Investigation of Cannabinoid Receptor Agonist Dronabinol in Patients With Functional Chest Pain

Study Overview
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Brief Summary
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In a recent study, Dronabinol was shown to reduce symptoms in patients with Functional Chest Pain (non-cardiac chest pain). Additionally, metabolic measures and patients' weights were not adversely affected by this regiment. In fact, some cholesterol measures trended in a favorable direction with Dronabinol. The study lasted 28 days and patients took Dronabinol twice daily. The goal of this current study focuses on reducing the dose of Dronabinol to see if the same goals can be achieved. More so, the study will be extended to 12 weeks to gain a more longitudinal picture of therapy with Dronabinol. It is hypothesized that reducing the dose and extending the duration will continue to show an improvement in symptoms as well as no adverse metabolic outcomes.

Detailed Description
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About 200,000 new cases of Functional Chest Pain (FCP) are diagnosed annually in USA. FCP is associated with poor quality of life and high health care expenditure. Gastroesophageal reflux disease (GERD), esophageal motility disorders, and psychological disorders may cause FCP. However, the mechanism(s) for FCP continue to be explored and include central and peripheral hypersensitivity as well as biomechanical dysfunction of the esophageal wall. CB1 receptor activation in synaptic clefts fine tunes neuronal firing and may in fact quell the over excitation associated with hypersensitivity. Dronabinol, a cannabinoid receptor agonist with a preference for CB1 over CB2, is believed to reduce the esophageal hypersensitivity. CB1 receptors are located primarily on central and peripheral neurons (including the enteric nervous system) and myenteric plexus where they modulate neurotransmitter release. Activation of pre-junctional CB1 receptors may reduce excitatory enteric transmission and conceivably improve esophageal hyperreactivity and hypersensitivity, the hallmarks of FCP. Previously, it was shown that Chest Pain Symptoms were greatly reduced when patients took 5 mg Dronabinol twice daily. Patients had very few side effects from this regiment although sedation was reported. The goal of this study focuses on reducing the dose of Dronabinol to 5 mg every other day, or essentially, one quarter of the dose. The effect of Dronabinol varies with CB1 receptor density in various tissues. It is hypothesized that at this reduced dose relief of chest pain will still be achieved without the sedating effects. More so, Dronabinol at 5 mg twice daily failed to produce any adverse metabolic outcomes including measures of glucose, LDL, triglycerides, leptin, or transaminases. Dronabinol treatment tended to improve some of these measures although the study only lasted 28 days. Currently the hypothesis is that lower doses at a protracted time course will again fail to perturb homeostasis.

Official Title
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Investigation of Cannabinoid Receptor Agonist Dronabinol in Patients With Functional Chest Pain

Conditions
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Esophageal Diseases

Intervention / Treatment
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* Drug: Dronabinol
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least one episode of chest pain a week in the past month. Previous negative cardiac evaluation (EKG ± non invasive stress test ± coronary angiogram). Negative esophageal evaluation for a motility disorder (eg: achalasia) and GERD (normal endoscopy, normal 24 hr pH study, or unresponsive to 6 weeks of BID PPI therapy) Exclusion Criteria: Subjects requiring narcotics or other pain medications, Subjects with known GERD (unless responsive to PPI therapy and on a stable dose), esophagitis, Barrett's esophagus or peptic stricture on endoscopy Subjects with previous upper gastrointestinal surgery Pregnancy Subjects with diabetes, neuromuscular disorders, cardiac disorders, or other severe co-morbidities (Cardiovascular, respiratory, renal, hepatic, hematologic, endocrine, neurologic). Subjects with upper airway symptoms (such as hoarseness, wheezing or laryngospasm) Medications such as baclofen, sucralfate and prokinetic agents or any agent considered a sedative, hypnotic, or psychoactive drug. Known history of substance abuse. Subject unable to consent. Patient has history of comorbid psychiatric conditions including mania and schizophrenia. Patients will also be excluded who currently have a diagnosis of depression or undergoing treatment for depression.

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Dronabinol<br>Patients who receive Dronabinol 5 mg, every other night, orally. | Drug: Dronabinol<br>* Dronabinol 5 mg, every other night, orally<br>* Other names: Marinol;|
| Placebo Comparator: Placebo<br>Patients who receive Placebo every other night, orally | Drug: Placebo<br>* Placebo--no drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chest Pain | Patient will fill out a Chest Pain Questionnaire and symptom diary daily of symptoms which will be normalized to a numerical value for comparison among groups. | Daily assessment for 12 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Chest Pain Intensity | Patient will fill out a Chest Pain Questionnaire and symptom diary daily of symptoms which will be normalized to a numerical value for comparison among groups. | Daily assessment for 12 weeks | 
| GERD Symptom Checklist | Patients will fill out a questionnaire pertaining to GERD symptoms which will be normalized to a numerical value for comparison among groups. | Baseline, 2, 4, 8, and 12 weeks | 
| Short Form 36 | A general health-related quality of life questionnaire that examines 8 domains: Physical Functioning, Role Functioning Physical, Role Functioning Emotional, Mental Health, Vitality, Bodily Pain, General Health, and Social Functioning | Baseline, 2, 4, 8, and 12 weeks | 
| Esophageal Hypersensitivity and Distention | Sensory thresholds for first sensation, discomfort, and pain in the esophagus. Frequency, amplitude, area under the curve (AUC) of reactive esophageal contractions | Baseline, 4, 8, and 12 weeks | 
| Beck Depression Index | Analysis of depressive symptoms normalized to a numerical value for comparison among groups. | Baseline, 2, 4, 8, and 12 weeks | 
| Metabolic Parameters | Total cholesterol will be measured and reported in mg/dL. | Baseline, 2, 4, 8, and 12 weeks | 
| Weight | Patient mass will be measured in kg. | Baseline, 2, 4, 8, and 12 weeks | 
| Beck Anxiety Index | Analysis of anxious symptoms normalized to a numerical value for comparison among groups. | Baseline, 2, 4, 8, and 12 weeks | 
| Waist Circumference | Patient's waist in cm will be measured. | Baseline, 2, 4, 8, and 12 weeks | 
| Non-HDL Cholesterol | Non-HDL cholesterol will be measured and reported in mg/dL. | Baseline, 2, 4, 8, and 12 weeks | 
| HDL Cholesterol | HDL cholesterol will be measured and reported in mg/dL. | Baseline, 2, 4, 8, and 12 weeks | 
| Triglycerides | Triglycerides will be measured and reported in mg/dL. | Baseline, 2, 4, 8, and 12 weeks | 
| Glucose | Glucose will be measured and reported in mg/dL. | Baseline, 2, 4, 8, and 12 weeks | 
| Insulin | Insulin will be measured and reported in µU/mL. | Baseline, 2, 4, 8, and 12 weeks | 
| Leptin | Leptin will be measured and reported in ng/mL. | Baseline, 2, 4, 8, and 12 weeks | 
| ALT | Leptin will be measured and reported in IU/L. | Baseline, 2, 4, 8, and 12 weeks | 
| AST | Leptin will be measured and reported in IU/L. | Baseline, 2, 4, 8, and 12 weeks | 
| LDH | LDH will be measured and reported in IU/L. | Baseline, 2, 4, 8, and 12 weeks | 
| CRP | CRP will be measured and reported in mg/L. | Baseline, 2, 4, 8, and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional Chest Pain, Non-Cardiac Chest Pain, Esophageal Hypersensitivity