QTc interval prolongation associated with intravenous methadone.

Numerous medications prolong the rate-corrected QT (QTc) interval and induce arrhythmias by blocking ionic current through cardiac potassium channels composed of subunits expressed by the human ether-a-go-go-related gene (HERG). Recent reports suggest that high doses of methadone cause torsades de pointes. To date, no controlled study has described an association between methadone and QTc prolongation. The only commercial formulation of parenteral methadone available in the United States contains the preservative chlorobutanol. The objectives of this study are to determine: (1) whether the administration of intravenous (i.v.) methadone causes QTc prolongation in humans; (2) whether methadone and/or chlorobutanol block cardiac HERG potassium currents (IHERG) in vitro. Over 20 months, we identified every inpatient with at least one electrocardiogram (ECG) performed on i.v. methadone. For each patient, we measured QTc intervals for every available ECG performed on and off i.v. methadone. Concurrent methadone doses were also recorded. Similar data were collected for a separate group of inpatients treated with i.v. morphine. In a separate set of experiments IHERG was evaluated in transfected human embryonic kidney cells exposed to increasing concentrations of methadone, chlorobutanol, and the two in combination. Mean difference (+/- standard error) per patient in QTc intervals on and off methadone was 41.7 (+/- 7.8)ms, p<0.0001. Mean difference in QTc intervals on and off morphine was 9.0 (+/- 6.1)ms, p=0.15. The approximately linear relationship between QTc measurements and log-dose of methadone was significant (p<0.0001). Methadone and chlorobutanol independently block IHERG in a concentration-dependent manner with IC50 values of 20 +/- 2 microM and 4.4 +/- 0.3 mM, respectively. Chlorobutanol potentiates methadone's ability to block IHERG. Methadone in combination with chlorobutanol is associated with QTc interval prolongation. Our data strongly suggest that methadone in combination with chlorobutanol is associated with QTc interval prolongation.

A safe and effective method for converting patients from transdermal to intravenous fentanyl for the treatment of acute cancer-related pain.

BACKGROUND: The delayed effects (12-16 hours) of transdermal fentanyl make dose titration difficult during acute exacerbations of cancer pain. Patients at the authors' institution routinely are switched from transdermal to intravenous (IV) fentanyl using a 1:1 (transdermal:IV) conversion during severe episodes of pain. METHODS: The authors evaluated nine consecutive hospitalized patients with cancer who had severe pain for up to 6 days following the conversion from transdermal to IV fentanyl. Pain intensity was rated using an 11-point (0-10) verbal numeric rating scale (NRS). All 9 patients initially reported their pain intensity with movement as >or= 8 during treatment with transdermal fentanyl. Eight patients initially reported their pain at rest as >or= 8. In each patient, all transdermal patches were removed, and a continuous infusion (CI) delivering IV fentanyl at the same hourly rate was initiated simultaneously. Demand boluses of IV fentanyl equivalent in dosage to 50-100% of the CI rate remained available by patient-controlled analgesia (PCA). Pain intensity (0-10), sedation (0-3), and hourly fentanyl requirements (micrograms per hour) were assessed and recorded immediately prior to patch removal and at least once daily after the initiation of IV fentanyl. The CI and demand boluses were titrated whenever necessary on the basis of pain intensity and supplemental PCA use. RESULTS: All 9 patients reported mild levels (