Constipation in Patients with Symptoms of Gastroparesis: Analysis of Symptoms and Gastrointestinal Transit (2024)

Study Patients

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.

Symptom Assessment

Patients underwent history and physical examination. Medications that patients were using were recorded including proton pump inhibitors, histamine₂-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.

Gastric Emptying Scintigraphy (GES)

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 ^99mTc-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.

Wireless Motility Capsule (WMC)

For WMC testing (11,12), patients stopped proton pump inhibitors for 7 days, and histamine₂-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).

Statistical Methods

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.

Patients

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).

Constipation severity

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).

GI transit by GES and WMC

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 Analysis

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.

Constipation characteristics

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).

Change in constipation symptoms over time

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.

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