The prevalence and risk of sleep disorders in patients with functional dyspepsia: a meta-analysis

Read metadata

OBJECTIVE

Systematization of data on the incidence and risk of sleep disorders in patients with functional dyspepsia (FD).

MATERIAL AND METHODS

Studies were searched in the electronic databases MEDLINE/PubMed, EMBASE, Cochrane until October 2020. Publications with detailed descriptive statistics (sample size, number of patients with sleep disorders) were selected for the final analysis, allowing the resulting data to be included in the meta-analysis.

RESULTS

The final analysis included 10 studies with 7739 people (2354 patients with FD, 5385 controls). The generalized incidence of sleep disturbances in patients with FD was 53.23% (95% CI: 37.738—68.419). There was significant heterogeneity between the results (p<0.0001; I²=98.05%). An association was found between FD and sleep disorders (OR 2.884; 95% CI 2.518—3.304; I²=28.35%) compared with controls. In patients with epigastric pain syndrome (EPS), the generalized incidence of sleep disorders was 40.6% (95% CI 34.267—47.181; I²=0%), with postprandial distress syndrome (PDS) — 51.82% (95% CI 26.479—76.666; I²=94.76%), and at the intersection of EPS and PDS — 51.67% (95% CI 23.497—79.270; I²=95.34%).

CONCLUSION

The meta-analysis has demonstrated that sleep disorders are often associated with FD and are observed in about every second patient with this functional gastrointestinal disease. Further research is needed to investigate possible causal relationships between sleep disorders and FD.

Keywords:

dyspepsia

functional dyspepsia

sleep disturbances

sleep disorders

insomnia

dyssomnia

Authors:

D.N. Andreev

Burdenko Neurosurgical Center

ORCID: 0000-0001-5473-4905

Yu.A. Kucheryavy

Evdokimov Moscow State Medical and Dentistry University;
Ilya Hospital

I.V. Maev

A.I. Yevdokimov Moscow State University of Medicine and Dentistry

ORCID: 0000-0001-6114-564X

Received:

10.11.2020

Accepted:

09.12.2020

List of references:

Stanghellini V, Chan FK, Hasler WL, et al. Gastroduodenal Disorders. Gastroenterology. 2016;150(6):1380–1392. https://doi.org/10.1053/j.gastro.2016.02.011
Oh JH, Kwon JG, Jung HK, et al. Clinical Practice Guidelines for Functional Dyspepsia in Korea. J Neurogastroenterol Motil. 2020;26(1):29–50. https://doi.org/10.5056/jnm19209
Mahadeva S, Ford AC. Clinical and epidemiological differences in functional dyspepsia between the East and the West. Neurogastroenterol Motil. 2016;28(2):167–174. https://doi.org/10.1111/nmo.12657
Wauters L, Talley NJ, Walker MM, et al. Novel concepts in the pathophysiology and treatment of functional dyspepsia. Gut. 2020;69(3):591–600. https://doi.org/10.1136/gutjnl-2019-318536
Sibelli A, Chalder T, Everitt H, et al. A systematic review with meta-analysis of the role of anxiety and depression in irritable bowel syndrome onset. Psychol Med. 2016;46(15):3065–3080. https://doi.org/10.1017/S0033291716001987
Lin S, Gao T, Sun C, et al. The association between functional dyspepsia and depression: a meta-analysis of observational studies. Eur J Gastroenterol Hepatol. 2019;31(8):911–918. https://doi.org/10.1097/MEG.0000000000001451
Khanijow V, Prakash P, Emsellem HA, et al. Sleep Dysfunction and Gastrointestinal Diseases. Gastroenterol Hepatol (NY). 2015;11(12):817–825.
Bouchoucha M, Mary F, Bon C, et al. Sleep quality and functional gastrointestinal disorders. A psychological issue. J Dig Dis. 2018;19(2):84–92. https://doi.org/10.1111/1751-2980.12577
Li L, Wu C, Gan Y, et al. Insomnia and the risk of depression: a meta-analysis of prospective cohort studies. BMC Psychiatry. 2016;16(1):375. https://doi.org/10.1186/s12888-016-1075-3
Alvaro PK, Roberts RM, Harris JK. A Systematic Review Assessing Bidirectionality between Sleep Disturbances, Anxiety, and Depression. Sleep. 2013;36(7):1059–1068. https://doi.org/10.5665/sleep.2810
Zamani M, Alizadeh-Tabari S, Zamani V. Systematic review with meta-analysis: the prevalence of anxiety and depression in patients with irritable bowel syndrome. Aliment Pharmacol Ther. 2019;50(2):132–143. https://doi.org/10.1111/apt.15325
Wang B, Duan R, Duan L. Prevalence of sleep disorder in irritable bowel syndrome: A systematic review with meta-analysis. Saudi J Gastroenterol. 2018;24(3):141–150. https://doi.org/10.4103/sjg.SJG_603_17
David D, Mertz H, Fefer L, et al. Sleep and duodenal motor activity in patients with severe non-ulcer dyspepsia. Gut. 1994;35(7):916–925. https://doi.org/10.1136/gut.35.7.916
Fass R, Fullerton S, Tung S, Mayer EA. Sleep disturbances in clinic patients with functional bowel disorders. Am J Gastroenterol. 2000;95(5):1195–2000. https://doi.org/10.1111/j.1572-0241.2000.02009.x
Lu CL, Lang HC, Chang FY, et al. Prevalence and health/social impacts of functional dyspepsia in Taiwan: a study based on the Rome criteria questionnaire survey assisted by endoscopic exclusion among a physical check-up population. Scand J Gastroenterol. 2005;40(4):402–411. https://doi.org/10.1080/00365520510012190
Lacy BE, Everhart K, Crowell MD. Functional dyspepsia is associated with sleep disorders. Clin Gastroenterol Hepatol. 2011;9(5):410–414. https://doi.org/10.1016/j.cgh.2011.02.010
Yamawaki H, Futagami S, Shimpuku M, et al. Impact of sleep disorders, quality of life and gastric emptying in distinct subtypes of functional dyspepsia in Japan. J Neurogastroenterol Motil. 2014;20(1):104–112. https://doi.org/10.5056/jnm.2014.20.1.104
Futagami S, Yamawaki H, Izumi N, et al. Impact of sleep disorders in Japanese patients with functional dyspepsia (FD): nizatidine improves clinical symptoms, gastric emptying and sleep disorders in FD patients. J Gastroenterol Hepatol. 2013;28(8):1314–1320. https://doi.org/10.1111/jgh.12236
Fang YJ, Liou JM, Chen CC, et al. Distinct aetiopathogenesis in subgroups of functional dyspepsia according to the Rome III criteria. Gut. 2015;64(10):1517–1528. https://doi.org/10.1136/gutjnl-2014-308114
Zhao W, Jin H, Xu M, et al. Sleep Quality of Functional Gastrointestinal Disorder Patients in Class-Three Hospitals: A Cross-Sectional Study in Tianjin, China. Biomed Res Int. 2018;2018:3619748. https://doi.org/10.1155/2018/3619748
Kim SY, Choung RS, Lee SK, et al. Self-reported Sleep Impairment in Functional Dyspepsia and Irritable Bowel Syndrome. J Neurogastroenterol Motil. 2018;24(2):280–288. https://doi.org/10.5056/jnm17098
Park JK, Huh KC, Kwon JG, et al. Sleep disorders in patients with functional dyspepsia: A multicenter study from the Korean Society of Neurogastroenterology and Motility. J Gastroenterol Hepatol. 2020. https://doi.org/10.1111/jgh.15198
Huang ZP, Wang K, Duan YH, Yang G. Correlation between lifestyle and social factors in functional dyspepsia among college freshmen. J Int Med Res. 2020;48(8):300060520939702. https://doi.org/10.1177/0300060520939702
Onen SH, Alloui A, Gross A, et al. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res. 2001;10(1):35–42. https://doi.org/10.1046/j.1365-2869.2001.00240.x
Zybach K, Friesen CA, Schurman JV. Therapeutic effect of melatonin on pediatric functional dyspepsia: A pilot study. World J Gastrointest Pharmacol Ther. 2016;7(1):156–161. https://doi.org/10.4292/wjgpt.v7.i1.156
Ford AC, Luthra P, Tack J, et al. Efficacy of psychotropic drugs in functional dyspepsia: systematic review and meta-analysis. Gut. 2017;66(3):411–420. https://doi.org/10.1136/gutjnl-2015-310721
Dooley M, Plosker GL. Zaleplon: a review of its use in the treatment of insomnia. Drugs. 2000;60(2):413–445. https://doi.org/10.2165/00003495-200060020-00014
Stone BM, Turner C, Mills SL, et al. Noise-induced sleep maintenance insomnia: hypnotic and residual effects of zaleplon. Br J Clin Pharmacol. 2002;53(2):196–202. https://doi.org/10.1046/j.-5251.2001.01520.x
Bódizs R. Sleep-modulation and hypnotics: effects of benzodiazepine-receptor’s agonists. Neuropsychopharmacol Hung. 2006;8(3):113–125.
Ebbens MM, Verster JC. Clinical evaluation of zaleplon in the treatment of insomnia. Nat Sci Sleep. 2010;2:115–126. https://doi.org/10.2147/nss.s6853
Ancoli-Israel S, Richardson GS, Mangano RM, et al. Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med. 2005;6(2):107–113. https://doi.org/10.1016/j.sleep.2004.10.015

Close metadata

Functional dyspepsia (FD) is a gastrointestinal disease of unknown etiology based on motor and sensory disorders of the gastroduodenal zone. This disease manifested by epigastric pain or burning, feeling of fullness or early satiety without clear data on organic (secondary) lesion [1, 2]. There are 2 clinical forms of FD depending on predominant symptoms: epigastric pain syndrome (EPS) and postprandial distress syndrome (PDS) [1]. According to recent epidemiological data on FD in the world, prevalence of this disease is 9.8—20.2% in western population and 5.3—12.8% in eastern population [3].

In accordance with the Rome IV criteria (2016), functional diseases of the gastrointestinal tract are considered as disorders of interaction "brain — gastrointestinal tract" [4]. These nosologies are characterized by common association with psychological disorders, including depression, anxiety and sleep disorders [5-8]. Bi-directional relationships of depression and sleep disorders were observed in some large trials [9, 10]. Recent meta-analyses have shown that patients with irritable bowel syndrome (IBS) more often have depressive disorders (odds ratio (OR) 2.72, 95% confidence interval (CI) 2.45—3.02) and sleep disorders (OR 2.618, 95% CI 2.052—3.341) compared to healthy people [11, 12]. A positive association between FD and depression was found in another meta-analysis that summarized the results of 23 observational trials (OR 2.28, 95% CI 2.02—3.81) [6]. At the same time, incidence of sleep disorders in patients with FD has been studied to a lesser extent. Some earlier studies have demonstrated a relationship between FD and dyssomnia [13—15]. Moreover, cross-sectional studies revealed more significant symptoms of FD and regression of the quality of life in people with sleep disorders [16, 17].

The purpose of this meta-analysis was to systematize data on the prevalence and risk of sleep disorders in patients with FD.

Material and methods

Data searching was carried out in MEDLINE/PubMed, EMBASE, Cochrane databases until October 2020. We analyzed headings and abstracts in the above-mentioned databases. The following keywords were used: “functional dyspepsia [Title] sleep [Title / Abstract]”, or “functional dyspepsia [Title] insomnia [Title / Abstract]”, or “functional gastrointestinal [Title] sleep [Title / Abstract]) ", or "functional gastrointestinal [Title] insomnia [Title / Abstract])" and several equivalents. In case of duplication of certain report in different electronic databases, only one manuscript was selected for the final analysis.

Inclusion criteria were relevant reports in periodicals; manuscripts with a detailed descriptive statistics (sample size, number of sleep-impaired patients) and available inclusion of data into meta-analysis; trials of adults with FD.

Two researchers extracted data independently using the standardized forms. We analyzed the year of publication, country, diagnostic criteria of FD, methods for assessing sleep disorders, total sample size and number of patients with sleep disorders. Any disagreement was resolved by consensus.

Statistical analysis was carried out using MedCalc 19.5.3 software package (Belgium) on Microsoft Windows 10 (USA). The results are shown as frequencies of sleep disturbances in patients with FD (%) and 95% CI. Between-study heterogeneity was assessed using Cochrane's Q test and I² test. Significant heterogeneity was determined by p <0.05 and I²> 50. The probability of significant publication bias was assessed using funnel plot, Begg-Mazumdar correlation test and Egger’s test.

Results

Analysis of electronic databases revealed 62 manuscripts for further analysis. Fourteen studies were excluded as not original articles (11 — reviews; 3 — other irrelevant works). Other 48 studies were comprehensively analyzed for compliance with inclusion criteria and duplicate results. After that, 38 studies were excluded (Fig. 1). Ten original trials were included in this meta-analysis (Table) [13—15, 17—23].

Fig. 1. CONSORT-chart detailing the research selection strategy.

Table. Characteristics of selected studies

Reference	Country	FD criteria	Assessment of sleep disorders	Number of patients with FD	Number of control people
[13]	USA	Chronic upper abdominal pain or discomfort associated with bloating, nausea, and / or early satiety lasting at least 3 months	Sleep disorder questionnaire for 6 months	65	43
[14]	USA	Chronic upper abdominal pain or discomfort associated with bloating, nausea, and / or early satiety lasting at least 3 months	Sleep disorder questionnaire for 6 months	75	205
[15]	Taiwan	Rome II criteria	Sleep disorder questionnaire for 6 months	239	1249
[18]	Japan	Rome III criteria	PSQI >5.5	94	57
[17]	Japan	Rome III criteria	PSQI >5.5	79	44
[19]	Taiwan	Rome III criteria	BSRS-5	491	1031
[20]	China	Rome III criteria	PSQI >8	920	No
[21]	South Korea	Rome III criteria	PSQI >6	62	1800
[22]	South Korea	Rome III criteria	PSQI ≥8.5	201	325
[23]	China	Rome IV criteria	Insomnia questionnaire	128	631

The final analysis included 10 studies involving 7739 people (2354 patients with FD, 5385 — control group). These trials were performed in the USA [13, 14], Japan [17, 18], South Korea [21, 22], China [20, 23] and Taiwan [15, 19]. In most studies, the authors used the Rome II — IV criteria to diagnose FD [15, 17—23] and the validated Pittsburgh Sleep Qualitative Index (PSQI) questionnaire for assessment of sleep disorders [17, 18, 20—22].

Pooled incidence of sleep disorders in patients with FD was 53.23% (95% CI 37.738—68.419) (Fig. 2). We used random-effect model due to significant heterogeneity of data (p <0.0001; I² = 98.05%). We found a significant association of sleep disorders and FD compared to the control group (OR 2.884, 95% CI 2.518—3.304; I² = 28.35%) (Fig. 3). Pooled incidence of sleep disorders was 49.62% in the studies used the Rome II — IV criteria for FD diagnosis (95% CI 31.746—67.547; I² = 98.48%).

Fig. 2. Forest diagram showing the generalized frequency of sleep disorders in patients with PD.

Fig. 3. Forest diagram showing the total number of sleep disorders in patients with PD.

Incidence of sleep disorders in patients with different clinical forms of FD was analyzed in 3 studies [17, 19, 22]. Pooled incidence of sleep disorders in patients with EPS was 40.6% (95% CI 34.267—47.181; I² = 0%), with PDS — 51.82% (95% CI 26.479—76.666; I² = 94.76%), with a combination of EPS and PDS — 51.67% (95% CI 23.497—79.270; I² = 95.34%).

The probability of significant publication bias was assessed using funnel plot, Begg-Mazumdar correlation test and Egger’s test. Visual analysis of funnel plot (Fig. 4) revealed no significant asymmetry. Moreover, significant publication bias was excluded according to Begg-Mazumdar test (Kendall's tau 0.1667; p = 0.5316) and Egger's test (p = 0.7296).

Fig. 4. Funnel-shaped scatter plot for estimating the probability of publication bias in the calculation OSH of sleep disorders in patients with PD.

Discussion

FD is one of the most common diseases of the gastrointestinal tract. This disease significantly impairs the patient's quality of life [1]. Sleep disorders are common in patients with FD, while several studies have shown that people with dyssomnia have more severe symptoms of disease [16, 17].

According to modern data, incidence of sleep disorders in patients with FD varies over a wide range (25.8 — 87%) [13—15, 17—23]. This meta-analysis of 10 studies has shown that the incidence of sleep disturbances in patients with FD is 53.23% (95% CI 37.738—68.419). Moreover, a significant association was revealed between sleep disorders and FD (OR 2.884, 95% CI 2.518—3.304). Our results are similar to the data of a recent meta-analysis devoted to the incidence of sleep disorders in patients with IBS. This value was 37.6% (95% CI 31.4—44.3%) with OR 2.618 (95% CI 2.052—3.341) [12]. These findings once again demonstrate that psychological disorders are common in patients with functional gastrointestinal diseases. At the same time, the mechanisms underlying these associations are still unclear. Perhaps, chronic pain pattern in patients with FD and IBS can directly lead to dyssomnia. Moreover, experimental studies of healthy volunteers revealed that induced sleep disturbances can result some changes in pain thresholds followed by hyperalgesia. The last one is typical for functional gastrointestinal disorders [24]. Thus, correction of sleep disorders in patients with FD can be considered as one of the objectives in complex treatment of these patients. No significant advantages of melatonin were observed compared to placebo in a recent pilot randomized controlled trial of patients with FD [25]. A meta-analysis revealed an efficacy of psychotropic drugs in FD therapy (RR 0.78, 95% CI 0.68—0.91; NNT 6, 95% CI 4—16). However, this efficacy was limited by antipsychotics and tricyclic antidepressants [26]. These drugs are often used to correct dyssomnia in some countries.

Importantly, all studies included in this meta-analysis were represented by case-control trials and cohort studies. These researches did not analyze an efficacy of certain psychotropic drugs in correction of insomnia in patients with FD. However, the identified risk of sleep disorders in patients with this functional disease should orient the scientific community to the need for further study of this issue in prospective controlled studies. At the same time, modern hypnotics with a shorter half-life are advisable for correction of sleep disorders. Zaleplon is one of these drugs. Zaleplon was synthesized by the last of the so-called Z-drugs and characterized by selective action on α1 subunit of GABAA receptor complex [27, 28]. This mechanism ensures a “pure” hypnotic effect in contrast to conventional benzodiazepine drugs. Zaleplon has the shortest half-life (1 hour). Therefore, its administration is not associated with post-hypnotic effects the next morning [27, 28]. This drug does not disturb the architecture of sleep and contributes to endogenous melatonin release. These processes ensure more physiological sleep [29]. Regarding the safety profile, Zaleplon has optimal characteristics. Indeed, this drug does not affect cognitive functions, memory, psychomotor reactions and ability to drive a car [30]. In a 12-month analysis, Zaleplon did not cause addiction and rebound insomnia [31]. Sonata Adamed is the only Zaleplon in the Russian Federation. This drug is produced in Poland in accordance with EU GMP standards. Unlike other Z-drugs, Zaleplon is prescribed on a standard prescription No. 107-1/U.

There are several limitations of our study. First, the analyzed studies were characterized by significant heterogeneity regarding diagnostic criteria of FD and assessment of sleep disorders. Second, all studies used subjective sleep quality analysis tools (questionnaires) rather objective ones (polysomnography). At the same time, this meta-analysis is the first research summarizing various studies on the prevalence of sleep disorders in patients with FD.

Conclusion

Thus, sleep disorders are often associated with FD and observed in approximately every the 2nd patient with this functional gastrointestinal disease. Further studies are required to investigate the possible causal relationships between sleep disorders and FD.

The authors declare no conflicts of interest.