Effects of Garlic Supplements on Opioids in Healthy Volunteers

• Sponsor: Fred Hutchinson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00499460
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 21
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Healthy, No Evidence of Disease	Dietary Supplement: garlic powder tablets; Drug: oxycodone	Phase 4

Detailed Description

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Participant)
• Primary Purpose: Basic Science
• Official Title: Modulation of Opioid Effects by Garlic Supplements
• Study Start Date: Nov 1, 2006
• Actual Primary Completion Date: Aug 1, 2008
• Actual Study Completion Date: Aug 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Other: Arm I 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; Each Garlicin tablet has a claimed allicin content of 3,200 microgram per tablet; Other Names: Nature's Way Garlicin ; Drug: oxycodone; Single administration of three 5-mg oxycodone tablets or a 15-mg dose; Other Names: oxycodone hydrochoride, Roxicodone
Other: Arm II 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; Each Garlicin tablet has a claimed allicin content of 3,200 microgram per tablet; Other Names: Nature's Way Garlicin ; Drug: oxycodone; Single administration of three 5-mg oxycodone tablets or a 15-mg dose; Other Names: oxycodone hydrochoride, Roxicodone

Outcome Measures

Primary Outcome Measures

1. Oxycodone Oral Clearance [Serial blood sampling over 24 hours after a 15-mg oral dose of oxycodone]

   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.

Secondary Outcome Measures

1. Cold Pressor Tolerance AUC [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]

   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.

2. Somatic Side Effects Total Score [SSE scores at 150 min after a single 15-mg oral dose of oxycodone]

   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.

3. Cognitive-Affective Side Effects Total Score [CASE scores at 150 min after a single 15-mg oral dose of oxycodone]

   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.

4. Oral Midazolam Test [Serial blood sampling over 6 hours after a 5-mg oral test dose of midazolam]

   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.

5. Oral Digoxin Test [Serial blood sampling over 4 hours after a 0.5-mg oral test dose of digoxin]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Fred Hutchinson Cancer Research Center	Seattle	Washington	United States	98109-1024

Sponsors and Collaborators

• Fred Hutchinson Cancer Center
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Danny D Shen, PhD, Fred Hutchinson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Danny Shen, Principal Investigator, Fred Hutchinson Cancer Center
• ClinicalTrials.gov Identifier: NCT00499460
• Other Study ID Numbers: 2040.00; IR-6130; CDR0000551927; R21CA118334
• First Posted: Jul 11, 2007
• Last Update Posted: Apr 7, 2017
• Last Verified: Apr 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Danny Shen, Principal Investigator, Fred Hutchinson Cancer Center: Healthy, No Evidence of Disease
• Additional relevant MeSH terms: Oxycodone

Study Results

Participant Flow

Recruitment Details	Recruitment period was between November 2006 and August 2008. Healthy subjects were recruited from the University of Washington and Fred Hutchinson Cancer Research Center campuses through public notices.

Arm/Group Title	Garlic First, Then Placebo	Placebo First, Then Garlic
Arm/Group Description	Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral garlic powder (Nature's Way Garlicin tablet) twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral placebo tablet twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29.	Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral placebo tablet twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral garlic powder (Nature's Way Garlicin tablet) twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29.
Period Title: Intervention 1 (30 Days)
STARTED	8	7
COMPLETED	6	7
NOT COMPLETED	2	0
Period Title: Intervention 1 (30 Days)
STARTED	6	7
COMPLETED	6	6
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	Garlic First, Then Placebo	Placebo First, Then Garlic	Total
Arm/Group Description	Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral garlic powder (Nature's Way Garlicin tablet) twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral placebo tablet twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29.	Two 30-day treatment periods separated by a washout of at least 4 weeks. In Period 1, participants receive oral placebo tablet twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29. In Period 2, participants receive oral garlic powder (Nature's Way Garlicin tablet) twice daily on days 1-30, and undergo testings with oxycodone on day 28 and a combination of oral midazolam and digoxin on day 29.	Total of all reporting groups
Overall Participants	6	6	12
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.3 (5.2)	30.5 (6.0)	29.9 (5.8)
Sex: Female, Male (Count of Participants)
Female	3 50%	3 50%	6 50%
Male	3 50%	3 50%	6 50%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	1 16.7%	0 0%	1 8.3%
Not Hispanic or Latino	5 83.3%	6 100%	11 91.7%
Unknown or Not Reported	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	1 16.7%	1 8.3%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	0 0%	0 0%
White	6 100%	5 83.3%	11 91.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	6 100%	6 100%	12 100%

Outcome Measures

1. Primary Outcome

Title	Oxycodone Oral Clearance
Description	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.
Time Frame	Serial blood sampling over 24 hours after a 15-mg oral dose of oxycodone

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Garlic	Placebo
Arm/Group Description	Mean and standard deviation of oxycodone oral clearance following garlic powder treatment were calculated by pooling data from the active treatment period in each assigned arm	Mean and standard deviation of oxycodone oral clearance following placebo treatment were calculated by pooling data from the placebo treatment period in each assigned arm
Measure Participants	12	12
Mean (Standard Deviation) [L/min]	1.82 (0.40)	2.04 (0.51)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Garlic, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The primary hypothesis being tested is that garlic powder treatment increases metabolic clearance of oxycodone through enzyme induction and results in lower exposure to oxycodone.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance probability for the treatment variable in the Generalized Linear Model
	Method	Generalized Estimating Equations
	Comments	Response variable is oxycodone oral clearance. Explanatory variables include treatment, period and gender, along with their interaction terms.

2. Secondary Outcome

Title	Cold Pressor Tolerance AUC
Description	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.
Time Frame	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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Garlic	Placebo
Arm/Group Description	Mean and standard deviation of Cold Pressor Test Tolerance AUC following garlic powder treatment were calculated by pooling data from the active treatment period in each assigned arm	Mean and standard deviation of Cold Pressor Test Tolerance AUC following placebo treatment were calculated by pooling data from the placebo treatment period in each assigned arm
Measure Participants	12	12
Mean (Standard Deviation) [log (sec*min)]	3.513 (0.904)	3.715 (0.604)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Garlic, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The secondary hypothesis being tested is that powder garlic treatment lowers Cold Pressor Test tolerance (i.e., diminished analgesic response) after oxycodone administration due to a more rapid metabolic clearance and lower exposure to oxycodone.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance probability for the treatment variable in the Generalized Linear Model
	Method	Generalized Estimating Equations
	Comments	Response variable is log Tolerance AUC. Explanatory variables include treatment, period and gender, along with their interaction terms.

3. Secondary Outcome

Title	Somatic Side Effects Total Score
Description	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.
Time Frame	SSE scores at 150 min after a single 15-mg oral dose of oxycodone

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Garlic	Placebo
Arm/Group Description	Mean and standard deviation of SSE Total Score following garlic powder treatment were calculated by pooling data from the active treatment period in each assigned arm	Mean and standard deviation of SSE Total Score following placebo treatment were calculated by pooling data from the placebo treatment period in each assigned arm
Measure Participants	12	12
Mean (Standard Deviation) [units on a scale]	0.560 (0.140)	0.711 (0.184)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Garlic, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The secondary hypothesis being tested is that garlic powder treatment lowers opioid side effects after oxycodone administration due to a more rapid metabolic clearance and lower exposure to oxycodone.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance probability for the treatment variable in the Generalized Linear Model
	Method	Generalized Estimating Equations
	Comments	Response variable is total SSE rating score. Explanatory variables include treatment, period, time and gender, along with their interaction terms.

4. Secondary Outcome

Title	Cognitive-Affective Side Effects Total Score
Description	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.
Time Frame	CASE scores at 150 min after a single 15-mg oral dose of oxycodone

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Garlic	Placebo
Arm/Group Description	Mean and standard deviation of CASE Total Score following garlic powder treatment were calculated by pooling data from the active treatment period in each assigned arm	Mean and standard deviation of CASE Total Score following placebo treatment were calculated by pooling data from the placebo treatment period in each assigned arm
Measure Participants	12	12
Mean (Standard Deviation) [units on a scale]	1.884 (0.118)	1.714 (0.147)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Garlic, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The secondary hypothesis being tested is that garlic powder treatment lowers opioid side effects after oxycodone administration due to a more rapid metabolic clearance and lower exposure to oxycodone.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments	Significance probability for the treatment variable in the Generalized Linear Model
	Method	Generalized Estimating Equations
	Comments	Response variable is total CASE rating score. Explanatory variables include treatment, period, time and gender, along with their interaction terms.

5. Secondary Outcome

Title	Oral Midazolam Test
Description	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.
Time Frame	Serial blood sampling over 6 hours after a 5-mg oral test dose of midazolam

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Garlic	Placebo
Arm/Group Description	Mean and standard deviation of oral midazolam AUC following garlic powder treatment were calculated by pooling data from the active treatment period in each assigned arm	Mean and standard deviation of oral midazolam AUC following placebo treatment were calculated by pooling data from the placebo treatment period in each assigned arm
Measure Participants	12	12
Mean (Standard Deviation) [(ng/mL)*min]	2491 (789)	2495 (825)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Garlic, Placebo
	Comments	The secondary hypothesis being tested is that garlic powder induces CYP3A-mediated metabolism resulting in a lower oral midazolam AUC.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 1 sided
	Comments	Garlic powder versus placebo

6. Secondary Outcome

Title	Oral Digoxin Test
Description	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.
Time Frame	Serial blood sampling over 4 hours after a 0.5-mg oral test dose of digoxin

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Garlic	Placebo
Arm/Group Description	Mean and standard deviation of oral digoxin AUC following garlic powder treatment were calculated by pooling data from the active treatment period in each assigned arm	Mean and standard deviation of oral digoxin AUC following placebo treatment were calculated by pooling data from the placebo treatment period in each assigned arm
Measure Participants	12	12
Mean (Standard Deviation) [(ng/mL)*min]	231 (50)	226 (58)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Garlic, Placebo
	Comments
	Type of Statistical Test	Superiority
	Comments	The secondary hypothesis being tested is that garlic powder treatment induces intestinal P-glycoprotein, reduces the bioavailability and hence AUC of orally administered digoxin.
Statistical Test of Hypothesis	p-Value	>0.05
	Comments
	Method	t-test, 1 sided
	Comments	Garlic powder versus placebo

Adverse Events

Time Frame	Adverse event data were collected from all enrolled subjects over the 3-month duration of their study.
Adverse Event Reporting Description	Adverse event collection relied on subject self-reporting during the 30-day garlic or placebo treatment. Subjects were monitored by pulse oximetry and observed for opioid side effects by trained nurses on the oxycodone test day. Blood pressure and heart rate were monitored on the oral digoxin and midazolam test day.
Arm/Group Title	Garlic		Placebo
Arm/Group Description	Data for all subjects during their active garlic treatment period in both arms were pooled.		Data for all subjects during their placebo treatment period in both arms were pooled.
All Cause Mortality
	Garlic		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Serious Adverse Events
	Garlic		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)
Other (Not Including Serious) Adverse Events
	Garlic		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/15 (0%)		0/15 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.