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Pain catastrophizing in the aging population has not been studied in great detail. Existing investigations have reported conflicting results on the effects of age on pain catastrophizing in relation to pain responses. This study investigated the relationship between pain catastrophizing, and its individual components (rumination, magnification, and helplessness), and the responses to standardized experimental pain stimuli in old and young, healthy adults.

Background: To investigate the analgesic effects of vibro-acupuncture (VA), a novel acuvibrator was developed. Objectives: To compare the analgesic effects of VA with those of manual acupuncture (MA) and placebo acupuncture (PA) on subjects with normal sensory perception (Study I), experimentally induced acute pain (Study II), and clinical chronic pain (Study III). Methods: Thirty healthy volunteers (21 males, age: 20-30 years) participated in Study I. Fourteen healthy volunteers (8 males, age: 20-32 years) participated in Study II in which experimental pain was induced by injection of hypertonic saline. Fourteen patients suffering from unilateral epicondylalgia (9 males, age: 30-61 years) participated in Study III. All participants received VA, MA, and PA at LI4 and LI10 points in a randomized, crossover, and double-blinded manner. Quantitative sensory testing (QST) was performed on the ipsilateral forearm before and after each treatment. Data were analyzed using repeated-measures (RM) ANOVA. Results: A significantly higher vibration detection threshold (VDT) was observed after treatment of VA than after MA and PA (p < 0.001). No significant treatment effect on experimental pain intensity was detected (p > 0.086). Significantly lower pain intensity (p = 0.005) and a smaller drawing area (p = 0.011) of unilateral epicondylalgia were found after VA treatment than after PA. Conclusion: A specific effect on the VDT beyond that of MA and PA was evoked by VA. Patients with epicondylitis showed significantly lower pain intensity during VA than during PA. This study indicated that VA may be beneficial in individuals with clinical chronic musculoskeletal pain; however, further studies are needed. [ABSTRACT FROM AUTHOR]

Aims: To investigate the effects of local intramuscular injection of the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine on chronic myofascial pain and mandibular function in temporomandibular disorder patients. Methods: Fourteen myofascial temporomandibular disorder pain patients (10 women and 4 men) were recruited. The subjects completed 2 sessions in a doubleblinded randomized and placebo-controlled trial. They received a single injection of 0.2 mL ketamine or placebo (buffered isotonic saline [NaCl], 155 mmol/L) into the most painful part of the masseter muscle. The primary outcome parameters were spontaneous pain assessed on an electronic visual analog scale and numeric rating scale. In addition, numeric rating scale of unpleasantness, numeric rating scale of pain relief, pressure pain threshold, pressure pain tolerance, completion of a McGill Pain Questionnaire and pain drawing areas, maximum voluntary bite force and maximum voluntary jaw opening were obtained. Paired t tests and analysis of variance were performed to compare the data. Results: There were no main effects of the treatment on the outcome parameters except for a significant effect of time for maximum voluntary bite force (analysis of variance; P = .030) and effects of treatment, time, and interactions between treatment and time for maximum voluntary jaw opening (analysis of variance; P < .047). Conclusion: These results suggest that peripheral NMDA receptors do not play a major role in the pathophysiology of chronic myofascial temporomandibular disorder pain. Although there was a minor effect of ketamine on maximum voluntary jaw opening, local administration may not be promising treatment for these patients. [ABSTRACT FROM AUTHOR]

Introduction Quantitative sensory tests (QST) can be used for profiling anti-nociceptive effects of analgesics. However, anti-nociceptive effects detected by QST are not necessarily associated with analgesic effects in pain patients. As part of a large investigation on low back pain, this paper describes the immediate analgesic and anti-nociceptive effects of oxycodone in chronic low-back pain and ranks different QST according to their ability to reflect this effect. The results are expected to support the selection of QST for future studies on potential novel opioid agonists in human pain. Methods In this randomized, placebo-controlled and double-blinded cross-over study, 50 patients with chronic low-back pain received a single oral dose of oxycodone 15 mg or active placebo, and underwent multiple QST testing. The intensity of low-back pain was recorded during 2 h. The areas under the ROC curves and 95% confidence intervals were determined, whereby responder status (≥30% pain reduction) was set as reference variable and changes in QST from baseline were set as classifiers. Results Significant analgesic effect on low-back pain as well as anti-nociceptive effects for almost all QST parameters were observed. The QST with the highest area under the curve were heat pain detection threshold (0.65, 95%-CI 0.46 to 0.83), single-stimulus electrical pain threshold (0.64, 95%-CI 0.47 to 0.80) and pressure pain detection threshold (0.63, 95%-CI 0.48 to 0.79). Conclusions The results suggest that anti-nociceptive effects assessed by QST fairly reflect clinical efficacy of oxycodone on low-back pain. Pressure pain detection threshold, heat pain detection threshold and single-stimulus electrical pain threshold may be more suitable to sort out potential non-responders rather than identifying potential responders to opioid medication. Future pre-clinical human research may consider these results when investigating the analgesic effect of opioid agonists by means of QST. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose. The aim of this study was to evaluate pressure pain sensitivity on leg and arm in 98 healthy persons (50 women) using cuff algometry. Furthermore, associations with sex and physical activity level were investigated. Method. Normal physical activity level was defined as Godin Leisure-Time Exercise Questionnaire (GLTEQ) score ≤ 45 and high activity level as GLTEQ> 45. A pneumatic double-chamber cuff was placed around the arm or leg where a single chamber was inflated. The cuff inflation rate (1 kPa/s) was constant, and pain intensity was registered continuously on a 10 cm electronic visual analogue scale (VAS). The pain detection threshold (PDT) was defined as when the pressure was perceived as painful, and pain tolerance (PTT) was when the subject terminated the cuff inflation. For PTT, the corresponding VAS score was recorded (VAS-PTT). The protocol was repeated with two chambers inflated. Result. Only single cuff results are given. For women compared with men, the PDT was lower when assessed in the arm (P 5 0.002), PTTs were lower in the arm and leg (P < 0.001), and the VASPTT was higher in the arm and leg (P < 0.033). Highly active participants compared with less active had higher PDT (P 5 0.027) in the leg. Women showed facilitated spatial summation (P < 0.014) in the arm and leg and a steeper VAS slope (i.e., the slope of the VAS pressure curve between PDT and PPT) in the arm and leg (P < 0.003). Conclusion. This study indicates that reduced pressure pain sensitivity is associated both with male sex and physical activity level. [ABSTRACT FROM AUTHOR]

This experimental, translational, experimental pain, single-center, randomized, double-blind, single-dose, 3-treatment, 3-period cross-over proof-of-concept volunteer trial studied the efficacy of a novel TRPV1 antagonist (V116517) on capsaicin- and UV-B-induced hyperalgesia. Heat and pressure pain thresholds, von Frey stimulus-response functions, and neurogenic inflammation were assessed together with safety. Each treatment period was 4 days. The 3 single oral treatments were 300 mg V116517, 400 mg celecoxib (a COX-2 inhibitor), and placebo. The heat pain detection and tolerance thresholds were increased significantly (P < 0.0001) by V116517. Heat pain detection and tolerance thresholds showed significantly less capsaicin hyperalgesia after V116517 (P = 0.004 and P < 0.0001, respectively). Celecoxib reduced UV-B-provoked pressure pain sensitization (P = 0.01). Laser Doppler flowmetry and erythema index after UV-B were significantly (P < 0.0001) reduced by celecoxib. Stimulus-response function in capsaicin-treated areas showed significant differences between both celecoxib and placebo and between V116517 and placebo. The body temperature showed no change, and no side effects were reported for any of the treatments. The TRPV1 antagonists and the COX-2 inhibitor showed different antihyperalgesic profiles indicating different clinical targets. In addition, the preclinical profile of V116517 in rat models of UV-B and capsaicin-induced hypersensitivity was compared with the human experimental data and overall demonstrated an alignment between 2 of the 3 end points tested. The TRPV1 antagonist showed a potent antihyperalgesic action without changing the body temperature but heat analgesia may be a potential safety issue. [ABSTRACT FROM AUTHOR]

Objective. Patellofemoral pain (PFP) is common among young individuals. Female adolescents with PFP present typically with localized mechanical hyperalgesia around the knee, but the effect of central pain mechanisms are unknown. This study aimed to compare temporal summation of pain, conditioned pain modulation (CPM), and widespread hyperalgesia in young female adults with PFP and age-matched pain-free controls. Design. Cross-sectional study. Setting and Subjects. Twenty young female adults (19-21 years old) with long-standing PFP were compared with 20 pain-free controls from the same population-based cohort. Methods. Cuff algometry was used to assess the pain detection threshold. Temporal summation of pain was assessed by recording the pain intensity on a visual analog scale during repeated cuff pressure stimulations at pain tolerance intensity on the lower leg. CPM was recorded as an increase in the cuff pain detection threshold in response to experimental conditioning pain imposed on the contralateral arm. Handheld pressure algometry was used to assess pressure pain thresholds (PPTs) on the knee, shin, and forearm. The examiner was blinded to the type of subject assessed. Results. Compared with pain-free controls, young females with PFP showed no decrease in cuff pain thresholds (P< 0.40) or facilitated temporal summation (P < 0.15) but had a lower CPM response (P< 0.04) and lower PPTs (P< 0.005). Conclusions. Young female adults with long-standing PFP demonstrated impaired CPM. This is important because PFP, a peripheral pathology, might have important central components that need to be studied in order to understand its extent and therapeutic implications. [ABSTRACT FROM AUTHOR]

Human experimental pain studies are of value to study basic pain mechanisms under controlled conditions. The aim of this study was to investigate whether genetic variation across selected mu-, kappa- and delta-opioid receptor genes ( OPRM1, OPRK1and OPRD1, respectively) influenced analgesic response to oxycodone in healthy volunteers. Experimental multimodal, multitissue pain data from previously published studies carried out in Caucasian volunteers were used. Data on thermal skin pain tolerance threshold ( PTT) ( n = 37), muscle pressure PTT ( n = 31), mechanical visceral PTT ( n = 43) and thermal visceral PTT ( n = 41) were included. Genetic associations with pain outcomes were explored. Nineteen opioid receptor genetic polymorphisms were included in this study. Variability in oxycodone response to skin heat was associated with OPRM1 single-nucleotide polymorphisms ( SNPs) rs589046 ( P < 0.0001) and rs563649 ( P < 0.0001). Variability in oxycodone response to visceral pressure was associated with four OPRM1 SNPs: rs589046 ( P = 0.015), rs1799971 ( P = 0.045) , rs9479757 ( P = 0.009) and rs533586 ( P = 0.046). OPRM1 SNPs were not associated with oxycodone visceral heat threshold, however, one OPRD1 rs419335 reached significance ( P = 0.015). Another OPRD1 SNP rs2234918 ( P = 0.041) was associated with muscle pressure. There were no associations with OPRK1 SNPs and oxycodone response for any of the pain modalities. Associations were found between analgesic effects of oxycodone and OPRM1 and OPRD1 SNPs; therefore, variation in opioid receptor genes may partly explain responder characteristics to oxycodone. [ABSTRACT FROM AUTHOR]

Objective Methods of blinding have been infrequently investigated. This study assessed data collector blinding within an investigation of endogenous pain modulation. Design Participants (N = 33; 52% women) were randomly assigned to an order of an exercise bout with intramuscular control injections, quiet rest with intramuscular algesic injections, and a control condition. Data collectors (N = 4; 50% women) recorded participants' pain responses and then left the room before the injection and exercise procedures were administered by other personnel. Immediately after the procedures, the data collectors returned to collect additional pain responses and record their suspicions regarding the assigned condition, their confidence level in their suspicions (0-100 mm scale), and the reason/s for their suspicions. Results Data collectors correctly identified control and algesic injections in 90.4 and 73.1% of the sessions, respectively, and quiet rest and exercise in 94.2 and 69.2% of the sessions, respectively. The confidence of the data collectors in their suspicions was 60.17 mm (SD = 34.54) for injections and 62.19 mm (SD = 34.95) for exercise. However, data collectors only had correct suspicions and confidence of at least 90 mm for 26.2% of the injections and 29.4% of the exercise bouts. Participants' pain responses were the primary reason for data collectors' suspicions. Neither the amount of experience nor the sexual composition of the participant-data collector dyad influenced the blinding. Conclusions Collection of participants' pain responses led to frequent episodes of unblinding. However, it may be misleading to only consider the frequency of correct suspicions as successful or unsuccessful blinding [ABSTRACT FROM AUTHOR]

Objectives: The study investigates the impact of age and gender on (1) experimental pressure pain detection thresholds (PPDT) and pressure pain tolerance thresholds (PPTolT) and (2) participants' self-reports of pain intensity and unpleasantness at suprathreshold and subthreshold levels. Methods: twenty young (20–34, mean age = 24.6 ± 3.6 years, ten female) and twenty elderly (65–88, mean age = 73.6 ± 6.6 years, ten female) healthy volunteers were compared. Mini-Mental State Examination (MMSE 28–30) assessed intact cognitive functioning. Pain thresholds were assessed together with the sensory intensity ratings to 1.3 × PPDT (pain) and 0.2 × PPDT (no pain). Results: PPDT and PPTolT significantly decreased with age and were lower in young females as compared with young males. No gender differences were observed in the elderly group. PPDT decreased significantly with age in males but not in females. Conversely, the intensity and unpleasantness of the pain stimulus were significantly rated lower in the elderly as compared with the young. No gender differences were observed in the report of intensity and unpleasantness of the stimulations. Discussion: a mismatch in pain sensitivity, tolerance, and pain self-reports was observed. Findings suggest that pain experiences in the elderly differ from the experiences in the young on multiple dimensions: sensory, affective, and cognitive. Findings may also indicate that the elderly appraise pain experiences using different psychological strategies. [ABSTRACT FROM AUTHOR]

Background: Musculoskeletal pain from the upper extremity and shoulder region is commonly reported by computer users. However, the functional status of central pain mechanisms, i.e., central sensitization and conditioned pain modulation (CPM), has not been investigated in this population. The aim was to evaluate sensitization and CPM in computer users with and without chronic musculoskeletal pain. Methods: Pressure pain threshold (PPT) mapping in the neck-shoulder (15 points) and the elbow (12 points) was assessed together with PPT measurement at mid-point in the tibialis anterior (TA) muscle among 47 computer users with chronic pain in the upper extremity and/or neckshoulder pain (pain group) and 17 pain-free computer users (control group). Induced pain intensities and profiles over time were recorded using a 0 -10 cm electronic visual analogue scale (VAS) in response to different levels of pressure stimuli on the forearm with a new technique of dynamic pressure algometry. The efficiency of CPM was assessed using cuffinduced pain as conditioning pain stimulus and PPT at TA as test stimulus. Results: The demographics, job seniority and number of working hours/week using a computer were similar between groups. The PPTs measured at all 15 points in the neck-shoulder region were not significantly different between groups. There were no significant differences between groups neither in PPTs nor pain intensity induced by dynamic pressure algometry. No significant difference in PPT was observed in TA between groups. During CPM, a significant increase in PPT at TA was observed in both groups (P < 0.05) without significant differences between groups. For the chronic pain group, higher clinical pain intensity, lower PPT values from the neck-shoulder and higher pain intensity evoked by the roller were all correlated with less efficient descending pain modulation (P < 0.05). Conclusions: This suggests that the excitability of the central pain system is normal in a large group of computer users with low pain intensity chronic upper extremity and/or neck-shoulder pain and that increased excitability of the pain system cannot explain the reported pain. However, computer users with higher pain intensity and lower PPTs were found to have decreased efficiency in descending pain modulation. [ABSTRACT FROM AUTHOR]

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 cm2). 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 cm2 probe was significantly lower than the PPT obtained with the 0.5 cm2 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. [ABSTRACT FROM AUTHOR]

Background Generalized hyperalgesia, a widespread increased sensitivity to painful stimuli, has been demonstrated in a range of chronic pain conditions including low-back pain. The evidence suggests, that generalized hyperalgesia may be an important factor in the development of chronicity, but it is not commonly assessed in clinical practice. Whereas a range of tools and procedures for the quantitative sensory testing of pain sensitivity is available for laboratory pain research, most experimental pain stimuli are not well suited for clinical practice. In the current study, a simple and inexpensive mechanical spring-clamp was tested as a potential experimental pain stimulus. Methods Ten seconds of mechanical pressure was applied to the thumb of 242 study participants: Healthy volunteers and low-back-pain patients (hospital and primary care). Pain intensity was measured by visual analogue scale before and after conditioned pain modulation by coldpressor test (CPT). Correlation to pressure pain threshold (PPT) of the infraspinatus muscle and cold-pressor test pain intensity, time to pain onset and time to non-tolerance, was examined. Test/re-test reliability of clamp pain was also assessed and the stimulus-response relationship was examined with a set of 6 different clamps. Conclusions Clamp pain was sensitive to changes in pain sensitivity provoked by conditioned pain modulation (CPM). Test/re-test reliability of the spring-clamp pain was better for healthy volunteers over a period of days, than for hospital patients over a period of weeks. A strong correlation (ρ = 0.73, P > 0.0001) was found between clamp force and evoked pain intensity. Correlation to other pain stimuli varied, with a strong correlation between pre and post-CPM clamp pain intensity (ρ = 0.81, P > 0.0001), moderate correlation between clamp pain and PPT (ρ = -0.43, P > 0.0001), as well as CPT pain intensity (ρ = 0.32, P > 0.0001) and a weak correlation with time to onset of CPT pain (ρ = -0.14, P < 0.05). The application of mechanical pressure is commonly employed to assess general pain sensitivity, and a simple spring-clamp seems a potentially useful instrument for quantitative sensory testing in a clinical setting. [ABSTRACT FROM AUTHOR]

Objective To study sensitization in women with dysmenorrhea using a standardized experimental model. Women with dysmenorrhea experience intense visceral pain during menstruation. The dysmenorrhea pain mechanisms are not known but sensitization may play a role. Design Prospective experimental study. Sample Ten women with dysmenorrhea and 10 control women having uterine cervical distensions in the mid-follicular period (days 6-10). Setting University clinic. Method Cervical distension was delivered as three phasic stimuli with 1 min between distensions and as a prolonged (1 min) distension. Main outcome measure Sensory intensity rated on a continuous visual analog scale. Results Distension-induced pain was described as dull and aching and referred to the pelvis, lower back and lower abdomen. Larger evoked referred pain areas were present in women with dysmenorrhea compared with control women ( p < 0.05). The pain threshold to the first stimulus was significantly higher in patients than controls ( p < 0.04), but decreased significantly with repeated distensions ( p < 0.01). For the prolonged distension the pain rating increased significantly ( p < 0.008) in women with dysmenorrhea, but decreased ( p < 0.02) in control women. Conclusions Pain sensitization (temporal summation, i.e. increase in pain during prolonged stimulation, and facilitation of referred pain areas as an indicator of central nervous system changes) is present in women with dysmenorrhea. The study provided new information on a poorly understood yet widespread condition and a basis for clinical studies to develop a biomarker tests for objective assessment of dysmenorrhea. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The transition from acute to chronic musculoskeletal pain is not well understood. To understand this transition, it is important to know how peripheral and central sensitization are manifested and how they can be assessed. A variety of human pain biomarkers have been developed to quantify localized and widespread musculoskeletal pain. In addition, human surrogate models may be used to induce sensitization in otherwise healthy volunteers. Pain can arise from different musculoskeletal structures (e.g. muscles, joints, ligaments, or tendons), and differentiating the origin of pain from those different structures is a challenge. Tissue specific pain biomarkers can be used to tease these different aspects. Chronic musculoskeletal pain patients in general show signs of local/central sensitization and spread of pain to degrees which correlate to pain intensity and duration. From a management perspective, it is therefore highly important to reduce pain intensity and try to minimize the duration of pain. [ABSTRACT FROM AUTHOR]

Abstract: Background and purpose: Conditioned pain modulation (CPM) is a phenomenon in which pain is inhibited by heterotopic noxious stimulation. It is not known how the experimental condition affects the magnitude of the CPM response and the inter- and intra-individual variations. It is important to get the information of the test–retest reliability and inter-individual variations of CPM to apply CPM as a diagnostic tool or for screening analgesic compounds. This study evaluated (1) the magnitude of CPM, (2) the inter-individual coefficient of variation (inter-CV) and (3) the intra-individual coefficient of variation (intra-CV) to (A) different stimulus modalities to evoke CPM and (B) different assessment sites. Methods: Twelve healthy men (age 19–38 years) participated in this study. Cold pressor pain (CPP) (immersing the hand into cold water), tourniquet pain (cuff around the upper arm) and mechanical pressure pain (craniofacial region) were used in randomized order as conditioning stimuli (CS). The test stimulus (TS) was pressure pain applied to the right masseter muscle, left forearm and leg (bilateral tibialis anterior: TA). The responses were pressure pain thresholds (PPT), pressure pain tolerance (PPTol) thresholds and the pain intensity which was assessed on a visual analogue scale (VAS, 0–10cm) following 1.4 and 1.6× PPT applied to TA. The TS was applied before, during and 10min after the CS. The intra-individual CV was estimated between different days. Results: CPP induced the most powerful CPM on PPT (66.3±10.0% increase), VAS ratings (41.5±5.3% reduction) and PPTol (32.6±4.6% increase), especially at TA, and resulted in the smallest inter-CV (41.4–60.1%). Independently of the CS, the inter-CV in general showed that the recordings from the orofacial region and the forearm had smaller values than from the leg. The smallest intra-CV value was obtained in pain ratings with CPP (27.0%). Conclusions: This study suggests that (1) the CPP evokes the largest CPM, (2) the leg as the assessment site results in the largest CPM responses and (3) the CPP causes the smallest inter- and intra-CV. Implication: The present investigation implicates that the CPP is the most efficient conditioning stimulus to induce CPM when assessed by pressure pain thresholds. [Copyright &y& Elsevier]

Abstract: Musculoskeletal pain impairs postural control and stability. Nine subjects stood as quietly as possible on a moveable force platform before, during, and after experimental pain in the right leg muscles. A moveable force platform was used to measure the center of pressure and provided unexpected perturbations. Lower limb muscle activity, joint angles, and foot pressure distributions were measured. Hypertonic saline was used to induce pain in the vastus lateralis, vastus medialis, or biceps femoris muscle of the right leg. Compared to baseline and control sessions, pain in the knee extensor muscles during quiet standing evoked: 1) larger sway area, greater medial-lateral center of pressure displacement and higher speed (P < .05); 2) increased sway displacement in the anterior-posterior direction (P < .05); and 3) increased electromyography (EMG) activity for left tibialis anterior and left erector spinae muscles (P < .05). Pain provoked longer time to return to an equilibrium posture after forward EMG activity for, and pain in vastus medialis muscle decreased the time for the maximum hip flexion during this perturbation (P < .05). These results show that muscle pain impairs postural stability during quiet standing and after unexpected perturbation, which suggest that people suffering from leg muscle pain are more vulnerable to falls. Perspective: This article presents the acute responses to leg muscle pain on the postural control. This measure could potentially help clinicians who seek to assess how pain responses may contribute to patient’s postural control and stability during quiet standing and after recovering from unexpected perturbations. [Copyright &y& Elsevier]

Abstract: Introduction and aim: Pain sensitivity has been linked to the melanocortin-1 receptor (MC1R) gene. A mutation in MC1R can result in pale skin and red hair in humans and may modulate pain responses in general. Human studies have shown that women with non-functional MC1R''s were sensitive to experimental induced cold and heat pain. A study demonstrated that females with red hair required higher dose of anesthesia than females with dark hair to experience analgesia to electrical stimulation. Moreover, women expressing non-functional MC1Rs display greater analgesia from opioid analgesia. If redheads in general respond differently to pain and analgesics, this is of clinical importance. The aim of this study was therefore to investigate pain sensitivity and experimentally induced sensitisation in red haired females. Method: Twenty healthy females with pale skin and red hair (mean age 32 years, range 20–55) and 20 healthy females with blond/dark hair (mean age 31 years, range 20–51) participated in this study. The pain tolerance thresholds to heat and pressure stimulation were determined. Hyperalgesia was induced experimentally by applying 0.075% topical capsaicin cream for 30min. The secondary pin-prick hyperalgesic area was estimated with a calibrated filament (von Frey hair, 15g) and the area of allodynia by a soft brush. This was done 0, 30, 60, and 90min after cream removal. Results: Neither heat nor pressure pain tolerance thresholds were changed in the two groups. The secondary pin-prick hyperalgesic areas were significantly smaller for red haired females than blond/dark haired females (P =0.014). There were no significant differences in the allodynic areas. Discussion: As the secondary hyperalgesic response evoked by topical capsaicin is a central phenomenon, the observed smaller pin-prick hyperalgesic area in the red haired females could indicate a central role of MCRs in development or maintenance of hyperalgesia. Central involvement of MC1Rs or dysfunction of peripheral MC1Rs activating central MC4Rs has been suggested to influence pain sensitivity. The difference observed between red haired and non-red haired females may have implications for pain management regimens as compounds interacting with sensitisation such as NMDA-antagonists or alpha-2-delta-ligands may exert different types of action in people with MC1R mutation. Conclusion: The present study showed that red haired females were less sensitive to topical capsaicin induced pin-prick hyperalgesia compared with blond/dark haired females. Implications: The smaller hyperalgesic area in redheads could be a manifestation of central anti-hyperalgesic involvement of MCRs and could have an influence on the treatment of pain as well as in studies investigating anti-hyperalgesic drugs. [Copyright &y& Elsevier]

Recent studies have shown that the nociceptive withdrawal reflex threshold (NWR-T) and the electrical pain threshold (EP-T) are reliable measures in pain-free populations. However, it is necessary to investigate the reliability of these measures in patients with chronic pain in order to translate these techniques from laboratory to clinic. The aims of this study were to determine the test-retest reliability of the NWR-T and EP-T after single and repeated (temporal summation) electrical stimulation in a group of patients with chronic low back pain, and to investigate the association between the NWR-T and the EP-T. To this end, 25 patients with chronic pain participated in three identical sessions, separated by 1 week in average, in which the NWR-T and the EP-T to single and repeated stimulation were measured. Test-retest reliability was assessed using intra-class correlation coefficient (ICC), coefficient of variation (CV), and Bland-Altman analysis. The association between the thresholds was assessed using the coefficient of determination (r (2)). The results showed good-to-excellent reliability for both NWR-T and EP-T in all cases, with average ICC values ranging 0.76-0.90 and average CV values ranging 12.0-17.7%. The association between thresholds was better after repeated stimulation than after single stimulation, with average r (2) values of 0.83 and 0.56, respectively. In conclusion, the NWR-T and the EP-T are reliable assessment tools for assessing the sensitivity of spinal nociceptive pathways in patients with chronic pain. [ABSTRACT FROM AUTHOR]

Background: The purpose of this study was to evaluate how acute pain changes the postural control and stability during quiet standing and after unexpected perturbations. Methods: Nine subjects stood as quiet as possible on a movable force platform that recorded the centre of pressure position and provided unexpected floor perturbations, before, during and after experimental calf muscle pain. Bilateral surface electromyography from the tibialis anterior and medial gastrocnemius muscles was recorded. The foot pressure distributions were measured using pressure insoles. Intramuscular injections of hypertonic saline were administrated (right leg) to induce acute pain in the tibialis anterior and/or medial gastrocnemius muscles, and an isotonic injection was used as control. Findings: Simultaneous pain in tibialis anterior and medial gastrocnemius altered the postural control. During quiet standing: higher medial-lateral centre of pressure speed and increased total sway displacement (P <0.05), weight moved to the non-painful side, (P <0.05) and plantar centre of pressure of the left foot was shifted towards the heel’s direction (P <0.05). During forward perturbation: higher mean displacement in the medial-lateral direction (P <0.05). After the perturbation: larger sway area (P <0.05). Pain only in the medial gastrocnemius muscle increased medial-lateral centre of pressure speed (P <0.05) during the quiet standing. Pain only in the tibialis anterior muscle increased peak pressure on the contralateral foot (P <0.05). Interpretation: These findings suggest that large acute painful areas on the calf muscles impair the postural control and potentially increase the risk factors for falls. Further strategies aiming to reduce pain in patients may lead to improvement in balance. [Copyright &y& Elsevier]

Abstract: Pain is the dominant symptom in osteoarthritis (OA) and sensitization may contribute to the pain severity. This study investigated the role of sensitization in patients with painful knee OA by measuring (1) pressure pain thresholds (PPTs); (2) spreading sensitization; (3) temporal summation to repeated pressure pain stimulation; (4) pain responses after intramuscular hypertonic saline; and (5) pressure pain modulation by heterotopic descending noxious inhibitory control (DNIC). Forty-eight patients with different degrees of knee OA and twenty-four age- and sex-matched control subjects participated. The patients were separated into strong/severe (VAS⩾6) and mild/moderate pain (VAS<6) groups. PPTs were measured from the peripatellar region, tibialis anterior (TA) and extensor carpi radialis longus muscles before, during and after DNIC. Temporal summation to pressure was measured at the most painful site in the peripatellar region and over TA. Patients with severely painful OA pain have significantly lower PPT than controls. For all locations (knee, leg, and arm) significantly negative correlations between VAS and PPT were found (more pain, more sensitization). OA patients showed a significant facilitation of temporal summation from both the knee and TA and had significantly less DNIC as compared with controls. No correlations were found between standard radiological findings and clinical/experimental pain parameters. However, patients with lesions in the lateral tibiofemoral knee compartment had higher pain ratings compared with those with intercondylar and medial lesions. This study highlights the importance of central sensitization as an important manifestation in knee OA. [Copyright &y& Elsevier]

The aim of the current study was to evaluate bilaterally warm/cold detection and heat/cold pain thresholds over the hand/wrist in patients with carpal tunnel syndrome (CTS). A total of 25 women with strictly unilateral CTS (mean 42 ± 10 years), and 20 healthy matched women (mean 41 ± 8 years) were recruited. Warm/cold detection and heat/cold pain thresholds were assessed bilaterally over the carpal tunnel and the thenar eminence in a blinded design. Self-reported measures included both clinical pain history (intensity, location and area) and Boston Carpal Tunnel Questionnaire. No significant differences between groups for both warm and cold detection thresholds in either carpal tunnel or thenar eminence ( P > 0.5) were found. Further, significant differences between groups, but not between sides, for both heat and cold pain thresholds in both the carpal tunnel and thenar eminence were found (all P < 0.001). Heat pain thresholds ( P < 0.01) were negatively correlated, whereas cold pain thresholds ( P < 0.001) were positively correlated with hand pain intensity and duration of symptoms. Our findings revealed bilateral thermal hyperalgesia (lower heat pain and reduced cold pain thresholds) but not hypoesthesia (normal warm/cold detection thresholds) in patients with strictly unilateral CTS when compared to controls. We suggest that bilateral heat and cold hyperalgesia may reflect impairments in central nociceptive processing in patients with unilateral CTS. The bilateral thermal hyperalgesia associated with pain intensity and duration of pain history supports a role of generalized sensitization mechanisms in the initiation, maintenance and spread of pain in CTS. [ABSTRACT FROM AUTHOR]

AIM Experimental pain models may help to evaluate the mechanisms of analgesics and target the clinical indications for their use. This review, the second in a series of two, addresses how the efficacy of non-opioid analgesics have been assessed in human volunteers using experimental pain models. METHODS A literature search was completed for randomized controlled studies that included human experimental pain models, healthy volunteers and non-opioid analgesics. RESULTS Nonsteroidal anti-inflammatory drugs worked against various types of acute pain as well as in hyperalgesia. Analgesia from paracetamol was difficult to detect in experimental pain and the pain needed to be assessed with very sensitive methods like evoked brain potentials. The N-methyl-D-aspartate antagonists exemplified by ketamine generally needed strong, long-lasting or repeated pain in the skin for detectable analgesia, whereas pain in muscle and viscera generally was more easily attenuated. Gabapentin worked well in several models, particularly those inducing hyperalgesia, whereas lamotrigine was weak in modulation of experimental pain. Imipramine attenuated pain in most experimental models, whereas amitriptyline had weaker effects. Delta-9-tetrahydrocannabinol attenuated pain in only a few models. CONCLUSIONS Pain induction and assessment are very important for the sensitivity of the pain models. Generally, experimental pain models need to be designed with careful consideration of the pharmacological mechanisms and pharmacokinetics of analgesics. The drawback with the different study designs is also discussed. This knowledge can aid the decisions that need to be taken when designing experimental pain studies for compounds entering Phase I and II trials. [ABSTRACT FROM AUTHOR]

AIM Experimental pain models may help to evaluate the mechanisms of action of analgesics and target the clinical indications for their use. This review addresses how the efficacy of opioids can be assessed in human volunteers using experimental pain models. The drawback with the different study designs is also discussed. METHOD A literature search was completed for randomized controlled studies which included human experimental pain models, healthy volunteers and opioids. RESULTS Opioids with a strong affinity for the µ-opioid receptor decreased the sensation in a variety of experimental pain modalities, but strong tonic pain was attenuated more than short lasting pain and non-painful sensations. The effects of opioids with weaker affinity for the µ-opioid receptor were detected by a more narrow range of pain models, and the assessment methods needed to be more sensitive. CONCLUSION The way the pain is induced, assessed and summarized is very important for the sensitivity of the pain models. This review gives an overview of how different opioids perform in experimental pain models. Generally experimental pain models need to be designed with careful consideration of pharmacological mechanisms and pharmacokinetics of analgesics. This knowledge can aid the decisions needed to be taken when designing experimental pain studies for compounds entering phase 1 clinical trials. [ABSTRACT FROM AUTHOR]

Abstract: Quantification of the human painful sensory experience is an essential step in the translation of knowledge from animal nociception to human pain. Translational models for assessment of pain are very important, as such models can be used in: 1) basic mechanistic studies in healthy volunteers; 2) clinical studies for diagnostic and monitoring purposes; 3) pharmacological studies to evaluate analgesic efficacy of new and existing compounds. Quantitative pain assessment, or quantitative sensory testing (QST), provides psychophysical methods that systematically document alterations and reorganization in nervous system function and, in particular, the nociceptive system. QST is defined as the determination of thresholds or stimulus response curves for sensory processing under normal and pathophysiological conditions. The modern concept of advanced QST for experimental pain assessment is a multimodality, multitissue approach where different pain modalities (thermal, mechanical, electrical, and chemical) are applied to different tissues (skin, muscles, and viscera) and the responses are assessed by psychophysical methods (thresholds and stimulus-response functions). Many new and advanced technologies have been developed to help relieve evoked, standardized, and painful reactions. Assessing pain has become a question of solving a multi-input, multi-output problem, with the solution providing the possibility of teasing out which pain pathways and mechanisms are involved, impaired, or affected. Perspective: Many methodologies have been developed for quantitative assessment of pain perception and involved mechanisms. This paper describes the background for the different methods, the use in basic pain experiments on healthy volunteers, how they can be applied in drug profiling, and the applications in clinical practice. [Copyright &y& Elsevier]

Abstract: The aim was to investigate the efficacy of a combination of low-dose remifentanil (REMI) and ketamine (KET) compared to the single drugs and placebo (P) on whiplash associated pain (WAD) in a double-blind, randomized, placebo-controlled, cross-over study. Twenty patients with chronic (>1 year) WAD were included. Four different drug combinations were tested in four sessions: placebo/placebo (P/P), placebo/remifentanil (P/REMI), ketamine/placebo (KET/P) and ketamine/remifentanil (KET/REMI). Target concentrations were 1 and 2ng/ml (stepwise) for remifentanil and 100ng/ml for ketamine. Habitual pain intensity was assessed on a visual analogue scale (VAS). Experimental pain was assessed with electrical stimulation (single and repeated) of tibialis anterior (TA) muscle, pressure pain algometry applied over infraspinatus (IS) and TA muscles and VAS scores after intramuscular hypertonic saline infusion in TA. KET/REMI significantly reduced habitual pain. KET/REMI infused at low REMI target concentration (1ng/ml) significantly elevated electrical intramuscular pain thresholds (single and repeated). Pain thresholds to electrical stimulation were similarly increased by both P/REMI and KET/REMI at 2ng/ml target concentration. Pressure pain thresholds were increased by both KET/REMI and P/REMI. VAS-scores after intramuscular saline were also similarly decreased by both REMI combinations. Seven out of 20 subjects were non-responders (<50% pain relief). No correlation was found between effects on spontaneous pain and experimental pain. KET/REMI showed an analgesic effect on habitual pain. Experimental pain was attenuated by both combinations containing the opioid, however, KET seemed to enhance the effect of REMI on electrical pain thresholds when a low REMI target concentration was used. [Copyright &y& Elsevier]

Background and Objectives: Gabapentin is used for treatment of neuropathic pain, but its effect on different somatic pain modalities and integrative mechanisms are not completely understood. The aim of this double-blind, placebo-controlled experimental pain study, conducted on 20 healthy volunteers, was to examine the effect of a single dose of 1200 mg gabapentin on multi-modal experimental cutaneous and muscle pain models. Methods: The following pain models were applied: (1) pain thresholds to single and repeated cutaneous and intramuscular electrical stimulation (temporal summation to 5 stimuli delivered at 2 Hz); (2) stimulus-response function relating pain intensity scores (visual analog scale, VAS) to increasing current intensities for electrical skin and muscle stimuli (single and repeated, determined at baseline); and (3) the pain intensity (VAS) and pain areas after intramuscular injection of hypertonic saline. Pain assessments were performed prior to, and at 4, 6, and 8 hours after medication. Results: When responses were averaged across the post-dose times, gabapentin: (1) significantly increased the temporal summation pain threshold in skin compared with placebo (P = .03); (2) significantly reduced the area under the pain intensity curve to hypertonic saline injections in the muscle (P = .02); and (3) significantly reduced the area of pain evoked by hypertonic saline (P = .03). Conclusions: Gabapentin reduces temporal summation of skin stimuli at pain threshold intensities; this may have potential as a biomarker for drugs with efficacy on neurogenic pain. The data also suggest that tonic muscle pain is responsive to gabapentin treatment and suggest further clinical studies. [Copyright &y& Elsevier]

Objectives. To investigate possible differences between patients with non-erosive gastroesophageal reflux disease (NERD) and controls in a) sensitivity of the distal esophagus after mechanical and thermal stimuli and b) the referred pain areas. Material and methods. Fifteen healthy subjects (mean age 39±19.4 years) and 13 NERD patients (mean age 44.4±21 years) were enrolled in the study. Pain evoked by mechanical and thermal stimuli was assessed using a newly designed multimodal stimulation probe. Results. The patients were less sensitive to mechanical stimulation as assessed by the cross-sectional area (p<0.001) and volume (p=0.007). After thermal stimulation, the patients were hypersensitive to heat stimuli (p=0.04), whereas no significant difference was seen to cold stimuli. The referred pain areas were larger in patients compared with the pain areas in controls after mechanical (p=0.03) and heat stimuli (p=0.01), but not after cold stimuli. Balloon distension resulted in a significant higher number of reactive esophageal contractions in patients as compared with controls (p=0.001). Conclusions. The present study showed that NERD patients were hypersensitive to heat stimuli of the esophagus, with an increase in referred pain to the evoked visceral pain. The data indicate that peripheral sensitization of heat-sensitive pathways together with facilitation of central pain mechanisms are important in the pathogenesis of NERD. [ABSTRACT FROM AUTHOR]

Objectives: The primary objective of this study is to compare the effects of ibuprofen with placebo on post-exercise induced muscle soreness. The secondary objective is to explore the effects of glucosamine sulphate versus placebo on post-exercise induced muscle soreness. Ibuprofen is a nonsteroidal anti-inflammatory drug which relieves pain and reduces inflammation. Glucosamine sulphate is a naturally occurring amino monosaccharide in the human body. It is biosynthesized from glucose, and is used to form glycosamineglycan, a constituent of proteoglycans, and an important component of the extracellular matrix of articular cartilage. Methods: Ibuprofen 1,200 mg/day, 1,500 mg/day glucosamine sulphate, or placebo was given orally daily for 22 days to three groups, each consisting of 20 healthy men [aged 24.3 ± 3.1 years] in a double-blind, randomized controlled parallel group study. Subjects carried out an intensive eccentric exercise of the first dorsal interosseous muscle of the left hand on a standardized hand exerciser on day 14. Muscle tenderness was assessed by the pressure pain stimulation on days 0, 14 [before exercise], 14 [immediately after exercise], 15, 16 [the days of maximal tenderness], and 22. Results: Muscle tenderness on days 0 and 14 [before exercise] was not different in the three groups. Muscle tenderness was significantly increased in the group consuming 1,500 mg/day glucosamine sulphate as compared with the placebo group day 15 and day 16 after the exercise [P < 0.033]. There was no significant difference between ibuprofen versus placebo. None of the participants reported any serious adverse effects. Conclusion: Glucosamine sulphate facilitates muscle tenderness whereas systemic administration of ibuprofen is not capable of inhibiting experimentally induced muscle tenderness/soreness. [ABSTRACT FROM AUTHOR]

Objective. Animal experiments and clinical observations have indicated a different working profile of oxycodone compared to morphine, and it has previously been shown that oxycodone attenuates visceral pain better than morphine. The objective of this study was to test the effects of oxycodone and morphine on experimental pain in patients with pain caused by chronic pancreatitis. Material and methods. Ten patients took part in this blinded, cross-over study. The analgesic effects of morphine (30 mg, oral), oxycodone (15 mg, oral) and placebo were tested against multimodal (mechanical, thermal and electrical) experimental pain in the skin, muscles and oesophagus. Pain was assessed at baseline and 30, 60 and 90 min after drug administration. Results. In the skin and muscles, oxycodone was more effective than placebo and morphine on mechanically (skin: F=12.4, p<0.001, muscle: F=11.0, p<0.001) and thermally (skin: F=8.5, p<0.001) evoked pain. In oesophageal heat pain, the effect of morphine was equal to that of placebo, while oxycodone attenuated pain better than both morphine and placebo (F=9.5, p<0.001). Both morphine and oxycodone were more effective in attenuating mechanical pain in the oesophagus than placebo (F=8.6, p<0.001). After electrical stimulation no differences were seen between the opioids and placebo in any tissue studied. Conclusions. Oxycodone was a stronger analgesic than morphine in several pain modalities in the skin, muscle and oesophagus. [ABSTRACT FROM AUTHOR]

Objective. Patients with non-cardiac chest pain (NNCP) suffer from unexplained and often intractable pain which can pose a major clinical problem. The aim of this study was to investigate nociceptive processing in NNCP patients and their response to experimentally acid-induced oesophageal hyperalgesia using a multimodal stimulation protocol. Material and methods. Ten highly selected patients with NCCP (mean age 43 years, 1 M) were compared with an age- and gender-matched group of 20 healthy subjects. After preconditioning, the distal oesophagus was painfully distended with a balloon using "impedance planimetry". This method assesses the luminal cross-sectional area of the oesophagus based on the electrical impedance of the fluid inside the balloon. The baseline distensions were done before and after pharmacological relaxation of the smooth muscle with 20 mg butylscopolamine. After baseline distensions, a series of up to 10 mechanical stimuli was performed (temporal summation). The stimulations were repeated after sensitization of the oesophagus induced by acid perfusion. The sensory intensities were assessed during the stimulations and the referred pain area was mapped. Results. At baseline distensions, no differences were seen between patients and controls before and after relaxation of the smooth muscles. The patients tolerated fewer repeated distensions than controls (4.8±0.5 versus 9.1±0.9; p=0.04) and had an increased size of the referred pain areas to the mechanical stimulations (32.9±6.2 versus 64.9±18.3 cm2; p=0.01). After sensitization with acid, the patients developed hyperalgesia (p<0.001), whereas no significant changes were seen in controls. Conclusions. NCCP patients showed facilitated central pain mechanisms (temporal summation and visceral hyperalgesia after sensitization). This could be used in the diagnosis and understanding of the symptoms in these patients. [ABSTRACT FROM AUTHOR]

Abstract: The sensitivity of tendon and tendon–bone junction is not fully described although these tissues have high clinical impacts. This study assessed (1) pain intensity and referred pain caused by hypertonic saline injection to the proximal tendon–bone junction (PTBJ), tendon and muscle belly sites of tibialis anterior muscle and (2) pressure pain sensitivity, pre, during and post hypertonic saline injections. Eighteen subjects (14 males and 4 females) participated. Subjects also had constant mechanical stimulation for 120s at 130% of baseline pressure pain threshold (PPT) during which VAS parameters were recorded. VAS parameters after hypertonic saline for PTBJ (VAS area, VAS peak), and tendon sites (VAS area, duration and time to maximum VAS) were significantly (P<0.05) higher than muscle belly. During hypertonic saline pain all three sites displayed local and frequently enlarged and referred pain areas. Hypertonic saline pain at the PTBJ and tendon transiently increased pressure sensitivity at these sites (P<0.05). When referred pain was caused by mechanical stimulation it occurred predominantly at the PTBJ and tendon sites (86% cases). Constant mechanical stimulation caused steadily increasing pain (summation of pain) at all sites. Hypertonic saline pain at the tendon and PTBJ caused significantly higher (P<0.001) final VAS scores compared to the muscle belly site. The results indicate the PTBJ and tendon sites are more sensitive and susceptible to sensitisation by hypertonic saline than muscle belly. Furthermore, there may be site specific central changes reflected by the differences in the results regarding sensitivity and summation over time. [Copyright &y& Elsevier]

Abstract: It is believed that mechanical stimuli of the human gut activate afferents responding to either noxious or normal, physiologic stimuli. They might be able to sensitize without relation to the contractile state of the smooth muscle. The current study aimed to verify the above characteristics by using a statistical model based on correlation analysis. The esophagus was distended with a bag in 32 healthy subjects by using an inflation rate of 25 mL/min. The luminal cross-sectional areas and sensory ratings were determined during the distentions. The stimuli were repeated after relaxation of the smooth muscle with butylscopolamine and after sensitization with hydrochloride acid. A positive correlation between the sensory responses to distention was found in the nonpainful and painful ranges, respectively, but correlations between nonpainful and painful ratings were nonsignificant. Relaxation of the smooth muscle did not influence the correlations, and sensitization resulted in inter-individual differences and disappearance of the above clustering into painful and nonpainful correlations. In conclusion, afferent nerves encoding high-threshold and low-threshold mechanical stimuli of the human esophagus are not correlated and thus probably represent different populations. The response characteristics have no physiologic relationship to the contractile state of the smooth muscle, and sensitization affects all types of afferents. Perspectives: The article adds information about sensory processing of mechanical gut stimuli in human beings. This might increase our understanding of visceral pain in health and disease and guide the statistical analysis of experimental data obtained in the gastrointestinal tract. [Copyright &y& Elsevier]