Tariquidar-ondansetron Combination in Neuropathic Pain

Study Overview
=================
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: Be tolerable in patients with neuropathic pain. Increase the cerebrospinal fluid (CSF) to plasma ratio of ondansetron after intravenous administration, compare to ondansetron alone Result in a greater reduction in pain intensity than with ondansetron alone.

Official Title
-----------------
Administration of Ondansetron With P-glycoprotein Inhibitor Tariquidar in Patients With Neuropathic Pain

Conditions
-----------------
Neuropathic Pain

Intervention / Treatment
-----------------
* Drug: Ondansetron 16 mg with Tariquidar
* Drug: Ondansetron 16 mg with Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18-65; Documented diagnosis of neuropathic pain due to damage or disease affecting the peripheral nervous system; At least Probable neuropathic pain grading1; Pain duration >3 months; Average pain intensity ≥4 on 0-10 numerical rating scale (NRS). Exclusion Criteria: Current pregnancy or lactation; Moderate-severe kidney or liver dysfunction; Active cardiac arrhythmias (non-sinus rhythm), Long QT syndrome, or QTc interval >450msec; Congestive heart failure Abnormal troponin values at screening visit; Current treatment with MAO inhibitors, mirtazapine, SSRI antidepressants, or SNRI medications duloxetine or venlafaxine; Current treatment with tapentadol, tramadol, or fentanyl; Current treatment with P-glycoprotein substrate drugs with narrow therapeutic window, e.g. digoxin; Current treatment with tricyclic antidepressant medications (e.g. amitriptyline, desipramine, imipramine) at a dose >25mg/day; 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; 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.); Current treatment with anticoagulant drugs;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: Prospective, randomized, double blind, crossover study
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Ondansetron + Tariquidar<br> | Drug: Ondansetron 16 mg with Tariquidar<br>* 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.<br>|
| Placebo Comparator: Ondansetron + Placebo<br> | Drug: Ondansetron 16 mg with Placebo<br>* 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.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Concertation-time Profile of Ondansetron in Plasma | Venous blood sampling for plasma concentrations of ondansetron will be obtained: at 0, 15, 30, 60, 90, 120, 180, and 240 minutes from the beginning of ondansetron infusion, and compared between the two sessions (with placebo vs tariquidar) | up to 8 weeks following consent | 
| Cerebrospinal Fluid to Plasma Concentration Ratio of Ondansetron | Cerebrospinal fluid to plasma concentration ratio of ondansetron, compared between the two sessions, with placebo vs tariquidar | up to 8 weeks following consent | 
| Cerebrospinal Fluid Penetration of Ondansetron - Area Under the Curve (AUC) | Cerebrospinal fluid penetration of intravenous ondansetron will be determined as AUCCSF0-∞ of ondansetron, and compared between the two sessions, with placebo vs tariquidar | up to 8 weeks following consent | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Pain Intensity | Change in spontaneous pain intensity (measured on 0-10 numerical rating scale; 0=no pain, 10=worst imaginable pain) from baseline to 60-120 minutes after ondansetron IV infusion, compared between two sessions with and without tariquidar. | up to 8 weeks following consent | 
| Conditioned Pain Modulation (CPM) Magnitude (ΔCPM) | The difference between self-report intensity of pain (0-100 scale) as a response to a standard contact heat stimulus, compared to the same experiment performed with ice-water conditioning applied to the contralateral extremity. A larger negative value of CPM represents more efficient pain modulation. | up to 8 weeks following consent | 
| 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. | up to 8 weeks following consent | 
| Change in Neuropathic Pain Symptom Score | Changes in Neuropathic Pain Symptom Inventory (NPSI) total score and sub-scores (burning pain, paroxysmal pain, paresthesia/dysesthesia score) will be compared between treatment sessions. Each subscore is scored on a 0-10 scale: 0=no symptom, 10=worst imaginable symptom | up to 8 weeks following consent |