Paolo L. Manfredi

Self-reported symptom experience of critically ill cancer patients receiving intensive care.

ObjectiveTo characterize the symptom experience of a cohort of intensive care unit (ICU) patients at high risk for hospital death. DesignProspective analysis of patients with a present or past diagnosis of cancer who were consecutively admitted to a medical ICU during an 8-month period. SettingAcademic, university-affiliated, tertiary-care, urban medical center. PatientsOne hundred cancer patients treated in a medical ICU. InterventionAssessment of symptoms. MeasurementsPatients’ self-reports of symptoms using the Edmonton Symptom Assessment Scale (ESAS), and ratings of pain or discomfort associated with ICU diagnostic/therapeutic procedures and of stress associated with conditions in the ICU. Main Results Hospital mortality for the group was 56%. Fifty patients had the capacity to respond to the ESAS, among whom 100% provided symptom reports. Between 55% and 75% of ESAS responders reported experiencing pain, discomfort, anxiety, sleep disturbance, or unsatisfied hunger or thirst that they rated as moderate or severe, whereas depression and dyspnea at these levels were reported by approximately 40% and 33% of responders, respectively. Significant pain, discomfort, or both were associated with common ICU procedures, but most procedure-related symptoms were controlled adequately for a majority of patients. Inability to communicate, sleep disruption, and limitations on visiting were particularly stressful among ICU conditions studied. ConclusionsAmong 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.

QTc interval prolongation associated with intravenous methadone

&NA; 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 &mgr;M and 4.4±0.3 mM, respectively. Chlorobutanol potentiates methadones 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.

Intravenous methadone for cancer pain unrelieved by morphine and hydromorphone: clinical observations

Abstract Methadone is a very effective second‐line opioid for treatment of cancer pain. However, the starting doses of methadone indicated on opioid conversion charts may over‐estimate the dose of intravenous (i.v.) methadone needed. In this report, we describe four patients with cancer‐related pain treated with continuous i.v. morphine and hydromorphone. Because of persistent pain and opioid side effects limiting increases in opioid dose, each patient was switched to i.v. methadone. All four patients had excellent pain relief without significant side effects at a dose that, according to the available conversion charts, was approximately 3% of the calculated equi‐analgesic dose of hydromorphone. When converting from continuous i.v. hydromorphone to continuous i.v. methadone, much lower doses than those suggested by the opioid conversion charts should be used as starting doses.

Pitfalls of opioid rotation: substituting another opioid for methadone in patients with cancer pain

&NA; The successful use of methadone in cancer pain has been supported by numerous case reports and clinical studies. Methadone is usually used as a second or third line opioid medication. As the use of methadone increases we are facing the challenge of converting methadone to other opioids as part of sequential opioid trials. Data on the equianalgesic ratios for the substitution of other opioids for methadone are lacking. We present prospective data on 13 consecutive rotations from methadone to a different opioid. The opioid rotation was followed by escalation of pain and/or severe dysphoria, not controlled by a rapid increase in the dose of the second opioid, in 12 of the 13 patients. Only one patient was successfully maintained on the second opioid after the discontinuation of methadone, while 12 patients required a switch back to methadone. We conclude that opioid rotation from methadone to another opioid is often complicated by worsening pain and dysphoria. These symptoms may not improve despite upward titration of the second opioid. A uniformly accepted conversion ratio for substituting methadone with another opioid is currently not available. More data on the rotation from methadone to other opioids are needed.

Methadone Analgesia in Cancer Pain Patients on Chronic Methadone Maintenance Therapy

Methadone is currently best known for its use as the maintenance drug in opioid addiction. The main concern when using methadone for the treatment of pain is its long and unpredictable half-life, which is associated with the risk of delayed toxicity. This may result in side effects such as sedation and respiratory depression if careful titration and close observation of individual patient responses are not performed. For this reason, methadone is often viewed as a second line opioid, after other opioids with a more predictable dose-response have been tried. We report six patients with long-term exposure to methadone as a treatment for heroin dependency, who were also treated with methadone for cancer pain. The first five patients were at least partially refractory to the analgesic effects of opioids other than methadone. All six patients achieved analgesia without sedation or respiratory depression from aggressive upward methadone titration. Methadone analgesia can be considered early in the course of treatment of patients with chronic exposure to methadone who develop new or worsening pain requiring opioid therapy.

Inappropriate use of naloxone in cancer patients with pain

Opioid overdose is rarely the primary cause of altered mental status in cancer patients receiving opioid therapy. The inappropriate administration of naloxone to reverse an abnormal mental status can cause severe withdrawal symptoms and pain. To illustrate this problem, we report the case of a patient inappropriately treated with naloxone and the results of a retrospective review of the medical records of 15 consecutive patients with cancer treated with naloxone in the emergency department over a 5-month period. We offer guidelines for a more thoughtful approach to the management of patients with cancer who present with encephalopathy.

Outcome of cancer pain consultations

All major cancer centers in the United States are equipped with pain management consultation services. We report on the outcome of such consultations within 24 hours from the intervention.

High-dose epidural infusion of opioids for cancer pain: Cost issues

The safety and efficacy of intraspinal opioids as therapy for selected patients with cancer pain are well-established. The choice of the appropriate drug is influenced by many variables that are to date incompletely elucidated. The cost of therapy is an increasingly important component of decision-making. This report describes the management of a patient who achieved excellent pain control with the administration of epidural sufentanil and bupivacaine. Daily Average Wholesale Price for sufentanil was, however,

A pilot trial of intravenous pamidronate for chronic low back pain.

698. Until the data comparing the efficacy of different epidurally administered opioids in the treatment of cancer pain are available, we suggest that treatment with more costly opioids be reserved for patients for whom analgesia cannot be achieved after maximizing epidural morphine analgesia with aggressive side-effect management.

Central pain in cancer patients

Summary Pamidronate is an aminobisphosphonate with analgesic properties. In this study, intravenous pamidronate decreased pain intensity for 6 months in patients with low back pain. ABSTRACT Intravenous (i.v.) bisphosphonates relieve pain in conditions such as Pagets disease of bone, metastatic bone disease, and multiple myeloma. Based on positive findings from a prior case series, we conducted a randomized placebo‐controlled study to assess the analgesic effect of i.v. pamidronate in subjects with chronic low back pain (CLBP) and evidence of degenerative disease of the spine. Four groups of 11 subjects (7 active, 4 placebo) were enrolled at escalating dose levels of 30, 60, 90, and 180 mg pamidronate (the latter administered as two 90 mg infusions). Primary outcomes were safety and change from baseline in average daily pain scores, recorded at 1, 2, 3, and 6 months postinfusion using electronic diaries. Secondary outcomes included responder rate, daily worst pain, and pain‐related interference with daily function. There were no pamidronate‐related serious adverse events or other significant safety findings. A statistically significant overall treatment difference in pain scores was observed, with clinically meaningful effects persisting for 6 months in the 180 mg pamidronate group. Least squares mean changes in daily average pain score were −1.39 (SE = 0.43) for placebo, and −1.53 (0.71), −1.26 (0.81), −1.42 (0.65), and −4.13 (0.65) for pamidronate 30, 60, 90, and 180 mg, respectively (P = 0.012 for pamidronate 180 mg vs placebo). The proportion of responders, changes in worst pain, and pain interference with daily function were also significantly improved for pamidronate 180 mg compared with placebo. In conclusion, i.v. pamidronate, administered as two 90 mg infusions, decreased pain intensity for 6 months in subjects with CLBP.