5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Physical Dependence

NCT01549652 | Completed Results

• 2 other identifiers: 5HT3 198211R01DA029078
• Study Type: interventional
• Target: 133
• Locations: 1 country
• Sites: 1

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. This study aims to test the use of the drug ondansetron to reduce the symptoms associated with opioid withdrawal and to prevent the progression of opioid physical dependence, thereby allowing future investigators to better test the role of physical dependence in the development of addiction and also possibly improving acceptance of abstinence-based programs for addiction.

Conditions

Opioid Withdrawal; Physical Dependence

Outcome Measures

Primary Outcomes (2)

• Change in Objective Opioid Withdrawal Score (OOWS) From Baseline (Prevention of Opioid Withdrawal)

  Originally developed by Handelsman, the Objective Opioid Withdrawal Scale (OOWS) score is a well-characterized measure of opioid withdrawal in humans, calculated as the sum of a 13-item physician assessment documenting physically observable signs of withdrawal, which are rated as present (1) or absent (0) during the observation period. The minimum score of 0 means the patient is not showing any signs of opioid withdrawal. The maximum score of 13 signifies all signs of opioid withdrawal to the largest extent possible. Immediately prior to ondansetron or placebo administration a baseline OOWS score was taken. 30 minutes later participants received naloxone, then 15 minutes later an OOWS score was taken. If deemed necessary by the clinician, participants may have received a second naloxone dose (25 minutes following 1st naloxone dose), then 15 minutes later an OOWS score was taken. Change from the baseline OOWS score to the score assessed following the last naloxone dose is reported.

  Baseline; 15 minutes following last naloxone dose

• Change in Objective Opioid Withdrawal Score From Baseline (Prevention of Physical Dependence)

  Originally developed by Handelsman, the OOWS score is a well-characterized measure of opioid withdrawal in humans, calculated as the sum of a 13-item physician assessment documenting physically observable signs of withdrawal, which are rated as present (1) or absent (0) during the observation period. The maximum score is 13 and suggests the patient is showing all signs of opioid withdrawal to the largest extent possible. The minimum score of 0 suggests the patient is not showing any signs of opioid withdrawal. Immediately prior to ondansetron or placebo administration a baseline OOWS score was taken. 30 minutes later participants received naloxone, then 15 minutes later an OOWS score was taken. If necessary (as deemed by the clinician), participants may have received a second naloxone dose (25 minutes following 1st naloxone dose), then 15 minutes later an OOWS score was taken. Change from the baseline OOWS score to the score assessed following the last naloxone dose is reported.

  Baseline; 15 minutes following last naloxone dose

Secondary Outcomes (10)

• Change in Subjective Opioid Withdrawal Score (SOWS) From Baseline (Prevention of Opioid Withdrawal)

  Baseline; 15 minutes following last naloxone dose

• Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Opioid Withdrawal)

  2 study days 1 month apart (at the start of each study visit)

• Profile of Mood States (POMS) Change in Score From Baseline (Prevention of Opioid Withdrawal)

  Baseline; 15 minutes following last naloxone dose

• Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Opioid Withdrawal)

  2 study days 1 month apart (at the start of each study visit)

• Change in Roland-Morris Disability Index (RMDI) From Baseline (Prevention of Opioid Withdrawal)

  2 study days 1 month apart (at the start of each study visit)

Study Arms (2)

Prevention of Opioid Withdrawal

EXPERIMENTAL

Chronic back pain patients will titrate onto sustained release oral morphine for 30 days, and then will be randomized to take either ondansetron 8 mg or matching placebo thirty minutes prior to naloxone-induced withdrawal in clinic (Naloxone 0.4 mg/70 kg; if deemed necessary by the clinician to induce withdrawal, a second naloxone dose may be administered at 0.8 mg/70 kg). Participants will return to their titrated morphine dose for one week and then return for the opposite pre-treatment followed by naloxone-induced withdrawal in clinic. Participants will then taper back to their original dose of morphine for one week.

Drug: Ondansetron; Drug: Placebo; Drug: Morphine; Drug: Naloxone 0.4 mg/70 kg; Drug: Naloxone 0.8 mg/70 kg

Prevention of Physical Dependence

EXPERIMENTAL

Chronic back pain patients will titrate onto sustained release oral morphine for 30 days; during morphine treatment, participants will be randomized to take either ondansetron 8 mg or matching placebo three times daily along with the oral morphine treatment. After thirty days, participants will return to the lab to undergo naloxone-induced withdrawal in clinic (Naloxone 0.4 mg/70 kg; if deemed necessary by the clinician to induce withdrawal, a second naloxone dose may be administered at 0.8 mg/70 kg). Participants will then taper back to their original dose of morphine for one week.

Drug: Ondansetron; Drug: Placebo; Drug: Morphine; Drug: Naloxone 0.4 mg/70 kg; Drug: Naloxone 0.8 mg/70 kg

Interventions

Ondansetron DRUG

Ondansetron 8 mg oral tablet

Also known as: Zofran

Prevention of Opioid Withdrawal; Prevention of Physical Dependence

Placebo DRUG

Placebo to Match Ondansetron

Prevention of Opioid Withdrawal; Prevention of Physical Dependence

Morphine DRUG

Sustained release oral morphine, beginning at 30 mg/d, titrated up by 15 mg/d every 2 days until adequate analgesia is achieved

Prevention of Opioid Withdrawal; Prevention of Physical Dependence

Naloxone 0.4 mg/70 kg DRUG

Naloxone 0.4 mg/70 kg intravenous

Prevention of Opioid Withdrawal; Prevention of Physical Dependence

Naloxone 0.8 mg/70 kg DRUG

Naloxone 0.8 mg/70 kg intravenous

Prevention of Opioid Withdrawal; Prevention of Physical Dependence

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Diagnosis of chronic low-back pain and who may be taking up to 30 mg equivalent of morphine per day (such as Vicodin, Percocet, etc)
• years old
• Eligible to escalate opioid therapy dose, as determined by the treating physician or PI
• At low risk for addiction as determined by the PI and an addiction expert, Dr. Ian Carroll.

You may not qualify if:

• History of cardiovascular disease
• History of peripheral neuropathic pain, scleroderma, or other condition that would preclude cold water forearm immersion
• History of addiction or chronic pain conditions other than low-back pain, d) history of cardiac arrhythmia
• History of hepatic disease
• Use of steroid or nerve-stimulating medications
• Any condition precluding opioid use
• Pregnancy

Sponsors & Collaborators

• Stanford University: lead
• National Institute on Drug Abuse (NIDA): collaborator

Study Sites (1)

Stanford University

Stanford, California, 94305, United States

Location

Related Publications (14)

• Chu LF, Liang DY, Li X, Sahbaie P, D'arcy N, Liao G, Peltz G, David Clark J. From mouse to man: the 5-HT3 receptor modulates physical dependence on opioid narcotics. Pharmacogenet Genomics. 2009 Mar;19(3):193-205. doi: 10.1097/FPC.0b013e328322e73d.

  PMID: 19214139 BACKGROUND

• Atlas SJ, Nardin RA. Evaluation and treatment of low back pain: an evidence-based approach to clinical care. Muscle Nerve. 2003 Mar;27(3):265-84. doi: 10.1002/mus.10311.

  PMID: 12635113 BACKGROUND

• Betses M, Brennan T. Abusive prescribing of controlled substances--a pharmacy view. N Engl J Med. 2013 Sep 12;369(11):989-91. doi: 10.1056/NEJMp1308222. Epub 2013 Aug 21. No abstract available.

  PMID: 23964897 BACKGROUND

• Birnbaum HG, White AG, Schiller M, Waldman T, Cleveland JM, Roland CL. Societal costs of prescription opioid abuse, dependence, and misuse in the United States. Pain Med. 2011 Apr;12(4):657-67. doi: 10.1111/j.1526-4637.2011.01075.x. Epub 2011 Mar 10.

  PMID: 21392250 BACKGROUND

• Chu LF, D'Arcy N, Brady C, Zamora AK, Young CA, Kim JE, Clemenson AM, Angst MS, Clark DJ. Analgesic tolerance without demonstrable opioid-induced hyperalgesia: a double-blinded, randomized, placebo-controlled trial of sustained-release morphine for treatment of chronic nonradicular low-back pain. Pain. 2012 Aug;153(8):1583-1592. doi: 10.1016/j.pain.2012.02.028. Epub 2012 Jun 16.

  PMID: 22704854 BACKGROUND

• Clark JD. Chronic pain prevalence and analgesic prescribing in a general medical population. J Pain Symptom Manage. 2002 Feb;23(2):131-7. doi: 10.1016/s0885-3924(01)00396-7.

  PMID: 11844633 BACKGROUND

• Colthup PV, Felgate CC, Palmer JL, Scully NL. Determination of ondansetron in plasma and its pharmacokinetics in the young and elderly. J Pharm Sci. 1991 Sep;80(9):868-71. doi: 10.1002/jps.2600800913.

  PMID: 1839313 BACKGROUND

• Compton P, Athanasos P, Elashoff D. Withdrawal hyperalgesia after acute opioid physical dependence in nonaddicted humans: a preliminary study. J Pain. 2003 Nov;4(9):511-9. doi: 10.1016/j.jpain.2003.08.003.

  PMID: 14636819 BACKGROUND

• Compton P, Miotto K, Elashoff D. Precipitated opioid withdrawal across acute physical dependence induction methods. Pharmacol Biochem Behav. 2004 Feb;77(2):263-8. doi: 10.1016/j.pbb.2003.10.017.

  PMID: 14751453 BACKGROUND

• Handelsman L, Cochrane KJ, Aronson MJ, Ness R, Rubinstein KJ, Kanof PD. Two new rating scales for opiate withdrawal. Am J Drug Alcohol Abuse. 1987;13(3):293-308. doi: 10.3109/00952998709001515.

  PMID: 3687892 BACKGROUND

• Plosker GL, Milne RJ. Ondansetron: a pharmacoeconomic and quality-of-life evaluation of its antiemetic activity in patients receiving cancer chemotherapy. Pharmacoeconomics. 1992 Oct;2(4):285-304. doi: 10.2165/00019053-199202040-00005.

  PMID: 10147044 BACKGROUND

• Meert TF. Effects of various serotonergic agents on alcohol intake and alcohol preference in Wistar rats selected at two different levels of alcohol preference. Alcohol Alcohol. 1993 Mar;28(2):157-70.

  PMID: 8517886 BACKGROUND

• Chu LF, Sun J, Clemenson A, Erlendson MJ, Rico T, Cornell E, Obasi H, Sayyid ZN, Encisco EM, Yu J, Gamble JG, Carroll I, Clark JD. Ondansetron Does Not Reduce Withdrawal in Patients With Physical Dependence on Chronic Opioid Therapy. J Addict Med. 2017 Sep/Oct;11(5):342-349. doi: 10.1097/ADM.0000000000000321.

  PMID: 28514235 RESULT

• Chu LF, Rico T, Cornell E, Obasi H, Encisco EM, Vertelney H, Gamble JG, Crawford CW, Sun J, Clemenson A, Erlendson MJ, Okada R, Carroll I, Clark JD. Ondansetron does not prevent physical dependence in patients taking opioid medications chronically for pain control. Drug Alcohol Depend. 2018 Feb 1;183:176-183. doi: 10.1016/j.drugalcdep.2017.06.043. Epub 2017 Aug 14.

  PMID: 29278818 RESULT

MeSH Terms

Interventions

Ondansetron; Morphine; Naloxone

Intervention Hierarchy (Ancestors)

Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Carbazoles; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds, 3-Ring; Morphine Derivatives; Morphinans; Opiate Alkaloids; Alkaloids; Heterocyclic Compounds, Bridged-Ring; Heterocyclic Compounds, 4 or More Rings; Phenanthrenes; Polycyclic Aromatic Hydrocarbons; Polycyclic Compounds

Limitations and Caveats

Aim 1: Use of a single 8mg dose of ondansetron as well as a lack of biochemical data is a limitation of this study. Aim 2: Use of 8mg of ondansetron instead of varying doses is a limitation of this study.

Results Point of Contact

• Title: Dr. Larry F. Chu
• Organization: Stanford University School of Medicine Department of Anesthesiology

lchu@stanford.edu

6507236632

Study Officials

• Larry F Chu, MD, MS

  Stanford University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principle Investigator

Study Record Dates

• First Submitted: February 13, 2012
• First Posted: March 9, 2012
• Study Start: April 1, 2011
• Primary Completion: April 1, 2015
• Study Completion: October 1, 2016
• Last Updated: January 7, 2019
• Results First Posted: January 7, 2019

Record last verified: 2019-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)