Effects of Garlic Supplements on Opioids in Healthy Volunteers

Study Overview
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Brief Summary
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RATIONALE: Garlic supplements may alter the pharmacokinetics of oxycodone, thereby affecting its effectiveness as an opioid analgesic for the relief of moderate or severe pain. PURPOSE: This randomized phase 4 trial is studying how garlic supplements may change the pharmacokinetics of oxycodone and its analgesic and side effects in healthy volunteers.

Detailed Description
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OBJECTIVES: To determine whether CYP3A (Cytochrome P450 3A) and/or P-glycoprotein mediated interactions exist between garlic supplements and oxycodone (a commonly used oral opioid analgesic) in healthy volunteers. OUTLINE: This is a single-blind, randomized, crossover study. Participants are randomized to 1 of 2 arms. Each arm entails two 30-day treatment periods, with a washout of at least 4 weeks in between. Arm I: In Period 1, participants receive oral garlic powder twice daily on days 1-28 and oral oxycodone on day 28. In Period 2, participants receive oral placebo twice daily on days 1-28 and oral oxycodone on day 28. Arm II: In Period 1, participants receive oral placebo twice daily on days 1-28 and oral oxycodone on days 28. In Period 2, participants receive oral garlic powder twice daily on days 1-28 and oral oxycodone on day 28. In both periods of each arm, participants receive a combination of oral midazolam and oral digoxin for CYP3A and P-glycoprotein phenotyping on day 29. Blood samples are collected periodically and analyzed by liquid chromatography-mass spectrometry (LC-MS). Blood and urine samples are collected after receiving oxycodone for pharmacokinetic characterization. Plasma concentrations of oxycodone and its metabolites are measured by LC-MS. Response to experimentally induced pain by the Cold Pressor Test (CPT) is assessed at baseline and periodically after oxycodone treatment. Subjective ratings of opioid side effects are assessed by validated questionnaires for somatic side effects and cognitive function impairments.

Official Title
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Modulation of Opioid Effects by Garlic Supplements

Conditions
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Healthy, No Evidence of Disease

Intervention / Treatment
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* Dietary Supplement: garlic powder tablets
* Drug: oxycodone


Participation Criteria
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Eligibility Criteria
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INCLUSION CRITERIA: Healthy volunteer Body mass index 20-32 EXCLUSION CRITERIA: Not pregnant No history of cardiopulmonary, liver, renal, endocrine, neurologic, or psychiatric disease No anemia No known adverse reactions to opioids, benzodiazepines, cardiac glycosides, or garlic supplements No known allergy or hypersensitivity to sulfur-containing food or drugs No significant gastrointestinal intolerance to lactose in dairy products No recent history of alcohol or substance abuse No history of or concurrent heavy daily consumption of allium vegetables (i.e., garlic, shallots, leeks, and chives) No handicaps due to visual and hearing impairments No resting heart rate < 50 beats per minutes No abnormal cardiac rhythm by EKG No unusually sensitive response or resistance to pain stimulation (Cold Pressor Test) Must be right handed No color blindness No history of learning disabilities or dyslexia Must be literate and proficient in English Must be a nonsmoker No concurrent medication except oral contraceptives No concurrent grapefruit or grapefruit juice No other concurrent over-the-counter herbal products or herbal tea

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 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: Randomized
Intervention Model: Crossover Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Arm I<br>Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral garlic powder tablet twice daily on days 1-30, oral oxycodone on day 28, and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral placebo twice daily on days 1-30, oral oxycodone on day 28, and a combination of oral midazolam and digoxin on day 29. | Dietary Supplement: garlic powder tablets<br>* Each Garlicin tablet has a claimed allicin content of 3,200 microgram per tablet<br>* Other names: Nature's Way Garlicin;Drug: oxycodone<br>* Single administration of three 5-mg oxycodone tablets or a 15-mg dose<br>* Other names: oxycodone hydrochoride, Roxicodone;|
| Other: Arm II<br>Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral placebo twice daily on days 1-30, oral oxycodone on day 28, and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral garlic powder tablet twice daily on days 1-30, oral oxycodone on day 28, and a combination of oral midazolam and digoxin on day 29. | Dietary Supplement: garlic powder tablets<br>* Each Garlicin tablet has a claimed allicin content of 3,200 microgram per tablet<br>* Other names: Nature's Way Garlicin;Drug: oxycodone<br>* Single administration of three 5-mg oxycodone tablets or a 15-mg dose<br>* Other names: oxycodone hydrochoride, Roxicodone;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxycodone Oral Clearance | Oxycodone oral clearance is computed by Dose/AUC, where AUC is the area under the plasma oxycodone concentration-time curve from time zero to infinity. Oral clearance is a measure of the rate at which oxycodone is cleared from the body via metabolism. | Serial blood sampling over 24 hours after a 15-mg oral dose of oxycodone | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cold Pressor Tolerance AUC | Cold Pressor Test measures response to experimentally induced pain, in this case by immersion of a subject's hand in icy-cold water. Tolerance is the duration of time a subject is able to keep his/her hand immersed in the cold water. A prolongation in tolerance time indicates analgesic response to oxycodone treatment. Cold Pressor Tolerance AUC is the area under the tolerance versus time curve over a 300-min period after a test dose of oxycodone. Because of non-normality in sample distribution, log transformed AUC estimates were analyzed by Generalized Linear Model. | Repeated testing for tolerance to Cold Pressor Test just before and at 45, 90, 150 and 300 min after a single 15-mg oral dose of oxycodone | 
| Somatic Side Effects Total Score | Subjects rated the bodily side effects they experienced at 90, 150 and 300 min after oxycodone administration on a 35-item Somatic Side Effects (SSE) questionnaire. Total score (i.e., average of the scores for all 35 items) ranges on a numerical scale from 0 (no somatic side effects) to a maximum of 4 (extreme somatic aide effects). Only the peak SSE scores at 150 min are reported herein. | SSE scores at 150 min after a single 15-mg oral dose of oxycodone | 
| Cognitive-Affective Side Effects Total Score | Subjects rated the mental side effects they experienced at 90, 150 and 300 min after oxycodone administration on a 36-item Cognitive-Affective Side Effects (CASE) questionnaire. Total score (i.e., average of the scores for all 36 items) ranges on a numerical scale from 0 (no somatic side effects) to a maximum of 4 (extreme somatic aide effects). Only the peak CASE scores at 150 min are reported herein. | CASE scores at 150 min after a single 15-mg oral dose of oxycodone | 
| Oral Midazolam Test | Midazolam when given orally is a probe substrate for the in vivo intestinal and hepatic activity of CYP3A (Cytochrome P450 3A) enzymes. The phenotype index in this case is the area under the plasma midazolam concentration from time zero to 360 min after a 5-mg oral test dose. A decrease in oral midazolam AUC indicates enhanced activity of CYP3A enzymes, possibly as a result of enzyme induction. | Serial blood sampling over 6 hours after a 5-mg oral test dose of midazolam | 
| Oral Digoxin Test | Digoxin when given orally is a probe substrate for the efflux activity of P-glycoprotein in the small intestine. The phenotype index in this case is the area under the plasma digoxin concentration from time zero to 240 min after a 0.5-mg oral test dose. A decrease in oral digoxin AUC indicates an enhanced activity of P-glycoprotein, possibly as a result of transporter upregulation. | Serial blood sampling over 4 hours after a 0.5-mg oral test dose of digoxin | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy, No Evidence of Disease