Clinical trial NCT01549652: 5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Physical Dependence
Official title: 5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Physical Dependence
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Opioid Withdrawal
Physical Dependence
Lead sponsor: Stanford University
Sponsor class: OTHER
Collaborators: name: National Institute on Drug Abuse (NIDA)
First posted: 2012-03-09
Enrollment: 133
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility criteria: 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

Primary outcomes:
measure: Change in Objective Opioid Withdrawal Score (OOWS) From Baseline (Prevention of Opioid Withdrawal)
timeFrame: Baseline; 15 minutes following last naloxone dose
measure: Change in Objective Opioid Withdrawal Score From Baseline (Prevention of Physical Dependence)
timeFrame: Baseline; 15 minutes following last naloxone dose
Secondary outcomes:
measure: Change in Subjective Opioid Withdrawal Score (SOWS) From Baseline (Prevention of Opioid Withdrawal)
timeFrame: Baseline; 15 minutes following last naloxone dose
measure: Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Opioid Withdrawal)
timeFrame: 2 study days 1 month apart (at the start of each study visit)
measure: Profile of Mood States (POMS) Change in Score From Baseline (Prevention of Opioid Withdrawal)
timeFrame: Baseline; 15 minutes following last naloxone dose
measure: Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Opioid Withdrawal)
timeFrame: 2 study days 1 month apart (at the start of each study visit)
measure: Change in Roland-Morris Disability Index (RMDI) From Baseline (Prevention of Opioid Withdrawal)
timeFrame: 2 study days 1 month apart (at the start of each study visit)
measure: Change in Subjective Opioid Withdrawal Score From Baseline (Prevention of Physical Dependence)
timeFrame: Baseline; 15 minutes following last naloxone dose
measure: Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Physical Dependence)
timeFrame: 2 study days 1 month apart (at the start of each study visit)
measure: Profile of Mood States (POMS) Change in Score From Baseline (Prevention of Physical Dependence)
timeFrame: Baseline; 15 minutes following last naloxone dose
measure: Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Physical Dependence)
timeFrame: 2 study days 1 month apart (at the start of each study visit)
measure: Change in Roland-Morris Disability (RMDI) Index From Baseline (Prevention of Physical Dependence)
timeFrame: 2 study days 1 month apart (at the start of each study visit)
Other outcomes:
Locations:
city: Stanford
country: United States
facility: Stanford University
state: California
Study officials:
affiliation: Stanford University
name: Larry F Chu, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
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citation: 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.
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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 Sep/Oct;11(5):342-349. doi: 10.1097/ADM.0000000000000321.
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 pain control. Drug Alcohol Depend. 2018 Feb 1;183:176-183. doi: 10.1016/j.drugalcdep.2017.06.043. Epub 2017 Aug 14.