Pregabalin and Colonic Function

Study Overview
=================
Brief Summary
-----------------
This study is being done to evaluate the effects of pregabalin, a drug approved for anticonvulsive therapy and for neuropathic pain, on colonic and sensory functions in healthy individuals. The specific study hypotheses were as follows: 1) pregabalin increases sensation thresholds, decreases sensation ratings, and increases compliance in response to balloon distension in the colon; 2) pregabalin reduces colonic phasic and tonic motility in response to a standardized meal; and 3) sensation ratings are lower with higher colonic compliance.

Detailed Description
-----------------
The treatment of patients with irritable bowel syndrome and chronic abdominal pain is advancing with several effective options for symptoms related to bowel dysfunction and bloating/distension. However, there are no approved or effective centrally or peripherally acting visceral analgesics. Pregabalin has been proposed as a treatment for visceral pain, based on the pharmacological actions, and efficacy in neuropathic pain. This was a trial of healthy adults to compare the effects of oral pregabalin, 75 mg and 200 mg versus placebo on sensation and contraction of the colon using validated methods. All participants presented on the study day after an overnight bowel preparation with an oral colonic lavage solution and a 12-hour fast. Flexible colonoscopy to the splenic flexure was performed without sedation by one investigator. The barostat catheter (constructed at Mayo Clinic, Rochester, MN) incorporating six manometric point sensors 5 cm apart was introduced into the colon over a guidewire, and the polyethylene balloon (10 cm long, cylindrical shape with a maximum volume of 600 ml) was placed in the mid-descending or junction of the sigmoid and descending colon. A rigid-piston barostat was used to measure intraballoon pressure and volume throughout the study. After an initial inflation to a volume of 75 ml to ensure unfolding of the balloon, the operating pressure was identified as the distension pressure at which respiratory excursions were recorded clearly from the barostat tracing, and the intraballoon pressure was set 2 mm Hg above the minimal distension pressure. A conditioning distention from 0 to 36 mm Hg in increments of 4 mm Hg every 15 seconds was performed over a period of 3 minutes. After an equilibration period of 10 minutes, colonic compliance was assessed by the ascending methods of limit (ramp-like increases of 4 mm Hg at 30 section intervals). During the assessment of colonic compliance, participants reported their thresholds for first perception, gas and pain. After another 10 minute equilibration period, fasting colonic tone was measured at operating pressure for a period of 10 minutes. Randomized-order phasic distentions were then applied at 16, 24, 30, and 36 mm Hg above the operating pressure to measure the sensations of gas and pain. Each distention lasted 1 minute and was followed by an equilibration period at the operating pressure for 2 minutes. A 100-mm visual analog scale (VAS) was used to assess the rating of arousal and stress experienced by each participant before performing the phasic distentions. During the distentions, participants also used the 100-mm VAS to rate the intensity of gas and pain perception at 30 seconds from the start of the distention. Colonic compliance, fasting tone, pressure thresholds for first perception, gas, and pain, and VAS scores of gas and pain during the phasic distentions were measured before administering the study medication and 1 hour after drug administration. After the postdrug assessment of sensation with phasic distentions, a 30-min assessment of fasting colonic tone was measured in each participant; this provided a baseline to compare the effect of a standard 750-ml chocolate milkshake meal across treatment groups. Postprandial tone was measured over 60 minutes, with the main focus on the first 30 minutes. When the recording was completed, the balloon was deflated and the tube removed by gentle traction.

Official Title
-----------------
Effect of Pregabalin on Colonic Sensorimotor Function in Healthy Adults.

Conditions
-----------------
Healthy

Intervention / Treatment
-----------------
* Drug: Pregabalin
* Drug: Placebo
* Other: Bowel preparation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria: - Healthy males or females Exclusion criteria: Abdominal surgery other than appendectomy, laparoscopic cholecystectomy, cesarean section, vaginal or laparoscopic hysterectomy or tubal ligation A history of chronic gastrointestinal or systemic illnesses that could affect gastrointestinal motility Any history of hypertension Use of medications that may alter gastrointestinal motility or interact with the study medications Use of any of the study medications within the past 30 days Pregnancy Chronic renal insufficiency (serum creatinine >1.5 mg/dL) Psychiatric or psychologic dysfunction.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pregabalin 75 mg<br>Subjects randomized to this arm received a single dose of pregabalin 75 mg orally | Drug: Pregabalin<br>* FDA approved medication (capsules) at 75 mg and 200 mg doses<br>* Other names: Lyrica;Other: Bowel preparation<br>* Polyethylene glycol electrolyte solution bowel preparation<br>* Other names: GoLYTELY;|
| Experimental: Pregabalin 200 mg<br>Subjects randomized to this arm received a single dose of pregabalin 200 mg orally | Drug: Pregabalin<br>* FDA approved medication (capsules) at 75 mg and 200 mg doses<br>* Other names: Lyrica;Other: Bowel preparation<br>* Polyethylene glycol electrolyte solution bowel preparation<br>* Other names: GoLYTELY;|
| Placebo Comparator: Placebo<br>Subjects randomized to this arm received a single dose of placebo medication orally | Drug: Placebo<br>* Placebo capsules<br>Other: Bowel preparation<br>* Polyethylene glycol electrolyte solution bowel preparation<br>* Other names: GoLYTELY;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensory Threshold for Pain | The sensory threshold for first perception of pain was measured by stepwise inflation of the balloon in increments of 4 mm Hg at 60 second intervals. The balloon was placed in the mid-descending or junction of the sigmoid and descending colon. During this assessment participants were asked to report when they had the first perception of pain. The investigator recorded the threshold pressure at which the participants reported this sensation. | approximately 60 minutes after drug administration | 
| Sensation Ratings for Pain and Gas at 30 mm Hg Distension Above Baseline Operating Pressure | The 30 mm Hg distension refers to inflation of the balloon placed in placed in the mid-descending or junction of the sigmoid and descending colon. Pain and gas were individually measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes. For the pain VAS, 0 means no pain and 100 mm means extreme pain. For the gas VAS, 0 means no gas sensation and 100 mm means extreme gas sensation. The investigator measures the mark made by the participant in mm and records this for the value of either pain or gas. | Approximately 60 minutes after drug administration | 
| Colonic Compliance | Colonic compliance is a measure of the stiffness of the colon, that is, what pressure was needed to reach half the maximum value of the colon. After the barostat balloon catheter was inserted in the mid-descending or junction of the sigmoid and descending colon, the balloon was inflated. After an initial conditioning distension to 20 mm Hg, colonic compliance was measured by step-wise inflation with increments of 4 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. | Approximately 60 minutes after drug administration | 
| Postprandial Colonic Tone [Reported] as the Symmetric Percent [Change]in Baseline Colonic Barostat Balloon Volume | The symmetric percent reduction in baseline colonic barostat balloon volume during the first 30 minutes postprandially (PP) corrected for the preprandial (30 min) tone, (symmetric percent change= 100*log_e[fasting/PP]). A positive symmetric percent change reflects a decrease in barostat balloon volume indicating a reduction in colonic tone. (The balloon was placed in the mid-descending or junction of the sigmoid and descending colon.) | The first 30 minutes postprandially, and preprandial (30 minutes) | 
| Postprandial Motility Index Over 30 Minutes | The first 30 minute postprandial motility index (MI), MI = log_e [(number of contractions * sum of amplitudes)+1] | 30 minutes after the meal | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sensory Threshold for Gas | The sensory threshold for first perception of gas was measured by stepwise inflation of the balloon in increments of 4 mm Hg at 60 second intervals. (The balloon was placed in the mid-descending or junction of the sigmoid and descending colon.) During this assessment participants were asked to report when they had the first perception of gas. The investigator recorded the threshold pressure at which the participants reported this sensation. | Approximately 60 minutes after drug administration | 
| Sensation Ratings for Pain at 16, 24, and 36 mm Hg Distension | The mm Hg distensions refer to the barostat balloon, which was placed in the mid-descending or junction of the sigmoid and descending colon. Pain sensation was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes. For the pain VAS, 0 means no pain and 100 mm means extreme pain. The investigator measures the mark made by the participant in mm and records this for the value of pain. | Approximately 60 minutes after drug administration | 
| Sensation Ratings for Gas at 16, 24, and 36 mm Hg Distension | The mm Hg distensions refer to the barostat balloon, which was placed in the mid-descending or junction of the sigmoid and descending colon. Gas sensation was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes. For the gas VAS, 0 means no gas sensation and 100 mm means extreme gas sensation. The investigator measures the mark made by the participant in mm and records this for the value of either pain or gas. | Approximately 60 minutes after drug administration | 
| Gas Sensation Rating Averaged Across 4 Distension Pressures (16, 24, 30, and 36 mg Hg) | The mm Hg distensions refer to the barostat balloon, which was placed in the mid-descending or junction of the sigmoid and descending colon. Gas sensation was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes. For the gas VAS, 0 means no gas sensation and 100 mm means extreme gas sensation. The investigator measures the mark made by the participant in mm and records this for the value of gas. The values across the 4 distension pressures were averaged for this outcome measure. | Approximately 60 minutes after drug administration | 
| Pain Sensation Rating Averaged Across 4 Distension Pressures (16, 24, 30, and 36 mg Hg) | The mm Hg distensions refer to the barostat balloon, which was placed in the mid-descending or junction of the sigmoid and descending colon. Pain sensation was measured by a 100 mm long Visual Analog Scale (VAS). The VAS does not have any pre-set marks between the extremes. For the pain VAS, 0 means no pain and 100 mm means extreme pain. The investigator measures the mark made by the participant in mm and records this for the value of pain. The values across the 4 distension pressures were averaged for this outcome measure. | Approximately 60 minutes after drug administration | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pregabalin, motor, sensation, colon, pain, gas