Jeremy D. Gale

Effect of a second‐generation α2δ ligand (pregabalin) on visceral sensation in hypersensitive patients with irritable bowel syndrome

Background: Visceral hypersensitivity is an important pathophysiological factor in irritable bowel syndrome (IBS). Pre-clinical studies suggest that the α2δ ligand pregabalin reduces both visceral allodynia and hyperalgesia, but is inactive on basal sensitivity. Aim: To assess the effect of pregabalin on the perception of rectal distension in hypersensitive IBS patients. Methods: Twenty-six patients with Rome-II-defined IBS (aged 18–46 years, 7 male) were included in a randomized, double-blind, placebo-controlled, parallel-group study in which they received either 3 weeks oral pregabalin (titrated: 50 mg tid days 1–3, 100 mg tid days 4–7, 150 mg tid days 8–11; fixed 200 mg tid days 12–21 ±4) or placebo control. Rectal sensitivity was assessed using a barostat technique, in which sensory thresholds were determined using the ascending method of limits, followed by tracking both before and after treatment. Only patients with a pain threshold of ⩽28 mmHg were included in the study. Results: Pregabalin significantly increased the sensory thresholds from baseline for first sensation (p = 0.045), desire to defecate (p = 0.008) and pain (p = 0.048) compared with placebo control. In addition, pregabalin significantly increased rectal compliance (p<0.0001), although this appeared to be unrelated to the changes in sensitivity. Despite the occurrence of mild dizziness and somnolence, pregabalin was generally well tolerated. Conclusions: Pregabalin increased distension sensory thresholds to normal levels in IBS patients with rectal hypersensitivity. A concomitant increase in rectal compliance appeared to be unrelated to the reduction in sensitivity. These data suggest that α2δ ligands are worthy of further investigation in the treatment of visceral pain disorders, including IBS.

An experimental study of viscero-visceral hyperalgesia using an ultrasound-based multimodal sensory testing approach

Abstract Widespread visceral hypersensitivity and the overlap of symptom complexes observed in functional gastrointestinal disorders may be related to central sensitization and neuroplastic changes. A multimodal and multi‐segmental model was developed to evaluate viscero‐visceral hyperalgesia induced by experimental esophageal sensitization in healthy volunteers. Twelve healthy subjects were studied using a double‐blinded, placebo‐controlled design. The sensitivity to mechanical and heat stimulations was assessed in the proximal esophagus, duodenum and rectum before and after perfusion of the distal esophagus with acid or saline. A special‐designed probe was used allowing cross‐sectional ultrasound imaging during mechanical and heat stimulation of the esophagus and duodenum. Another probe was used for mechanical stimulation of the rectum. The referred somatic pain areas to gut pain stimulations were also assessed. Following acid perfusion 11 of 12 volunteers showed increased sensitivity to one or more stimulation modalities. An overall increased sensitivity to mechanical stretch in the three gut segments was seen (P=0.0001). Posthoc analysis showed that this was mainly due to increased sensitivity in the rectum (P<0.001). No changes were seen to thermal stimulations (all P‐values>0.4). The somatic referred pain area to duodenal stimulations increased (P=0.04), while it was unaffected to esophageal and rectal stimulations (P>0.3). The present method demonstrated a new approach to assess multimodal sensitivity to experimental sensitization of the esophagus and related viscero‐visceral hyperalgesia. Central mechanisms can explain the remote hyperalgesia to mechanical visceral stimulation and the increase in referred pain areas. The present method may be used to explore pathophysiology and pharmacological interventions in patients with visceral hypersensitivity.

Multimodal sensory testing of the rectum and rectosigmoid: development and reproducibility of a new method

Abstract  Evaluation of rectal and rectosigmoid sensation is important in basic, clinical and pharmacological studies. New methods to evoke and assess multimodal (electrical, thermal and mechanical) experimental pain of the upper gut activate distinct pathways and mimics clinical pain. The aims of the current study were to characterize the sensory response and reproducibility to multimodal stimulation of rectum and the rectosigmoid. A multimodal rectal probe was developed. Mucosal electrostimulation was delivered at the recto‐sigmoid junction. In Rectum, impedance planimetry was used for measurement of cross‐sectional area (CSA) during distension. Circulation of water within the bag at either 4 or 60 °C was applied for thermal stimulation. The method was tested in 12 healthy volunteers (six men mean age 32 years) on two subsequent days. Mechanical and sensory responses and referred pain areas were assessed. Stimulation with electrical, thermal and mechanical modalities resulted in different sensory perceptions. The relationship between stimulus intensity and sensory response was linear for all modalities. Sensory response to different modalities did not differ between investigation days (all P‐values > 0.1). Approximately 75% of subjects felt referred pain in distinct skin locations. Between‐days reproducibility was good for all modalities [intra‐class correlation (ICC) ≥0.6]. At sensory threshold, CSA showed best reproducibility (ICC ≥ 0.9). At pain detection threshold stretch ratio, CSA and electrostimulation showed best reproducibility (ICC = 1.0; 0.9; 0.9). The present model was easily implemented, robust and showed good reproducibility. It can be used to study pathophysiology or pharmacological interventions in healthy controls and in patients with diseases involving the distal hindgut.

Macroscopic, microscopic and biochemical characterisation of spontaneous colitis in a transgenic mouse, deficient in the multiple drug resistance 1a gene

A novel animal model of spontaneous colonic inflammation, the multiple drug‐resistant (mdr1) a−/− mouse, was identified by Panwala and colleagues in 1998. The aim of our study was to further characterise this model, specifically by measuring cytokines that have been implicated in inflammatory bowel disease (IBD) (IL‐8 and IFN‐γ) in the colon/rectum of mdr1a−/− mice, and by determining the sensitivity of these, together with the macroscopic, microscopic and disease signs of colitis, to dexamethasone (0.05, 0.3 and 2 mg kg−1 subcutaneously (s.c.) daily for 7 days). All mdr1a−/− mice had microscopic evidence of inflammation in the caecum and colon/rectum, while control mice with the same genetic background did not. Significant increases in colon/rectum and caecal weights and also in cytokine levels (both IFN‐γ and IL‐8) in homogenised colon/rectum were observed in mdr1a−/− mice compared to mdr1a+/+ mice. Dexamethasone reduced the increases in tissue weights and also microscopic grading of colitis severity, but had no effect on IFN‐γ or IL‐8. This study supports the similarity of the gastrointestinal inflammation present in mdr1a−/− mice to that of human IBD, in particular Crohns disease. This has been demonstrated at the macroscopic and microscopic levels, and was supported further by elevations in colonic levels of IFN‐γ and IL‐8 and the disease signs observed. The incidence of colitis was much higher than previously reported, with all mice having microscopic evidence of colitis. The limited variance between animals in the parameters measured suggests that this model is reproducible.

Central pain mechanisms following combined acid and capsaicin perfusion of the human oesophagus

Visceral afferents originating from different gut‐segments converge at the spinal level. We hypothesized that chemically‐induced hyperalgesia in the oesophagus could provoke widespread visceral hypersensitivity and also influence descending modulatory pain pathways. Fifteen healthy volunteers were studied at baseline, 30, 60 and 90 min after randomized perfusion of the distal oesophagus with either saline or 180 ml 0.1 M HCl + 2 mg capsaicin. Electro‐stimulation of the oesophagus, 8 cm proximal to the perfusion site, rectosigmoid electrical stimulation and rectal mechanical and heat stimulations were used. Evoked brain potentials were recorded after electrical stimulations before and after oesophageal perfusion. After the perfusion, rectal hyperalgesia to heat (P < 0.01, 37%) and mechanical (P = 0.01, 11%) stimulations were demonstrated. In contrast, hypoalgesia to electro‐stimulation was observed in both the oesophagus (P < 0.03, 23%) and the sigmoid colon (P < 0.001, 18%). Referred pain areas to electro‐stimulation in oesophagus were reduced by 13% after perfusion (P = 0.01). Evoked brain potentials to rectosigmoid stimulations showed decreased latencies and amplitudes of P1, N1 and P2 (P < 0.05), whereas oesophagus‐evoked brain potentials were unaffected after perfusion. In conclusion, modality‐specific hyperalgesia was demonstrated in the lower gut following chemical sensitization of the oesophagus, reflecting widespread central hyperexcitability. Conversely, hypoalgesia to electrical stimulation, decreases in referred pain and latencies of evoked brain potentials was seen. This outcome may reflect a counterbalancing activation of descending inhibitory pathways. As these findings are also seen in the clinical setting, the model may be usable for future basic and pharmacological studies.

Effects of a 5-HT4 receptor agonist on oesophageal function and gastro-oesophageal reflux: studies using combined impedance-manometry and combined impedance-pH

5‐HT4 receptor agonists are used as promotility agents of the stomach, small and large intestine. There is limited information on the influence of 5‐HT4 receptor agonists on oesophageal function and gastro‐oesophageal reflux.

Alpha 2 delta (α2δ) ligands, gabapentin and pregabalin: What is the evidence for potential use of these ligands in irritable bowel syndrome

Irritable bowel syndrome (IBS) is a complex disorder that is characterized by abdominal pain and altered bowel habit, and often associates with other gastrointestinal symptoms such as feelings of incomplete bowel movement and abdominal bloating, and extra-intestinal symptoms such as headache, dyspareunia, heartburn, muscle pain, and back pain. It also frequently coexists with conditions that may also involve central sensitization processes, such as fibromyalgia, irritable bladder disorder, and chronic cough. This review examines the evidence to date on gabapentin and pregabalin which may support further and continued research and development of the α2δ ligands in disorders characterized by visceral hypersensitivity, such as IBS. The distribution of the α2δ subunit of the voltage-gated calcium channel, possible mechanisms of action, pre-clinical data which supports an effect on motor–sensory mechanisms and clinical evidence that points to potential benefits in patients with IBS will be discussed.

Digital image analysis of collagen assessment of progression of fibrosis in recurrent HCV after liver transplantation

BACKGROUND & AIMS Histological assessment of fibrosis progression is currently performed by staging systems which are not continuous quantitative measurements. We aimed at assessing a quantitative measurement of fibrosis collagen proportionate area (CPA), to evaluate fibrosis progression and compare it to Ishak stage progression. METHODS We studied a consecutive cohort of 155 patients with recurrent HCV hepatitis after liver transplantation (LT), who had liver biopsies at one year and were subsequently evaluated for progression of fibrosis using CPA and Ishak staging, and correlated with clinical decompensation. The upper quartile of distribution of fibrosis rates (difference in CPA or Ishak stage between paired biopsies) defined fast fibrosers. RESULTS Patients had 610 biopsies and a median follow-up of 116 (18-252) months. Decompensation occurred in 29 (18%) patients. Median Ishak stage progression rate was 0.42 units/year: (24 (15%) fast fibrosers). Median CPA fibrosis progression rate was 0.71%/year (36 (23%) fast fibrosers). Clinical decompensation was independently associated by Cox regression only with CPA (p=0.007), with AUROCs of 0.81 (95% CI 0.71-0.91) compared to 0.68 (95% CI 0.56-0.81) for Ishak stage. Fast fibrosis defined by CPA progression was independently associated with histological de novo hepatitis (OR: 3.77), older donor age (OR: 1.03) and non-use/discontinuation of azathioprine before 1 year post-LT (OR: 3.85), whereas when defined by Ishak progression, fast fibrosers was only associated with histological de novo hepatitis. CONCLUSIONS CPA fibrosis progression rate is a better predictor of clinical outcome than progression by Ishak stage. Histological de novo hepatitis, older donor age and non-use/discontinuation of azathioprine are associated with rapid fibrosis progression in recurrent HCV chronic hepatitis after liver transplantation.

Advantages of a wholly Bayesian approach to assessing efficacy in early drug development: a case study.

This paper illustrates how the design and statistical analysis of the primary endpoint of a proof-of-concept study can be formulated within a Bayesian framework and is motivated by and illustrated with a Pfizer case study in chronic kidney disease. It is shown how decision criteria for success can be formulated, and how the study design can be assessed in relation to these, both using the traditional approach of probability of success conditional on the true treatment difference and also using Bayesian assurance and pre-posterior probabilities. The case study illustrates how an informative prior on placebo response can have a dramatic effect in reducing sample size, saving time and resource, and we argue that in some cases, it can be considered unethical not to include relevant literature data in this way.

A selective, high affinity 5-HT 2B receptor antagonist inhibits visceral hypersensitivity in rats

Background  RS‐127445 is a selective, high affinity 5‐HT2Breceptor antagonist. We investigated whether 5‐HT2Breceptor antagonists can reduce colonic visceral hypersensitivity caused by restraint stress or by proximal colonic inflammation.