Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential.

INTRODUCTION: Chronic breathlessness is a common and distressing symptom of advanced disease with few effective treatments. Central nervous system mechanisms are important in respiratory sensation and control. Consequently, drugs which may modify processing and perception of afferent information in the brain may have a role. Antidepressants have been proposed; however, current evidence is limited. Of potentially suitable antidepressants, mirtazapine is an attractive option given its tolerability profile, low cost, and wide availability, along with additional potential benefits. Areas covered: The paper provides an overview of the physiology of breathlessness, with an emphasis on central mechanisms, particularly the role of fear circuits and the associated neurotransmitters. It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease. The evidence was identified by a literature search performed in PubMed through to October 2018. Expert opinion: Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease. Mirtazapine is a promising candidate to pursue, with definitive randomized controlled trials required to determine its efficacy and safety in this setting.

Development and testing of a cancer appetite and symptom questionnaire.

BACKGROUND: Poor appetite and weight loss are common in patients with cancer, contributing to an increase in morbidity and mortality. Early identification of those at greatest risk is problematic. The Council on Nutrition Appetite Questionnaire (CNAQ) is short and easy to use, although it is not specific to cancer populations. The present study aimed to build on the CNAQ to develop a cancer appetite and symptom questionnaire (CASQ) for predicting weight loss in patients with cancer. METHODS: The content validity of the CNAQ was assessed by an expert panel (n = 41) using the content validity index (CVI). The resulting CASQ was tested for reliability among patients receiving radiotherapy (n = 34). Predictive validity of the CASQ was determined in patients with lung or upper gastrointestinal cancer (n = 185), comparing CASQ scores (possible range 0-48) recorded at baseline with percentage weight change after 12 weeks. RESULTS: In all but one CNAQ item, the CVI was above the minimum level of agreement (>0.70). Comments from expert panel members led to minor modifications and the introduction of new items resulting in the 12-item CASQ. The intraclass correlation coefficient of the CASQ was 0.80 [95% confidence interval (CI) = 0.68-0.92] and the difference between total scores at two time points was -0.20 (95% CI = -1.21 to 0.80). The optimum cut-off point of the instrument to predict >10% weight loss was 29/30 (area under curve = 0.75; sensitivity 71%, specificity 66%, positive predictive value 19%, negative predictive value 95%) [Correction added on 30 April 2012, after first online publication: in the preceding sentence, <10% was corrected to >10%]. CONCLUSIONS: The CASQ can predict weight loss among patients with lung and upper gastrointestinal cancer. Acknowledgment of the low positive predictive value is needed if the instrument is to be used within clinical practice.

Researching breathlessness in palliative care: consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup.

Breathlessness is common in advanced disease and can have a devastating impact on patients and carers. Research on the management of breathlessness is challenging. There are relatively few studies, and many studies are limited by inadequate power or design. This paper represents a consensus statement of the National Cancer Research Institute Palliative Care Breathlessness Subgroup. The aims of this paper are to facilitate the design of adequately powered multi-centre interventional studies in breathlessness, to suggest a standardised, rational approach to breathlessness research and to aid future 'between study' comparisons. Discussion of the physiology of breathlessness is included.

Randomised, placebo controlled trial of nebulised furosemide for breathlessness in patients with cancer.

BACKGROUND: Breathlessness is a common and difficult symptom to treat in patients with cancer. Case reports suggest that nebulised furosemide can relieve breathlessness in such patients but few data are available. METHOD: Patients with primary or secondary lung cancer and a Dyspnoea Exertion Scale score of >or=3 were recruited. Following familiarisation, patients received either nebulised furosemide 40 mg or nebulised 0.9% saline under double blind conditions or no treatment, in random order on 3 consecutive days. Patients undertook number reading and arm exercise tests to assess breathlessness and its impact, and were asked to report subjective benefit and any preference between nebulised treatments. RESULTS: 15 patients took part. There were no differences between furosemide, saline and no treatment in the outcomes of the number reading test (eg, mean number read per breath was 6.7, 6.4 and 6.7, respectively) or arm exercise test (eg, mean Borg score at maximum equivalent workload was 2.3, 2.5 and 2.7, respectively). No adverse effects were reported, although there was a small fall in forced expiratory volume in 1 s and forced vital capacity following saline. Six patients considered that their breathlessness improved with nebulised treatment, three preferring saline, one furosemide and two reporting they were of equal benefit. CONCLUSIONS: Our findings do not support a beneficial effect from nebulised furosemide in patients with cancer related breathlessness. Listed on the National Research Register (N0170118249) and the UK Clinical Research Network Portfolio Database (1428).

Potential for drug interactions involving cytochrome P450 in patients attending palliative day care centres: a multicentre audit.

AIM: To determine the potential for drug interactions involving cytochrome P450 (CYP) in patients receiving palliative day care. METHODS: Drugs used by patients attending four specialist palliative day care centres were reviewed to identify combinations that could result in a pharmacokinetic interaction via any of the five main human forms of CYP. RESULTS: Of 160 patients, 145 (91%) were prescribed at least one drug that was a substrate, inhibitor or inducer of one of the five main CYP isoforms. Twenty-four drug combinations, involving 34 patients, could have given rise to a clinically important interaction. CONCLUSIONS: Prescribers should be aware that in this group of patients, one in five are at risk of a clinically important CYP-mediated drug interaction.

Inhibition of histone deacetylase activity causes cell type-specific induction of the PDGF-B promoter only in the absence of activation by its enhancer.

There is a strong correlation between the acetylation status of nucleosomal histones and transcriptional activity. Here we show that the histone deacetylase inhibitor trichostatin A (TSA) activates reporter gene constructs driven by the human platelet-derived growth factor B (PDGF-B) gene promoter. This activation showed an inverse correlation with the cell type-specific transcriptional activities of the promoter. The TSA response was minimal in three tumor cell lines that exhibit high-level promoter activity. In JEG-3 choriocarcinoma cells, however, where the basal promoter activity is considerably lower, there was a strong response to TSA. This was in contrast to constructs that included a PDGF-B enhancer, which were refractory to TSA effects, indicating a possible function of the enhancer in modulating acetylation status. Analysis of PDGF-B promoter mutants with respect to TSA induction revealed no specific TSA-responsive element, but suggested that association of nonacetylated histones to the PDGF-B promoter may be a default process in the absence of enhancer activation. TSA treatment of JEG-3 cells, either alone or in combination with the demethylating agent 5-azacytidine, failed to activate the silenced endogenous PDGF-B transcript, however, which appears to be repressed by additional mechanisms.

The sequential activation and repression of the human PDGF-B gene during chronic hypoxia reveals antagonistic roles for the depletion of oxygen and glucose.

Hypoxia and glucose deprivation, are important during many physiological and pathological processes. Cells respond to these stimuli by activating genes involved in the regulation of metabolism and angiogenesis. Platelet derived growth factor-B (PDGF-B) is involved in the regulation of angiogenesis and tumour progression and is induced by hypoxia. Most known hypoxia-induced genes are activated by the hypoxia inducible factor (HIF-1), via its binding to specific response elements. The mechanism of hypoxic induction and the effect of low glucose on PDGF-B expression have not been characterised. We show that PDGF-B exhibits a novel, biphasic regulation (induction, followed by repression below basal levels) in bladder carcinoma cells cultured under chronic hypoxia. We show that the repression observed after long-term hypoxia is due to glucose-depletion and that this can also abrogate short-term hypoxic induction. This is in contrast to the previous results showing that hypoxia/hypoglycaemia elicit the same response. We also show that a putative hypoxia response element in the PDGF-B promoter is not sufficient for hypoxic induction, although it does function as a hypoxia independent enhancer element in hepatocellular carcinoma cells.

The safety and efficacy of a single dose (500 mg or 1 g) of intravenous magnesium sulfate in neuropathic pain poorly responsive to strong opioid analgesics in patients with cancer.

Neuropathic pain may respond poorly to morphine and is often difficult to relieve. Recent attention has been drawn to the role of the N-methyl-D-aspartate (NMDA) receptor in the potentiation of neuropathic pain. Magnesium is known to block the NMDA receptor. It reduces the neuropathic pain response in animals, and attenuates postoperative pain and migraine in humans. We have examined the safety, tolerability, and efficacy of two intravenous doses of magnesium sulfate in 12 patients with neuropathic pain due to malignant infiltration of the brachial or lumbosacral plexus. The first six patients received 500 mg, the remainder 1 g. Apart from a mild feeling of warmth at the time of the injection, both doses were well tolerated. After receiving 500 mg, three patients experienced complete pain relief and two experienced partial pain relief for up to 4 hours duration; pain was unchanged in one patient. After receiving 1 g, one patient experienced complete relief and four experienced partial pain relief of similar duration; pain was unchanged in one patient. Intravenous magnesium sulfate in these doses appears to be safe and well tolerated. A useful analgesic effect may be obtained in some patients and further evaluation is warranted.

Cultural relativism: occupation and independence reconsidered.

In this article, findings from a qualitative study of a cohort of occupational therapy students in Auckland, New Zealand are presented. The study focussed on the experiences of students as they learned to work with people from different social and cultural backgrounds over a 3-year period. As well as identifying curriculum and teaching/learning processes that enhance intercultural competence development, the data that emerged from the study also highlight important issues about how occupation and independence are conceptualised across cultures. A review of the trans-disciplinary and occupational therapy literature dealing with theoretical, conceptual and educational issues relating to cross-cultural practice is followed by a presentation of narrative extracts that address the key concepts of occupation and independence. These are then discussed with reference to relevant occupational therapy literature. In conclusion, implications for future research and practice are explored focussing on a need for occupation and independence to be reconsidered as culturally relative constructions.

Using bisphosphonates to control the pain of bone metastases: evidence-based guidelines for palliative care.

This work was undertaken by the Science Committee of the Association for Palliative Medicine of Great Britain and Ireland (APM) as a demonstration project in developing clinical guidelines relevant to palliative care from a pragmatic approach to literature review and grading of clinical evidence. CANCERLIT and Embase were searched for relevant papers written in English, published since 1980. Each study identified was rated against agreed criteria for levels of evidence. Most studies were not specifically designed to define speed of response, and were not undertaken in palliative care patients. Thus, careful reading and grading of each study was necessary. Sufficient evidence was identified to make recommendations for clinical practice in a palliative care population of patients, and areas for future research have been identified. Bisphosphonates appear to have a role in managing pain from metastases which has been refractory to conventional analgesic management and where oncological or orthopaedic intervention is delayed or inappropriate.

Audit of cancer pain management in a cancer centre.

Despite the availability of effective methods of controlling pain, many patients continue to receive inadequate pain relief. An audit was carried out on a single day to identify the prevalence, severity and management of cancer pain in adults in the two teaching hospitals in the Nottingham Cancer Centre. Of 186 patients with cancer, 52 had experienced pain as a result of their cancer during their admission. Of these 52 patients, 47 were assessed. More than half had unrelieved pain that was 'severe' at it s worst and interfered greatly with activities. Compared with patients whose pain had been relieved, patients with uncontrolled pain were likely to have spent less time in hospital, to have not had a formal assessment or reassessment of their pain and not to have a pain-care plan in the nursing notes or to have been seen by the hospital specialist palliative care team. We use our results to highlight areas of good practice, to identify where improvements could be made, and to inform the development of local standards and future audits.

Reading numbers aloud: a measure of the limiting effect of breathlessness in patients with cancer.

BACKGROUND: Progress in the treatment of breathlessness at rest or on minimum exertion in patients with cancer requires a practical and valid method of measuring symptoms. A study was undertaken to explore the practicality, repeatability, and sensitivity of reading numbers as a form of exercise test in this group of patients. METHODS: Thirty patients with cancer and 30 age matched healthy subjects read numbers aloud as quickly and clearly as they could for 60 seconds. After five readings the maximum number of numbers read and the number read per breath was noted. This procedure was carried out twice in one day and one week later to assess within and between day repeatability. The sensitivity of the test was assessed by making measurements in 13 patients with cancer before and after drainage of their pleural effusion. RESULTS: The concept was easily understood by all subjects. Twelve patients were unable to complete five readings in all tests due to tiredness. Compared with control subjects patients read fewer numbers in the three tests (87-89% of control) and fewer numbers per breath (59-60% of control). Repeatability was good both within and between days. After drainage of their effusion all patients were less breathless and there was an increase in both the maximum number of numbers read (23%) and the number read per breath (60%). CONCLUSIONS: The number of numbers read and the number read per breath over 60 seconds was practical, easy to carry out, showed good repeatability within and between days and was sensitive to the improvement seen following drainage of a pleural effusion. It may be a useful measure of the limiting effect of breathlessness in this group of patients.