Constipation in Patients With Symptoms of Gastroparesis: Analysis of Symptoms and Gastrointestinal Transit.

Patients with symptoms of gastroparesis were enrolled in Gastroparesis Registry 2 (GpR2) at 8 centers of the Gastroparesis Clinical Research Consortium (GpCRC). Patients had gastroparesis symptoms ≥12 weeks and no organic disease on endoscopy. Attribution of gastroparesis to diabetic versus idiopathic versus postfundoplication was made by investigators based on patient self-report and medical record review. Patients underwent history and physical examination. Medications that patients were using were recorded including proton pump inhibitors, histamine 2 -receptor antagonists, prokinetics, opiates, anticholinergics, cannabinoids, polyethylene glycol preparations, and laxatives. Symptoms were quantified using modified Patient Assessment of Upper Gastrointestinal Disorders Symptoms (PAGI-SYM) questionnaires enumerating 22 symptoms; severity of each of these over past 2 weeks were graded by the patient from 0 (no symptoms) to 5 (most severe) ( 6 ). Overall gastroparesis severity was determined by the Gastroparesis Cardinal Symptom Index (GCSI) score ( 7 ). Symptoms of lower abdominal pain, lower abdominal discomfort, constipation and diarrhea were quantified using the similar 0 to 5 scale for lower GI symptoms. Rome III questionnaires were administered, primarily functional dyspepsia, irritable bowel syndrome, and functional constipation questionnaires ( 8 ). At study visits (enrollment, 24 weeks, 48 weeks), symptoms and treatments were assessed and questionnaires were filled out. Patients received standard of care during follow-up, allowing adjustments or additions of treatments for their care including gastroparesis and constipation. Studies were approved by Institutional Review Boards at Clinical Centers and Data Coordinating Center. Patients provided written informed consent. Authors had access to study data and reviewed and approved the final manuscript. Patients underwent scintigraphy to quantify solid and liquid gastric emptying. Patients stopped medications that could affect gastrointestinal motility for 72 hours and came in the morning after fasting overnight. Diabetic patients had glucose checked to ensure <275 mg/dl. GES was performed using standard low-fat, Eggbeaters® meal over 4 hours ( 9 , 10 ). The solidphase meal was comprised of 99m Tc-sulfur colloid-labeled egg substitute meals which included 120 g EggBeaters®, 2 slices of bread, 30 g strawberry jam, 120 mL water (255 kcal, 72% carbohydrate, 24% protein, 2% fat, 2% fiber). Gastric retention of Tc-99m >60% at 2 hrs and/or >10% at 4 hrs was considered delayed gastric emptying. For WMC testing ( 11 , 12 ), patients stopped proton pump inhibitors for 7 days, and histamine 2 -receptor antagonists, prokinetics, opiates, anticholinergics, cannabinoids, isotonic polyethylene glycol electrolyte preparations, and laxatives for 3 days. On evening before testing, insulin-requiring diabetics injected half of their usual long-acting insulin dose. Patients fasted overnight before testing. Glucose measurements were obtained in diabetic patients to ensure fasting glucose <275 mg/dL. Patients ingested one SmartBar® (Medtronic) (255 kcal, 66% carbohydrate, 17% protein, 2% fat, 3% fiber) over 10 minutes with 50 mL water. The WMC was swallowed with 50 mL of water. Patients did not eat for 6 hours after WMC ingestion, then resuming their normal diet. They returned in 4–7 days. Gastric emptying times (GET) were calculated from WMC ingestion to when the capsule passed into the duodenum (abrupt ≥2 pH unit increase to levels ≥4). Small bowel transit times (SBTT) were calculated from end of GET period to ileocecal junction passage (pH decreased ≥1.0 pH unit for at least 10 minutes ≥30 minutes after pyloric passage). WMC evacuation was detected by abrupt decrease in temperature. Colon transit times (CTT) were calculated from end of SBTT period to time of anal capsule expulsion. Normal gastrointestinal transit included gastric emptying times (GET) ≤5 hours, small bowel transit times (SBTT) ≤6 hours, and colon transit times (CTT) ≤59 hours ( 12 ). Baseline patient characteristics were compared by increasing constipation severity categories with trend p-values. Similar tables compared colonic transit delay to normal colonic transit and delayed gastric emptying to normal gastric emptying. Data are presented as means±SD for normally distributed variables, median (interquartile range) for non-normally distributions, or N (%) for categorical measures. P-values were determined by Fisher’s exact test or Cochran-Armitage test for categorical and binary measures, by two-sided t-tests or ANOVA for normally distributed continuous variables, and by Kruskal-Wallis tests for non- normally distributed continuous measures. Multivariable logistic regression analyses were performed to assess independent factors related to constipation symptom severity in patients with symptoms of gastroparesis. Changes in measures between baseline and 48-week visit were assessed both by baseline constipation severity categories and by change in constipation score between baseline and the 48-week visit, with trend p-values presented. Changes from baseline to 48-week visit are presented as adjusted means (adjusted for baseline value) and standard error and p-values were determined by ANCOVA tests adjusting for baseline values. P-values <0.05 were considered statistically significant.

506 patients were enrolled in GpR2. Of 419 patients who swallowed the WMC, 338 (81%) patients had full WMC data for analysis and formed the data set for this manuscript. 81 patients had missing WMC data due to equipment issues (16 patients), inability to calculate all values (32 patients), or no confirmation of capsule elimination at the time the receiver was returned (4–7 days) (23 patients). Four participants required endoscopic retrieval of WMC retained in the stomach (3 patients had normal GES, and one had mild delay (13% retention at 4 hours)). The 338 patients with successful WMC recordings were younger and included more idiopathic gastroparesis patients as compared to 168 patients without WMC data available; symptoms of gastroparesis and constipation were similar among those having WMC data and those that did not ( Supplemental Table 1 ). At enrollment, patients were asked to list symptoms that led to their evaluation for gastroparesis. Symptoms prompting gastroparesis evaluation in these 338 patients included nausea (90% of patients), abdominal pain (80%), bloating (70%), vomiting (67%), early satiety (65%), postprandial fullness (62%), GERD symptoms (58%), constipation (53%) ( Table 1 ). Of the 53% (n=178) patients reporting constipation as a symptom leading to evaluation of gastroparesis, 40 (22.5%) had IBS-C, 68 (38.2%) had IBS-M, and 19 (10.7%) had functional constipation using the Rome III criteria at the baseline visit. Of symptoms on the enrollment PAGI-SYM, the main symptom of the patients included nausea/vomiting in 38%, loss of appetite 13%, bloating 11%, upper abdominal pain 16%, GERD symptoms 8%, and constipation 19 patients (5.7%). Of the 338 patients with symptoms of gastroparesis, 242 (71.5%) had delayed gastric emptying by scintigraphy and 298 (88.2%) met Rome III criteria for functional dyspepsia. Presence of functional dyspepsia was not different if patients had delayed or normal gastric emptying (87% vs 92%; p=0.26). Using PAGI-SYM, constipation was rated by patients as none in 75 (22.2%), very mild in 39 (11.5%), mild in 28 (8.3%), moderate in 82 (24.3%), severe in 57 (16.9%), very severe in 57 (16.9%) patients. For statistical analysis, the none, very mild, and mild severities of constipation were combined, and severe and very severe constipation were combined. Severity of constipation was rated by the 338 patients to be severe/very severe in 114 (34%) patients, moderate in 82 (24%), and none/very mild/mild in 142 (42%) ( Table 2 ). There was a trend for the patients that had severe/very severe constipation to be idiopathic in etiology than those with none/very mild/mild constipation (70% vs 63%; p=0.10). Obese patients had less severe constipation (p=0.06). The BMI of patients with severe/very severe constipation was significantly less than the others (p=0.003). Symptoms of gastroparesis assessed using PAGI-SYM increased in severity with increasing severity of constipation: nausea/vomiting subscore (p<0.0001), early satiety/postprandial fullness subscore (p<0.0001), bloating subscore (p<0.0001), GCSI total score (p<0.0001), and upper and lower abdominal pain subscores (p<0.0001). Using Rome III diagnostic questionnaire, 226 patients (67%) met criteria for IBS, 62 (18%) for IBS-C, 46 (14%) for IBS-D, 111 (33%) for IBS-M, and 32 (9%) for functional constipation. There were increasing percentages of patients with IBS, IBS-C, and functional constipation and decreasing percentages of patients with IBS-D with increasing severity of constipation as assessed by PAGI-SYM ( Table 2 ). 80% of patients with none/very mild/mild constipation had functional dyspepsia compared to 95% of patients with moderate constipation and 94% of patients with severe/very severe constipation (p<0.05). Increasing symptoms of constipation were associated with increasing use of medications used for constipation (p<0.0001), but not associated with use of opiates (p=0.52), tricyclic antidepressants (p=0.61), 5HT3 receptor antagonists (p=0.19), or marijuana (p=0.15). Increasing severity of constipation was not associated with gastric retention on GES (2-hour retention [p=0.64] or 4-hour retention [p=0.62]). Severity of constipation was similar between patients with gastroparesis and patients with symptoms of gastroparesis but with normal gastric emptying ( Table 1 ). Severe/very severe constipation was reported by 40% of patients with normal gastric emptying and 31% of patients with delayed gastric emptying (p=0.35). Colonic transit times were similar in patients with normal compared to delayed gastric emptying. Increasing severity of constipation was associated with increasing small bowel transit time (p=0.008), colonic transit time (p=0.003), and whole gut transit time (p=0.001) ( Table 2 ). Delayed colonic transit (>59 hours on WMC) was present in 108 patients (32%) of patients. Delayed colonic transit time (>59 hours on WMC) was associated with increasing severity of constipation (p=0.02), but gastroparesis symptoms were not significantly different ( Supplementary Table 2 ). Multivariable logistic regression analysis was performed to assess independent factors related to constipation severity in patients with symptoms of gastroparesis ( Table 3 ). Two multivariate models were used: Model B which was adjusted for all covariates, whereas Model C was adjusted for all covariates except opioid narcotics and constipation medication use. Similar findings were seen with each. Using model B, independent factors that significantly associated with constipation severity included GCSI (OR=1.85; 95% CI 1.30–2.67; p=0.001), lower abdominal pain subscore (OR=1.34; 95% CI 1.06–1.69; p=0.02), colonic transit time (OR=1.04; 95% CI 1.00–1.07; p=0.045), and use of constipation medications (OR=5.09; 95% CI 2.75–9.41; p>0.001). Use of opiates was not statistically associated with constipation, although there was an association between use of opiates and use of medications for constipation. Increasing severity of constipation using the PAGI-SYM was significantly associated with increasing frequency of having fewer than 3 bm per week, having hard or lumpy stools, staining with bowel movements, feeling of incomplete evacuation, sensation that stool could not be passed, use of manual maneuvers to have a bowel movement ( Table 4 ). For patients with severe/very severe constipation, 52% had infrequent bowel movements most of the time, 50% described hard or lumpy stools at least 75% of the time, 48% had straining most of the time, 54% had feeling of incomplete evacuation, and 20% has use of manual maneuvers most of the time ( Table 4 ). Delayed colonic transit time was associated with having fewer than 3 bowel movements per week, having hard or lumpy stools ( Table 5 ). While in the registry, patients received standard of care during follow-up, allowing treatments for their clinical care, which could include nutritional, pharmacological, and surgical treatments for gastroparesis and/or constipation. Supplemental Table 3 shows the patients with follow up at 48 weeks (n=166) to those with no follow-up at 48 weeks (n=172). Patients with follow up were slightly older (44 vs 41 years; p=0.03) and higher BMI (29.2 vs 27.6; p=0.07). Table 6 shows the change in symptoms of constipation and gastroparesis over time, comparing symptoms at baseline and at 48 weeks in the 166 of the 338 patients with this data available. Of the 59 patients with severe/very severe constipation at baseline, 49% remained with severe/very severe constipation, 27% improved to moderate constipation, and 24% improved to non/very mild/mild constipation. In these 59 patients, GCSI improved from 3.2 to 2.9, with an adjusted mean change of −0.1. Of the 67 patients with non/very mild/mild constipation, 75% remained with none/very mild/mild constipation, 15% increased to moderate constipation, and 10% increased to severe/very severe constipation. In these 67 patients, GCSI slightly increased from 2.2 to 2.3, though the adjusted mean change shows a slight decrease of −0.1. Change in GCSI from baseline to 48 weeks did not significantly differ by constipation severity when adjusted for baseline values (p=0.79). Relationships between the change in constipation symptom severity over 48 weeks, and the change in GCSI and gastric emptying over the 48 weeks is shown in Supplemental Table 4 . There was a slight decrease in GCSI in patients that had decrease in constipation and a slight increase in GCSI in patients that had an increase in constipation severity, although this did not reach statistical significance (p=0.21). There was no relation with the change in constipation severity with change in gastric emptying (p=0.76). We assessed the effect of taking constipation medications on upper and lower GI symptoms. Patients taking constipation medications continuously from baseline to week 48 tended to decrease constipation severity, whereas patients not using constipation medications tended to have an increase in constipation severity at week 48 ( Supplemental Table 5 ). However, there was no significant change in GCSI in patients taking constipation medications and those not taking constipation medications.

This study has shown that constipation is an important symptom in some patients with gastroparesis. Severe/very severe constipation and delayed colon transit occurs in a third of patients with symptoms of gastroparesis. The severity of constipation was associated with severity of gastroparesis symptoms, but not related to the delay in gastric emptying. Severity of constipation was associated with GI transit delays, particularly in the colon. Many patients with symptoms of gastroparesis and constipation also met symptom criteria for IBS. Symptoms were quantified using a modified PAGI-SYM questionnaire. Symptoms added to the PAGI-SYM included lower abdominal pain, lower abdominal discomfort, constipation, diarrhea. Constipation was graded by the patient from none to very severe using a modified version of the PAGI-SYM, rather than numerous detailed symptoms as used in PAC-SYM ( 13 ). Using this patient-driven approach, a third of patients with gastroparesis symptoms viewed themselves as having severe or very severe constipation. With increasing severity of constipation, gastric emptying was similar, but colonic transit was progressively more delayed. Similar to symptoms of gastroparesis, there was an increase in prevalence of functional dyspepsia associated with worsening constipation severity; this probably reflects the overlap of symptoms in functional dyspepsia (early satiety, postprandial fullness, abdominal pain/burning) and gastroparesis (nausea, vomiting, early satiety, postprandial fullness, abdominal pain) ( 14 ). This study investigated the prevalence of delayed colonic transit in patients with symptoms of gastroparesis, and related it to symptoms of constipation. Delayed colon transit occurred in a third of patients with symptoms of gastroparesis. Delayed colonic transit was associated with an increased severity of constipation. In other studies using WMC, delayed whole gut transit was seen in 18% of patients with gastroparesis ( 3 ). In studies using ROM, 17% of subjects with nausea had whole gut transit delay ( 15 ). Other studies have reported a 65% prevalence of slow transit constipation by ROM in patients with delayed gastric empting ( 4 ). In studies using whole gut transit scintigraphy, 31% of subjects with upper GI symptoms had delayed whole gut transit ( 16 ). In contrast to these retrospective studies, our study was a prospective study with data collected in a standardized form with validated surveys and has detailed transit data involving all gut regions. Although constipation has been show to lead to delayed gastric emptying ( 5 ), in the present study, the severity of constipation was not related to delay in gastric emptying, measured by either GES or WMC. The severity of constipation, colonic transit times, and number of patients with delayed colonic transit were similar in patients with delayed gastric emptying and patients with normal gastric emptying. Constipation in patients with gastroparesis is not related to the gastric retention, but is associated with delay in colonic transit. Constipation in some patients with gastroparesis may represent a diffuse GI motility disorder. As there is not an association of delayed gastric emptying and constipation, the association of constipation with upper GI symptoms in these patients may be, in part, more perceptual (sensory augmentation). There may also be more diffuse increased visceral perception that explains the upper GI symptoms coexisting with constipation symptoms. Functional dyspepsia has been shown to coexist with functional constipation and IBS ( 17 , 18 ). The Rome III questionnaire was used to look into the presence of functional GI disorders as well as to look at defecation characteristics. With increasing severity of constipation, there was increasing prevalence of IBS, IBS-C, IBS-M, and functional constipation. For severe/very severe constipation, 76% had IBS, 33% had IBS-C, 36% had IBS-M, 9% had functional constipation. Increasing severity of constipation by PAGI-SYM was associated with a variety of abnormal defecation symptoms. Some of these symptoms are often thought of as symptoms of dyssynergic defecation. In epidemiological studies, at least 25% of patients with symptoms of chronic constipation endorse symptoms suggestive of rectal evacuation disorders such as excessive straining or sense of incomplete evacuation ( 19 ). The association of defecation disorders and nausea and vomiting, traditionally thought as upper GI symptoms has been reported in a previous study where about half the patients had abnormal evacuation ( 20 ). We then explored the change in constipation severity over time and the change in gastroparesis symptoms. During the 48 week follow up period, patients were treated clinically which could have included treatments for gastroparesis and constipation. We were not able to demonstrate that treatment of constipation helps relieve the gastroparesis symptoms. While there was a slight decrease in GCSI in patients that had decrease in constipation and a slight increase in GCSI in patients that had an increase in constipation severity, this did not reach statistical significance. The information obtained in this study has therapeutic importance, as constipation in gastroparesis may be better treated with a promotility agent that works on the whole GI tract. Prucalopride, a 5HT-4 receptor agonist which was approved for treatment of chronic constipation ( 21 ), was shown to be helpful in improving gastric emptying and symptoms of gastroparesis ( 22 ). The study is not without limitations. Patients rated severity of their constipation in a none to very severe scale. We used the general patient-driven term constipation, rather than specific items on stool frequency, stool characteristics. We categorized patients with Rome III surveys into IBS, IBS-C, and functional constipation which helps support our use of constipation severity assessments. Patients were seen at academic medical centers and probably reflect more symptomatic patients or patients that may have other disorders that impact on their symptoms. A number of our patients were taking narcotic analgesics, which themselves can produce symptoms and delay gastric emptying and delay colonic transit. However, it did not appear that opiates were associated with constipation or delayed colonic transit. In conclusion, this study shows that constipation is an important symptom in some patients with gastroparesis. Severe/very severe constipation and delayed colon transit occurs in a third of patients with symptoms of gastroparesis. The severity of constipation is associated with severity of gastroparesis symptoms, but not related to the delay in gastric emptying. Severity of constipation is associated with GI transit delays, particularly in the colon. In addition, many of the patients with symptoms of gastroparesis with constipation had criteria for IBS, which might additionally be a cause of constipation.

Gastroparesis symptoms include nausea, vomiting, early satiety, postprandial fullness, and perhaps, abdominal pain ( 1 ). Patients with gastroparesis can also have constipation which can be an important symptom in some patients. In development of patient reported outcomes (PROs) for gastroparesis, constipation was reported by 53% of patients ( 2 ). Reasons for constipation in patients with gastroparesis are multifactorial. First, constipation could be secondary to delayed gastric emptying; this would delay delivery of triturated food into the small intestine and then the colon. Second, constipation could be result of medications, such as opiate analgesics, tricyclic antidepressants, or anticholinergics. Third, constipation could be part of a diffuse GI motility disorder involving stomach, small intestine, and colon. Colonic transit and whole gut transit time by wireless motility capsule (WMC) were found to be longer in gastroparesis compared to healthy controls ( 3 ). Gastroparesis patients have a high rate of slow transit constipation by radiopaque marker studies than patients with symptoms of gastroparesis with normal gastric emptying ( 4 ). Fourth, perhaps constipation and delayed colonic transit could be the primary problem with a secondary delay in gastric emptying. Volitional suppression of bowel movements is associated with delayed gastric emptying ( 5 ). The NIH Gastroparesis Registry enrolls patient with symptoms of gastroparesis, both delayed and normal gastric emptying, giving opportunity to look at relationships of gastric emptying and constipation. This study investigates prevalence of constipation in patients with symptoms of gastroparesis, and its cause by relating it to gastric and colonic transit delays, as well as medications, dietary, exercise factors, and presence of irritable bowel syndrome (IBS). The aims were to: 1) Determine prevalence of constipation and delayed colonic transit in patients with symptoms of gastroparesis; 2) Correlate severity of constipation to severity of symptoms of gastroparesis; 3) Relate severity of constipation to GI transit delays assessed by gastric emptying scintigraphy (GES) and WMC. Relationship between change in constipation severity and change in gastroparesis symptoms and gastric emptying over time was explored.