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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Ondansetron, then Placebo | Other | Some participants received ondansetron pretreatment during the second session, and then placebo during the third session. |
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| Placebo, then Ondansetron | Other | Some participants received placebo pretreatment during the second session, and then ondansetron pretreatment during the third session. |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Ondansetron | Drug | 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. |
| Measure | Description | Time Frame |
|---|---|---|
| Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | 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. | 36 minutes |
| Measure | Description | Time Frame |
|---|---|---|
| Objective Opioid Withdrawal Scale Score 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. |
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Inclusion Criteria
Exclusion Criteria
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| Name | Affiliation | Role |
|---|---|---|
| Dr Larry Fu-nien Chu | Stanford University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Stanford University School of Medicine | Stanford | California | 94305 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 14751453 | Background | Compton P, Miotto K, Elashoff D. Precipitated opioid withdrawal across acute physical dependence induction methods. Pharmacol Biochem Behav. 2004 Feb;77(2):263-8. doi: 10.1016/j.pbb.2003.10.017. | |
| 14636819 | Background | 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. doi: 10.1016/j.jpain.2003.08.003. |
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| ID | Title | Description |
|---|---|---|
| FG000 | Placebo Run-in | 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. |
| FG001 | Ondansetron, Then Placebo | 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. |
| FG002 | Placebo, Then Ondansetron | 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. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Study Session 1 |
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| Study Session 2 |
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| Study Session 3 |
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| ID | Title | Description |
|---|---|---|
| BG000 | All Study Participants | 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. |
| Units | Counts |
|---|---|
| Participants |
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| 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 | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | 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. | Posted | Number | correlation coefficient | 36 minutes |
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Adverse events data was collected across all study sessions (total of 3 weeks).
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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 | Ondansetron | 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. |
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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.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Larry Chu | Stanford University School of Medicine | (650) 723-6632 | lchu@stanford.edu |
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| ID | Term |
|---|---|
| D019966 | Substance-Related Disorders |
| ID | Term |
|---|---|
| D064419 | Chemically-Induced Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| D017294 | Ondansetron |
| ID | Term |
|---|---|
| D007093 | Imidazoles |
| D001393 | Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
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| 5 Minutes Following Ondansetron or Placebo Administration |
| Objective Opioid Withdrawal Scale Score 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. | 15 Minutes Following Ondansetron or Placebo Administration |
| Subjective Opioid Withdrawal Scale (SOWS) Score 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. | 20 minutes following Ondansetron or Placebo administration |
| 9699686 | Background | 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. doi: 10.1176/ajp.155.8.1009. |
| 7762544 | Background | 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. doi: 10.3109/00952999509095229. |
| 17602127 | Background | 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. doi: 10.1192/bjp.bp.106.031120. |
| 8799580 | Background | 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. doi: 10.1111/j.1476-5381.1996.tb15504.x. |
| 9537805 | Background | 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. doi: 10.1016/s0014-2999(97)01349-6. |
| 12377164 | Background | 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. |
| 26059463 | Result | Chu LF, Lin JC, Clemenson A, Encisco E, Sun J, Hoang D, Alva H, Erlendson M, Clark JD, Younger JW. Acute opioid withdrawal is associated with increased neural activity in reward-processing centers in healthy men: A functional magnetic resonance imaging study. Drug Alcohol Depend. 2015 Aug 1;153:314-22. doi: 10.1016/j.drugalcdep.2015.04.019. Epub 2015 May 27. |
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| years |
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| Sex: Female, Male | Count of Participants | Participants |
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| Region of Enrollment | Number | participants |
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| Weight | Mean | Standard Deviation | kilograms |
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| Height | Mean | Standard Deviation | centimeters |
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| OG000 | All Ondansetron | 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. |
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| Secondary | Objective Opioid Withdrawal Scale Score 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. | Participants completing the protocol were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | 5 Minutes Following Ondansetron or Placebo Administration |
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| Secondary | Objective Opioid Withdrawal Scale Score 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. | Participants completing the protocol were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | 15 Minutes Following Ondansetron or Placebo Administration |
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| Secondary | Subjective Opioid Withdrawal Scale (SOWS) Score 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. | Participants completing the protocol were included in the analysis. | Posted | Mean | Standard Deviation | units on a scale | 20 minutes following Ondansetron or Placebo administration |
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| 0 |
| 10 |
| 0 |
| 10 |
| EG001 | Placebo | 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. | 0 | 10 | 0 | 10 |
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| D002227 |
| Carbazoles |
| D007211 | Indoles |
| D006574 | Heterocyclic Compounds, 2-Ring |
| D000072471 | Heterocyclic Compounds, Fused-Ring |
| D006575 | Heterocyclic Compounds, 3-Ring |