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.
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.
Cancer patients commonly undergo surgical procedures. The perioperative period is characterized by immunosuppression and may predispose already immunosupressed cancer patients to tumor spread. Cancer patients typically show depression of both cellular and humoral immune functions. Possible mediating factors for immunosuppression during the perioperative period include anesthetic agents, opioids, surgery, blood transfusions, temperature changes, pain, and psychological stress. A surgically mediated decrease in natural killer (NK) cell activity has been implicated as the major contributing factor associated with an increase in metastasis. The decreased NK cell activity during the perioperative period is associated with increased risk of mortality and cancer. Commonly used anesthetic agents and opioids are known to inhibit NK cell activity. Despite the in vivo evidence of anesthetic- and analgesic-agent-mediated immunosupression, surgery by itself results in a three- to four-fold increase in retention of metastasis when compared to the groups in which anesthesia and analgesia were combined. The negative consequences associated with perioperative immunosuppression may be decreased by several strategies, including aggressive pain control, selection of specific anesthetic and analgesic agents, avoidance of unnecessary transfusions, and delay of elective surgeries until the patient's nutritional and immune status is optimized. Recognizing and neutralizing its mediating factors, perioperative immunosuppression in cancer patients may be reduced.
Disability in patients with advanced cancer often results from bed rest, deconditioning, and neurologic and musculoskeletal complications of cancer or cancer treatment. Terminally ill patients have a high prevalence of weakness, pain, fatigue, and dyspnea in addition to other symptoms. Rehabilitation and palliative care have emerged as two important parts of comprehensive medical care for patients with advanced disease; this article discusses the relationship between the two and the possible role of rehabilitation interventions in the care of terminally ill patients. Palliative care and rehabilitation share common goals and therapeutic approaches. Both disciplines have a multidisciplinary model of care, which aims to improve patients' levels of function and comfort. There is scarce evidence that rehabilitation interventions can impact function and symptom management in terminally ill patients. However, clinical experience suggests that the application of the fundamental principles of rehabilitation medicine is likely to improve their care. Physical function and independence should be maintained as long as possible to improve patients' quality of life and reduce the burden of care for the caregivers. Future research on the rehabilitation of terminally ill patients should focus on better understanding the role of rehabilitation and defining appropriate interventions. The development of an evidence‐based body of knowledge will ensure that these patients receive appropriate rehabilitation interventions. Cancer 2001;92:1049–52. © 2001 American Cancer Society.
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