Opioid Use, Unspecified With WithdrawalPhase 4NCT02025855
Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit
A Phase 4 study testing Methadone in people with Opioid Use, Unspecified With Withdrawal and Opioid-Induced Disorders, run by Henry Ford Health System at 1 site in United States.
Trial summary
The purpose of this study is to determine if administering methadone to mechanically ventilated patients in the medical intensive care unit (ICU) requiring continuous infusions of sedatives and analgesics will decrease the time of mechanical ventilation, when initiated within 48 hours of their admission. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Opioid Use, Unspecified With Withdrawal, Opioid-Induced Disorders, Delirium
- What is being tested?
- Methadone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 9 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2014to Oct 2017
- Phase
- Phase 4
- 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 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Mechanically ventilated patients with opioid consumption greater than or equal to 1,200 mcg of fentanyl or equivalent consumption of another opioid per day during the first 48 hours of intubation.
Who cannot join
- Allergy to methadone
- Admitted for head injury
- Admitted for seizure
- Seizure during admission, prior to enrollment
- Subjects at high risk for developing a prolonged corrected QT (QTc) interval
- Gastric residual volume ≥200 mL
Show all 14Show fewer
- Suspected obstruction or ileus
- Nausea and vomiting
- Recent abdominal surgery
- Active upper or lower gastrointestinal bleeding
- Active order for no medications by mouth or Total parenteral nutrition (TPN)
- Pregnancy
- Subjects receiving neuromuscular blocker infusions
- Subjects taking antipsychotics at baseline
Trial locations and contacts
1 site in 1 country.
About this study
The purpose of this study is to determine if administering methadone to mechanically ventilated patients in the medical intensive care unit (ICU) requiring continuous infusions of sedatives and analgesics will decrease the time of mechanical ventilation, when initiated within 48 hours of their admission. Patients meeting enrollment criteria will be randomly assigned to receive methadone or placebo in addition to standard care. Methadone is a long acting pain medication that is approved by the Food and Drug Administration (FDA) to manage withdrawal from opioids and moderate to severe pain. Both of these indications are a frequent concern for critically ill patients that require mechanical ventilation. These patients often require intravenous (IV) opioids to manage the pain they experience due to their illness, procedures, and mechanical ventilation. During this time patients can develop physical dependence, which leads to withdrawal symptoms when the opioids are stopped or the dose is reduced. These symptoms can include agitation, pain, diarrhea and several others. Currently this is managed by a slow reduction in the dose of the IV opioid, but this can lead to prolonged time on mechanical ventilation, which has been associated with increased morbidity. Administering oral methadone to patients experiencing withdrawal symptoms has been shown to reduce and even eliminate these symptoms in the outpatient setting. This should also benefit patients in the ICU experiencing withdrawal from intravenous opioids required during their stay. It may allow for the other opioids to be discontinued more quickly, allowing for a shorter duration of mechanical ventilation.
The level of pain and sedation will be assessed between groups randomized to either methadone or placebo in addition to current intravenous sedative and analgesic agents. The duration of mechanical ventilation will be assessed between both groups. Opioid withdrawal symptoms may manifest or be mistaken for delirium symptoms. ICU delirium is often managed with antipsychotic medications. To assess if methadone can reduce the need for antipsychotic medication, all administered antipsychotic doses will be recorded and total consumption will be compared between the two groups. Methadone has been associated with abnormal heart rhythms in rare instances. To ensure patient safety, data from the heart monitor will be collected and compared between the two groups to assess for QT interval prolongation.
- Being tested
- Methadone, Placebo
- Keywords
- Iatrogenic opioid abstinence syndrome, Methadone, Mechanical ventilation, ICU delirium, Continuous sedation
- Medical subject headings
- Delirium
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MethadoneDrug
PlaceboDrug
| Study group | Role | What they receive |
|---|---|---|
| Methadone | Experimental | Methadone will be administered at a dose calculated from the subjects total daily opioid requirements, with a maximum methadone dose of 60 mg per day. The methadone will be administered every 8 hours as 5 mg capsules that will be given via an enteral feeding tube. Receives: Drug: Methadone |
| Placebo | Placebo comparator | This will be a capsule containing only lactose and will be given every 8 hours via an enteral feeding tube. The number of placebo capsules will be calculated based on the subjects opioid requirements. This will ensure the same number of capsules will be given despite which arm the patient is enrolled in. Receives: Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time to Extubation
The time to extubation will be calculated and compared for both groups.
Measured: Up to 14 days
Secondary outcomes (5)
Cumulative Opioid Consumption
Cumulative doses of opioids will be collected and converted to morphine equivalents for analysis.
Measured: Up to 14 days
Level of Sedation
Levels of pain and sedation will be assessed per institutional policy, which utilizes the Motor Agitation Assessment Scale (MAAS). Average daily scores will be collected and compared for each group. The MAAS is scored from 0 (patient unresponsive) to 6 (dangerously agitated, uncooperative patient).
Measured: Up to 14 days
Corrected QT Interval
QTc intervals will be calculated and documented at baseline and every 24 hours after to ensure it does not become prolonged. These values will be compared between groups by taking the median of the baseline and daily values.
Measured: Up to 14 days
Cumulative Antipsychotic Use
The number of doses of antipsychotic medications will be collected and compared as a surrogate marker for presumed delirium.
Measured: Up to 14 days
Cumulative Benzodiazepine Consumption
Doses of all benzodiazepines will be collected and compared between groups to determine if methadone reduces consumption.
Measured: Up to 14 days
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted1 Jan 2014 (estimated)
- Study startJan 2014
- Primary completionOct 2017
- Study completionOct 2017
Why it stopped: PI no longer practicing at study institution.
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 (8)Papers the sponsor has linked to this study.
- Other trials for Opioid Use, Unspecified With WithdrawalStudies of the same condition, open and under way.
- 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 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 9 participants (actual)
Sponsor and investigators
- Lead sponsor
- Henry Ford Health System
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Thomas L Smoot, PharmD, Principal investigator, Henry Ford Health System
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02025855
- Sponsor's protocol ID
- Smoot_8503
- Status last verified
- Dec 2025
- First submitted
- 30 Dec 2013
- Last updated
- 5 Dec 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
Publications
Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998 Aug;114(2):541-8. doi: 10.1378/chest.114.2.541.
PubMed 9726743Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care. 2012 Dec 12;16(2):R49. doi: 10.1186/cc11250.
PubMed 22420584Lugo RA, MacLaren R, Cash J, Pribble CG, Vernon DD. Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy. 2001 Dec;21(12):1566-73. doi: 10.1592/phco.21.20.1566.34471.
PubMed 11765307Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005 Apr 1;95(7):915-8. doi: 10.1016/j.amjcard.2004.11.055.
PubMed 15781034Tobias JD, Schleien CL, Haun SE. Methadone as treatment for iatrogenic narcotic dependency in pediatric intensive care unit patients. Crit Care Med. 1990 Nov;18(11):1292-3. doi: 10.1097/00003246-199011000-00024. No abstract available.
PubMed 1977561Johnson PN, Boyles KA, Miller JL. Selection of the initial methadone regimen for the management of iatrogenic opioid abstinence syndrome in critically ill children. Pharmacotherapy. 2012 Feb;32(2):148-57. doi: 10.1002/PHAR.1001. Epub 2012 Jan 24.
PubMed 22392424Bowens CD, Thompson JA, Thompson MT, Breitzka RL, Thompson DG, Sheeran PW. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011 Sep;12(5):504-11. doi: 10.1097/PCC.0b013e3181fe38f5.
PubMed 21076361Hovav E, Weinstock M. Temporal factors influencing the development of acute tolerance to opiates. J Pharmacol Exp Ther. 1987 Jul;242(1):251-6.
PubMed 3612531
Study at a glance
From the registry record, last updated by the sponsor on 5 Dec 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Adjunct Methadone to Decrease the Duration of Mechanical Ventilation in the Medical Intensive Care Unit
- ClinicalTrials.gov ID
- NCT02025855
- Acronym / sponsor ID
- Smoot_8503
- Keywords
- Iatrogenic opioid abstinence syndrome, Methadone, Mechanical ventilation, ICU delirium, Continuous sedation
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: PI no longer practicing at study institution.
- Enrolment
- 9 participants (actual)
- Lead sponsor
- Henry Ford Health SystemUniversity, hospital or other
- Study start
- Jan 2014
- Primary completion
- Oct 2017 (actual)
- Study completion
- Oct 2017 (actual)
- First posted
- 1 Jan 2014 (estimated)
- Results
- Posted 5 Dec 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to determine if administering methadone to mechanically ventilated patients in the medical intensive care unit (ICU) requiring continuous infusions of sedatives and analgesics will decrease the time of mechanical ventilation, when initiated within 48 hours of their admission. Patients meeting enrollment criteria will be randomly assigned to receive methadone or placebo in addition to standard care. Methadone is a long acting pain medication that is approved by the Food and Drug Administration (FDA) to manage withdrawal from opioids and moderate to severe pain. Both of these indications are a frequent concern for critically ill patients that require mechanical ventilation. These patients often require intravenous (IV) opioids to manage the pain they experience due to their illness, procedures, and mechanical ventilation. During this time patients can develop physical dependence, which leads to withdrawal symptoms when the opioids are stopped or the dose is reduced. These symptoms can include agitation, pain, diarrhea and several others. Currently this is managed by a slow reduction in the dose of the IV opioid, but this can lead to prolonged time on mechanical ventilation, which has been associated with increased morbidity. Administering oral methadone to patients experiencing withdrawal symptoms has been shown to reduce and even eliminate these symptoms in the outpatient setting. This should also benefit patients in the ICU experiencing withdrawal from intravenous opioids required during their stay. It may allow for the other opioids to be discontinued more quickly, allowing for a shorter duration of mechanical ventilation.
The level of pain and sedation will be assessed between groups randomized to either methadone or placebo in addition to current intravenous sedative and analgesic agents. The duration of mechanical ventilation will be assessed between both groups. Opioid withdrawal symptoms may manifest or be mistaken for delirium symptoms. ICU delirium is often managed with antipsychotic medications. To assess if methadone can reduce the need for antipsychotic medication, all administered antipsychotic doses will be recorded and total consumption will be compared between the two groups. Methadone has been associated with abnormal heart rhythms in rare instances. To ensure patient safety, data from the heart monitor will be collected and compared between the two groups to assess for QT interval prolongation.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Methadone | Experimental | Drug: MethadoneMethadone will be administered at a dose calculated from the subjects total daily opioid requirements, with a maximum methadone dose of 60 mg per day. The methadone will be administered every 8 hours as 5 mg capsules that will be given via an enteral feeding tube. |
| Placebo | Placebo comparator | Drug: PlaceboThis will be a capsule containing only lactose and will be given every 8 hours via an enteral feeding tube. The number of placebo capsules will be calculated based on the subjects opioid requirements. This will ensure the same number of capsules will be given despite which arm the patient is enrolled in. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (1 listed)
- Mechanically ventilated patients with opioid consumption greater than or equal to 1,200 mcg of fentanyl or equivalent consumption of another opioid per day during the first 48 hours of intubation.
Key exclusion criteria (14 listed)
- Allergy to methadone
- Admitted for head injury
- Admitted for seizure
- Seizure during admission, prior to enrollment
- Subjects at high risk for developing a prolonged corrected QT (QTc) interval
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 |
|---|---|---|
| Methadone | Drug | Methadone |
| Placebo | Drug | Placebo |
Primary outcome
Time to Extubation
Time frame: Up to 14 days
The time to extubation will be calculated and compared for both groups.
5 secondary outcomes
Cumulative Opioid Consumption
Time frame: Up to 14 days
Level of Sedation
Time frame: Up to 14 days
Corrected QT Interval
Time frame: Up to 14 days
Cumulative Antipsychotic Use
Time frame: Up to 14 days
Cumulative Benzodiazepine Consumption
Time frame: Up to 14 days
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 5 Dec 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 9726743Kollef MH, Levy NT, Ahrens TS, Schaiff R, Prentice D, Sherman G. The use of continuous i.v. sedation is associated with prolongation of mechanical ventilation. Chest. 1998 Aug;114(2):541-8. doi: 10.1378/chest.114.2.541.
- Background: PubMed 22420584Wanzuita R, Poli-de-Figueiredo LF, Pfuetzenreiter F, Cavalcanti AB, Westphal GA. Replacement of fentanyl infusion by enteral methadone decreases the weaning time from mechanical ventilation: a randomized controlled trial. Crit Care. 2012 Dec 12;16(2):R49. doi: 10.1186/cc11250.
- Background: PubMed 11765307Lugo RA, MacLaren R, Cash J, Pribble CG, Vernon DD. Enteral methadone to expedite fentanyl discontinuation and prevent opioid abstinence syndrome in the PICU. Pharmacotherapy. 2001 Dec;21(12):1566-73. doi: 10.1592/phco.21.20.1566.34471.
- Background: PubMed 15781034Martell BA, Arnsten JH, Krantz MJ, Gourevitch MN. Impact of methadone treatment on cardiac repolarization and conduction in opioid users. Am J Cardiol. 2005 Apr 1;95(7):915-8. doi: 10.1016/j.amjcard.2004.11.055.
- Background: PubMed 1977561Tobias JD, Schleien CL, Haun SE. Methadone as treatment for iatrogenic narcotic dependency in pediatric intensive care unit patients. Crit Care Med. 1990 Nov;18(11):1292-3. doi: 10.1097/00003246-199011000-00024. No abstract available.
- Background: PubMed 22392424Johnson PN, Boyles KA, Miller JL. Selection of the initial methadone regimen for the management of iatrogenic opioid abstinence syndrome in critically ill children. Pharmacotherapy. 2012 Feb;32(2):148-57. doi: 10.1002/PHAR.1001. Epub 2012 Jan 24.
- Background: PubMed 21076361Bowens CD, Thompson JA, Thompson MT, Breitzka RL, Thompson DG, Sheeran PW. A trial of methadone tapering schedules in pediatric intensive care unit patients exposed to prolonged sedative infusions. Pediatr Crit Care Med. 2011 Sep;12(5):504-11. doi: 10.1097/PCC.0b013e3181fe38f5.
- Background: PubMed 3612531Hovav E, Weinstock M. Temporal factors influencing the development of acute tolerance to opiates. J Pharmacol Exp Ther. 1987 Jul;242(1):251-6.
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.
Thomas L Smoot, PharmD principal investigator
Henry Ford Health System
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Methadone in people with Opioid Use, Unspecified With Withdrawal and Opioid-Induced Disorders, run by Henry Ford Health System 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 1 inclusion and 14 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: stopped early, as of the sponsor's last update on 5 Dec 2025. 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. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Dec 2025). 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?
Time to Extubation (time frame: Up to 14 days). 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 NCT02025855, which also lists 8 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 5 Dec 2025.