. 6 participants of the M-Diet group and 7 of the FMD group underwent diffusion-weighted high-resolution magnetic resonance neurography (MRN) of the right leg before and after the diet intervention.ResultsClinical neuropathy scores did not differ between study groups at baseline (64% in the M-Diet group and 47% in the FMD group had DSPN) and no change was found after intervention. The differences in sensory NCV and sensory nerve action potential (SNAP) of sural nerve were comparable between study groups. Motor NCV of tibial nerve decreased by 12% in the M-Diet group (P=0.04), but did not change in the FMD group (P=0.39). Compound motor action potential (CMAP) of tibial nerve did not change in M-Diet group (P=0.8) and increased in the FMD group by 18% (P=0.02). Motor NCV and CMAP of peroneal nerve remained unchanged in both groups. In QST M-diet-group showed a decrease by 45% in heat pain threshold (P=0.02), FMD group showed no change (P=0.50). Changes in thermal detection, mechanical detection and mechanical pain did not differ between groups. MRN analysis showed stable fascicular nerve lesions irrespective of the degree of structural pathology. Fractional anisotropy and T2-time did not change in both study groups, while a correlation with the clinical degree of DSPN could be confirmed for both.ConclusionsOur study shows that six-month periodic fasting was safe in preserving nerve function and had no detrimental effects on somatosensory nerve function in T2D patients.Clinical trial registrationhttps://drks.de/search/en/trial/DRKS00014287, identifier DRKS00014287.

Objective: The objective of this blinded parallel-arm randomized controlled trial was to investigate the effect of resistance training (RT) on pain, maximal strength, and shoulder function in breast cancer survivors (BCS) with persistent pain after treatment. Methods: Twenty BCS with self-reported pain ≥1.5 yr after treatment were randomized to an experimental group (EXP, n = 10), who performed a supervised progressive total body heavy RT program 2 times per week for 12 wk, or a control group (CON, n = 10), who was instructed to continue their everyday life. Perceived pain intensity, pressure pain threshold (PPT) levels, one-repetition maximum (1RM), and active range of motion were collected pre- and postintervention and at 3 months follow-up. Results: There was a significant 11% decrease in peak pain intensity (P < 0.05) for both groups, a significant 48% increase in 1RM (P < 0.05), and a significant 35% increase in PPT levels (P < 0.001) for EXP, but not for CON. For EXP, maximal strength at follow-up was still significantly greater than at preintervention (P < 0.05), whereas PPT levels had reverted to baseline levels. There was no change in active range of motion (P < 0.05) and no change in arm circumference (P < 0.05). Conclusions: RT had a significant effect on 1RM and PPT of BCS with persistent pain after treatment, demonstrating both a functional and analgesic effect of progressive RT in this population. Strength was largely maintained after detraining, whereas PPT levels were not, indicating that the process of RT rather than the gain in strength may be associated with analgesia. [ABSTRACT FROM AUTHOR]

In humans, exposure to electromagnetic millimeter waves (MMW) has a hypoalgesic effect. In animals, this effect has been shown to depend on innervation density of the area exposed. This study aims to assess hypoalgesic and parasympathetic effects of MMW applied on the palmar side of the wrist in healthy participants. In a within-subject design, 10 healthy participants had the palmar side of their wrist exposed to MMW (61.25 GHz, 17 mW/cm2) for 30 minutes, 1 h, & 1 h30, and 30 minutes of sham exposure. Experimental pain was induced after the exposure sessions with the Cold Pressor Test, and pain threshold and pain tolerance values were compared to that of the sham condition. Participants' heart rate and blood pressure were measured before and after exposures. Finally, innocuity of the exposure system was controlled with a pre-post exposure visual examination scale and skin temperature measured by a thermal camera. Exposure to 30 minutes, but not 1 h or 1 h30, of MMW led to significant increases in pain thresholds compared to the sham condition, but no increase of pain tolerance. All conditions led to decreased heart rate, while no change in blood pressure was observed. No change in skin state or temperature was observed for any of the conditions. MMW applied on the inner part of the wrist diminish pain sensations more effectively than placebo, and seem to increase parasympathetic activities, while remaining innocuous. Building a miniaturized MMW emission system to be worn on the wrist would provide access to ambulatory MMW therapy for pain management. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the exercise‐induced hypoalgesic (EIH) effects of different types of physical exercise in individuals with neck pain. Design: Systematic review with meta‐analysis. Literature Search: An electronic search of six databases was completed to include studies assessing EIH effects on neck pain. Study Selection Criteria: Randomized controlled trials, controlled trials, and observational studies that assessed before and immediate after‐effects of a single session of physical exercise in people with neck pain were included. Two reviewers independently screened records, extracted outcomes, assessed the risk of bias, and rated the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Data synthesis: EIH is characterized by increased pain threshold, pain tolerance, and/or decreased sensitivity to painful stimuli or unpleasantness, which may last up to 30 min after a single bout of exercise. EIH is usually measured with quantitative sensory testing (QST) and is mostly taken as the difference between pre‐ and postexercise pressure pain threshold (PPT). Data were pooled and analyzed using a fixed‐effect meta‐analysis. Results: Eleven articles were included in this review; nine with low risk of bias and two with some concerns about the risk of bias. Three studies with chronic whiplash‐associated disorders (WAD) were included in the meta‐analysis; isometric exercise had a larger EIH effect at the local testing site compared with submaximal aerobic exercises (MD = −0.21, [95% CI = −0.43, 0.00], p = 0.05, I2 = 92%), submaximal aerobic and isometric exercises had equal EIH effects at the remote testing site (MD = 0.01, [95% CI = −0.33, 0.35], p = 0.95, I2 = 0%), and submaximal aerobic exercises exerted comparably larger EIH effect at the remote testing site than local testing site (MD = −0.01, [95% CI = −0.20, 0.18], p = 0.93, I2 = 56%). The certainty of evidence (GRADE) for these analyses was low to very low. According to the descriptive analysis of the studies of chronic nonspecific neck pain, isometric and range of motion (ROM) exercises have shown EIH effects. Active stretching exercises have illustrated contradictory effects. Conclusion: Isometric and ROM exercises exerted hypoalgesia at local and remote sites. A larger EIH effect following submaximal aerobic exercises was exerted at the remote testing site compared with the local site. [ABSTRACT FROM AUTHOR]

“Nonspecific shoulder pain” encompasses various non-traumatic musculoskeletal shoulder disorders, diverging from diagnostic terminologies that refer to precise tissue-oriented clinical diagnosis. Blood flow restriction (BFR) training, involving partial arterial inflow and complete venous outflow restriction, has exhibited acute hypoalgesic effects primarily in healthy populations by increasing their pain thresholds. This study aims to examine whether a single BFR session with low-load exercises can alleviate pain perception among nonspecific shoulder pain patients. Conducted as a single-blind crossover randomised clinical trial, 48 adults (age range: 18 to 40) presenting with nonspecific shoulder pain will partake in two trial sessions. Random assignment will place participants into BFR or sham BFR groups and ask them to perform one exercise with BFR. Subsequently, participants will complete a shoulder girdle loading regimen comprising six exercises. The second session will involve participants switching treatment groups. Pain pressure thresholds (PPTs), shoulder pain and disability via the shoulder pain and disability index (SPADI), maximal voluntary isometric contraction (MVIC) of shoulder external rotators, pain during active abduction, and peak pain during shoulder external rotation will be evaluated using the numeric pain rating scale (NPRS). Immediate post-exercise assessments will include patient-perceived pain changes using the global rating of change scale (GROC) and participant-rated perceived exertion (RPE), employing a modified Borg’s scale (Borg CR10) post-BFR or sham BFR exercise session. Each session will encompass three assessment periods, and a combination of mixed-effect models and descriptive statistics will underpin the analysis. This protocol was approved by Cyprus National Bioethics Committee (ΕΕΒΚ/2023/48), and was registered in ClinicalTrials.gov (Registration number: NCT05956288). Conclusion: The anticipated outcomes of this study illuminated the acute effects of BFR training on pain perception within the context of nonspecific shoulder pain, potentially advancing strategies for managing pain intensity using BFR techniques.

Low-intensity exercise with blood flow restriction (LIE-BFR) has been proposed as an effective intervention to induce hypoalgesia in both healthy individuals and patients with knee pain. Nevertheless, there is no systematic review reporting the effect of this method on pain threshold. We aimed to evaluate the following: (i) the effect of LIE-BFR on pain threshold compared to other interventions in patients or healthy individuals; and (ii) how different types of applications may influence hypoalgesic response. We included randomized controlled trials assessing the effectiveness of LIE-BFR alone or as an additive intervention compared with controls or other interventions. Pain threshold was the outcome measure. Methodological quality was assessed using the PEDro score. Six studies with 189 healthy adults were included. Five studies were rated with ‘moderate’ and ‘high’ methodological quality. Due to substantial clinical heterogeneity, quantitative synthesis could not be performed. All studies used pressure pain thresholds (PPTs) to assess pain sensitivity. LIE-BFR resulted in significant increases in PPTs compared to conventional exercise at local and remote sites 5 min post-intervention. Higher-pressure BFR results in greater exercise-induced hypoalgesia compared to lower pressure, while exercise to failure produces a similar reduction in pain sensitivity with or without BFR. Based on our findings, LIE-BFR can be an effective intervention to increase pain threshold; however, the effect depends on the exercise methodology. Further research is necessary to investigate the effectiveness of this method in reducing pain sensitivity in patients with pain symptomatology.

Peripheral neuropathy is a frequent complication of chronic diabetes that most commonly presents as a distal degenerative polyneuropathy with sensory loss. Around 20% to 30% of such patients may also experience neuropathic pain. The underlying pathogenic mechanisms are uncertain, and therapeutic options are limited. Rodent models of diabetes have been used for more than 40 years to study neuropathy and evaluate potential therapies. For much of this period, streptozotocin-diabetic rats were the model of choice. The emergence of new technologies that allow relatively cheap and routine manipulations of the mouse genome has prompted increased use of mouse models of diabetes to study neuropathy. In this article, we describe the commonly used mouse models of type 1 and type 2 diabetes, and provide protocols to phenotype the structural, functional, and behavioral indices of peripheral neuropathy, with a particular emphasis on assays pertinent to the human condition. © 2016 by John Wiley & Sons, Inc.

Objective: In this proof-of-concept study we sought to explore whether the combination of conditioning procedure based on a surreptitious reduction of a noxious stimulus (SRPS) could enhance rTMS hypoalgesic effects [i.e., increase heat pain threshold (HPT)] and augment intervention expectations in a healthy population. Methods: Forty-two healthy volunteers (19–35 years old) were enrolled in a randomized crossover-controlled study and were assigned to one of two groups: (1) SRPS and (2) No SRPS. Each participant received two consecutive sessions of active or sham rTMS over the M1 area of the right hand on two visits (1) active, (2) sham rTMS separated by at least one-week interval. HPT and the temperature needed to elicit moderate heat pain were measured before and after each rTMS intervention on the right forearm. In the SRPS group, conditioning consisted of deliberately decreasing thermode temperature by 3°C following intervention before reassessing HPT, while thermode temperature was held constant in the No SRPS group. Intervention expectations were measured before each rTMS session. Results: SRPS conditioning procedure did not enhance hypoalgesic effects of rTMS intervention, neither did it modify intervention expectations. Baseline increases in HPT were found on the subsequent intervention session, suggesting variability of this measure over time, habituation or a possible "novelty effect." Conclusion: Using a SRPS procedure in healthy volunteers did not enhance rTMS modulating effects on experimental pain sensation (i.e., HPT). Future studies are therefore needed to come up with a conditioning procedure which allows significant enhancement of rTMS pain modulating effects in healthy volunteers. [ABSTRACT FROM AUTHOR]

Pain is the most common reason for a physician visit, which accounts for a considerable proportion of the global burden of disease and greatly affects patients' quality of life. Therefore, there is an urgent need to identify new therapeutic targets involved in pain. Exercise-induced hypoalgesia (EIH) is a well known phenomenon observed worldwide. However, the available evidence demonstrates that the mechanisms of EIH remain unclear. One of the most accepted hypotheses has been the activation of several endogenous systems in the brain. Recently, the concept that the muscle acts as a secretory organ has attracted increasing attention. Proteins secreted by the muscle are called myokines, playing a critical role in communicating with other organs, such as the brain. This review will focus on several myokines and discuss their roles in EIH. [ABSTRACT FROM AUTHOR]

This study examined the effect of aerobic exercise with and without blood flow restriction (BFR) on exercise-induced hypoalgesia and endogenous opioid and endocannabinoid systems. In a randomized crossover design, pain-free individuals performed 20 min of cycling in four experimental trials: 1) low-intensity aerobic exercise (LI-AE) at 40% V_O2max; 2) LI-AE with low-pressure BFR (BFR40); 3) LI-AE with high-pressure BFR (BFR80); and 4) high-intensity aerobic exercise (HI-AE) at 70% V_O2max. Pressure pain thresholds (PPTs) were assessed before and 5 min postexercise. Circulating concentrations of beta-endorphin and 2-arachidonoylglycerol were assessed before and 10 min postexercise. In the exercising legs, postexercise PPTs were increased following BFR40 and BFR80 compared with LI-AE (23-32% vs. 1-2% increase, respectively). The increase in PPTs was comparable to HIAE (17-20% increase) with BFR40 and greater with BFR80 (30-32% increase). Both BFR80 and HI-AE increased PPTs in remote areas of the body (increase of 26-28% vs. 19-21%, respectively). Postexercise circulating beta-endorphin concentration was increased following BFR40 (11%) and HI-AE (14%), with the greatest change observed following BFR80 (29%). Postexercise circulating 2-arachidonoylglycerol concentration was increased following BFR40 (22%) and BFR80 (20%), with the greatest change observed following HI-AE (57%). Addition of BFR to LI-AE can trigger both local and systemic hypoalgesia that is not observed follow LI-AE alone and activate endogenous opioid and endocannabinoid systems of pain inhibition. Compared with HI-AE, local and systemic hypoalgesia following LI-AE with high-pressure BFR is greater and comparable, respectively. LI-AE with BFR may help pain management in load-compromised individuals. NEW & NOTEWORTHY We have shown that performing blood flow restriction (BFR) during low-intensity aerobic exercise can trigger local and systemic hypoalgesia, which is not typically observed with this intensity of exercise. High-pressure BFR triggers greater and comparable hypoalgesia than high-intensity aerobic exercise in the exercising limbs and remote areas of the body, respectively. Performing BFR during low-intensity aerobic exercise activates the opioid and endocannabinoid systems, providing novel insight into potential mechanisms of hypoalgesia with BFR exercise. [ABSTRACT FROM AUTHOR]

In this study, electroencephalography (EEG) was utilized to explore the neurophysiological mechanisms of aerobic exercise-induced hypoalgesia (EIH) and provide a theoretical basis for the application of aerobic exercise in pain assessment and treatment. Forty-five healthy subjects were randomly divided into moderate-intensity aerobic exercise [70% heart rate reserve (HRR)], low-intensity aerobic exercise (50% HRR), or control groups (sitting). Aerobic exercise was performed with cycling. Pressure pain threshold (PPT), heat pain threshold (HPT), event-related potential (ERP) induced by contact heat stimulus and pain scoring were measured before and after the intervention. We found that moderate-intensity aerobic exercise can increase the PPT (rectus femoris: t = −2.71, p = 0.017; tibialis anterior muscle: t = −2.36, p = 0.033) and HPT (tibialis anterior muscle: t = −2.219, p = 0.044) of proximal intervention sites rather than distal sites, and decreased pain scorings of contact heat stimulus. After moderate-intensity aerobic exercise, alpha oscillation power reflecting the central descending inhibitory function was enhanced (t = −2.31, p < 0.05). Low-intensity aerobic exercise mainly reduced the pain unpleasantness rating (Block 1: t = 2.415, p = 0.030; Block 2: t = 3.287, p = 0.005; Block 4: t = 2.646, p = 0.019; Block 5: t = 2.567, p = 0.022). Aerobic exercise had an overall EIH effect. Its hypoalgesic effect was related to exercise intensity and affected by the site and type of pain stimulus. Moderate-intensity aerobic exercise effectively reduced the sensitivity to various painful stimuli, and low-intensity aerobic exercise selectively inhibited the negative emotional pain response. The hypoalgesic mechanism of aerobic exercise involves the enhancement of the central descending inhibitory function. [ABSTRACT FROM AUTHOR]

In this study, electroencephalography (EEG) was utilized to explore the neurophysiological mechanisms of aerobic exercise-induced hypoalgesia (EIH) and provide a theoretical basis for the application of aerobic exercise in pain assessment and treatment. Forty-five healthy subjects were randomly divided into moderate-intensity aerobic exercise [70% heart rate reserve (HRR)], low-intensity aerobic exercise (50% HRR), or control groups (sitting). Aerobic exercise was performed with cycling. Pressure pain threshold (PPT), heat pain threshold (HPT), event-related potential (ERP) induced by contact heat stimulus and pain scoring were measured before and after the intervention. We found that moderate-intensity aerobic exercise can increase the PPT (rectus femoris: t = −2.71, p = 0.017; tibialis anterior muscle: t = −2.36, p = 0.033) and HPT (tibialis anterior muscle: t = −2.219, p = 0.044) of proximal intervention sites rather than distal sites, and decreased pain scorings of contact heat stimulus. After moderate-intensity aerobic exercise, alpha oscillation power reflecting the central descending inhibitory function was enhanced (t = −2.31, p < 0.05). Low-intensity aerobic exercise mainly reduced the pain unpleasantness rating (Block 1: t = 2.415, p = 0.030; Block 2: t = 3.287, p = 0.005; Block 4: t = 2.646, p = 0.019; Block 5: t = 2.567, p = 0.022). Aerobic exercise had an overall EIH effect. Its hypoalgesic effect was related to exercise intensity and affected by the site and type of pain stimulus. Moderate-intensity aerobic exercise effectively reduced the sensitivity to various painful stimuli, and low-intensity aerobic exercise selectively inhibited the negative emotional pain response. The hypoalgesic mechanism of aerobic exercise involves the enhancement of the central descending inhibitory function.

BackgroundSomatosensory impairments and pain are common symptoms following stroke. However, the condition of perception and pain threshold for pressure stimuli and the factors that can influence this in individuals with stroke are still unclear. This study aimed to investigate the gender differences in pressure pain threshold (PPT) and positive somatosensory signs for pressure stimuli, and explore the effects of joint pain, motor function, and activities of daily living (ADL) on pain threshold in post-stroke patients.DesignA cross-sectional study.MethodsA total of 60 participants with stroke were recruited, and their pain condition, motor functions, and ADL were evaluated by the Fugl-Meyer assessment of joint pain scale, motor function scale, and Barthel index, respectively. PPTs in eight tested points at the affected and unaffected sides were assessed.ResultsSignificant differences in PPTs were found between male and female patients in all measured muscles (p < 0.05). Positive somatosensory signs for pressure stimuli, including hypoalgesia and hyperalgesia, were frequently found at the affected side, particularly in the extremity muscles, but such signs were not significantly influenced by gender (p > 0.05). More equal PPTs between both sides and relatively lower PPTs at the affected side in the trunk and medial gastrocnemius muscles (p < 0.05) were observed in patients with less pain, better motor functions, and ADL.ConclusionGender differences widely exist in post-stroke survivors either at the affected or unaffected side, which are multifactorial. Sensory loss and central and/or peripheral sensitization, such as hypoalgesia and hyperalgesia for pressure stimuli, caused by a brain lesion are common signs in male and female stroke patients. Moreover, patients who are in a better condition show a more symmetrical pain sensitivity between both sides in the trunk and in female lower extremities, indicating the bidirectional improvement of somatosensory abnormalities caused by a possible neural plasticity.

Pain is essential for our survival because it helps to protect us from severe injuries. Nociceptive signals may be exacerbated by continued physical activities but can also be interrupted or overridden by physical movements, a process called movement‐induced hypoalgesia. Several neural mechanisms have been proposed to account for this effect, including the reafference principle, non‐nociceptive interference, and top‐down descending modulation. Given that the hypoalgesic effects of these mechanisms temporally overlap during movement execution, it is unclear whether movement‐induced hypoalgesia results from a single neural mechanism or from the joint action of multiple neural mechanisms. To address this question, we conducted five experiments on 129 healthy humans by assessing the hypoalgesic effect after movement execution. Combining psychophysics and electroencephalographic recordings, we quantified the relationship between the strength of voluntary movement and the hypoalgesic effect, as well as the temporal and spatial characteristics of the hypoalgesic effect. Our findings demonstrated that movement‐induced hypoalgesia results from the joint action of multiple neural mechanisms. This investigation is the first to disentangle the distinct contributions of different neural mechanisms to the hypoalgesic effect of voluntary movement, which extends our understanding of sensory attenuation arising from voluntary movement and may prove instrumental in developing new strategies for pain management. [ABSTRACT FROM AUTHOR]

Background: Somatosensory impairments and pain are common symptoms following stroke. However, the condition of perception and pain threshold for pressure stimuli and the factors that can influence this in individuals with stroke are still unclear. This study aimed to investigate the gender differences in pressure pain threshold (PPT) and positive somatosensory signs for pressure stimuli, and explore the effects of joint pain, motor function, and activities of daily living (ADL) on pain threshold in post-stroke patients. Design: A cross-sectional study. Methods: A total of 60 participants with stroke were recruited, and their pain condition, motor functions, and ADL were evaluated by the Fugl-Meyer assessment of joint pain scale, motor function scale, and Barthel index, respectively. PPTs in eight tested points at the affected and unaffected sides were assessed. Results: Significant differences in PPTs were found between male and female patients in all measured muscles (p < 0.05). Positive somatosensory signs for pressure stimuli, including hypoalgesia and hyperalgesia, were frequently found at the affected side, particularly in the extremity muscles, but such signs were not significantly influenced by gender (p > 0.05). More equal PPTs between both sides and relatively lower PPTs at the affected side in the trunk and medial gastrocnemius muscles (p < 0.05) were observed in patients with less pain, better motor functions, and ADL. Conclusion: Gender differences widely exist in post-stroke survivors either at the affected or unaffected side, which are multifactorial. Sensory loss and central and/or peripheral sensitization, such as hypoalgesia and hyperalgesia for pressure stimuli, caused by a brain lesion are common signs in male and female stroke patients. Moreover, patients who are in a better condition show a more symmetrical pain sensitivity between both sides in the trunk and in female lower extremities, indicating the bidirectional improvement of somatosensory abnormalities caused by a possible neural plasticity. [ABSTRACT FROM AUTHOR]

To review past literature regarding exercise-induced hypoalgesia and pain reduction following blood flow restriction interventions, and to discuss potential mechanisms as well as future considerations towards the efficacy of blood flow restriction in pain reduction following exercise. To be eligible for inclusion, studies had to include acute exercise, or long-term training interventions, with blood flow restriction, along with including pre and post intervention pain measurements. A total of 13 studies met the inclusion criteria. Among these 13 studies, 3 studies examined exercise-induced hypoalgesia after an acute bout of resistance exercise with blood flow restriction, and 10 studies investigated pain reduction following long-term blood flow restriction training. Existing literature suggests that low load resistance exercise with blood flow restriction may serve as an effective pain management method for those who are unable or unwilling to train with high loads. Several potential mechanisms have been suggested, however, the roles of these mechanisms are still unclear and require further clarification. Future research should consider implementing different methods of blood flow restriction application, and research study design to clarify the utility and efficacy of blood flow restriction as a pain management tool, by itself or in combination with exercise. • Low load exercise in combination with blood flow restriction can reduce pain following a single bout of exercise. • Repeated application of blood flow restricted exercise can reduce pain in those rehabilitating from injury. • Low load blood flow restricted exercise may serve as a viable method for those who are unable to train with higher loads. [ABSTRACT FROM AUTHOR]

Methylmercury (MeHg), the causal substrate in Minamata disease, can lead to severe and chronic neurological disorders. The main symptom of Minamata disease is sensory impairment in the four extremities; however, the sensitivity of individual sensory modalities to MeHg has not been investigated extensively. In the present study, we performed stimulus-response behavioral experiments in MeHg-exposed rats to compare the sensitivities to pain, heat, cold, and mechanical sensations. MeHg (6.7 mg/kg/day) was orally administered to 9-week-old Wistar rats for 5 days and discontinued for 2 days, then administered daily for another 5 days. The four behavioral experiments were performed daily on each rat from the beginning of MeHg treatment for 68 days. The pain sensation decreased significantly from day 11 onwards, but recovered to control levels on day 48. Other sensory modalities were not affected by MeHg exposure. These findings suggest that the pain sensation is the sensory modality most susceptive to MeHg toxicity and that this sensitivity is reversible following discontinuation of the exposure. [ABSTRACT FROM AUTHOR]

• Participants rinsed with capsaicin ∼28 times over 2 weeks. • Capsaicin burn was reduced in the treatment group. • No changes were observed for sucrose, menthol, or SOA. • Papillae biopsies were performed. • TRPV1 expression did not predict changes in burn. Responses to capsaicin are reduced following repeated exposure, a phenomenon known as capsaicin desensitization. Heavy consumers of chilies consistently report reduced oral burn relative to infrequent consumers, presumably due to chronic desensitization. However, the mechanism(s) underlying capsaicin desensitization remain poorly understood. We hypothesized that reduced response to capsaicin due to repeated oral exposure may result from a change in the expression of the capsaicin receptor (TRPV1) gene. To test this, we conducted two longitudinal desensitization studies in healthy human volunteers. In Study 1, 51 adults completed a 17-day capsaicin desensitization protocol. The study consisted of three in-person visits where they were asked to sample stimuli, including 3, 6, and 9 ppm capsaicin, and rate intensity on a general labeled magnitude scale (gLMS). Between days 3 & 17, participants rinsed at home with 6 ppm capsaicin (n = 31) or a control (n = 20) solution (20 uM sucrose octaccetate; SOA) twice a day. Before and after the oral exposure protocol, a clinician collected fungiform papillae. Participants randomized to the capsaicin rinse showed a statistically significant reduction in oral burn ratings that was not observed in controls, indicating repeated low-dose exposure can systematically induce desensitization. TRPV1 expression was not associated with reported capsaicin burn, and there was no evidence of a decrease in TRPV1 expression following capsaicin exposure. In Study 2, participants (n = 45) rinsed with 6 ppm capsaicin in a similar protocol, rating capsaicin, vanillyl butyl ether (VBE), cinnamaldehyde, ethanol, menthol, and sucrose on days 1, 3, & 17. Burn from capsaicin, VBE, cinnamaldehyde, and ethanol all showed a statistically significant change – capsaicin, VBE and cinnamaldehyde burn all dropped ∼20 %, and a larger reduction was seen for ethanol – while menthol cooling and sucrose sweetness did not change. Collectively, this suggests reductions in oral burn following chronic capsaicin exposure generalizes to other stimuli (i.e., cross desensitization) and this cannot be explained by a change in TRPV1 mRNA expression. More work is needed to elucidate the underlying mechanism for capsaicin desensitization in the oral cavity. [ABSTRACT FROM AUTHOR]

Abstract Background Few studies have investigated the effects of mobilization with movement (MWM) in patients with knee osteoarthritis (OA) compared to other procedures. Sham procedures are generally more appropriate control than using no or usual treatments. Moreover, studies investigating the widespread hypoalgesic effects of MWM in patients with knee OA are lacking. The aim was to investigate the effect of MWM on function and pain in patients with knee OA compared to sham MWM. Methods This is a randomized double-blind (patients and assessor) controlled trial. Forty adult patients with knee OA of grade II and above were recruited to receive either MWM treatment or sham MWM for the knee. The outcome measures included the following: a visual analogue scale (VAS) for pain, the pressure pain threshold (PPT) test, the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) Index, the timed up and go (TUG) test, knee strength and knee range of motion (ROM). The measurements were taken at baseline, immediately after intervention and 2 days later. Results Compared with sham MWM, MWM resulted in greater immediate improvement in pain [mean difference (95% CI): − 2.2 (− 2.8, − 1.6)], PPT at both the knee [176 (97, 254)] and shoulder [212 (136, 288)], TUG time [− 1.6 (− 2.1, − 1.1)], knee flexor strength [2.0 (1.3, 2.7)] and extensor strength [5.7 (4.1, 7.2)] and knee flexion ROM [12.8 (9.6, 15.9)] (all, p

Abstract Background Changes in blood pressure (BP) may affect pain. However, the interaction effect of resistance training and green tea on BP and pain has not been studied. The primary aim of this study was to evaluate the impact of resistance training and green tea extract (GTE) on pain variables in hypertensive patients. Secondary aim included determining the effects of BP alterations on pain responses. Methods In a randomized, double-blind, placebo-controlled study, 30 middle-aged sedentary women were randomly divided into resistance training and green tea extract (GR, n = 8), resistance training (R, n = 8), green tea (G, n = 7), and control groups (C, n = 7). The study period consisted of 3 weeks of GTE (~ 245 mg total polyphenols) consumption twice a day followed by 6 weeks of interaction with resistance training. GR and R groups performed two circuits of training with ten repetitions at 50% of 1RM 2 days a week while other two groups had no any regular exercise training. R and C groups also received placebo capsules (maltodextrin) with the same timing. Pain threshold and perception, BP, and heart rate were recorded following the first and last session of training at rest and 5th and 15th minute. Results Pain perception of training groups after the last session was significantly higher than control conditions, and at this time, the magnitude of BP responses was lower in training groups. In proportion to pain threshold, there were no significant differences between groups. Conclusion It seems that training-induced hypotension can alter pain perception in hypertensive women through changes in baroreceptor activation.

Abstract Background Manipulation-induced hypoalgesia (MIH) represents reduced pain sensitivity following joint manipulation, and has been documented in various populations. It is unknown, however, whether MIH following high-velocity low-amplitude spinal manipulative therapy is a specific and clinically relevant treatment effect. Methods This systematic critical review with meta-analysis investigated changes in quantitative sensory testing measures following high-velocity low-amplitude spinal manipulative therapy in musculoskeletal pain populations, in randomised controlled trials. Our objectives were to compare changes in quantitative sensory testing outcomes after spinal manipulative therapy vs. sham, control and active interventions, to estimate the magnitude of change over time, and to determine whether changes are systemic or not. Results Fifteen studies were included. Thirteen measured pressure pain threshold, and four of these were sham-controlled. Change in pressure pain threshold after spinal manipulative therapy compared to sham revealed no significant difference. Pressure pain threshold increased significantly over time after spinal manipulative therapy (0.32 kg/cm2, CI 0.22–0.42), which occurred systemically. There were too few studies comparing to other interventions or for other types of quantitative sensory testing to make robust conclusions about these. Conclusions We found that systemic MIH (for pressure pain threshold) does occur in musculoskeletal pain populations, though there was low quality evidence of no significant difference compared to sham manipulation. Future research should focus on the clinical relevance of MIH, and different types of quantitative sensory tests. Trial registration Prospectively registered with PROSPERO (registration CRD42016041963).

The aim of this review was to investigate if exercise induced hypoalgesia (EIH) occurs following isometric muscle contraction in people with local musculoskeletal symptoms. Systematic review. MEDLINE, EMBASE, CINAHL & SportDiscus electronic databases were searched (inception to April 2020). Two authors independently evaluated eligibility. Randomised controlled and crossover (repeated measures) trials that measured the effects of isometric exercise in participants with localised musculoskeletal pain during, and up to 2 hours after isometric exercise were included. Other inclusion criteria included comparison to another intervention, or comparison to healthy controls. Primary outcomes were experimentally induced pain thresholds and secondary outcomes included measures of pain sensitivity from clinical testing. 13 studies with data from 346 participants were included for narrative synthesis. EIH was reported in some upper and lower limb studies but there were no consistent data to show isometric exercises were superior to comparison interventions. There was no consistent evidence for EIH following isometric exercise in people with musculoskeletal pain. These findings are different to those reported in asymptomatic populations (where EIH is consistently demonstrated) as well as conditions associated with widespread symptoms such as fibromyalgia (where isometric exercise may induce hyperalgesia). Although well tolerated when prescribed, isometric exercise did not induce EIH consistently for people seeking care for local musculoskeletal symptoms. The variance in the dose, location of contraction and intensity of protocols included in this review may explain the inconsistent findings. Further work is required to better understand endogenous analgesia in musculoskeletal pain conditions. • This review found no consistence evidence for EIH following isometric exercise. • Isometric exercise cannot be prescribed with certainty to induce an EIH response in local musculoskeletal conditions. • Consistent reporting of isometric exercise parameters may be beneficial to guide future research. [ABSTRACT FROM AUTHOR]

The aim of this study was to examine the mechanisms underlying hypoalgesia induced by spinal manipulation (SM). Eighty-two healthy volunteers were assigned to one of the four intervention groups: no intervention, SM at T4 (homosegmental to pain), SM at T8 (heterosegmental to pain) or light mechanical stimulus at T4 (placebo). Eighty laser stimuli were applied on back skin at T4 to evoke pain and brain activity related to Aδ- and C-fibers activation. The intervention was performed after 40 stimuli. Laser pain was decreased by SM at T4 (p = 0.028) but not T8 (p = 0.13), compared with placebo. However, brain activity related to Aδ-fibers activation was not significantly modulated (all p > 0.05), while C-fiber activity could not be measured reliably. This indicates that SM produces segmental hypoalgesia through inhibition of nociceptive processes that are independent of Aδ fibers. It remains to be clarified whether the effect is mediated by the inhibition of C-fiber activity. [ABSTRACT FROM AUTHOR]

Ryousuke Nakajima,1 Airi Uehara,1 Shiori Takehana,1 Youichi Akama,2 Yoshihito Shimazu,1 Mamoru Takeda1 1Laboratory of Food and Physiological Sciences, Department of Life and Food Sciences, School of Life and Environmental Sciences, Azabu University, Chuo-ku, Sagamihara, Kanagawa 252-5201, Japan; 2Department of Emergency, Minami Touhoku Hospital, Iwanuma, Miyagi 989-2483, Japan Background: Acute application of decanoic acid (DA) in vivo suppresses the excitability of spinal trigeminal nucleus caudalis (SpVc) wide dynamic range (WDR) neurons associated with the short-term mechanical hypoalgesia via muscarinic M2 receptor signaling; however, the effect of DA on nociceptive trigeminal ganglion (TG) and SpVc nociceptive-specific (NS) neuronal excitability under in vivo conditions remains to be determined. The present study investigated whether this effect could be observed in naive rats. Results: Extracellular single-unit recordings were made from TG and SpVc NS neurons of pentobarbital-anesthetized rats in response to orofacial noxious mechanical stimuli. DA inhibited the mean firing frequency of both TG and SpVc NS neurons, reaching a maximum inhibition of discharge frequency within 1–5 minutes and reversing after approximately 10-minutes; however, this DA-induced suppression of SpVc NS neuronal firing frequency did not occur in rats administered with methoctramine intravenously prior to stimulation. Conclusion: This in vivo study indicated that firing of TG and SpVc NS neurons induced by mechanical hypoalgesia through peripheral M2 receptors could be inhibited by acutely administered DA, implicating the potential of DA in the future treatment of trigeminal pain. Perspective: This article presents that the acute DA application suppresses the excitability of TG and SpVc NS neurons associated with mechanical hypoalgesia via peripheral M2 receptor signaling, supporting DA as a potential therapeutic agent in complementary and alternative medicine for the attenuation of nociception. Keywords: decanoic acid, trigeminal spinal nucleus, nociception, hypoalgesia, single-unit recording, complementary alternative medicine

The primary goal of this study was to investigate the effects of attention-deficit/hyperactivity disorder (ADHD) medications on exercise-induced hypoalgesia (EIH), heart rate, and perceived exertion. Thirty college-age students (10 Controls, 10 ADHD diagnosis, and 10 ADHD diagnosis with medications) completed 2 sessions: 1) a maximal testing session and 2) an experimental session consisting of 3 consecutive dynamic resistance exercise circuits comprised of 12 repetitions of 9 exercises at 60% of 1-repetition maximum using a 1:1 work to rest ratio. All participants, regardless of condition (Controls vs. ADHD without medications vs. ADHD with medications), displayed EIH accompanied by an increase in blood lactate, heart rate, and perceived exertion for the duration of the exercise bout. Therefore, the effects of resistance exercise are not altered by ADHD diagnosis or psychostimulant medication use for ADHD. These findings are intriguing given the known ergogenic and hypoalgesic effects of caffeine, a less potent stimulant.

Introduction: Persistent post-traumatic headache remains a poorly understood clinical entity. Although there are currently no accepted therapies for persistent post-traumatic headache, its clinical symptoms, which primarily resemble those of migraine or tension-type headache, often serve to guide treatment. However, evidence-based justification for this treatment approach remains lacking given the paucity of knowledge regarding the characteristics of these two major persistent post-traumatic headache phenotypes and their etiology.Methods: We compared clinical features and quantitative sensory testing profiles between two distinct cohorts of persistent post-traumatic headache subjects that exhibited symptoms resembling either migraine (n = 15) or tension-type headache (n = 13), as well as to headache-free subjects that had suffered traumatic brain injury (n = 19), and to healthy controls (n = 10). We aimed to determine whether the two persistent post-traumatic headache subgroups could be discriminated based on additional clinical features, distinct quantitative sensory testing profiles, or the interaction of pain severity with the level of post-traumatic stress disorder.Results: Persistent post-traumatic headache subjects with migraine-like symptoms reported that bright light and focused attention aggravated their pain, while stress and nervousness were reported to aggravate the headache in subjects with tension-type headache-like symptoms. Quietness was better in alleviating migraine-like persistent post-traumatic headache, while anti-inflammatory medications provided better relief in tension-type headache-like persistent post-traumatic headache. The two persistent post-traumatic headache subgroups exhibited distinct quantitative sensory testing profiles with subjects exhibiting tension-type headache-like persistent post-traumatic headache displaying a more pronounced cephalic and extracephalic thermal hypoalgesia that was accompanied by cephalic mechanical hyperalgesia. While both persistent post-traumatic headache subgroups had high levels of post-traumatic stress disorder, there was a positive correlation with pain severity in subjects with tension-type headache-like symptoms, but a negative correlation in subjects with migraine-like symptoms.Conclusions: Distinct persistent post-traumatic headache symptoms and quantitative sensory testing profiles may be linked to different etiologies, potentially involving various levels of neuropathic and inflammatory pain, and if confirmed in a larger cohort, could be used to further characterize and differentiate between persistent post-traumatic headache subgroups in studies aimed to improve treatment. [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the association of resting blood pressure with pain response and evaluate the cardiovascular effects of anterior-to-posterior [AP] versus lateral [LAT] techniques of cervical spine non-thrust manipulation [NTM]. Methods: Forty-three (23 females) participants with non-chronic neck pain (mean age 29.00 ± SD 9.09 years) randomly received AP or LAT NTM to the cervical spine. Blood pressure and heart rate were measured before, during, and after the intervention. Disability and pain were measured pre- and post-intervention. Results: Resting systolic blood pressure (SBP) was significantly associated with average pain reduction two days later on univariate and multivariate analyses (coefficients −0.029 ± SD 0.013, p = 0.036; −0.026 ± 0.012, p = 0.032). No significant differences existed between AP and LAT NTM groups in disability, pain reduction, and cardiovascular variables. The decrease in 'worst neck pain' rating 2-days post-intervention was clinically significant within the AP (mean −2.43 ± SD 2.66) group. Mixed-effect model ANOVA revealed a significant change in SBP over time (estimate −1.94 ± SD 0.70, p = 0.007). Discussion: This spinal NTM study was the first to relate resting SBP with short-term pain reduction, demonstrating SBP-related hypoalgesia. In normotensive individuals with unilateral non-chronic neck pain, each 10 mmHg higher resting SBP was associated with a 0.29-unit decrease in average pain at follow-up when holding baseline pain constant. AP and LAT NTM equally reduced short-term pain and decreased SBP during-intervention, suggesting SBP-sympathoinhibition. These techniques have previously been shown to be sympatho-excitatory when delivered under different dosage parameters. SBP's mediating and moderating role should be investigated. "Level of Evidence: 1b." [ABSTRACT FROM AUTHOR]

This study aimed to investigate and compare the magnitude of exercise-induced hypoalgesia (EIH) with low-intensity blood flow restriction (BFR) resistance exercise (RE) at varying pressures to other intensities of resistance exercise and examine endogenous mechanisms of pain reduction. Twelve individuals performed four experimental trials involving unilateral leg press exercise in a randomized crossover design: low-load RE at 30% of one repetition maximum (1RM), high-load RE (70% 1RM), and BFR-RE (30% 1RM) at a low and high pressure. BFR pressure was prescribed relative to limb occlusion pressure at 40% and 80% for the low- and high-pressure trials. Pressure pain thresholds (PPT) were assessed before and 5 min and 24 h following exercise in exercising and non-exercising muscles. Venous blood samples were collected at the same timepoints to determine plasma concentrations of betaendorphin and 2-arachidonoylglycerol. High-pressure BFR-RE increased PPTs in the exercising limb to a greater extent than all other trials. Comparable systemic EIH effects were observed with HLRE and both BFR-RE trials. PPTs in the exercising limb remained elevated above baseline at 24 h post-exercise following both BFR-RE trials. Post-exercise plasma beta-endorphin concentration was elevated during the BFR-RE trials. No changes to 2-arachidonoylglycerol concentration were observed. High pressure BFR-RE causes a greater EIH response in the exercising limb that persists for up to 24 h following exercise. The reduction in pain sensitivity with BFR-RE is partly driven by endogenous opioid production of beta-endorphin. BFR-RE should be investigated as a possible pain-modulation tool in individuals with acute and chronic pain. NEW & NOTEWORTHY High-pressure blood flow restriction (BFR) causes a greater hypoalgesia response in the exercising limb (48%) compared with light and heavy load resistance exercise (10 – 34%). Performing light load resistance exercise with BFR causes systemic hypoalgesia comparable with heavy load resistance exercise (10 –18%). BFR resistance exercise prolonged the exercise-induced hypoalgesia response for 24 h in the exercising limb (15% and 24%, respectively). Activation of endogenous opioid production and a conditioned pain modulation effect partly mediate the relationship between exercise and hypoalgesia. [ABSTRACT FROM AUTHOR]

• Chronic swimming exercise induces mechanical muscle hypoalgesia. • Mechanical muscle hypoalgesia is dependent of PPARγ receptors activation. • PPARγ receptors contributes to this process by modulation of the cytokine CINC-1. • PPARγ receptors could potentiate musculoskeletal pain control by physical exercise. Regular physical exercise has been described as a good strategy for prevention or reduction of musculoskeletal pain. The Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) has been investigated as a promising target for the control of inflammatory pain. Therefore, the aim of this study was to evaluate whether activation of PPARγ receptors is involved in the reduction of acute muscle pain by chronic exercise and, in this case, whether this process is modulated by inflammatory cytokines. To this end, Wistar rats were submitted to swimming physical training for a period of 10 weeks, 5 days per week, 40 min/day, in an intensity of 4% of the body mass. Muscle hyperalgesia was measured by Randall Selitto test and pro-inflammatory cytokines were quantified by ELISA. The results showed that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia and the increase in muscle levels of Cytokine-induced neutrophil chemoattractant 1 (CINC-1) induced by carrageenan into gastrocnemius muscle. In addition, local pre-treatment with the selective PPARγ receptors antagonist GW9662 reversed the mechanical muscle hypoalgesia and the modulation of CINC-1 levels induced by swimming physical training. These data suggest that swimming physical training prevented the onset of acute mechanical muscle hyperalgesia by a mechanism dependent of PPARγ receptors, which seems to contribute to this process by modulation of the pro-inflammatory cytokine CINC-1, and highlight the potential of PPARγ receptors as a target to control musculoskeletal pain and to potentiate the reduction of musculoskeletal pain induced by exercise. [ABSTRACT FROM AUTHOR]

Background Pain perception is critical for detection of noxious bodily insults. Gastrointestinal hypoalgesia in inflammatory bowel disease (IBD) is a poorly understood phenomenon previously linked to poor patient outcomes. We aimed to evaluate the risk factors associated with this condition and to discern characteristics that might differentiate these patients from pain-free quiescent counterparts. Methods We performed a retrospective analysis using an IBD natural history registry based in a single tertiary care referral center. We compared demographic and clinical features in 3 patient cohorts defined using data from simultaneous pain surveys and ileocolonoscopy: a) active IBD without pain (hypoalgesic IBD); b) active IBD with pain; and c) inactive IBD without pain. Results One hundred fifty-three IBD patients had active disease and 43 (28.1%) exhibited hypoalgesia. Hypoalgesic IBD patients were more likely to develop non-perianal fistulae (P=0.03). On logistic regression analysis, hypoalgesic IBD was independently associated with male sex, advancing age and mesalamine use, and inversely associated with anxious/depressed state and opiate use. Hypoalgesic IBD patients were demographically and clinically similar to the pain- free quiescent IBD cohort (n=59). Platelet count and C-reactive protein were more likely to be pathologically elevated in hypoalgesic IBD (P=0.03), though >25% did not exhibit elevated inflammatory markers. Conclusions Hypoalgesia is common in IBD, particularly in male and older individuals, and is associated with an increased incidence of fistulae and corticosteroid use. Novel noninvasive diagnostic tools are needed to screen for this population, as inflammatory markers are not always elevated. [ABSTRACT FROM AUTHOR]