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• W2141063943 abstract "See “Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study,” by Talley NJ, Locke GR, Saito YA, et al, on page 340. See “Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study,” by Talley NJ, Locke GR, Saito YA, et al, on page 340. Functional dyspepsia, a prevalent disorder with chronic upper abdominal symptoms, is a management challenge, particularly among patients referred to tertiary centers. The literature is dominated by investigations into acid suppressant or Helicobacter pylori eradication regimens. However, many patients with functional dyspepsia do not respond to these measures. Proton pump inhibitors and histamine2 antagonists provide only 7%–10% and 7%–35% therapeutic gains over placebo, respectively.1Lacy B.E. Talley N.J. Locke G.R. et al.Review article: current treatment options and management of functional dyspepsia.Aliment Pharmacol Ther. 2012; 36: 3-15Crossref PubMed Scopus (164) Google Scholar Benefits of H pylori treatments are lower (therapeutic gain 6%–14%) than for peptic ulcers. Delayed symptom responses to H pylori eradication raise questions about its true effectiveness in this condition. Thus, there remains a clear unmet need for proven therapies for refractory functional dyspepsia. Difficulties in defining effective therapies for functional dyspepsia stem partly from its heterogeneous pathogenesis. Altered gut motor and sensory functions, psychological dysfunction, and immune dysregulation are proposed to contribute to dyspepsia. Delayed gastric emptying is found in 20%-35% of patients with functional dyspepsia, which correlates poorly with symptoms.2Carbone F. Tack J. Gastroduodenal mechanisms underlying functional gastric disorders.Dig Dis. 2014; 32: 222-229Crossref PubMed Scopus (53) Google Scholar Some trials of prokinetic drugs that accelerate gastric emptying show benefits in functional dyspepsia, but studies exhibited significant heterogeneity raising questions regarding magnitudes of benefit.1Lacy B.E. Talley N.J. Locke G.R. et al.Review article: current treatment options and management of functional dyspepsia.Aliment Pharmacol Ther. 2012; 36: 3-15Crossref PubMed Scopus (164) Google Scholar Impairments in gastric relaxation (or accommodation) after eating are observed in 40% of functional dyspeptics and may contribute to early satiety, weight loss, and abdominal pain.2Carbone F. Tack J. Gastroduodenal mechanisms underlying functional gastric disorders.Dig Dis. 2014; 32: 222-229Crossref PubMed Scopus (53) Google Scholar Beneficial effects of agents that promote accommodation, including the serotonin 5-HT1A agonist buspirone, have been reported.3Tack J. Janssen P. Masaoka T. et al.Buspirone, a fundus-relaxing drug, in patients with functional dyspepsia.Clin Gastroenterol Hepatol. 2012; 10: 1239-1245Abstract Full Text Full Text PDF PubMed Scopus (197) Google Scholar Exaggerated perception of gastric distention is found in 34% of functional dyspepsia patients, especially with increased postprandial pain, belching, and weight loss.2Carbone F. Tack J. Gastroduodenal mechanisms underlying functional gastric disorders.Dig Dis. 2014; 32: 222-229Crossref PubMed Scopus (53) Google Scholar Furthermore, some patients report heightened perception of acid in the stomach and duodenum, suggesting potential mechanisms for proton pump inhibitor effectiveness. Because of theoretical capabilities to reverse luminal hypersensitivity and psychological dysfunction, a robust literature has characterized the utility of antidepressants in irritable bowel syndrome (IBS), but their benefits in functional dyspepsia are less established. In a Cochrane review, tricyclic antidepressants reduced IBS symptoms more than placebo in 9 trials (relative risk [RR] 0.68; 95% CI, 0.56–0.83).4Ford A.C. Talley N.J. Schoenfeld P.S. et al.Efficacy of antidepressants and psychological therapies in irritable bowel syndrome: systematic review and meta-analysis.Gut. 2009; 58: 367-378Crossref PubMed Scopus (464) Google Scholar Serotonin reuptake inhibitors produced similar benefits in 5 IBS trials (RR, 0.62; 95% CI, 0.45–0.87). An older metaanalysis of antidepressant/anxiolytic agents suggested efficacy in functional dyspepsia, but funnel plot asymmetry reflective of publication bias raised concerns about the validity of these observations.1Lacy B.E. Talley N.J. Locke G.R. et al.Review article: current treatment options and management of functional dyspepsia.Aliment Pharmacol Ther. 2012; 36: 3-15Crossref PubMed Scopus (164) Google Scholar More recently, in a small crossover study of 7 patients with functional dyspepsia, the tricyclic drug amitriptyline reduced symptoms more than placebo but did not reverse gastric hypersensitivity.5Mertz H. Fass R. Kodner A. et al.Effect of amitriptyline on symptoms, sleep, and visceral perception in patients with functional dyspepsia.Am J Gastroenterol. 1998; 93: 160-165Crossref PubMed Scopus (209) Google Scholar In another controlled trial in 38 patients with dyspepsia, amitriptyline did not improve postprandial symptoms and could not increase nutrient tolerance during satiety testing.6Braak B. Klooker T.K. Wouters M.M. et al.Randomised clinical trial: the effects of amitriptyline on drinking capacity and symptoms in patients with functional dyspepsia, a double-blind placebo-controlled study.Aliment Pharmacol Ther. 2011; 34: 638-648Crossref PubMed Scopus (53) Google Scholar Studies with other antidepressant classes have yielded inconsistent results. For example, the serotonin reuptake inhibitor sertraline was superior to placebo in 193 patients over 8 weeks,7Tan V.P. Cheung T.K. Wong W.M. et al.Treatment of functional dyspepsia with sertraline: a double-blind randomized placebo-controlled pilot study.World J Gastroenterol. 2012; 18: 6127-6133Crossref PubMed Scopus (53) Google Scholar whereas the serotonin–norepinephrine reuptake inhibitor venlafaxine and placebo were similarly effective in a 20-week investigation of 160 dyspepsia patients.8Van Kerkhoven L.A. Laheij R.J. Aparicio N. et al.Effect of the antidepressant venlafaxine in functional dyspepsia: a randomized, double-blind, placebo-controlled trial.Clin Gastroenterol Hepatol. 2008; 6: 746-752Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar These varied findings from studies with small samples or potential methodologic limitations have not been compelling enough to routinely advocate antidepressants for functional dyspepsia treatment. Against this backdrop, the article by Talley and coworkers in the current issue of Gastroenterology provides the most comprehensive characterization of antidepressant responses in functional dyspepsia to date.9Talley N.J. Locke G.R. Saito Y.A. et al.Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study.Gastroenterology. 2015; 149: 340-349Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar Importantly, patients were stratified by symptom subtype. Because recruitment began in 2006 before the Rome III criteria were widely adopted, subjects were enrolled as dysmotility-like (nonpainful upper abdominal sensations with fullness, early satiety, bloating, or nausea) or ulcer-like (predominant upper abdominal pain) dyspepsia based on Rome II definitions.10Talley N.J. Stanghellini V. Heading R.C. et al.Functional gastroduodenal disorders.Gut. 1999; 45: II37-42Crossref PubMed Scopus (916) Google Scholar Patients with normal versus delayed solid phase gastric emptying were considered separately. Additional physiologic testing quantifying maximally tolerated ingestion of liquid nutrient solutions was performed to estimate gastric accommodation and sensation. Significant treatment effects over 12 weeks were seen, with the greatest benefits observed with amitriptyline and lesser responses noted with escitalopram and placebo. In subgroup analyses, patients with ulcer-like dyspepsia more often exhibited higher adequate relief on amitriptyline versus placebo with an odds ratio of 3.1 (95% CI, 1.1–9.0). Delayed gastric emptying related to lower odds for amitriptyline responses with an odds ratio of 0.4 (95% CI, 0.2–0.8). In contrast, escitalopram did not offer benefits superior to placebo for any patient subgroup. Benefits afforded by amitriptyline were modest. The P value for the difference in overall treatment effect was borderline significant at .05; direct comparisons between the amitriptyline and placebo arms excluding those on escitalopram showed only a statistical trend (P = .07). These observations parallel those of large tricyclic trials in other functional conditions such as IBS. In one prominent placebo-controlled study, the tricyclic agent desipramine did not decrease functional lower bowel symptoms when intention-to-treat calculations were performed and symptom improvements were detected only when per protocol analyses excluded patients who did not attend a sufficient number of study visits.11Drossman D.A. Toner B.B. Whitehead W.E. et al.Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.Gastroenterology. 2003; 125: 19-31Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar An important consequence of this study is its characterization of dyspepsia subgroups more likely to respond to tricyclics. Amitriptyline selectively benefitted patients with ulcer-like dyspepsia, but was not superior to placebo for nonpainful dysmotility-like symptoms. These observations are consistent with analgesic actions for tricyclic drugs observed with other chronic pain syndromes. In a prior analysis of 41 tricyclic clinical trials, analgesic effects were prominent for chronic and intermittent pain from several conditions, including peripheral neuropathy, migraines, and musculoskeletal pain.12Lynch M.E. Antidepressants as analgesics: a review of randomized controlled trials.J Psychiatry Neurosci. 2001; 26: 30-36PubMed Google Scholar The lesser benefits of selective serotonin reuptake inhibitors in somatic pain syndromes parallel the lack of escitalopram benefit in a study by Talley et al. However, the lack of effect on dysmotility-type symptoms contrasts with small, uncontrolled series that have observed reductions in functional nausea and vomiting with tricyclic drugs.13Prakash C. Lustman P.J. Freedland K.E. et al.Tricyclic antidepressants for functional nausea and vomiting: clinical outcome in 37 patients.Dig Dis Sci. 1998; 43: 1951-1956Crossref PubMed Scopus (81) Google Scholar Although this study used older Rome II definitions, it is reasonable to propose amitriptyline would be effective for epigastric pain syndrome but not postprandial distress syndrome as defined by the current Rome III criteria.9Talley N.J. Locke G.R. Saito Y.A. et al.Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study.Gastroenterology. 2015; 149: 340-349Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar, 14Tack J. Talley N.J. Camilleri M. et al.Functional gastroduodenal disorders.Gastroenterology. 2006; 130: 1466-1479Abstract Full Text Full Text PDF PubMed Scopus (1453) Google Scholar Unfortunately, epigastric pain syndrome comprises only a small minority of functional dyspepsia cases. Thus, the larger group of dyspeptics with dysmotility symptoms would not be reasonable candidates for tricyclic treatment. These findings complement those of the National Institute of Diabetes and Digestive and Kidney Diseases–funded Nortriptyline for Idiopathic Gastroparesis (NORIG) study conducted by the Gastroparesis Clinical Research Consortium, which randomized 130 patients with idiopathic gastroparesis to nortriptyline versus placebo for 15 weeks.15Parkman H.P. Van Natta M.L. Abell T.L. et al.Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial.JAMA. 2013; 310: 2640-2649Crossref PubMed Scopus (125) Google Scholar Nortriptyline and placebo responses were identical using a primary outcome of 50% reduction in gastroparesis symptoms over 2 consecutive study visits. The NORIG study is relevant to the Talley et al study because 86% of patients with idiopathic gastroparesis satisfy Rome III criteria for functional dyspepsia and many more present with symptoms mimicking postprandial distress syndrome (91%) than epigastric pain syndrome (1%).16Parkman H.P. Yates K. Hasler W.L. et al.Clinical features of idiopathic gastroparesis vary with sex, body mass, symptom onset, delay in gastric emptying, and gastroparesis severity.Gastroenterology. 2011; 140: 101-115Abstract Full Text Full Text PDF PubMed Scopus (235) Google Scholar This lack of tricyclic responsiveness in the NORIG cohort with delayed gastric emptying and dysmotility symptoms replicates the findings of the nonresponders in the Talley et al study. Thus, although there were differences in study design and enrolled patients, the conclusions from these two trials were remarkably consistent. Findings of these two investigations could be interpreted to support a role for gastric emptying testing to facilitate patient selection for dyspepsia therapy, especially for ulcer-like symptoms. This is surprising because gastric emptying delays show little relation to symptom profiles in functional dyspepsia or gastroparesis.17Pasricha P.J. Colvin R. Yates K. et al.Characteristics of patients with chronic unexplained nausea and vomiting and normal gastric emptying.Clin Gastroenterol Hepatol. 2011; 9: 567-576Abstract Full Text Full Text PDF PubMed Scopus (177) Google Scholar Furthermore, 1 metaregression analysis noted no correlation of gastric emptying parameters and symptom responses to prokinetic treatment.18Janssen P. Harris M.S. Jones M. et al.The relation between symptom improvement and gastric emptying in the treatment of diabetic and idiopathic gastroparesis.Am J Gastroenterol. 2013; 108: 1382-1391Crossref PubMed Scopus (186) Google Scholar In the Talley et al study, only patients with normal emptying exhibited beneficial tricyclic responses. Similar results were seen with the 5-HT3 antagonist alosetron, which selectively reduced symptoms in dyspeptics with normal gastric emptying but worsened them in those with delays.19Talley N.J. Van Zanten S.V. Saez L.R. et al.A dose-ranging, placebo-controlled, randomized trial of alosetron in patients with functional dyspepsia.Aliment Pharmacol Ther. 2001; 15: 525-537Crossref PubMed Scopus (107) Google Scholar Perhaps we all have been barking up the wrong tree by trying to find patients with gastric emptying impairments. Instead, it might be more appropriate to select for tricyclic treatment those patients with dyspepsia who have normal gastric emptying. Diagnostic utilities of other tests of gastric physiology are less well defined. Both the Talley et al study and the NORIG trial related satiety responses during liquid nutrient ingestion to tricyclic effectiveness. Satiety testing has been proposed as a surrogate marker for accommodation, but also is influenced by hypersensitivity to distention and gastric emptying.2Carbone F. Tack J. Gastroduodenal mechanisms underlying functional gastric disorders.Dig Dis. 2014; 32: 222-229Crossref PubMed Scopus (53) Google Scholar In the Talley et al study, satiety test results did not differ between amitriptyline, escitalopram, and placebo, suggesting that the benefits of tricyclic treatment for epigastric pain may result from reduced gastric sensitivity or central nervous system effects.9Talley N.J. Locke G.R. Saito Y.A. et al.Effect of amitriptyline and escitalopram on functional dyspepsia: a multicenter, randomized controlled study.Gastroenterology. 2015; 149: 340-349Abstract Full Text Full Text PDF PubMed Scopus (229) Google Scholar However, in preliminary NORIG analyses, idiopathic gastroparesis patients with impaired nutrient tolerance (<250 mL) showed trends to superior responses to nortriptyline compared to placebo (P = .06).20Parkman H. Van Natta M. Abell T. et al.Nortriptyline for idiopathic gastroparesis: a multicenter, randomized, double-masked, placebo-controlled trial (NORIG) (abstract).Gastroenterology. 2013; 144: S1Abstract Full Text PDF Google Scholar Further work is needed to confirm whether satiety tests or other measures of gastric physiology can predict treatment responses in dyspepsia. The authors should be congratulated for persevering to the completion of their laudable study. A 6-year period was required to randomize 292 patients at 8 sites. Similarly, it took >3 years to enroll 130 patients with idiopathic gastroparesis at 6 centers for the NORIG trial and >5 years to recruit 216 patients with functional bowel disorders into the desipramine trial at 2 institutions.11Drossman D.A. Toner B.B. Whitehead W.E. et al.Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders.Gastroenterology. 2003; 125: 19-31Abstract Full Text Full Text PDF PubMed Scopus (567) Google Scholar, 15Parkman H.P. Van Natta M.L. Abell T.L. et al.Effect of nortriptyline on symptoms of idiopathic gastroparesis: the NORIG randomized clinical trial.JAMA. 2013; 310: 2640-2649Crossref PubMed Scopus (125) Google Scholar These medications were approved in the 1960s and are widely used as non-narcotic analgesics. One report noted that >25% of patients referred for upper endoscopy for unexplained dyspepsia were already prescribed psychotropic medications at the time of their procedure.8Van Kerkhoven L.A. Laheij R.J. Aparicio N. et al.Effect of the antidepressant venlafaxine in functional dyspepsia: a randomized, double-blind, placebo-controlled trial.Clin Gastroenterol Hepatol. 2008; 6: 746-752Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar Recruiting patients into tricyclic antidepressant trials is difficult because of the availability of these drugs and their routine use for pain control. In conclusion, the Talley et al investigation demonstrated modest efficacy of a tricyclic agent, but not a selective serotonin reuptake inhibitor in reducing symptoms in patients with functional dyspepsia. Adequate relief was restricted to the relatively small subset with epigastric ulcer-like pain (Figure 1). The lack of efficacy in patients with dyspepsia with delayed gastric emptying suggests the possible utility of scintigraphic testing to select patients with normal rather than abnormal emptying profiles for amitriptyline therapy. Given the difficulties in conducting trials with this drug class, this careful investigation may represent the definitive description of the utility of tricyclic antidepressants for functional dyspepsia. Effect of Amitriptyline and Escitalopram on Functional Dyspepsia: A Multicenter, Randomized Controlled StudyGastroenterologyVol. 149Issue 2PreviewAntidepressants are frequently prescribed to treat functional dyspepsia (FD), a common disorder characterized by upper abdominal symptoms, including discomfort or postprandial fullness. However, there is little evidence of the efficacy of these drugs in patients with FD. We performed a randomized, double-blind, placebo-controlled trial to evaluate the effects of antidepressant therapy on symptoms, gastric emptying (GE), and meal-induced satiety in patients with FD. Full-Text PDF" @default.
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• W2141063943 title "Amitriptyline for Functional Dyspepsia: Importance of Symptom Profile and Making a Case for Gastric Emptying Testing" @default.
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