Examining the Nocebo Effect in Trials of Neuromodulators for Use in Disorders of Gut-Brain Interaction.
Journal
The American journal of gastroenterology
ISSN: 1572-0241
Titre abrégé: Am J Gastroenterol
Pays: United States
ID NLM: 0421030
Informations de publication
Date de publication:
01 04 2023
01 04 2023
Historique:
received:
28
07
2022
accepted:
02
11
2022
medline:
31
3
2023
pubmed:
24
12
2022
entrez:
23
12
2022
Statut:
ppublish
Résumé
Nocebo effects are believed to influence the rate of reported adverse events (AE) and subject withdrawal in both the treatment and placebo groups of randomized clinical trials (RCT). Neuromodulators are commonly prescribed to treat disorders of gut-brain interaction (DGBI), but adherence to these medications is often limited by side effects such as headache, dry mouth, fatigue, and altered bowel habits. We performed a systematic review and meta-analysis to assess the proportion and risk difference of patients who experienced side effects leading to withdrawal in the placebo arm vs the treatment arm of RCT of neuromodulators for DGBI. We also sought to estimate the risk of developing any AE in the placebo arm of these studies and the rate of specific individual AEs. We searched MEDLINE, Embase, Web of Science Core Collection, and the Cochrane Central Register of Controlled Trials Searches to identify RCT that included terms for DGBI and for commonly prescribed neuromodulators. We calculated pooled proportions of patients experiencing an AE leading to withdrawal in the active treatment group vs the placebo group with 95% confidence intervals (CI), the pooled proportions of patients experiencing any AE, the pooled proportions of patients experiencing specific AE such as dizziness and headache, the pooled proportions of patients experiencing severe AE, and corresponding pooled risk differences with 95% CI. There were 30 RCT included representing 2,284 patients with DGBI. Twenty-seven RCT reported data on AE leading to withdrawal. The pooled proportion of total patients with AE leading to withdrawal in the placebo group was 4% (95% CI 0.02-0.04). The pooled proportion of patients with AE leading to withdrawal who received neuromodulators was 9% (95% CI 0.06-0.13). In the 12 studies reporting data on patients experiencing at least 1 AE, the pooled proportion of patients experiencing any AE in the placebo group was 18% (95% CI 0.08-0.30), compared with 43% (95% CI 0.24-0.63) in the neuromodulator group. Thus, approximately 44% of the rate of withdrawal (0.04/0.09) and 42% of the rate reporting any side effects (0.18/0.43) in the neuromodulator group may be attributed to nocebo effects in the right context. Subgroup analysis by sex, medication class, risk of bias, and specific DGBI revealed differing withdrawal rates. There was no statistically significant difference in patients experiencing individual AE of dizziness, headache, or diarrhea. Rates of dry mouth, fatigue, and constipation were higher in treatment groups compared with those in placebo groups. Patients with DGBI in RCT randomized to placebo groups frequently experience AE and AE that lead to withdrawal consistent with a strong nocebo effect. Nonspecific AE such as dizziness, headaches, and diarrhea occurred similarly in patients receiving placebo compared with those receiving neuromodulators.
Identifiants
pubmed: 36563308
doi: 10.14309/ajg.0000000000002108
pii: 00000434-202304000-00024
doi:
Types de publication
Systematic Review
Meta-Analysis
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
692-701Informations de copyright
Copyright © 2022 by The American College of Gastroenterology.
Références
Drossman DA, Tack J, Ford AC, et al. Neuromodulators for functional gastrointestinal disorders (disorders of gut-brain interaction): A Rome foundation working team report. Gastroenterology 2018;154(4):1140–71.e1.
Sperber AD, Bangdiwala SI, Drossman DA, et al. Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome foundation global study. Gastroenterology 2021;160(1):99–114.e3.
Ballou S, McMahon C, Lee HN, et al. Effects of irritable bowel syndrome on daily activities vary among subtypes based on results from the IBS in America survey. Clin Gastroenterol Hepatol 2019;17(12):2471–8.e3.
Black CJ, Ford AC. Global burden of irritable bowel syndrome: Trends, predictions and risk factors. Nat Rev Gastroenterol Hepatol 2020;17(8):473–86.
Lembo AJ. Understanding the placebo and nocebo effects in patients with irritable bowel syndrome. Gastroenterol Hepatol (N Y) 2020;16(7):374–6.
Ford AC, Moayyedi P. Meta-analysis: Factors affecting placebo response rate in the irritable bowel syndrome. Aliment Pharmacol Ther 2010;32(2):144–58.
Huang X, Oshima T, Tomita T, et al. Meta-analysis: Placebo response and its determinants in functional dyspepsia. Am J Gastroenterol 2021;116(11):2184–96.
Kaptchuk TJ, Kelley JM, Conboy LA, et al. Components of placebo effect: Randomised controlled trial in patients with irritable bowel syndrome. BMJ 2008;336(7651):999–1003.
Ballou S, Iturrino J, Rangan V, et al. Improving medication tolerance: A pilot study in disorders of gut-brain interaction treated with tricyclic antidepressants. J Clin Gastroenterol 2022;56(5):452–6.
Carlino E, Vase L. Can knowledge of placebo and nocebo mechanisms help improve randomized clinical trials? Int Rev Neurobiol 2018;138:329–57.
Barberio B, Savarino EV, Black CJ, et al. Adverse events in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: Systematic review and meta-analysis. Neurogastroenterol Motil 2022;34(6):e14279.
Lacy BE, Pimentel M, Brenner DM, et al. ACG clinical guideline: Management of irritable bowel syndrome. Am J Gastroenterol 2021;116(1):17–44.
Lembo A, Sultan S, Chang L, et al. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with diarrhea. Gastroenterology 2022;163(1):137–51.
Chang L, Sultan S, Lembo A, et al. AGA clinical practice guideline on the pharmacological management of irritable bowel syndrome with constipation. Gastroenterology 2022;163(1):118–36.
Keefer L, Ko CW, Ford AC. AGA clinical practice update on management of chronic gastrointestinal pain in disorders of gut-brain interaction: Expert review. Clin Gastroenterol Hepatol 2021;19(12):2481–8.e1.
Rief W, Nestoriuc Y, von Lilienfeld-Toal A, et al. Differences in adverse effect reporting in placebo groups in SSRI and tricyclic antidepressant trials: A systematic review and meta-analysis. Drug Saf 2009;32(11):1041–56.
Amanzio M, Corazzini LL, Vase L, et al. A systematic review of adverse events in placebo groups of anti-migraine clinical trials. Pain 2009;146(3):261–9.
Hauser W, Bartram C, Bartram-Wunn E, et al. Adverse events attributable to nocebo in randomized controlled drug trials in fibromyalgia syndrome and painful diabetic peripheral neuropathy: Systematic review. Clin J Pain 2012;28(5):437–51.
Drossman DA, Toner BB, Whitehead WE, et al. Cognitive-behavioral therapy versus education and desipramine versus placebo for moderate to severe functional bowel disorders 1 1This study was registered with ClinicalTrials.gov (trial registry no. NCT00006157). Gastroenterology 2003;125(1):19–31.
Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ 2021;372:n71.
Higgins JPT, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011;343(2):d5928.
Nyaga VN, Arbyn M, Aerts M. Metaprop: A stata command to perform meta-analysis of binomial data. Arch Public Health 2014;72(1):39.
Freeman MF, Tukey JW. Transformations related to the angular and the square root. Ann Math Stat 1950;21(4):607–11.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7(3):177–88.
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994;50(4):1088–101.
Tan VP, Cheung TK, Wong WM, et al. Treatment of functional dyspepsia with sertraline: A double-blind randomized placebo-controlled pilot study. World J Gastroenterol 2012;18(42):6127–33.
Braak B, Klooker TK, Wouters MM, 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(6):638–48.
Kotikula I, Thinrungroj N, Pinyopornpanish K, et al. Randomised clinical trial: The effects of pregabalin vs placebo on functional dyspepsia. Aliment Pharmacol Ther 2021;54(8):1026–32.
Cheong PK, Ford AC, Cheung CKY, et al. Low-dose imipramine for refractory functional dyspepsia: A randomised, double-blind, placebo-controlled trial. Lancet Gastroenterol Hepatol 2018;3(12):837–44.
Tack J, Ly HG, Carbone F, et al. Efficacy of mirtazapine in patients with functional dyspepsia and weight loss. Clin Gastroenterol Hepatol 2016;14(3):385–92.e4.
Kaosombatwattana U, Pongprasobchai S, Limsrivilai J, et al. Efficacy and safety of nortriptyline in functional dyspepsia in asians: A randomized double-blind placebo-controlled trial. J Gastroenterol Hepatol 2018;33(2):411–7.
van Kerkhoven LA, Laheij RJ, Aparicio N, et al. Effect of the antidepressant venlafaxine in functional dyspepsia: A randomized, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol 2008;6(7):746–52.
Talley NJ, Locke GR, Saito YA, et al. Effect of amitriptyline and escitalopram on functional dyspepsia: A multicenter, randomized controlled study. Gastroenterology 2015;149(2):340–9.e2.
Hashash JG, Abdul-Baki H, Azar C, et al. Clinical trial: A randomized controlled cross-over study of flupenthixol + melitracen in functional dyspepsia. Aliment Pharmacol Ther 2008;27(11):1148–55.
Lee H, Kim JH, Min BH, et al. Efficacy of venlafaxine for symptomatic relief in young adult patients with functional chest pain: A randomized, double-blind, placebo-controlled, crossover trial. Am J Gastroenterol 2010;105(7):1504–12.
Cox ID, Hann CM, Kaski JC. Low dose imipramine improves chest pain but not quality of life in patients with angina and normal coronary angiograms. Eur Heart J 1998;19(2):250–4.
Doraiswamy PM, Varia I, Hellegers C, et al. A randomized controlled trial of paroxetine for noncardiac chest pain. Psychopharmacol Bull 2006;39(1):15–24.
Varia I, Logue E, O'Connor C, et al. Randomized trial of sertraline in patients with unexplained chest pain of noncardiac origin. Am Heart J 2000;140(3):367–72.
Vahedi H, Merat S, Rashidioon A, et al. The effect of fluoxetine in patients with pain and constipation-predominant irritable bowel syndrome: A double-blind randomized-controlled study. Aliment Pharmacol Ther 2005;22(5):381–5.
Khalilian A, Ahmadimoghaddam D, Saki S, et al. A randomized, double-blind, placebo-controlled study to assess efficacy of mirtazapine for the treatment of diarrhea predominant irritable bowel syndrome. BioPsychoSocial Med 2021;15(1):3.
Vahedi H, Merat S, Momtahen S, et al. Clinical trial: The effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2008;27(8):678–84.
Limsrivilai J, Charatcharoenwitthaya P, Pausawasdi N, et al. Imipramine for treatment of esophageal hypersensitivity and functional heartburn: A randomized placebo-controlled trial. Am J Gastroenterol 2016;111(2):217–24.
Ostovaneh MR, Saeidi B, Hajifathalian K, et al. Comparing omeprazole with fluoxetine for treatment of patients with heartburn and normal endoscopy who failed once daily proton pump inhibitors: Double-blind placebo-controlled trial. Neurogastroenterology Motil 2014;26(5):670–8.
Seddighnia A, Tadayon Najafabadi B, Ghamari K, et al. Vortioxetine effects on quality of life of irritable bowel syndrome patients: A randomized, double-blind, placebo-controlled trial. J Clin Pharm Ther 2020;45(1):97–104.
Kuiken SD, Tytgat GNJ, Boeckxstaens GEE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable bowel syndrome: A double blind, randomized, placebo-controlled study. Clin Gastroenterol Hepatol 2003;1(3):219–28.
Abdul-Baki H, Hajj IIE, Azar C, et al. A randomized controlled trial of imipramine in patients with irritable bowel syndrome. World J Gastroenterol 2009;15(29):3636–42.
Tabas G, Beaves M, Wang J, et al. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: A double-blind, placebo-controlled trial. Am J Gastroenterol 2004;99(5):914–20.
Vork L, Mujagic Z, Drukker M, et al. The Experience Sampling Method-Evaluation of treatment effect of escitalopram in IBS with comorbid panic disorder. Neurogastroenterology Motil 2019;31(1):e13515.
Afshar H, Sharbafchi M, Adhamian P, et al. Effects of venlafaxine on gastrointestinal symptoms, depression, anxiety, stress, and quality of life in patients with the moderate-to-severe irritable bowel syndrome. J Res Med Sci 2020;25(1):116.
Masand PS, Pae CU, Krulewicz S, et al. A double-blind, randomized, placebo-controlled trial of paroxetine controlled-release in irritable bowel syndrome. Psychosomatics 2009;50(1):78–86.
Tack J, Broekaert D, Fischler B, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2005;55(8):1095–103.
Ladabaum U, Sharabidze A, Levin TR, et al. Citalopram provides little or no benefit in nondepressed patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2010;8(1):42–8.e1.
Talley NJ, Kellow JE, Boyce P, et al. Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: A double-blind, randomized, placebo-controlled trial. Dig Dis Sci 2008;53(1):108–15.
Tanum L, Malt UF. A new pharmacologic treatment of functional gastrointestinal disorder. A double-blind placebo-controlled study with mianserin. Scand J Gastroenterol 1996;31(4):318–25.
Thiwan S, Drossman DA, Morris CB, et al. Not all side effects associated with tricyclic antidepressant therapy are true side effects. Clin Gastroenterol Hepatol 2009;7(4):446–51.
Ballou S, Hassan R, Nee J, et al. Are They side effects? Extra-intestinal symptoms reported during clinical trials of IBS may Be more severe at baseline. Clin Gastroenterol Hepatol 2022;20(12):2888–94.e1.
Enck P, Klosterhalfen S. Placebo responses and placebo effects in functional gastrointestinal disorders. Front Psychiatry 2020;11:797.
Barberio B, Savarino EV, Black CJ, et al. Placebo response rates in trials of licensed drugs for irritable bowel syndrome with constipation or diarrhea: Meta-analysis. Clin Gastroenterol Hepatol 2022;20(5):e923–e944.
Ma C, Panaccione NR, Nguyen TM, et al. Adverse events and nocebo effects in inflammatory bowel disease: A systematic review and meta-analysis of randomized controlled trials. J Crohns Colitis 2019;13(9):1201–16.