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

Study Overview
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Brief Summary
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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
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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.

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

Conditions
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Opioid Withdrawal, Physical Dependence

Intervention / Treatment
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* Drug: Ondansetron
* Drug: Placebo
* Drug: Morphine
* Drug: Naloxone 0.4 mg/70 kg
* Drug: Naloxone 0.8 mg/70 kg


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Prevention of Opioid Withdrawal<br>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<br>* Ondansetron 8 mg oral tablet<br>* Other names: Zofran;Drug: Placebo<br>* Placebo to Match Ondansetron<br>Drug: Morphine<br>* Sustained release oral morphine, beginning at 30 mg/d, titrated up by 15 mg/d every 2 days until adequate analgesia is achieved<br>Drug: Naloxone 0.4 mg/70 kg<br>* Naloxone 0.4 mg/70 kg intravenous<br>Drug: Naloxone 0.8 mg/70 kg<br>* Naloxone 0.8 mg/70 kg intravenous<br>|
| Experimental: Prevention of Physical Dependence<br>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<br>* Ondansetron 8 mg oral tablet<br>* Other names: Zofran;Drug: Placebo<br>* Placebo to Match Ondansetron<br>Drug: Morphine<br>* Sustained release oral morphine, beginning at 30 mg/d, titrated up by 15 mg/d every 2 days until adequate analgesia is achieved<br>Drug: Naloxone 0.4 mg/70 kg<br>* Naloxone 0.4 mg/70 kg intravenous<br>Drug: Naloxone 0.8 mg/70 kg<br>* Naloxone 0.8 mg/70 kg intravenous<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | 
| 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) | 
| 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 | 
| 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) | 
| 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) | 
| 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 | 
| 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) | 
| 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 | 
| 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) | 
| 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) |