Functional Magnetic Resonance Imaging of Opioid Withdrawal in Healthy Human Volunteers

• Sponsor: Stanford University (Other)
• Overall Status: Completed
• CT.gov ID: NCT01006707
• Collaborator: (none)
• Enrollment: 15
• Location: 1
• Arms: 2
• Duration (Months): 32
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Opioid medications are commonly used for pain relief. When given over time, physical dependence can occur. This results in unpleasant side effects--such as agitation and nausea--if opioid medications are suddenly stopped. However, we do not know how withdrawal affects the brain. We know that a medication named Ondansetron can help ease or prevent symptoms associated with opioid withdrawal. Through imaging of the brain by fMRI, we hope to see how opioid withdrawal, with and without the administration of ondansetron, affects brain activity.

Condition or Disease	Intervention/Treatment	Phase
Substance-Related Disorders	Drug: Ondansetron	N/A

Detailed Description

During the study, each participant attended three separate lab-based acute opioid withdrawal sessions. The first session was undertaken in a mock MRI scanner and was designed to determine if participants could tolerate withdrawal in the scanning environment. Participants who were able to successfully and safely tolerate opioid withdrawal while in the scanner were approved to continue with the following study sessions. Participants were then pretreated intravenously (IV) with either 0.9% normal saline placebo or 8mg ondansetron. Later, participants in all sessions received IV naloxone (10mg/70kg) to precipitate opioid withdrawal. Participants were assigned to ondansetron or placebo pretreatment conditions in a randomized, double-blinded, and counter-balanced order. Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS) were assessed throughout the study to quantify withdrawal. Study timeline progressed as follows: T=-165, 8mg ondansetron or placebo infusion, T=-135, Morphine infusion (10mg/70kg), T=-41 preparation for MRI, T=-21, start MRI, T=-13, baseline OOWS/SOWS, T=-9, start of fMRI, T=0 Naloxone induced withdrawal, T=5, OOWS, T=15, OOWS, T=20, Retrospective OOWS.

Study Design

• Study Type: Interventional
• Actual Enrollment: 15 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Triple (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: fMRI Imaging of Opioid Withdrawal in Healthy Human Volunteers
• Study Start Date: Nov 1, 2010
• Actual Primary Completion Date: Jul 1, 2013
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Other: Ondansetron, then Placebo Some participants received ondansetron pretreatment during the second session, and then placebo during the third session.	Drug: Ondansetron; In this cross-over study, the blinded patient will receive saline placebo in one session and ondansetron in the other. The order is decided with a randomization table. If ondansetron is randomly chosen, an 8mg IV Bolus will be given at the start of the study for 30 minutes by the unblinded investigator.; Other Names: Zofran
Other: Placebo, then Ondansetron Some participants received placebo pretreatment during the second session, and then ondansetron pretreatment during the third session.	Drug: Ondansetron; In this cross-over study, the blinded patient will receive saline placebo in one session and ondansetron in the other. The order is decided with a randomization table. If ondansetron is randomly chosen, an 8mg IV Bolus will be given at the start of the study for 30 minutes by the unblinded investigator.; Other Names: Zofran

Outcome Measures

Primary Outcome Measures

1. Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration [36 minutes]

   Changes are reporting using Spearman's correlation coefficient, using within-subject factors of time (pre-naloxone, post-naloxone) and pre-treatment (placebo, ondansetron). Changes in Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS) with correlation coefficient >0.45 are reported. The OOWS consists of 13 observable physical symptoms assessed over a 5-minute observation period and scored as present (score of 1) or absent (score of 0). The total OOWS scores is determined by summing the scores of the 13 items. OOWS scores can range from 0 to 13; lower scores correspond to fewer symptoms. SOWS consists of 16 physical and emotional symptoms rated by the participant on a scale from 0 (not at all) to 4 (extremely), to indicate the extent to which the symptom describes how they are feeling at the time. The total SOWS score is determined by summing the scores of the 16 items. Scores range from 0 to 64; lower scores correspond to fewer symptoms.

Secondary Outcome Measures

1. Objective Opioid Withdrawal Scale Score 5 Minutes Following Ondansetron or Placebo Administration [5 Minutes Following Ondansetron or Placebo Administration]

   The OOWS consists of 13 observable physical symptoms that are assessed over a five-minute observation period and scored as present (score of 1) or absent (score of 0). The total OOWS scores is determined by summing the scores of the 13 items. OOWS scores can range from a low of 0 to a high of 13. A score of 0 would suggest that no objective signs of withdrawal were observed while a score of 13 would suggest that every observable sign of withdrawal was observed.

2. Objective Opioid Withdrawal Scale Score 15 Minutes Following Ondansetron or Placebo Administration [15 Minutes Following Ondansetron or Placebo Administration]

   The OOWS consists of 13 observable physical symptoms that are assessed over a five-minute observation period and scored as present (score of 1) or absent (score of 0). The total OOWS scores is determined by summing the scores of the 13 items. OOWS scores can range from a low of 0 to a high of 13. A score of 0 would suggest that no objective signs of withdrawal were observed while a score of 13 would suggest that every observable sign of withdrawal was observed.

3. Subjective Opioid Withdrawal Scale (SOWS) Score 20 Minutes Following Ondansetron or Placebo Administration [20 minutes following Ondansetron or Placebo administration]

   The SOWS consists of 16 physical and emotional symptoms that are rated by the participant on a scale from 0 (not at all) to 4 (extremely), to indicate the extent to which the symptom describes how they are feeling at the time. The total SOWS score is determined by summing the scores of the 16 items. Scores range from a low of 0 to a high of 64. A score of 0 would suggest that the individual is experiencing no symptoms of withdrawal while a score of 64 would suggest that the individual is experiencing all 16 symptoms of withdrawal to the fullest extent possible.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 35 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

Inclusion Criteria

• Patients will be healthy male volunteers, ages 18-35.

Exclusion Criteria

• Females were excluded due to menstrual cycle modulation of opioid response.

• We will exclude individuals with Raynaud's disease or a history of coronary artery disease.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Stanford University School of Medicine	Stanford	California	United States	94305

Sponsors and Collaborators

• Stanford University

Investigators

• Principal Investigator: Dr Larry Fu-nien Chu, Stanford University

Study Documents (Full-Text)

None provided.

More Information

Publications

• Compton P, Athanasos P, Elashoff D. Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain. 2003 Nov;4(9):511-9.
• Compton P, Miotto K, Elashoff D. Precipitated opioid withdrawal across acute physical dependence induction methods. Pharmacol Biochem Behav. 2004 Feb;77(2):263-8.
• Hui SC, Sevilla EL, Ogle CW. Prevention by the 5-HT3 receptor antagonist, ondansetron, of morphine-dependence and tolerance in the rat. Br J Pharmacol. 1996 Jun;118(4):1044-50.
• Krystal JH, Woods SW, Kosten TR, Rosen MI, Seibyl JP, van Dyck CC, Price LH, Zubal IG, Hoffer PB, Charney DS. Opiate dependence and withdrawal: preliminary assessment using single photon emission computerized tomography (SPECT). Am J Drug Alcohol Abuse. 1995 Feb;21(1):47-63.
• Lowe AS, Williams SC, Symms MR, Stolerman IP, Shoaib M. Functional magnetic resonance neuroimaging of drug dependence: naloxone-precipitated morphine withdrawal. Neuroimage. 2002 Oct;17(2):902-10.
• Pinelli A, Trivulzio S, Tomasoni L. Effects of ondansetron administration on opioid withdrawal syndrome observed in rats. Eur J Pharmacol. 1997 Dec 11;340(2-3):111-9.
• Stein EA, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, Hoffmann RG, Hawkins M, Rao SM, Bandettini PA, Bloom AS. Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry. 1998 Aug;155(8):1009-15.
• Williams TM, Daglish MR, Lingford-Hughes A, Taylor LG, Hammers A, Brooks DJ, Grasby P, Myles JS, Nutt DJ. Brain opioid receptor binding in early abstinence from opioid dependence: positron emission tomography study. Br J Psychiatry. 2007 Jul;191:63-9.

• Responsible Party: Larry Fu-nien Chu, Associate Professor of Anesthesia, Stanford University
• ClinicalTrials.gov Identifier: NCT01006707
• Other Study ID Numbers: SU-10212009-4200
• First Posted: Nov 3, 2009
• Last Update Posted: Nov 17, 2017
• Last Verified: Oct 1, 2017

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Substance-Related Disorders; Ondansetron

Study Results

Participant Flow

Arm/Group Title	Placebo Run-in	Ondansetron, Then Placebo	Placebo, Then Ondansetron
Arm/Group Description	Participants received pretreatment with placebo to match ondansetron in Study Session 1 prior to randomization to cross-over treatment arms in Study Sessions 2 and 3.	Participants received pretreatment with ondansetron (8mg IV Bolus) in Study Session 2 then placebo to match ondansetron in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.	Participants received pretreatment with placebo to match ondansetron in Study Session 2 then ondansetron (8mg IV Bolus) in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.
Period Title: Study Session 1
STARTED	15	0	0
COMPLETED	10	0	0
NOT COMPLETED	5	0	0
Period Title: Study Session 1
STARTED	0	4	6
COMPLETED	0	4	6
NOT COMPLETED	0	0	0
Period Title: Study Session 1
STARTED	0	4	6
COMPLETED	0	4	6
NOT COMPLETED	0	0	0

Baseline Characteristics

Arm/Group Title	All Study Participants
Arm/Group Description	All participants received placebo during Study Session 1 (placebo run-in), then were randomized to receive pretreatment with ondansetron (8mg IV Bolus) in Study Session 2 then placebo to match ondansetron in Study Session 3, or pretreatment with placebo to match ondansetron in Study Session 2 then ondansetron (8mg IV Bolus) in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.
Overall Participants	10
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	27.1 (4.3)
Sex: Female, Male (Count of Participants)
Female	0 0%
Male	10 100%
Region of Enrollment (participants) [Number]
United States	10 100%
Weight (kilograms) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kilograms]	74.33 (4.4)
Height (centimeters) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [centimeters]	177.9 (4.8)

Outcome Measures

1. Primary Outcome

Title	Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration
Description	Changes are reporting using Spearman's correlation coefficient, using within-subject factors of time (pre-naloxone, post-naloxone) and pre-treatment (placebo, ondansetron). Changes in Objective Opioid Withdrawal Scale (OOWS) and Subjective Opioid Withdrawal Scale (SOWS) with correlation coefficient >0.45 are reported. The OOWS consists of 13 observable physical symptoms assessed over a 5-minute observation period and scored as present (score of 1) or absent (score of 0). The total OOWS scores is determined by summing the scores of the 13 items. OOWS scores can range from 0 to 13; lower scores correspond to fewer symptoms. SOWS consists of 16 physical and emotional symptoms rated by the participant on a scale from 0 (not at all) to 4 (extremely), to indicate the extent to which the symptom describes how they are feeling at the time. The total SOWS score is determined by summing the scores of the 16 items. Scores range from 0 to 64; lower scores correspond to fewer symptoms.
Time Frame	36 minutes

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	All Ondansetron
Arm/Group Description	All participants received pretreatment with ondansetron (8mg IV Bolus) and with placebo to match ondansetron. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.
Measure Participants	10
Left inferior frontal gyrus, orbital (OOWS)	0.519
Right inferior frontal gyrus, orbital (OOWS)	0.562
Right superior frontal gyrus, medial (SOWS)	0.478
Right inferior frontal gyrus, orbital (SOWS)	0.486
Left superior temporal gyrus (OOWS)	-0.612
Left caudate head (SOWS)	0.475

2. Secondary Outcome

Title	Objective Opioid Withdrawal Scale Score 5 Minutes Following Ondansetron or Placebo Administration
Description	The OOWS consists of 13 observable physical symptoms that are assessed over a five-minute observation period and scored as present (score of 1) or absent (score of 0). The total OOWS scores is determined by summing the scores of the 13 items. OOWS scores can range from a low of 0 to a high of 13. A score of 0 would suggest that no objective signs of withdrawal were observed while a score of 13 would suggest that every observable sign of withdrawal was observed.
Time Frame	5 Minutes Following Ondansetron or Placebo Administration

Outcome Measure Data

Analysis Population Description

Participants completing the protocol were included in the analysis.

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	Participants received pretreatment with ondansetron (8mg IV Bolus) in Study Session 2 then placebo to match ondansetron in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.	Participants received pretreatment with placebo to match ondansetron in Study Session 2 then ondansetron (8mg IV Bolus) in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.
Measure Participants	10	10
Mean (Standard Deviation) [units on a scale]	1 (0.5)	2 (1.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Ondansetron, Placebo
	Comments	Results were considered significant at p<0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.042
	Comments
	Method	ANOVA
	Comments

3. Secondary Outcome

Title	Objective Opioid Withdrawal Scale Score 15 Minutes Following Ondansetron or Placebo Administration
Description	The OOWS consists of 13 observable physical symptoms that are assessed over a five-minute observation period and scored as present (score of 1) or absent (score of 0). The total OOWS scores is determined by summing the scores of the 13 items. OOWS scores can range from a low of 0 to a high of 13. A score of 0 would suggest that no objective signs of withdrawal were observed while a score of 13 would suggest that every observable sign of withdrawal was observed.
Time Frame	15 Minutes Following Ondansetron or Placebo Administration

Outcome Measure Data

Analysis Population Description

Participants completing the protocol were included in the analysis.

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	Participants received pretreatment with ondansetron (8mg IV Bolus) in Study Session 2 then placebo to match ondansetron in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.	Participants received pretreatment with placebo to match ondansetron in Study Session 2 then ondansetron (8mg IV Bolus) in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded
Measure Participants	10	10
Mean (Standard Deviation) [units on a scale]	2.7 (1.1)	2.2 (1.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Ondansetron, Placebo
	Comments	Results were considered significant at p<0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.322
	Comments
	Method	ANOVA
	Comments

4. Secondary Outcome

Title	Subjective Opioid Withdrawal Scale (SOWS) Score 20 Minutes Following Ondansetron or Placebo Administration
Description	The SOWS consists of 16 physical and emotional symptoms that are rated by the participant on a scale from 0 (not at all) to 4 (extremely), to indicate the extent to which the symptom describes how they are feeling at the time. The total SOWS score is determined by summing the scores of the 16 items. Scores range from a low of 0 to a high of 64. A score of 0 would suggest that the individual is experiencing no symptoms of withdrawal while a score of 64 would suggest that the individual is experiencing all 16 symptoms of withdrawal to the fullest extent possible.
Time Frame	20 minutes following Ondansetron or Placebo administration

Outcome Measure Data

Analysis Population Description

Participants completing the protocol were included in the analysis.

Arm/Group Title	Ondansetron	Placebo
Arm/Group Description	Participants received pretreatment with ondansetron (8mg IV Bolus) in Study Session 2 then placebo to match ondansetron in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.	Participants received pretreatment with placebo to match ondansetron in Study Session 2 then ondansetron (8mg IV Bolus) in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.
Measure Participants	10	10
Mean (Standard Deviation) [units on a scale]	5.7 (4.5)	8.1 (7.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	All Ondansetron, Placebo
	Comments	Results were considered significant at p<0.05.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.261
	Comments
	Method	ANOVA
	Comments

Adverse Events

Time Frame	Adverse events data was collected across all study sessions (total of 3 weeks).
Arm/Group Title	Ondansetron		Placebo
Arm/Group Description	Participants received placebo during Study Session 1 (placebo run-in), then received pretreatment with ondansetron (8mg IV Bolus) in Study Session 2 then placebo to match ondansetron in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.		Participants received placebo during Study Session 1 (placebo run-in), then received pretreatment with placebo to match ondansetron in Study Session 2 then ondansetron (8mg IV Bolus) in Study Session 3. Bolus was be given at the start of the study for 30 minutes by the unblinded investigator.
All Cause Mortality
	Ondansetron		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ondansetron		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Ondansetron		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

Opioid withdrawal model not necessarily generalizable to individuals with chronic pain and chronic opioid usage; short duration of scan; potential physiological noise in data; unable to obtain strong assessments of OOWS and SOWS during the scan.

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.