Single Dose IV Methadone for Post-Op Pain

Kanecia Obie Zimmerman22 enrolled

Overview

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

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

Allocation

Purpose

OTHER

Masking

NONE

Enrollment

Conditions

Pain, Postoperative

Interventions

methadone hydrochloride 0.1mg/kgDRUG

Single dose of methadone hydrochloride administered via intravenous (IV)

Eligibility

Sex: ALLMin age: 18 YearsMax age: 40 YearsHealthy volunteers:

Medical Language ↔ Plain English

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

Locations (1)

Duke Early Phase Unit (DEPRU

Durham, North Carolina, United States

Outcomes

Primary Outcomes

Pharmacokinetics (PK) in Adults - Systemic Clearance (CL)

Time frame: 96 hours after dosing

Pharmacokinetics (PK) in Adults - Volume of Distribution

Time frame: 96 hours after dosing

Pharmacokinetics (PK) in Adults - Elimination Half-life

Time frame: 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.

Time frame: 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.

Time frame: 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.

Time frame: 96 hours after dosing

Pharmacokinetics (PK) in Adults - Tmax

Tmax is the time corresponding to maximum concentration post-dose.

Time frame: 96 hours after dosing

Pharmacokinetics (PK) in Adults - Cmin

Cmin is the observed minimum concentration post-dose.

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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.

Time frame: 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.

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 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).

Time frame: 96 hours after dosing

Pharmacodynamics (PD) in Adults - Maximum End-expired CO2 Concentration

Measured in mmHg

Time frame: 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".

Time frame: 96 hours after dosing