Among critically ill cancer patients, multiple distressing symptoms were common in the ICU, often at significant levels of severity. Symptom assessment may suggest more effective strategies for symptom control and may direct decisions about appropriate use of ICU therapies.

We have evaluated the ability of various opioid agonists, including methadone, L-␣-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K ϩ current (I HERG ) in human cells stably transfected with the HERG potassium channel gene. Our results show that LAAM, methadone, fentanyl, and buprenorphine were effective inhibitors of I HERG , with IC 50 values in the 1 to 10 M range. The other drugs tested were far less potent with respect to I HERG inhibition. Compared with the reported maximal plasma concentration (C max ) after administration of therapeutic doses of these drugs, the ratio of IC 50 /C max was highest for codeine and morphine (Ͼ455 and Ͼ400, respectively), thereby indicating that these drugs have the widest margin of safety (of the compounds tested) with respect to blockade of I HERG . In contrast, the lowest ratios of IC 50 /C max were observed for LAAM and methadone (2.2 and 2.7, respectively). Further investigation showed that methadone block of I HERG was rapid, with steady-state inhibition achieved within 1 s when applied at its IC 50 concentration (10 M) for I HERG block. Results from "envelope of tails" tests suggest that the majority of block occurred when the channels were in the open and/or inactivated states, although ϳ10% of the available HERG K ϩ channels were apparently blocked in a closed state. Similar results were obtained for LAAM. These results demonstrate that LAAM and methadone can block I HERG in transfected cells at clinically relevant concentrations, thereby providing a plausible mechanism for the adverse cardiac effects observed in some patients receiving LAAM or methadone.Torsades de pointes is a potentially fatal form of ventricular arrhythmia that typically occurs under conditions where cardiac repolarization is delayed (as indicated by prolonged QT intervals from electrocardiographic recordings) (Goodman and Peter, 1995;Viskin, 1999). These conditions can be precipitated by drugs that block the cardiac potassium channels responsible for mediating ventricular repolarization. Remarkably, many different types of drugs, including some antiarrhythmics, antihistamines, antibiotics, gastrointestinal prokinetics, and antipsychotics (Faber et al., 1994;De Ponti et al., 2001), have been shown to cause QT prolongation, primarily through interference with the rapid component of the delayed rectifier potassium current, I Kr (Antzelevitch et al., 1996;January et al., 2000;Tamargo, 2000;Tseng, 2001). The human ether-a-go-go-related gene (HERG) gene encodes for the major channel protein that underlies I Kr , and a recently developed cell line that was stably transfected with the HERG gene (Zhou et al., 1998) has proven useful for evaluating drugs suspected of causing delays in cardiac repolarization (Mohammad et al., 1997;Ferreira et al., 2001).In April 2001, the United States Food and Drug Administration issued a new warning about adverse cardiac events (Deamer et al., 2001) associated with th...