G. Dimcevski

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.

Differential effect of opioids in patients with chronic pancreatitis: An experimental pain study

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.

Dysmenorrhoea is associated with hypersensitivity in the sigmoid colon and rectum

Abstract Dysmenorrhoea patients experience intense visceral pain during menstruation. Recurrent and/or intense visceral pain can induce facilitation of somatic and visceral nociceptive processing which can lead to viscero‐somatic (referred) and viscero‐visceral hyperalgesia. Our aim was to study if dysmenorrhoea is associated with hypersensitivity in the referred somatic skin area or in the large bowel, i.e., viscero‐visceral hyperalgesia. We measured skin sensitivity in the referred area of the sigmoid colon as well as stimulus–response relationships in the sigmoid colon and rectum. The latter were measured using mechanical (balloon) distension applied via a Barostat in 11 dysmenorrhoea patients without gastro‐intestinal complaints and 10 healthy and age matched women, again without gastrointestinal complaints. We found no skin hypersensitivity in the colonic referred area. In contrast, significantly lower distension volumes were seen at each threshold in dysmenorrhoea patients, particularly in the sigmoid colon. The mean reduction in colonic distension volume thresholds for dysmenorrhoea patients vs. controls was 57% at the detection threshold and 39% at the pain threshold. There were no differences in compliance between the groups. These findings suggest that, despite the absence of overt gastro‐intestinal symptoms or viscero‐somatic sensitisation, dysmenorrhoea patients demonstrate intestinal hypersensitivity. This can be regarded as the result of centrally mediated viscero‐visceral hyperalgesia due to recurrent intense menstrual pain.

Cortical changes to experimental sensitization of the human esophagus

Topographical organization in the neocortex shows experience-dependent plasticity. We hypothesized that experimental sensitization of the esophagus results in changes of the topographical distribution of the evoked potentials and the corresponding dipole source activities to painful stimulation. An endoscopic method was used to deliver 35 electrical stimuli at the pain threshold to a fixed area of the mucosa in 10 healthy volunteer men and women. The stimulations were repeated after 30 min (reproducibility experiment), and after 60 min following perfusion of 200 ml 0.1 N hydrochloric acid (sensitization experiment). During stimulation the electroencephalogram was recorded from 64 surface electrodes. The sensitization resulted in a decrease in the pain threshold (F=6.2; P=0.004). The topographic distribution of the evoked potentials showed reproducible negative (N1, N2) and positive (P1, P2) components. After acid perfusion a reduced latency and a change in localization was seen for the P1 subdivided into frontal and occipital components (F=29.5, P<0.001; F=53.7, P<0.001). Furthermore the sensitization resulted in a reduction of the latency for P2 (F=6.2, P=0.009). The source analysis showed consistent dipolar activity in the bilateral opercular-insular cortex before and after acid perfusion. For the anterior cingulate dipole there was a reduction in latency (P=0.03) and a posterior shift (P=0.0002) following acid perfusion. The findings indicate that short-term sensitization of the esophagus results in central neuroplastic changes involving the cingulate gyrus, which also showed pathological activation in functional diseases of the gut, thus reflecting the importance of this region in visceral pain and hyperalgesia.

Assessment of experimental pain from skin, muscle, and esophagus in patients with chronic pancreatitis

Objectives: Comprehensive experimental methods are of major relevance assessing pain mechanisms in patients with chronic pain. Chronic pancreatitis is thought to involve the sensory response in other visceral organs and somatic tissue. We, therefore, aimed at exploring the pain mechanisms in chronic pancreatitis (CP) using a multimodal and multitissue stimulation approach. Methods: Ten patients (mean age, 50 years) with CP and 13 healthy controls (mean age, 35 years) participated. None of the patients took analgesics regularly. All were exposed to multimodal (mechanical, thermal, and electrical) experimental pain in the skin, muscles, and esophagus. Results: The patients were hyposensitive to mechanical stimulations of the skin (P = 0.001), but there were no differences in the pain to thermal and electrical stimulations. In the muscle and esophagus, no differences in pain thresholds were found. The difference between single and repeated stimulations reflecting the degree of central sensitization was 17% in controls and 36% in patients (P = 0.001). The referred pain area to electrical stimulation was 30.1 cm2 in the patients and 7.7 cm2 for the controls (P = 0.02). Conclusions: The findings suggest that the balance among central hyperexcitability, neuroplastic changes, and descending pain-modulating pathways may explain the pain response to experimental multimodal stimulations in CP. This will likely also reflect the clinical pain mechanisms and may have important impact in selection of treatment, where drugs with potential effects on these mechanisms should be used.

Cerebral processing of painful oesophageal stimulation: a study based on independent component analysis of the EEG

Background and aims: Independent component analysis (ICA) of the electroencephalogram (EEG) overcomes many of the classical problems in EEG analysis. We used ICA to determine the brain responses to painful stimulation of the oesophagus. Methods: Twelve subjects with a median age of 41 years were included. With a nasal endoscope, two series of 35 electrical stimuli at the pain threshold were given to the distal oesophagus and the EEG was subjected to ICA. The sessions were separated by 30 minutes. For each component head models, event related images, spectral perturbation, coherence analysis, and dipoles were extracted. The most valid components were found according to time/frequency information and reliability in both experiments. Results: Reliable components with the most valid dipoles were found in the thalamus, insula, cingulate gyrus, and sensory cortex. Time locked activities were consistent with upstream activation of these areas, and cross coherence analysis of the sources demonstrated dynamic links in the β(14–25 Hz) and γ(25–50 Hz) bands between the suggested networks of neurones. The thalamic components were time and phase locked intermittently, starting around 50 ms. In the cingulate gyrus, the posterior areas were always firstly activated, followed by the middle and anterior regions. Components with dipoles in the sensory cortex were localised in several regions of the somatosensory area. Conclusions: The method gives new information relating to the localisation and dynamics between neuronal networks in the brain to pain evoked from the human oesophagus, and should be used to increase our understanding of clinical pain.

Viscero-somatic reflexes in referred pain areas evoked by capsaicin stimulation of the human gut

The interaction between visceral pain and the sympathetic nervous system is only sparsely investigated in quantitative human studies. Referred visceral pain can be evoked experimentally by application of substances such as capsaicin (the pungent substance of chilli pepper) to the gut. The aim of the present study was to induce referred visceral pain from the small and large intestine in 32 volunteers via the stomal opening in patients with ileo‐ or colostomy and quantify the viscero‐somatic reflex responses in these referred pain areas by thermography and laser doppler flowmetry.

FC5.2 The “human visceral homonculus” to pain evoked in the oesophagus, stomach, duodenum and sigmoid colon

patients participated in this study. Patients were instructed to silently read a word immediately after visual presentation of the word. Totally 100 words were presented. Using synthetic aperture magnetometry (SAM), local oscillatory changes were obtained as spatial distribution of Student’s t statistics by comparing 1 s before and after stimulus onset. Language dominance was determined by the laterality index derived from maximum t values of the left and right frontal desynchronization. Language dominance and localization were compared with Wada test (N = 48) and stimulation mapping (N = 12, subdural electrodes: 10, intraoperative cortical stimulation: 2), respectively. Results: Language dominance by SAM was concordant with Wada test in 42 cases (87.5%). Localization of the frontal language areas could be detected in 72 patients (93.5%). Localization of the frontal language areas by SAM was compared with stimulation mapping in eight cases. Estimated frontal language areas were well concordant with stimulation mapping. However, there was a tendency that the anterior part of the frontal language areas was not detected. Discussion: Our method is a noninvasive alternative to Wada test. As for language localization, our method is useful to determine the stimulation sites for invasive mapping. Additional tasks such as sentence reading might improve to detect the anterior part of the frontal language areas.