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Opioids for Chronic Refractory Breathlessness: Right Patient, Right Route?

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Abstract

Chronic breathlessness at rest or on minimal exertion despite optimal treatment of the underlying chronic cause(s) is termed chronic refractory breathlessness. This is prevalent across the community and is an independent indicator of poor prognosis. This narrative review focuses on the palliation of chronic refractory breathlessness in people predominantly with non-cancer diagnoses. Breathlessness is a complex sensation with at least three dimensions—intensity, distress/unpleasantness and its impact on function. It is the conscious representation of a mismatch between central ventilatory drive (the demand to breathe) and the responding respiratory output (the ability to breathe). Measurement relies on subjective reports by patients using a choice of uni- and multi-variable tools; the minimal clinically important difference is the smallest change conceived as clinically meaningful by the patients. Exogenous and endogenous opioids work centrally to reduce the sensation of breathlessness, with morphine as a mu opioid receptor agonist the most widely studied. Regular, low doses of sustained-release morphine have been shown to safely reduce breathlessness in this setting without evidence of respiratory depression nor obtundation. Patients should be initiated at a dosage of 10 mg/24 h and titrated by 10 mg if there is no benefit once in steady state. The highest dosage in the only dose-ranging study published to date was only 30 mg/24 h. Predictors of response to opioids for chronic refractory breathlessness include younger people with more severe breathlessness at baseline. Future research should address whether upward titration delivers further clinical benefit and whether all underlying aetiologies respond as predictably to opioids.

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References

  1. Pratter MR, Abouzgheib W, Akers S, et al. An algorithmic approach to chronic dyspnea. Respir Med. 2011;105(7):1014–21.

    Article  PubMed  Google Scholar 

  2. Currow DC, Plummer JL, Crockett A, et al. A community population survey of prevalence and severity of dyspnea in adults. J Pain Symptom Manage. 2009;38(4):533–45.

    Article  PubMed  Google Scholar 

  3. Currow D, Smith J, Davidson P, et al. Do the trajectories of dyspnea differ in prevalence and intensity by diagnosis at the end of life? A consecutive cohort study. J Pain Symptom Manage. 2010;39(4):680–90.

    Article  PubMed  Google Scholar 

  4. Hammond EC. Some preliminary findings on physical complaints from a prospective study of 1,064,004 men and women. Am J Public Health Nations Health. 1964;54:11–23.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Frostad A, Soyseth V, Haldorsen T, et al. Respiratory symptoms and 30 year mortality from obstructive lung disease and pneumonia. Thorax. 2006;61(11):951–6.

    Article  CAS  PubMed  Google Scholar 

  6. Gift AG, Plaut SM, Jacox A. Psychologic and physiologic factors related to dyspnea in subjects with chronic obstructive pulmonary disease. Heart Lung. 1986;15(6):595–601.

    CAS  PubMed  Google Scholar 

  7. Hui D, Morgado M, Vidal M, et al. Dyspnea in hospitalized advanced cancer patients: subjective and physiologic correlates. J Palliat Med. 2013;16(3):274–80.

    Google Scholar 

  8. Parshall MB, Schwartzstein RM, Adams L, et al. An official American Thoracic Society statement: update on the mechanisms, assessment, and management of dyspnea. Am J Respir Crit Care Med. 2012;185(4):435–52.

    Article  PubMed  Google Scholar 

  9. Banzett RB, Pedersen SH, Schwartzstein RM, et al. The affective dimension of laboratory dyspnea: air hunger is more unpleasant than work/effort. Am J Respir Crit Care Med. 2008;177(12):1384–90.

    Article  PubMed  Google Scholar 

  10. Wan L, Van Diest I, De Peuter S, et al. Repeated breathlessness experiences induced by hypercapnia: differential effects on intensity and unpleasantness. Chest. 2009;135(2):455–61.

    Article  PubMed  Google Scholar 

  11. von Leupoldt A, Dahme B. Differentiation between the sensory and affective dimension of dyspnea during resistive load breathing in normal subjects. Chest. 2005;128(5):3345–9.

    Article  Google Scholar 

  12. Jennings AL, Davies AN, Higgins JP, et al. A systematic review of the use of opioids in the management of dyspnoea. Thorax. 2002;57(11):939–44.

    Article  PubMed  Google Scholar 

  13. Abernethy AP, Currow DC, Frith P, et al. Randomised, double blind, placebo controlled crossover trial of sustained release morphine for the management of refractory dyspnoea. BMJ. 2003;327(7414):523–8.

    Article  CAS  PubMed  Google Scholar 

  14. Oxberry SG, Torgerson DJ, Bland JM, et al. Short-term opioids for breathlessness in stable chronic heart failure: a randomized controlled trial. Eur J Heart Fail. 2011;13(9):1006–12.

    Article  CAS  PubMed  Google Scholar 

  15. Mancini I, Body JJ. Assessment of dyspnea in advanced cancer patients. Support Care Cancer. 1999;7(4):229–32.

    Article  CAS  PubMed  Google Scholar 

  16. Gift AG. Validation of a vertical visual analogue scale as a measure of clinical dyspnea. Rehabil Nurs Off J Assoc Rehabil Nurs. 1989;14(6):323–5.

    Article  CAS  Google Scholar 

  17. Gift AG, Narsavage G. Validity of the numeric rating scale as a measure of dyspnea. Am J Crit Care. 1998;7(3):200–4.

    CAS  PubMed  Google Scholar 

  18. Reuben DB, Mor V. Dyspnea in terminally ill cancer patients. Chest. 1986;89(2):234–6.

    Article  CAS  PubMed  Google Scholar 

  19. Lush MT, Janson-Bjerklie S, Carrieri VK, et al. Dyspnea in the ventilator-assisted patient. Heart Lung. 1988;17(5):528–35.

    CAS  PubMed  Google Scholar 

  20. O’Donnell DE, Lam M, Webb KA. Measurement of symptoms, lung hyperinflation, and endurance during exercise in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 1998;158(5 Pt 1):1557–65.

    Article  PubMed  Google Scholar 

  21. Fletcher CM. The clinical diagnosis of pulmonary emphysema; an experimental study. Proc R Soc Med. 1952;45(9):577–84.

    CAS  PubMed  Google Scholar 

  22. Mahler DA, Weinberg DH, Wells CK, et al. The measurement of dyspnea: contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest. 1984;85(6):751–8.

    Article  CAS  PubMed  Google Scholar 

  23. Yorke J, Moosavi SH, Shuldham C, et al. Quantification of dyspnoea using descriptors: development and initial testing of the Dyspnoea-12. Thorax. 2010;65(1):21–6.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  24. Uronis HE, Shelby RA, Currow DC, et al. Assessment of the psychometric properties of an English version of the cancer dyspnea scale in people with advanced lung cancer. J Pain Symptom Manage. 2012;44(5):741–9.

    Article  PubMed  Google Scholar 

  25. Guyatt GH, Berman LB, Townsend M, et al. A measure of quality of life for clinical trials in chronic lung disease. Thorax. 1987;42(10):773–8.

    Article  CAS  PubMed  Google Scholar 

  26. Jones PW, Quirk FH, Baveystock CM. The St George’s Respiratory Questionnaire. Respir Med. 1991;85 Suppl B:25–31 (discussion 3–7).

    Google Scholar 

  27. Johnson MJ, Bland JM, Oxberry SG, et al. Clinically important differences in the intensity of chronic refractory breathlessness. J Pain Symptom Manag. 2013;46(6):957–63.

    Google Scholar 

  28. Karras DJ, Sammon ME, Terregino CA, et al. Clinically meaningful changes in quantitative measures of asthma severity. Acad Emerg Med Off J Soc Acad Emerg Med. 2000;7(4):327–34.

    Article  CAS  Google Scholar 

  29. Ander DS, Aisiku IP, Ratcliff JJ, et al. Measuring the dyspnea of decompensated heart failure with a visual analog scale: how much improvement is meaningful? Congest Heart Fail (Greenwich, Conn). 2004;10(4):188–91.

    Article  Google Scholar 

  30. Mahler DA, Murray JA, Waterman LA, et al. Endogenous opioids modify dyspnoea during treadmill exercise in patients with COPD. Eur Respir J. 2009;33(4):771–7.

    Article  CAS  PubMed  Google Scholar 

  31. Gourlay GK, Plummer J, Cherry DA, et al. A comparison of Kapanol (a new sustained-release morphine formulation), MST Continus, and morphine solution in cancer patients: pharmacokinetic aspects of morphine and morphine metabolites. Seventh World Pain Congress, 1994. p. 631–43.

  32. Mahler DA. Understanding mechanisms and documenting plausibility of palliative interventions for dyspnea. Curr Opin Support Palliat Care. 2011;5(2):71–6.

    Article  PubMed  Google Scholar 

  33. Mahler DA, Gifford AH, Waterman LA, et al. Effect of increased blood levels of beta-endorphin on perception of breathlessness. Chest. 2013;143(5):1378–85.

    Article  CAS  PubMed  Google Scholar 

  34. Jensen D, Alsuhail A, Viola R, et al. Inhaled fentanyl citrate improves exercise endurance during high-intensity constant work rate cycle exercise in chronic obstructive pulmonary disease. J Pain Symptom Manage. 2012;43(4):706–19.

    Article  CAS  PubMed  Google Scholar 

  35. Davenport PW, Vovk A. Cortical and subcortical central neural pathways in respiratory sensations. Respir Physiol Neurobiol. 2009;167(1):72–86.

    Article  PubMed  Google Scholar 

  36. von Leupoldt A, Sommer T, Kegat S, et al. The unpleasantness of perceived dyspnea is processed in the anterior insula and amygdala. Am J Respir Crit Care Med. 2008;177(9):1026–32.

    Article  Google Scholar 

  37. Evans KC, Banzett RB, Adams L, et al. BOLD fMRI identifies limbic, paralimbic, and cerebellar activation during air hunger. J Neurophysiol. 2002;88(3):1500–11.

    PubMed  Google Scholar 

  38. Mahler DA. Opioids for refractory dyspnea. Expert Rev Respir Med. 2013;7(2):123–35.

    Article  CAS  PubMed  Google Scholar 

  39. Bellofiore S, Di Maria GU, Privitera S, et al. Endogenous opioids modulate the increase in ventilatory output and dyspnea during severe acute bronchoconstriction. Am Rev Respir Dis. 1990;142(4):812–6.

    Article  CAS  PubMed  Google Scholar 

  40. Gifford AH, Mahler DA, Waterman LA, et al. Neuromodulatory effect of endogenous opioids on the intensity and unpleasantness of breathlessness during resistive load breathing in COPD. COPD. 2011;8(3):160–6.

    Article  PubMed  Google Scholar 

  41. Currow DC, McDonald C, Oaten S, et al. Once-daily opioids for chronic dyspnea: a dose increment and pharmacovigilance study. J Pain Symptom Manag. 2011;42(3):388–99.

    Article  CAS  Google Scholar 

  42. Ben-Aharon I, Gafter-Gvili A, Leibovici L, et al. Interventions for alleviating cancer-related dyspnea: a systematic review and meta-analysis. Acta Oncol. 2012;51(8):996–1008.

    Article  CAS  PubMed  Google Scholar 

  43. Oxberry SG, Bland JM, Clark AL, et al. Repeat dose opioids may be effective for breathlessness in chronic heart failure if given for long enough. J Palliat Med. 2013;16(3):250–5.

    Article  PubMed  Google Scholar 

  44. Currow DC, Quinn S, Greene A, et al. The longitudinal pattern of response when morphine is used to treat chronic refractory dyspnea. J Palliat Med. 2013;16(8):881–6.

    Article  PubMed  Google Scholar 

  45. Johnson MJ, Bland JM, Oxberry SG, et al. Opioids for chronic refractory breathlessness: patient predictors of beneficial response. Eur Respir J. 2013;42(3):758–66.

    Article  PubMed  Google Scholar 

  46. Rocker G, Horton R, Currow D, et al. Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. Thorax. 2009;64(10):910–5.

    Article  CAS  PubMed  Google Scholar 

  47. Clemens KE, Quednau I, Klaschik E. Is there a higher risk of respiratory depression in opioid-naive palliative care patients during symptomatic therapy of dyspnea with strong opioids? J Palliat Med. 2008;11(2):204–16.

    Article  PubMed  Google Scholar 

  48. Johnson MJ, Abernethy AP, Currow DC. The evidence base for oxygen for chronic refractory breathlessness: issues, gaps, and a future work plan. J Pain Symptom Manag. 45(4):763–75.

  49. Krajnik M, Schafer M, Sobanski P, et al. Local pulmonary opioid network in patients with lung cancer: a putative modulator of respiratory function. Pharmacol Rep. 2010;62(1):139–49.

    CAS  PubMed  Google Scholar 

  50. Shohrati M, Ghanei M, Harandi AA, et al. Effect of nebulized morphine on dyspnea of mustard gas-exposed patients: a double-blind randomized clinical trial study. Pulm Med. 2012;2012:610921.

    Article  PubMed Central  PubMed  Google Scholar 

  51. Mahler DA, Selecky PA, Harrod CG, et al. American College of Chest Physicians consensus statement on the management of dyspnea in patients with advanced lung or heart disease. Chest. 2010;137(3):674–91.

    Article  PubMed  Google Scholar 

  52. Marciniuk DD, Goodridge D, Hernandez P, et al. Managing dyspnea in patients with advanced chronic obstructive pulmonary disease: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2011;18(2):69–78.

    PubMed Central  PubMed  Google Scholar 

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Acknowledgements

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Competing interest

DC Currow, M Ekstrom and AP Abernethy declare no competing interests.

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Authors and Affiliations

  1. Discipline, Palliative and Supportive Services and Flinders Centre for Clinical Change, Flinders University, Sturt Road, Bedford Park, SA, 5042, Australia

    David C. Currow & Amy P. Abernethy

  2. Lund University, Lund, Sweden

    Magnus Ekstrom

  3. Center for Learning Health Care, Duke University, Durham, NC, USA

    Amy P. Abernethy

  4. Health Sciences Building, Repatriation General Hospital, Daws Road, Daw Park, SA, 5041, Australia

    David C. Currow

Authors
  1. David C. Currow
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Correspondence to David C. Currow.

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Currow, D.C., Ekstrom, M. & Abernethy, A.P. Opioids for Chronic Refractory Breathlessness: Right Patient, Right Route?. Drugs 74, 1–6 (2014). https://doi.org/10.1007/s40265-013-0162-8

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  • DOI: https://doi.org/10.1007/s40265-013-0162-8

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