Substance-Related Disorders
Conditions
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.
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.
Interventions
DRUGOndansetron
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.
Sponsors
Stanford University
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
MALE
Age
18 Years to 35 Years
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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. | 10 |
| Total | 10 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Study Session 1 | Could not tolerate withdrawal in scanner | 3 | 0 | 0 |
| Study Session 1 | Lost to Follow-up | 2 | 0 | 0 |
Baseline characteristics
| Characteristic | All Study Participants |
|---|---|
| Age, Continuous | 27.1 years STANDARD_DEVIATION 4.3 |
| Height | 177.9 centimeters STANDARD_DEVIATION 4.8 |
| Region of Enrollment United States | 10 participants |
| Sex: Female, Male Female | 0 Participants |
| Sex: Female, Male Male | 10 Participants |
| Weight | 74.33 kilograms STANDARD_DEVIATION 4.4 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
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.
Time frame: 36 minutes
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| All Ondansetron | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | Left inferior frontal gyrus, orbital (OOWS) | 0.519 correlation coefficient |
| All Ondansetron | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | Right inferior frontal gyrus, orbital (OOWS) | 0.562 correlation coefficient |
| All Ondansetron | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | Right superior frontal gyrus, medial (SOWS) | 0.478 correlation coefficient |
| All Ondansetron | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | Right inferior frontal gyrus, orbital (SOWS) | 0.486 correlation coefficient |
| All Ondansetron | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | Left superior temporal gyrus (OOWS) | -0.612 correlation coefficient |
| All Ondansetron | Brain Regions With Increases or Decreases in Amplitude of Low Frequency Fluctuations (ALFF) Associated With Ondansetron Administration | Left caudate head (SOWS) | 0.475 correlation coefficient |
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.
Time frame: 15 Minutes Following Ondansetron or Placebo Administration
Population: Participants completing the protocol were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Ondansetron | Objective Opioid Withdrawal Scale Score 15 Minutes Following Ondansetron or Placebo Administration | 2.7 units on a scale | Standard Deviation 1.1 |
| Placebo | Objective Opioid Withdrawal Scale Score 15 Minutes Following Ondansetron or Placebo Administration | 2.2 units on a scale | Standard Deviation 1.1 |
Comparison: Results were considered significant at p\<0.05.p-value: 0.322ANOVA
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.
Time frame: 5 Minutes Following Ondansetron or Placebo Administration
Population: Participants completing the protocol were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Ondansetron | Objective Opioid Withdrawal Scale Score 5 Minutes Following Ondansetron or Placebo Administration | 1 units on a scale | Standard Deviation 0.5 |
| Placebo | Objective Opioid Withdrawal Scale Score 5 Minutes Following Ondansetron or Placebo Administration | 2 units on a scale | Standard Deviation 1.3 |
Comparison: Results were considered significant at p\<0.05.p-value: 0.042ANOVA
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.
Time frame: 20 minutes following Ondansetron or Placebo administration
Population: Participants completing the protocol were included in the analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| All Ondansetron | Subjective Opioid Withdrawal Scale (SOWS) Score 20 Minutes Following Ondansetron or Placebo Administration | 5.7 units on a scale | Standard Deviation 4.5 |
| Placebo | Subjective Opioid Withdrawal Scale (SOWS) Score 20 Minutes Following Ondansetron or Placebo Administration | 8.1 units on a scale | Standard Deviation 7.2 |
Comparison: Results were considered significant at p\<0.05.p-value: 0.261ANOVA