Central neuromodulators (antidepressants, antipsychotics, and other central nervous system−targeted medications) are increasingly used for treatment of functional gastrointestinal disorders (FGIDs), ...now recognized as disorders of gut−brain interaction. However, the available evidence and guidance for the use of central neuromodulators in these conditions is scanty and incomplete. In this Rome Foundation Working Team report, a multidisciplinary team summarized available research evidence and clinical experience to provide guidance and treatment recommendations.
The working team summarized the literature on the pharmacology of central neuromodulators and their effects on gastrointestinal sensorimotor function and conducted an evidence-based review on their use for treating FGID syndromes. Because of the paucity of data for FGIDs, we included data for non-gastrointestinal painful disorders and specific symptoms of pain, nausea, and vomiting. This information was combined into a final document comprising a synthesis of available evidence and recommendations for clinical use guided by the research and clinical experience of the experts on the committee.
The evidence-based review on neuromodulators in FGID, restricted by the limited available controlled trials, was integrated with open-label studies and case series, along with the experience of experts to create recommendations using a consensus (Delphi) approach. Due to the diversity of conditions and complexity of treatment options, specific recommendations were generated for different FGIDs. However, some general recommendations include: (1) low to modest dosages of tricyclic antidepressants provide the most convincing evidence of benefit for treating chronic gastrointestinal pain and painful FGIDs and serotonin noradrenergic reuptake inhibitors can also be recommended, though further studies are needed; (2) augmentation, that is, adding a second treatment (adding quetiapine, aripiprazole, buspirone α2δ ligand agents) is recommended when a single medication is unsuccessful or produces side effects at higher dosages; (3) treatment should be continued for 6−12 months to potentially prevent relapse; and (4) implementation of successful treatment requires effective communication skills to improve patient acceptance and adherence, and to optimize the patient−provider relationship.
Based on systematic and selectively focused review and the consensus of a multidisciplinary panel, we have provided summary information and guidelines for the use of central neuromodulators in the treatment of chronic gastrointestinal symptoms and FGIDs. Further studies are needed to confirm and refine these recommendations.
Background
Post‐dural (post‐lumbar or post‐spinal) puncture headache (PDPH) is one of the most common complications of diagnostic, therapeutic or inadvertent lumbar punctures. Many drug options have ...been used to prevent headache in clinical practice and have also been tested in some clinical studies, but there are still some uncertainties about their clinical effectiveness.
Objectives
To assess the effectiveness and safety of drugs for preventing PDPH in adults and children.
Search methods
The search strategy included the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2012, Issue 5), MEDLINE (from 1950 to May 2012), EMBASE (from 1980 to May 2012) and CINAHL (from 1982 to June 2012). There was no language restriction.
Selection criteria
We considered randomised controlled trials (RCTs) that assessed the effectiveness of any drug used for preventing PDPH.
Data collection and analysis
Review authors independently selected studies, assessed risks of bias and extracted data. We estimated risk ratios (RR) for dichotomous data and mean differences (MD) for continuous outcomes. We calculated a 95% confidence interval (CI) for each RR and MD. We did not undertake meta‐analysis because participants' characteristics or assessed doses of drugs were too different in the included studies. We performed an intention‐to‐treat (ITT) analysis.
Main results
We included 10 RCTs (1611 participants) in this review with a majority of women (72%), mostly parturients (women in labour) (913), after a lumbar puncture for regional anaesthesia. Drugs assessed were epidural and spinal morphine, spinal fentanyl, oral caffeine, rectal indomethacin, intravenous cosyntropin, intravenous aminophylline and intravenous dexamethasone.
All the included RCTs reported data on the primary outcome, i.e. the number of participants affected by PDPH of any severity after a lumbar puncture. Epidural morphine and intravenous cosyntropin reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to placebo. Also, intravenous aminophylline reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to no intervention, while intravenous dexamethasone increased it. Spinal morphine increased the number of participants affected by pruritus when compared to placebo, and epidural morphine increased the number of participants affected by nausea and vomiting when compared to placebo. Oral caffeine increased the number of participants affected by insomnia when compared to placebo.
The remainder of the interventions analysed did not show any relevant effect for any of the outcomes.
None of the included RCTs reported the number of days that patients stayed in hospital.
Authors' conclusions
Morphine and cosyntropin have shown effectiveness for reducing the number of participants affected by PDPH of any severity after a lumbar puncture, when compared to placebo, especially in patients with high risk of PDPH, such as obstetric patients who have had an inadvertent dural puncture. Aminophylline also reduced the number of participants affected by PDPH of any severity after a lumbar puncture when compared to no intervention in patients undergoing elective caesarean section. Dexamethasone increased the risk of PDPH, after spinal anaesthesia for caesarean section, when compared to placebo. Morphine also increased the number of participants affected by adverse events (pruritus and nausea and vomiting)
There is a lack of conclusive evidence for the other drugs assessed (fentanyl, caffeine, indomethacin and dexamethasone).
These conclusions should be interpreted with caution, owing to the lack of information, to allow correct appraisal of risk of bias and the small sample sizes of studies.
Up to 20% of people worldwide develop gastrointestinal symptoms following a meal
, leading to decreased quality of life, substantial morbidity and high medical costs. Although the interest of both ...the scientific and lay communities in this issue has increased markedly in recent years, with the worldwide introduction of gluten-free and other diets, the underlying mechanisms of food-induced abdominal complaints remain largely unknown. Here we show that a bacterial infection and bacterial toxins can trigger an immune response that leads to the production of dietary-antigen-specific IgE antibodies in mice, which are limited to the intestine. Following subsequent oral ingestion of the respective dietary antigen, an IgE- and mast-cell-dependent mechanism induced increased visceral pain. This aberrant pain signalling resulted from histamine receptor H
-mediated sensitization of visceral afferents. Moreover, injection of food antigens (gluten, wheat, soy and milk) into the rectosigmoid mucosa of patients with irritable bowel syndrome induced local oedema and mast cell activation. Our results identify and characterize a peripheral mechanism that underlies food-induced abdominal pain, thereby creating new possibilities for the treatment of irritable bowel syndrome and related abdominal pain disorders.
Background
This is an update of the original Cochrane review, last published in 2009 (Huertas‐Ceballos 2009). Recurrent abdominal pain (RAP), including children with irritable bowel syndrome, is a ...common problem affecting between 4% and 25% of school‐aged children. For the majority of such children, no organic cause for their pain can be found on physical examination or investigation. Many dietary inventions have been suggested to improve the symptoms of RAP. These may involve either excluding ingredients from the diet or adding supplements such as fibre or probiotics.
Objectives
To examine the effectiveness of dietary interventions in improving pain in children of school age with RAP.
Search methods
We searched CENTRAL, Ovid MEDLINE, Embase, eight other databases, and two trials registers, together with reference checking, citation searching and contact with study authors, in June 2016.
Selection criteria
Randomised controlled trials (RCTs) comparing dietary interventions with placebo or no treatment in children aged five to 18 years with RAP or an abdominal pain‐related, functional gastrointestinal disorder, as defined by the Rome III criteria (Rasquin 2006).
Data collection and analysis
We used standard methodological procedures expected by Cochrane. We grouped dietary interventions together by category for analysis. We contacted study authors to ask for missing information and clarification, when needed. We assessed the quality of the evidence for each outcome using the GRADE approach.
Main results
We included 19 RCTs, reported in 27 papers with a total of 1453 participants. Fifteen of these studies were not included in the previous review. All 19 RCTs had follow‐up ranging from one to five months. Participants were aged between four and 18 years from eight different countries and were recruited largely from paediatric gastroenterology clinics. The mean age at recruitment ranged from 6.3 years to 13.1 years. Girls outnumbered boys in most trials. Fourteen trials recruited children with a diagnosis under the broad umbrella of RAP or functional gastrointestinal disorders; five trials specifically recruited only children with irritable bowel syndrome. The studies fell into four categories: trials of probiotic‐based interventions (13 studies), trials of fibre‐based interventions (four studies), trials of low FODMAP (fermentable oligosaccharides, disaccharides, monosaccharides and polyols) diets (one study), and trials of fructose‐restricted diets (one study).
We found that children treated with probiotics reported a greater reduction in pain frequency at zero to three months postintervention than those given placebo (standardised mean difference (SMD) ‐0.55, 95% confidence interval (CI) ‐0.98 to ‐0.12; 6 trials; 523 children). There was also a decrease in pain intensity in the intervention group at the same time point (SMD ‐0.50, 95% CI ‐0.85 to ‐0.15; 7 studies; 575 children). However, we judged the evidence for these outcomes to be of low quality using GRADE due to an unclear risk of bias from incomplete outcome data and significant heterogeneity.
We found that children treated with probiotics were more likely to experience improvement in pain at zero to three months postintervention than those given placebo (odds ratio (OR) 1.63, 95% CI 1.07 to 2.47; 7 studies; 722 children). The estimated number needed to treat for an additional beneficial outcome (NNTB) was eight, meaning that eight children would need to receive probiotics for one to experience improvement in pain in this timescale. We judged the evidence for this outcome to be of moderate quality due to significant heterogeneity.
Children with a symptom profile defined as irritable bowel syndrome treated with probiotics were more likely to experience improvement in pain at zero to three months postintervention than those given placebo (OR 3.01, 95% CI 1.77 to 5.13; 4 studies; 344 children). Children treated with probiotics were more likely to experience improvement in pain at three to six months postintervention compared to those receiving placebo (OR 1.94, 95% CI 1.10 to 3.43; 2 studies; 224 children). We judged the evidence for these two outcomes to be of moderate quality due to small numbers of participants included in the studies.
We found that children treated with fibre‐based interventions were not more likely to experience an improvement in pain at zero to three months postintervention than children given placebo (OR 1.83, 95% CI 0.92 to 3.65; 2 studies; 136 children). There was also no reduction in pain intensity compared to placebo at the same time point (SMD ‐1.24, 95% CI ‐3.41 to 0.94; 2 studies; 135 children). We judged the evidence for these outcomes to be of low quality due to an unclear risk of bias, imprecision, and significant heterogeneity.
We found only one study of low FODMAP diets and only one trial of fructose‐restricted diets, meaning no pooled analyses were possible.
We were unable to perform any meta‐analyses for the secondary outcomes of school performance, social or psychological functioning, or quality of daily life, as not enough studies included these outcomes or used comparable measures to assess them.
With the exception of one study, all studies reported monitoring children for adverse events; no major adverse events were reported.
Authors' conclusions
Overall, we found moderate‐ to low‐quality evidence suggesting that probiotics may be effective in improving pain in children with RAP. Clinicians may therefore consider probiotic interventions as part of a holistic management strategy. However, further trials are needed to examine longer‐term outcomes and to improve confidence in estimating the size of the effect, as well as to determine the optimal strain and dosage. Future research should also explore the effectiveness of probiotics in children with different symptom profiles, such as those with irritable bowel syndrome.
We found only a small number of trials of fibre‐based interventions, with overall low‐quality evidence for the outcomes. There was therefore no convincing evidence that fibre‐based interventions improve pain in children with RAP. Further high‐quality RCTs of fibre supplements involving larger numbers of participants are required. Future trials of low FODMAP diets and other dietary interventions are also required to facilitate evidence‐based recommendations.
Background & Aims Chronic stress alters the hypothalamic–pituitary–adrenal axis, increases gut motility, and increases the perception of visceral pain. We investigated whether epigenetic mechanisms ...regulate chronic stress-induced visceral pain in the peripheral nervous systems of rats. Methods Male rats were subjected to 1 hour of water avoidance stress each day, or given daily subcutaneous injections of corticosterone, for 10 consecutive days. L4–L5 and L6–S2 dorsal root ganglia (DRG) were collected and compared between stressed and control rats (placed for 1 hour each day in a tank without water). Levels of cannabinoid receptor 1 (CNR1), DNA (cytosine-5-)-methyltransferase 1 (DNMT1), transient receptor potential vanilloid type 1 (TRPV1), and EP300 were knocked down in DRG neurons in situ with small interfering RNAs. We measured DNA methylation and histone acetylation at genes encoding the glucocorticoid receptor (NR3C1), CNR1, and TRPV1. Visceral pain was measured in response to colorectal distention. Results Chronic stress was associated with increased methylation of the Nr3c1 promoter and reduced expression of this gene in L6–S2, but not L4–L5, DRGs. Stress also was associated with up-regulation in DNMT1-associated methylation of the Cnr1 promoter and down-regulation of glucocorticoid-receptor–mediated expression of CNR1 in L6–S2, but not L4–L5, DRGs. Concurrently, chronic stress increased expression of the histone acetyltransferase EP300 and increased histone acetylation at the Trpv1 promoter and expression of the TRPV1 receptor in L6–S2 DRG neurons. Knockdown of DNMT1 and EP300 in L6–S2 DRG neurons of rats reduced DNA methylation and histone acetylation, respectively, and prevented chronic stress-induced increases in visceral pain. Conclusions Chronic stress increases DNA methylation and histone acetylation of genes that regulate visceral pain sensation in the peripheral nervous system of rats. Blocking epigenetic regulatory pathways in specific regions of the spinal cord might be developed to treat patients with chronic abdominal pain.
Visceral hypersensitivity is one feature of irritable bowel syndrome (IBS). Bacterial dysbiosis might be involved in the activation of nociceptive sensory pathways, but there have been few studies of ...the role of the mycobiome (the fungal microbiome) in the development of IBS. We analyzed intestinal mycobiomes of patients with IBS and a rat model of visceral hypersensitivity.
We used internal transcribed spacer 1-based metabarcoding to compare fecal mycobiomes of 18 healthy volunteers with those of 39 patients with IBS (with visceral hypersensitivity or normal levels of sensitivity). We also compared the mycobiomes of Long-Evans rats separated from their mothers (hypersensitive) with non-handled (normally sensitive) rats. We investigated whether fungi can cause visceral hypersensitivity using rats exposed to fungicide (fluconazole and nystatin). The functional relevance of the gut mycobiome was confirmed in fecal transplantation experiments: adult maternally separated rats were subjected to water avoidance stress (to induce visceral hypersensitivity), then given fungicide and donor cecum content via oral gavage. Other rats subjected to water avoidance stress were given soluble β-glucans, which antagonize C-type lectin domain family 7 member A (CLEC7A or DECTIN1) signaling via spleen-associated tyrosine kinase (SYK), a SYK inhibitor to reduce visceral hypersensitivity, or vehicle (control). The sensitivity of mast cells to fungi was tested with mesenteric windows (ex vivo) and the human mast cell line HMC-1.
α diversity (Shannon index) and mycobiome signature (stability selection) of both groups of IBS patients differed from healthy volunteers, and the mycobiome signature of hypersensitive patients differed from that of normally sensitive patients. We observed mycobiome dysbiosis in rats that had been separated from their mothers compared with non-handled rats. Administration of fungicide to hypersensitive rats reduced their visceral hypersensitivity to normal levels of sensitivity. Administration of cecal mycobiomes from rats that had been separated from their mothers (but not non-handled mycobiome) restored hypersensitivity to distension. Administration of soluble β-glucans or a SYK inhibitor reduced visceral hypersensitivity, compared with controls. Particulate β-glucan (a DECTIN-1 agonist) induced mast cell degranulation in mesenteric windows and HMC-1 cells responded to fungal antigens by release of histamine.
In an analysis of patients with IBS and controls, we associated fungal dysbiosis with IBS. In studies of rats, we found fungi to promote visceral hypersensitivity, which could be reduced by administration of fungicides, soluble β-glucans, or a SYK inhibitor. The intestinal fungi might therefore be manipulated for treatment of IBS-related visceral hypersensitivity.
Many patients with gastroparesis are prescribed opioids for pain control, but indications for opioid prescriptions and the relationship of opioid use to gastroparesis manifestations are undefined. We ...characterized associations of use of potent vs weaker opioids and presentations of diabetic and idiopathic gastroparesis.
We collected data on symptoms, gastric emptying, quality of life, and health care resource use from 583 patients with gastroparesis (>10% 4-h scintigraphic retention) from the National Institute of Diabetes and Digestive and Kidney Diseases Gastroparesis Consortium, from January 2007 through November 2016. Patients completed medical questionnaires that included questions about opioid use. The opioid(s) were categorized for potency relative to oral morphine. Symptom severities were quantified by Patient Assessment of Upper Gastrointestinal Disorders Symptoms questionnaires. Subgroup analyses compared patients on potent vs weaker opioids and opioid effects in diabetic vs idiopathic etiologies.
Forty-one percent of patients were taking opioids; 82% of these took potent agents (morphine, hydrocodone, oxycodone, methadone, hydromorphone, buprenorphine, or fentanyl). Abdominal pain was the reason for prescription for 61% of patients taking opioids. Mean scores for gastroparesis, nausea/vomiting, bloating/distention, abdominal pain, and constipation scores were higher in opioid users (P ≤ .05). Opioid use was associated with greater levels of gastric retention, worse quality of life, increased hospitalization, and increased use of antiemetic and pain modulator medications compared with nonusers (P ≤ .03). Use of potent opioids was associated with worse gastroparesis, nausea/vomiting, upper abdominal pain, and quality-of-life scores, and more hospitalizations compared with weaker opioids (tapentadol, tramadol, codeine, or propoxyphene) (P ≤ .05). Opioid use was associated with larger increases in gastric retention in patients with idiopathic vs diabetic gastroparesis (P = .008).
Opioid use is prevalent among patients with diabetic or idiopathic gastroparesis, and is associated with worse symptoms, delays in gastric emptying, and lower quality of life, as well as greater use of resources. Potent opioids are associated with larger effects than weaker agents. These findings form a basis for studies to characterize adverse outcomes of opioid use in patients with gastroparesis and to help identify those who might benefit from interventions to prevent opioid overuse.
Abdominal pain can be an important symptom in some patients with gastroparesis (Gp).
Aims
(1) To describe characteristics of abdominal pain in Gp; (2) describe Gp patients reporting abdominal pain.
...Methods
Patients with idiopathic gastroparesis (IG) and diabetic gastroparesis (DG) were studied with gastric emptying scintigraphy, water load test, wireless motility capsule, and questionnaires assessing symptoms Patient Assessment of Upper GI Symptoms (PAGI-SYM) including Gastroparesis Cardinal Symptom Index (GCSI), quality of life (PAGI-QOL, SF-36), psychological state Beck Depression Inventory (BDI), State-Trait Anxiety Index (STAI), PHQ-15 somatization scale.
Results
In total, 346 Gp patients included 212 IG and 134 DG. Ninety percentage of Gp patients reported abdominal pain (89% DG and 91% IG). Pain was primarily in upper or central midline abdomen, described as cramping or sickening. Upper abdominal pain was severe or very severe on PAGI-SYM by 116/346 (34%) patients, more often by females than by males, but similarly in IG and DG. Increased upper abdominal pain severity was associated with increased severity of the nine GCSI symptoms, depression on BDI, anxiety on STAI, somatization on PHQ-15, the use of opiate medications, decreased SF-36 physical component, and PAGI-QOL, but not related to severity of delayed gastric emptying or water load ingestion. Using logistic regression, severe/very severe upper abdominal pain associated with increased GCSI scores, opiate medication use, and PHQ-15 somatic symptom scores.
Conclusions
Abdominal pain is common in patients with Gp, both IG and DG. Severe/very severe upper abdominal pain occurred in 34% of Gp patients and associated with other Gp symptoms, somatization, and opiate medication use.
ClinicalTrials.gov Identifier: NCT01696747.
Knowledge of optimal diagnostic workup, etiology, and response to treatment of chronic abdominal pain after Roux-en-Y gastric bypass (RYGB) is limited.
To define the etiology of chronic abdominal ...pain presenting at the 5-year follow-up after RYGB and to evaluate response to treatment.
Oslo University Hospital (tertiary referral center for obesity surgery).
Of 234 patients operated during a randomly selected 12-month period, 165 (71%) returned for 5-year follow-up, and 160 responded to study questionnaires. Of these, 54 (34%) reported chronic abdominal pain and were invited to participate in a structured diagnostic and treatment algorithm. These patients were contacted for the evaluation of their response to treatment.
Fifty-one of 54 patients (94%) reporting chronic abdominal pain at the 5-year follow-up were included in the study. Of the 45 patients with onset of symptoms post-RYGB, 28 (62%) underwent one or more radiologic evaluations, 10 (22%) underwent endoscopy, and 13 (29%) underwent laparoscopy. Diagnosis and treatment were established for 34 patients (76%), whereas 11 (24%) had abdominal pain of unknown cause. The most common etiology was internal herniation (n = 6), dumping (n = 6), food intolerance (n = 6), gallstones (n = 5), and irritable bowel syndrome (n = 4). After a median follow-up of 13.0 months (standard deviation, 11.5), 37 (82%) patients reported remission or improvement of symptoms, 6 had unchanged symptoms, and 2 patients were lost to follow-up.
The etiology of long-term chronic abdominal pain post-RYGB is diverse. A multidisciplinary team can help most patients with dedicated follow-up, but a subset of patients has symptoms of unknown etiology.
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