Palonosetron and Hydroxyzine to Reduce Opioid Withdrawal

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

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).

Study Overview

• Status: Completed
• Conditions: Substance-Related Disorders
• Intervention / Treatment: Drug: Palonosetron; Drug: Hydroxyzine; Other: Placebo

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 Type: Interventional
• Enrollment (Actual): 10
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 35 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Male

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: TRIPLE

Number of Arms

6

Arms and Interventions

Participant Group / 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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 Names: 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

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)

Collaborators and Investigators

• Sponsor: Stanford University

Publications and helpful links

General Publications

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Study record dates

Study Major Dates

• Study Start: April 1, 2008
• Primary Completion (ACTUAL): August 1, 2008
• Study Completion (ACTUAL): August 1, 2008

Study Registration Dates

• First Submitted: April 15, 2008
• First Submitted That Met QC Criteria: April 17, 2008
• First Posted (ESTIMATE): April 18, 2008

Study Record Updates

• Last Update Posted (ACTUAL): June 5, 2017
• Last Update Submitted That Met QC Criteria: April 25, 2017
• Last Verified: April 1, 2017

More Information

Terms related to this study

• Keywords: Hydroxyzine; Palonosetron; Acute opioid withdrawal
• Additional Relevant MeSH Terms: Mental Disorders; Chemically-Induced Disorders; Substance-Related Disorders; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Antiemetics; Gastrointestinal Agents; Dermatologic Agents; Serotonin Agents; Serotonin Antagonists; Serotonin 5-HT3 Receptor Antagonists; Histamine H1 Antagonists; Histamine Antagonists; Histamine Agents; Antipruritics; Palonosetron; Hydroxyzine
• Other Study ID Numbers: SU-04152008-1099

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Study Data/Documents

1. Published Manuscript
   Information identifier: PMID: 27712113
   Information comments: Link to the manuscript which was published in The American Journal of Drug and Alcohol Abuse