Introduction

Chronic diarrhea is a debilitating disorder affecting up to 5% of the population. Opioids inhibit gastrointestinal motility via μ-opioid receptors in the enteric nervous system, and opioids have been used in the management of diarrhea for centuries. However, a lack of clinical evidence regarding their efficacy, along with concerns about potential opioid-induced sedation and addiction, limits their use in the clinic. Opium tincture (raw opium dissolved in ethanol) has recently shown anti-propulsive effects in a healthy cohort (1), but no evidence of its effects on the enteric and central nervous system (CNS) in chronic diarrhea patients exists.

Aims & Methods

We aimed to investigate the anti-propulsive effects of opium tincture and its secondary effects on the CNS in a randomized, double-blinded, placebo-controlled, cross-over trial in subjects with chronic diarrhea (defined as a minimum of three daily bowel movements for the past week) refractory to loperamide and targeted treatment (if known etiology). Opium tincture or placebo was administered for seven days in two study periods separated by 14 days. The end titration daily dose was 30 drops (~15mg of oral morphine). Bowel movements were assessed using the Bristol Stool Form Scale, while a wireless motility capsule recorded gastrointestinal transit times. CNS effects in terms of change in pupil size, reaction time, and working memory were also investigated. Signs of addiction were evaluated using the Subjective Opiate Withdrawal Scale.

Results

Eleven subjects (mean age: 45 ±17 years, 46% males) with chronic diarrhea were included (idiopathic: 4; bile acid malabsorption: 3; inflammatory bowel disease: 2; microscopic colitis: 1; irritable bowel syndrome: 1). The number of daily bowel movements was reduced during treatment with opium tincture compared to placebo (overall estimated difference between treatments: -0.7 (-1.1 - -0.3), p=0.002). In line with this, opium tincture prolonged the colonic transit time (opium tincture: median 17h (interquartile range 15-40h) vs. placebo: 12h (4-16h), p=<0.001). Opium tincture induced miosis in most subjects, but no indication of sedation or addiction was found.

Conclusion

Opium tincture induced anti-propulsive effects in subjects with chronic diarrhea refractory to standard treatment, evident as a reduced number of bowel movements and prolonged colonic transit. No CNS involvement besides miosis was observed. These results suggest that opium tincture is a relevant treatment strategy for selected patients with chronic diarrhea, especially because no evidence of opioid-induced sedation or addiction was found. However, studies on the long-term effects are needed.

References

1. Okdahl T, Mark EB, Nedergaard RB, et al. Effects of opium tincture on the enteric and central nervous systems: A randomized controlled trial. Basic Clin Pharmacol Toxicol. 2023 Feb 27;

Disclosure

The study was sponsored by an unrestricted grant by Pharmanovia. Pharmanovia had no influence on the design, analysis, or reporting of the study.

Introduction

Opium tincture in oral solution has been used for antidiarrheal treatment for centuries, and it is often used to treat chronic idiopathic diarrhea as a secondary choice after loperamide and bulking agents. However, the underlying mechanisms of opium tincture on gastrointestinal function are not evident and have not been investigated in clinical trials. This study aimed to investigate the effects of opium tincture on gastrointestinal motility, intestinal volumes, and water content of different gut segments assessed by magnetic resonance imaging (MRI).

Aims & Methods

Twenty healthy volunteers were included in a randomized, placebo-controlled, cross-over study with 9-day treatment (30 drops per day of opium tincture corresponding to 15 mg of oral morphine or placebo). MRI was performed on day 1 (before treatment) and day 9 (during treatment) using a pan-alimentary scan protocol. Images were obtained during fasting and after a 285-kcal granola bar meal. MRI measurements included assessments of gastric volume, gastric emptying half-time, gastric motility, small bowel volume, small bowel water content, small bowel motility, colon volume, colon water content, and whole gut transit. Data was analyzed using repeated measure mixed models and adjusted using baseline data as a covariate and a Bonferroni post hoc correction.

Results

The median age of the included subjects was 24 years (range 20-72 years), and 10 subjects were female. Opium tincture delayed gastric half-emptying time as compared to placebo (mean [95% confidence intervals] values: 38.5 [35.3-41.6] min vs. 32.8 [29.9-35.8] min, p=0.004). Opium tincture increased gastric meal volumes 15 and 30 minutes after the meal as compared to placebo (ps<0.018). Gastric contraction amplitude and frequency were not affected by treatment. Small bowel endpoints were not different between treatments (all p>0.05). Ascending-, transverse-, and descending colon volumes were increased after opium tincture as compared to placebo (ascending: 226 [197-253] ml vs 168 [140-195] ml, p=0.003; transverse: 208 [180-236] ml vs. 158 [131-185] ml, p=0.017; descending: 155 [125-184] ml vs. 110 [83-138] ml, p=0.045). T1-relaxation time (a proxy for water content) of the descending colon chyme was decreased during opium tincture as compared to placebo, indicating dryer feces (517 [425-609] ms vs. 690 [595-786] ms, p=0.030). Whole gut transit time was delayed during opium tincture as compared to placebo (p=0.027).

Conclusion

Opium tincture as compared to placebo induces changes in gastric and colonic motility and volumes as measured using a pan-alimentary MRI framework in a population of healthy volunteers. Based on the current results, opium tincture seems to affect the gastrointestinal tract in ways that are relevant for treating diarrhea. An improved understanding of how opioids affect gut functions may lead to a better understanding of and optimized management of diarrhea.

Introduction

The principal treatment option for treating chronic lymphoproliferative disorders (CLPD) is chemotherapy. The central concept in chemotherapy (CT) is adherence to the dose and drug administration regimens. It is impotent that infusion of CT agents in high doses is associated with an increased risk of chemotherapy-induced injury of the entire gastrointestinal tract (GIT).
The clinical manifestations of chemotherapy-induced mucositis are diarrhea. The presence of chemotherapy-induced injury mucositis can be assessed by the level of N-acetylneuraminic acid (NANA) and citrulline in the blood. The primary mechanism of the cytotoxic influence of CT agents is strongly associated with oxidative stress.

Aims & Methods

The aim is to investigate the effect of S-ademetionine on plasma NANA and citrulline levels in patients with CLPD during chemotherapy-induced injury The aim is to investigate the effect of S-ademetionine on plasma NANA and citrulline levels in patients with CLPD during chemotherapy-induced injury GIT.
Materials and methods: 24 patients with CLPD were examined (15 (75%) patients with B-cell chronic lymphocytic leukemia and 10 (25%) patients with Small B-cell non-Hodgkin lymphoma, 7 (28 %) females and 18 (72 %) males, ages 30-76. The inclusion criteria were the progression of B-CLL, Small B-NHL, and diarrheal syndrome on the background of CT. The examinations were conducted twice: before CT and after 3 courses of CT. Patients were analyzed the concentration of NANA in the blood, and the concentration of the citrulline in the plasma.
All patients received CT: BR (bendamustine, rituximab), FCR (fludarabine, cyclophosphamide, rituximab), R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone). Depending on the inclusion of S-ademetionine as an adjuvant treatment, patients were divided into groups: І (n=13) – patients with CLPD, who received only CT. ІІ (n=14) – patients with CLPD, who received S-ademetionine at a dose of 1000 mg/day intravenously for 10 days, then 500 mg twice a day for 20 days. ІІІ (n=20) – the control group of 20 practically healthy individuals (9 (45 %) females and 11 (55 %) males, ages 22-26).

Results

Patients in both groups with CLPD had pre-existed mucosal injury characterized by 1.25 (p=0.0025) and 1.26 times (р=0.006) higher blood NANA concentration than the control group. The conduction of CT was associated with injury enterocytes, which was characterized by 1,66 times (p=0,0002) lower plasma citrulline level in patients of group I compared to the initial examination. The infusion of S-ademetionine attenuated intestinal dysfunction associated with 1,23 times (p=0,0005) higher blood citrulline level after the CT compared to group I.

Conclusion

The infusion of S-ademetionine as adjuvant treatment in patients with CLPD provided effective prophylaxis of GIT injury that was associated with higher blood citrulline levels after the conduction of CT.

Disclosure

No

Introduction

Gastrointestinal symptoms can originate from different segments of the gastrointestinal tract, however, symptoms seldom overlap with clinical findings. Magnetic resonance imaging (MRI) has lately shown promising results when investigating volume and motility disturbances in diseases like diabetes mellitus and Crohn’s disease. MRI offers the possibility of examining the full gastrointestinal tract in one examination; however, to our knowledge, intrasubject physiological variability has not been investigated in detail. The current study aimed to describe day-to-day intrasubject physiological variability in MRI-assessed segmental volumes and motility of the gastrointestinal tract in healthy volunteers.

Aims & Methods

Forty healthy volunteers were investigated with MRI at fasting and 0, 15, and 45 minutes after a 285-kcal meal. MRI measurements included gastric emptying half-time, small bowel motility, whole gut transit capsules, and volume assessments of the stomach, small bowel, and colon. The MRI protocol was repeated after a mean period of 10.5 weeks (a minimum of five weeks and a maximum of 24 weeks). Assessments of variability were performed using the intraclass correlation coefficient and [95% confidence intervals].

Results

Gastric emptying half-time was moderately reproducible with an ICC of 0.56 [0.28-0.75]. Gastric meal volumes showed overall poor reproducibility with the highest ICC at the fasting scan with an ICC of 0.35 [0.03-0.61], while gastric gas volumes showed poor to moderate reproducibility with the highest ICC of 0.56 [0.29-0.75] at the 0-minute scan. Small bowel motility showed the highest reproducibility at the fasting scan with an ICC of 0.60 [0.34-0.77] and the lowest reproducibility at the 45-minute scan with an ICC of 0.13 [-0.37-0.56]. Small bowel volumes at fasting were moderately reproducible with an ICC of 0.64 [0.40-0.79], while colon volume had an ICC of 0.45 [0.15-0.67]. Whole gut transit capsules showed poor reproducibility with an ICC of 0.30 [-0.15-0.66].

Conclusion

Intrasubject physiological variation in MRI-assessed segmental volumes and motility of the gastrointestinal tract was high, and most comparisons resulted in indications of poor to moderate variability when interpreting the ICC values. When designing clinical studies or performing clinical patient examinations that include MRI-based assessments of the gastrointestinal tract, the normal physiological variation must be considered.

Introduction

Irritable bowel syndrome (IBS) is among the most prevalent gastrointestinal conditions. However, its therapeutic management poses challenges, with many current recommendations resting on a low level of evidence.

Aims & Methods

Our objective is to conduct a systematic review with meta-analysis of randomized, double-blind, placebo-controlled trials to assess the efficacy of antidepressants in treating IBS. ​
Systematic review with meta-analysis performed according to PRISMA guidelines and registered on the PROSPERO platform (CRD42024502427). PubMed, EMBASE, and The Cochrane Library platforms were searched from inception to January 2024. Only randomized, double-blind, placebo-controlled trials, conducted in patients with IBS patients, with a minimum treatment period of 4 weeks, were included. The quality of evidence was assessed using the revised version of the Cochrane tool (RoB 2). A random-effects model was used. Heterogeneity was assessed by the I² statistics. Funnel plots and the Egger test were used to assess publication bias. Statistical analysis was performed using STATA v16.

Results

The search strategy identified 1340 studies, of which 16 were included, totaling 1428 patients. Among these studies, 733 patients were assigned to the antidepressant group and 698 to the placebo group. In the intervention group, 405 (55.3%) patients reported improvement, compared to only 227 (32.5%) patients in the placebo group. The meta-analysis showed that the use of antidepressants in patients with IBS provides a benefit in overall symptom improvement (OR=3.02; 95% CI 2.16-4.2) compared to placebo.
A subgroup analysis of 9 studies, comprising 1008 patients, assessed the efficacy of tricyclic antidepressants (TCAs) in the same setting and revealed similar results (OR=3.39, 95% CI 2.24-5.12), as did the sub-analysis of 6 studies (including 363 patients) evaluating the efficacy of selective serotonin reuptake inhibitors (SSRIs) (OR= OR=2.39, 95% CI 1.14-5.01). The efficacy also extends to patients refractory to first-line measures (6 studies including 713 patients) (OR=2.96, 95% CI 1.67-5.25) and to patients without psychopathology (8 studies including 471 patients) (OR=2.92, 95% CI 1.6-5.31). Concerning symptoms, a sub analysis also confirmed the efficacy of antidepressants specifically both in the improvement of abdominal pain (OR=4.33, 95% CI 2.1-8.93) and in abdominal distension (OR=2.68, 95% CI 1.42-5.04).
Only in the sub-analysis assessing the efficacy of SSRIs and of the improvement of abdominal pain, I² was slightly >60%, indicating substantial heterogeneity, but <75%. Causes of heterogeneity were searched. Publication bias was detected, and potential sources were identified. Sub-analysis without the studies identified as sources of this bias revealed similar results with lower heterogeneity.

Conclusion

Antidepressants, including both TCAs and SSRIs, demonstrate efficacy in patients with IBS, presenting a validated treatment option supported by evidence. Moreover, these medications can be beneficial to patients resistant to initial treatments and those lacking psychopathological symptoms.

References

Drossman DA, Tack J, Ford AC, Szigethy E, Törnblom H, Van Oudenhove L. Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut−Brain Interaction): A Rome Foundation Working Team Report. Gastroenterology 2018;154:1140-1171.e1. https://doi.org/10.1053/j.gastro.2017.11.279.
Lacy BE, Pimentel M, Brenner DM, Chey WD, Keefer LA, Long MD, et al. ACG Clinical Guideline: Management of Irritable Bowel Syndrome. Am J Gastroenterol 2021;116:17–44. https://doi.org/10.14309/ajg.0000000000001036.
Lovell RM, Ford AC. Global Prevalence of and Risk Factors for Irritable Bowel Syndrome: A Meta-analysis. Clin Gastroenterol Hepatol 2012;10:712-721.e4. https://doi.org/10.1016/j.cgh.2012.02.029.
Vasant DH, Paine PA, Black CJ, Houghton LA, Everitt HA, Corsetti M, et al. British Society of Gastroenterology guidelines on the management of irritable bowel syndrome. Gut 2021;70:1214–40. https://doi.org/10.1136/gutjnl-2021-324598.

Disclosure

FP received speaker fees from Abbvie, Falk, Ferring, Janssen, Pfizer, Pharmakern, Takeda and Tillotts. The other authors have no conflict of interest.