Single Dose IV Methadone for Post-Op Pain

Pharmacokinetics, Pharmacodynamics, and Safety of a Single Dose Intravenous Methadone in Healthy Adult Volunteers (MTH02)

Status

Completed

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT05425420

Acronym

MTH02

Enrollment

Registered

2022-06-21

Start date

2023-08-11

Completion date

2024-01-20

Last updated

2025-02-10

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Pain, Postoperative

Brief summary

Single-center, open label, single-session study to evaluate methadone pharmacokinetics and pharmacodynamic in adults.

Detailed description

The Adult Methadone study will be conducted at a single site, Duke Early Phase Research Unity (DEPRU), to enroll 24 participants. Participants will be treated/monitored overnight with Methadone hydrochloride IV (FDA approved and commercially available), with daily follow-up visits for 1 week total. The study aims to provide information on the disposition and clinical effects of intravenous methadone to update the drug label.

Interventions

DRUGmethadone hydrochloride 0.1mg/kg

Single dose of methadone hydrochloride administered via intravenous (IV)

Study design

Allocation

Intervention model

SINGLE_GROUP

Primary purpose

OTHER

Masking

NONE

Intervention model description

Subjects will be studied on one occasion in the Early Phase Research Unit at Duke University Medical Center for administration of drug, collection of blood samples, and measurements of drug effect. Study drug is intravenous methadone hydrochloride Plasma samples collections are obtained up to 96 hr after dosing. Dark-adapted pupil diameter is measured by infrared camera. Responses to thermal skin stimulation are recorded. Respiratory rate and end-tidal carbon dioxide concentrations are measured. Subject self-assessment of methadone effect is performed using verbal analog scales. Blood samples obtained during the study will be analyzed for plasma concentrations of methadone.

Eligibility

Sex/Gender

ALL

Age

18 Years to 40 Years

Healthy volunteers

Yes

Inclusion criteria

1. 18 to \< 40 years of age at the time of enrollment 2. Provide informed consent

Exclusion criteria

1. History of cardiac dysfunction 2. History of or current QTc prolongation, defined as \> 470 ms in males and \> 480 ms in females 3. Known hypersensitivity to methadone hydrochloride or any other ingredient in the methadone hydrochloride injection 4. Known acute bronchial asthma or hypercarbia (known history of known PaCO2 above 45 mm HG) 5. Receipt of a serotonergic drug or buproprion within 7 days prior to study enrollment 6. Receipt of benzodiazepines, muscle relaxants, or other opioids within 7 days prior to study enrollment 7. Receipt of a moderate or strong CYP2B6 inhibitor or inducer - either prescription or non-prescription medications, herbals,34 or foods known to be metabolized by or affecting CYP2B6 - within 30 days prior to study enrollment 1. CYP2B6 inhibitors include clopidogrel, prasugrel, thioTEPA, ticlopidine, voriconazole, macrolide antibiotics, azole-antifungal agents, fluconazole, Alstonia boonei, Mangifera indica, and Picralima nitida 2. CYP2B6 inducers include artemisinin antimalarials, barbiturates, carbamazepine, cyclophosphamide, efavirenz, lopinavir, methimazole, nelfinavir, phenobarbital, phenytoin, primidone, rifampicin/rifampin, ritonavir, abacavir, amprenavir, nevirapine, telaprevir 8. Receipt of zidovudine, desipramine, or other drugs that may increase serum concentration when combined with methadone within 30 days prior to study enrollment 9. Known or suspected gastrointestinal obstruction, including paralytic ileus 10. Significant respiratory depression (respiratory rate less than 8 breaths/min or oxygen saturation (SpO2) \<95%) 11. BMI ≥ 33 and BMI ≤ 17 12. Known history of moderate-to-severe liver (Child Class B or C) or kidney disease (serum creatinine \> 1.5) 13. Known history of drug or alcohol addiction (prior or present addiction or treatment for addiction) 14. Females who are pregnant or nursing

Design outcomes

Primary

Measure	Time frame	Description
Pharmacokinetics (PK) in Adults - Systemic Clearance (CL)	96 hours after dosing	—
Pharmacokinetics (PK) in Adults - Volume of Distribution	96 hours after dosing	—
Pharmacokinetics (PK) in Adults - Elimination Half-life	96 hours after dosing	—
Pharmacokinetics (PK) in Adults - Plasma AUC0-96	96 hours after dosing	Plasma AUC0-96 is the area under the plasma concentration versus time curve from time zero to 96 hours post-dose.
Pharmacokinetics (PK) in Adults - AUC0-inf	96 hours after dosing	AUC0-inf is the area under the curve from time 0 extrapolated to infinite time.
Pharmacokinetics (PK) in Adults - Cmax	96 hours after dosing	Cmax: A pharmacokinetic measure used to determine drug dosing. Cmax is the highest concentration of a drug in the blood, cerebrospinal fluid, or target organ after a dose is given.
Pharmacokinetics (PK) in Adults - Tmax	96 hours after dosing	Tmax is the time corresponding to maximum concentration post-dose.
Pharmacokinetics (PK) in Adults - Cmin	96 hours after dosing	Cmin is the observed minimum concentration post-dose.
Pharmacokinetics (PK) in Adults - Elimination Rate Constant	96 hours after dosing	Elimination rate constant (ke)-s a value used in pharmacokinetics to describe the rate at which a drug is removed from the human system.

Secondary

Measure	Time frame	Description
Pharmacodynamics (PD) in Adults - Dark-adapted Pupillometry	96 hours after dosing	Dark-adapted pupillometry measured pupil diameter using a goggle-based, camera-like device. A goggle-based system effectively allowed the participant to be in the dark while room lights were on for research staff.
Pharmacodynamics (PD) in Adults - Maximum Sedation Score	96 hours after dosing	Maximum sedation score obtained via the Modified Observer's Assessment of Alertness/Sedation (MOAA/S). The MOAA/S has a scale of 0 to 5, where 0 = Does not respond to painful trapezius squeeze and 5 = Responds readily to name spoken in normal tone.
Pharmacodynamics (PD) in Adults - Thermal Pain Tolerance Threshold	96 hours after dosing	The thermal pain tolerance threshold is the highest tolerated temperature change. Thermal pain tolerance was measured by a 3 cm2 computer-controlled Peltier-type thermal stimulator. The stimulator delivered painful heat stimuli to the volar side of the forearm. The thermode system's baseline temperature was set at 32°C. The computer-controlled thermode system was programmed to gradually increase the stimulus (0.8°C/sec) until participants pressed a stop button, which indicates maximum tolerable temperature was reached and initiated immediate thermode cooling. The maximum tolerable temperature was recorded.
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Alertness/Sedation	96 hours after dosing	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for alertness/sedation ranges from 0 (almost asleep) to 100 (wide awake).
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Energy Level	96 hours after dosing	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for energy level ranges from 0 (no energy) to 100 (full of energy).
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Confusion	96 hours after dosing	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for confusion ranges from 0 (clear headed) to 100 (confused).
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Clumsiness	96 hours after dosing	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for clumsiness ranges from 0 (well-coordinated) to 100 (extremely clumsy).
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Anxiety	96 hours after dosing	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for anxiety ranges from 0 (calm/relaxed) to 100 (extremely nervous).
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Nausea	96 hours after dosing	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for nausea ranges from 0 (no nausea) to 100 (worst nausea).
Pharmacodynamics (PD) in Adults - Maximum End-expired CO2 Concentration	96 hours after dosing	Measured in mmHg

Countries

United States

Participant flow

Participants by arm

Arm	Count
Open Label Methadone IV All participants will be treated with Methadone Hydrochloride IV (over 10 minutes) and monitored overnight. Methadone hydrochloride 0.1mg/kg: Single dose of methadone hydrochloride administered via intravenous (IV)	22
Total	22

Withdrawals & dropouts

Period	Reason	FG000
Overall Study	Failure to Meet Continuation Criteria	2
Overall Study	Physician Decision	1

Baseline characteristics

Characteristic	Open Label Methadone IV
Age, Continuous	29.4 years STANDARD_DEVIATION 5.05
Ethnicity (NIH/OMB) Hispanic or Latino	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	21 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants
Race (NIH/OMB) Asian	3 Participants
Race (NIH/OMB) Black or African American	12 Participants
Race (NIH/OMB) More than one race	1 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants
Race (NIH/OMB) White	6 Participants
Region of Enrollment United States	22 Participants
Sex: Female, Male Female	7 Participants
Sex: Female, Male Male	15 Participants

Adverse events

Event type	EG000 affected / at risk
deaths Total, all-cause mortality	0 / 22
other Total, other adverse events	10 / 22
serious Total, serious adverse events	0 / 22