How successful are we in relieving terminal dyspnea in cancer patients? A real-world multicenter prospective observational study

  • Masanori MoriEmail author
  • Tatsuya Morita
  • Yoshinobu Matsuda
  • Hirohide Yamada
  • Keisuke Kaneishi
  • Yoshihisa Matsumoto
  • Naoki Matsuo
  • Takuya Odagiri
  • Etsuko Aruga
  • Hiroaki Watanabe
  • Ryohei Tatara
  • Hiroki Sakurai
  • Akira Kimura
  • Hideki Katayama
  • Akihiko Suga
  • Tomohiro Nishi
  • Akemi Naito Shirado
  • Toshio Watanabe
  • Aya Kuchiba
  • Takuhiro Yamaguchi
  • Satoru Iwase
Original Article



Parenteral morphine is widely used for dyspnea of imminently dying cancer patients, but the outcomes to expect over time remain largely unknown. We examined outcomes after the administration of parenteral morphine infusion over 48 h in cancer patients with a poor performance status.


This was a multicenter prospective observational study. Inclusion criteria were metastatic/locally advanced cancer, ECOG performance status = 3–4, a dyspnea intensity ≥ 2 on a Support Team Assessment Schedule, Japanese version (STAS-J), and receiving specialized palliative care. After initiating parenteral morphine infusion, we measured dyspnea STAS-J as well as Memorial Delirium Assessment Scale (MDAS), item 9, and Communication Capacity Scale (CCS), item 4, every 6 h over 48 h.


We enrolled 167 patients (median survival = 4 days). The mean age was 70 years, 80 patients (48%) had lung cancer, and 109 (65%) had lung metastases. The mean STAS-J scores decreased from 3.1 (95% confidence interval (CI) = 3.0–3.2) at the baseline to 2.1 (95%CI = 1.9–2.2) at 6 h, and remained 1.6–1.8 over 12–48 h. The proportion of patients with dyspnea relief (STAS-J ≤ 1) increased to 39% at 6 h, and ranged between 49 and 61% over 12–48 h. In contrast, up to 6.6 and 20% of patients showed hyperactive delirium (MDAS item 9 ≥ 2) and an inability to communicate (CCS item 4 = 3), respectively, over 48 h.


Overall, terminal dyspnea was relatively well controlled with parenteral morphine, though a significant number of patients continued to suffer from dyspnea. Future efforts are needed to improve outcomes following standardized dyspnea treatment using patient-reported outcomes for imminently dying patients.


Dyspnea Morphine Outcomes Cancer Palliative care 


Funding information

This work was funded by a Health Labour Sciences Research Grant from the Ministry of Health, Labour and Welfare. The funding source had no involvement in the study design; collection, analysis, or interpretation of data; writing of the manuscript; or the decision to submit the manuscript for publication.

Compliance with ethical standards

This study was conducted in accordance with the ethical standards of the Helsinki Declaration and the ethical guidelines for epidemiological research presented by the Ministry of Health, Labour and Welfare in Japan. The study was approved by the Institutional Review Boards (IRBs) of all participating institutions. The IRBs waived the requirement for obtaining written informed consent in this observational study based on the aforementioned ethical guidelines.

Conflict of interest

AK received honoraria for speaking at symposia by Chugai Pharmaceutical Co., Ltd. The other authors declare that they have no conflict of interest.


  1. 1.
    Chiu TY, Hu WY, Lue BH, Yao CA, Chen CY, Wakai S (2004) Dyspnea and its correlates in taiwanese patients with terminal cancer. J Pain Symptom Manag 28(2):123–132. CrossRefGoogle Scholar
  2. 2.
    O’Driscoll M, Corner J, Bailey C (1999) The experience of breathlessness in lung cancer. Eur J Cancer Care 8(1):37–43CrossRefGoogle Scholar
  3. 3.
    Seow H, Barbera L, Sutradhar R, Howell D, Dudgeon D, Atzema C, Liu Y, Husain A, Sussman J, Earle C (2011) Trajectory of performance status and symptom scores for patients with cancer during the last six months of life. J Clin Oncol 29(9):1151–1158. CrossRefPubMedGoogle Scholar
  4. 4.
    Tanaka K, Akechi T, Okuyama T, Nishiwaki Y, Uchitomi Y (2002) Prevalence and screening of dyspnea interfering with daily life activities in ambulatory patients with advanced lung cancer. J Pain Symptom Manag 23(6):484–489CrossRefGoogle Scholar
  5. 5.
    Walsh D, Donnelly S, Rybicki L (2000) The symptoms of advanced cancer: relationship to age, gender, and performance status in 1,000 patients. Support Care Cancer 8(3):175–179CrossRefGoogle Scholar
  6. 6.
    Ben-Aharon I, Gafter-Gvili A, Paul M, Leibovici L, Stemmer SM (2008) Interventions for alleviating cancer-related dyspnea: a systematic review. J Clin Oncol 26(14):2396–2404. CrossRefPubMedGoogle Scholar
  7. 7.
    Bruera E, MacEachern T, Ripamonti C, Hanson J (1993) Subcutaneous morphine for dyspnea in cancer patients. Ann Intern Med 119(9):906–907CrossRefGoogle Scholar
  8. 8.
    Mazzocato C, Buclin T, Rapin CH (1999) The effects of morphine on dyspnea and ventilatory function in elderly patients with advanced cancer: a randomized double-blind controlled trial. Ann Oncology 10(12):1511–1514CrossRefGoogle Scholar
  9. 9.
    Navigante AH, Castro MA, Cerchietti LC (2010) Morphine versus midazolam as upfront therapy to control dyspnea perception in cancer patients while its underlying cause is sought or treated. J Pain Symptom Manag 39(5):820–830. CrossRefGoogle Scholar
  10. 10.
    Navigante AH, Cerchietti LC, Castro MA, Lutteral MA, Cabalar ME (2006) Midazolam as adjunct therapy to morphine in the alleviation of severe dyspnea perception in patients with advanced cancer. J Pain Symptom Manag 31(1):38–47. CrossRefGoogle Scholar
  11. 11.
    Viola R, Kiteley C, Lloyd NS, Mackay JA, Wilson J, Wong RK, Supportive Care Guidelines Group of the Cancer Care Ontario Program in Evidence-Based C (2008) The management of dyspnea in cancer patients: a systematic review. Support Care Cancer 16(4):329–337. CrossRefPubMedGoogle Scholar
  12. 12.
    Hui D, dos Santos R, Chisholm GB, Bruera E (2015) Symptom expression in the last seven days of life among cancer patients admitted to acute palliative care units. J Pain Symptom Manag 50(4):488–494. CrossRefGoogle Scholar
  13. 13.
    Hui D, dos Santos R, Chisholm G, Bansal S, Silva TB, Kilgore K, Crovador CS, Yu X, Swartz MD, Perez-Cruz PE, Leite Rde A, Nascimento MS, Reddy S, Seriaco F, Yennu S, Paiva CE, Dev R, Hall S, Fajardo J, Bruera E (2014) Clinical signs of impending death in cancer patients. Oncologist 19(6):681–687. CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Mori M, Matsunuma R, Suzuki K, Matsuda Y, Watanabe H, Yamaguchi T (2019) Palliative care physicians' practice in the titration of parenteral opioids for dyspnea in terminally-ill cancer patients: a nationwide survey. J Pain Symptom Manag.
  15. 15.
    Kvale PA, Selecky PA, Prakash UB, American College of Chest P (2007) Palliative care in lung cancer: ACCP evidence-based clinical practice guidelines (2nd edition). Chest 132(3 Suppl):368S–403S. CrossRefPubMedGoogle Scholar
  16. 16.
    Hui D, Dos Santos R, Chisholm G, Bansal S, Souza Crovador C, Bruera E (2015) Bedside clinical signs associated with impending death in patients with advanced cancer: preliminary findings of a prospective, longitudinal cohort study. Cancer 121(6):960–967. CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Cohen MH, Anderson AJ, Krasnow SH, Spagnolo SV, Citron ML, Payne M, Fossieck BE Jr (1991) Continuous intravenous infusion of morphine for severe dyspnea. South Med J 84(2):229–234CrossRefGoogle Scholar
  18. 18.
    Yamaguchi T, Goya S, Kohara H, Watanabe H, Mori M, Matsuda Y, Nakamura Y, Sakashita A, Nishi T, Tanaka K (2016) Treatment recommendations for respiratory symptoms in cancer patients: clinical guidelines from the Japanese Society for Palliative Medicine. J Palliat Med 19(9):925–935. CrossRefPubMedGoogle Scholar
  19. 19.
    Morita T, Tsuneto S, Shima Y (2002) Definition of sedation for symptom relief: a systematic literature review and a proposal of operational criteria. J Pain Symptom Manag 24(4):447–453CrossRefGoogle Scholar
  20. 20.
    Pirovano M, Maltoni M, Nanni O, Marinari M, Indelli M, Zaninetta G, Petrella V, Barni S, Zecca E, Scarpi E, Labianca R, Amadori D, Luporini G (1999) A new palliative prognostic score: a first step for the staging of terminally ill cancer patients. Italian multicenter and study group on palliative care. J Pain Symptom Manag 17(4):231–239CrossRefGoogle Scholar
  21. 21.
    Glare P, Virik K (2001) Independent prospective validation of the PaP score in terminally ill patients referred to a hospital-based palliative medicine consultation service. J Pain Symptom Manag 22(5):891–898CrossRefGoogle Scholar
  22. 22.
    Higginson IJ, McCarthy M (1993) Validity of the support team assessment schedule: do staffs’ ratings reflect those made by patients or their families? Palliat Med 7(3):219–228CrossRefGoogle Scholar
  23. 23.
    Miyashita M, Matoba K, Sasahara T, Kizawa Y, Maruguchi M, Abe M, Kawa M, Shima Y (2004) Reliability and validity of the Japanese version of the Support Team Assessment Schedule (STAS-J). Palliat Support Care 2(4):379–385CrossRefGoogle Scholar
  24. 24.
    Miyashita M, Yasuda M, Baba R, Iwase S, Teramoto R, Nakagawa K, Kizawa Y, Shima Y (2010) Inter-rater reliability of proxy simple symptom assessment scale between physician and nurse: a hospital-based palliative care team setting. Eur J Cancer Care 19(1):124–130. CrossRefGoogle Scholar
  25. 25.
    Breitbart W, Rosenfeld B, Roth A, Smith MJ, Cohen K, Passik S (1997) The memorial delirium assessment scale. J Pain Symptom Manag 13(3):128–137CrossRefGoogle Scholar
  26. 26.
    Lawlor PG, Nekolaichuk C, Gagnon B, Mancini IL, Pereira JL, Bruera ED (2000) Clinical utility, factor analysis, and further validation of the memorial delirium assessment scale in patients with advanced cancer: assessing delirium in advanced cancer. Cancer 88(12):2859–2867CrossRefGoogle Scholar
  27. 27.
    Matsuoka Y, Miyake Y, Arakaki H, Tanaka K, Saeki T, Yamawaki S (2001) Clinical utility and validation of the Japanese version of Memorial Delirium Assessment Scale in a psychogeriatric inpatient setting. Gen Hosp Psychiatry 23(1):36–40CrossRefGoogle Scholar
  28. 28.
    Morita T, Tsunoda J, Inoue S, Chihara S, Oka K (2001) Communication Capacity Scale and Agitation Distress Scale to measure the severity of delirium in terminally ill cancer patients: a validation study. Palliat Med 15(3):197–206CrossRefGoogle Scholar
  29. 29.
    Bush SH, Lawlor PG, Ryan K, Centeno C, Lucchesi M, Kanji S, Siddiqi N, Morandi A, Davis DHJ, Laurent M, Schofield N, Barallat E, Ripamonti CI, Committee EG (2018) Delirium in adult cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 29(Supplement_4):iv143–iv165. CrossRefPubMedGoogle Scholar
  30. 30.
    Bush SH, Leonard MM, Agar M, Spiller JA, Hosie A, Wright DK, Meagher DJ, Currow DC, Bruera E, Lawlor PG (2014) End-of-life delirium: issues regarding recognition, optimal management, and the role of sedation in the dying phase. J Pain Symptom Manag 48(2):215–230. CrossRefGoogle Scholar
  31. 31.
    Hui D, Frisbee-Hume S, Wilson A, Dibaj SS, Nguyen T, De La Cruz M, Walker P, Zhukovsky DS, Delgado-Guay M, Vidal M, Epner D, Reddy A, Tanco K, Williams J, Hall S, Liu D, Hess K, Amin S, Breitbart W, Bruera E (2017) Effect of Lorazepam with haloperidol vs haloperidol alone on agitated delirium in patients with advanced cancer receiving palliative care: a randomized clinical trial. Jama 318(11):1047–1056. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Masanori Mori
    • 1
    Email author
  • Tatsuya Morita
    • 2
  • Yoshinobu Matsuda
    • 3
  • Hirohide Yamada
    • 4
  • Keisuke Kaneishi
    • 5
  • Yoshihisa Matsumoto
    • 6
  • Naoki Matsuo
    • 7
  • Takuya Odagiri
    • 8
  • Etsuko Aruga
    • 9
  • Hiroaki Watanabe
    • 8
  • Ryohei Tatara
    • 10
  • Hiroki Sakurai
    • 11
  • Akira Kimura
    • 12
  • Hideki Katayama
    • 13
  • Akihiko Suga
    • 14
  • Tomohiro Nishi
    • 15
  • Akemi Naito Shirado
    • 16
  • Toshio Watanabe
    • 17
  • Aya Kuchiba
    • 18
  • Takuhiro Yamaguchi
    • 19
  • Satoru Iwase
    • 20
  1. 1.Palliative Care TeamSeirei Mikatahara General HospitalHamamatsuJapan
  2. 2.Palliative and Supportive Care DivisionSeirei Mikatahara General HospitalHamamatsuJapan
  3. 3.Department of Psychosomatic Internal MedicineNational Hospital Organization Kinki-Chuo Chest Medical CenterSakaiJapan
  4. 4.Seirei Hamamatsu General HospitalHamamatsuJapan
  5. 5.Department of Palliative Care UnitJCHO Tokyo Shinjuku Medical CenterTokyoJapan
  6. 6.Department of Palliative MedicineNational Cancer Center Hospital EastKashiwaJapan
  7. 7.Hospice Medical CorporationJunkei-kai Sotoasahikawa HospitalSotoasahikawaJapan
  8. 8.Komaki City HospitalKomaki CityJapan
  9. 9.Department of Palliative MedicineTeikyo University School of MedicineTokyoJapan
  10. 10.Osaka City General HospitalOsakaJapan
  11. 11.Department of Palliative TherapyCancer Institute HospitalTokyoJapan
  12. 12.Department of Palliative and Supportive CareObihiro Kousei General HospitalObihiroJapan
  13. 13.Department of Palliative and Supportive CareOkayama University HospitalOkayamaJapan
  14. 14.Department of Palliative MedicineShizuoka Saiseikai General HospitalSurugaJapan
  15. 15.Kawasaki Municipal Ida HospitalKawasaki-shiJapan
  16. 16.Miyazaki Medical Association HospitalMiyazakiJapan
  17. 17.Toyama Prefectural Central HospitalToyama-shiJapan
  18. 18.Biostatistics Division, CRASNational Cancer CenterTokyoJapan
  19. 19.Division of BiostatisticsTohoku University Graduate School of MedicineSendaiJapan
  20. 20.Department of Emergency & Palliative Medicine, Faculty of MedicineSaitama Medical UniversitySaitamaJapan

Personalised recommendations