Palonosetron and Hydroxyzine to Reduce Opioid Withdrawal

• ClinicalTrials.gov Identifier: NCT00661674
• Recruitment Status: Completed
• First Posted: April 18, 2008
• Results First Posted: June 5, 2017
• Last Update Posted: June 5, 2017
• Sponsor: Stanford University
• Information provided by (Responsible Party): Larry Fu-nien Chu, Stanford University

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Substance-Related Disorders	Drug: Palonosetron; Drug: Hydroxyzine; Other: Placebo	Not Applicable

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 10 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment

Intervention 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 (Participant, Care Provider, Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Study Start Date: April 2008
• Actual Primary Completion Date: August 2008
• Actual Study Completion Date: August 2008

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sequence 1: Placebo, Combo, Palonosetron; 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; 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; Other Name: Aloxi; Drug: Hydroxyzine; 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; Other Name: Vistaril, Atarax; Other: Placebo; 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
Experimental: Sequence 2: Palonosetron, Combo, Placebo; 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; 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; Other Name: Aloxi; Drug: Hydroxyzine; 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; Other Name: Vistaril, Atarax; Other: Placebo; 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
Experimental: Sequence 3: Combo, Placebo, Palonosetron; 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; 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; Other Name: Aloxi; Drug: Hydroxyzine; 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; Other Name: Vistaril, Atarax; Other: Placebo; 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
Experimental: Sequence 4: Placebo, Palonosetron, Combo; 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; 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; Other Name: Aloxi; Drug: Hydroxyzine; 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; Other Name: Vistaril, Atarax; Other: Placebo; 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
Experimental: Sequence 5: Combo, Palonosetron, Placebo; 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; 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; Other Name: Aloxi; Drug: Hydroxyzine; 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; Other Name: Vistaril, Atarax; Other: Placebo; 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
Experimental: Sequence 6: Palonosetron, Placebo, Combo; 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; 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; Other Name: Aloxi; Drug: Hydroxyzine; 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; Other Name: Vistaril, Atarax; Other: Placebo; 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

Outcome Measures

Primary Outcome Measures :

1. OOWS Score [ Time Frame: Change from baseline in OOWS score at 180 minutes (15 minutes post naloxone administration) ]

   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

Secondary Outcome Measures :

1. SOWS Score [ Time Frame: Change from baseline in SOWS score at 180 minutes (15 minutes post naloxone administration) ]

   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

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 35 Years (Adult)
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

United States, California

Stanford University School of Medicine

Stanford, California, United States, 94305

Sponsors and Collaborators

Stanford University

Investigators

• Principal Investigator: Dr Larry Fu-nien Chu; Stanford University

More Information

Study Data/Documents: Published Manuscript 

Identifier: PMID: 27712113
Link to the manuscript which was published in The American Journal of Drug and Alcohol Abuse

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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Erlendson MJ, D'Arcy N, Encisco EM, Yu JJ, Rincon-Cruz L, Peltz G, Clark JD, Chu LF. Palonosetron and hydroxyzine pre-treatment reduces the objective signs of experimentally-induced acute opioid withdrawal in humans: a double-blinded, randomized, placebo-controlled crossover study. Am J Drug Alcohol Abuse. 2017 Jan;43(1):78-86. doi: 10.1080/00952990.2016.1210614. Epub 2016 Aug 11.

• Responsible Party: Larry Fu-nien Chu, Professor of Anesthesia, Stanford University
• ClinicalTrials.gov Identifier: NCT00661674
• Other Study ID Numbers: SU-04152008-1099
• First Posted: April 18, 2008
• Results First Posted: June 5, 2017
• Last Update Posted: June 5, 2017
• Last Verified: April 2017

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

Keywords provided by Larry Fu-nien Chu, Stanford University:

Palonosetron; Hydroxyzine; Acute opioid withdrawal

Additional relevant MeSH terms:

Substance-Related Disorders; Chemically-Induced Disorders; Mental Disorders; Palonosetron; Hydroxyzine; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Physiological Effects of Drugs; Gastrointestinal Agents; Serotonin 5-HT3 Receptor Antagonists; Serotonin Antagonists; Serotonin Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Antipruritics; Dermatologic Agents; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents