Single Dose IV Methadone for Post-Op Pain

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.

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.

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