Opioid suppression of conditioned anticipatory brain responses to breathlessness

© 2017 The Authors Opioid painkillers are a promising treatment for chronic breathlessness, but are associated with potentially fatal side effects. In the treatment of breathlessness, their mechanisms of action are unclear. A better understanding might help to identify safer alternatives. Learned associations between previously neutral stimuli (e.g. stairs) and repeated breathlessness induce an anticipatory threat response that may worsen breathlessness, contributing to the downward spiral of decline seen in clinical populations. As opioids are known to influence associative learning, we hypothesized that they may interfere with the brain processes underlying a conditioned anticipatory response to breathlessness in relevant brain areas, including the amygdala and the hippocampus. Healthy volunteers viewed visual cues (neutral stimuli) immediately before induction of experimental breathlessness with inspiratory resistive loading. Thus, an association was formed between the cue and breathlessness. Subsequently, this paradigm was repeated in two identical neuroimaging sessions with intravenous infusions of either low-dose remifentanil (0.7 ng/ml target-controlled infusion) or saline (randomised). During saline infusion, breathlessness anticipation activated the right anterior insula and the adjacent operculum. Breathlessness was associated with activity in a network including the insula, operculum, dorsolateral prefrontal cortex, anterior cingulate cortex and the primary sensory and motor cortices. Remifentanil reduced breathlessness unpleasantness but not breathlessness intensity. Remifentanil depressed anticipatory activity in the amygdala and the hippocampus that correlated with reductions in breathlessness unpleasantness. During breathlessness, remifentanil decreased activity in the anterior insula, anterior cingulate cortex and sensory motor cortices. Remifentanil-induced reduction in breathlessness unpleasantness was associated with increased activity in the rostral anterior cingulate cortex and nucleus accumbens, components of the endogenous opioid system known to decrease the perception of aversive stimuli. These findings suggest that in addition to effects on brainstem respiratory control, opioids palliate breathlessness through an interplay of altered associative learning mechanisms. These mechanisms provide potential targets for novel ways to develop and assess treatments for chronic breathlessness

Breathlessness in the elderly during the last year of life sufficient to restrict activity

OBJECTIVES: Breathlessness is prevalent in older people. Symptom control at the end of life is important. This study investigated relationships between age, clinical characteristics and breathlessness sufficient to have people spend at least one half a day in that month in bed or cut down on their usual activities (restricting breathlessness) during the last year of life. DESIGN: Secondary data-analysis SETTING: General community PARTICIPANTS: 754 non-disabled persons, aged 70 and older. Monthly telephone interviews were conducted to determine the occurrence of restricting breathlessness. The primary outcome was the percentage of months with restricting breathlessness reported during the last year of life. RESULTS: Data regarding breathlessness were available for 548/589 (93.0%) decedents (mean age 86.7 years (range 71 to 106; males 38.8%). 311/548 (56.8%) reported restricting breathlessness at some time-point during the last year of life but no-one reported this every month. Frequency increased in the months closer to death irrespective of cause. Restricting breathlessness was associated with anxiety, (0.25 percentage point increase in months breathlessness per percentage point months reported anxiety, 95% CI 0.16 to 0.34, P<0.001), depression (0.14, 0.05 to 0.24, P=0.002) and mobility problems (0.07, 0.03 to 0.1, P=0.001). Percentage months of restricting breathlessness increased if chronic lung disease was noted at the most recent comprehensive assessment (6.62 percentage points, 95% CI 4.31 to 8.94, P<0.001), heart failure (3.34, 0.71 to 5.97, P<0.01), and ex-smoker status (3.01, 0.94 to 5.07, P=0.002), but decreased with older age (─0.19, ─0.37 to ─0.02, P=0.03). CONCLUSION: Restricting breathlessness increased in this elderly population in the months preceding death from any cause. Breathlessness should be assessed and managed in the context of poor prognosis

Effects of low dose morphine on perceived sleep quality in patients with refractory breathlessness : a hypothesis generating study

© 2015 Asian Pacific Society of Respirology. Background and objective The management of chronic refractory breathlessness is one of the indications for regular low-dose (≤30 mg/24 h) oral sustained release morphine. Morphine may disrupt sleep in some conditions and improve sleep quality in others. This study aimed to determine any signal of regular, low-dose morphine on perceived sleep disruption due to breathlessness and perceived sleep quality. Methods This is a secondary analysis of data from 38 participants with refractory breathlessness (30 male; 33 with COPD) aged 76 ± 0.9 years who completed a double-blind, randomized, placebo-controlled, cross-over study in which they received 20 mg oral sustained release morphine daily and placebo for 4 days each. Participant ratings of sleep disruption due to breathlessness and perceived sleep quality were obtained daily throughout the 8-day trial. Results Perceived sleep disruption due to breathlessness over the 4-day period ranged between 13% and 32% of participants for placebo and 13% and 26% for morphine, decreasing by each day of the study during the morphine arm. Most participants reported 'very good' or 'quite good' sleep throughout the trial and were less likely to perceive poor sleep quality during the morphine arm (odds ratio = 0.55, 95% confidence interval: 0.34-0.88, P = 0.01). Participants who reported decreased breathlessness during the 4 days on morphine were also likely to report improved sleep quality with morphine (P = 0.039). Conclusion Four days of low-dose morphine improved perceived sleep quality in elderly participants with refractory breathlessness. Regular low-dose morphine targeted to reduce refractory breathlessness may yield associated benefits by reducing sleep disruption and improving sleep quality

Can variability in the effect of opioids on refractory breathlessness be explained by genetic factors?

© 2015, BMJ Publishing Group. All rights reserved. Objectives: Opioids modulate the perception of breathlessness with a considerable variation in response, with poor correlation between the required opioid dose and symptom severity. The objective of this hypothesis-generating, secondary analysis was to identify candidate single nucleotide polymorphisms (SNP) from those associated with opioid receptors, signalling or pain modulation to identify any related to intensity of breathlessness while on opioids. This can help to inform prospective studies and potentially lead to better tailoring of opioid therapy for refractory breathlessness. Setting: 17 hospice/palliative care services (tertiary services) in 11 European countries. Participants: 2294 people over 18 years of age on regular opioids for pain related to cancer or its treatment. Primary outcome measures: The relationship between morphine dose, breathlessness intensity (European Organisation for Research and Treatment of Cancer Core Quality of Life Questionnaire; EORTCQLQC30 question 8) and 112 candidate SNPs from 25 genes (n=588). Secondary outcome measures: The same measures for people on oxycodone (n=402) or fentanyl (n=429). Results: SNPs not in Hardy-Weinberg equilibrium or with allele frequencies ( < 5%) were removed. Univariate associations between each SNP and breathlessness intensity were determined with Benjamini-Hochberg false discovery rate set at 20%. Multivariable ordinal logistic regression, clustering over country and adjusting for available confounders, was conducted with remaining SNPs. For univariate morphine associations, 1 variant on the 5-hydroxytryptamine type 3B (HTR3B) gene, and 4 on the β-2-arrestin gene (ARRB2) were associated with more intense breathlessness. 1 SNP remained significant in the multivariable model: people with rs7103572 SNP (HTR3B gene; present in 8.4% of the population) were three times more likely to have more intense breathlessness (OR 2.86; 95% CIs 1.46 to 5.62; p=0.002). No associations were seen with fentanyl nor with oxycodone. Conclusions: This large, exploratory study identified 1 biologically plausible SNP that warrants further study in the response of breathlessness to morphine therapy

Blinded patient preference for morphine compared to placebo in the setting of chronic refractory breathlessness – an exploratory study

Context Patients’ preference for morphine therapy has received little attention in the setting of chronic refractory breathlessness. However, this is one important factor in considering longer term therapy. Objectives The aim of this secondary analysis is to explore blinded patient preference of morphine compared to placebo for this indication and to define any predictors of preference. Methods Data were pooled from three randomized, double-blind, crossover, placebo-controlled studies of morphine (four days each) in chronic refractory breathlessness. Blinded patient preferences were chosen at the end of each study. A multivariable regression model was used to establish patient predictors of preference. Results Sixty-five participants provided sufficient data (60 males; median age 74 years; heart failure 55%, chronic obstructive pulmonary disease 45%; median Eastern Cooperative Oncology Group performance status 2). Forty-three percent of participants preferred morphine (32% placebo and 25% no preference). Morphine preference and younger age were strongly associated: odds ratio = 0.85, 95% confidence interval 0.78, 0.93;

The independent association of overweight and obesity with breathlessness in adults: a cross-sectional, population-based study

Obesity is an independent risk factor for chronic breathlessness and should be assessed in people with this symptom

Treating breathlessness via the brain: changes in brain activity over a course of pulmonary rehabilitation

Breathlessness in chronic obstructive pulmonary disease (COPD) is often discordant with airway pathophysiology ("over-perception"). Pulmonary rehabilitation profoundly affects breathlessness, without influencing lung function. Learned associations influence brain mechanisms of sensory perception. We hypothesised that improvements in breathlessness with pulmonary rehabilitation may be explained by changing neural representations of learned associations.In 31 patients with COPD, we tested how pulmonary rehabilitation altered the relationship between brain activity during a breathlessness-related word-cue task (using functional magnetic resonance imaging), and clinical and psychological measures of breathlessness.Changes in ratings of breathlessness word cues positively correlated with changes in activity in the insula and anterior cingulate cortex. Changes in ratings of breathlessness-anxiety negatively correlated with activations in attention regulation and motor networks. Baseline activity in the insula, anterior cingulate cortex and prefrontal cortex correlated with improvements in breathlessness and breathlessness-anxiety.Pulmonary rehabilitation is associated with altered neural responses related to learned breathlessness associations, which can ultimately influence breathlessness perception. These findings highlight the importance of targeting learned associations within treatments for COPD, demonstrating how neuroimaging may contribute to patient stratification and more successful personalised therapy

Palliative care for people with non-malignant lung disease: summary of current evidence and future direction

Background: The physical and psychosocial needs of patients with chronic non-malignant lung disease are comparable to those with lung cancer. This article will focus on chronic obstructive pulmonary disease, interstitial lung disease and cystic fibrosis as examples of life-limiting, non-curable and non-malignant lung diseases. The need for supportive and palliative care: Recent national guidance has demanded that palliative care is inclusive of all patients with life-limiting disease, irrespective of diagnosis, and that specialist palliative care teams are involved in the management of patients on a basis of need rather than prognosis. What is known: Despite medical therapy, most patients with moderate to severe chronic obstructive pulmonary disease, interstitial lung disease and cystic fibrosis experience pain, fatigue and dyspnoea, with the majority not getting relief from dyspnoea towards the end of life. Furthermore, dyspnoea causes social isolation and difficulty performing activities of daily living and impairs quality of life. There is an increasing evidence base for the assessment of supportive and palliative care needs, symptom interventions, prognostication, models of service delivery and implications of these for clinical practice and research in non-malignant lung diseases. What is unknown: Despite advances, much still remains unknown regarding assessment, management and prognostication in individual chronic non-malignant lung diseases. Although different service models are being used in clinical practice, the optimal model(s) of service delivery remain unknown. Implication for future research, policy and practice: We describe key areas for further research, which include the need for large, high-quality trials of pharmacological and non-pharmacological interventions and their combinations as well as evaluation of the efficacy and cost-effectiveness of models of care. As access to palliative care is poor for these patients, the barriers to referral need to be understood and reduced, which along with effective working between palliative care teams, with respiratory services backup, should optimise delivery of care in patients with life-limiting non-malignant lung disease

Breathing SPACE – a practical approach to the breathless patient.

Breathlessness is a common symptom which may have multiple causes in any one individual and causes which may change over time. Breathlessness campaigns encourage people to see their GP if they are unduly breathless. Members of the London Respiratory Network collaborated to develop a tool which would encourage a holistic approach to breathlessness, which was applicable both at the time of diagnosis and during ongoing management. This has led to the development of the aide memoire “Breathing SPACE” which encompasses 5 key themes – Smoking, Pulmonary disease, Anxiety/psychosocial factors, Cardiac disease and Exercise/fitness. A particular concern was to ensure that high value interventions (smoking cessation and exercise interventions) are prioritised across the life-course and throughout the course of disease management. The approach is relevant both to well people and in those with an underling diagnosis or diagnoses. The inclusion of anxiety draws attention to the importance of mental health issues. Parity of esteem requires the physical health problems of people with mental illness to be addressed. The SPACE mnemonic also addresses the problem of underdiagnosis of heart disease in people with lung disease and vice versa, as well as the systematic undertreatment of these conditions where they do co-occur