Safe and Appropriate Use of Methadone in Hospice and Palliative Care: Expert Consensus White Paper.

Methadone has several unique characteristics that make it an attractive option for pain relief in serious illness, but the safety of methadone has been called into question after reports of a disproportionate increase in opioid-induced deaths in recent years. The American Pain Society, College on Problems of Drug Dependence, and the Heart Rhythm Society collaborated to issue guidelines on best practices to maximize methadone safety and efficacy, but guidelines for the end-of-life scenario have not yet been developed. A panel of 15 interprofessional hospice and palliative care experts from the U.S. and Canada convened in February 2015 to evaluate the American Pain Society methadone recommendations for applicability in the hospice and palliative care setting. The goal was to develop guidelines for safe and effective management of methadone therapy in hospice and palliative care. This article represents the consensus opinion of the hospice and palliative care experts for methadone use at end of life, including guidance on appropriate candidates for methadone, detail in dosing, titration, and monitoring of patients' response to methadone therapy.

The use of very-low-dose methadone and haloperidol for pain control in the hospital setting: a preliminary report.

OBJECTIVE: Our aim was to evaluate the use of very-low-dose methadone with haloperidol in the acute-care setting. METHODS: We reviewed the records of 735 hospitalized patients receiving a palliative care consultation between 2011 and 2014. All patients with pain on opiates were offered conversion to methadone, 2.5 mg/day to 15 mg/day, in conjunction with scheduled haloperidol. Additional doses of haloperidol or short-acting opiates were given as needed for pain. Patients receiving an opiate at a morphine-equivalent daily dose (MEDD) of ≥40 mg had pain scores assessed daily, before and after conversion. Descriptive statistics were used to summarize the results. RESULTS: Forty-three patients underwent conversion from another opiate (median MEDD, 78.5 mg) to methadone (median daily dose, 5 mg) and haloperidol (median daily dose, 1.5 mg). The median pain score was 5 in the week prior to conversion, 1 in week 1 after conversion (p<0.001 for difference), and zero in week 2. Similar results were seen for patients with cancer and noncancer diagnoses and for those with the highest and lowest initial opiate doses. CONCLUSION: The use of very-low-dose methadone in conjunction with haloperidol in the acute-care setting resulted in improved pain control after conversion from typical opiates.

The use of very-low-dose methadone for palliative pain control and the prevention of opioid hyperalgesia.

BACKGROUND: Opioid dose escalation may cause hyperalgesia, mediated by the N-methyl-D-aspartate (NMDA) pathway. Methadone is an atypical opioid that inhibits hyperalgesia through NMDA-blockade, especially at low doses. OBJECTIVE: To evaluate the efficacy of using very-low-dose methadone as the sole long-acting opioid agent in a hospice practice. DESIGN: A retrospective, observational study of the use of methadone, ≤15 mg daily, with as-needed short-acting opiates. Adjuvant nonopioid medications included haloperidol, which may have NMDA-blocking effects. SETTING/SUBJECTS: We reviewed the records of 240 patients admitted to a community-based hospice from July 1, 2011 to April 1, 2012, with data collected until hospice discharge or until April 30, 2012. MEASUREMENTS: Descriptive statistics were used to summarize patient demographics, medication regimens, and reported pain scores measured on a numeric rating scale from 0 to 10. RESULTS: All patients received short-acting opiates, in a morphine-equivalent dose of 5 mg every 4 hours as needed, while 40% also received methadone at a median daily dose of 5 mg. Of those on methadone, almost half received scheduled haloperidol. The population had a median reported pain score of 0 and a peak score of 3, with similar results seen for cancer and noncancer groups. Two-thirds of patients never reported a pain score greater than 3. CONCLUSION: The use of very-low-dose methadone in conjunction with adjuvant haloperidol resulted in excellent pain control without dose escalation or opioid-induced hyperalgesia, for both cancer and noncancer diseases. We conclude that low-dose methadone should be part of first-line treatment in palliative pain management.

Systematic review of cancer presentations with a median survival of six months or less.

OBJECTIVE: To report cancer presentations with a median survival of 6 months or less and the effect of treatment on survival. METHODS: We searched the MEDLINE database to find studies on solid and hematologic cancers that reported presentations consistently shown to have a median survival of 6 months or less. Independent prognostic factors were combined if their combination resulted in greater than 50% 6-month-mortality. For each terminal presentation, we evaluated whether treatment improved survival. RESULTS: The search identified 1500 potentially relevant articles, of which 650 were evaluated and 383 were included. Despite different cancer characteristics, a fairly universal picture of terminal disease included decreasing performance status, advancing age, weight loss, metastatic disease, disease recurrence, and laboratory abnormalities indicating extensive disease. Most of the prognostic indicators found were continuous, independent risk factors for mortality. We found little evidence that treatment improved survival at these terminal stages, with increased risk for toxicity. CONCLUSION: This systematic review summarizes prognostic factors in advanced cancer that are consistently associated with a median survival of 6 months or less. There is little evidence that treatment prolongs survival at this stage.

Effect of KRAS mutational status in advanced colorectal cancer on the outcomes of anti-epidermal growth factor receptor monoclonal antibody therapy: a systematic review and meta-analysis.

BACKGROUND: Emerging data suggest that somatic KRAS mutation in advanced colorectal cancer is a strong predictor of non-response to anti-epidermal growth factor receptor antibody (anti-EGFR) therapy. PATIENTS AND METHODS: A comprehensive search through March 2010 identified randomized controlled trials in metastatic colorectal cancer that evaluated chemotherapy regimens or best supportive care, with and without anti-EGFR therapy. Outcomes included progression-free survival (PFS), median overall survival (OS), and predictive test performance. RESULTS: In pooled data from 8 trials with 5325 patients, the addition of anti-EGFR to standard chemotherapy resulted in improved PFS (HR 0.66 [95% CI, 0.53-0.82]) in patients with wild-type KRAS in the tumor tissue, but not in patients with KRAS mutation (HR 1.07 [95% CI, 0.91-1.27]). Anti-EGFR treatment in the wild-type group did not significantly improve median OS. As a predictive biomarker, KRAS mutation had a positive likelihood ratio of 2.0 (95% CI, 1.45-2.76) in predicting nonresponse to anti-EGFR treatment. CONCLUSION: In patients with advanced colorectal cancer, the addition of anti-EGFR treatment to standard chemotherapy improves PFS for those with wild-type, but not mutant KRAS status. KRAS gene mutation testing provides a fair biomarker in predicting non-response to anti-EGFR treatment.

Gene expression profiles as predictors of poor outcomes in stage II colorectal cancer: A systematic review and meta-analysis.

PURPOSE: The use of adjuvant therapy in stage II colorectal cancer (CRC) remains controversial. There is a need to identify more effective predictors than the traditional staging system to aid therapeutic decision-making. We performed a systematic review and meta-analysis of gene expression profiles (GEPs) to assess their utility for risk stratification and prediction of poor outcomes in stage II CRC. PATIENTS AND METHODS: We performed a comprehensive literature search through December 2007. Studies were included if they reported GEP-based assays in patients with stage II CRC, and either subsequent cancer recurrence or death within 3 years. The prognostic likelihood ratio (LR) and odds ratio (OR) were calculated with 95% confidence intervals and pooled using the fixed-effects method. The weighted average sensitivity, specificity, and accuracy were also reported. RESULTS: Eight cohorts involving 271 patients contributed to the analysis. The average accuracy, sensitivity, and specificity were 81.9%, 76.2%, and 84.5%, respectively, with a prognostic LR of 4.7 (95% CI, 3.2-6.8) and a prognostic OR of 15.1 (95% CI, 7.9-28.6). No evidence for significant interstudy heterogeneity was noted in either analysis. Subgroup analysis found no difference in results for the prediction of cancer recurrence or death. CONCLUSION: This analysis demonstrates the promising potential of using GEP assays as predictors of poor outcomes in stage II CRC, such as cancer recurrence or death. To maximize their utility and availability, further studies will be needed to identify and validate specific gene signatures for poor prognosis in stage II CRC.

Do inhaled anticholinergics increase or decrease the risk of major cardiovascular events?: a synthesis of the available evidence.

There has been recent uncertainty about whether the inhaled anticholinergic agents ipratropium bromide and tiotropium bromide increase or decrease cardiovascular risk in the treatment of patients with chronic obstructive pulmonary disease (COPD). This article synthesizes the available data in order to understand the controversy. COPD is a common cause of hospitalizations and is a rapidly increasing cause of mortality worldwide. Despite the heavy burden of COPD-related illness, the leading cause of hospitalization in COPD patients is cardiovascular disease. This link between COPD and cardiovascular disease is in part due to the fact that both diseases share common risk factors, such as tobacco smoking and advanced age. It is also hypothesized that systemic inflammation in COPD increases the risk for cardiac events such as myocardial infarction. Inhaled anticholinergics reduce COPD-related hospitalizations and respiratory deaths compared with placebo, and tiotropium bromide is more effective than ipratropium bromide. In randomized trials, patients receiving tiotropium bromide have lower discontinuation rates than those receiving placebo and, therefore, contribute more person-years to the analyses. In a recent large 4-year tiotropium bromide trial, the proportion of patients who died was similar in the tiotropium bromide and placebo groups, whereas the death rate per person-years was lower with tiotropium bromide, indicating longer overall survival. There has been conflicting evidence concerning cardiovascular risk associated with inhaled anticholinergics. One meta-analysis found that the risk for major cardiovascular events was higher with anticholinergics compared with placebo or active comparator controls, whereas two subsequent meta-analyses that included new trial data found no difference in risk. In a recent pooled safety analysis, when incidence rates of events over time were evaluated, tiotropium bromide was associated with a lower rate of major cardiovascular events and cardiovascular deaths compared with placebo. This risk reduction was mainly because of a reduction in serious cardiac events such as myocardial infarction and congestive heart failure. In conclusion, inhaled anticholinergics, especially tiotropium bromide, reduce COPD-related hospitalizations and deaths, and may improve total survival over time. Many COPD patients have concomitant cardiovascular disease processes. Thus, trials may observe more cardiovascular events associated with anticholinergics than with placebo, but this differential is eliminated when evaluating the rate of events per person-years of exposure. New evidence indicates that tiotropium bromide may actually reduce the incidence of cardiovascular events and deaths over time. It is possible that the reduction in respiratory morbidity could improve functional status and reduce adverse cardiac outcomes over time. Further studies are needed to address this important issue.

Hormone therapy for younger postmenopausal women: how can we make sense out of the evidence?

The Women's Health Initiative (WHI) trials have provided us with valuable information on the effect of hormone therapy (HT) in older postmenopausal women. These results have been generalized to women of all ages, despite the fact that the trials were not powered to evaluate the effect of HT in younger women who initiate treatment shortly after menopause. Pooled data from the WHI and other randomized trials now reveal that HT in younger women is associated with a reduction in coronary heart disease events and total mortality, a benefit that is not seen in older women.

Mortality associated with hormone replacement therapy in younger and older women: a meta-analysis.

OBJECTIVE: To assess mortality associated with hormone replacement in younger and older postmenopausal women. DESIGN: A comprehensive search of MEDLINE, CINAHL, and EMBASE databases was performed to identify randomized controlled trials of hormone replacement therapy from 1966 to September 2002. The search was augmented by scanning selected journals through April 2003 and references of identified articles. Randomized trials of greater than 6 months' duration were included if they compared hormone replacement with placebo or no treatment, and reported at least 1 death. MEASUREMENTS: Outcomes measured were total deaths and deaths due to cardiovascular disease, cancer, or other causes. Odds ratios (OR) for total and cause-specific mortality were reported separately for trials with mean age of participants less than and greater than 60 years at baseline. MAIN RESULTS: Pooled data from 30 trials with 26,708 participants showed that the OR for total mortality associated with hormone replacement was 0.98 (95% confidence interval [CI], 0.87 to 1.12). Hormone replacement reduced mortality in the younger age group (OR, 0.61; CI, 0.39 to 0.95), but not in the older age group (OR, 1.03; CI, 0.90 to 1.18). For all ages combined, treatment did not significantly affect the risk for cardiovascular or cancer mortality, but reduced mortality from other causes (OR, 0.67; CI, 0.51 to 0.88). CONCLUSIONS: Hormone replacement therapy reduced total mortality in trials with mean age of participants under 60 years. No change in mortality was seen in trials with mean age over 60 years.

Screening and treatment of latent tuberculosis among healthcare workers at low, moderate, and high risk for tuberculosis exposure: a cost-effectiveness analysis.

OBJECTIVE: To evaluate cost-effective screening and treatment strategies for healthcare workers (HCWs) at risk for tuberculosis exposure. DESIGN: A Markov model was developed to track three hypothetical cohorts of HCWs at low, moderate, and high risk for tuberculosis exposure. For those found to be tuberculin reactors at entry, the choice was for isoniazid treatment or no treatment. For those without tuberculin reactivity, the choice of screening intervals was 6 months, 1 year, 2 years, or 5 years. Outcomes measured were tuberculosis cases, death, life expectancy, and cost. Assumptions were derived from published data and analyses. RESULTS: Treatment of initial reactors with isoniazid in all three risk groups was associated with a net savings of $14,800 to $15,700 for each tuberculosis case prevented. For those without evidence of infection at entry, the most cost-effective screening interval was 1 year for high-risk groups, 2 years for moderate-risk groups, and 5 years for low-risk groups, with a net savings $0.20 to $26 per HCW per year. Screening at a more frequent interval was still cost-effective. CONCLUSIONS: For HCWs found to be tuberculin reactors, treatment of their latent infection is to their benefit and is associated with a net cost-savings. Regular tuberculin screening of HCWs can be cost-effective or result in a net cost-savings. Each institution could use its own skin test surveillance data to create an optimum screening program for its employees. However, for most HCWs, a 1-year screening interval would be a cost-effective and safe choice.