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

Opioid Withdrawal Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01549652
• Other study ID #: 5HT3 19821
• Secondary ID: 1R01DA029078
• Status: Completed
• Phase: N/A
• Start date: April 2011
• Est. completion date: October 2016

Study information

• Verified date: January 2019
• Source: Stanford University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This study will be split into two separate investigations, aim 1 and aim 2.

Study aim 1 (Prevention of Opioid Withdrawal) will investigate whether ondansetron, a 5HT3-receptor antagonist, can reduce or prevent withdrawal signs and symptoms in patients physically dependent on opioids to treat chronic back pain. In this aim, study participants will be titrated onto sustained release oral morphine for 30 days after which time they will return to the lab to undergo naloxone-induced withdrawal with either 8 mg ondansetron pre-treatment (30 min prior to naloxone-induced withdrawal) or placebo. Participants will then return to their titrated dose of oral morphine for one week before returning for the second study session in which they will receive the opposite pre-treatment (8 mg ondansetron or placebo) 30 minutes prior to naloxone-induced withdrawal. Objective opioid withdrawal score (OOWS), subjective opioid withdrawal score (SOWS) and Profile of Mood States (POMS) will be assessed at baseline and five or seven times during the study sessions at 30 and 37 days post titration. Beck Depression Inventory, Roland-Morris Questionnaire and State-Trait Anxiety Inventory and VAS Pain Score will be assessed at baseline as well as at both study sessions (30 and 37 days post titration).

Study aim 2 (Prevention of Physical Dependence) will investigate whether ondansetron, a 5HT3 receptor antagonist, can prevent physical dependence in patients taking opioids chronically for controlling chronic back pain. Participants will taper onto sustained release oral morphine for 10 days then will maintain the effective dose for twenty days (total of 30 days) while simultaneously taking 8 mg ondansetron or placebo three times daily with morphine dose. After 30 days of morphine plus 8 mg ondansetron or placebo, study participants will return to the lab to undergo naloxone-induced withdrawal. OOWS, SOWS, POMS, pain visual analogue scale (VAS), Beck Depression Inventory and Roland Morris Disability Index will be administered at baseline and at the beginning of each study session (30 days post titration). Furthermore OOWS, SOWS and POMS will be administered twice during the first study session and at least five times during the second study session (Day 30): at the beginning of the session, after IV insertion, and after naloxone-induced opioid withdrawal.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 133
• Est. completion date: October 2016
• Est. primary completion date: April 2015
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• 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)

• 18-60 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.

Exclusion Criteria:

• 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

Related Conditions & MeSH terms

• Opioid Withdrawal
• Physical Dependence
• Substance Withdrawal Syndrome

Intervention

Drug:
• Ondansetron
Ondansetron 8 mg oral tablet
• Placebo
Placebo to Match Ondansetron
• Morphine
Sustained release oral morphine, beginning at 30 mg/d, titrated up by 15 mg/d every 2 days until adequate analgesia is achieved
• Naloxone 0.4 mg/70 kg
Naloxone 0.4 mg/70 kg intravenous
• Naloxone 0.8 mg/70 kg
Naloxone 0.8 mg/70 kg intravenous

Locations

Country	Name	City	State
United States	Stanford University	Stanford	California

Sponsors (2)

Lead Sponsor	Collaborator
Stanford University	National Institute on Drug Abuse (NIDA)

Country where clinical trial is conducted

United States, 

References & Publications (14)

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. Review. — View Citation

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. — View Citation

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. — View Citation

Chu LF, D'Arcy N, Brady C, Zamora AK, Young CA, Kim JE, Clemenson AM, Angst MS, Clark JD. 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):1583-92. doi: 10.1016/j.pain.2012.02.028. Epub 2012 Jun 16. — View Citation

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. — View Citation

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 pai — View Citation

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 Se — View Citation

Clark JD. Chronic pain prevalence and analgesic prescribing in a general medical population. J Pain Symptom Manage. 2002 Feb;23(2):131-7. — View Citation

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. — View Citation

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. — View Citation

Compton P, Miotto K, Elashoff D. Precipitated opioid withdrawal across acute physical dependence induction methods. Pharmacol Biochem Behav. 2004 Feb;77(2):263-8. — View Citation

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. — View Citation

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. — View Citation

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. Review. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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	Change in Subjective Opioid Withdrawal Score (SOWS) From Baseline (Prevention of Opioid Withdrawal)	The Subjective Opioid Withdrawal Score (SOWS) score is calculated as the sum of 16 subjective patient-reported symptom scores 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. A maximum score of 64 would suggest the patient is experiencing the symptoms of withdrawal to the maximum extent possible while the lowest score of 0 would suggest the patient is not experiencing any of the symptoms of withdrawal. Immediately prior to ondansetron or placebo administration a baseline SOWS score was taken. 30 minutes later participants received naloxone, then 15 minutes later an SOWS 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 SOWS score was taken. Change from the baseline SOWS score to the score assessed following the last naloxone dose is reported	Baseline; 15 minutes following last naloxone dose
Secondary	Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Opioid Withdrawal)	The Beck Depression Inventory (a 21-item self-report multiple-choice inventory) yields a single summed score between 0 and 63; higher scores indicate more severe depression. Change is from baseline score (taken at the beginning of the first study visit, prior to beginning of titration into morphine) to the score taken after taking morphine for 30 days (score taken prior to receiving ondansetron or placebo, at the beginning of second study visit).	2 study days 1 month apart (at the start of each study visit)
Secondary	Profile of Mood States (POMS) Change in Score From Baseline (Prevention of Opioid Withdrawal)	Profile of Mood States (POMS) is a 65-question survey of how participants have been feeling over the past week, assessing tension, depression, anger, fatigue, confusion and vigor. Each question is on a 5-point scale: 0 (not at all) to 4 (extremely). Overall score range: 0 to 200 (lower scores corresponding to fewer symptoms), calculated by adding total scores for tension, depression, anger, fatigue and confusing, and subtracting that total score from the total score for vigor. Immediately prior to ondansetron or placebo administration a baseline POMS score was taken. 30 minutes later participants received naloxone, then 15 minutes later a POMS 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 POMS score was taken. Change from the baseline POMS score to the score assessed following the last naloxone dose is reported.	Baseline; 15 minutes following last naloxone dose
Secondary	Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Opioid Withdrawal)	The VAS is a 0 to 100 millimeter scale where 0 corresponds to no pain and 100 to extreme pain, used by participants to indicated their level of pain over the last two weeks. Change is from baseline score for average level of pain (taken at the beginning of the first study visit, prior to beginning of titration into morphine) to the score taken after taking morphine for 30 days (score taken prior to receiving ondansetron or placebo, at the beginning of second study visit).	2 study days 1 month apart (at the start of each study visit)
Secondary	Change in Roland-Morris Disability Index (RMDI) From Baseline (Prevention of Opioid Withdrawal)	The Roland-Morris Disability Index is a 24-question instrument used to assess level of disability from lower back pain. Scores range from 0-24 with lower scores corresponding to fewer symptoms. Change is from baseline score (taken at the beginning of the first study visit, prior to beginning of titration into morphine) to the score taken after taking morphine for 30 days (score taken prior to receiving ondansetron or placebo, at the beginning of second study visit).	2 study days 1 month apart (at the start of each study visit)
Secondary	Change in Subjective Opioid Withdrawal Score From Baseline (Prevention of Physical Dependence)	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. A maximum score of 64 would suggest the patient is experiencing the symptoms of withdrawal to the maximum extent possible while the lowest score of 0 would suggest the patient is not experiencing any of the symptoms of withdrawal. Immediately prior to ondansetron or placebo administration a baseline SOWS score was taken. 30 minutes later participants received naloxone, then 15 minutes later an SOWS 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 SOWS score was taken. Change from the baseline SOWS score to the score assessed following the last naloxone dose is reported	Baseline; 15 minutes following last naloxone dose
Secondary	Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Physical Dependence)	The Beck Depression Inventory (a 21-item self-report multiple-choice inventory) yields a single summed score between 0 and 63; higher scores indicate more severe depression. Change is from baseline score (taken at the beginning of the first study visit, prior to beginning of titration into morphine) to the score taken after taking morphine for 30 days (score taken at the beginning of second study visit).	2 study days 1 month apart (at the start of each study visit)
Secondary	Profile of Mood States (POMS) Change in Score From Baseline (Prevention of Physical Dependence)	(Profile of Mood States) POMS is a 65-question survey of how participants have been feeling over the past week, assessing tension, depression, anger, fatigue, confusion and vigor. Each question is on a 5-point scale: 0 (not at all) to 4 (extremely). Overall score range: 0 to 200 (lower scores corresponding to fewer symptoms), calculated by adding total scores for tension, depression, anger, fatigue and confusing, and subtracting that total score from the total score for vigor. Immediately prior to ondansetron or placebo administration a baseline POMS score was taken. 30 minutes later participants received naloxone, then 15 minutes later a POMS 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 POMS score was taken. Change from the baseline POMS score to the score assessed following the last naloxone dose is reported.	Baseline; 15 minutes following last naloxone dose
Secondary	Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Physical Dependence)	The VAS is a 0 to 100 millimeter scale where 0 corresponds to no pain and 100 to extreme pain, used by participants to indicated their level of pain over the last two weeks. Change is from baseline score for average level of pain (taken at the beginning of the first study visit, prior to beginning of titration into morphine) to the score taken after taking morphine for 30 days (score taken at the beginning of second study visit).	2 study days 1 month apart (at the start of each study visit)
Secondary	Change in Roland-Morris Disability (RMDI) Index From Baseline (Prevention of Physical Dependence)	The Roland-Morris Disability Index is a 24-question instrument used to assess level of disability from lower back pain. Scores range from 0-24 with lower scores corresponding to fewer symptoms. Change is from baseline score (taken at the beginning of the first study visit, prior to beginning of titration into morphine) to the score taken after taking morphine for 30 days (score taken at the beginning of second study visit).	2 study days 1 month apart (at the start of each study visit)