Sensory and biomechanical properties of the esophagus in non-erosive reflux disease.

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.

Ultrasonographic study of mechanosensory properties in human esophagus during mechanical distension.

AIM: To study the esophageal geometry and mechanosensation using endoscopic ultrasonography during volume-controlled ramp distensions in the distal esophagus. METHODS: Twelve healthy volunteers underwent distension of a bag. During distension up to moderate pain the sensory intensity was assessed on a visual analogue scale (VAS). The esophageal deformation in terms of multidimensional stretch ratios and strains was calculated at different volumes and VAS levels. Distensions were done before and during administration of the anti-cholinergic drug butylscopolamine. RESULTS: The stimulus-response (volume-VAS) curve did not differ without or with the administration of butylscopolamine. Analysis of stretch ratios demonstrated tensile stretch in circumferential direction, compression in radial direction and a small tensile stretch in longitudinal direction. A strain gradient existed throughout the esophageal wall with the largest circumferential deformation at the mucosal surface. The sensation intensity increased exponentially as function of the strains. CONCLUSION: The method provides information of esophageal deformation gradients that correlate to the sensation intensity. Hence, it can be used to study mechanosensation in the human esophagus. Further studies are needed to determine the exact deformation stimulus for the esophageal mechanoreceptors.

Central sensitization in patients with non-cardiac chest pain: a clinical experimental study.

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.

Pain and mechanical properties of the rectum in patients with active ulcerative colitis.

BACKGROUND: The pain, urgency, and incontinence in ulcerative colitis may be related to changes in viscoelastic properties of the gut wall or to alterations of the sensory pathways. In the present study, we used an advanced rectal probe to study the mechanosensory and smooth muscle properties in patients with active disease. METHODS: Nine patients with ulcerative colitis (mean age 39.5 years) with exacerbation limited to the rectum and sigmoid colon and 17 age-matched healthy subjects were included. The rectum was distended before and after pharmacological relaxation of the smooth muscle until moderate pain was reported, and the cross-sectional area, volume, pressure, tension, and strain were computed. To investigate central integration of a tonic stimulus, the bag was finally distended to the pain threshold; then, the cross-sectional area was held constant for 2 min. RESULTS: The patients were hypersensitive to mechanical stimuli as assessed by the cross-sectional area (F = 21.7; P < 0.001). There were no differences in compliance or stiffness between the 2 groups, but the hypersensitivity was abolished after muscle relaxation. Together with the muscle analysis, this finding demonstrated that the smooth muscles were tonically contracted in the inflamed rectum, resulting in a decreased rectal circumference. The tonic distensions did not evoke central integration of the pain response, indicating that hyperalgesia is more likely related to peripheral factors. CONCLUSIONS: Patients with active ulcerative colitis have hypersensitivity and increased tone of the smooth muscles, which may explain the symptoms. Drugs that affect smooth muscle contraction may be helpful in difficult cases.

Multi-modal and tissue-differentiated experimental pain assessment: reproducibility of a new concept for assessment of analgesics.

Experimental pain models for assessment of analgesic effect needs to be reproducible, valid and responding in a uniform way to changes in pain level. The pain system differs in various tissue types and analgesics may have different effects in different tissues. This study assessed the reproducibility of an experimental model using mechanical, thermal and electrical stimulations. Pain was evoked in three tissues: Skin, muscle and viscera. Pain was evoked and assessed in 24 healthy volunteers. The experiment was repeated three times with 30 min. intervals and twice with a weekly interval. Systematic bias, intra-class correlation (ICC) and coefficient of variation (CV) and valid sample sizes for analgesic testing were assessed. The model proved to be feasible. Most tests were unbiased, showing stable means except for the mechanical and thermal stimulation in viscera, which showed decreasing pain thresholds when the tests were repeated with 30 min. intervals. Generally the pain tests showed relatively high CV (mean 71%, range 8-145%). The pain tests showed high ICC's (>0.80) when repeated on the same day. When the tests were repeated with an interval of one week, ICC was smaller (mean 0.79 range 0.49-0.96). This means that these tests are useful for analgesic testing recruiting useful sample sizes in a crossover (mean 31 range 2-84) and a parallel study (mean 59 range 3-164) design. Application of this experimental pain model in a cross-over study design with appropriate base-line recordings offers a unique opportunity of revealing analgesic effects on pain arising from different tissues.

Gender differences in pain and biomechanical responses after acid sensitization of the human esophagus.

Our aims were to investigate gender differences to multimodal stimulations of the esophagus after experimentally induced sensitization. Thirty healthy age-matched subjects, 13 males and 17 females, were included. Pain evoked by mechanical and thermal stimuli was assessed before and after perfusion of the lower esophagus with 0.1 N hydrochloric acid. Males were more sensitive to the baseline mechanical stimuli (P < 0.01) and tolerated a lower volume of acid (P = 0.04). After acid perfusion, males were more sensitive than females to distensions (cross-sectional area P = 0.001 and volume P = 0.001). Acid perfusion sensitized both males (P = 0.03) and females (P = 0.04) to heat stimulation but not to cold stimulation (males, P = 0.09; females, P = 0.8). The referral areas for pain evoked by mechanical and thermal stimuli were larger in females compared with males both before and after acid perfusion (P = 0.002). In females only the referred pain area increased to heat stimulations (P = 0.02). Acid infusion resulted in a more hyperreactive esophagus (P = 0.03) but the hyperreactivity was not gender-dependent. In conclusion, males were more sensitive to mechanical and chemical esophageal stimuli and showed acid-evoked mechanical hyperalgesia. Females had significantly larger referred pain areas to the stimulations. The differentiated response to peripheral and central pain mechanisms may explain the gender-related differences seen in several gastrointestinal disorders.

Sensory-motor responses to mechanical stimulation of the esophagus after sensitization with acid.

AIM: Sensitization most likely plays an important role in chronic pain disorders, and such sensitization can be mimicked by experimental acid perfusion of the esophagus. The current study systematically investigated the sensory and motor responses of the esophagus to controlled mechanical stimuli before and after sensitization. METHODS: Thirty healthy subjects were included. Distension of the distal esophagus with a balloon was performed before and after perfusion with 0.1 mol/L hydrochloric acid for 30 min. An impedance planimetry system was used to measure cross-sectional area, volume, pressure, and tension during the distensions. A new model allowed evaluation of the phasic contractions by the tension during contractions as a function of the initial muscle length before the contraction (comparable to the Frank-Starling law for the heart). Length-tension diagrams were used to evaluate the muscle tone before and after relaxation of the smooth muscle with butylscopolamine. RESULTS: The sensitization resulted in allodynia and hyperalgesia to the distension volumes, and the degree of sensitization was related to the infused volume of acid. Furthermore, a nearly 50% increase in the evoked referred pain was seen after sensitization. The mechanical analysis demonstrated hyper-reactivity of the esophagus following acid perfusion, with an increased number and force of the phasic contractions, but the muscle tone did not change. CONCLUSION: Acid perfusion of the esophagus sensitizes the sensory pathways and facilitates secondary contractions. The new model can be used to study abnormal sensory-motor mechanisms in visceral organs.

Statistical modeling of the response characteristics of mechanosensitive stimuli in the human esophagus.

UNLABELLED: 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 non-painful and painful ranges, respectively, but correlations between non-painful 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 non-painful 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.

Differences between male and female responses to painful thermal and mechanical stimulation of the human esophagus.

It is uncertain to what degree sensation and pain relating to the gut are influenced by sex. The aim of the study was to explore sex differences to experimental multimodal stimulation of the esophagus in 22 age-matched males and females. A probe was positioned in the lower part of the esophagus. Mechanical stimuli were applied as distensions with a bag using an impedance planimetric method. The distensions were done before and after relaxation of the smooth muscle. Thermal stimulation was done with recirculating water at 1 and 60 degrees C in the bag. The sensory intensities were assessed during the stimulations, and the referred pain area was drawn at maximum pain intensities. An increased sensation to mechanical stimuli was found in the males for volume, pressure, and tension (P = 0.003, P = 0.02, P = 0.005), whereas cross-sectional area and strain showed no sex difference (P = 0.06, P = 0.9). Sex differences were not found for the cold and warmth stimulations (P = 0.6, P = 0.1). The mean size of the referred pain areas to the different stimuli was 23.6 cm2 in males and 48.7 cm2 in females (P = 0.002). As strain is believed to be the major determinant for the sensory response to mechanical stimulation of the gut, we conclude that no robust sex differences were observed in the assessments of the multimodal stimulations. However, the larger referred pain area in females reflects sex differences in central pain processing, which may explain the female preponderance in functional disorders relating to the gut.

Cold and heat pain assessment of the human oesophagus after experimental sensitisation with acid.

The aim of the present study was to investigate the effect of thermal stimulation of the oesophagus before and after sensitisation with acid. In 17 healthy subjects a stimulation bag was used to re-circulate water at 5 and 60 degrees C for up to 90 s in the lower part of the oesophagus. The area under the temperature curve was used to assess the caloric load. The thermal stimuli were repeated after perfusion of the oesophagus with acid. The evoked pain intensity and referred pain areas (at the pain threshold) were assessed. At baseline the subjects were able to tolerate less caloric load (42%) for the heat compared to the cold stimuli (P = 0.007). The heat stimuli resulted in an increased referred pain area as compared with the cold stimuli (P = 0.03). Following acid perfusion there was a selective sensitisation to the heat pain stimuli as only 36% of the initial caloric load was tolerated (P = 0.012) whereas the sensation to the cold stimuli was unchanged. After acid perfusion, the referred pain area to the heat pain stimulation increased 49% (P = 0.04) but was not changed to cold stimulation (P = 0.82). After sensitisation the words used to describe the sensations to heat pain stimuli shifted from a warmth quality towards a more burning quality in most subjects. This multi-modal sensory testing study showed that acid sensitises the oesophagus to heat but not to cold pain. This may account for the modality-specific symptoms and hypersensitivity reported in patients suffering from, e.g. gastro-oesophageal reflux disease.