PainPhase 1NCT00715988
Methadone Pharmacokinetics and Cardiac Effects in Newborns
A Phase 1 study testing Methadone HCl Inject 10 mg/ml (will require dilution) and Methadone in people with Pain, run by University of Utah at 2 sites in United States.
Trial summary
The Primary objectives of this proposal are to determine the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 weeks post menstrual age (PMA) who are 1 week old and older and establish any correlations of the kinetics with PMA to determine the bioavailability for… Read more about this study
- Who is it for?
- Ages 29 to 48 weeks
- Conditions the study is for
- Pain
- What is being tested?
- Methadone HCl Inject 10 mg/ml (will require dilution) and Methadone
- Type of treatment
- Pill or oral medicine, Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7 participants
- Where
- 2 sitesUnited States
- Study dates
- Oct 2007to 10 Feb 2017
- Phase
- Phase 1
- Are there results?
- None posted in the registry
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 29 to 48 weeks
- All sexes
- No healthy volunteers
- Child
Who may be able to join
- Patients must be in the NICU or PICU with continuous cardiorespiratory monitoring
- PMA between 29 0/7 to 48 6/7 weeks (EGA at birth (wks) + postnatal age wks) at the start of study
- Weight >1499 gm at the time of enrollment
- Postnatal age of 3 days or more
- Arterial or venous catheter suitable for blood sampling with a separate i.v. infusion site is preferred, but not essential
- Currently being treated with methadone bolus doses or fentanyl or morphine in bolus doses or by infusion for clinical indications and expected to be treated for at least 1-2 more days with opioids for study of single dose pharmacokinetics and to be treated for 3-5 days more during the study of bioavailability
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- Hematocrit ≥35%
- Parental permission
- Approval by the patient's attending physician
- Treatment Scheme 1, studied for 48 hr after a single i.v. dose of methadone
- Feeding or not feeding
- Mechanically ventilated
- Treatment Scheme 2 studied for 24 to 48 hr after a single i.v. dose of methadone AND again after a single enteral dose of methadone after the end of sampling after the first dose; order of doses is randomized. If the caregiver feels the patient is too sedated at the end of pK sampling after Dose, 1, then Dose 2 will be delayed until patient is judged to need analgesic treatment.
- Tolerating enteral feeding for 3 consecutive days before study
Who cannot join
- Clinically diagnosed liver dysfunction
- Clinically diagnosed kidney dysfunction with urine output <1.0 ml/kg/hr
- Gastrointestinal malformation or dysfunction that might interfere with enteral drug absorption
- Congenital anomalies or other conditions thought to be incompatible with life
- History of arrhythmias, excluding bradycardia associated with apnea
- Unstable cardiorespiratory status
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- Serum K+ <3.0 mEq/L
- QTc[H] >0.449 ms using Hodges correction =QT + 1.75(rate - 60).
- Family history of unexplained early cardiac deaths, syncope, or long QT syndrome in primary relatives: siblings, parents, grandparents, or aunts/uncles.
- Treatment with inhibitors and inducers of CYP3A4, CYP2B6, CYP2D6 and PGP including:
- amiodarone, carbamazepine, ciprofloxacin, clarithromycin, clotrimazole, dexamethasone, erythromycin, ethosuximide, fluconazole, fluoxetine, fluvoxamine, grapefruit juice, indinavir, itraconazole, ketoconazole, metronidazole, miconazole, nelfinavir, paroxetine, phenobarbital, phenytoin, quercetin, quinidine, rifabutin, rifampin, ritonavir, saquinavir, sulfadimidine, sulfinpyrazone, troleandomycin
Trial locations and contacts
2 sites in 1 country.
United States2 sites
University of Utah
Salt Lake City, Utah, 84108
Primary Children's Medical Center
Salt Lake City, Utah, 84113
About this study
Official title: Safety and Single Dose Population Pharmacokinetics and Bioavailability of Methadone and Its Enantiomers in Newborns and Young Infants At 29-48 Weeks Post Menstrual Age
The Primary objectives of this proposal are to determine the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 weeks post menstrual age (PMA) who are 1 week old and older and establish any correlations of the kinetics with PMA to determine the bioavailability for enterally administered methadone in these newborns and young infants.
The secondary objectives of this proposal are to explore possible genotypic changes in CYP3A4-3A7-3A5, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 and PGO on the kinetics of methadone in neonates and young infants and to test the safety of methadone in this population by correlating the plasma concentrations of the methadone enantiomers, S-methadone and R-methadone, with changes in cardiac repolarization by measurement of corrected QT, heart rate, and blood pressure.
Read the detailed description
Painful procedures are frequent during the NICU care of sick newborns. Newborns are capable of perceiving pain by the time in fetal development when they reach our current limits of viability around 23-24 weeks post menstrual age.1 Painful procedures include suctioning during mechanical ventilation, thoracostomy tube placement, heel lance and venipuncture for blood sampling, and care following surgical procedures such as PDA ligation and bowel resection. Simons et al recently reported on the number of painful procedures in a large NICU in Rotterdam and provided a review of the frequency of such procedures from other NICU's.2 This review shows that before discharge from the NICU, newborns may experience as many as 376 painful procedures and as many as 61 painful procedures in a single day (or more if all procedures were not observed or reported). The most frequent procedures were heel lance and suctioning, both associated with the need for mechanical ventilation. Topical treatment of pain from heel lance has not been successful with EMLA3 or tetracaine.4
During initial NICU care for infants supported with mechanical ventilation, systemic analgesia is usually provided with parenteral treatment with fentanyl or morphine. Most neonates are extubated soon after birth, and continued systemic treatment with analgesics is not needed. Other neonates have problems associated with chronic pain or continued painful procedures, such as surgical problems, chronic lung disease, airway anomalies, pulmonary hypoplasia and pulmonary hypertension following ECMO and congenital diaphragmatic hernia repair. These patients often require mechanical ventilation for weeks and sometimes months. During that prolonged care, systemic analgesia is changed to enteral dosing to reduce risks of infection associated with central catheters and to reduce the number of intravenous catheter insertions.
Morphine and fentanyl administered enterally do not provide reliable systemic concentrations and effects due to first-pass metabolism. Fentanyl undergoes first-pass metabolism by CYP3A4 during passage through the intestines and liver. Morphine undergoes first pass hepatic metabolism primarily by UGT2B7. In addition for morphine, one of its major metabolites, the 3-glucuronide, is anti-analgesic and can cause dysphoria. An effective and well-characterized systemic analgesic that can be administered enterally is needed for the care of infants who require prolonged analgesic treatment and methadone can meet those needs.
Methadone treatment in adults provides effective systemic analgesia after enteral administration through binding to the mu opioid receptor with a wide range of reported half-lives of 5 to 130 hrs,5 2 to 50 hrs,6 and 33 to 46 hrs; 7 and bioavailability ranging from 41 to 95%.8, 9
Recently, methadone was reported to prolong QTc in adults receiving large doses of methadone during chronic treatment, often with additional predisposing factors for QT prolongation. Methadone is dispensed in a racemic mixture whose enantiomers have different potency for analgesia and for binding to the myocardium to potentially prolong QT. In addition the different enantiomers exhibit complex kinetics in adults as they undergo metabolism, primarily by CYP3A4, CYP2B6, and CYP2C19. This study will evaluate kinetics and bioavailability of methadone enantiomers and its effects on QT of neonates and young infants.
- Conditions
- Pain
- Being tested
- Methadone HCl Inject 10 mg/ml (will require dilution), Methadone
- Keywords
- Methadone, analgesia, newborns, QT prolongation, Young Infants
- Medical subject headings
- Pain, Agnosia, Long QT Syndrome
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Methadone HCl Inject 10 mg/ml (will require dilution)Drug
Also called Dolophine, Methadose, Methadose Oral
Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 mg/ml (will require dilution)
MethadoneDrug
Also called Dolophine, Methadose, Methadose Oral
Methadone HCl oral solution 5 mg/ml Methadone HCl inject 10 ml/ml (will require dilution) Single dose
| Study group | Role | What they receive |
|---|---|---|
| Scheme 1 | Experimental | Patients who are feeding or not feeding and mechanically ventilated, >/=3 d of age and 29 0/7wks-48 6/7 wks PMA, treated with i.v. bolus doses or infusion of fentanyl, morphine or methadone for clinical indications, with arterial/venous line in place \& expected treatment for at least 1-2 more days. Pk sampling = 0.5 ml blood samples x6/infant. ECG monitoring. Three patients will be enrolled in 5 PMA groups. Should apnea or hypotension occur, dosages for Treatment Scheme 2 will be reduced (50%); more patients will be studied in Treatment Scheme 1 to insure that the lower dose is well tolerated \& effective. Receives: Drug: Methadone |
| Scheme 2 | Experimental | Patients defined in Scheme 1, tolerating feeds for >/= 3 days will be studied twice, after i.v. methadone and after enteral methadone after the end of sampling after the first dose. 4-5 samples will be obtained after dose 1 and after dose 2 depending on PMA and weight. Patients will be divided into groups based on PMA.. Receives: Drug: Methadone HCl Inject 10 mg/ml (will require dilution) |
What is being measured
The primary outcome is the main question the study is designed to answer.
Find the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 wks PMA who are 1 week old and older
Measured: 48 hours
Secondary outcomes (1)
Measure the effects of R and S enantiomers of methadone on QT interval in newborns
Measured: 48 hours
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted15 Jul 2008 (estimated)
- Study startOct 2007
- Primary completionSep 2012
- Study completion10 Feb 2017
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for PainStudies of the same condition, open and under way.
- More trials run by University of UtahThe 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 1
- Primary purpose
- Supportive care
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 7 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Utah
- Sponsor type
- University, hospital or other
- Collaborators
- Case Western Reserve University, Children's Mercy Hospital Kansas City, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Responsible party
- Principal investigator, Robert Ward, University of Utah
- Investigators
- Robert Ward, M.D., Principal investigator, University of Utah
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00715988
- Sponsor's protocol ID
- 24569
- Other IDs
- 1U10HD045986-01
- Status last verified
- May 2022
- First submitted
- 10 Jul 2008
- Last updated
- 1 Jun 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- Yes: Data shared with other investigators leading to publication of the pediatric population pharmacokinetics of methadone
Publications
Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014 Jun;24(6):591-601. doi: 10.1111/pan.12385. Epub 2014 Mar 26.
PubMed 24666686
Study at a glance
From the registry record, last updated by the sponsor on 1 Jun 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Safety and Single Dose Population Pharmacokinetics and Bioavailability of Methadone and Its Enantiomers in Newborns and Young Infants At 29-48 Weeks Post Menstrual Age
- ClinicalTrials.gov ID
- NCT00715988
- Acronym / sponsor ID
- 24569
- Conditions
- Pain
- Keywords
- Methadone, analgesia, newborns, QT prolongation, Young Infants
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7 participants (actual)
- Lead sponsor
- University of UtahUniversity, hospital or other
- Collaborators
- Case Western Reserve University, Children's Mercy Hospital Kansas City, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- Study start
- Oct 2007
- Primary completion
- Sep 2012 (actual)
- Study completion
- 10 Feb 2017 (actual)
- First posted
- 15 Jul 2008 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The Primary objectives of this proposal are to determine the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 weeks post menstrual age (PMA) who are 1 week old and older and establish any correlations of the kinetics with PMA to determine the bioavailability for enterally administered methadone in these newborns and young infants.
The secondary objectives of this proposal are to explore possible genotypic changes in CYP3A4-3A7-3A5, CYP2B6, CYP2C8, CYP2C19, and CYP2D6 and PGO on the kinetics of methadone in neonates and young infants and to test the safety of methadone in this population by correlating the plasma concentrations of the methadone enantiomers, S-methadone and R-methadone, with changes in cardiac repolarization by measurement of corrected QT, heart rate, and blood pressure.
Detailed description
Painful procedures are frequent during the NICU care of sick newborns. Newborns are capable of perceiving pain by the time in fetal development when they reach our current limits of viability around 23-24 weeks post menstrual age.1 Painful procedures include suctioning during mechanical ventilation, thoracostomy tube placement, heel lance and venipuncture for blood sampling, and care following surgical procedures such as PDA ligation and bowel resection. Simons et al recently reported on the number of painful procedures in a large NICU in Rotterdam and provided a review of the frequency of such procedures from other NICU's.2 This review shows that before discharge from the NICU, newborns may experience as many as 376 painful procedures and as many as 61 painful procedures in a single day (or more if all procedures were not observed or reported). The most frequent procedures were heel lance and suctioning, both associated with the need for mechanical ventilation. Topical treatment of pain from heel lance has not been successful with EMLA3 or tetracaine.4
During initial NICU care for infants supported with mechanical ventilation, systemic analgesia is usually provided with parenteral treatment with fentanyl or morphine. Most neonates are extubated soon after birth, and continued systemic treatment with analgesics is not needed. Other neonates have problems associated with chronic pain or continued painful procedures, such as surgical problems, chronic lung disease, airway anomalies, pulmonary hypoplasia and pulmonary hypertension following ECMO and congenital diaphragmatic hernia repair. These patients often require mechanical ventilation for weeks and sometimes months. During that prolonged care, systemic analgesia is changed to enteral dosing to reduce risks of infection associated with central catheters and to reduce the number of intravenous catheter insertions.
Morphine and fentanyl administered enterally do not provide reliable systemic concentrations and effects due to first-pass metabolism. Fentanyl undergoes first-pass metabolism by CYP3A4 during passage through the intestines and liver. Morphine undergoes first pass hepatic metabolism primarily by UGT2B7. In addition for morphine, one of its major metabolites, the 3-glucuronide, is anti-analgesic and can cause dysphoria. An effective and well-characterized systemic analgesic that can be administered enterally is needed for the care of infants who require prolonged analgesic treatment and methadone can meet those needs.
Methadone treatment in adults provides effective systemic analgesia after enteral administration through binding to the mu opioid receptor with a wide range of reported half-lives of 5 to 130 hrs,5 2 to 50 hrs,6 and 33 to 46 hrs; 7 and bioavailability ranging from 41 to 95%.8, 9
Recently, methadone was reported to prolong QTc in adults receiving large doses of methadone during chronic treatment, often with additional predisposing factors for QT prolongation. Methadone is dispensed in a racemic mixture whose enantiomers have different potency for analgesia and for binding to the myocardium to potentially prolong QT. In addition the different enantiomers exhibit complex kinetics in adults as they undergo metabolism, primarily by CYP3A4, CYP2B6, and CYP2C19. This study will evaluate kinetics and bioavailability of methadone enantiomers and its effects on QT of neonates and young infants.
Study design
- Primary purpose
- Supportive care
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Scheme 1 | Experimental | Drug: MethadonePatients who are feeding or not feeding and mechanically ventilated, >/=3 d of age and 29 0/7wks-48 6/7 wks PMA, treated with i.v. bolus doses or infusion of fentanyl, morphine or methadone for clinical indications, with arterial/venous line in place \& expected treatment for at least 1-2 more days. Pk sampling = 0.5 ml blood samples x6/infant. ECG monitoring. Three patients will be enrolled in 5 PMA groups. Should apnea or hypotension occur, dosages for Treatment Scheme 2 will be reduced (50%); more patients will be studied in Treatment Scheme 1 to insure that the lower dose is well tolerated \& effective. |
| Scheme 2 | Experimental | Drug: Methadone HCl Inject 10 mg/ml (will require dilution)Patients defined in Scheme 1, tolerating feeds for >/= 3 days will be studied twice, after i.v. methadone and after enteral methadone after the end of sampling after the first dose. 4-5 samples will be obtained after dose 1 and after dose 2 depending on PMA and weight. Patients will be divided into groups based on PMA.. |
Who may qualify
- Ages
- 29 to 48 weeks
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Child
Key inclusion criteria (14 listed)
- Patients must be in the NICU or PICU with continuous cardiorespiratory monitoring
- PMA between 29 0/7 to 48 6/7 weeks (EGA at birth (wks) + postnatal age wks) at the start of study
- Weight >1499 gm at the time of enrollment
- Postnatal age of 3 days or more
- Arterial or venous catheter suitable for blood sampling with a separate i.v. infusion site is preferred, but not essential
Key exclusion criteria (11 listed)
- Clinically diagnosed liver dysfunction
- Clinically diagnosed kidney dysfunction with urine output <1.0 ml/kg/hr
- Gastrointestinal malformation or dysfunction that might interfere with enteral drug absorption
- Congenital anomalies or other conditions thought to be incompatible with life
- History of arrhythmias, excluding bradycardia associated with apnea
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 HCl Inject 10 mg/ml (will require dilution)Also: Dolophine, Methadose, Methadose OralMethadone HCl oral solution 5 mg/ml Methadone HCl inject 10 mg/ml (will require dilution) | Drug | Scheme 2 |
| MethadoneAlso: Dolophine, Methadose, Methadose OralMethadone HCl oral solution 5 mg/ml Methadone HCl inject 10 ml/ml (will require dilution) Single dose | Drug | Scheme 1 |
Primary outcome
Find the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 wks PMA who are 1 week old and older
Time frame: 48 hours
1 secondary outcome
Measure the effects of R and S enantiomers of methadone on QT interval in newborns
Time frame: 48 hours
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 1 Jun 2022.
- Derived from this study: PubMed 24666686Ward RM, Drover DR, Hammer GB, Stemland CJ, Kern S, Tristani-Firouzi M, Lugo RA, Satterfield K, Anderson BJ. The pharmacokinetics of methadone and its metabolites in neonates, infants, and children. Paediatr Anaesth. 2014 Jun;24(6):591-601. doi: 10.1111/pan.12385. Epub 2014 Mar 26.
- Individual participant dataSharing planned: Yes. Data shared with other investigators leading to publication of the pediatric population pharmacokinetics of methadone
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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.
Robert Ward, M.D. principal investigator
University of Utah
2 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Methadone HCl Inject 10 mg/ml (will require dilution) and Methadone in people with Pain, run by University of Utah at 2 sites 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 14 inclusion and 11 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 1 Jun 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 2 sites 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.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
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?
Find the population kinetics for methadone and its enantiomers in preterm newborns and infants at 29 weeks to 48 wks PMA who are 1 week old and older (time frame: 48 hours). 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 NCT00715988, which also lists 1 linked publication.
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 1 Jun 2022.