Pain Biomarker Study

Study Overview
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Brief Summary
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This study investigates molecular and physical biomarkers of headaches in order to better understand mechanisms of these diseases. There are 3 main parts: Use of capsaicin (active ingredient in hot chili peppers) to trigger release of calcitonin gene related peptide - the hypothesis is that this will be different in headache subjects compared to controls (and if so might be used to predict how these patients will respond to certain medications that modulate calcitonin gene-related peptide). Subjects will be given capsaicin as a cream applied to the forehead or the inner nostril, or a hot sauce that is ingested. Use of capsaicin to trigger eye watering - the hypothesis is that oxygen gas will slow down the amount of eye watering. Cluster headache patients respond very powerfully to oxygen gas but to very little else. The mechanism for oxygen is unknown but in rodents there is data that it works on the parasympathetic / lacrimal gland system. This study translates rodent data into humans in a non-invasive way to confirm the mechanism of this very effective treatment. Use of ice water to trigger headaches - brain freeze causes a very short-lived but intense headache that may cause similar biomarker release as other headache disorders. This may be a useful human model for other headache disorders.

Official Title
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The Pain Biomarker Study: Changes in Circulating Pain Signalling Molecules With Activation of Pain Receptors

Conditions
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Migraine, Cluster Headache, Trigeminal Autonomic Cephalgia, Hemicrania Continua, Paroxysmal Hemicrania, SUNCT, Short-Lasting Unilateral Neuralgiform Headache With Conjunctival Injection and Tearing

Intervention / Treatment
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* Drug: Oral capsaicin
* Drug: Topical capsaicin
* Drug: Intranasal capsaicin
* Other: Cold Water Irrigation
* Other: Medical Air
* Drug: Low Flow Oxygen
* Drug: High Flow Oxygen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of one of the following: a. Diagnosis of a primary headache disorder according to the International Headache Classification, including migraine with aura, migraine without aura, chronic migraine, tension headache, cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and hemicrania continua; b. Diagnosed by a pain medicine physician with lumbar radiculopathy (possibly including neuropathic features, nerve impingement on MRI, or electromyography (EMG) report suggestive of lumbar radiculopathy); or c. Healthy control subject with no history of debilitating headaches or debilitating back pain / radiculopathy pain, and no headaches or back pain within the previous 3 months. Able to provide HIPAA authorization to share prior medical records/imaging Age 18 and older Exclusion Criteria: The following items exclude the subject from all portions of the study: a. Known history of cardiovascular or neurovascular diseases. These diseases may include carotid stenosis of >50%, vertebral stenosis, peripheral vascular disease, angina or myocardial infarction, stroke, or vascular malformations; b. History of brain tumors or epilepsy; c. Active pregnancy or lactation; d. Daily cigarette, tobacco or nicotine use; e. Life expectancy less than 1 year, co-existing disease or other characteristic that precludes appropriate diagnosis of headache or spine pain; f. Active drug / alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements; or g. Inability or unwillingness of subject to give informed consent (e.g., ward of the state) The following items exclude the subject only from the capsaicin portion of the study: a. Known allergy to capsaicin or hot peppers The following items exclude the subject only from the oxygen portion of the study: a. Pulmonary or other non-headache diseases that require the use of supplemental oxygen The following items exclude the subject only from the cold water irrigation (ice water) portion of the study: a. Trauma, fractures, or congenital abnormalities of the soft palate

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Oral capsaicin<br> | Drug: Oral capsaicin<br>* Subjects will drink a solution with capsaicin<br>|
| Sham Comparator: Oral capsaicin and Medical Air<br> | Drug: Oral capsaicin<br>* Subjects will drink a solution with capsaicin<br>Other: Medical Air<br>* Subjects will be exposed to medical air<br>|
| Experimental: Oral Capsaicin and Low Flow Oxygen<br> | Drug: Oral capsaicin<br>* Subjects will drink a solution with capsaicin<br>Drug: Low Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 1-9 L/min<br>|
| Experimental: Oral capsaicin and High Flow Oxygen<br> | Drug: Oral capsaicin<br>* Subjects will drink a solution with capsaicin<br>Drug: High Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 10-25 L/min<br>|
| Experimental: Topical capsaicin<br> | Drug: Topical capsaicin<br>* Capsaicin cream will be applied to the skin of the forehead, cheek, or leg<br>|
| Sham Comparator: Topical capsaicin and Medical Air<br> | Drug: Topical capsaicin<br>* Capsaicin cream will be applied to the skin of the forehead, cheek, or leg<br>Other: Medical Air<br>* Subjects will be exposed to medical air<br>|
| Experimental: Topical capsaicin and Low Flow Oxygen<br> | Drug: Topical capsaicin<br>* Capsaicin cream will be applied to the skin of the forehead, cheek, or leg<br>Drug: Low Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 1-9 L/min<br>|
| Experimental: Topical capsaicin and High Flow Oxygen<br> | Drug: Topical capsaicin<br>* Capsaicin cream will be applied to the skin of the forehead, cheek, or leg<br>Drug: High Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 10-25 L/min<br>|
| Experimental: Intranasal capsaicin<br> | Drug: Intranasal capsaicin<br>* Capsaicin cream will be applied to the nostril<br>|
| Sham Comparator: Intranasal capsaicin and Medical Air<br> | Drug: Intranasal capsaicin<br>* Capsaicin cream will be applied to the nostril<br>Other: Medical Air<br>* Subjects will be exposed to medical air<br>|
| Experimental: Intranasal capsaicin and Low Flow Oxygen<br> | Drug: Intranasal capsaicin<br>* Capsaicin cream will be applied to the nostril<br>Drug: Low Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 1-9 L/min<br>|
| Experimental: Intranasal capsaicin and High Flow Oxygen<br> | Drug: Intranasal capsaicin<br>* Capsaicin cream will be applied to the nostril<br>Drug: High Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 10-25 L/min<br>|
| Experimental: Cold water irrigation<br> | Other: Cold Water Irrigation<br>* Subjects will be asked to drink up to 2000 ml of cold water or ice water (temperature 0-10 degrees Celsius) as fast as possible, either continuously or intermittently (i.e. 200-800 ml at a time)<br>|
| Sham Comparator: Cold water irrigation and Medical Air<br> | Other: Cold Water Irrigation<br>* Subjects will be asked to drink up to 2000 ml of cold water or ice water (temperature 0-10 degrees Celsius) as fast as possible, either continuously or intermittently (i.e. 200-800 ml at a time)<br>Other: Medical Air<br>* Subjects will be exposed to medical air<br>|
| Experimental: Cold water irrigation and Low Flow Oxygen<br> | Other: Cold Water Irrigation<br>* Subjects will be asked to drink up to 2000 ml of cold water or ice water (temperature 0-10 degrees Celsius) as fast as possible, either continuously or intermittently (i.e. 200-800 ml at a time)<br>Drug: Low Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 1-9 L/min<br>|
| Experimental: Cold water irrigation and High Flow Oxygen<br> | Other: Cold Water Irrigation<br>* Subjects will be asked to drink up to 2000 ml of cold water or ice water (temperature 0-10 degrees Celsius) as fast as possible, either continuously or intermittently (i.e. 200-800 ml at a time)<br>Drug: High Flow Oxygen<br>* Subjects will be exposed to oxygen gas between 10-25 L/min<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activation of trigeminoautonomic reflex as assessed by change in Calcitonin gene-related peptide (CGRP) levels from before stimulation to after stimulation. |  | 10 minutes before pain stimulation and 10 minutes, 20 minutes, 30 minutes, 60 minutes, and 90 minutes after pain stimulation | 
| Activation of trigeminoautonomic reflex as assessed by tear fluid production | The amount of tear fluid after each intervention will be measured via Schirmer strips | 90 minutes after pain stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Activation of trigeminoautonomic reflex as assessed by change in pituitary adenylate cyclase activating polypeptide-38 (PACAP-38) levels levels from before stimulation to after stimulation. |  | 10 minutes before pain stimulation and 10 minutes, 20 minutes, 30 minutes, 60 minutes, and 90 minutes after pain stimulation | 
| Activation of trigeminoautonomic reflex as assessed by saliva production |  | 90 minutes after pain stimulation | 
| Activation of trigeminoautonomic reflex as assessed by nasal fluid production |  | 90 minutes after pain stimulation | 
| Activation of trigeminoautonomic reflex as assessed by tactile threshold measurement with von Frey Filaments |  | 90 minutes after pain stimulation | 
| Activation of trigeminoautonomic reflex as assessed by dermal blood flow |  | 90 minutes after pain stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain Freeze, Capsaicin