Hans Gregersen

Experimental Pain in Gastroenterology. A Reappraisal of Human Studies

Abdominal pain is of frequent occurrence, even in the normal population (1), and pain is probably the most prevalent symptom in the gastroenterology clinic. Consequently, characterization of gut pain is one of the most important issues in the diagnosis and assessment of organ dysfunction, and research leading to a better insight into pain mechanisms in the gastrointestinal (GI) tract will improve the treatment of patients (2). In clinical work, characterization of pain is confounded by many other symptoms caused by the diseases, such as complaints relating to psychological, cognitive and social aspects of the illness. Moreover, many diseases are typically associated with systemic reactions such as fever and general malaise, which can be difficult to distinguish from the symptoms relating to pain. Finally, the patients are typically treated with different therapeutic interventions that may cause sedation and changes in gut motor function. All such confounders can influence the perception of pain, making its assessment in clinical studies difficult. A possible way to overcome this problem is to use experimental models, where the investigator can control the pain ‘input’ e.g., the nature, localization, intensity, frequency and duration of the stimulus, and provide reproducible measures of the ‘output’ e.g., the psychophysical, behavioural or the neurophysiological response (3, 4). Experimental models have been used in different animal species, where the investigators can study the neuronal activity in anaesthetized or spinalized animals directly, with invasive techniques or with assessment of behaviour (for review, see (5)). The neurobiology of the pain system differs, however, between the species, and this limits the interpolation of findings from animal studies to man. Moreover, pain is the net effect of complex multidimensional mechanisms that involve most parts of the central nervous system. Therefore, although nociceptive reflexes or electrophysiological recordings from selected pathways in the animal nervous system are important in basic research, the central pain mechanisms and associated complex reactions are typically suppressed, and animal experiments can only to some degree reflect the experience of clinical pain in humans. Consequently, the interest in human experimental pain studies has increased rapidly during the last decade (6), and also in gastroenterology the focus has been on developing methods for experimental induction and assessment of human pain.

Multi-modal induction and assessment of allodynia and hyperalgesia in the human oesophagus

Background and aims. Experimental pain models based on single stimuli have to some degree limited visceral pain studies in humans. Hence, the aim of this study was to investigate the effect of multi‐modal visceral pain stimuli of the oesophagus in healthy subjects before and after induction of visceral hyperalgesia. We used a multi‐modal psychophysical assessment regime and a neurophysiological method (nociceptive reflex) for the characterisation of the experimentally induced hyperalgesia.

Gut pain and hyperalgesia induced by capsaicin: a human experimental model.

&NA; Human experimental visceral pain models using chemical stimulation are needed for the study of visceral hyperexcitability. Our aim was to stimulate the human gut with chemical activators (capsaicin, glycerol) and measure quantitatively the induced hyperexcitability to painful mechanical gut distension. Ten otherwise healthy subjects with an ileostoma participated. Increasing volumes of capsaicin 50 &mgr;g/ml (0.25, 0.5, 0.75, 1.0, 1.5, 2.0, and 3 ml), glycerol (2.5, 5, and 10 ml) or saline (2.5, 5, and 10 ml) intermingled with sham stimuli were randomly applied to the ileum via the stomal opening at three occasions separated by a week. After each application, pain intensity, qualities, and referred pain area were assessed together with the pain threshold to distension of the proximal gut. ‘Boring’ and ‘hot’ pain were evoked in all subjects by low doses (median 0.5 ml) of capsaicin. The median pain onset, peak pain, and pain duration were 55, 85, and 420 s, respectively. Referred somatic pain developed around the stomal opening with a correlation between the pain area and pain intensity. After application of capsaicin, significant hyperalgesia was found to distension of the gut (a 28% reduction pressure in pain threshold). No significant manifestations were found after application of glycerol and saline. Application of capsaicin to the human ileum induces pain and mechanical hyperalgesia. Specific activation of nociceptors in the gut mucosa provides new possibilities to study clinical relevant visceral pain mechanisms.

Review article: acidity and volume of the refluxate in the genesis of gastro-oesophageal reflux disease symptoms

Background A number of mechanisms, other than acid reflux, may be responsible for the symptoms of gastro‐oesophageal reflux disease.

Controlled mechanical distension of the human oesophagus: sensory and biomechanical findings.

Background: The relation between mechanical distension of the gut and the sensory response is poorly understood. The current experimental study aimed to examine the sensory response in the human oesophagus during on-line recording of the luminal pressure, cross-sectional area (CSA) and sensory rating using different distension rates before and during relaxation of the smooth muscle. Methods: An impedance planimetric probe for bag distension of the oesophagus was used in 13 healthy subjects aged 43 ± 15 years. Ramp distensions were done with an electromechanical pump using infusion rates of 10, 25 and 50 ml/min, with and without relaxation of the smooth muscle with butylscopolamine. The sensory intensity was measured using a 0–10 visual analogue scale (VAS), with 5 as the pain threshold. The pump was reversed at 8 on the scale, corresponding to medium pain intensity, and the pressure, volume, tension and CSA were evaluated. Finally, three isovolumetric experiments where the CSA was held constant for 2 min at initial VAS ratings of 3, 5 and 7 were performed. Results: A total of 104 distension profiles were investigated. The volume at maximal pain intensity (VAS = 8) increased as a function of the distension rate (P < 0.001), whereas the pressure, tension and CSA were not affected. When the smooth muscle was relaxed, there was a 29% fall in pressure at maximal pain intensity (P = 0.004), a 27% fall in tension (P = 0.003), whereas CSA did not change (P = 0.3). When the pressure was recorded as a function of the sensory intensity, there was an exponential increase after the pain threshold was reached, whereas the stimulus-response functions for tension, volume and CSA were nearly linear. In the isovolumetric experiments the ratings during the three sensory intensities were the same in the individual subjects, but the between-individual pain response was variable, probably reflecting individual differences in adaptation/central integration. Conclusions: The study allowed us to assess the strain-rate dependency of both perception and biomechanical properties in the oesophagus. It was demonstrated that the pain response was related to the CSA (and hence strain), independently of the contractile state of the muscle and biomechanical behaviour of the tissue. The findings support the fact that the pain-sensitive mechanoreceptors in the human oesophagus depend on circumferential wall stretch rather than on pressure, tension and volume. The model should be used in future studies to investigate whether changes in strain are responsible for the oesophageal sensation in health and disease.

Impedance planimetry: a new approach to biomechanical intestinal wall properties.

This paper surveys impedance planimetry, a technique based on the measurement of electrical impedance for estimation of active and passive biomechanical wall properties of the intact intestine. The paper mainly concerns methodological aspects of the recording technique and possible sources of error. Furthermore, the historical background concerning developments of the technique and physiological results during the last two decades are described.

The four-electrode impedance technique: a method for investigation of compliance in luminal organs.

A probe for measurement of related values of cross-sectional area (CA) and pressure has been developed to record characteristics of the walls in luminal organs. The aim of this study was to test the probe in vitro. CA was measured in the range 0.17 to 7.07 cm2 by means of the field gradient principle. Pressure was measured in the range 0 to 20 kPa (150 mmHg) by external transducers. After calibration both the pressure and the CA measuring system did measure the parameters adequately. The CA measuring system was dependent on the temperature and electrolyte concentration of the fluid, but was not affected by the size and form outside the excitation electrodes. The upper frequency limits for recordings of CA and pressure were 15.7 and 0.44 Hz, respectively. These in vitro results indicate that the tube assembly has characteristics sufficient for simultaneous measurement of CA and pressure in sphincter regions. These two variables can be used to describe mechanical wall properties such as compliance, hysteresis and creep.

Strain Distribution in the Layered Wall of the Esophagus

The function of the esophagus is to move food by peristaltic motion, which is the result of the interaction of the tissue forces in the esophageal wall and the hydrodynamic forces in the food bolus. To understand the tissue forces in the esophagus, it is necessary to know the zero-stress state of the esophagus, and the stress-strain relationships of the tissues. This article is addressed to the first topic: the representation of zero-stress state of the esophagus by the states of zero stress-resultant and zero bending moment of the mucosa-submucosa and the muscle layers. It is shown that at the states of zero stress-resultant and zero bending moment, these two layers are not tubes of smaller radii but are open sectors whose shapes are approximately cylindrical and more or less circular. When the sectors are approximated by circular sectors, we measured their radii, opening angles, and average thickness around the circumference. Data on the radii, thickness-to-radius ratios, and the opening angles of these sectors are presented. Knowing the zero-stress state of these two layers, we can compute the strain distribution in the wall at any in vivo state, as well as the residual strain in the esophageal wall at the no-load state. The results of the in vivo states are compared to those obtained by a conventional approach, which treats the esophageal wall as a homogeneous material, and to another popular simplification, which ignores the residual strains completely. It is shown that the errors caused by the homogeneous wall assumption are relatively minor, but those caused by ignoring the residual strains completely are severe.

Multimodal pain stimulations in patients with grade B oesophagitis

Aim: To obtain a better understanding of nociceptive processing in patients with oesophagitis. Patients and methods: Eleven patients with grade B oesophagitis were compared with an age and sex matched group of 16 healthy subjects. A probe was positioned in the lower part of the oesophagus. After preconditioning of the tissue, painful mechanical stimuli were applied as distensions with a bag using an impedance planimetric method. Distensions were done before and after pharmacological impairment of distension induced smooth muscle contractions. Thermal stimulation was performed by recirculating water at 1 and 60°C in the bag. The area under the temperature curve (AUC) represented caloric load. The referred pain area (being a proxy for the central pain mechanisms) to the mechanical stimuli was drawn at maximum pain intensities. Results: Patients were hyposensitive to mechanical stimuli, as assessed by the distending volume (F = 8.1, p = 0.005). After relaxation of smooth muscle with butylscopolamine, the difference between the two groups was more evident (F = 27.4, p<0.001). AUC for cold stimulation was 1048.6 (242.7) °C×s in controls and 889.8 (202.6) °C×s in patients (p = 0.5). For heat stimuli, AUC values were 323.3 (104.1) and 81.3 (32.3) °C×s in controls and patients, respectively (p = 0.04). The referred pain area to the mechanical stimulations was larger and more widespread in patients (49.3 (6.2) cm2 compared with controls 23.9 (7) cm2; p = 0.02). Conclusions: The data indicate that peripheral sensitisation of heat sensitive receptors and pathways combined with facilitation of central pain mechanisms may explain the symptoms in patients with oesophagitis.

A new technique for evaluating sphincter function in visceral organs: application of the functional lumen imaging probe (FLIP) for the evaluation of the oesophago–gastric junction

No quantitative method has been implemented routinely in clinical practice to assess the oesophago-gastric junction (OGJ). Using impedance planimetry a functional lumen imaging probe (FLIP) was constructed to measure eight cross-sectional areas (CSA) at 4 mm intervals inside a saline-filled bag. To validate the FLIP technique for profiling the OGJ, polymethylmethacrylate (Perspex) cylinders with different CSAs were measured ten times by the FLIP to assess reproducibility and accuracy. A geometric sphincter phantom was constructed and its geometry was measured with a 360 degrees radial ultrasound (US) mini-probe pulled through it at a rate of 1 mm s(-1). The measurements were compared with FLIP measurements. Safety and technique reproducibility were tested on a volunteer. Reproducibility and accuracy between the ten samples were good. The probe performed well with and without a balloon mounted on it except for the smallest CSA (38.5 mm(2)) where there was a difference of 22% from the actual value at one CSA measurement point. The FLIP imaged the phantom geometry as well as the radial scanning US mini-probe. Pilot studies on a volunteer showed that the probe could be placed in the OGJ and the balloon distensions revealed the geometry of the sphincter at various levels of distension. The technique may be useful in accessing the role of the OGJ in diseases such as gastroesophageal reflux disease (GORD) and achalasia and their treatments with surgical and endoscopic therapies.