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.

Benefit-risk assessment of transdermal fentanyl for the treatment of chronic pain.

Transdermal fentanyl is effective and well tolerated for the treatment of chronic pain caused by malignancy and non-malignant conditions when administered according to the manufacturer's recommendations. Compared with oral opioids, the advantages of transdermal fentanyl include a lower incidence and impact of adverse effects (constipation, nausea and vomiting, and daytime drowsiness), a higher degree of patient satisfaction, improved quality of life, improved convenience and compliance resulting from administration every 72 hours, and decreased use of rescue medication. Transdermal fentanyl is a useful analgesic for cancer patients who are unable to swallow or have gastrointestinal problems. Transdermal fentanyl forms a depot within the upper skin layers before entering the microcirculation. Therapeutic blood levels are attained 12-16 hours after patch application and decrease slowly with a half-life of 16-22 hours following removal. Patients with chronic pain should be titrated to adequate relief with short-acting oral or parenteral opioids prior to the initiation of transdermal fentanyl in order to prevent exacerbations of pain or opioid-related adverse effects. Transdermal fentanyl can then be initiated based on the 24-hour opioid requirement once adequate analgesia has been achieved. The prolonged elimination of transdermal fentanyl can become problematic if patients develop opioid-related adverse effects, especially hypoventilation. Adverse effects do not improve immediately after patch removal and may take many hours to resolve. Patients who experience opioid-related toxicity associated with respiratory depression should be treated immediately with an opioid antagonist such as naloxone and closely monitored for at least 24 hours. Because of the short half-life of naloxone, sequential doses or a continuous infusion of the opioid antagonist may be necessary. Transdermal fentanyl should be administered cautiously to patients with pre-existing conditions such as emphysema that may predispose them to the development of hypoventilation. Transdermal fentanyl is indicated only for patients who require continuous opioid administration for the treatment of chronic pain that cannot be managed with other medications. It is contraindicated in the management of acute and postoperative pain, as pain may decrease more rapidly in these circumstances than fentanyl blood levels can be adjusted, leading to the development of life-threatening hypoventilation. Cognitive and physical impairments such as confusion and abnormal co-ordination can occur with transdermal fentanyl. Therefore, patients should be instructed to refrain from driving or operating machinery immediately following the initiation of transdermal fentanyl, or after any dosage increase. Patients may resume such activities once the absence of these potential adverse effects is documented.

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 (

Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents.

We have evaluated the ability of various opioid agonists, including methadone, L-alpha-acetylmethadol (LAAM), fentanyl, meperidine, codeine, morphine, and buprenorphine, to block the cardiac human ether-a-go-go-related gene (HERG) K(+) 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 microM 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 (>455 and >400, 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 microM) 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 approximately 10% of the available HERG K(+) 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.