Single Dose IV Methadone for Post-Op Pain (MTH02)

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

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

Study Overview

• Status: Completed
• Conditions: Pain, Postoperative
• Intervention / Treatment: Drug: methadone hydrochloride 0.1mg/kg

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.

• Study Type: Interventional
• Enrollment (Actual): 22
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Early Phase Unit (DEPRU

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Single arm, Open label Methadone IV; All participants will be treated with Methadone Hydrochloride IV (over 10 minutes) and monitored overnight.	Drug: methadone hydrochloride 0.1mg/kg; Single dose of methadone hydrochloride administered via intravenous (IV)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Plasma AUC0-96 is the area under the plasma concentration versus time curve from time zero to 96 hours post-dose.	96 hours after dosing
Pharmacokinetics (PK) in Adults - AUC0-inf	AUC0-inf is the area under the curve from time 0 extrapolated to infinite time.	96 hours after dosing
Pharmacokinetics (PK) in Adults - Cmax	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.	96 hours after dosing
Pharmacokinetics (PK) in Adults - Tmax	Tmax is the time corresponding to maximum concentration post-dose.	96 hours after dosing
Pharmacokinetics (PK) in Adults - Cmin	Cmin is the observed minimum concentration post-dose.	96 hours after dosing
Pharmacokinetics (PK) in Adults - Elimination Rate Constant	Elimination rate constant (ke)-s a value used in pharmacokinetics to describe the rate at which a drug is removed from the human system.	96 hours after dosing

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamics (PD) in Adults - Dark-adapted Pupillometry	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.	96 hours after dosing
Pharmacodynamics (PD) in Adults - Thermal Pain Tolerance Threshold	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.	96 hours after dosing
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Alertness/Sedation	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).	96 hours after dosing
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Energy Level	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).	96 hours after dosing
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Confusion	Subjective self-assessment of methadone effects using a visual analog scale (VAS). The score for confusion ranges from 0 (clear headed) to 100 (confused).	96 hours after dosing
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Clumsiness	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).	96 hours after dosing
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Anxiety	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).	96 hours after dosing
Pharmacodynamics (PD) in Adults - Subjective Self-assessment of Methadone Effects - Nausea	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).	96 hours after dosing
Pharmacodynamics (PD) in Adults - Maximum End-expired CO2 Concentration	Measured in mmHg	96 hours after dosing
Pharmacodynamics (PD) in Adults - Maximum Sedation Score	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".	96 hours after dosing

Collaborators and Investigators

• Sponsor: Kanecia Obie Zimmerman
• Investigators: Principal Investigator: Kanecia Zimmerman, MD, MPH,PhD, DUMC, DCRI

Study record dates

Study Major Dates

• Study Start (Actual): August 11, 2023
• Primary Completion (Actual): January 20, 2024
• Study Completion (Actual): January 20, 2024

Study Registration Dates

• First Submitted: April 15, 2022
• First Submitted That Met QC Criteria: June 16, 2022
• First Posted (Actual): June 21, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 18, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pain; Neurologic Manifestations; Postoperative Complications; Pathologic Processes; Pain, Postoperative; Physiological Effects of Drugs; Peripheral Nervous System Agents; Central Nervous System Depressants; Sensory System Agents; Analgesics; Analgesics, Opioid; Narcotics; Respiratory System Agents; Antitussive Agents; Methadone
• Other Study ID Numbers: Pro00113821; Pro00106216 (Other Identifier: Duke site IRB#)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No