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A population-based study of inflammatory mechanisms and pain sensitivity.
Iordanova Schistad, E, Kong, XY, Furberg, AS, Bäckryd, E, Grimnes, G, Emaus, N, Rosseland, LA, Gordh, T, Stubhaug, A, Engdahl, B, et al
Pain. 2020;(2):338-350
Abstract
Two recent studies suggest that experimental pain sensitivity is associated with low-grade systemic inflammation. However, only 2 biomarkers have been identified, and the studies were conducted in adult individuals where confounding effects of comorbid diseases cannot be excluded. We therefore tested associations between pain sensitivity and 119 inflammation-related serum biomarkers in 827 healthy adolescents (15-19 years) in the population-based Tromsø Study: Fit Futures. The main outcome measure was cold-pressor pain tolerance (CPT), tested by placing the dominant hand in circulating cold (3°C) water for a maximum of 105 seconds. Secondary outcomes were heat and pressure pain threshold and tolerance. Twelve proteins and 6 fatty acids were significantly associated with CPT after adjustment for possible confounding factors and correction for multiple comparisons. Of these, all fatty acids and 10 proteins were protective, ie, higher biomarkers levels were associated with increased CPT, whereas 2 biomarkers were associated with lower tolerance. Taken together, these biomarkers predicted completion of the tolerance test with a C-statistic of 0.65. Results for heat and pressure pain tolerance were remarkably similar, strengthening the generalizability of our findings. In this cohort of young healthy individuals, we found a relationship between inflammation-related biomarkers and pain tolerance and thresholds. Biomarkers with anti-inflammatory and analgesic effects predominated, suggesting that the development of prophylactic dietary or pharmaceutical treatments may be possible.
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Efficacy and Safety of Botulinum Toxin Type A on Persistent Myofascial Pain: A Randomized Clinical Trial.
De la Torre Canales, G, Alvarez-Pinzon, N, Muñoz-Lora, VRM, Vieira Peroni, L, Farias Gomes, A, Sánchez-Ayala, A, Haiter-Neto, F, Manfredini, D, Rizzatti-Barbosa, CM
Toxins. 2020;(6)
Abstract
This study assessed the safety and efficacy of three different doses of BoNT-A for persistent myofascial pain (MFP). One hundred female subjects were randomly assigned into five groups (n = 20): oral appliance (OA), saline solution (SS) and three BoNT-A groups with different doses. Pain intensity and pressure pain threshold were evaluated up to 24 weeks after treatment. Adverse effects related to muscle contraction, masticatory performance, muscle thickness and mandibular bone volume were also assessed. Changes over time were compared within and between groups. The "nparLD" package and Wilcoxon signed-rank test were used to analyze the data. BoNT-A reduced pain intensity (p < 0.0001) and increased pressure pain threshold (p < 0.0001) for up to 24 weeks compared to the placebo. No differences were found between BoNT-A and OA at the last follow-up. A transient decline in masticatory performance (p < 0.05) and muscle contraction (p < 0.0001), and a decrease in muscle thickness (p < 0.05) and coronoid and condylar process bone volume (p < 0.05) were found as dose-related adverse effects of BoNT-A. Regardless of the dose, BoNT-A was as effective as OA on MFP. Notwithstanding, due to BoNT-A dose-related adverse effects, we suggest the use of low doses of BoNT-A in MFP patients that do not benefit from conservative treatments.
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Sex Differences in Associations of Cognitive Function with Perceptions of Pain in Older Adults.
Romano, RR, Anderson, AR, Failla, MD, Dietrich, MS, Atalla, S, Carter, MA, Monroe, TB
Journal of Alzheimer's disease : JAD. 2019;(3):715-722
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Abstract
BACKGROUND Sex differences in pain have been shown to exist in older adults with normal cognition and people with Alzheimer's disease. It is unknown if sex differences in pain in older adults exist in a range of communicative older adults with varying cognitive ability from no impairment to moderately severe cognitive impairment. OBJECTIVE This study proposes to compare the association between psychophysical responses to experimental thermal pain between males and females to determine if sex differences in pain exist across the cognitive spectrum. METHODS We conducted a secondary analysis of data from an age- and sex-matched between-groups cross-sectional study examining the psychophysical response to contact heat in people with and without dementia. RESULTS Median age of males (n = 38) and females (n = 38) was 73 (range: 68-87) with similar distributions of Mini-Mental State Examination (MMSE) scores (range: 11-30). Findings revealed inverse statistically significant associations with the threshold temperature of warmth (females: r = -0.41, p = 0.010; males: r = -0.33, p = 0.044). There was an apparent divergent pattern of MMSE associations with unpleasantness ratings between the groups. At the moderate pain threshold, that difference became statistically significant (p = 0.033). Females demonstrated a positive association of MMSE with unpleasantness (r = 0.30, p = 0.072), while males demonstrated an inverse association at that respective threshold (r = -0.20, p = 0.221). CONCLUSIONS Between-group findings suggest that patterns of responses to thermal stimulus intensity may differ between males and females with worsening cognition with females reporting significantly less unpleasantness with the percept of moderate pain and males reporting significantly higher unpleasantness with moderate pain perception.
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The Relationship between Rate of Algometer Application and Pain Pressure Threshold in the Assessment of Myofascial Trigger Point Sensitivity.
Linde, LD, Kumbhare, DA, Joshi, M, Srbely, JZ
Pain practice : the official journal of World Institute of Pain. 2018;(2):224-229
Abstract
BACKGROUND Pressure algometry is a commonly employed technique in the assessment of both regional and widespread musculoskeletal pain. Despite its acceptance amongst clinicians and scientists, the relationship between rate of pressure application (RoA) and pain pressure threshold (PPT) remains poorly understood. We set out to test the hypothesis that a strong, positive, linear relationship exists between the RoA and the PPT within the infraspinatus of young healthy subjects. METHODS Thirty-three participants were randomly recruited from the local university community. PPT measures were recorded from a clinically identified myofascial trigger point within the right infraspinatus muscle during pressure algometry. A total of 2 PPT measures were recorded using each of 3 different RoAs, including low (15 N/s), medium (35 N/s), and high (55 N/s). Three baseline trials were also conducted at 30 N/s. The Pearson's correlation coefficient between RoA and PPT was calculated for each subject and averaged across participants. RESULTS The mean(SD) correlation between subjects was 0.77 (0.19), and the mean (SD) slope of the linear regression was 0.13 (0.09). CONCLUSION Our results demonstrate that there is a strong, linear relationship between the RoA and PPT when using the pressure algometry technique. The low slope between RoA and PPT suggests clinicians can rely on PPT assessments despite small RoA fluctuations. Future research should explore this relationship further in a clinical population and in other muscles affected by chronic myofascial pain. Advancing cost-effective, reliable, and clinically feasible tools such as algometry is important to enhancing the diagnosis and management of chronic myofascial pain.
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Comparison of masseter muscle referred sensations after mechanical and glutamate stimulation: a randomized, double-blind, controlled, cross-over study.
Exposto, FG, Udagawa, G, Naganawa, T, Svensson, P
Pain. 2018;(12):2649-2657
Abstract
Referred sensations (RS) are commonly found in various musculoskeletal pain conditions. Experimental studies have shown that RS can be elicited through glutamate injection and mechanical stimulation. Despite this, differences and similarities between these modalities in RS outcomes remain unclear. The aim of this study was to assess differences between mechanical-induced and glutamate injection-induced RS in the trigeminal region. The present randomized, double-blind, controlled, cross-over study recruited 60 healthy participants who were assessed in 2 different sessions. In both sessions, pressure was applied to the masseter muscle with 4 different forces (0.5, 1, 2, and 4 kg), and glutamate (1 mol/L or 0.25 mol/L) was injected into the same area. Participants rated their perceived masseter sensations and rated and drew any RS they experienced. No difference was found in number of participants reporting RS after glutamate injection compared with mechanical stimulation. More participants reported RS when the stimulus was painful compared with a nonpainful stimulus. Furthermore, it was shown that the more intense the stimulus, the higher the frequency of RS. Finally, RS centre-of-gravity location was similar between the 2 sessions. In summary, RS was elicited in healthy individuals through both modalities, and no differences in frequency of RS were observed in the orofacial region. Hence, RS does not seem to be modality-dependent, and only the painfulness of the stimulus caused an increase in frequency of RS. Finally, RS location for each participant was similar in both sessions possibly indicating a preferred location of referral. These findings may have implications for our understanding of RS in craniofacial pain conditions.
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Pain thresholds, supra-threshold pain and lidocaine sensitivity in patients with erythromelalgia, including the I848Tmutation in NaV 1.7.
Helås, T, Sagafos, D, Kleggetveit, IP, Quiding, H, Jönsson, B, Segerdahl, M, Zhang, Z, Salter, H, Schmelz, M, Jørum, E
European journal of pain (London, England). 2017;(8):1316-1325
Abstract
OBJECTIVES Nociceptive thresholds and supra-threshold pain ratings as well as their reduction upon local injection with lidocaine were compared between healthy subjects and patients with erythromelalgia (EM). METHODS Lidocaine (0.25, 0.50, 1.0 or 10 mg/mL) or placebo (saline) was injected intradermally in non-painful areas of the lower arm, in a randomized, double-blind manner, to test the effect on dynamic and static mechanical sensitivity, mechanical pain sensitivity, thermal thresholds and supra-threshold heat pain sensitivity. RESULTS Heat pain thresholds and pain ratings to supra-threshold heat stimulation did not differ between EM-patients (n = 27) and controls (n = 25), neither did the dose-response curves for lidocaine. Only the subgroup of EM-patients with mutations in sodium channel subunits NaV 1.7, 1.8 or 1.9 (n = 8) had increased lidocaine sensitivity for supra-threshold heat stimuli, contrasting lower sensitivity to strong mechanical stimuli. This pattern was particularly clear in the two patients carrying the NaV 1.7 I848T mutations in whom lidocaine's hyperalgesic effect on mechanical pain sensitivity contrasted more effective heat analgesia. CONCLUSION Heat pain thresholds are not sensitized in EM patients, even in those with gain-of-function mutations in NaV 1.7. Differential lidocaine sensitivity was overt only for noxious stimuli in the supra-threshold range suggesting that sensitized supra-threshold encoding is important for the clinical pain phenotype in EM in addition to lower activation threshold. Intracutaneous lidocaine dose-dependently blocked nociceptive sensations, but we did not identify EM patients with particular high lidocaine sensitivity that could have provided valuable therapeutic guidance. SIGNIFICANCE Acute pain thresholds and supra-threshold heat pain in controls and patients with erythromelalgia do not differ and have the same lidocaine sensitivity. Acute heat pain thresholds even in EM patients with the NaV 1.7 I848T mutation are normal and only nociceptor sensitivity to intradermal lidocaine is changed. Only in EM patients with mutations in NaV 1.7, 1.8 or 1.9 supra-threshold heat and mechanical pain shows differential lidocaine sensitivity as compared to controls.
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High-Concentration L-Menthol Exhibits Counter-Irritancy to Neurogenic Inflammation, Thermal and Mechanical Hyperalgesia Caused by Trans-cinnamaldehyde.
Andersen, HH, Gazerani, P, Arendt-Nielsen, L
The journal of pain. 2016;(8):919-29
Abstract
UNLABELLED The transient receptor potential cation channel subfamily M 8 (TRPM8) agonist L-menthol has been used traditionally for its topical counterirritant properties. Although the use of topical L-menthol for pain is casuistically established, evidence regarding its efficacy is negligible. This study aimed to characterize the effect of L-menthol as a counterirritant on cutaneous pain and hyperalgesia provoked by topical application of the transient receptor potential cation channel, subfamily A, member 1 (TRPA1) agonist trans-cinnamaldehyde (CA). In a randomized, double-blinded study CA was applied to a 3 × 3-cm area of the volar forearm evoking neurogenic inflammation, pain, mechanical, and thermal hyperalgesia in 14 healthy volunteers. In different sessions, 10% CA alone or 40% L-menthol applied simultaneously with 10% CA were administered for 20 minutes, throughout which the subjects rated the pain intensity on a visual analogue scale of 0 to 10. Extensive quantitative sensory testing was conducted and superficial blood flow (neurogenic inflammation) was recorded. Administration of CA evoked spontaneous pain, neurogenic inflammation, thermal hyperalgesia, and primary and secondary mechanical hyperalgesia. Coadministration of topical L-menthol reduced spontaneous pain intensity (P < .01), neurogenic inflammation (P < .01), primary mechanical hyperalgesia (P < .05), secondary mechanical hyperalgesia (P < .05), and heat hyperalgesia (P < .05), but not cold hyperalgesia. L-menthol exhibited inhibitory effects on simultaneously established pain, hypersensitivity, and neurogenic inflammation in a human TRPA1-induced pain model. Potent TRPM8 agonists could be useful as topical antihyperalgesics. The study and the trial protocol is registered and approved by the local research ethics committee under the jurisdiction of the Danish Medicines Agency number N-20130005. The protocol also is registered at Clinicaltrials.gov under NCT02653703. PERSPECTIVE Drugs interacting with transient receptor potential channels are of great therapeutic potential. In the present study we established cutaneous pain and hyperalgesia using the TRPA1 agonist CA. Subsequently, we showed that the frequently used topical counterirritant and TRPM8 agonist, L-menthol, decreased evoked pain, hyperalgesia, and inflammation, indicating direct and indirect antinociceptive mechanisms.
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Variability in conditioned pain modulation predicts response to NSAID treatment in patients with knee osteoarthritis.
Edwards, RR, Dolman, AJ, Martel, MO, Finan, PH, Lazaridou, A, Cornelius, M, Wasan, AD
BMC musculoskeletal disorders. 2016;:284
Abstract
BACKGROUND Patients with painful knee osteoarthritis (OA) demonstrate hyperalgesia and altered pain-modulatory responses. While some prior work has demonstrated cross-sectional associations between laboratory and clinical pain measures, it is unknown whether individual variability in quantitative sensory testing (QST) responses at baseline can prospectively predict analgesic treatment responses. METHOD Patients with knee OA (n = 35) were compared on QST responses to a demographically-matched pain-free control group (n = 39), after which patients completed a month-long treatment study of diclofenac sodium topical gel (1 %), applied up to 4 times daily. RESULTS OA patients demonstrated reduced pain thresholds at multiple anatomic sites, as well as reduced conditioned pain modulation (CPM) and enhanced temporal summation of pain. The most pain-sensitive patients tended to report the most intense and neuropathic OA pain. Following diclofenac treatment, the knee OA cohort showed a roughly 30 % improvement in pain, regardless of the presence or absence of neuropathic symptoms. Baseline CPM scores, an index of endogenous pain-inhibitory capacity, were prospectively associated with treatment-related changes in clinical pain. Specifically, participants with higher CPM at baseline (i.e., better functioning endogenous pain-inhibitory systems) showed more reduction in pain at the end of treatment (p < .05). CONCLUSIONS These results support prior findings of amplified pain sensitivity and reduced pain-inhibition in OA patients. Moreover, the moderate to strong associations between laboratory-based measures of pain sensitivity and indices of clinical pain highlight the clinical relevance of QST in this sample. Finally, the prospective association between CPM and diclofenac response suggests that QST-based phenotyping may have utility in explaining inter-patient variability in long-term analgesic treatment outcomes. TRIAL REGISTRATION ClinicalTrials.Gov Identifier: NCT01383954 . Registered June 22, 2011.
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Differential effects of repetitive oral administration of monosodium glutamate on interstitial glutamate concentration and muscle pain sensitivity.
Shimada, A, Baad-Hansen, L, Castrillon, E, Ghafouri, B, Stensson, N, Gerdle, B, Ernberg, M, Cairns, B, Svensson, P
Nutrition (Burbank, Los Angeles County, Calif.). 2015;(2):315-23
Abstract
OBJECTIVE The aim of this study was to determine the relationship of high daily monosodium glutamate (MSG) consumption with glutamate concentrations in jaw muscle, saliva, and serum, and muscle pain sensitivity in healthy participants. METHODS A randomized, double-blinded, placebo-controlled study was conducted to investigate the effect of repetitive consumption of high-dose MSG on glutamate concentration in the masseter muscles measured by microdialysis and muscle pain sensitivity. In five contiguous experimental daily sessions, 32 healthy participants drank MSG (150 mg/kg) or NaCl (24 mg/kg) diluted with a 400 mL soda. The concentrations of glutamate before and after the ingestion were assessed in dialysate and plasma samples on the first and last days. Saliva glutamate concentration was assessed every day. Pressure pain threshold, pressure pain tolerance, autonomic parameters (heart rate, systolic and diastolic blood pressures) and reported side effects also were assessed. RESULTS No significant change was noted in the baseline concentration of glutamate in the masseter muscle, blood, or saliva, but the peak concentration in the masseter muscle increased significantly between day 1 and 5. A statistically significant increase in systolic and diastolic blood pressures after MSG administration was observed, as well as a significantly higher frequency of reports of nausea and headache in the MSG group. No robust effect of MSG on muscle sensitivity was found. CONCLUSION Interstitial glutamate concentration in the masseter muscle is not highly disturbed by excessive repetitive intake of MSG in healthy man.
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Pain sensitivity: a feasible way to predict the intensity of stress reaction caused by endotracheal intubation and skin incision?
Wang, H, Cai, Y, Liu, J, Dong, Y, Lai, J
Journal of anesthesia. 2015;(6):904-11
Abstract
PURPOSE Recent studies have shown that pain sensitivity has a significant relationship with clinical pain and may also predict the intensity of pain and analgesic consumption after surgery. However, the correlation between pre-operative pain sensitivity and stress response during anesthesia has not been investigated. Therefore, we aimed to explore the relationship between pre-operative pain sensitivity and stress responses during intubation and skin incision in this study. METHODS Fifty women (ASA I-II) aged 20-55 years, undergoing elective abdominal surgery requiring at least a 10-cm-long skin incision were studied. Pain sensitivity, including pain threshold and pain tolerance was measured before surgery. In this study, experimental pain was induced by potassium ion conducted via continuous current. When patients reported feeling pain or acted to stop pain, the intensity of the current was recorded to register pain threshold and pain tolerance. The State-Trait Anxiety Inventory (STAI) was used to examine the pre-operative mental status. General anesthesia was induced with intravenous fentanyl and a target-controlled infusion of propofol. Blood samples for norepinephrine (NE) detection were collected at 10 min after entering the operating theater, immediately before intubation, 2 min after intubation, immediately before skin incision and 2 min after incision. Mean arterial blood pressure (MAP) and heart rate (HR) were recorded at the same time. Pearson's correlation test (SPSS 13.0) was then used to analyze the relationship between pain sensitivity and the changes in MAP, HR and NE level. RESULTS A total of fifty women were enrolled in the study. Their pre-operative pain threshold and pain tolerance were 0.90 ± 0.40 mA and 2.53 ± 0.77 mA,respectively. Changes in MAP, HR and NE before and after intubation or skin incision were significantly related with pre-operative pain tolerance (P < 0.05); however, pain threshold was not correlated with changes in MAP, HR and NE (P > 0.05). The STAI score did not correlate with the stress response either (P > 0.05). CONCLUSIONS Pain tolerance had a significant relationship with stress response during intubation and skin incision. We may initially use pain tolerance to direct opioid usage in the future.