Circadian variation of rectal sensitivity and gastrointestinal peptides in healthy volunteers

Abstract  The aim of our study was to identify diurnal variation of perception of rectal distension and the release of gastroenteropancreatic hormones. In 12 healthy male volunteers (25 years, range 22–32), a rectal balloon distension was performed. Rectal perception thresholds (minimal, urge and pain) and rectal compliance were double-measured with a computer-controlled barostat at seven standardized time points during the day (from 16.00 to 14.00 hours the following day). Blood samples were taken 30 min before and after each rectal distension procedure to determine plasma levels of cholecystokinin (CCK), pancreatic polypeptide (PP) and motilin. Sensory thresholds for urge and pain varied significantly with the time of day, with higher threshold levels in the evening than in the morning hours. Bowel wall compliance showed as well-significant variance at pain threshold and was higher during daytime than in the evening or at night. In contrast to motilin, release of CCK and PP also showed a significant variation depending on daytime. Perception of rectal distension stimuli as well as compliance was independent of intake of food and peptide hormone levels, but CCK and PP levels increased with food, and PP levels decreased with rectal distension. Significant differences in the perception of rectal distension stimuli for urge and pain depending on daytime were found, but the release of gastrointestinal peptides seemed not to be involved. This circadian variation needs to be taken into account in patients and volunteer studies.     

The placebo response in functional dyspepsia – reanalysis of trial data

Abstract  Clinical trial data rarely identify factors contributing to the placebo response. We reanalysed the data from the placebo arm ( n  = 157) of a functional dyspepsia (FD) trial to determine predictors of placebo response including total GIS score, change in GIS score during run-in, type of FD symptoms, duration of illness, age, gender, body mass index (BMI), family occurrence of FD-like symptoms, smoking and alcohol consumption. The same response criteria were applied to the drug arm ( n  = 158) of the study. Based on the initial 40% response criterion of the study, 35 (22.2%) were classified as placebo responders (PR), whilst 122 (78.8%) were placebo non-responders (PnR). Response rates for the drug arm were 41.1 and 56.9% respectively. PR had significantly lower GIS scores compared to PnR at visit 1 (10.6 ± 0.6 and 12.3 ± 0.4, respectively, P  = 0.035), but not at visit 2 with study medication dispensing (10.9 ± 0.5 and 11.3 ± 0.4). Hence, PR symptoms increased during run-in by 4.2% whilst PnR symptoms decreased by 6.3% ( P  < 0.005). Gender, age and duration and type of FD symptoms were not different between PR and PnR. Smoking was less prevalent in PR (3%) compared to PnR (21%) ( P  < 0.025). Increasing the criteria for the placebo response resulted in higher BMI for PR than for PnR ( P  = 0.035). None of the predictors for placebo response were able to distinguish responders from non-responders to the drug. Variables predicting the PR point towards behavioural and biological mechanism of the PR, operating simultaneously and independently.     

Biofeedback therapy in fecal incontinence and constipation

Abstract  We examine the collected evidence for efficacy of biofeedback therapy (BFT) in incontinence and constipation by means of meta-analysis of randomized controlled trials. PubMed search was performed to identify treatment trials that match quality criteria (adequate control groups, randomization). They were entered into meta-analyses using fixed effect models and computing odds ratio (OR) and 95% confidence interval (CI) of treatment effects. For constipation, eight BFT trials were identified. In four trials, electromyographic (EMG) BFT was compared to non-BFT treatments (laxatives, placebo, sham training and botox injection), while in the remaining four studies EMG BFT was compared to other BFT (balloon pressure, verbal feedback) modes. Meta-analyses revealed superiority of BFT to non-BFT (OR: 3.657; 95% CI: 2.127–6.290, P  < 0.001) but equal efficacy of EMG BFT to other BF applications (OR: 1.436; CI: 0.692–3.089; P  = 0.319). For fecal incontinence, a total of 11 trials were identified, of which six compared BFT to other treatment options (sensory training, pelvic floor exercise and electrical stimulation) and five compared one BFT option to other modalities of BFT. BFT was equal effective than non-BFT therapy (OR: 1.189, CI: 0.689–2.051, P  = 0.535). No difference was found when various modes BFT were compared (OR: 1.278, CI: 0.736–2.220, P  = 0.384). Included trials showed a substantial lack of quality and harmonization, e.g. variable endpoints and missing psychological assessment across studies. BFT for pelvic floor dyssynergia shows substantial specific therapeutic effect while BFT for incontinence is still lacking evidence for efficacy. However, in both conditions the mode of BFT seems to play a minor role.     

The placebo response in functional bowel disorders: perspectives and putative mechanisms

The nature and determinants of the placebo response are widely unknown, as are the underlying psychological and biological mechanisms. High placebo response rates in functional bowel disorders (functional dyspepsia, irritable bowel syndrome) are similar to those in non-intestinal diseases (depression, pain, Parkinson's disease) and not too dissimilar to other organic gastrointestinal diseases (duodenal ulcer, inflammatory bowel diseases). Methodological reasons (regression to the mean, shift in signal detection through manipulation of expectations) and psycho-biological mechanisms (Pavlovian conditioning of biological processes) are proposed to explain a large component of the response variance in clinical trials. Psychobiological mechanisms of the placebo response in functional and organic diseases can also be identified in brain function studies (such as imaging).     

The story of O – is oxytocin the mediator of the placebo response?

Abstract  While the placebo responses in various medical conditions have been shown to follow a few basic principles such as expectancies, reward learning and Pavlovian conditioning, the underlying neurobiology and the mediating hormonal and/or neuromodulating processing have remained obscure. We here report the collected evidence that oxytocin (OXT), a 389-amino acid polypeptide located on chromosome 3p25 that is released in the brain (hypothalamus) and in peripheral tissue, is the central mediator of the placebo response: we hypothesize that exogenous OXT via an OXT agonist will enhance the placebo response, while exogenous OXT blockade by an antagonist will reduce the placebo response in placebo analgesia and other placebo models. It is furthermore proposed that the placebo response in trials may be predicted by circulating plasma OXT levels, the OXT receptor density in the brain and/or the presence of one or more of the single nucleotide polymorphisms of the OXT promoter gene.