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

British Society of Gastroenterology guidelines on the management of functional dyspepsia

Functional dyspepsia (FD) is a common disorder of gut-brain interaction, affecting approximately 7% of individuals in the community, with most patients managed in primary care. The last British Society of Gastroenterology (BSG) guideline for the management of dyspepsia was published in 1996. In the interim, substantial advances have been made in understanding the complex pathophysiology of FD, and there has been a considerable amount of new evidence published concerning its diagnosis and classification, with the advent of the Rome IV criteria, and management. The primary aim of this guideline, commissioned by the BSG, is to review and summarise the current evidence to inform and guide clinical practice, by providing a practical framework for evidence-based diagnosis and treatment of patients. The approach to investigating the patient presenting with dyspepsia is discussed, and efficacy of drugs in FD summarised based on evidence derived from a comprehensive search of the medical literature, which was used to inform an update of a series of pairwise and network meta-Analyses. Specific recommendations have been made according to the Grading of Recommendations Assessment, Development and Evaluation system. These provide both the strength of the recommendations and the overall quality of evidence. Finally, in this guideline, we consider novel treatments that are in development, as well as highlighting areas of unmet need and priorities for future research

The national prevalence of disorders of gut brain interaction in the United Kingdom in comparison to their worldwide prevalence: Results from the Rome foundation global epidemiology study

Background: There are minimal epidemiological data comparing the burden of disorders of gut brain interaction (DGBI) in the UK with other countries. We compared the prevalence of DGBI in the UK with other countries that participated in the Rome Foundation Global Epidemiology Study (RFGES) online. Methods: Participants from 26 countries completed the RFGES survey online including the Rome IV diagnostic questionnaire and an in-depth supplemental questionnaire with questions about dietary habits. UK sociodemographic and prevalence data were compared with the other 25 countries pooled together. Key Results: The proportion of participants with at least one DGBI was lower in UK participants compared with in the other 25 countries (37.6% 95% CI 35.5%–39.7% vs. 41.2%; 95% CI 40.8%–41.6%, p = 0.001). The UK prevalence of 14 of 22 Rome IV DGBI, including irritable bowel syndrome (4.3%) and functional dyspepsia (6.8%), was similar to the other countries. Fecal incontinence, opioid-induced constipation, chronic nausea and vomiting, and cannabinoid hyperemesis (p < 0.05) were more prevalent in the UK. Cyclic vomiting, functional constipation, unspecified functional bowel disorder, and proctalgia fugax (p < 0.05) were more prevalent in the other 25 countries. Diet in the UK population consisted of higher consumption of meat and milk (p < 0.001), and lower consumption of rice, fruit, eggs, tofu, pasta, vegetables/legumes, and fish (p < 0.001). Conclusions and Inferences: The prevalence and burden of DGBI is consistently high in the UK and in the rest of the world. Opioid prescribing, cultural, dietary, and lifestyle factors may contribute to differences in the prevalence of some DGBI between the UK and other countries

Insights into the evaluation and management of dyspepsia: recent developments and new guidelines

Dyspepsia is a very common gastrointestinal (GI) condition worldwide. We critically examine the recommendations of recently published guidelines for the management of dyspepsia, including those produced jointly by the American College of Gastroenterology and the Canadian Association of Gastroenterology, and those published by the UK National Institute for Health and Care Excellence. Dyspepsia is a symptom complex, characterized by a range of upper GI symptoms including epigastric pain or burning, early satiety, and post-prandial fullness. Although alarm features are used to help prioritize access to upper GI endoscopy, they are of limited utility in predicting endoscopic findings, and the majority of patients with dyspepsia will have no organic pathology identified at upper GI endoscopy. These patients are labelled as having functional dyspepsia (FD). The Rome IV criteria, which are used to define FD, further subclassify patients with FD as having either epigastric pain syndrome or post-prandial distress syndrome, depending on their predominant symptoms. Unfortunately, the Rome criteria perform poorly at identifying FD without the need for upper GI endoscopy. This has led to the investigation of alternative diagnostic approaches, including whether a capsaicin pill or combined serum biomarkers can accurately identify patients with FD. However, there is insufficient evidence to support either of these approaches at the present time. Patients with FD should be tested for H. pylori infection and be prescribed eradication therapy if they test positive. If they continue to have symptoms following this, then a trial of treatment with a proton pump inhibitor (PPI) should be given for up to 8 weeks. In cases where symptoms fail to adequately respond to PPI treatment, a tricyclic antidepressant may be of benefit, and should be continued for 6 to 12 months in patients who respond. Prokinetics demonstrate limited efficacy for treating FD, but could be considered if other strategies have failed. However, there are practical difficulties due to their limited availability in some countries and the risk of serious side effects. Patients with FD who fail to respond to drug treatments should be offered psychological therapy, where available. Overall, with the exception of recommendations relating to H. pylori testing and the prescription of PPIs, which are made on the basis of high-quality evidence, the evidence underpinning other elements of dyspepsia management is largely of low-quality. Consequently, there are still many aspects of the evaluation and management of dyspepsia that require further research

The serotonin receptor 3E variant is a risk factor for female IBS-D

Irritable bowel syndrome (IBS) is a gut-brain disorder of multifactorial origin. Evidence of disturbed serotonergic function in IBS accumulated for the 5-HT3 receptor family. 5-HT3Rs are encoded by HTR3 genes and control GI function, and peristalsis and secretion, in particular. Moreover, 5-HT3R antagonists are beneficial in the treatment of diarrhea predominant IBS (IBS-D). We previously reported on functionally relevant SNPs in HTR3A c.-42C > T (rs1062613), HTR3C p.N163K (rs6766410), and HTR3E c.*76G > A (rs56109847 = rs62625044) being associated with IBS-D, and the HTR3B variant p.Y129S (rs1176744) was also described within the context of IBS. We performed a multi-center study to validate previous results and provide further evidence for the relevance of HTR3 genes in IBS pathogenesis. Therefore, genotype data of 2682 IBS patients and 9650 controls from 14 cohorts (Chile, Germany (2), Greece, Ireland, Spain, Sweden (2), the UK (3), and the USA (3)) were taken into account. Subsequent meta-analysis confirmed HTR3E c.*76G > A (rs56109847 = rs62625044) to be associated with female IBS-D (OR = 1.58; 95% CI (1.18, 2.12)). Complementary expression studies of four GI regions (jejunum, ileum, colon, sigmoid colon) of 66 IBS patients and 42 controls revealed only HTR3E to be robustly expressed. On top, HTR3E transcript levels were significantly reduced in the sigma of IBS patients (p = 0.0187); more specifically, in those diagnosed with IBS-D (p = 0.0145). In conclusion, meta-analysis confirmed rs56109847 = rs62625044 as a risk factor for female IBS-D. Expression analysis revealed reduced HTR3E levels in the sigmoid colon of IBS-D patients, which underlines the relevance of HTR3E in the pathogenesis of IBS-D

No association between the common calcium-sensing receptor polymorphism rs1801725 and irritable bowel syndrome

Background The calcium-sensing receptor (CaSR) is a calcium (Ca2+) sensitive G protein-coupled receptor implicated in various biological processes. In particular, it regulates Ca2+/Mg2+- homeostasis and senses interstitial Ca2+ levels and thereby controls downstream signalling cascades. Due to its expression in the gut epithelium, the enteric nervous system and smooth muscles and its key function in regulation and coordination of muscular contraction and secretion, it represents an excellent candidate gene to be investigated in the pathophysiology of irritable bowel syndrome (IBS). Disturbed CaSR structure and function may impact gastrointestinal regulation of muscular contraction, neuronal excitation and secretion and consequently contribute to symptoms seen in IBS, such as disordered defecation as well as disturbed gut motility and visceral sensitivity. Methods We have therefore genotyped the functional CASR SNP rs1801725 in three case control samples from the UK, Belgium and the USA. Results Genotype frequencies showed no association in the three genotyped case–control samples, neither with IBS nor with IBS subtypes. Conclusions Although we could not associate the SNP to any of the established bowel symptom based IBS subtypes we cannot rule out association to altered Ca2+ levels and disturbed secretion and gut motility which were unfortunately not assessed in the patients genotyped. This underlines the necessity of a more detailed phenotyping of IBS patients and control individuals in future studies

Treatment of irritable bowel syndrome with diarrhoea using titrated ondansetron (TRITON): study protocol for a randomised controlled trial

Background: Irritable bowel syndrome with diarrhoea (IBS-D) affects up to 4% of the general population. Symptoms include frequent, loose, or watery stools with associated urgency, resulting in marked reduction of quality of life and loss of work productivity. Ondansetron, a 5HT3 receptor antagonist, has had an excellent safety record for over 20 years as an antiemetic, yet is not widely used in the treatment of IBS-D. It has, however, been shown to slow colonic transit and in a small randomised, placebo-controlled, cross-over pilot study, benefited patients with IBS-D. Methods: This trial is a phase III, parallel group, randomised, double-blind, multi-centre, placebo-controlled trial, with embedded mechanistic studies. Participants (n = 400) meeting Rome IV criteria for IBS-D will be recruited from outpatient and primary care clinics and by social media to receive either ondansetron (dose titrated up to 24 mg daily) or placebo for 12 weeks. Throughout the trial, participants will record their worst abdominal pain, worst urgency, stool frequency, and stool consistency on a daily basis. The primary endpoint is the proportion of “responders” in each group, using Food and Drug Administration (FDA) recommendations. Secondary endpoints include pain intensity, stool consistency, frequency, and urgency. Mood and quality of life will also be assessed. Mechanistic assessments will include whole gut transit, faecal tryptase and faecal bile acid concentrations at baseline and between weeks 8 and 11. A subgroup of participants will also undergo assessment of sensitivity (n = 80) using the barostat, and/or high-resolution colonic manometry (n = 40) to assess motor patterns in the left colon and the impact of ondansetron. Discussion: The TRITON trial aims to assess the effect of ondansetron across multiple centres. By defining ondansetron’s mechanisms of action we hope to better identify patients with IBS-D who are likely to respond