Sleep disorders are common in the United States; nearly 50% Functional Dyspepsia Is Associated With Sleep Disorders. Methods Survey Generation

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2011;9:410 414 Functional Dyspepsia Is Associated With Sleep Disorders BRIAN E. LACY,* KELLY EVERHART,* and MICHAEL D. CROWELL *Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire; Division of Gastroenterology, Mayo Clinic, Scottsdale, Arizona BACKGROUND & AIMS: Functional dyspepsia (FD) is highly prevalent. We evaluated sleep quality in FD patients, and quantified the relationship between disordered sleep, FD severity, and mental and physical well-being. METHODS: Study participants were adults who met Rome III criteria for FD. Demographics, tobacco and alcohol use, exercise, level of activity, and FD symptoms were determined based on data collected from 131 patients (mean age 50 15 years; 82% female and 94% Caucasian) who completed the Hospital Anxiety and Depression (HAD) questionnaire, the Short Form 12 Health Survey (SF-12), the Pittsburgh Sleep Quality Index (PSQI), and the Insomnia Severity Index (ISI). Healthy controls (n 50; mean age 44 11 years; 92% female) answered the same questions excluding those which focused on FD symptoms. RESULTS: The mean duration of FD symptoms was 106 98 months. The Hospital Anxiety and Depression score was higher in FD patients than in controls (P.001). Pittsburgh Sleep Quality Index and Insomnia Severity Index scores were higher in FD patients with moderate and severe symptoms compared with those with mild symptoms and controls (P.001). Multivariate logistic regression analysis associated FD (odds ratio [OR], 3.25; 95% confidence interval [CI], 1.47 7.20) and female sex (odds ratio, 2.36; 95% confidence interval, 0.99 5.7) with an increased likelihood for disordered sleep. CONCLUSIONS: FD is associated with disordered sleep. Sleep disturbances in FD patients appear to be associated with symptom severity and higher levels of anxiety. Further research is needed to determine whether disordered sleep promotes symptoms of FD. Keywords: Abdominal Pain; Mental Health; Stomach; Insomnia. Sleep disorders are common in the United States; nearly 50% of all adult Americans have at least 1 symptom of a sleep disturbance. 1 Common symptoms of a sleep disturbance include trouble falling asleep, early morning awakening, and daytime sleepiness. 2 Sleep disturbance has been associated with a variety of health problems, including decreased cognitive function, slowing of reflexes, cardiovascular disease, reduced work productivity, and impaired quality of life. 3 5 Numerous studies have demonstrated that irritable bowel syndrome (IBS) and gastroesophageal reflux disease (GERD) are associated with sleep disturbances. 6 11 Unlike GERD and IBS, the relationship between sleep disorders and functional dyspepsia (FD) has yet to be well characterized. Prior studies noted an association between sleep complaints and dyspepsia, however patients were not defined using Rome III criteria, and only 1 used a validated questionnaire. 12 14 Functional dyspepsia is a highly prevalent gastrointestinal (GI) disorder that reduces patients quality of life and imposes a significant economic burden on our health care system. 15 19 Sleep disturbances may influence FD symptom generation and physical and mental well-being. In order to elucidate the relationship between FD and impaired sleep, we used a questionnaire to assess FD severity, mental and physical health, and sleep disturbance in patients meeting Rome III criteria for FD. We hypothesized that patients with FD would experience more sleep disturbances than healthy volunteers, and that the severity of sleep disturbance would be related to the intensity of FD symptoms. The primary aim of this prospective study was to evaluate the extent and magnitude of sleep disorders in patients with FD with respect to those experienced by healthy volunteers. Secondary aims included evaluating the interactions between FD symptom severity, sleep disturbance, and physical and mental well-being. Methods Survey Generation A long-form prototype questionnaire was generated from patient interviews, clinical experience, and expert opinion. To establish content validity and usability, the survey was first administered to faculty and staff in the Division of Gastroenterology and Hepatology at the Dartmouth-Hitchcock Medical Center (DHMC). Revisions were guided by patient-solicited criticism. The final version of the questionnaire contained 61 questions (see Supplementary Appendix). The Rome III definition was used to distinguish patients with epigastric pain syndrome (EPS) from postprandial distress syndrome (PDS). 20 Sleep disturbance was assessed using 2 separate validated questionnaires: the Insomnia Severity Index (ISI) 2 and the Pittsburgh Sleep Quality Index (PSQI). 21 The Hospital Anxiety and Depression questionnaire (HAD) and the Short Form 12 Health Survey (SF-12) were included and scored as previously described. 22,23 Study Subjects After approval by the Dartmouth-Hitchcock Medical Center Institutional Review Board, we used the Dartmouth- Abbreviations used in this paper: BMI, body mass index; CI, confidence interval; EPS, epigastric pain syndrome; FD, functional dyspepsia; GERD, gastroesophageal reflux disease; HAD, hospital anxiety and depression; IBS, irritable bowel syndrome; ISI, Insomnia Severity Index; MCS, Mental Component Scale; OR, odds ratio; PCS, Physical Component Scale; PDS, postprandial distress syndrome; PSQI, Pittsburgh Sleep Quality Index; SF-12, Short Form 12 health survey. 2011 by the AGA Institute 1542-3565/$36.00 doi:10.1016/j.cgh.2011.02.010

May 2011 FD AND SLEEP 411 Hitchcock Data Reporting System (HDRS) to identify adult patients (age 18 years) with the diagnosis of dyspepsia (ICD-9 code 536.8), who had an office visit between September 2003 and March 2009. Medical charts were reviewed by the primary investigator to verify that patients met Rome III criteria for FD; all included patients had been evaluated within the preceding 12 months. Patients with comorbid conditions with symptoms that could confound the results of this study were excluded during the same review (ie, prior surgery to the upper gastrointestinal tract; history of ulcer disease; known malignancy; history of pancreatitis; known hepatobiliary disorders; sleep apnea). 20 A normal upper endoscopy was required within the previous 5 years. Chart review excluded patients with predominant GERD or IBS (Rome III criteria). Patients with a known diagnosis of insomnia and those patients on known medications for sleep disorders were excluded. Local healthy volunteers without any known gastrointestinal disorders filled out the same survey, excluding the questions that focused on FD. Statistical Analysis Data were assessed using the Statistical Package for the Social Sciences (SPSS version 18.0; SPSS, Inc, Chicago, IL). Normality of data sets was determined using SPSS Explore and Descriptive functions. Stem-and-leaf plots and histograms were used to evaluate variable distributions and assess outliers. Normality plots were used to display normal probability and detrended normal probability plots. Where appropriate, the Kolmogorov Smirnov statistic was used for testing normality. Frequency distributions were evaluated for all categorical variables (eg, gender). Student t test and analyses of variance (ANOVAs) were performed to evaluate differences in demographic variables such as weight, height, or body mass index (BMI) among groups. Tests for proportionality between groups were made using 2 tests with the Mantel Haenszel odds ratios used to test for independence between factors of interest. Multivariable logistic regression was used to estimate odds ratios and 95% confidence intervals using both conditional and unconditional entry methods while controlling for potential confounders (age, gender, BMI, tobacco, alcohol, exercise, anxiety, depression, and FD severity). Summary statistics include point estimates and standard deviations or 95% confidence intervals for all variables. All significance levels are set to P.05. Results Response Rate and Demographics Two hundred sixty patients, all of whom met inclusion and exclusion criteria, were mailed questionnaires. Twenty-five questionnaires were returned due to incorrect addresses; therefore, 235 patients were eligible for evaluation. Patients returned 131 questionnaires, yielding a response rate of 56%. FD symptoms had remitted in 10 patients (8%) at the time that they completed their questionnaires; these patients were subsequently excluded from analyses. Demographics of FD patients (n 121) are shown in Table 1. The mean age of 50 healthy controls was 44 11 years; 92% of the control population was female. Table 1. Demographics of FD Patients (n 121) Characteristic FD patients (n 121) Controls (n 50) Age, y 50 15 44 11 BMI 26.7 6.7 27.8 6.3 Gender (% female) 82 92 Race (%) Caucasian 94 98 Asian 2 2 Hispanic 2 Other 2 Tobacco use (%) 39 48 (P.30) Mean years tobacco 15.6 15.5 10.8 10.5 (P.19) use Alcohol use (past 56 72 (P.06) month) (%) Alcoholic drinks per 3.3 3.3 3.4 3.6 (P.93) week (n) Daily exercise (%) 66 59(P.40) Weekly vigorous 33 32 (P 1.0) activity (%) Duration of symptoms 106 98 mo Days per week with symptoms 4.2 2.1 BMI, body mass index calculated as weight (kg)/height (m 2 ). FD Symptoms The mean duration of FD symptoms was 106 98 months. Patients reported that FD symptoms were present 4.2 2.1 days per week. The severity of FD symptoms was self-rated as mild (37%), moderate (48%), or severe (15%). Using Rome III standards for diagnosis, 61% of FD patients met the criteria for EPS and 13% were subcategorized as having PDS; the remainder demonstrated characteristics of both EPS and PDS. Sleep The average number of hours of sleep per night was not significantly different between FD patients and controls (6.31 1.52 hours relative to 6.65 1.16 hours, respectively). Patients with FD symptoms reported taking more time to get to sleep each night than healthy controls (37 50 minutes relative to 21 17 minutes; P.002). Occasional sleep problems were relatively common in both FD patients and controls; 70% of the FD patient sample and 60% of the control sample reported problems falling asleep or staying asleep 1 to 3 days per month. However, FD patients identified more frequent sleep disturbances (4 or more days per month) compared with controls (P.004). Trouble falling asleep was reported by 43% (n 121) of FD patients, relative to 28% (n 50) of controls (P.005). Trouble staying asleep was reported by 64% of FD patients and 36% of controls (P.001). Significantly higher PSQI scores were found for patients with FD compared with healthy controls (9.39 4.31 vs 6.26 3.96, respectively; P.001). As illustrated in Figure 1, total PSQI scores were higher in FD patients with moderate symptoms and in patients with severe symptoms when compared with those with mild symptoms and to healthy controls (P.001). Total PSQI scores in patients with mild and moderate FD symptoms were not significantly different from each other.

412 LACY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 5 Figure 1. Mean PSQI and ISI scores and 95% confidence intervals grouped by FD severity. A significant linear trend was identified between FD severity and PSQI and ISI scores (P.001). Patients with moderate (Mod) and severe FD had higher PSQI and ISI scores than healthy controls and patients with mild FD symptoms (P.05). Total PSQI scores were also significantly higher in the Rome III subgroups of EPS (9.19 4.17), PDS (8.69 4.54), and mixed (10.23 4.51) relative to the sample of control (6.26 3.96; P.001); however, the subgroups did not differ from one another. Similarly, the ISI scores were significantly higher in FD patients compared with controls (3.53 1.51 vs 2.65 1.30, respectively; P.001). ISI scores were higher in FD patients with moderate and severe symptoms compared with those with mild symptoms and healthy controls (P.001; see Figure 1). Total ISI scores in patients with mild and moderate FD symptoms were not significantly different from each other (Figure 1). The ISI total scores were also significantly higher in the Rome III subgroups of EPS (3.54 1.54), PDS (3.63 1.59), and mixed (3.45 1.43) when compared with healthy controls (2.65 1.30; P.006); no distinction in total ISI scores characterized individual FD subgroups. Habits and Physical Activity No significant differences were found between FD patients and controls with regard to tobacco and alcohol use. Multivariate logistic regression analysis failed to reveal any significant relationship between alcohol and tobacco use and poor sleep. Increased physical activity was associated with less disrupted sleep in FD patients (odds ratio [OR], 0.421; 95% CI, 0.19 0.97). No significant association was found between exercise and FD severity or between exercise and the EPS and PDS subgroups. Anxiety, Depression, and Physical and Mental Health Scores on the HAD scale were significantly higher in FD patients when compared with healthy controls for both anxiety (15.42 8.02 vs 6.59 4.35, respectively; P.001) and depression (11.45 4.57 vs 3.19 3.34, respectively; P.001). The total HAD scale score was also significantly higher in the FD group relative to controls (26.87 10.75 vs 9.58 7.0, respectively; P.001). The mean total HAD score showed a significant linear trend with symptom severity among FD patients (P.001). The mean SD HAD score for healthy controls (9.58 7.00) was significantly lower than the HAD score for mild (24.64 8.74), moderate (27.21 8.07), and severe (28.11 13.02) FD patients. The HAD scores did not differ significantly between the Rome III subgroups (P.79). Increased anxiety subscale scores on the HAD were significantly associated with disturbed sleep (OR, 1.15; 95% CI, 1.07 1.22; P.001). Depression scores on the HAD were not significantly associated with disturbed sleep in multivariate analyses. The total HAD score was moderately, but statistically significantly correlated with the ISI mean score (0.42; P.001). The Physical Component Scale (PCS) T scores for the SF-12 was lower in FD patients relative to controls (43.71 11.09 vs 50.51 8.14, respectively; P.001). Significant differences were also noted between the FD group and controls for the Mental Component Scale (MCS) T scores (48.88 11.57 vs 44.62 11.83, respectively; P.04). Significant linear trends were identified that showed progressively lower PCS (P.001) and MCS (P.02) scores with increased FD symptom severity (Figure 2). No significant association was found between SF-12 PCS and MCS scores and the Rome III subgroups. The odds of reporting disturbed sleep were associated with lower PCS (OR, 0.92; 95% CI, 0.88 0.96; P.001) and MCS (OR 0.95; 95% CI, 0.92 0.98; P.003) scores. Discussion In our prospective study of sleep characteristics in patients meeting Rome III criteria for FD, we have shown that FD symptoms significantly affect sleep. A majority of FD patients (70%) noted problems falling asleep or staying asleep, a higher percentage than previously reported. 11 14 Our hypothesis that FD patients would experience more sleep disturbances than healthy volunteers was correct, using the parameters of time to fall asleep each night, trouble staying asleep, and frequency. PSQI scores were higher in FD patients with more severe symptoms, and the difference in PSQI scores between FD patients Figure 2. Mean SF-12 PCS and MCS component T scores (standardized scores with a mean of 50 and SD of 10) with 95% confidence intervals for healthy volunteers and FD patients grouped by self-reported FD symptom severity as mild, moderate (Mod), and severe. A significant linear trend was identified between FD severity and PCS and MCS scores (P.001). Lower PCS scores were found in patients with moderate (Mod) and severe FD compared with healthy controls (P.05). The mean MCS score was significantly lower in patients with severe FD compared with mild FD or healthy controls (P.05).

May 2011 FD AND SLEEP 413 with severe symptoms and mild symptoms was statistically significant. Our results suggest that sleep disturbance is a common phenomenon in all FD patients, and that more severe dyspeptic symptoms translate into further abnormalities in sleep function. These novel findings are supported by ISI scores, which demonstrated a similar pattern. Correlation between PSQI total and ISI mean was 0.75 for the combined sample of FD and controls (P.001). Our results demonstrate that anxiety and depression, as measured by the HAD questionnaire, are common in patients with FD. Given the chronicity of symptoms in this patient cohort (nearly 9 years, on average), this is unsurprising, because chronic disease states are associated with an increased prevalence of mood disorders. A trend toward higher HAD scores was demonstrated in patients with more severe FD symptoms compared with those with more mild symptoms; however, this trend was not statistically significant. Further analysis of HAD scores found that higher anxiety subscale scores were associated with impaired sleep in FD patients. Predictably, mental, and physical functioning were reduced in patients with FD. Physical component scores were lower in FD patients compared with healthy controls (P.001) and although mental component scores were reduced, these scores were not significantly lower than healthy controls (P.06). Analysis of SF-12 scores and PSQI scores showed that lower scores on both the physical and mental components of the SF-12 were associated with an increased risk of sleep disturbances on the PSQI. The impact of impaired sleep has received significant attention over the last decade. Sleep disturbances impair cognitive performance including problem solving, decision making, attention span, moral reasoning, and reaction time. 24 26 Disrupted sleep is also associated with obesity, diabetes, and heart disease. 5,27 29 Our findings add FD to the list of common medical disorders associated with poor sleep. Several studies have shown that IBS patients are more likely than healthy controls to suffer from disordered sleep. 10,30 34 Although the precise mechanism is unknown, abnormalities in rapid eye movement (REM) sleep and autonomic nervous system function have been proposed. 10,35 38 The relationship between GERD and sleep disorders is well recognized. 4,6 Individuals with GERD are more than twice as likely as healthy controls to suffer from sleep disorders. 7,8 Although the precise mechanism is not known, it is thought that gastroesophageal reflux (GER) affects sleep via 2 different mechanisms. One, gastroesophageal reflux awakens patients and either delays or prevents falling asleep, thus leading to sleep deprivation. Two, episodes of reflux may cause brief arousals, thereby leading to fragmented sleep. The tautological relationship between sleep disturbances and FD symptom expression is likely quite complex. Intuitively, it is easy to appreciate how dyspeptic symptoms could interfere with sleep, as abdominal pain may prevent or delay its onset and interrupt its continuation. However, the reverse is also a possibility: disrupted sleep could potentially lead to increased symptom expression in patients with FD. In support of this hypothesis, total sleep deprivation was shown to decrease mechanical pain thresholds in healthy volunteers. 39 In this same group of volunteers, recovery of slow wave sleep was found to be analgesic. A second study of healthy volunteers confirmed these preliminary conjectures, finding that the loss of 4 hours of sleep, or the loss of rapid eye movement sleep, led to hyperalgesia the next day. 40 In addition, total sleep deprivation was hyperalgesic in patients with erosive esophagitis. 41 Thus, it is possible that patients with FD may suffer from disordered sleep due to their dyspeptic symptoms, and this sleep loss may exacerbate FD symptoms the following day due to the hyperalgesic effect of sleep loss. Clinicians need to address both the chronic visceral pain that characterizes FD and disordered sleep, as disordered sleep may exacerbate FD symptoms. There are limitations to all research studies; ours is no exception. First, the less than dramatic statistical resolution between FD symptom subgroups may indicate the need to include a larger number of subjects in FD symptom studies. Second, although the PSQI is well accepted as a measure of sleep disorders, some recall bias is likely present. Third, our New England population may not be representative of all FD populations. Fourth, although patients with predominant symptoms of IBS were excluded from the study, some FD patients had coexisting, mild IBS symptoms. The impact of such a potential comorbidity was not evaluated in the current study and should be addressed in future studies. 42 Finally, although records were reviewed to exclude patients with known sleep disorders and those using prescription medications for insomnia, it is possible that the diagnosis of insomnia was not accurately reported. In conclusion, this prospective study demonstrates that sleep disturbances are common in patients with FD. Impaired sleep likely contributes to the reduced physical and mental functioning demonstrated in our patient population, and coexisting anxiety may play a role in symptom expression. Future FD clinical trials should include validated questionnaires to evaluate the extent and quality of sleep disturbance in these patients and to measure changes in sleep function contemporaneous with changes in FD symptoms. Supplementary Material Note: To access the supplementary material accompanying this article, visit the online version of Clinical Gastroenterology and Hepatology at www.cghjournal.org, and at doi:10.1016/ j.cgh.2011.02.010. References 1. National Sleep Foundation. Sleep in America poll. Executive summary. Washington, DC: NS Foundation, 2003:6 38. 2. Morin CM, Edinger JD. Sleep disorders: evaluation and diagnosis. In: Turners SMHM, ed. Adult psychopathology and diagnosis. New York: Wiley, 1997:483 507. 3. Akerstedt T. Psychosocial stress and impaired sleep. Scan J Work Environ Health 2006;32:493 501. 4. Dubois RW, Aguilar D, Fass R, et al. Consequences of frequent nocturnal gastro-oesophageal reflux disease among employed adults: symptom severity, quality of life and work productivity. Aliment Pharmacol Ther 2007;25:487 500. 5. Wallander MA, Johansson S, Ruigomez A, et al. Morbidity associated with sleep disorders in primary care: a longitudinal cohort study. Prim Care Compan J Clin Psych 2007;9:338 345. 6. Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on

414 LACY ET AL CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 9, No. 5 behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487 1493. 7. Jansson C, Nordenstedt H, Wallander MA, et al. A populationbased study showing an association between gastroesophageal reflux disease and sleep problems. Clin Gastroenterol Hepatol 2009;7:960 965. 8. Mody R, Bolge SC, Kannan H, et al. Effects of gastroesophageal reflux disease on sleep and outcomes. Clin Gastroenterol Hepatol 2009;7:953 959. 9. Elsenbruch S, Harnish MJ, Orr WC. Subjective and objective sleep quality in irritable bowel syndrome. Am J Gastroenterol 1999;94: 2447 2452. 10. Heitkemper M, Jarrett M, Burr R, et al. Subjective and objective sleep indices in women with irritable bowel syndrome. Neurogastroenterol Motil 2005;17:523 530. 11. Vege SS, Locke GR, Weaver AL, et al. Functional gastrointestinal disorders among people with sleep disturbances: a populationbased study. Mayo Clin Proc 2004;79:1501 1506. 12. Fass R, Fullerton S, Tung S, et al. Sleep disturbances in clinic patients with functional bowel disorders. Am J Gastroenterol 2000;95:1195 1200. 13. Gathaiya N, Locke GR, Camilleri M, et al. Novel associations with dyspepsia: a community-based study of familial aggregation, sleep dysfunction and somatization. Neurogastroenterol Motil 2009;21:922 927. 14. Cremonini F, Camilleri M, Zinsmeister AR, et al. Sleep disturbances are linked to both upper and lower gastrointestinal symptoms in the general population. Neurogastroenterol Motil 2009; 21:128 135. 15. El Serag HB, Talley NJ. Systematic review: the prevalence and clinical course of functional dyspepsia. Aliment Pharmacol Ther 2004;19:643 654. 16. El Serag HB, Talley NJ. Health-related quality of life in functional dyspepsia. Aliment Pharmacol Ther 2003;18:387 393. 17. Nyren O, Lindberg G, Lindstrom E, et al. Economic costs of functional dyspepsia. Pharmacoeconomics 1992;1:312 324. 18. Weiser KT, Kennedy AT, Lacy BE, et al. Functional dyspepsia: the economic impact to patients. Am J Gastroenterol 2007;102: S505. 19. Lacy BE, Cash BD. A 32-year-old woman with chronic abdominal pain. JAMA 2008;299:555 565. 20. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466 1479. 21. Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193 213. 22. Zigmond AS, Snaith RP. The Hospital Anxiety and Depression Survey. Acta Psychiatr Scand 1983;67:361 370. 23. Ware JE, Kosinski M, Keller SD. A 12-item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 1996;34:220 233. 24. Belenky G, Wesensten NJ, Thorne DR, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose response study. J Sleep Res 2003;12:1 12. 25. Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117 126. 26. Killgore WD, Killgore DB, Day LM, et al. The effects of 53 hours of sleep deprivation on moral judgement. Sleep 2007;30: 345 352. 27. Chaput JP, Despres JP, Bouchard C, et al. The association between sleep duration and weight gain in adults: a 6-year prospective study from the Quebec family study. Sleep 2008;31: 517 523. 28. Ayas NT, White DP, Al-Delaimy WK, et al. A prospective study of self-reported sleep duration and incident diabetes in women. Diabetes Care 2004;27:282 284. 29. Hublin C, Partinen M, Koskenvuo M, et al. Sleep and mortality: a population-based 22-year follow-up study. Sleep 2007;30:1245 1253. 30. Whorwell PJ, McCallum M, Creed FH, et al. Non-colonic features of irritable bowel syndrome. Gut 1986;27:37 40. 31. Goldsmith G, Levin JS. Effect of sleep quality on symptoms of irritable bowel syndrome. Dig Dis Sci 1993;38:1809 1814. 32. Jarrett M, Heitkemper M, Cain KC, et al. Sleep disturbance influences gastrointestinal symptoms in women with irritable bowel syndrome. Dig Dis Sci 2000;45:952 959. 33. Elsenbruch S, Harnish MJ, Orr WC. Subjective and objective sleep quality in irritable bowel syndrome. Am J Gastroenterol 1999;94: 2447 2452. 34. Thompson JJ, Elsenbruch S, Harnish MJ, et al. Autonomic functioning during REM sleep differentiates IBS symptom subgroups. Am J Gastroenterol 2002;97:3147 3152. 35. Spiegel BMR, Gralnek IM, Bolus R, et al. Clinical determinants of health-related quality of life in patients with irritable bowel syndrome. Arch Intern Med 2004;164:1773 1780. 36. Kumar D, Thompson PD, Wingate DL, et al. Abnormal REM sleep in the irritable bowel syndrome. Gastroenterology 1992;103: 12 17. 37. Orr WC, Crowell MD, Lin B, et al. Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis. Gut 1997; 41:390 393. 38. Jarrett ME, Burr RL, Cain KC, et al. Autonomic nervous system function during sleep among women with irritable bowel syndrome. Dig Dis Sci 2008;53:694 703. 39. 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; 10:35 42. 40. Roehrs T, Hyde M, Blaisdell B, et al. Sleep loss and REM sleep loss are hyperalgesic. Sleep 2006;29:145 151. 41. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787 1795. 42. Talley NJ, Dennis EH, Schettler-Duncan VA, et al. Overlapping upper and lower gastrointestinal symptoms in irritable bowel syndrome patients with constipation or diarrhea. Am J Gastroenterol 2003;98:2454 2459. Reprint requests Address requests for reprints to: Brian E. Lacy, PhD, MD, Division of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Area 4C, 1 Medical Center Drive, Lebanon, New Hampshire 03756. e-mail: brian.lacy@hitchcock.org; fax: (603) 650-5225. Conflicts of interest The authors disclose no conflicts.