Single Dose IV Methadone for Post-Op Pain

Phase 1

Completed

Conditions: Pain, Postoperative

Interventions: Drug: methadone hydrochloride 0.1mg/kg

Registration Number: NCT05425420

Lead Sponsor: Kanecia Obie Zimmerman

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 22

Inclusion Criteria

18 to < 40 years of age at the time of enrollment
Provide informed consent

Exclusion Criteria

History of cardiac dysfunction
History of or current QTc prolongation, defined as > 470 ms in males and > 480 ms in females
Known hypersensitivity to methadone hydrochloride or any other ingredient in the methadone hydrochloride injection
Known acute bronchial asthma or hypercarbia (known history of known PaCO2 above 45 mm HG)
Receipt of a serotonergic drug or buproprion within 7 days prior to study enrollment
Receipt of benzodiazepines, muscle relaxants, or other opioids within 7 days prior to study enrollment
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
Receipt of zidovudine, desipramine, or other drugs that may increase serum concentration when combined with methadone within 30 days prior to study enrollment
Known or suspected gastrointestinal obstruction, including paralytic ileus
Significant respiratory depression (respiratory rate less than 8 breaths/min or oxygen saturation (SpO2) <95%)
BMI ≥ 33 and BMI ≤ 17
Known history of moderate-to-severe liver (Child Class B or C) or kidney disease (serum creatinine > 1.5)
Known history of drug or alcohol addiction (prior or present addiction or treatment for addiction)
Females who are pregnant or nursing

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Single arm, Open label Methadone IV	methadone hydrochloride 0.1mg/kg	All participants will be treated with Methadone Hydrochloride IV (over 10 minutes) and monitored overnight.

Primary Outcome Measures

Name	Time	Method
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.
Pharmacokinetics (PK) in Adults - Volume of Distribution	96 hours after dosing
Pharmacokinetics (PK) in Adults - Systemic Clearance (CL)	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.

Secondary Outcome Measures

Name	Time	Method
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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - Maximum End-expired CO2 Concentration	96 hours after dosing	Measured in mmHg