Analgesia and central side-effects: two separate dimensions of morphine response.

AIMS: To present a statistical model for defining interindividual variation in response to morphine and to use this model in a preliminary hypothesis-generating multivariate genetic association study. METHODS: Two hundred and sixty-four cancer patients taking oral morphine were included in a prospective observational study. Pain and morphine side-effect scores were examined using principal components analysis. The resulting principal components were used in an exploratory genetic association study of single nucleotide polymorphisms across the genes coding for the three opioid receptors, OPRM1, OPRK1 and OPRD1. Associations in multivariate models, including potential clinical confounders, were explored. RESULTS: Two principal components corresponding to residual pain and central side-effects were identified. These components accounted for 42 and 18% of the variability in morphine response, respectively, were independent of each other and only mildly correlated. The genetic and clinical factors associated with these components were markedly different. Multivariate regression modelling, including clinical and genetic factors, accounted for only 12% of variability in residual pain on morphine and 3% of variability in central side-effects. CONCLUSIONS: Although replication is required, this data-driven analysis suggests that pain and central side-effects on morphine may be two separate dimensions of morphine response. Larger study samples are necessary to investigate potential genetic and clinical associations comprehensively.

Quality of transition to end-of-life care for cancer patients in the intensive care unit.

BACKGROUND: There have been few studies that have evaluated the quality of end-of-life care (EOLC) for cancer patients in the ICU. The aim of this study was to explore the quality of transition to EOLC for cancer patients in ICU. METHODS: The study was undertaken on medical patients admitted to a specialist cancer hospital ICU over 6 months. Quantitative and qualitative methods were used to explore quality of transition to EOLC using documentary evidence. Clinical parameters on ICU admission were reviewed to determine if they could be used to identify patients who were likely to transition to EOLC during their ICU stay. RESULTS: Of 85 patients, 44.7% transitioned to EOLC during their ICU stay. Qualitative and quantitative analysis of the patients' records demonstrated that there was collaborative decision-making between teams, patients and families during transition to EOLC. However, 51.4 and 40.5% of patients were too unwell to discuss transition to EOLC and DNACPR respectively. In the EOLC cohort, 76.3% died in ICU, but preferred place of death known in only 10%. Age, APACHE II score, and organ support, but not cancer diagnosis, were identified as associated with transition to EOLC (p = 0.017, p < 0.0001 and p = 0.001). CONCLUSIONS: Advanced EOLC planning in patients with progressive disease prior to acute deterioration is warranted to enable patients' wishes to be fulfilled and ceiling of treatments agreed. Better documentation and development of validated tools to measure the quality EOLC transition on the ICU are needed.

Plasma morphine and metabolite concentrations are associated with clinical effects of morphine in cancer patients.

CONTEXT: Morphine is the opioid of choice for cancer-related pain, but for many patients the benefits of morphine are outweighed by its side effect profile. Morphine is metabolized to morphine-3-glucuronide and morphine-6-glucuronide; however, little is known about the contribution of these metabolites to analgesia and morphine-related side effects. OBJECTIVES: We investigated the association between plasma morphine and metabolite concentrations and the clinical effects of morphine in cancer patients. METHODS: A prospective study was performed in cancer patients taking oral morphine for moderate-to-severe cancer pain. Subjects who responded well to morphine (responders) and subjects who failed to respond to morphine because of lack of analgesia and/or the presence of intolerable side effects (nonresponders/switchers) were recruited. Pain and toxicity scores were recorded and blood samples were analyzed for plasma morphine, morphine-3-glucuronide, and morphine-6-glucuronide concentrations. RESULTS: Results showed that 1) morphine responders have higher plasma morphine and metabolite concentrations compared with nonresponders, 2) lower pain scores are associated with higher plasma morphine and metabolite concentrations, 3) central side effects are associated with a higher metabolite:plasma morphine ratio, and 4) myoclonus is associated with extremely high concentrations of plasma morphine and metabolites. CONCLUSION: This study has shown that plasma morphine and metabolite concentrations are associated with the clinical effects of morphine therapy. These results are important because they demonstrate the relevance of measuring plasma metabolite concentrations in clinical trials and the potential for metabolite data to deepen our understanding of factors that influence an individual's response to morphine.