Effect of a Cannabinoid Agonist on Colonic Sensory Functions in Patients With Irritable Bowel Syndrome

Phase 2

Completed

Conditions: Irritable Bowel Syndrome

Interventions: Drug: Placebo
Drug: Dronabinol

Registration Number: NCT01786109

Lead Sponsor: Michael Camilleri

Brief Summary: Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. There are still no effective and safe medications approved for the treatment of abdominal pain associated with bowel symptoms in IBS. This study will investigate the effects of an approved medication, Dronabinol, on the movement of food through the stomach and colon in subjects with a history of diarrhea-predominant Irritable Bowel Syndrome (D-IBS).

Detailed Description: Irritable bowel syndrome (IBS) affects about 15% of the U.S. population. Despite increasing understanding of the pathophysiology of IBS, there is no effective medication approved for the treatment of abdominal pain associated with IBS. Cannabinoid receptors (CBR) are on cholinergic neurons in the brain stem, stomach and colon. A cannabinoid receptor 1 (CB1) antagonist, rimonabant, is effective in induction of weight loss; however, the mechanism of this benefit is unclear. Human studies from this lab show that a CBR agonist, dronabinol, inhibits gastric and colonic motility, which may alter appetite or satiation in obesity, and may have potential in the treatment of IBS. The overall focus of the study is on the mechanisms involved in the modulation of gastric and colonic motor and sensory functions by cannabinoid receptors (CBR) in health and in IBS. CB1 receptors are also involved in nociception and in mediating inflammation which are increasingly recognized as being potential pathophysiological mechanisms in IBS.

All participants underwent the following procedures:

1. Documentation of eligibility, screening questionnaires and physical examination, including exclusion of rectal evacuation disorder by standard clinical evaluation within the past 12 months; this was important to ensure the diarrhea was not secondary to "retention with overflow".

2. Bowel preparation with PEG and electrolyte-containing oral colonic lavage solution, followed by a 12 hour fast.

3. Colonic testing of compliance, tone, motility and sensation measurement. Colonic compliance, fasting tone, sensory thresholds and sensory ratings in response to random-order phasic distensions were performed before treatment was administered. Then medication was ingested, and after 60 minutes, the same studies were performed that is compliance, fasting tone, sensory thresholds and sensory ratings in response to random-order phasic distensions. Participants also filled in responses to questionnaires (using 100 mm VAS scales) to describe their sense of tiredness, peace, worry and activity at the time of the measurements of sensation. Finally, participants ingested a standard chocolate 1000 kcal milkshake meal, and postprandial colonic tone and motility were measured for one hour.

4. With appropriate consent, a venous blood sample was obtained from each participant for DNA extraction; this will be used in ongoing pharmacogenomics studies.

Note: This study is related to NCT01253408, part A of the same protocol. Part A explored the effect of dronabinol on gastric and colonic motor functions.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 75

Inclusion Criteria

Age 18-75 years
Positive for IBS symptoms by Rome III criteria
No prior abdominal surgery (except appendectomy or cholecystectomy
Score of 10 or less on either Anxiety or Depression on the Hospital Anxiety/Depression Inventory

Exclusion Criteria

Patients with significant depression (score of greater than 10 on Hospital Depression Inventory
Patients with anxiety (score of greater than 10 on Hospital Anxiety Inventory. However, patients on stable doses of selective serotonin inhibitors (SSRIs) or low dose of tricyclic antidepressants will be eligible.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	One dose of placebo was taken orally with water.
Dronabinol 2.5 mg	Dronabinol	One dose of dronabinol 2.5 mg was taken orally with water.
Dronabinol 5 mg	Dronabinol	One dose of dronabinol 5 mg was taken orally with water.

Primary Outcome Measures

Name	Time	Method
Colonic Compliance at Pressure at Half-Maximum Volume (Pr 1/2)	1 hour after drug was ingested	Colonic compliance is a measure of the "stiffness" of the colon, that is, what pressure was needed to reach half the maximum volume of the colon. After the barostat catheter was inserted in the colon, the catheter was connected to a barostat machine. After an initial conditioning distension to 20 mm Hg, colonic compliance was measured by step-wise inflation with increments of 4 mm Hg up to 64 mm Hg. Colonic compliance was analyzed by a validated linear interpolation method. The pressure at half maximum volume serves as a summary of colonic compliance.

Secondary Outcome Measures

Name	Time	Method
Postprandial Change in Colonic Tone	1 hour after ingestion of standard meal	Colonic tone is a measurement of the volume of the colon. Colonic tone was assessed by noting the changes in the balloon volume in the presence of a constant operating pressure in the balloon (in the barostat-manometric assembly placed in the colon.)
Post-treatment Sensory Threshold for First Perception of Pain	1 hour after drug was ingested	The sensory threshold for first perception of pain was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.
Post-Treatment Overall Sensory Rating in Response to 16, 24, 32, and 40 mm Hg Distensions	1 hour after drug was ingested	The sensory rating was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes of 0 for no pain and 100 mm for extreme pain. The investigator measures the mark made by the participant in mm and records this for the value of pain.
Fasting Colonic Tone	After 12 hour fast, before drug administered	Colonic tone is a measurement of the volume of the colon. Colonic tone was assessed by noting the changes in the balloon volume in the presence of a constant operating pressure in the balloon (in the barostat-manometric assembly placed in the colon.)
Postprandial Colonic Motility Index	1 hour after ingestion of standard meal	Colonic phasic pressure activity is summarized as a motility index (MI)=log_e\[number of contractions \* sum of amplitudes) + 1\]. A normal fasting average motility index (MI) would be about 12. An increase in MI means an increase in the phasic contractions (in contrast to tone) which is measured as a change in volume of the barostat balloon. (Therefore, an increase in MI means that the meal is moving more quickly through the colon.)
Post-treatment Sensory Threshold for First Sensation	1 hour after drug was ingested	The sensory threshold for first sensation was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.
Post-Treatment Sensory Threshold for First Perception of Gas	1 hour after drug was ingested	The sensory threshold for first perception of gas was measured by stepwise inflation in increments of 4 mm Hg at 60 second intervals up to a maximum pressure of 64 mm Hg. During this assessment participants were asked to report when they had the first sensation. The investigator recorded the threshold pressure at which the participants reported this sensation.