Single Dose IV Methadone for Post-Op Pain

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

Detailed Description
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The Adult Methadone study will be conducted at a single site, Duke Early Phase Research Unity (DEPRU), to enroll 20 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.

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

Conditions
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Pain, Postoperative

Intervention / Treatment
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* Drug: methadone hydrochloride 0.1mg/kg


Participation Criteria
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Eligibility Criteria
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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 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 - in last 30 days CYP2B6 inhibitors include clopidogrel, prasugrel, thioTEPA, ticlopidine, voriconazole, macrolide antibiotics, azole-antifungal agents, fluconazole, Alstonia boonei, Mangifera indica, and Picralima nitida 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 Known or suspected gastrointestinal obstruction, including paralytic ileus Significant respiratory depression BMI ≥ 33 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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Intervention Model: Single Group Assignment
Interventional 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.
Masking: None (Open Label)


Arms and Interventions

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

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK) in Adults | Systemic clearance | 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 (area under the plasma concentration versus time curve from time zero to 96 hours post-dose). | 96 hours, after dosing | 
| Pharmacokinetics (PK) in Adults | 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 | AUC0-∞:the area under the curve from time 0 extrapolated to infinite time. | 96 hours, after dosing | 
| Pharmacokinetics (PK) in Adults | Time to maximum concentration (Tmax) | 96 hours after dosing | 
| Pharmacokinetics (PK) in Adults | Minimum concentration (Cmin) | 96 hours after dosing | 
| Pharmacokinetics (PK) in Adults | 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 | 96 hours, after dosing | 
| Pharmacodynamics (PD) in Adults | Thermal Pain tolerance thresholds (highest tolerated temperature change) | 96 hours, after dosing | 
| Pharmacodynamics (PD) in Adults | Subjective self-assessment of methadone effects using visual analog scale (VAS) | 96 hours, after dosing | 
| Pharmacodynamics (PD) in Adults | Maximum end-expired CO2 concentration | 96 hours, after dosing | 
| Pharmacodynamics (PD) in Adults | Maximum sedation score, to obtain the score the Modified Observer's Assessment of Alertness/Sedation, MOAA/S using a 1-5 scale | 96 hours, after dosing | 
| Pharmacodynamics (PD) in Adults | VAS is a self assessment that indicate levels of alertness/sedation on a scale of 0-100 | 96 hours, after dosing | 
| Characterize the safety profile in Adults | Adverse events (AEs) | 24 hours of identification/site awareness | 
| Serious adverse events (SAEs) | Safety follow-up from baseline to the final visit (96 hours) | 24 hours of identification/site awareness | 
| Suspected Unexpected Serious Adverse Reactions (SUSARs) | Suspected-Change in QTc, or a SAR that is both serious and unexpected | 24 hours of identification/site awareness |