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Background: Total knee replacement (TKR) is the gold standard treatment for end-stage chronic osteoarthritis pain, yet many patients report chronic postoperative pain after TKR. The search for preoperative predictors for chronic postoperative pain following TKR has been studied with inconsistent findings., Methods: This study investigates the predictive value of quantitative sensory testing (QST) and PainDETECT for postoperative pain 3, 6 and 12 months post-TKR. We assessed preoperative and postoperative (3 and 6 months) QST measures in 77 patients with knee OA (KOA) and 41 healthy controls, along with neuropathic pain scores in patients (PainDETECT). QST parameters included pressure pain pressure threshold (PPT), pain tolerance threshold (PTT), conditioned pain modulation (CPM) and temporal summation (TS) using cuff algometry, alongside mechanical hyperalgesia and temporal summation to repeated pinprick stimulation., Results: Compared to healthy controls, KOA patients at baseline demonstrated hyperalgesia to pinprick stimulation at the medial knee undergoing TKR, and cuff pressure at the calf. Lower cuff algometry PTT and mechanical pinprick hyperalgesia were associated with preoperative KOA pain intensity. Moreover, preoperative pinprick pain hyperalgesia explained 25% of variance in pain intensity 12 months post-TKR and preoperative neuropathic pain scores also captured 30% and 20% of the variance in postoperative pain at 6 and 12 months respectively. A decrease in mechanical pinprick hyperalgesia from before surgery to 3 months after TKR was associated with lower postoperative pain at the 12 months post-TKR follow-up., Conclusion: Our findings suggest that preoperative pinprick hyperalgesia and neuropathic-like pain symptoms show predictive value for the development of chronic post-TKR pain., Significance Statement: This study's findings hold significant implications for chronic pain management in knee osteoarthritis patients, particularly those undergoing total knee replacement surgery (TKR). Mechanical hyperalgesia and neuropathic pain-like characteristics predict postoperative pain 1 year after TKR, emphasizing the importance of understanding pain phenotypes in OA for selecting appropriate pain management strategies. The normalization of hyperalgesia after surgery correlates with better long-term outcomes, further highlighting the therapeutic potential of addressing abnormal pain processing mechanisms pre- and post-TKR., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Objectives: Muscle pain can be associated with hyperalgesia that may spread outside the area of primary injury due to both peripheral and central sensitization. However, the influence of endogenous pain inhibition is yet unknown. This study investigated how endogenous pain inhibition might influence spreading hyperalgesia in experimental muscle pain., Methods: Conditioned pain modulation (CPM) was assessed in 30 male volunteers by cold pressor test at the non-dominant hand as conditioning and pressure pain thresholds (PPT) at the dominant 2nd toe as test stimuli. Subjects were classified as having inhibitory or facilitating CPM based on published reference values. Subsequently, muscle pain and hyperalgesia were induced by capsaicin injection into the non-dominant supraspinatus muscle. Before and 5, 10, 15, 20, 30, 40, 50 and 60 min later, PPTs were recorded at the supraspinatus, infraspinatus and deltoid muscle, ring finger and toe., Results: Compared to baseline, PPTs decreased at the supraspinatus, infraspinatus and deltoid muscle (p≤0.03), and increased at the finger and toe (p<0.001). In facilitating CPM (n=10), hyperalgesia occurred at 5, 10, 15, 20 and 40 min (p≤0.026). In inhibitory CPM (n=20), hyperalgesia only occurred after 10 and 15 min (p≤0.03). At the infraspinatus muscle, groups differed after 5 and 40 min (p≤0.008)., Conclusions: The results suggest that facilitating CPM is associated with more spreading hyperalgesia than inhibitory CPM. This implies that poor endogenous pain modulation may predispose to muscle pain and spreading hyperalgesia after injury, and suggest that strategies to enhance endogenous pain modulation may provide clinical benefits., (© 2023 Walter de Gruyter GmbH, Berlin/Boston.)

Objectives: Existing equipment for quantitative sensory testing is generally expensive and not easily applicable in a clinical setting thus simple bed-side devices are warranted. Pressure hyperalgesia is a common finding in patients with musculoskeletal pain and an experimental model is delayed-onset muscle soreness (DOMS). DOMS is characterised by muscle hyperalgesia and some studies report facilitation of temporal summation of pain. This study aimed to detect DOMS induced muscle hyperalgesia and temporal summation of pain using a newly developed bed-side quantitative sensory testing device to deliver standardised pressure., Methods: Twenty-two healthy participants participated in two sessions with the second session approximately 48 h after baseline. Pressure pain intensities were assessed from the gastrocnemius muscle with four probes calibrated to apply 2, 4, 6 and 8 kg, respectively. Temporal summation of pain (10 stimuli delivered at 0.5 Hz using the 6 kg probe) intensities were assessed from the same location. DOMS was evoked in the gastrocnemius muscle by an eccentric exercise. Sleepiness and physical activity were measured with the Epworth Sleepiness Scale and the Global Physical Activity Questionnaire to investigate if they were associated with the quantitative sensory testing measures., Results: Pressure pain intensity was significantly increased 48 h after induction of DOMS when compared to baseline for all four probes (p<0.05). Temporal summation of pain was not statistically significant affected by DOMS and sleep quality and physical activity did not associate with any of the measures., Conclusions: This study introduces a simple, bed-side assessment tool for the assessment of pressure pain intensity and hence hyperalgesia and temporal summation of pain., (© 2022 Walter de Gruyter GmbH, Berlin/Boston.)

Heat/capsaicin sensitization and electrical high-frequency stimulation (HFS) are well-known models of secondary hyperalgesia, a phenomenon related to chronic pain conditions. This study investigated whether priming with heat/capsaicin would facilitate hyperalgesia to HFS in healthy subjects. Heat/capsaicin priming consisted of a 45°C heat stimulation for 5 min followed by a topical capsaicin patch (4 × 4 cm) for 30 min on the volar forearm of 20 subjects. HFS (100 Hz, 5 times 1 s, minimum 1.5 mA) was subsequently delivered through a transcutaneous pin electrode approximately 1.5 cm proximal to the heat/capsaicin application. Two sessions were applied in a crossover design; traditional HFS (HFS) and heat/capsaicin sensitization followed by HFS (HFS + HEAT/CAPS). Heat pain threshold (HPT), mechanical pain sensitivity (MPS), and superficial blood perfusion were assessed at baseline, after capsaicin removal, and up to 40 min after HFS. MPS was assessed with pin-prick stimulation (128 mN and 256 mN) in the area adjacent to both HFS and heat/capsaicin, distal but adjacent to heat/capsaicin and in a distal control area. HPT was assessed in the area of heat/capsaicin. Higher sensitivity to 128 mN pin-prick stimulation (difference from baseline and control area) was observed in the HFS + HEAT/CAPS session than in the HFS session 20 and 30 min after HFS. Furthermore, sensitivity was increased after HFS + HEAT/CAPS compared with after heat/capsaicin in the area adjacent to both paradigms, but not in the area distal to heat/capsaicin. Results indicate that heat/capsaicin causes priming of the central and peripheral nervous system, which facilitates secondary mechanical hyperalgesia to HFS. NEW & NOTEWORTHY High-frequency electrical stimulation (HFS) and heat/capsaicin sensitization are well-known models of secondary hyperalgesia. The results from the current study indicate that increased sensitivity to 128 mN pin-prick stimulation can be obtained when HFS is delivered following an already established heightened central hyperexcitability provoked by heat/capsaicin sensitization.

Subpopulations of primary nociceptors (C- and Aδ-fibers), express the TRPV1 receptor for heat and capsaicin. During cutaneous inflammation, these afferents may become sensitized, leading to primary hyperalgesia. It is known that TRPV1 + nociceptors are involved in heat hyperalgesia; however, their involvement in mechanical hyperalgesia is unclear. This study explored the contribution of capsaicin-sensitive nociceptors in the development of mechanical and heat hyperalgesia in humans following ultraviolet-B (UVB) irradiation. Skin areas in 18 healthy volunteers were randomized to treatment with 8% capsaicin/vehicle patches for 24 h. After patches removal, one capsaicin-treated area and one vehicle area were irradiated with 2xMED (minimal erythema dose) of UVB. 1, 3 and 7 days post-UVB exposure, tests were performed to evaluate the development of UVB-induced cutaneous hyperalgesia: thermal detection and pain thresholds, pain sensitivity to supra-threshold heat stimuli, mechanical pain threshold and sensitivity, touch pleasantness, trans-epidermal water loss (TEWL), inflammatory response, pigmentation and micro-vascular reactivity. Capsaicin pre-treatment, in the UVB-irradiated area (Capsaicin + UVB area), increased heat pain thresholds (P < 0.05), and decreased supra-threshold heat pain sensitivity (P < 0.05) 1, 3 and 7 days post-UVB irradiation, while mechanical hyperalgesia resulted unchanged (P > 0.2). No effects of capsaicin were reported on touch pleasantness (P = 1), TEWL (P = 0.31), inflammatory response and pigmentation (P > 0.3) or micro-vascular reactivity (P > 0.8) in response to the UVB irradiation. 8% capsaicin ablation predominantly defunctionalizes TRPV1 + -expressing cutaneous nociceptors responsible for heat pain transduction, suggesting that sensitization of these fibers is required for development of heat hyperalgesia following cutaneous UVB-induced inflammation but they are likely only partially necessary for the establishment of robust primary mechanical hyperalgesia., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

We investigated if dynamic pressure pain sensitivity in the symptomatic area is associated with pressure sensitivity in local and distant pain-free areas in cluster headache (CH). A pressure algometry set consisting of 8 rollers with fixed pressure levels ranging from 500 to 5300 g was used to assess dynamic pressure pain sensitivity in men with episodic CH. Each roller was moved from an anterior-to-posterior direction over the temporalis muscle. The load level of the first painful roller was considered the dynamic pain threshold (DPT). Further, pain elicited during DPT (roller evoked pain) was also assessed. We used a pressure algometer to determine pressure pain thresholds (PPTs) over the temporalis muscle, C5/C6 joint, second metacarpal, and tibialis anterior. Patients were assessed in an asymptomatic (remission) phase, at least 6 months after their last cluster period and without taking pharmacological treatment. Forty men with episodic CH (mean age 42 years) were included. Both outcomes, DPTs (r = 0.781, P < 0.001) and roller-evoked pain (r = 0.586; P < 0.001) were bilaterally correlated. Further, DPT, but not roller-evoked pain, was moderately associated with PPTs measured at the symptomatic (temporalis: r = 0.665, P < 0.001) and distant pain-free (C5-C6 joint: r = 0.389, P = 0.013; second metacarpal: r = 0.551, P < 0.001; and, tibialis anterior: r = 0.308, P = 0.035) points. Dynamic pressure sensitivity in the trigeminal area was correlated to pressure pain sensitivity at both symptomatic and distant pain-free areas in men with CH supporting the use of roller pressure algometry. Dynamic pressure algometry may be a new tool for assessing the status of sensitization in primary headaches.

Background: A method for assessing dynamic muscle hyperalgesia (dynamic pressure algometry) has been developed and applied in tension-type and migraine headaches., Objectives: To investigate differences in dynamic pressure pain assessment over the trigeminal area between men with cluster headache (CH) and headache-free controls, and the association between dynamic and static pressure pain sensitivity., Study Design: A case-control study., Setting: Tertiary urban hospital., Methods: Forty men with episodic CH and 40 matched controls participated. Dynamic pressure pain sensitivity was assessed with a dynamic pressure algometry set consisting of 8 rollers with different fixed levels (500, 700, 850, 1,350, 1,550, 2,200, 3,850, and 5,300 g). Each roller was moved at a speed of 0.5 cm/sec over a diagonal line covering the temporalis muscle from an anterior to posterior direction. The dynamic pressure threshold (DPT; load level of the first painful roller) and the pain intensity perceived at the DPT level (roller-evoked pain) were assessed. Static pressure pain thresholds (PPT) were also assessed with a digital pressure algometer applied statically over the mid-muscle belly of the temporalis. Patients were assessed in a remission phase, at least 3 months from the last cluster attack, and without preventive medication., Results: Side-to-side consistency between DPTs (r = 0.781, P < 0.001), roller-evoked pain on DPT (r = 0.586; P < 0.001), and PPTs (r = 0.874; P < 0.001) were found in men with CH. DPT was moderately, bilaterally, and side-to-side associated with PPTs (0.663 > r > 0.793, all P < 0.001). Men with CH had bilateral lower DPT and PPT and reported higher levels of roller-evoked pain (all P < 0.001) than headache-free controls., Limitations: Only men with episodic CH were included., Conclusions: This study supports that a dynamic pressure algometry is as valid as a static pressure algometry for assessing pressure pain sensitivity in patients with CH. Assessing both dynamic and static pain sensitivity may provide new opportunities for differentiated diagnostics., Key Words: Cluster headache, dynamic pressure pain, pressure pain threshold.

Background: Pain sensitivity in chronic neck pain patients may be influenced by health conditions related to higher levels of widespread pressure pain hypersensitivity (sensitization). Trigger points have also been reported to play a role in the sensitization process., Objectives: To investigate the association between pressure pain thresholds, trigger points, and health conditions in patients with chronic neck pain., Design: Original research, preliminary study., Setting: A private clinic., Subjects: Thirty-four chronic mechanical neck pain patients and 34 chronic whiplash-associated neck pain patients, giving a final sample of 68 chronic neck pain patients., Methods: Patients underwent an assessment of pressure pain thresholds over the upper trapezius, extensor carpi radialis longus, and tibialis anterior muscles and were screened for the presence of trigger points in the upper trapezius muscle. Further, information about health history conditions was obtained and collected in a form., Results: Significantly negative correlations between all pressure pain thresholds and duration of health history conditions were found (all P < 0.02). Significantly lower pressure pain thresholds (all P < 0.01) were found in patients with active trigger points as compared with those with latent trigger points., Conclusion: Widespread pressure pain hypersensitivity was associated with duration of health history conditions, suggesting that long-lasting health complaints may act as a triggering/perpetuating factor, driving sensitization in individuals with chronic neck pain. Active trigger points may be associated with higher widespread pressure hypersensitivity., (© 2019 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Joint inflammation is present in a subpopulation of knee osteoarthritis (OA) patients. Proinflammatory cytokines are known to sensitize the peripheral and central pain pathways. This can be mechanistically assessed by pressure pain thresholds and temporal summation of pain (TSP). Nonsteroidal anti-inflammatory drugs (NSAIDs) combined with paracetamol are recommended as OA treatment. The current study hypothesized that evidence of central sensitization would predict poor responses to peripherally directed therapies in knee OA and therefore aimed to investigate the value of mechanistic pain profiling for predicting pain outcome of treatment with NSAIDs plus paracetamol. One hundred thirty-two patients received ibuprofen 1200 mg/daily, paracetamol 3 g/daily, and pantoprazole 20 mg/daily for 3 weeks. Before administration, cuff pain detection, tolerance threshold, and TSP were assessed. Worst pain within the last 24 hours and pain during activity (visual analogue scales) were assessed before and after treatment. Facilitated TSP was found at baseline in the nonresponders to the 3-weeks treatment as compared to responders for both the 30% and 50% pain alleviation criteria (P < 0.02). Linear regression models identified facilitated TSP (P < 0.01) and low clinical pain scores (P < 0.001) as independent factors for prediction of poor pain alleviation by the treatment. In conclusion, this study found that mechanistic pain profiling can predict pain alleviation of NSAIDs and paracetamol. Facilitated TSP and low clinical pain scores before treatment are independent predictors of poor pain alleviation after NSAIDs and paracetamol. This study adds to the growing evidence that a subgroup of knee OA patients with manifested central sensitization may require special management attention.

Objective To investigate the association between trigger points (TrPs) and widespread pressure pain sensitivity in people with tension-type headache (TTH) and to determine if this association is different between frequent episodic (FETTH) or chronic (CTTH) headache. Design A cross-sectional study. Methods One hundred and fifty-seven individuals (29% male) with TTH participated. Clinical features of headache, i.e., intensity, duration, and frequency, were recorded in a headache diary. Active and latent TrPs were bilaterally explored in the temporalis, masseter, suboccipital, upper trapezius, sternocleidomastoid, and splenius capitis muscles. Pressure pain thresholds (PPT) were assessed over the trigeminal area (i.e., temporalis muscle), extra-trigeminal (i.e., C5/C6 zygapophyseal joint), and two distant pain-free points (i.e., second metacarpal and tibialis anterior muscle). Results Eighty (51%) patients were classified as FETTH, whereas 77 (49%) were classified as CTTH. No differences in the number of either active or latent TrPs (all p > 0.171) or widespread pressure pain sensitivity (all p > 0.351) were observed between FETTH and CTTH groups. The number of active and latent TrPs was significantly and negatively associated with PPTs: The higher the number of active or latent TrPs, the lower the widespread PPT, and the more generalized sensitization. This association was stronger within the FETTH group than the CTTH group. Conclusions This study found that the number of TrPs in head and neck/shoulder muscles was associated with widespread pressure hypersensitivity independently of the frequency of headache.

Objectives: Widespread pressure hyperalgesia, facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM) have been found in knee osteoarthritis (KOA) patients compared with controls and these parameters have further been suggested to be altered in the elderly. This study investigated the influence of age on pressure hyperalgesia, TSP, and CPM in patients with KOA and controls., Materials and Methods: One hundred thirty-three severe KOA patients and 50 age-matched and sex-matched asymptomatic controls were assessed by cuff algometry and handheld pressure algometry. Pain sensitivity was assessed around the head of the gastrocnemius muscle to identify mild pain detection threshold (MPDT) and pressure tolerance threshold (PTT). TSP was assessed by visual analogue scale scores of the pain evoked by 10 repetitive cuff stimulations. CPM was assessed as the difference in PTT before and during cuff-induced tonic arm pain. Pressure pain thresholds (PPTs) were assessed by handheld algometry at the tibialis anterior muscle. Two subgroups were analyzed in the age range below and above 65 years. Pearson correlations between age and pain parameters were applied., Results: Patients demonstrated reduced MPDT, PTT, and PPT (P<0.01), facilitated TSP (P<0.02), and a trend toward impaired CPM (P=0.06) compared with controls. A negative correlation was found between MPDT, PTT, and PPT and age (P<0.05) but no age-related association was found for TSP and CPM., Discussion: Pressure hyperalgesia was affected by age whereas dynamic pain mechanisms such as TSP and CPM were unaffected suggesting that these parameters are robust for a larger age range and reliable for long-term follow-up studies.

Background: Identification of subgroups of patients with different levels of sensitization and clinical features can help to identify groups at risk and the development of better therapeutic strategies. The aim of this study was to identify subgroups of patients with tension type headache (TTH) with different levels of sensitization, clinical pain features, and psychological outcomes., Methods: A total of 197 individuals with TTH participated. Headache intensity, frequency, and duration and medication intake were collected with a 4-weeks diary. Pressure pain thresholds were assessed bilaterally over the temporalis muscle, C5-C6 joint, second metacarpal and tibialis anterior muscle to determine widespread pressure pain hyperalgesia. The Hospital Anxiety and Depression Scale assessed anxiety and depression. The State-Trait Anxiety Inventory evaluated the state and trait levels of anxiety. The Headache Disability Inventory evaluated the burden of headache. Health-related quality of life was determined with the SF-36 questionnaire. Groups were considered as positive (three or more criteria) or negative (less than three criteria) on a clinical prediction rule: headache duration <8.5 h/day; headache frequency <5.5 days/week; bodily pain <47 and vitality <47.5., Results: The ANCOVA revealed that subjects in group 1 (positive rule, n = 89) exhibited longer headache history, shorter headache duration, lower headache frequency, higher widespread pressure hyperalgesia, higher anxiety trait levels, and lower quality of life (all, P < 0.01) than those subjects within group 2 (negative rule, n = 108). Differences were similar between men and women., Conclusions: This study identified a subgroup of patients with TTH with higher sensitization, higher chronicity of headaches and worse quality of life but lower frequency and duration of headache episodes. This subgroup of individuals with TTH may need particular attention and specific therapeutic programs for avoiding potential chronification.

Objective: Previous studies suggest that trigger points (TrPs) contribute to migraine pain, but no data is available on the effects of TrPs on pressure pain sensitivity. Our objective was to investigate the association between the number of TrPs and widespread pressure hypersensitivity in women with episodic migraines., Methods: Ninety-five women with episodic migraines participated. Clinical features of migraines, that is, intensity, duration, frequency, and onset, were collected. Active and latent TrPs were bilaterally explored in the temporalis, masseter, suboccipital, sternocleidomastoid, upper trapezius, and splenius capitis musculature. Pressure pain thresholds (PPTs) were assessed over the trigeminal area (i.e., temporalis muscle), extratrigeminal (i.e., C5/C6 zygapophyseal joint), and a distant pain-free point (i.e., tibialis anterior muscle)., Results: Active TrPs in the temporalis and upper trapezius muscles were the most prevalent. The number of active but not latent TrPs was significantly and negatively associated with PPTs: the higher the number of active TrPs, the lower the widespread PPT and the more generalized sensitization., Conclusions: This study found that the number of active but not latent TrPs in head and neck and shoulder muscles was associated with widespread pressure hypersensitivity in women with episodic migraines, suggesting a potential contribution of active TrPs as contributors for sensitization processes in migraines., (© 2017 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Background and Purpose: Acid has long been thought to play an important role in the pain process. Animal study showed that repeated acid stimulation induced central sensitization. The purpose of the study is to investigate muscle pain and hyperalgesia evoked by intramuscular infusion of saline at different pH levels, and to compare the effect of a single versus repeated acid infusions., Methods: Twenty healthy subjects received infusions of buffered saline (pH 5.0, 6.0, and 7.4) into the brachioradialis muscle in a randomized order. Twelve of the subjects received repeated infusions. The subjects rated the pain intensity on visual analogue scale (VAS). Thermal pain sensitivity, and pressure pain threshold (PPT) were assessed in both arm before, during, immediately after, one hour after, and one day after the infusion. A McGill Pain Questionnaire and pain mapping were completed after each infusion., Results: The pH 5 solution caused significantly higher pain and larger areas than pH 6.0 or 7.4. The local PPTs were significantly decreased (hyperalgesia) during and immediately after infusion of all three solutions. No significant differences were detected between the first and second infusion., Conclusions: The intensity of acid-induced muscle pain is pH-dependent. All three solutions induced pressure hyperalgesia at the infusion site. Repeated infusions did not induce increased pain or prolonged hyperalgesia as compared with a single injection. Human intramuscular acidic saline infusion could not produce chronic pain model., Implications: The acid-induced pain model may reflect the early stage responses to tissue injury of clinical conditions. Repeated intramuscular acidic saline injection model of prolonged hyperalgesia in rodents could not be translated into a human for modelling chronic musculoskeletal pain., (Copyright © 2017 Scandinavian Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Despite being a ubiquitous animal pain model, the natural TRPA1-agonist allyl isothiocyanate (AITC, also known as "mustard oil") has only been sparsely investigated as a potential human surrogate model of pain, sensitization, and neurogenic inflammation. Its dose-response as an algogenic, sensitizing irritant remains to be elucidated in human skin. Three concentrations of AITC (10%, 50%, and 90%) and vehicle (paraffin) were applied for 5 minutes to 3 × 3 cm areas on the volar forearms in 14 healthy volunteers, and evoked pain intensity (visual analog scale 0-100 mm) and pain quality were assessed. In addition, a comprehensive battery of quantitative sensory tests was conducted, including assessment of mechanical and thermal sensitivity. Neurogenic inflammation was quantified using full-field laser perfusion imaging. Erythema and hyperpigmentation were assessed before, immediately after, and ≈64 hours after AITC exposure. AITC induced significant dose-dependent, moderate-to-severe spontaneous burning pain, mechanical and heat hyperalgesia, and dynamic mechanical allodynia (P < 0.05). No significant differences in induced pain hypersensitivity were observed between the 50% and 90% AITC concentrations. Acute and prolonged inflammation was evoked by all concentrations, and assessments by full-field laser perfusion imaging demonstrated a significant dose-dependent increase with a ceiling effect from 50% to 90%. Topical AITC application produces pain and somatosensory sensitization in a dose-dependent manner with optimal concentrations recommended to be >10% and ≤50%. The model is translatable to humans and could be useful in pharmacological proof-of-concept studies of TRPA1-antagonists, analgesics, and anti-inflammatory compounds or for exploratory clinical purposes, eg, loss- or gain-of-function in peripheral neuropathies.

Objective: To compare the short-term effects of manual therapy and exercise on pain, related disability, range of motion, and pressure pain thresholds between subjects with mechanical neck pain and whiplash-associated disorders., Methods: Twenty-two subjects with mechanical neck pain and 28 with whiplash-associated disorders participated. Clinical and physical outcomes including neck pain intensity, neck-related disability, and pain area, as well as cervical range of motion and pressure pain thresholds over the upper trapezius and tibialis anterior muscles, were obtained at baseline and after the intervention by a blinded assessor. Each subject received six sessions of manual therapy and specific neck exercises. Mixed-model repeated measures analyses of covariance (ANCOVAs) were used for the analyses., Results: Subjects with whiplash-associated disorders exhibited higher neck-related disability ( P  = 0.021), larger pain area ( P  = 0.003), and lower pressure pain thresholds in the tibialis anterior muscle ( P  = 0.009) than those with mechanical neck pain. The adjusted ANCOVA revealed no between-group differences for any outcome (all P  > 0.15). A significant main effect of time was demonstrated for clinical outcomes and cervical range of motion with both groups experiencing similar improvements (all P  < 0.01). No changes in pressure pain thresholds were observed in either group after treatment ( P  > 0.222)., Conclusions: The current clinical trial found that subjects with mechanical neck pain and whiplash-associated disorders exhibited similar clinical and neurophysiological responses after a multimodal physical therapy intervention, suggesting that although greater signs of central sensitization are present in subjects with whiplash-associated disorders, this does not alter the response in the short term to manual therapy and exercises., (© 2016 American Academy of Pain Medicine. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com)

Objective: To investigate differences in widespread pressure pain hyperalgesia in the trigemino-cervical and extra-trigeminal (distant pain-free) regions in women with frequent episodic (FETTH) and chronic (CTTH) tension-type headache., Background: It seems that people with tension-type headache exhibit central sensitization. No study has investigated differences between FETTH and CTTH in terms of widespread pressure pain hypersensitivity., Methods: Forty-three women with FETTH, 42 with CTTH, and 45 women without headache diagnosis were recruited. Pressure pain thresholds (PPTs) were bilaterally assessed over trigeminal area (ie, temporalis muscle), extra-trigeminal (ie, C5/C6 zygapophyseal joint), and two distant points (ie, second metacarpal and tibialis anterior muscle) by a blinded assessor. Clinical features of the headache were collected with a 4-week headache diary. Anxiety and depression were assessed using the Hospital Anxiety and Depression Scale (HADS)., Results: The ANCOVA revealed that PPTs were significantly decreased bilaterally over trigeminal (mean differences ranging from 97.5 to 101.5 kPa), extra-trigeminal (from 94.3 to 114.5 kPa), and distant points (from 99.4 to 208.6 kPa) in both FETTH and CTTH groups compared with controls (all, P < .001). No differences between FETTH and CTTH were observed (all points, P > .217). Anxiety (all, P > .803) or depression (P > .206) did not influence pressure pain hyperalgesia. No associations between widespread pressure hypersensitivity and headache features were observed (all, P > .110)., Conclusions: Current results suggest the presence of similar local and widespread pressure hyperalgesia, not associated with anxiety or depression, in women with FETTH and CTTH supporting that localized and central manifestations are involved in both the episodic and chronic forms of tension-type headache., (© 2016 American Headache Society.)

Objective: To investigate differences in topographical pressure pain sensitivity maps of the scalp between patients with migraine and healthy controls considering the chronicity (episodic/chronic) and side (strictly unilateral/bilateral) of the symptoms., Background: It seems that the trigeminal area is sensitized in migraine. No study has investigated topographical pressure sensitivity maps of the scalp in patients with migraine., Methods: Pressure pain thresholds (PPTs) were assessed from 21 points distributed over the scalp in 86 patients with episodic migraine, 76 with chronic migraine, and 42 healthy age and matched healthy controls in a blinded design. Topographical pressure pain sensitivity maps based on interpolation of the PPTs were constructed. Clinical features of migraine, anxiety, and depression (Hospital Anxiety and Depression Scale, HADS) were collected., Results: The multivariate ANCOVA revealed significant differences in PPT between points (F = 55.674; P < .001) and groups (F = 5.316; P = .006), but not sides (F = 0.880; P = .417). No significant effect of gender (F = 0.897; P = .656), depression (F = 1.109; P = .220), or anxiety (F = 0.981; F = 0.569) was found. Post hoc comparisons revealed: (1) lower PPTs in both migraine groups than in healthy controls in all points (P < .001); (2) no significant differences between chronic or episodic migraine (P > .335) except for Fp1 (P = .045) and Fp2 (P = .017) points where subjects with chronic migraine had lower PPTs than those with episodic migraine; (3) no differences between bilateral/unilateral migraine (P > .417). An anterior to posterior gradient was found, with the lowest PPTs located in frontal regions and the highest PPTs in occipital areas (all groups, P < .001)., Conclusions: We found that patients with migraine exhibited generalized pressure pain hypersensitivity in the head as compared to healthy controls and that hypersensitivity was similar between episodic/chronic and unilateral/bilateral migraine. Topographical pressure pain sensitivity maps revealed an anterior to posterior gradient of pressure pain sensitivity in both migraine and control groups., (© 2016 American Headache Society.)

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., (Copyright © 2016 American Pain Society. Published by Elsevier Inc. All rights reserved.)

Objectives: Adolescent females with patellofemoral pain (PFP) have localized (around the knee) and distal (tibialis anterior muscle) hyperalgesia assessed by decreased pressure pain thresholds (PPT). This may have implications for treating PFP as both localized and central pain mechanisms may contribute to the manifestations of pain. The objective of this study was to compare the change in localized and distal hyperalgesia among female adolescents with PFP deeming themselves recovered compared with those not recovered 3 months after patient education with or without exercise therapy., Methods: This is an ancillary analysis of a cluster randomized controlled trial investigating the effect of patient education with or without exercise therapy on self-reported recovery in 121 adolescents with PFP. PPTs were measured at 4 sites around the knee and on tibialis anterior in a random subsample of 57 female adolescents. Changes in localized and distal hyperalgesia from baseline to follow-up were compared with self-reported recovery. Adolescents were categorized as recovered if they rated themselves as "completely recovered" or "strongly recovered" on a 7-point Likert scale., Results: Thirty-nine adolescents (68%) were available for follow-up at 3 months and 10 adolescents reported being recovered. Recovered adolescents had a 68 kPa (95% CI, 1, 136; P=0.047) larger improvement in PPT around the knee and a 76 kPa (95% CI, -29, 181; P=0.16) nonsignificant improvement in PPT on the tibialis anterior compared with adolescents not recovered., Conclusions: Female adolescents with PFP who rated themselves as recovered had a larger reduction in localized hyperalgesia compared with those not recovered.

Objective: Cutaneous allodynia (pain from a non-painful stimulus) is a sign that can be observed among women with chronic pelvic pain. Dysmenorrhea is recognized as a common cause of chronic pelvic pain in women. This study was conducted to explore the frequency of allodynia and the relationship between allodynia and severe dysmenorrhea., Methods: We enrolled women in this study if they had experienced chronic pelvic pain for more than six months. Women provided information regarding their chronic pelvic pain and menstrual function, specifically the severity of their menstrual pain. In addition to a gynaecological assessment, women were tested for allodynia and pain pressure thresholds., Results: Abdominal allodynia was present in 62.1% of 181 women who participated. Women with allodynia had a significantly greater rate of severe dysmenorrhea and significantly greater duration of severe dysmenorrhea. Pain pressure thresholds were demonstrated to decrease significantly in relation to increasing duration of severe dysmenorrhea., Conclusion: There is a greater frequency of chronic pain among women with a history of severe dysmenorrhea. Women who experienced prolonged severe dysmenorrhea were shown to have a progressive increase in pain sensitivity (reflected in reduced pain pressure thresholds). These findings support efforts to manage dysmenorrhea early in a woman's life with approaches to suppress menstrual function., (Copyright © 2016 The Society of Obstetricians and Gynaecologists of Canada/La Société des obstétriciens et gynécologues du Canada. Published by Elsevier Inc. All rights reserved.)

Objectives: Disturbed endogenous pain modulation is likely one of the mechanisms underlying central hypersensitivity and might be a contributing factor for the development and maintenance of chronic pain. To our knowledge, no study has investigated endogenous pain modulation in both acute and chronic low back pain (LBP). We tested the hypothesis that endogenous pain inhibition is impaired in patients with acute and chronic LBP., Materials and Methods: We evaluated 40 patients with acute LBP, 34 patients with chronic LBP and 30 pain-free controls for their conditioned pain modulation (CPM), with pressure pain tolerance and cold pressor as test and conditioning stimulus, respectively. Measurements were repeated up to 10 minutes after cold pressor test., Results: There was no difference in CPM among the groups immediately after cold pressor test. However, the decline in CPM effect was significantly faster in chronic and acute LBP patients than in controls, with no evidence for differences between pain groups., Discussion: The present study provides evidence for some alterations of endogenous modulation in both acute and chronic LBP. CPM was still detected in both patient groups, indicating that endogenous modulation, although effective for a shorter duration, is partially functioning in patients with LBP.

Background: Nerve growth factor (NGF) plays a pivotal role in survival, growth, and differentiation of the nervous system. Increased levels of NGF have been reported in human pain disorders. Experimental injection of NGF in humans is known to evoke long-lasting mechanical sensitization and subsequent allodynia and hyperalgesia., Methods: Reproducibility of intradermal injection of NGF was investigated. Twenty healthy male volunteers were included (mean age 24 years, range 19 to 31). The experiment consisted of 3 identical treatment periods with period 1 stimulating the right arm, period 2 the left arm, and period 3 stimulating the right arm again (period one and three were separated by at least 21 days). Pain intensity was assessed in response to several phasic stimuli in 3 adjacent sites of the volar forearm: pressure; pinprick; brush; and heat before and after NGF injection. Additionally, areas of allodynia and secondary hyperalgesia were assessed. Rekindling with pressure was performed 1 hour and 24 hours after injection. Reproducibility was assessed with intraclass correlation coefficient (ICC 3,1)., Results: ICC values > 0.6 for all phasic stimuli and for the area of hyperalgesia. After NGF injection, pressure pain (P < 0.001) and heat pain (P < 0.01) sensitivity increased significantly. After rekindling, the area of hyperalgesia (von Frey 26 g) was significantly increased (P = 0.03) and sensitivity to pinprick was increased (P < 0.02)., Conclusion: Intradermal NGF injection is capable of inducing reproducible allodynia and hyperalgesia, and the model is recommended for future experimental and pharmacological pain studies., (© 2014 World Institute of Pain.)

Objective: Cutaneous hyperalgesia is prominent in the ultraviolet-B (UVB) model of inflammatory pain. This study investigated possible interactions between cutaneous and deep tissues hyperalgesia., Methods: A total of 16 healthy volunteers participated in the study. Skin inflammation was induced unilaterally by UVB irradiation (three times of the individual minimal erythema dose) in square-shaped areas on the upper-trapezius and lower-back. Moderate delayed onset muscle soreness (DOMS) was induced bilaterally in the low-back by eccentric exercise. Cutaneous blood flow, mechanical thresholds, pressure pain thresholds (PPTs), temporal summation to repetitive pressure stimulation, and stimulus-response functions (SR curve) relating graded pressure stimulations and pain intensity were measured within and outside the irradiated areas, before and 24 hours after irradiation and eccentric muscle exercise., Results: Compared with baseline (P < 0.05): the assessments 24 hours after irradiation demonstrated: 1) increased superficial blood flow inside and outside the irradiated areas and in the DOMS site; 2) reduced mechanical thresholds within the irradiated areas; 3) left-shifted SR curve function within and outside the irradiated areas; and 4) facilitated temporal summation of pain inside the irradiated areas and in the DOMS site. There was no significant influence of muscle hyperalgesia on skin measures in normal or UVB-inflamed skin., Conclusions: Moderate degrees of muscle sensitization could not facilitate UVB-induced cutaneous mechanical sensitivity, whereas UVB-induced neurogenic inflammation is enhanced when the DOMS is present., (Wiley Periodicals, Inc.)

Background: This is a case report of sensory assessment in a woman with severe chronic pelvic pain following uterine artery embolization, and a discussion of a commonly observed sensory manifestation (allodynia) associated with chronic pelvic pain due to gynaecological conditions. Allodynia, as a common sensory abnormality can be readily detected at the bedside and represents the development of pain sensitization. Emergence of abdominal and perineal allodynia (assessed by cotton swap stroking and/or questionnaire) is associated with the development of the clinical features of sensitization: continuous pelvic pain, muscle tenderness, and reduced pressure pain thresholds., Case: A uterine artery embolization was performed on a 42-year-old woman to treat a postpartum hemorrhage. The woman experienced severe pain immediately following the procedure, and it had persisted for one year when she was referred for chronic unrelenting pain. She was found to have extensive allodynia, myofascial dysfunction, and reduced pain thresholds. A hysterectomy was undertaken. As the pain persisted, botulinum toxin was administered to the lower abdomen in the region of reduced pain thresholds. Partial resolution of pain, physical limitation, and allodynia resolved one year after the hysterectomy and shortly after the injections of four tender regions of the anterior cutaneous nerves with 2.5 and 5.0 IU of botulinum toxin., Conclusion: Testing for allodynia is a validated bedside test for pain sensitization. A clinical trial of botulinum toxin is indicated for the management of chronic pelvic pain associated with allodynia and pain sensitization.

Topical high-concentration L-menthol is the only established human experimental pain model to study mechanisms underlying cold hyperalgesia. We aimed at investigating the combinatorial effect of cold stimuli and topical L-menthol on cold pain and secondary mechanical hyperalgesia. Analogue to the heat-capsaicin model on skin sensitization, we proposed that cold/menthol enhances or prolong L-menthol-evoked sensitization. Topical 40% L-menthol or vehicle was applied (20 minutes) on the volar forearms of 20 healthy females and males (age, 28.7 ± 0.6 years). Cold stimulation of 5°C for 5 minutes was then applied to the treated area 3 times with 40-minute intervals. Cold detection threshold and pain, mechanical hyperalgesia (pinprick), static and dynamic mechanical allodynia (von Frey and brush), skin blood flow (laser speckle), and temperature (thermocamera) were assessed. Cold detection threshold and cold pain threshold (CPT) increased after L-menthol and remained high after the cold rekindling cycles (P < 0.001). L-menthol evoked secondary hyperalgesia to pinprick (P < 0.001) particularly in females (P < 0.05) and also induced secondary allodynia to von Frey and brush (P < 0.001). Application of cold stimuli kept these areas enlarged with a higher response in females to brush after the third cold cycle (P < 0.05). Skin blood flow increased after L-menthol (P < 0.001) and stayed stable after cold cycles. Repeated application of cold on skin treated by L-menthol facilitated and prolonged L-menthol-induced cold pain and hyperalgesia. This model may prove beneficial for testing analgesic compounds when a sufficient duration of time is needed to see drug effects on CPT or mechanical hypersensitivity.

Clinical research has consistently detected alteration in central pain processing leading to hypersensitivity. Most methods used in humans are reliable and have face validity to detect widespread central hypersensitivity. However, construct validity is difficult to investigate due to lack of gold standards. Reference values in the pain-free population have been generated, but need replication. Research on pain biomarkers that reflect specific central hypersensitivity processes is warranted. Few studies have analyzed the prognostic value of central hypersensitivity. Most medications acting at central level and some non-pharmacological approaches, including psychological interventions, are likely to attenuate central hypersensitivity., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Musculoskeletal pain is often associated with a nonhomogeneous distribution of mechanical hyperalgesia. Consequently, new methods able to detect this distribution are needed., Objective: To develop and test a new method for assessing muscle hyperalgesia with high temporal and spatial resolution that provides complementary information compared with information obtained by traditional static pressure algometry., Methods: The dynamic pressure algometer was tested bilaterally on the tibialis anterior muscle in 15 healthy subjects and compared with static pressure algometry. The device consisted of a wheel that was rolled over the muscle tissue with a fixed velocity and different predefined forces. The pain threshold force was determined and pain intensity to a fixed-force stimulation was continuously rated on a visual analogue scale while the wheel was rolling over the muscle. The pressure pain sensitivity was evaluated before, during, and after muscle pain and hyperalgesia induced unilaterally by either injection of hypertonic saline (0.5 mL, 6%) into the tibialis anterior or eccentric exercise evoking delayed-onset muscle soreness (DOMS)., Results: The intraclass correlation coefficient was >0.88 for the dynamic thresholds; thus, the method was reliable. Compared with baseline, both techniques detected hyperalgesia at the saline injection site and during DOMS (P<0.05). The dynamic algometer also detected the widespread, patchy distribution of sensitive loci during DOMS, which was difficult to evaluate using static pressure algometry., Discussion and Conclusion: The present study showed that dynamic pressure algometry is a reliable tool for evaluating muscle hyperalgesia (threshold and pain rating) with high temporal and spatial resolution. It can be applied as a simple clinical bed-side test and as a quantitative tool in pharmacological profiling studies.

Objective: To determine the presence of widespread pressure hyperalgesia in multiple sclerosis (MS) patients with and without pain and its association with pain and fatigue., Methods: A total of 108 individuals with definite MS, 49 men and 59 women (mean age, 44±8 y) and 108 age-matched and sex-matched pain-free controls (mean age, 44±9 y) were included. Fifty patients (n=58, 54%) reported pain and 50 (46%) did not. Pressure pain threshold (PPT) was bilaterally assessed over supraorbital, infraorbital, mental, median, radial and ulnar nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscle by an assessor blinded to the patient's condition. The intensity of pain was assessed with a numerical pain rate scale (0 to 10), fatigue was determined with the Fatigue Impact Scale, and depression was evaluated with the Beck Depression Inventory., Results: The analyses of covariance revealed that PPT were significantly decreased bilaterally over the supraorbital, infraorbital, mental, median, ulnar and radial nerve trunks, C5-C6 joint, second metacarpal, and tibialis anterior muscles in patients with MS compared with pain-free controls (all, P<0.001). No significant differences existed between MS patients with pain and those without pain (all P>0.944). Patients with pain exhibited higher fatigue and depression than those patients without pain (P<0.05). PPT was not associated with any clinical variable, that is, pain, depression, or fatigue., Conclusions: Our study found widespread pressure pain hyperalgesia in individuals with MS as compared with pain-free controls. No differences existed between MS patients with pain and those without pain in the presence of widespread pressure sensitivity. Current results suggest that MS is associated with sensory hyperexcitability of the central nervous system or dysfunction in endogenous pain modulatory systems.

Hyperalgesia in different musculoskeletal structures including bones is a major clinical problem. An experimental bone hyperalgesia model was developed in the present study. Hyperalgesia was induced by three different weights impacted on the shinbone in 16 healthy male and female subjects. The mechanical impact pain threshold (IPT) was measured as the height from which three weights (165, 330, and 660 g) should be dropped to elicit pain at the shinbone. Temporal summation of pain to repeated impact stimuli was assessed. All these stimuli caused bone hyperalgesia. The pressure pain threshold (PPT) was assessed by a computerized pressure algometer using two different probes (1.0 and 0.5 cm(2)). All parameters were recorded before (0), 24, 72, and 96 h after the initial stimulations. The IPTs were lowest 24 h after hyperalgesia induction for all three weights and the effect lasted up to 72 h (p < 0.05). The PPT obtained with the 1.0 cm(2) probe was significantly lower than the PPT obtained with the 0.5 cm(2) probe, regardless of the time. Females developed more pronounced hyperalgesia reflected in reduced IPTs and PPTs (p < 0.05). Temporal summation was significantly (p < 0.05) facilitated after induction of hyperalgesia with the strongest facilitation in males. The developed bone pain and hyperalgesia model may provide the basis for studying this fundamental mechanism of bone-related hyperalgesia and be used for profiling compounds developed for this target.

Background and Aims: A limited number of quantitative sensory pain tests (QST) were selected on the basis of ease of application and interpretation in a clinical setting. QST results were summarized as a composite score on a scale of 0 to 4 that was deemed to facilitate clinical interpretation. The QST set was used to investigate differences in pain sensitivity between low-back pain (LBP) subgroups and was correlated with important clinical parameters., Materials and Methods: A total of 198 LBP patients and 44 controls were recruited and data were collected on: LBP intensity and duration, improvement in LBP, functional status, psychological profile, quality of life, and current work situation. QST consisted of pressure-pain threshold of the infraspinatus muscle, pain intensity with sustained mechanical pressure on the thumb nailbed, conditioned pain modulation, and pain tolerance assessed by cold-pressor test., Results: Chronic, but not acute LBP patients scored significantly higher on the composite score of pain sensitivity than controls. A weak linear correlation between the composite score of pain sensitivity and intensity of clinical LBP and disability was found. A contingency was found between a high pain sensitivity (dichotomized composite score of pain sensitivity) and the lack of improvement in LBP. Pain sensitivity did not correlate with LBP duration, psychological profile, or sick leave., Conclusions: Pain sensitivity may be important for the prognosis of LBP, but QST is not currently part of routine clinical examination of LBP patients. The selected set of pain tests and the composite score of pain sensitivity could serve as a clinically applicable QST procedure in the examination of LBP.

Intradermal injections of glutamate and capsaicin are attractive to use in human experimental pain models because hyperalgesia and allodynia mimic isolated aspects of clinical pain disorders. The aim of the present study was to investigate the reproducibility of these models. Twenty healthy male volunteers (mean age 24 years; range 18-38 years) received intradermal injections of glutamate and capsaicin in the volar forearm. Magnitudes of secondary pinprick hyperalgesia and brush-evoked allodynia were investigated using von Frey filaments (gauges 10, 15, 60 and 100 g) and brush strokes. Areas of secondary hyperalgesia and allodynia were quantified immediately after injection and after 15, 30 and 60 min. Two identical experiments separated by at least 7 days were performed. Reproducibility across and within volunteers (inter- and intra-individual variation, respectively) was assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CV). Secondary pinprick hyperalgesia was observed as a marked increase in the visual analogue scale (VAS) response to von Frey gauges 60 and 100 g (P < 0.001) after glutamate injection. For capsaicin, secondary pinprick hyperalgesia was detected with all von Frey gauges (P < 0.001). Glutamate evoked reproducible VAS response to all von Frey gauges (ICC > 0.60) and brush strokes (ICC > 0.83). Capsaicin injection was reproducible for secondary hyperalgesia (ICC > 0.70) and allodynia (ICC > 0.71). Intra-individual variability was generally lower for the VAS response to von Frey and brush compared with areas of secondary hyperalgesia and allodynia. In conclusion, glutamate and capsaicin yield reproducible hyperalgesic and allodynic responses, and the present model is well suited for basic research, as well as for assessing the modulation of central phenomena., (© 2014 Wiley Publishing Asia Pty Ltd.)

Hip disorder patients typically present with extensive pain referral and hyperalgesia. To better understand underlying mechanisms, an experimental hip pain model was established in which pain referrals and hyperalgesia could be studied under standardized conditions. In 16 healthy subjects, pain was induced by hypertonic saline injection into the gluteus medius tendon (GMT), adductor longus tendon (ALT), or gluteus medius muscle (GMM). Isotonic saline was injected contralaterally as control. Pain intensity was assessed on a visual analogue scale (VAS), and subjects mapped the pain distribution. Before, during, and after injections, passive hip joint pain provocation tests were completed, together with quantitative sensory testing as follows: pressure pain thresholds (PPTs), cuff algometry pain thresholds (cuff PPTs), cutaneous pin-prick sensitivity, and thermal pain thresholds. Hypertonic saline injected into the GMT resulted in higher VAS scores than hypertonic injections into the ALT and GMM (P<.05). Referred pain areas spread to larger parts of the leg after GMT and GMM injections compared with more regionalized pain pattern after ALT injections (P<.05). PPTs at the injection site were decreased after hypertonic saline injections into GMT and GMM compared with baseline, ALT injections, and isotonic saline. Cuff PPTs from the thigh were decreased after hypertonic saline injections into the ALT compared with baseline, GMT injections, and isotonic saline (P<.05). More subjects had positive joint pain provocation tests after hypertonic compared with isotonic saline injections (P<.05), indicating that this provocation test also assessed hyperalgesia in extra-articular soft tissues. The experimental models may open for better understanding of pain mechanisms associated with painful hip disorders., (Copyright © 2014 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Objectives: Widespread central hypersensitivity and altered conditioned pain modulation (CPM) have been documented in chronic pain conditions. Information on their prognostic values is limited. This study tested the hypothesis that widespread central hypersensitivity (WCH) and altered CPM, assessed during the chronic phase of low back and neck pain, predict poor outcome., Methods: A total of 169 consecutive patients with chronic low back or neck pain, referred to the pain clinic during 1 year, were analyzed. Pressure pain tolerance threshold at the second toe and tolerance time during cold pressor test at the hand assessed WCH. CPM was measured by the change in pressure pain tolerance threshold (test stimulus) after cold pressor test (conditioning stimulus). A structured telephone interview was performed 12 to 15 months after testing to record outcome parameters. Linear regression models were used, with average and maximum pain intensity of the last 24 hours at follow-up as endpoints. Multivariable analyses included sex, age, catastrophizing scale, Beck Depression Inventory, pain duration, intake of opioids, and type of pain syndrome., Results: Statistically significant reductions from baseline to follow-up were observed in pain intensity (P<0.001). No evidence for an association between the measures of WCH or CPM and intensity of chronic pain at follow-up was found., Discussion: A major predictive value of the measures that we used is unlikely. Future studies adopting other assessment modalities and possibly standardized treatments are needed to further elucidate the prognostic value of WCH and altered CPM in chronic pain.

Background: Chronic stress is prevalent in patients with ischemic heart disease (IHD) and worsens the long-term prognosis. Chronic stress is vaguely defined, but is associated with depressive symptoms, reduced psychological wellbeing, and reduced quality of life (QOL). Stress seems to induce hyperalgesia.The aim of the present study was to evaluate hyperalgesia by pressure pain sensitivity (PPS) in patients with IHD, and compare PPS to questionnaires measuring depressive symptoms, reduced psychological wellbeing, and QOL as markers of stress. Design. A cross-sectional study of 361 subjects with IHD., Methods: PPS was measured on the sternum, and compared to the questionnaires: Clinical stress symptoms score (CSS), Major Depression Inventory (MDI), WHO-5 Wellbeing Index, and SF-36 QOL score., Results: PPS correlated to CSS (r = 0.20, p < 0.001), MDI (r = 0.14, p = 0.02), SF-36 mental component summary score (MCS) (r = - 0.10, p = 0.049), SF-36 physical component summary score (PCS) (r = - 0.17, p = 0.001), and self-perceived stress level (r = 0.15, p = 0.006). CSS correlated similarly (r = 0.5-0.7, all p < 0.001). Comparing subjects within the lowest vs. highest tertiles of PPS and CSS, the mean MDI score was 4 vs. 15, WHO-5 was 77 vs. 53, SF-36 PCS was 53 vs. 43, and SF-36 MCS was 58 vs. 46; all p < 0.001., Conclusions: PPS reflected to a modest degree markers of chronic stress in IHD. PPS and CSS together might be useful as easy-to use tools for evaluating these markers in IHD patients.

Background and Objectives: Quantitative sensory testing (QST) is widely used to investigate peripheral and central sensitization. However, the comparative performance of different QST for diagnostic or prognostic purposes is unclear. We explored the discriminative ability of different quantitative sensory tests in distinguishing between patients with chronic neck pain and pain-free control subjects and ranked these tests according to the extent of their association with pain hypersensitivity., Methods: We performed a case-control study in 40 patients and 300 control subjects. Twenty-six tests, including different modalities of pressure, heat, cold, and electrical stimulation, were used. As measures of discrimination, we estimated receiver operating characteristic curves and likelihood ratios., Results: The following quantitative sensory tests displayed the best discriminative value: (1) pressure pain threshold at the site of the most severe neck pain (fitted area under the receiver operating characteristic curve, 0.92), (2) reflex threshold to single electrical stimulation (0.90), (3) pain threshold to single electrical stimulation (0.89), (4) pain threshold to repeated electrical stimulation (0.87), and (5) pressure pain tolerance threshold at the site of the most severe neck pain (0.86). Only the first 3 could be used for both ruling in and out pain hypersensitivity., Conclusions: Pressure stimulation at the site of the most severe pain and parameters of electrical stimulation were the most appropriate QST to distinguish between patients with chronic neck pain and asymptomatic control subjects. These findings may be used to select the tests in future diagnostic and longitudinal prognostic studies on patients with neck pain and to optimize the assessment of localized and spreading sensitization in chronic pain patients.

Study Design: Cross-sectional study., Objectives: To compare pressure pain thresholds (PPTs) between adolescent females diagnosed with patellofemoral pain syndrome (PFPS) and gender- and age-matched controls without musculoskeletal pain., Background: PFPS is prevalent among adolescents and may be associated with reduced PPT both locally and remotely from the site of reported pain. This may indicate altered central processing of nociceptive information. However, this has never been investigated in adolescents with PFPS., Methods: Adolescents with PFPS and a comparison group without musculoskeletal pain were recruited from a population-based cohort of students from 4 upper secondary schools, aged 15 to 19 years. All 2846 students within that age range were invited to answer an online questionnaire regarding musculoskeletal pain. The students who reported knee pain were contacted by telephone and offered a clinical examination by an experienced rheumatologist, who made a diagnosis. PPTs were measured at 4 sites around the knee and 1 site on the tibialis anterior in the 57 female adolescents diagnosed with PFPS and in 22 female adolescents without musculoskeletal pain., Results: Adolescents with PFPS, compared to controls, had significantly lower PPTs (26%-37% [100-178 kPa]) at each of the 4 sites around the knee, suggesting localized hyperalgesia. On the tibialis anterior, adolescents with PFPS had a 33% (159 kPa) lower PPT (distal hyperalgesia) compared with controls., Conclusion: These findings suggest that adolescent females with PFPS have localized and distal hyperalgesia. These findings may have implications for treating PFPS, as both peripheral and central mechanisms may be driving the pain. Registered at clinicaltrials.gov (NCT01438762).

Background: Multiple Chemical Sensitivity (MCS) is a chronic condition characterized by recurrent, non-specific symptoms in response to chemically unrelated exposures in non-toxic concentrations. Although the pathophysiology of MCS remains unknown, central sensitization may be an important factor contributing to the clinical manifestations., Purpose: To use quantitative sensory testing (QST) to study central hyperexcitability and multiple aspects of central sensory processing in MCS patients without comorbid overlapping disorders and to compare the results with those among matched controls., Methods: 15 MCS patients and 15 healthy matched controls underwent QST to assess the following aspects of pain: capsaicin-induced secondary punctate hyperalgesia, stimulus response function (SRF) to punctate mechanical stimuli before and after capsaicin injection, temporal summation to punctate stimuli post capsaicin injection, pressure pain thresholds, heat pain thresholds, tonic heat stimulation and conditioning pain modulation (CPM: formerly known as diffuse noxious inhibitory control or DNIC)., Results: The mean area of capsaicin-induced secondary punctate hyperalgesia was significantly larger in MCS patients than in controls at 5, 30 and 60 min post capsaicin injection (p=0.01). In addition MCS patients reported higher ratings in response to punctate mechanical stimuli assessed by SRF compared with controls (p<0.001). The CPM test induced significantly higher pain ratings in patients than in controls (p=0.002). We found no group differences in pressure pain and heat pain thresholds, temporal summation to punctate stimuli post capsaicin injection, capsaicin and tonic heat pain ratings or CPM effect., Conclusion: Increased capsaicin-induced secondary punctate hyperalgesia was demonstrated in MCS patients without comorbid, overlapping disorders, suggesting facilitated central sensitization in MCS., (Copyright © 2012 Elsevier GmbH. All rights reserved.)

The mechanisms underlying phantom limb pain are not fully known, but hypersensitivity appears to be a central element. Menthol has previously been suggested as a model for hypersensitivity, but it has not yet been investigated if different levels of neuropathic pain may influence the effects of menthol or if topical application of menthol may act as a model for hypersensitivity in patients with phantom limb pain. In the present study, menthol (l-menthol 40%) was applied to the affected and non-affected sides in 24 upper-limb amputees with different levels of phantom limb pain to test if menthol could induce cold allodynia and exacerbate wind-up-like pain. The average level of phantom limb pain was significantly related to cold allodynia (P=0.044). Prior to application of menthol, the level of phantom limb pain was significantly related to the level of wind-up-like pain following both brush (P=0.040) and pinprick (P=0.033) stimulation. After application of menthol, the level of phantom limb pain was only related to wind-up-like pain following brush (P=0.011) but not pinprick stimulation (P=0.233). This study indicates that menthol does influence hypersensitivity in phantom limb pain patients, and it is the first study to show that menthol may exacerbate wind-up-like pain in this group of neuropathic pain patients. The findings suggest that menthol may act as a model for studying sensitization in phantom limb patients., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

OBJECTIVE.: To assess pain sensitivity and spreading hyperalgesia in lateral epicondylalgia (LE). SUBJECTS.: Twenty-two women with LE, and 38 controls were included. OUTCOME MEASURES.: Computerized cuff pressure algometry was used for assessment of pressure-pain threshold and tolerance. The stimulus was applied using a single (stimulation-area: 241 cm(2) ) or double-chambered (stimulation-area: 482 cm(2) ) tourniquet on the arm and leg. Spatial summation was expressed as the ratio between pressure-pain thresholds to single and double cuff-chamber stimulation. During 10-minute constant pressure stimulation at intensity relative to the individual pain threshold, the pain intensity was continuously recorded using an electronic visual analogue scale (VAS), and from this the degree of temporal summation was estimated. For LE, a Doppler ultrasound examination of the elbow was made to identify inflammation. RESULTS.: In LE compared with controls the pressure-pain threshold and tolerance were on average reduced by respectively 31% (nonsignificant) and 18% (nonsignificant) on the lower arm and by 32% (P < 0.05) and 22% (P < 0.05) on the lower leg (spreading sensitization). Within the LE group, pressure-pain thresholds were on average reduced by 20% (P < 0.05) and pain tolerance by 10% (nonsignificant) on the painful compared with the asymptomatic side. Spatial summation (P < 0.01) and temporal summation (P < 0.05) was facilitated in LE compared with controls. In LE patients without signs of peripheral inflammation assessed by Doppler ultrasound, temporal summation was significantly stronger than in patients with ongoing inflammation (P < 0.01). CONCLUSION.: Patients with LE may be subgrouped based on pain hypersensitivity and Doppler ultrasound into clinically meaningful subgroups with varying duration of symptoms and different degrees of central sensitization. These groups may require different pain management strategies., (Wiley Periodicals, Inc.)

Background and Aims: Compounds that act on GABA-receptors produce anti-hyperalgesia in animal models, but little is known on their effects in humans. The aim of this study was to explore the potential usefulness of GABA-agonism for the control of pain in humans. Two agonists at the benzodiazepine-binding site of GABAA-receptors (clobazam and clonazepam) were studied using multiple experimental pain tests. Positive results would support further investigation of GABA agonism for the control of clinical pain., Methods: In a randomized double-blind crossover design, 16 healthy male volunteers received clobazam 20 mg, clonazepam 1 mg and tolterodine 1 mg (active placebo). The area of static hyperalgesia after intradermal capsaicin injection was the primary endpoint. Secondary endpoints were: area of dynamic hyperalgesia, response to von Frey hair stimulation, pressure pain thresholds, conditioned pain modulation, cutaneous and intramuscular electrical pain thresholds (1, 5 and 20 repeated stimulation), and pain during cuff algometry., Results: For the primary endpoint, an increase in the area of static hyperalgesia was observed after administration of placebo (p<0.001), but not after clobazam and clonazepam. Results suggestive for an anti-hyperalgesic effect of the benzodiazepines were obtained with all three intramuscular pain models and with cuff algometry. No effect could be detected with the other pain models employed., Conclusions: Collectively, the results are suggestive for a possible anti-hyperalgesic effect of drugs acting at the GABAA-receptors in humans, particularly in models of secondary hyperalgesia and deep pain. The findings are not conclusive, but support further clinical research on pain modulation by GABAergic drugs. Because of the partial results, future research should focus on compounds acting selectively on subunits of the GABA complex, which may allow the achievement of higher receptor occupancy than unselective drugs. Our data also provide information on the most suitable experimental models for future investigation of GABAergic compounds., Trial Registration: ClinicalTrials.gov NCT01011036.

Background: Dynamic mechanical allodynia is traditionally induced by manual brushing of the skin. Brushing force and speed have been shown to influence the intensity of brush-evoked pain. There are still limited data available with respect to the optimal stroke number, length, force, angle and speed. Therefore, an automated brushing device (ABD) was developed, for which brushing angle and speed could be controlled to enable quantitative assessment of dynamic mechanical allodynia., Objectives: To compare the ABD with manual brushing using capsaicin-induced allodynia, and to investigate the role of stroke angle and speed on pain intensity., Methods: Experimental dynamic mechanical allodynia was induced by an intradermal injection of capsaicin (100 µg) into the volar forearm of 12 healthy, male volunteers. Dynamic mechanical allodynia was rated on a 10 cm visual analogue scale (VAS) after each set of strokes at angles of 30°, 60° and 90° with speeds of 17 mm⁄s, 21 mm⁄s and 25 mm⁄s for each angle. A two-way ANOVA with repeated measures was performed to assess the influence of brushing parameters. To evaluate test-retest reliability, Bland-Altman 95% limits of agreement, including a coefficient of repeatability and an intraclass correlation coefficient (ICC), were determined., Results: The angle and speed exhibited a significant impact on pain intensity (P<0.001 and P<0.015, respectively). Post hoc analysis showed that the highest pain intensity was recorded with an angle of 30° regardless of brushing speed. The ABD demonstrated superior test-retest reliability (coefficient of repeatability = 1.9 VAS; ICC=0.91) compared with manual brushing (coefficient of repeatability = 2.8 VAS; ICC=0.80; P<0.05). The most reliable combination of parameters (coefficient of repeatability = 1.3 VAS; ICC=0.97) was an angle of 60° and a speed of 21 mm⁄s., Conclusions: A controlled, automatic brushing method can be used for quantitative investigations of allodynic reactions, and is more reliable for quantitative assessment of dynamic mechanical allodynia compared with traditional manual brushing.

Objectives: To determine the differences in pain, disability, depression, and pressure sensitivity between men and women with fibromyalgia syndrome (FMS), and to analyze the relationship between pain and pressure sensitivity in FMS., Design: A cross-sectional study., Setting: Gender differences in pain sensitivity in individuals with FMS have not been yet clarified., Patients: Twenty-four men (age: 52 ± 6 years) and 24 age-matched women (age: 52 ± 5 years) with FMS diagnosed according to 1990 American College of Rheumatology criteria participated., Outcome Measures: Pressure pain thresholds (PPTs) over the 18 tender points and over the second metacarpal and tibialis anterior muscle were assessed. The intensity and duration of pain, tender point count, the Fibromyalgia Impact Questionnaire, and depression (Beck Depression Inventory-II) were calculated., Results: Women reported higher intensity of pain, tender point count, and depression than men (P < 0.01). Men reported a longer history of pain and disability than women (P = 0.005). Women showed bilateral lower PPT over suboccipital, cervical spine, second rib, supraspinatus, lateral epicondyle, gluteal region, and second metacarpal than men (P < 0.05). Negative associations between tender point count and PPT were found in men and women. In men, negative correlations between the intensity of ongoing pain and PPT over the cervical spine were found. No significant association between PPT and other clinical outcome was seen., Conclusions: Women with FMS showed higher pain severity and lower PPT than men, whereas men exhibited longer duration of symptoms and disability. In men with FMS, the intensity of ongoing pain was positively correlated to pressure hyperalgesia over the neck. This study suggests that FMS could show a different phenotype in women and men and confirm that women exhibit lower PPT than men., (Wiley Periodicals, Inc.)

Objective: Widespread deep tissue pain hyperalgesia was evaluated in women with chronic whiplash associated disorder (n = 25) and controls (n = 10) using computerized cuff pressure algometry and hypertonic saline infusion., Methods: A pneumatic double-chamber cuff was placed around: (i) the arm and (ii) the leg. Cuff inflation rate was constant and the pain intensity was registered continuously on a visual analogue scale (VAS); thresholds of detection and tolerance were extracted. For assessment of spatial summation the protocol was repeated with a single-chamber cuff inflated around the leg. Temporal summation of pain was assessed from the leg with constant cuff pressure stimulation at 2 different pressure intensities for 10 min. Hypertonic saline was infused in the tibialis anterior muscle., Results: Cuff pressure pain thresholds were lower in subjects with whiplash associated disorder compared with controls (p < 0.05). Tonic pressure stimulation evoked higher maximal VAS and larger areas under the VAS curve in subjects with whiplash associated disorder compared with controls (p < 0.05). The pain threshold and tolerance were higher during single cuff than double cuff stimulation. The area under the VAS curve after intramuscular saline infusion was larger in whiplash associated disorder (p < 0.05)., Conclusion: The results indicated widespread hyperalgesia in chronic whiplash associated disorder and facilitated temporal summation outside the primary pain area, suggesting involvement of central sensitization.

The activation of 5-hydroxytryptamine-3 (5-HT-3) receptors in spinal cord can enhance intrinsic spinal mechanisms of central hypersensitivity, possibly leading to exaggerated pain responses. Clinical studies suggest that 5-HT-3 receptor antagonists may have an analgesic effect. This randomized, double-blind, placebo-controlled crossover study tested the hypothesis that the 5-HT-3 receptor antagonist tropisetron attenuates pain and central hypersensitivity in patients with chronic low back pain. Thirty patients with chronic low back pain, 15 of whom were women (aged 53 ± 14 years) and 15 men (aged 48 ± 14 years), were studied. A single intravenous injection of 0.9% saline solution, tropisetron 2mg, and tropisetron 5mg was administrated in 3 different sessions, in a double-blind crossover manner. The main outcome was the visual analogue scale (VAS) score of spontaneous low back pain before, and 15, 30, 60, and 90 minutes after drug administration. Secondary outcomes were nociceptive withdrawal reflexes to single and repeated electrical stimulation, area of reflex receptive fields, pressure pain detection and tolerance thresholds, conditioned pain modulation, and area of clinical pain. The data were analyzed by analysis of variance and panel multiple regressions. All 3 treatments reduced VAS scores. However, there was no statistically significant difference between tropisetron and placebo in VAS scores. Compared to placebo, tropisetron produced a statistically significant increase in pain threshold after single electrical stimulation, but no difference in all other secondary outcomes was found. A single-dose intravenous administration of tropisetron in patients with chronic low back pain had no significant specific effect on intensity of pain and most parameters of central hypersensitivity., (Copyright © 2011 International Association for the Study of Pain. All rights reserved.)

Chronic pain is often associated with hyperalgesia in cross-sectional studies. In the present study, a random cohort of 40-year-old individuals (n = 264) from the general population was assessed for low back pain (LBP) status and pressure pain threshold (PPT), with follow-up assessment 4 and 8 years later. Low PPT at baseline as a potential risk factor for the development of LBP was investigated longitudinally and the association between LBP and hyperalgesia was studied cross-sectionally at baseline and 8-year follow-up. Generalized (p  < 0.03) and localized pressure hyperalgesia (p < 0.02) was found in participants with long-lasting LBP, but not with recent LBP (p > 0.08). Of the participants without recent or long-lasting LBP, those with a low PPT at baseline (lower 10% percentile) had no increased risk of developing LBP (p > 0.05). The findings indicate that PPT decreases as a consequence of long-lasting pain, whereas a low PPT seems not to constitute a separate risk factor for the development of LBP.

Unlabelled: Our aim was to quantify spatial differences in pressure and thermal pain sensitivity maps between patients with unilateral lateral epicondylalgia (LE) and age- and sex-matched controls. Pressure (PPT), cold (CPT), and heat (HPT) pain thresholds were assessed over 12 points forming a 3 × 4 matrix (4 points in the superior part, 4 points in the middle, and 4 points in the lower part around the lateral epicondyle) bilaterally in 16 subjects with strictly unilateral LE and 16 age- and sex-matched controls in a blinded design. Topographical pain sensitivity maps to pressure and thermal stimulation over the elbow in patients with LE and healthy controls were calculated. A multilevel 3-way ANCOVA test was applied to detect differences in topographical maps between groups. Subjects with LE showed bilateral lower PPT, higher CPT (pain at higher temperature) and lower HPT (pain at lower temperature) at all the measurement points as compared to controls (all, P < .01). PPT were lower at points over the extensor carpi radialis brevis (ECRB) muscle as compared to points over the extensor digitorum communis muscle (P < .01) and over the extensor carpi ulnaris muscle (P < .001). CPT and HPT were not significantly different between points (P > .05). Topographical pressure and thermal pain sensitivity maps revealed bilateral hyperalgesia in patients with strictly unilateral LE. LE patients exhibited heterogeneously distributed pressure pain hyperalgesia while cold or heat maps were homogenous. The most sensitive localizations for PPT assessment corresponded to the muscle belly of the ECRB. Our results confirm the role of ECRB muscle in LE and argue for evidence of peripheral and central sensitization mechanisms in patients with strictly unilateral symptoms., Perspective: Topographical pressure and thermal sensitivity maps revealed bilateral hyperalgesia in patients with strictly unilateral lateral epicondylalgia (LE). LE patients exhibited heterogeneously distributed pressure pain hyperalgesia while cold or heat pain maps were homogenous. The most sensitive localizations for PPT assessment corresponded to the muscle belly of the ECRB., (Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.)

The aim of this study was to test the hypothesis that nuclear factor-kappa B (NF-κB) is involved in TRPV4-NO pathway in thermal hyperalgesia following chronic compression of the dorsal root ganglion (DRG) (the procedure hereafter termed CCD) in rat. Intrathecal administration of two NF-κB inhibitors, pyrrolidine dithiocarbamate (PDTC; 10(-1) to 10(-2)M) and BAY (100-50 μM), both induced significantly dose-dependent increase in the paw withdrawal latency (PWL) and decrease in nitric oxide (NO) content in DRG when compared with control rats. Pretreatment with 4α-phorbol 12,13-didecanoate (4α-PDD, transient receptor potential vanilloid 4 (TRPV4) synthetic activator, 1 nm) attenuated the suppressive effects of PDTC (10(-1)M) and BAY (100 μM) on CCD-induced thermal hyperalgesia and NO production. In addition, Western blot analysis indicated that CCD rats exhibited nuclear NF-κB protein expression and low levels of cytoplasmic inhibitory-kappa B (I-κB) expression; the increase in NF-κB expression and decrease in I-κB expression were reversed after intrathecal injection of PDTC. In conclusion, our data suggested that NF-κB could be involved in TRPV4-NO pathway in CCD-induced thermal hyperalgesia., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Objective: Pressure algometry is used for assessment of pain sensitivity. In this study the relation between tissue characteristics and pressure pain thresholds was investigated., Methods: Three-dimensional finite-element computer-models were developed to simulate the tissue stress and strain distribution during pressure stimulation on muscles with different hardness (I, II, III, IV (hardest)) and subcutaneous adipose tissue thickness (normal and thicker). The computer model was validated based on data recorded by computer-controlled pressure-induced muscle pain in 8 and 16 partecipants, respectively., Results: The experimental pressure-indentation curve fitted the outcome of the FE model (R>0.73). Stress and strain were extracted from the models at a known painful pressure stimulation level. PPT and PPTO were not significantly different in subjects with normal and thick adipose tissue in accordance with the simulation model where the strain in muscle tissue was comparable in the two conditions. The strain in adipose tissue was larger in subjects with thick adipose tissue compared with normal adipose thickness. In relaxed muscle (hardness I) the principal strain peaked at 0.12 in the adipose tissue, was reduced to 0.07 in the muscle tissue and 0.05 in the harder muscle. Significantly higher PPT and PPTO were recorded in harder compared with softer muscles (P<0.02)., Discussion: The pressure pain sensitivity of the deep layer is related to the amount of muscle strain, which is affected by the muscle hardness and the thickness of adipose tissue. This is clinically relevant as these two factors are not taken into consideration when pressure pain assessments are performed in clinical routine.

During the last decade, a multi-modal approach has been established in human experimental pain research for assessing pain thresholds and responses to various experimental pain modalities. Studies have concluded that differences in responses to pain stimuli are mainly related to variation between individuals rather than variation in response to different stimulus modalities. In a factor analysis of 272 consecutive volunteers (137 men and 135 women) who underwent tests with different experimental pain modalities, it was determined whether responses to different pain modalities represent distinct individual uncorrelated dimensions of pain perception. Volunteers underwent single painful electrical stimulation, repeated painful electrical stimulation (temporal summation), test for reflex receptive field, pressure pain stimulation, heat pain stimulation, cold pain stimulation, and a cold pressor test (ice water test). Five distinct factors were found representing responses to 5 distinct experimental pain modalities: pressure, heat, cold, electrical stimulation, and reflex-receptive fields. Each of the factors explained approximately 8% to 35% of the observed variance, and the 5 factors cumulatively explained 94% of the variance. The correlation between the 5 factors was near null (median ρ=0.00, range -0.03 to 0.05), with 95% confidence intervals for pairwise correlations between 2 factors excluding any relevant correlation. Results were almost similar for analyses stratified according to gender and age. Responses to different experimental pain modalities represent different specific dimensions and should be assessed in combination in future pharmacological and clinical studies to represent the complexity of nociception and pain experience., (Copyright © 2011 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)