Palonosetron and Hydroxyzine to Reduce Opioid Withdrawal

Study Overview
=================
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. We are interested in knowing if a medication named Ondansetron can help ease or prevent symptoms associated with opioid withdrawal. We are also interested in knowing if a similar (but more potent FDA-approved drug, palonosetron) can more effectively treat withdrawal symptoms with or without combination with an antihistamine called hydroxyzine (vistaril).

Detailed Description
-----------------
We hope to learn if Palonosetron and/or combination with hydroxyzine can be used to prevent or attenuate the signs and symptoms of opioid withdrawal. If we find that it can help prevent these symptoms, it may become a new treatment that can aid patients suffering from these symptoms.

Official Title
-----------------
Examination of Palonosetron and Hydroxyzine Pre-treatment as a Possible Method to Reduce the Objective Signs of Experimentally-induced Acute Opioid Withdrawal in Humans: a Double-blind, Randomized, Placebo-controlled Crossover Study

Conditions
-----------------
Substance-Related Disorders

Intervention / Treatment
-----------------
* Drug: Palonosetron
* Drug: Hydroxyzine
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Healthy males Ages 18-35 No allergies to morphine or palonosetron No history of addiction or substance abuse Exclusion Criteria: Female Younger than 18 or older than 35 History of substance abuse Raynaud's disease or coronary artery disease Allergies to morphine or palonosetron

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 35 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

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

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Interventional Model Description: There were three treatment arms to the study: Placebo, Palonosetron, and Palonosetron + Hydroxyzine (Combo). Participants were not randomized in between these arms, all participants completed each arm of the study in a cross-over study methodology (Placebo, Palonosetron, Palonosetron + Hydroxyzene (combo). Participants were individually randomized into the order in which they participated in each arm. Per sequence each individual participant underwent the following randomization schedule: Participant 1: Placebo, Combo, Palonosetron Participant 2: Palonosetron, Combo, Placebo Participant 3: Palonosetron, Combo, Placebo Participant 4: Combo, Placebo, Palonosetron Participant 5: Placebo, Palonosetron, Combo Participant 6: Combo, Palonosetron, Placebo Participant 7: Combo, Placebo, Palonosetron Participant 8: Combo, Palonosetron, Placebo Participant 9: Palonosetron, Placebo, Combo Participant 10: Placebo, Combo, Palonosetron
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sequence 1: Placebo, Combo, Palonosetron<br>At T = 0 (minutes), healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either placebo (0.9% normal saline), palonosetron IV (0.75mg), or palonosetron IV (0.75mg) and hydroxyzine per os (PO) (100mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10mg/70kg). At T = 165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. Week 1: Placebo Week 2: Palonosetron + Hydroxyzine Combo Week 3: Palonosetron | Drug: Palonosetron<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Aloxi;Drug: Hydroxyzine<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Vistaril, Atarax;Other: Placebo<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>|
| Experimental: Sequence 2: Palonosetron, Combo, Placebo<br>At T = 0 (minutes), healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either placebo (0.9% normal saline), palonosetron IV (0.75mg), or palonosetron IV (0.75mg) and hydroxyzine per os (PO) (100mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10mg/70kg). At T = 165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. Week 1: Palonosetron Week 2: Palonosetron + Hydroxyzine Combo Week 3: Placebo | Drug: Palonosetron<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Aloxi;Drug: Hydroxyzine<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Vistaril, Atarax;Other: Placebo<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>|
| Experimental: Sequence 3: Combo, Placebo, Palonosetron<br>At T = 0 (minutes), healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either placebo (0.9% normal saline), palonosetron IV (0.75mg), or palonosetron IV (0.75mg) and hydroxyzine per os (PO) (100mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10mg/70kg). At T = 165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. Week 1: Palonosetron + Hydroxyzine Combo Week 2: Placebo Week 3: Palonosetron | Drug: Palonosetron<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Aloxi;Drug: Hydroxyzine<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Vistaril, Atarax;Other: Placebo<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>|
| Experimental: Sequence 4: Placebo, Palonosetron, Combo<br>At T = 0 (minutes), healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either placebo (0.9% normal saline), palonosetron IV (0.75mg), or palonosetron IV (0.75mg) and hydroxyzine per os (PO) (100mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10mg/70kg). At T = 165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. Week 1: Placebo Week 2: Palonosetron only Week 3: Palonosetron + Hydroxyzine Combo | Drug: Palonosetron<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Aloxi;Drug: Hydroxyzine<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Vistaril, Atarax;Other: Placebo<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>|
| Experimental: Sequence 5: Combo, Palonosetron, Placebo<br>At T = 0 (minutes), healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either placebo (0.9% normal saline), palonosetron IV (0.75mg), or palonosetron IV (0.75mg) and hydroxyzine per os (PO) (100mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10mg/70kg). At T = 165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. Week 1: Palonosetron + Hydroxyzine Combo Week 2: Palonosetron only Week 3: Placebo | Drug: Palonosetron<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Aloxi;Drug: Hydroxyzine<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Vistaril, Atarax;Other: Placebo<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>|
| Experimental: Sequence 6: Palonosetron, Placebo, Combo<br>At T = 0 (minutes), healthy (non-opioid dependent, non-substance abuser) male volunteers (N=10) were pre-treated with either placebo (0.9% normal saline), palonosetron IV (0.75mg), or palonosetron IV (0.75mg) and hydroxyzine per os (PO) (100mg) in a crossover study design. This was followed at T = 30 by intravenous morphine (10mg/70kg). At T = 165, 10mg/70kg naloxone IV was given to precipitate opioid withdrawal. The objective opioid withdrawal score (OOWS) and subjective opioid withdrawal score (SOWS) were determined 5 and 15 minutes after naloxone administration (T = 170, 180, respectively). Baseline measurements were recorded at T = -30 and T = -15. Week 1: Palonosetron only Week 2: Placebo Week 3:Palonosetron + Hydroxyzine Combo | Drug: Palonosetron<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Aloxi;Drug: Hydroxyzine<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>* Other names: Vistaril, Atarax;Other: Placebo<br>* Over 3 study visits, patients will receive one of the following treatment regimens: Placebo saline IV and sugar pill 0.75 mg Palonosetron IV and sugar pill 0.75 mg Palonosetron IV and 100 mg hydroxyzine PO<br>|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| OOWS Score | The OOWS is a 13-item instrument documenting physically observable signs of withdrawal, which are rated as present (1) or absent (0) during the observation period. Maximum score possible = 13, minimum score possible = 0. T=15 minutes post naloxone administration coordinates with T = 180 (min) for the entire study session. OOWS scores at T=180 is the primary outcome measure of the study compared with baseline OOWS scores at T=-30 (30 minutes prior to study medication administration). Reported time frames are in relation to time past since administration of study medications. Mean post-Naloxone OOWS scores (+/- SEM) were determined for pretreatment groups | Change from baseline in OOWS score at 180 minutes (15 minutes post naloxone administration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SOWS Score | The SOWS score is composed of 16 subjective symptoms rated on a scale of 0 to 4 (0=not at all, 4=extremely) based on what subjects were experiencing at the time of testing. 15 minutes post naloxone administration coordinates with T = 180 (min) for the entire study session. The highest score possible (64) would indicate that the individual was experiencing every symptom of opioid withdrawal to the fullest extent possible while the lowest score (0) would indicate that the individual was not experiencing any symptoms of opioid withdrawal. Mean post-naloxone SOWS scores (+/- SEM) were computed for pretreatment groups: Placebo, palonosetron, and palonosetron with hydroxyzine | Change from baseline in SOWS score at 180 minutes (15 minutes post naloxone administration) | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Palonosetron, Hydroxyzine, Acute opioid withdrawal