Neuropathic Pain
Conditions
Brief summary
Prospective, randomized, double-blind, placebo controlled, cross-over proof of concept study. To determine the pharmacokinetics and tolerability of co-administration of 5-HT3R antagonist ondansetron with a P-glycoprotein inhibitor tariquidar, in patients with neuropathic pain.
Detailed description
The investigators hypothesize that co-administration of a 5-HT3 receptor antagonist ondansetron (single 16mg dose) with p-glycoprotein inhibitor tariquidar (single 4mg/kg dose) vs placebo in a cross-over prospective randomized study, will: 1. Be tolerable in patients with neuropathic pain. 2. Increase the cerebrospinal fluid (CSF) to plasma ratio of ondansetron after intravenous administration, compare to ondansetron alone 3. Result in a greater reduction in pain intensity than with ondansetron alone.
Interventions
DRUGOndansetron 16 mg with Tariquidar
In randomized order, each participant will receive two IV infusions of ondansetron, 3 weeks apart; one with placebo (D5W), and one with tariquidar (4mg/kg dose in D5W) administered IV over 60 minutes. Ondansetron will be diluted in 100mL 0.9% normal saline, and tariquidar will be diluted in 500mL D5W.
DRUGOndansetron 16 mg with Placebo
In randomized order, each participant will receive two IV infusions of ondansetron, 3 weeks apart; one with placebo (D5W), and one with tariquidar (4mg/kg dose in D5W) administered IV over 60 minutes. Ondansetron will be diluted in 100mL 0.9% normal saline, and tariquidar will be diluted in 500mL D5W.
Sponsors
Washington University School of Medicine
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Prospective, randomized, double blind, crossover study
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age 18-65; 2. Documented diagnosis of neuropathic pain due to damage or disease affecting the peripheral nervous system; 3. At least Probable neuropathic pain grading1; 4. Pain duration \>3 months; 5. Average pain intensity ≥4 on 0-10 numerical rating scale (NRS).
Exclusion criteria
1. Current pregnancy or lactation; 2. Moderate-severe kidney or liver dysfunction; 3. Active cardiac arrhythmias (non-sinus rhythm), Long QT syndrome, or QTc interval \>450msec; 4. Congestive heart failure 5. Abnormal troponin values at screening visit; 6. Current treatment with MAO inhibitors, mirtazapine, SSRI antidepressants, or SNRI medications duloxetine or venlafaxine; 7. Current treatment with tapentadol, tramadol, or fentanyl; 8. Current treatment with P-glycoprotein substrate drugs with narrow therapeutic window, e.g. digoxin; 9. Current treatment with tricyclic antidepressant medications (e.g. amitriptyline, desipramine, imipramine) at a dose \>25mg/day; 10. Ongoing use of any of the following medications with known effects on Pgp function: carbamazepine, phenytoin, phenobarbital, cyclosporine, clarithromycin, erythromycin, ritonavir, verapamil, rifampicin, St. John's wort; 11. Current treatment with QT-prolonging drugs, and drugs known to have a significant interaction with ondansetron or other P-glycoprotein substrates (see section 2.3.3.); 12. Current treatment with anticoagulant drugs;
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Concertation-time Profile of Ondansetron in Plasma, Measured by the Area Under the Concentration-time Curve (AUC) | Measurements over 240 minutes, extrapolated to infinity | AUCinf for Ondansetron concentration in plasma based on venous blood sampling for plasma concentrations of ondansetron obtained at 0, 15, 30, 60, 90, 120, 180, and 240 minutes from the beginning of ondansetron infusion. |
| Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron | anytime between 0-240 minutes | The level of ondansetron in plasma and CSF (cerebrospinal fluid) in samples, taken around the same time, was measured, and the ratio of the two values was calculated. This ratio (partition coefficient, Kp) of ondansetron, compared between the two sessions, with placebo vs tariquidar |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % Change in Pain Intensity | baseline to 90 minutes after ondansetron IV infusion | Change in spontaneous pain intensity (measured on a 0-10 numerical rating scale; 0=no pain, 10=worst imaginable pain) from baseline to 90 minutes after ondansetron IV infusion, compared between two sessions with and without tariquidar. Values are presented as a percentage change from baseline. |
| Conditioned Pain Modulation (CPM) Magnitude (ΔCPM) | Baseline and 90 minutes after the end of ondansetron infusion | Conditioned Pain Modulation (CPM) is a psychophysical test to assess the efficiency of descending pain inhibition. CPM is calculated as difference in heat pain threshold with and without pain conditioning - i.e. immersion of a hand in cold water. Conditioned Pain Modulation (CPM) Negative CPM values represent efficient pain modulation/inhibition. This test was administered at baseline, and again 90-min after the end of ondansetron infusion. CPM values can range from -100 to 100, CPM\<0 (i.e. decreased pain to heat stimulus following conditioning) implies descending pain inhibition. CPM Magnitude (ΔCPM) is the calculated by subtracting the measurement of CPM at baseline \[possible range of CPM scores 0-100\] from the measurement of CPM 90 min after the intervention \[possible range of CPM scores 0-100\]. A larger negative ΔCPM value indicates increased pain modulation efficiency following treatment, and therefore, a desired outcome. |
| Correlation Between CPM Magnitude (ΔCPM) and Change in Pain Intensity | 0-240 min from infusion | The association between baseline Conditioned Pain Modulation (CPM) magnitude (ΔCPM) and the % pain reduction from baseline will be determined by bivariate regression. |
| Change in Neuropathic Pain Symptom Inventory (NPSI) Score | baseline to 70 min after infusion | Changes in the Neuropathic Pain Symptom Inventory (NPSI) total score will be compared between treatment sessions. NPSI is a questionnaire used to assess and quantify neuropathic pain by asking patients to rate the severity of different pain sensations on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. The version administered in the study consists of seven questions, each rated on a scale from 0 to 10, with the total score being the sum of all ratings. The possible range of the NPSI score of the version administered in the study is 70, and, since we measure the difference in scores, the changes in the NPSI score of the version administered in the study is -70 to 70. Higher NPSI scores indicate more severe neuropathic pain symptoms. Since the analysis is conducted on changes in NPSI scores from baseline, a more negative value corresponds to a greater reduction in neuropathic pain symptoms following treatment. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Ondansetron With Tariquidar First, Then Ondansetron With Placebo The study group where patients received Ondansetron with Tariquidar during Visit 1, and Ondansetron with Placebo at Visit 2 per the randomization schedule. The washout period between two visits was 3 weeks.
Ondansetron 16 mg was administered IV over 60 minutes with tariquidar (4mg/kg dose in D5W) or with placebo (D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. | 12 |
| Ondansetron With Placebo First, Then Ondansetron With Tariquidar The study group where patients received Ondansetron with Placebo during Visit 1, and Ondansetron with Tariquidar at Visit 2 per the randomization schedule. The washout period between two visits was 3 weeks.
Ondansetron 16 mg was administered IV over 60 minutes with placebo (D5W) or with tariquidar (4mg/kg dose in D5W). Ondansetron was diluted in 100mL 0.9% normal saline, and tariquidar was diluted in 500mL D5W. | 12 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Wash-out (3 Weeks) | Protocol Violation | 1 | 0 |
Baseline characteristics
| Characteristic | Ondansetron With Placebo First, Then Ondansetron With Tariquidar | Total | Ondansetron With Tariquidar First, Then Ondansetron With Placebo |
|---|---|---|---|
| Age, Continuous | 49.33 years STANDARD_DEVIATION 12.16 | 50.92 years STANDARD_DEVIATION 12.35 | 52.5 years STANDARD_DEVIATION 12.87 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 12 Participants | 24 Participants | 12 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 12 Participants | 23 Participants | 11 Participants |
| Sex: Female, Male Female | 8 Participants | 16 Participants | 8 Participants |
| Sex: Female, Male Male | 4 Participants | 8 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 24 |
| other Total, other adverse events | 12 / 23 | 19 / 24 |
| serious Total, serious adverse events | 0 / 23 | 0 / 24 |
Outcome results
Primary
Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron
The level of ondansetron in plasma and CSF (cerebrospinal fluid) in samples, taken around the same time, was measured, and the ratio of the two values was calculated. This ratio (partition coefficient, Kp) of ondansetron, compared between the two sessions, with placebo vs tariquidar
Time frame: anytime between 0-240 minutes
Population: Participant who had both CSF and plasma samples drawn at the same time, at both sessions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ondansetron + Tariquidar | Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron | 0.132 ratio | Standard Error 0.017 |
| Ondansetron + Placebo | Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron | 0.112 ratio | Standard Error 0.018 |
p-value: 0.05695% CI: [-0.0005895, 0.03513063]t-test, 2 sided
Primary
Concertation-time Profile of Ondansetron in Plasma, Measured by the Area Under the Concentration-time Curve (AUC)
AUCinf for Ondansetron concentration in plasma based on venous blood sampling for plasma concentrations of ondansetron obtained at 0, 15, 30, 60, 90, 120, 180, and 240 minutes from the beginning of ondansetron infusion.
Time frame: Measurements over 240 minutes, extrapolated to infinity
Population: participants who completed both sessions
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ondansetron + Tariquidar | Concertation-time Profile of Ondansetron in Plasma, Measured by the Area Under the Concentration-time Curve (AUC) | 0.89 mg*hr/L | Standard Deviation 0.29 |
| Ondansetron + Placebo | Concertation-time Profile of Ondansetron in Plasma, Measured by the Area Under the Concentration-time Curve (AUC) | 0.87 mg*hr/L | Standard Deviation 0.45 |
p-value: 0.865195% CI: [-0.2624635, 0.2216122]t-test, 2 sided
Secondary
Change in Neuropathic Pain Symptom Inventory (NPSI) Score
Changes in the Neuropathic Pain Symptom Inventory (NPSI) total score will be compared between treatment sessions. NPSI is a questionnaire used to assess and quantify neuropathic pain by asking patients to rate the severity of different pain sensations on a scale of 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. The version administered in the study consists of seven questions, each rated on a scale from 0 to 10, with the total score being the sum of all ratings. The possible range of the NPSI score of the version administered in the study is 70, and, since we measure the difference in scores, the changes in the NPSI score of the version administered in the study is -70 to 70. Higher NPSI scores indicate more severe neuropathic pain symptoms. Since the analysis is conducted on changes in NPSI scores from baseline, a more negative value corresponds to a greater reduction in neuropathic pain symptoms following treatment.
Time frame: baseline to 70 min after infusion
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ondansetron + Tariquidar | Change in Neuropathic Pain Symptom Inventory (NPSI) Score | -8.6 units on a scale | Standard Error 7 |
| Ondansetron + Placebo | Change in Neuropathic Pain Symptom Inventory (NPSI) Score | -13.2 units on a scale | Standard Error 7.1 |
Secondary
% Change in Pain Intensity
Change in spontaneous pain intensity (measured on a 0-10 numerical rating scale; 0=no pain, 10=worst imaginable pain) from baseline to 90 minutes after ondansetron IV infusion, compared between two sessions with and without tariquidar. Values are presented as a percentage change from baseline.
Time frame: baseline to 90 minutes after ondansetron IV infusion
Population: All patients who received both treatments, excluding pharmacokinetic outlier (patient N 06)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ondansetron + Tariquidar | % Change in Pain Intensity | 37.2 % change from baseline | Standard Deviation 35.1 |
| Ondansetron + Placebo | % Change in Pain Intensity | 28.8 % change from baseline | Standard Deviation 28.7 |
Secondary
Conditioned Pain Modulation (CPM) Magnitude (ΔCPM)
Conditioned Pain Modulation (CPM) is a psychophysical test to assess the efficiency of descending pain inhibition. CPM is calculated as difference in heat pain threshold with and without pain conditioning - i.e. immersion of a hand in cold water. Conditioned Pain Modulation (CPM) Negative CPM values represent efficient pain modulation/inhibition. This test was administered at baseline, and again 90-min after the end of ondansetron infusion. CPM values can range from -100 to 100, CPM\<0 (i.e. decreased pain to heat stimulus following conditioning) implies descending pain inhibition. CPM Magnitude (ΔCPM) is the calculated by subtracting the measurement of CPM at baseline \[possible range of CPM scores 0-100\] from the measurement of CPM 90 min after the intervention \[possible range of CPM scores 0-100\]. A larger negative ΔCPM value indicates increased pain modulation efficiency following treatment, and therefore, a desired outcome.
Time frame: Baseline and 90 minutes after the end of ondansetron infusion
Population: All patients who completed both CPM procedures
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ondansetron + Tariquidar | Conditioned Pain Modulation (CPM) Magnitude (ΔCPM) | 0.1 score on a scale of 0-100 | Standard Error 8.2 |
| Ondansetron + Placebo | Conditioned Pain Modulation (CPM) Magnitude (ΔCPM) | 1.8 score on a scale of 0-100 | Standard Error 10.4 |
Secondary
Correlation Between CPM Magnitude (ΔCPM) and Change in Pain Intensity
The association between baseline Conditioned Pain Modulation (CPM) magnitude (ΔCPM) and the % pain reduction from baseline will be determined by bivariate regression.
Time frame: 0-240 min from infusion
Population: All patients who completed CPM and reported spontaneous pain intensity at corresponding time points
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ondansetron + Tariquidar | Correlation Between CPM Magnitude (ΔCPM) and Change in Pain Intensity | 0.02 r2 |
| Ondansetron + Placebo | Correlation Between CPM Magnitude (ΔCPM) and Change in Pain Intensity | 0.01 r2 |