Opioid WithdrawalNCT01549652
5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Physical Dependence
A study testing Ondansetron, Morphine and Naloxone 0.4 mg/70 kg in people with Opioid Withdrawal and Physical Dependence, run by Stanford University at 1 site in United States.
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. Read more about this study
- Who is it for?
- Ages 18 to 60 years
- Conditions the study is for
- Opioid Withdrawal, Physical Dependence
- What is being tested?
- Ondansetron, Morphine and Naloxone 0.4 mg/70 kg
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 133 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2011to Oct 2016
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 60 years
- All sexes
- No healthy volunteers
- Adult
Who may be able to join
- 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.
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this 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. 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.
Read the 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.
- Conditions
- Opioid Withdrawal, Physical Dependence
- Being tested
- Ondansetron, Placebo, Morphine, Naloxone 0.4 mg/70 kg, Naloxone 0.8 mg/70 kg
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
OndansetronDrug
Also called Zofran
Ondansetron 8 mg oral tablet
PlaceboDrug
Placebo to Match Ondansetron
MorphineDrug
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 kgDrug
Naloxone 0.4 mg/70 kg intravenous
Naloxone 0.8 mg/70 kgDrug
Naloxone 0.8 mg/70 kg intravenous
| Study group | Role | What they receive |
|---|---|---|
| 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. Receives: 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. Receives: Drug: Ondansetron; Drug: Placebo; Drug: Morphine; Drug: Naloxone 0.4 mg/70 kg; Drug: Naloxone 0.8 mg/70 kg |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 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.
Measured: Baseline; 15 minutes following last naloxone dose
Secondary outcomes (10)
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
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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
Measured: 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).
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 2 study days 1 month apart (at the start of each study visit)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 Mar 2012 (estimated)
- Study startApr 2011
- Primary completionApr 2015
- Study completionOct 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (14)Papers the sponsor has linked to this study.
- Other trials for Opioid WithdrawalStudies of the same condition, open and under way.
- More trials run by Stanford UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind
- Who is masked
- Participant, Care provider, Outcomes assessor
- Enrolment
- 133 participants (actual)
Sponsor and investigators
- Lead sponsor
- Stanford University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Responsible party
- Principal investigator, Larry Fu-nien Chu, Stanford University
- Investigators
- Larry F Chu, MD, MS, Principal investigator, Stanford University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01549652
- Sponsor's protocol ID
- 5HT3 19821
- Other IDs
- 1R01DA029078
- Status last verified
- Jan 2019
- First submitted
- 13 Feb 2012
- Last updated
- 7 Jan 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
Publications
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.
PubMed 19214139Atlas 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.
PubMed 12635113Betses 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.
PubMed 23964897Birnbaum 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.
PubMed 21392250Chu 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.
PubMed 22704854Clark 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.
PubMed 11844633Colthup 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.
PubMed 1839313Compton 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.
PubMed 14636819Compton 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.
PubMed 14751453Handelsman 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.
PubMed 3687892Plosker 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.
PubMed 10147044Meert 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.
PubMed 8517886Chu 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.
PubMed 28514235Chu 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.
PubMed 29278818
Study at a glance
From the registry record, last updated by the sponsor on 7 Jan 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 5HT3 Antagonists to Treat Opioid Withdrawal and to Prevent the Progression of Physical Dependence
- ClinicalTrials.gov ID
- NCT01549652
- Acronym / sponsor ID
- 5HT3 19821
- Conditions
- Opioid Withdrawal, Physical Dependence
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 133 participants (actual)
- Lead sponsor
- Stanford UniversityUniversity, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Study start
- Apr 2011
- Primary completion
- Apr 2015 (actual)
- Study completion
- Oct 2016 (actual)
- First posted
- 9 Mar 2012 (estimated)
- Results
- Posted 7 Jan 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Triple blind (participant, care provider, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Prevention of Opioid Withdrawal | Experimental | Drug: Ondansetron, Drug: Placebo, Drug: Morphine, Drug: Naloxone 0.4 mg/70 kg, Drug: Naloxone 0.8 mg/70 kgChronic 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. |
| Prevention of Physical Dependence | Experimental | Drug: Ondansetron, Drug: Placebo, Drug: Morphine, Drug: Naloxone 0.4 mg/70 kg, Drug: Naloxone 0.8 mg/70 kgChronic 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. |
Who may qualify
- Ages
- 18 to 60 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
Key inclusion criteria (4 listed)
- 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.
Key exclusion criteria (7 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| OndansetronAlso: ZofranOndansetron 8 mg oral tablet | Drug | Prevention of Opioid Withdrawal, Prevention of Physical Dependence |
| PlaceboPlacebo to Match Ondansetron | Drug | Prevention of Opioid Withdrawal, Prevention of Physical Dependence |
| MorphineSustained release oral morphine, beginning at 30 mg/d, titrated up by 15 mg/d every 2 days until adequate analgesia is achieved | Drug | Prevention of Opioid Withdrawal, Prevention of Physical Dependence |
| Naloxone 0.4 mg/70 kgNaloxone 0.4 mg/70 kg intravenous | Drug | Prevention of Opioid Withdrawal, Prevention of Physical Dependence |
| Naloxone 0.8 mg/70 kgNaloxone 0.8 mg/70 kg intravenous | Drug | Prevention of Opioid Withdrawal, Prevention of Physical Dependence |
Primary outcome
Change in Objective Opioid Withdrawal Score (OOWS) From Baseline (Prevention of Opioid Withdrawal)
Time frame: Baseline; 15 minutes following last naloxone dose
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.
Change in Objective Opioid Withdrawal Score From Baseline (Prevention of Physical Dependence)
Time frame: Baseline; 15 minutes following last naloxone dose
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.
10 secondary outcomes
Change in Subjective Opioid Withdrawal Score (SOWS) From Baseline (Prevention of Opioid Withdrawal)
Time frame: Baseline; 15 minutes following last naloxone dose
Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Opioid Withdrawal)
Time frame: 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)
Time frame: Baseline; 15 minutes following last naloxone dose
Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Opioid Withdrawal)
Time frame: 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)
Time frame: 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)
Time frame: Baseline; 15 minutes following last naloxone dose
Beck Depression Inventory Score (BDIS) Change From Baseline (Prevention of Physical Dependence)
Time frame: 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)
Time frame: Baseline; 15 minutes following last naloxone dose
Change in Pain Visual Analog Scale (VAS) From Baseline (Prevention of Physical Dependence)
Time frame: 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)
Time frame: 2 study days 1 month apart (at the start of each study visit)
Results and safety
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Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Jan 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 19214139Chu 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.
- Background: PubMed 12635113Atlas 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.
- Background: PubMed 23964897Betses 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.
- Background: PubMed 21392250Birnbaum 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.
- Background: PubMed 22704854Chu 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.
- Background: PubMed 11844633Clark 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.
- Background: PubMed 1839313Colthup 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.
- Background: PubMed 14636819Compton 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.
- Background: PubMed 14751453Compton 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.
- Background: PubMed 3687892Handelsman 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.
- Background: PubMed 10147044Plosker 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.
- Background: PubMed 8517886Meert 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.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Larry F Chu, MD, MS principal investigator
Stanford University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Ondansetron, Morphine and Naloxone 0.4 mg/70 kg in people with Opioid Withdrawal and Physical Dependence, run by Stanford University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 4 inclusion and 7 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Jan 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 7 Jan 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Change in Objective Opioid Withdrawal Score (OOWS) From Baseline (Prevention of Opioid Withdrawal) (time frame: Baseline; 15 minutes following last naloxone dose). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01549652, which also lists 14 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Jan 2019.