Alfred D. Nelson

Opioid-induced constipation: advances and clinical guidance

Currently opioids are the most frequently used medications for chronic noncancer pain. Opioid-induced constipation is the most common adverse effect associated with prolonged use of opioids, having a major impact on quality of life. There is an increasing need to treat opioid-induced constipation. With the recent approval of medications for the treatment of opioid-induced constipation, there are several therapeutic approaches. This review addresses the clinical presentation and diagnosis of opioid-induced constipation, barriers to its diagnosis, effects of opioids in the gastrointestinal tract, differential tolerance to opiates in different gastrointestinal organs, medications approved and in development for the treatment of opioid-induced constipation, and a proposed clinical management algorithm for treating opioid-induced constipation in patients with noncancer pain.

Biomarkers for bile acid diarrhoea in functional bowel disorder with diarrhoea: a systematic review and meta-analysis

There is no universally available laboratory test to diagnose bile acid diarrhoea (BAD). Objective To conduct a systematic review and meta-analysis to identify a biomarker for idiopathic BAD in patients with functional bowel disorder (FBD) with diarrhoea. Design We searched multiple databases through 15 May 2015. Data were only available to estimate the diagnostic yield of each test (the prevalence of a positive test). Estimates were pooled across studies using the random effects model. Results We included 36 studies, enrolling 5028 patients (24 using 75selenium homotaurocholic acid test (75SeHCAT) retention of <10%, 6 using fasting serum C4, 3 using fasting serum fibroblast growth factor 19 (FGF19) and 2 based on total faecal bile acid (BA) excretion over 48 h). The diagnostic yields (and 95% CI) of abnormal tests were: 0.308 (0.247 to 0.377) for 75SeHCAT retention (<10%), 0.171 (0.134 to 0.217) for serum C4, 0.248 (0.147 to 0.385) for serum FGF19 and 0.255 (0.071 to 0.606) for total faecal BA excretion over 48 h. The majority of the analyses were associated with substantial heterogeneity. Performance characteristics relative to a gold standard test could not be estimated. Conclusions Overall, the test with the highest diagnostic yield conducted in the largest number of studies was 75SeHCAT retention, which is not widely available in many countries outside Europe and Canada. Using different diagnostic tests, 25% (average) of patients with lower FBD with diarrhoea has evidence of idiopathic BAD. These tests serve to identify idiopathic BAD among patients with FBD with diarrhoea. Further studies are required to appraise the performance characteristics of tests for idiopathic BAD.

Chronic opioid induced constipation in patients with nonmalignant pain: challenges and opportunities

With the recent introduction and approval of medications directed at the treatment of opioid induced constipation (OIC) in patients with nonmalignant pain, there is increased interest and understanding of the unmet need and opportunities to enhance patient management. The high incidence of OIC is associated with rapid increase of narcotic analgesic prescriptions for nonmalignant chronic pain. This review addresses briefly the mechanisms of action of opioids that lead to OIC, the differential tolerance of gastrointestinal organs to the effects of opioids, the size and scope of the problem, the definition and outcome measures for OIC, current differential diagnosis and management algorithms, and the pharmacology and efficacy of treatments for OIC in patients with nonmalignant pain.

Effects of ghrelin receptor agonist, relamorelin, on gastric motor functions and satiation in healthy volunteers

Synthetic human ghrelin accelerates gastric emptying, reduces gastric accommodation, and results in numerical increases in postprandial symptom scores. The ghrelin receptor agonist, relamorelin, accelerates gastric emptying in patients with diabetic gastroparesis.

Rectal Gas Volume Measured by Computerized Tomography Identifies Evacuation Disorders in Patients With Constipation

BACKGROUND & AIMS Approximately one third of patients who present to gastroenterology care with constipation have rectal evacuation disorders. We aimed to compare rectal gas volume, measured by computerized tomography (CT), in constipated patients with and without rectal evacuation disorders. METHODS In a retrospective study, we collected data from 1553 patients with constipation, evaluated over 20 years. We analyzed data from 141 patients evaluated by anorectal manometry, balloon expulsion tests, and colon transit tests, collecting records of abdominal and pelvic CT examinations. Patients were classified into 3 subgroups: those with rectal evacuation disorders, slow‐transit constipation, or normal‐transit constipation. Two observers used standard CT software to identify variable regions of interest on each cross‐sectional CT image that contained rectum and measured areas of gas in each slice; they then summated entire volumes of rectal gas. For the 3 groups, we compared rectal gas volume, maximal rectal gas transaxial area (measured by CT), and area of rectal gas (vertical) on the 2‐dimensional abdominal film (scout) using the Kruskal–Wallis test. RESULTS The intraclass correlation coefficient between 2 observers’ measurements of rectal gas volume was 0.99 (P < .001). There were overall group differences in rectal gas volume and the maximal rectal gas transaxial area (both P < .001). The median rectal gas volume was higher in patients with rectal evacuation disorders (13.84 cm3) than in patients with slow‐transit (2.51 cm3) or normal‐transit constipation (1.33 cm3, both P < .05). Similarly, the area of rectal gas, which correlated with the maximal rectal gas transaxial area (Spearman correlation coefficient, 0.7; P < .001), showed overall 3‐group differences (P = .033), with greater areas of rectal gas on the abdominal scout film in patients with rectal evacuation disorders than in those with normal‐transit constipation. CONCLUSIONS In an analysis of patients with constipation, we found rectal gas volume, determined by abdominal CT imaging, to be greater in patients with than without rectal evacuation disorders.

Opioid analgesic use among patients presenting with acute abdominal pain and factors associated with surgical diagnoses

The prevalence of chronic opioid use among non‐cancer patients presenting with acute abdominal pain (AAP) is unknown. The aim was to characterize opioid use, constipation, diagnoses, and risk factors for surgical diagnoses among non‐cancer patients presenting with AAP to an emergency department (ED).

Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial

OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose‐related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two‐dose NGM282 (1 and 6 mg, subcutaneously daily), parallel‐group, randomized, placebocontrolled, 14‐day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). Statistical analysis: overall ANCOVA at &agr; = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (&agr; = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose‐related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research.

A single-center, prospective, double-blind, sham-controlled, randomized study of the effect of a vibrating capsule on colonic transit in patients with chronic constipation

In an open‐label study of 26 patients with IBS‐C and chronic constipation, treatment with a vibrating (VIBRANT) capsule twice a week for 7.5 weeks resulted in 88.5% responders. Effects on colonic transit are unclear. We aimed to compare effects of VIBRANT and sham capsule treatment on colonic transit in patients with functional constipation.