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Beta-endorphins, which are naturally occurring narcotic substances, have been shown to alter the perception of breathlessness. Oral ketoconazole, an antifungal antibiotic, increases blood levels of beta-endorphins. The study hypothesis is that oral ketoconazole will reduce ratings of breathlessness induced by resistive breathing loads.
Beta-endorphins are naturally occurring narcotic substances (like morphine) that are released by the brain under stressful conditions, such as exercise and when breathing through a resistive load (a tube containing fine wire mesh). In one study of 8 patients with coronary artery disease, ketoconazole, an oral medication used to treat fungal infections, was administered (1,200 mg at 12 midnight and 600 mg at 6 am) and increased blood levels of beta-endorphins five fold. In a recent study performed at Dartmouth-Hitchcock Medical Center, we found that ketoconazole increased blood levels of beta-endorphins in all eight patients with chronic obstructive pulmonary disease (COPD). Mean values increased by 2.5 times at four hours compared with baseline values (p = 0.0078). Based on this significant response, we propose to study the effect of ketoconazole on patients' perception of breathlessness induced by resistive breathing loads in a randomized clinical trial. The hypothesis of the study is that ketoconazole will reduce ratings of breathlessness as mediated by the increased levels of beta-endorphins.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| ketoconazole | Experimental | 600 mg ketoconazole |
|
| inert powder | Placebo Comparator | inert powder in capsule |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| ketoconazole | Drug | 600 mg capsule oral once |
|
|
| Measure | Description | Time Frame |
|---|---|---|
| Unpleasantness of Breathlessness | The average of all ratings for the unpleasantness of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for unpleasantness through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of unpleasantness was obtained during RLB on a 100 mm Visual Analog Scale anchored at the bottom by "No Unpleasantness" and at the top by "Greatest Unpleasantness". | At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) |
| Intensity of Breathlessness | The average of all ratings for the intensity of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for intensity through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of breathlessness was obtained at 1 minute intervals during RLB on a 100 mm Visual Analog Scale anchored at the bottom by "No Intensity" and at the top by "Greatest Intensity". | At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) |
| Measure | Description | Time Frame |
|---|---|---|
| Change in Level of B-endorphin Immunoreactivity | Change between pre-treatment and post treatment serum levels of beta-endorphin immunoreactivity measured in pmol/L | At the end of resistance load breathing (4.5 hours after receiving the test article) |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Donald A Mahler, MD | Dartmouth-Hitchcock Medical Center | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Dartmouth-Hitchcock Medical Center | Lebanon | New Hampshire | 03756-0001 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21513438 | Background | Gifford AH, Mahler DA, Waterman LA, Ward J, Kraemer WJ, Kupchak BR, Baird JC. Neuromodulatory effect of endogenous opioids on the intensity and unpleasantness of breathlessness during resistive load breathing in COPD. COPD. 2011 Jun;8(3):160-6. doi: 10.3109/15412555.2011.560132. Epub 2011 Apr 22. | |
| 23715032 | Derived |
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23 subjects recruited; 1 excluded (did not meet inclusion/exclusion criteria); 2 withdrawn prior to randomization (1 could not tolerate breathing through the initial inspiratory resistance (15 cm H 2 O/L/s); 1 gave ratings of breathlessness of < 50 mm on the VAS for the highest resistance (50 cm H2O/L/s))
June 2011 - January 2012; medical center
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| ID | Title | Description |
|---|---|---|
| FG000 | First Ketoconazole, Then Inert Powder | Ketoconzaole (600 mg taken orally) in first intervention period and inert powder (in capsule taken orally) in second intervention period. |
| FG001 | First Inert Powder, Then Ketoconazole | Inert powder (in capsule taken orally) in first intervention period and Ketoconzaole (600 mg taken orally) in second intervention period. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| First Intervention (Day 2-3) |
| |||||||||||||
| Second Intervention (Day 4-6) |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Entire Study Population | Includes groups randomized to receive Ketoconazole first and inert powder first. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Unpleasantness of Breathlessness | The average of all ratings for the unpleasantness of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for unpleasantness through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of unpleasantness was obtained during RLB on a 100 mm Visual Analog Scale anchored at the bottom by "No Unpleasantness" and at the top by "Greatest Unpleasantness". | Posted | Mean | Standard Deviation | units on a scale | At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) |
|
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Ketoconazole | Ketoconazole(600 mg taken orally) |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Donald A. Mahler, M.D. | Dartmouth-Hitchcock | 603 650-5533 | Donald.a.mahler@hitchcock.org |
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| ID | Term |
|---|---|
| D029424 | Pulmonary Disease, Chronic Obstructive |
| D004417 | Dyspnea |
| ID | Term |
|---|---|
| D008173 | Lung Diseases, Obstructive |
| D008171 | Lung Diseases |
| D012140 | Respiratory Tract Diseases |
| D002908 | Chronic Disease |
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| ID | Term |
|---|---|
| D007654 | Ketoconazole |
| D000935 | Antifungal Agents |
| ID | Term |
|---|---|
| D010879 | Piperazines |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| D000890 | Anti-Infective Agents |
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| inert powder | Drug | oral once |
|
|
| Mahler DA, Gifford AH, Waterman LA, Ward J, Kraemer WJ, Kupchak BR, Harver A. Effect of increased blood levels of beta-endorphin on perception of breathlessness. Chest. 2013 May;143(5):1378-1385. doi: 10.1378/chest.12-1541. |
| NOT COMPLETED |
|
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| OG001 | Inert Powder | Inert powder (in capsule taken orally) |
|
|
| Primary | Intensity of Breathlessness | The average of all ratings for the intensity of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for intensity through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of breathlessness was obtained at 1 minute intervals during RLB on a 100 mm Visual Analog Scale anchored at the bottom by "No Intensity" and at the top by "Greatest Intensity". | Posted | Mean | Standard Deviation | units on a scale | At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) |
|
|
|
| Secondary | Change in Level of B-endorphin Immunoreactivity | Change between pre-treatment and post treatment serum levels of beta-endorphin immunoreactivity measured in pmol/L | Posted | Mean | Standard Deviation | pmol/L | At the end of resistance load breathing (4.5 hours after receiving the test article) |
|
|
|
| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Inert Powder | Inert powder (in capsule taken orally) | 0 | 10 | 0 | 10 |
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| D020969 |
| Disease Attributes |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D012120 | Respiration Disorders |
| D012818 | Signs and Symptoms, Respiratory |
| D012816 | Signs and Symptoms |
| D045506 | Therapeutic Uses |
| D020228 | Pharmacologic Actions |
| D020164 | Chemical Actions and Uses |