{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T02:48:24Z","timestamp":1788922104989,"version":"build-2803163510"},"reference-count":49,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T00:00:00Z","timestamp":1745366400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100000925","name":"National Health and Medical Research Council","doi-asserted-by":"publisher","award":["APP1065571"],"award-info":[{"award-number":["APP1065571"]}],"id":[{"id":"10.13039\/501100000925","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Respir Res"],"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Introduction<\/jats:title>\n            <jats:p>Stress activates the hypothalamic-pituitary-adrenal (HPA) axis of which cortisol is an end product. \u2018Allostatic load\u2019 is where systems including the HPA axis are exposed to high, cumulative, physiologic burdens (such as chronic breathlessness) leading to flatter diurnal cortisol slopes and poorer health outcomes. The aim of this hypothesis-generating study explored longitudinal changes in cortisol secretion and any associated changes in breathlessness after introducing regular, low dose morphine or placebo.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods<\/jats:title>\n            <jats:p>This was an optional, hypothesis-generating sub-study embedded in a multi-site, randomised, double-blind, placebo-controlled trial (RCT) of regular, low-dose morphine for chronic breathlessness and chronic obstructive pulmonary disease. In a blinded dose-increment algorithm by week three, doses were 0\u00a0mg-32\u00a0mg. Participants in the RCT could elect to continue in a six-month blinded extension. This sub-study excluded people who used non-inhaled corticosteroids in the previous month or were on subcutaneous insulin. Participants collected saliva for cortisol assays for two days at baseline, and ends of weeks 1, 3 and 12 at 3,6 and 12\u00a0h after waking, generating sufficient data to calculate diurnal cortisol slopes and areas under the curve (AUC). Samples were analysed using ELISA. Correlations between diurnal cortisol profiles (slope and AUC) and a range of measures were explored.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Twenty mostly female former smokers were in this sub-study. At baseline and the end of week 1, one-way ANOVA between-group analyses showed no significant differences in the log-transformed cortisol slope or ln-AUC. There was a strong correlation between the age-adjusted Charlson Comorbidity Index (CCI) and ln-AUC (<jats:italic>r<\/jats:italic>=-0.70, <jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) and moderate correlation with age (<jats:italic>r<\/jats:italic>=-0.43, <jats:italic>p<\/jats:italic>\u2009=\u20090.06). In the blinded extension study, there was a self-selecting blinded group (<jats:italic>n<\/jats:italic>\u2009=\u20097) all on active medication. Global impression of change (GIC) was highly correlated with the diurnal cortisol slope (rs\u2009=\u20090.98, <jats:italic>p<\/jats:italic>\u2009=\u20090.01), and with decrease in <jats:italic>average breathlessness<\/jats:italic> (<jats:italic>r<\/jats:italic>\u2009=\u20090.89, <jats:italic>p<\/jats:italic>\u2009=\u20090.04).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Discussion<\/jats:title>\n            <jats:p>This hypothesis-generating study did not show a relationship between the diurnal cortisol profile and morphine in people with chronic breathlessness and COPD. For the sub-group still on study at 12weeks, the cortisol curves became steeper as <jats:italic>average breathlessness<\/jats:italic> decreased and as global impression of change (GIC) improved, suggesting that reducing breathlessness may potentially positively impact the HPA axis in a sub-group of people.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Trial registration<\/jats:title>\n            <jats:p>Registration Number NCT02720822 date registered 28\/03\/2016.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/s12931-025-03230-9","type":"journal-article","created":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T14:23:15Z","timestamp":1745418195000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["The longitudinal impact of low-dose morphine on diurnal cortisol profiles in people with chronic breathlessness and chronic obstructive pulmonary disease (COPD): an exploratory study"],"prefix":"10.1186","volume":"26","author":[{"given":"Diana H.","family":"Ferreira","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richella","family":"Ryan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nina","family":"Smyth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Angela","family":"Clow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David C.","family":"Currow","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,4,23]]},"reference":[{"issue":"4","key":"3230_CR1","doi-asserted-by":"publisher","first-page":"383","DOI":"10.31887\/DCNS.2006.8.4\/ssmith","volume":"8","author":"SM Smith","year":"2006","unstructured":"Smith SM, Vale WW. The role of the hypothalamic-pituitary-adrenal axis in neuroendocrine responses to stress. Dialogues Clin Neurosci. 2006;8(4):383\u201395.","journal-title":"Dialogues Clin Neurosci"},{"issue":"9","key":"3230_CR2","doi-asserted-by":"publisher","first-page":"1244","DOI":"10.1001\/jama.1992.03480090092034","volume":"267","author":"GP Chrousos","year":"1992","unstructured":"Chrousos GP, Gold PW. The concepts of stress and stress system disorders. Overview of physical and behavioral homeostasis. JAMA. 1992;267(9):1244\u201352.","journal-title":"JAMA"},{"issue":"6","key":"3230_CR3","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1038\/nrn1683","volume":"6","author":"ER De Kloet","year":"2005","unstructured":"De Kloet ER, Jo\u00ebls M, Holsboer F. Stress and the brain: from adaptation to disease. Nat Rev Neurosci. 2005;6(6):463\u201375.","journal-title":"Nat Rev Neurosci"},{"issue":"6","key":"3230_CR4","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1038\/nrn2647","volume":"10","author":"YM Ulrich-Lai","year":"2009","unstructured":"Ulrich-Lai YM, Herman JP. Neural regulation of endocrine and autonomic stress responses. Nat Rev Neurosci. 2009;10(6):397\u2013409.","journal-title":"Nat Rev Neurosci"},{"key":"3230_CR5","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1146\/annurev.physiol.67.040403.120816","volume":"67","author":"E Charmandari","year":"2005","unstructured":"Charmandari E, Tsigos C, Chrousos G. Endocrinology of the stress response. Annu Rev Physiol. 2005;67:259\u201384.","journal-title":"Annu Rev Physiol"},{"issue":"1","key":"3230_CR6","first-page":"55","volume":"21","author":"RM Sapolsky","year":"2000","unstructured":"Sapolsky RM, Romero LM, Munck AU. How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions. Endocr Rev. 2000;21(1):55\u201389.","journal-title":"Endocr Rev"},{"key":"3230_CR7","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1111\/j.1749-6632.1998.tb09546.x","volume":"840","author":"BS McEwen","year":"1998","unstructured":"McEwen BS. Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci. 1998;840:33\u201344.","journal-title":"Ann N Y Acad Sci"},{"issue":"8","key":"3230_CR8","doi-asserted-by":"publisher","first-page":"4770","DOI":"10.1073\/pnas.081072698","volume":"98","author":"TE Seeman","year":"2001","unstructured":"Seeman TE, McEwen BS, Rowe JW, Singer BH. Allostatic load as a marker of cumulative biological risk: MacArthur studies of successful aging. Proc Natl Acad Sci U S A. 2001;98(8):4770\u201375.","journal-title":"Proc Natl Acad Sci U S A"},{"key":"3230_CR9","doi-asserted-by":"publisher","first-page":"247054701983364","DOI":"10.1177\/2470547019833647","volume":"3","author":"BS McEwen","year":"2019","unstructured":"McEwen BS. What is the confusion with cortisol? Chronic Stress. 2019;3:2470547019833647.","journal-title":"Chronic Stress"},{"key":"3230_CR10","doi-asserted-by":"crossref","unstructured":"Schulkin J. Allostasis, homeostasis, and the costs of physiological adaptation. Cambridge University Press; 2004.","DOI":"10.1017\/CBO9781316257081"},{"issue":"1","key":"3230_CR11","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1159\/000510696","volume":"90","author":"J Guidi","year":"2021","unstructured":"Guidi J, Lucente M, Sonino N, Fava GA. Allostatic load and its impact on health: A systematic review. Psychother Psychosom. 2021;90(1):11\u201327.","journal-title":"Psychother Psychosom"},{"issue":"19","key":"3230_CR12","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.1001\/archinte.1997.00440400111013","volume":"157","author":"TE Seeman","year":"1997","unstructured":"Seeman TE, Singer BH, Rowe JW, Horwitz R, Mcewen B. Price of adaptation\u2014allostatic load and its health consequences: MacArthur studies of successful aging. Arch Intern Med. 1997;157(19):2259\u201368.","journal-title":"Arch Intern Med"},{"issue":"10","key":"3230_CR13","doi-asserted-by":"publisher","first-page":"1010","DOI":"10.1016\/j.psyneuen.2005.04.006","volume":"30","author":"E Fries","year":"2005","unstructured":"Fries E, Hesse J, Hellhammer J, Hellhammer DH. A new view on hypocortisolism. Psychoneuroendocrinology. 2005;30(10):1010\u201316.","journal-title":"Psychoneuroendocrinology"},{"issue":"5","key":"3230_CR14","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.tem.2009.12.011","volume":"21","author":"N Nader","year":"2010","unstructured":"Nader N, Chrousos GP, Kino K. Interactions of the circadian CLOCK system and the HPA axis. Trends Endocrinol Metab. 2010;21(5):277\u201386.","journal-title":"Trends Endocrinol Metab"},{"key":"3230_CR15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1016\/j.psyneuen.2017.05.018","volume":"83","author":"EK Adam","year":"2017","unstructured":"Adam EK, Quinn ME, Tavernier R, McQuillan MT, Dahlke KA, Gilbert KE. Diurnal cortisol slopes and mental and physical health outcomes: A systematic review and meta-analysis. Psychoneuroendocrinology. 2017;83:25\u201341.","journal-title":"Psychoneuroendocrinology"},{"key":"3230_CR16","doi-asserted-by":"publisher","first-page":"43","DOI":"10.1016\/j.physbeh.2016.11.014","volume":"178","author":"RL Spencer","year":"2017","unstructured":"Spencer RL, Deak T. A users guide to HPA axis research. Physiol Behav. 2017;178:43\u201365.","journal-title":"Physiol Behav"},{"issue":"4","key":"3230_CR17","doi-asserted-by":"publisher","first-page":"313","DOI":"10.1016\/0306-4530(94)90013-2","volume":"19","author":"C Kirschbaum","year":"1994","unstructured":"Kirschbaum C, Hellhammer DH. Salivary cortisol in psychoneuroendocrine research: recent developments and applications. Psychoneuroendocrinology. 1994;19(4):313\u201333.","journal-title":"Psychoneuroendocrinology"},{"issue":"6","key":"3230_CR18","doi-asserted-by":"publisher","first-page":"434","DOI":"10.1038\/nrn2639","volume":"10","author":"SJ Lupien","year":"2009","unstructured":"Lupien SJ, McEwen BS, Gunnar MR, Heim C. Effects of stress throughout the lifespan on the brain, behaviour and cognition. Nat Rev Neurosci. 2009;10(6):434\u201345.","journal-title":"Nat Rev Neurosci"},{"key":"3230_CR19","first-page":"89","volume-title":"Human stress and the Hypothalamic\u2013Pituitary\u2013Adrenal Axis","author":"N Smyth","year":"2020","unstructured":"Smyth N, Clow A, Salivary, Bioscience. Human stress and the Hypothalamic\u2013Pituitary\u2013Adrenal Axis. Salivary Bioscience: Springer, Cham; 2020. pp. 89\u2013114."},{"issue":"6","key":"3230_CR20","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1093\/ageing\/afl106","volume":"35","author":"C Naughton","year":"2006","unstructured":"Naughton C, Bennett K, Feely J. Prevalence of chronic disease in the elderly based on a National pharmacy claims database. Age Ageing. 2006;35(6):633\u20136.","journal-title":"Age Ageing"},{"issue":"7644","key":"3230_CR21","doi-asserted-by":"publisher","first-page":"606","DOI":"10.1136\/bmj.39503.424653.80","volume":"336","author":"JC Milton","year":"2008","unstructured":"Milton JC, Hill-Smith I, Jackson SH. Prescribing for older people. BMJ. 2008;336(7644):606\u20139.","journal-title":"BMJ"},{"issue":"5","key":"3230_CR22","doi-asserted-by":"publisher","first-page":"1434","DOI":"10.1378\/chest.121.5.1434","volume":"121","author":"K Nishimura","year":"2002","unstructured":"Nishimura K, Izumi T, Tsukino M, Oga T, on Behalf of the Kansai COPD Registry and Research Group in Japan. Dyspnea is a better predictor of 5-year survival than airway obstruction in patients with COPD. Chest. 2002;121(5):1434\u201340.","journal-title":"Chest"},{"key":"3230_CR23","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.psyneuen.2017.01.025","volume":"79","author":"R Ryan","year":"2017","unstructured":"Ryan R, Clow A, Spathis A, Smyth N, Barclay S, Fallon M, Booth S. Salivary diurnal cortisol profiles in patients suffering from chronic breathlessness receiving supportive and palliative care services: A cross-sectional study. Psychoneuroendocrinology. 2017;79:134\u201345.","journal-title":"Psychoneuroendocrinology"},{"issue":"3","key":"3230_CR24","doi-asserted-by":"publisher","first-page":"318","DOI":"10.3390\/jpm14030318","volume":"14","author":"RM Rajnoveanu","year":"2024","unstructured":"Rajnoveanu RM, Harangus A, Todea DA, Man MA, Budin CE, Rajnoveanu AG. Opioids in treatment of refractory dyspnea in chronic obstructive pulmonary disease: yes, no or maybe. J Pers Med. 2024;14(3):318.","journal-title":"J Pers Med"},{"issue":"20","key":"3230_CR25","doi-asserted-by":"publisher","first-page":"2022","DOI":"10.1001\/jama.2022.20206","volume":"328","author":"M Ekstr\u00f6m","year":"2022","unstructured":"Ekstr\u00f6m M, Ferreira D, Chang S, Louw S, Johnson MJ, Eckert DJ, et al. Effect of regular, Low-Dose, Extended-release morphine on chronic breathlessness in chronic obstructive pulmonary disease: the BEAMS randomized clinical trial. JAMA. 2022;328(20):2022\u201332.","journal-title":"JAMA"},{"issue":"10","key":"3230_CR26","doi-asserted-by":"publisher","first-page":"1437","DOI":"10.1016\/j.psyneuen.2009.06.017","volume":"34","author":"DA Granger","year":"2009","unstructured":"Granger DA, Hibel LC, Fortunato CK, Kapelewski CH. Medication effects on salivary cortisol: tactics and strategy to minimize impact in behavioral and developmental science. Psychoneuroendocrinology. 2009;34(10):1437\u201348.","journal-title":"Psychoneuroendocrinology"},{"key":"3230_CR27","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1016\/j.psyneuen.2015.08.021","volume":"62","author":"JJ Joseph","year":"2015","unstructured":"Joseph JJ, Wang X, Spanakis E, Seeman T, Wand G, Needham B. Diurnal salivary cortisol, glycemia and insulin resistance: the multi-ethnic study of atherosclerosis. Psychoneuroendocrinology. 2015;62:327\u201335.","journal-title":"Psychoneuroendocrinology"},{"issue":"1","key":"3230_CR28","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1111\/nyas.13217","volume":"1391","author":"JJ Joseph","year":"2017","unstructured":"Joseph JJ, Golden SH. Cortisol dysregulation: the bidirectional link between stress, depression, and type 2 diabetes mellitus. Ann N Y Acad Sci. 2017;1391(1):20\u201334.","journal-title":"Ann N Y Acad Sci"},{"issue":"3","key":"3230_CR29","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1016\/0304-3959(94)00204-R","volume":"61","author":"GK Gourlay","year":"1995","unstructured":"Gourlay GK, Plummer JL, Cherry DA. Chronopharmacokinetic variability in plasma morphine concentrations following oral doses of morphine solution. Pain. 1995;61(3):375\u201381.","journal-title":"Pain"},{"issue":"10","key":"3230_CR30","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1016\/j.psyneuen.2009.06.011","volume":"34","author":"EK Adam","year":"2009","unstructured":"Adam EK, Kumari M. Assessing salivary cortisol in large-scale, epidemiological research. Psychoneuroendocrinology. 2009;34(10):1423\u201336.","journal-title":"Psychoneuroendocrinology"},{"issue":"4","key":"3230_CR31","doi-asserted-by":"publisher","first-page":"325","DOI":"10.1097\/01.JGP.0000201816.26786.5b","volume":"14","author":"HC Kraemer","year":"2006","unstructured":"Kraemer HC, Giese-Davis J, Yutsis M, O\u2019Hara R, Neri E, Gallagher-Thompson D, et al. Design decisions to optimize reliability of daytime cortisol slopes in an older population. Am J Geriatr Psychiatry. 2006;14(4):325\u201333.","journal-title":"Am J Geriatr Psychiatry"},{"issue":"3","key":"3230_CR32","doi-asserted-by":"publisher","first-page":"200","DOI":"10.4037\/ajcc1998.7.3.200","volume":"7","author":"AG Gift","year":"1998","unstructured":"Gift AG, Narsavage G. Validity of the numeric rating scale as a measure of dyspnea. Am J Crit Care. 1998;7(3):200\u20134.","journal-title":"Am J Crit Care"},{"issue":"4","key":"3230_CR33","doi-asserted-by":"publisher","first-page":"374","DOI":"10.1136\/thx.54.4.374b","volume":"54","author":"A Wilcock","year":"1999","unstructured":"Wilcock A, Crosby V, Clarke D, Tattersfield A. Repeatability of breathlessness measurements in cancer patients. Thorax. 1999;54(4):374\u201374.","journal-title":"Thorax"},{"issue":"7","key":"3230_CR34","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1136\/thx.54.7.581","volume":"54","author":"J Bestall","year":"1999","unstructured":"Bestall J, Paul E, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the medical research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax. 1999;54(7):581\u201386.","journal-title":"Thorax"},{"issue":"3","key":"3230_CR35","doi-asserted-by":"publisher","first-page":"226","DOI":"10.1093\/occmed\/kqm162","volume":"58","author":"C Stenton","year":"2008","unstructured":"Stenton C. The MRC breathlessness scale. Occup Med (Lond). 2008;58(3):226\u20137.","journal-title":"Occup Med (Lond)"},{"issue":"1","key":"3230_CR36","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1186\/1472-684X-4-7","volume":"4","author":"AP Abernethy","year":"2005","unstructured":"Abernethy AP, Shelby-James T, Fazekas BS, Woods D, Currow DC. The Australia-modified Karnofsky performance status (AKPS) scale: a revised scale for contemporary palliative care clinical practice [ISRCTN81117481]. BMC Palliat Care. 2005;4(1):7.","journal-title":"BMC Palliat Care"},{"issue":"10","key":"3230_CR37","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1007\/s11136-011-9903-x","volume":"20","author":"M Herdman","year":"2011","unstructured":"Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Oarkin D, et al. Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). Qual Life Res. 2011;20(10):1727\u201336.","journal-title":"Qual Life Res"},{"issue":"2","key":"3230_CR38","doi-asserted-by":"publisher","first-page":"386","DOI":"10.1111\/resp.12681","volume":"21","author":"RT Martins","year":"2016","unstructured":"Martins RT, Currow DC, Abernethy AP, Johnson MJ, Toson B, Eckert DJ. Effects of low-dose morphine on perceived sleep quality in patients with refractory breathlessness: A hypothesis generating study. Respirology. 2016;21(2):386\u201391.","journal-title":"Respirology"},{"issue":"2","key":"3230_CR39","doi-asserted-by":"publisher","first-page":"353","DOI":"10.1038\/bjc.1991.305","volume":"64","author":"P Hopwood","year":"1991","unstructured":"Hopwood P, Howell A, Maguire P. Screening for psychiatric morbidity in patients with advanced breast cancer: validation of two self-report questionnaires. Br J Cancer. 1991;64(2):353\u201356.","journal-title":"Br J Cancer"},{"issue":"6","key":"3230_CR40","doi-asserted-by":"publisher","first-page":"361","DOI":"10.1111\/j.1600-0447.1983.tb09716.x","volume":"67","author":"AS Zigmond","year":"1983","unstructured":"Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatrica Scandinavica. 1983;67(6):361\u201370.","journal-title":"Acta Psychiatrica Scandinavica"},{"issue":"2","key":"3230_CR41","doi-asserted-by":"publisher","first-page":"229","DOI":"10.1016\/j.ahj.2012.05.003","volume":"164","author":"SG Oxberry","year":"2012","unstructured":"Oxberry SG, Bland JM, Clark AL, Cleland JGF, Johnson MJ. Minimally clinically important difference in chronic breathlessness: every little helps. Am Heart J. 2012;164(2):229\u201335.","journal-title":"Am Heart J"},{"issue":"2","key":"3230_CR42","doi-asserted-by":"publisher","first-page":"89","DOI":"10.1016\/S0306-4530(96)00039-X","volume":"22","author":"JM Smyth","year":"1997","unstructured":"Smyth JM, Ockenfels MC, Gorin AA, Catley D, Porter LS, Kirschbaum C, et al. Individual differences in the diurnal cycle of cortisol. Psychoneuroendocrinology. 1997;22(2):89\u2013105.","journal-title":"Psychoneuroendocrinology"},{"issue":"12","key":"3230_CR43","doi-asserted-by":"publisher","first-page":"994","DOI":"10.1093\/jnci\/92.12.994","volume":"92","author":"SE Sephton","year":"2000","unstructured":"Sephton SE, Sapolsky RM, Kraemer HC, Spiegel D. Diurnal cortisol rhythm as a predictor of breast cancer survival. J Natl Cancer Inst. 2000;92(12):994\u20131000.","journal-title":"J Natl Cancer Inst"},{"issue":"6","key":"3230_CR44","doi-asserted-by":"publisher","first-page":"849","DOI":"10.1016\/j.conb.2011.06.008","volume":"21","author":"JS Menet","year":"2011","unstructured":"Menet JS, Rosbash M. When brain clocks lose track of time: cause or consequence of neuropsychiatric disorders. Curr Opin Neurobiol. 2011;21(6):849\u201357.","journal-title":"Curr Opin Neurobiol"},{"issue":"7","key":"3230_CR45","first-page":"2468","volume":"81","author":"E Van Cauter","year":"1996","unstructured":"Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab. 1996;81(7):2468\u201373.","journal-title":"J Clin Endocrinol Metab"},{"issue":"3","key":"3230_CR46","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1183\/09031936.00139812","volume":"42","author":"MJ Johnson","year":"2013","unstructured":"Johnson MJ, Bland JM, Oxberry SG, Abernethy AP, Currow DC. Opioids for chronic refractory breathlessness: patient predictors of beneficial response. Eur Resp J. 2013;42(3):758\u201366.","journal-title":"Eur Resp J"},{"issue":"3","key":"3230_CR47","doi-asserted-by":"publisher","first-page":"1800887","DOI":"10.1183\/13993003.00887-2018","volume":"52","author":"Z Ahmadi","year":"2018","unstructured":"Ahmadi Z, Sandberg J, Shannon-Honson A, Vandersman Z, Currow DC, Ekstrom M. Is chronic breathlessness less recognised and treated compared with chronic pain? A case-based randomised controlled trial. Eur Respir J. 2018;52(3):1800887.","journal-title":"Eur Respir J"},{"issue":"5","key":"3230_CR48","doi-asserted-by":"publisher","first-page":"2201603","DOI":"10.1183\/13993003.01603-2022","volume":"60","author":"S Kochovska","year":"2022","unstructured":"Kochovska S, Chang S, Ferreira D, Brunelli VN, Luckett T, Morgan L, et al. Invisibility of breathlessness in clinical consultations: a cross-sectional, National online survey. Eur Respir J. 2022;60(5):2201603.","journal-title":"Eur Respir J"},{"issue":"2","key":"3230_CR49","doi-asserted-by":"publisher","first-page":"00530","DOI":"10.1183\/23120541.00530-2022","volume":"9","author":"DH Ferreira","year":"2023","unstructured":"Ferreira DH, Ekstr\u00f6m M, Verberkt C, Janssen DJA, Currow DC. Is being able to walk to the letterbox life-changing? A qualitative assessment of measures of improvement in persistent breathlessness. ERJ Open Res. 2023;9(2):00530\u20132022.","journal-title":"ERJ Open Res"}],"container-title":["Respiratory Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-025-03230-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12931-025-03230-9\/fulltext.html","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12931-025-03230-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,4,23]],"date-time":"2025-04-23T15:04:43Z","timestamp":1745420683000},"score":1,"resource":{"primary":{"URL":"https:\/\/respiratory-research.biomedcentral.com\/articles\/10.1186\/s12931-025-03230-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,23]]},"references-count":49,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["3230"],"URL":"https:\/\/doi.org\/10.1186\/s12931-025-03230-9","relation":{},"ISSN":["1465-993X"],"issn-type":[{"value":"1465-993X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,23]]},"assertion":[{"value":"4 December 2024","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 April 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 April 2025","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Ethics approval was obtained from relevant Health Human Research Ethics Committees before recruitment commenced. All participants gave informed written consent.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"The authors DF, RR, NS, AC report no competing interests. DC is an unpaid advisory board member for Helsinn Pharmaceuticals. He is a paid consultant and receives payment for intellectual property with Mayne Pharma and is a consultant with Specialised Therapeutics Australia Pty. Ltd.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"This study was approved by the Hunter New England Human Research Ethics Committee (Reference 15\/12\/16\/3.06) in accordance with the Declaration of Helsinki.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics declaration"}},{"value":"Not applicable.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to publish"}}],"article-number":"156"}}