Supportive Care in Cancer

, Volume 27, Issue 4, pp 1335–1343 | Cite as

Which factors can aid clinicians to identify a risk of pain during the following month in patients with bone metastases? A longitudinal analyses

  • Ragnhild HabberstadEmail author
  • M. J. Hjermstad
  • C. Brunelli
  • S. Kaasa
  • M. I. Bennett
  • K. Pardon
  • P. Klepstad
Original Article



Explore clinical factors associated with higher pain intensity and future pain in patients with bone metastases to identify patients who can benefit from closer follow-up or pain-modifying interventions.


This is a secondary analysis of 606 patients with bone metastases included in a multicenter longitudinal study. The dependent variables were “average pain” and “worst pain” in the last 24 h (0–10 NRS). Twenty independent variables with potential association to pain intensity were selected based on previous literature. Cross-sectional analyses were performed with multiple linear regression to explore factors associated with pain intensity at baseline. Longitudinal data were analyzed with a generalized equation models to explore current factors associated with pain intensity at the next visit in 1 month.


Current pain intensity (p < 0.001), sleep disturbances (p 0.01 and 0.006), drowsiness (p 0.003 and 0.033) and male gender (p 0.045 and 0.001) were associated with higher average and worst pain intensity in 1 month. In addition, breakthrough pain was related to higher worst pain intensity (p 0.003) in 1 month. The same variables were also associated with higher average pain intensity at baseline.


Higher current pain intensity, sleep disturbances, drowsiness, male gender, and breakthrough pain are factors associated with higher pain intensity in patients with bone metastases at the next follow-up in 1 month. These factors should be assessed in clinical practice and may aid clinicians in identifying patients that can benefit from closer follow-up or interventions to prevent lack of future pain control.

Trial registration in



Cancer Pain Bone metastases Cancer-induced bone pain Associations 


Research funding

This work was supported by the Central Norway Regional Health Authority (grant no. 46055100), the Cancer Foundation St Olavs Hospital, Trondheim University Hospital (grant no. 6070), the Liaison Committee for Education, Research and Innovation in Central Norway, and an unrestricted grant from the Helsinn Group, Switzerland.

Compliance with ethical standards

Conflicts of interest

Kaasa S. hold stocks in EIR Solutions A/S. The other authors have no conflicts of interest.

We have collected all primary data and the journal may review the data on request.


  1. 1.
    Bruera E, Kuehn N, Miller MJ, Selmser P, Macmillan K (1991) The Edmonton symptom assessment system (ESAS): a simple method for the assessment of palliative care patients. J Palliat Care 7:6–9PubMedGoogle Scholar
  2. 2.
    Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S (2012) Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol 24:112–124CrossRefGoogle Scholar
  3. 3.
    Clare C, Royle D, Saharia K, Pearse H, Oxberry S, Oakley K, Allsopp L, Rigby AS, Johnson MJ (2005) Painful bone metastases: a prospective observational cohort study. Palliat Med 19:521–525CrossRefPubMedGoogle Scholar
  4. 4.
    Cleeland CS (2006) The measurement of pain from metastatic bone disease: capturing the patient’s experience. Clin Cancer Res 12:6236s–6242sCrossRefPubMedGoogle Scholar
  5. 5.
    Coleman RE (2006) Clinical features of metastatic bone disease and risk of skeletal morbidity. Clin Cancer Res 12:6243s–6249sCrossRefPubMedGoogle Scholar
  6. 6.
    Delaney A, Fleetwood-Walker SM, Colvin LA, Fallon M (2008) Translational medicine: cancer pain mechanisms and management. Br J Anaesth 101:87–94CrossRefPubMedGoogle Scholar
  7. 7.
    Delgado-Guay M, Yennurajalingam S, Parsons H, Palmer JL, Bruera E (2011) Association between self-reported sleep disturbance and other symptoms in patients with advanced cancer. J Pain Symptom Manag 41:819–827CrossRefGoogle Scholar
  8. 8.
    Evans C, McCarthy M (1985) Prognostic uncertainty in terminal care: can the Karnofsky index help? Lancet 1:1204–1206CrossRefPubMedGoogle Scholar
  9. 9.
    Fainsinger RL, Fairchild A, Nekolaichuk C, Lawlor P, Lowe S, Hanson J (2009) Is pain intensity a predictor of the complexity of cancer pain management? J Clin Oncol 27:585–590CrossRefPubMedGoogle Scholar
  10. 10.
    Fayers PM, Hjermstad MJ, Ranhoff AH, Kaasa S, Skogstad L, Klepstad P, Loge JH (2005) Which mini-mental state exam items can be used to screen for delirium and cognitive impairment? J Pain Symptom Manag 30:41–50CrossRefGoogle Scholar
  11. 11.
    Groenvold M, Petersen MA, Aaronson NK, Arraras JI, Blazeby JM, Bottomley A, Fayers PM, de Graeff A, Hammerlid E, Kaasa S, Sprangers MA, Bjorner JB, Group EQoL (2006) The development of the EORTC QLQ-C15-PAL: a shortened questionnaire for cancer patients in palliative care. Eur J Cancer 42:55–64CrossRefPubMedGoogle Scholar
  12. 12.
    Hagen NA, Stiles C, Nekolaichuk C, Biondo P, Carlson LE, Fisher K, Fainsinger R (2008) The Alberta Breakthrough Pain Assessment Tool for cancer patients: a validation study using a delphi process and patient think-aloud interviews. J Pain Symptom Manag 35:136–152CrossRefGoogle Scholar
  13. 13.
    Hjermstad MJ, Aass N, Aielli F, Bennett M, Brunelli C, Caraceni A, Cavanna L, Fassbender K, Feio M, Haugen DF, Jakobsen G, Laird B, Lohre ET, Martinez M, Nabal M, Noguera-Tejedor A, Pardon K, Pigni A, Piva L, Porta-Sales J, Rizzi F, Rondini E, Sjogren P, Strasser F, Turriziani A, Kaasa S, European Palliative Care Cancer Symptoms (2016) Characteristics of the case mix, organisation and delivery in cancer palliative care: a challenge for good-quality research BMJ Support Palliat CareGoogle Scholar
  14. 14.
    Holtan A, Aass N, Nordoy T, Haugen DF, Kaasa S, Mohr W, Kongsgaard UE (2007) Prevalence of pain in hospitalised cancer patients in Norway: a national survey. Palliat Med 21:7–13CrossRefPubMedGoogle Scholar
  15. 15.
    Im EO, Chee W (2006) Evaluation of the decision support computer program for cancer pain management. Oncol Nurs Forum 33:977–982CrossRefPubMedGoogle Scholar
  16. 16.
    Kane CM, Hoskin P, Bennett MI (2015) Cancer induced bone pain. BMJ 350:h315CrossRefPubMedGoogle Scholar
  17. 17.
    Kerba M, Wu JS, Duan Q, Hagen NA, Bennett MI (2010) Neuropathic pain features in patients with bone metastases referred for palliative radiotherapy. J Clin Oncol 28:4892–4897CrossRefPubMedGoogle Scholar
  18. 18.
    Kinnane N (2007) Burden of bone disease. Eur J Oncol Nurs 11(Suppl 2):S28–S31CrossRefPubMedGoogle Scholar
  19. 19.
    Knudsen AK, Brunelli C, Klepstad P, Aass N, Apolone G, Corli O, Montanari M, Caraceni A, Kaasa S (2012) Which domains should be included in a cancer pain classification system? Analyses of longitudinal data. Pain 153:696–703CrossRefPubMedGoogle Scholar
  20. 20.
    Knudsen AK, Brunelli C, Kaasa S, Apolone G, Corli O, Montanari M, Fainsinger R, Aass N, Fayers P, Caraceni A, Klepstad P, European Palliative Care Research C, European Pharmacogenetic S (2011) Which variables are associated with pain intensity and treatment response in advanced cancer patients?—Implications for a future classification system for cancer pain. Eur J Pain 15:320–327CrossRefPubMedGoogle Scholar
  21. 21.
    Laird BJ, Walley J, Murray GD, Clausen E, Colvin LA, Fallon MT (2011) Characterization of cancer-induced bone pain: an exploratory study. Support Care Cancer 19:1393–1401CrossRefPubMedGoogle Scholar
  22. 22.
    Lechner B, Chow S, Chow R, Zhang L, Tsao M, Danjoux C, Barnes E, DeAngelis C, Vuong S, Ganesh V, Chow E (2016) The incidence of neuropathic pain in bone metastases patients referred for palliative radiotherapy. Radiother Oncol 118:557–561CrossRefPubMedGoogle Scholar
  23. 23.
    Lozano-Ondoua AN, Symons-Liguori AM, Vanderah TW (2013) Cancer-induced bone pain: mechanisms and models. Neurosci Lett 557(Pt A):52–59CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lynch ME, Fischbach C (2014) Biomechanical forces in the skeleton and their relevance to bone metastasis: biology and engineering considerations. Adv Drug Deliv Rev 79-80:119–134CrossRefPubMedGoogle Scholar
  25. 25.
    Mantyh PW (2014) Bone cancer pain: from mechanism to therapy. Curr Opin Support Palliat Care 8:83–90CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Mercadante S (1997) Malignant bone pain: pathophysiology and treatment. Pain 69:1–18CrossRefPubMedGoogle Scholar
  27. 27.
    Mercadante S, Adile C, Ferrera P, Masedu F, Valenti M, Aielli F (2017) Sleep disturbances in advanced cancer patients admitted to a supportive/palliative care unit. Support Care Cancer 25:1301–1306CrossRefPubMedGoogle Scholar
  28. 28.
    Mercadante S, Portenoy RK (2016) Breakthrough cancer pain: twenty-five years of study. Pain 157:2657–2663CrossRefPubMedGoogle Scholar
  29. 29.
    Meuser T, Pietruck C, Radbruch L, Stute P, Lehmann KA, Grond S (2001) Symptoms during cancer pain treatment following WHO-guidelines: a longitudinal follow-up study of symptom prevalence, severity and etiology. Pain 93:247–257CrossRefPubMedGoogle Scholar
  30. 30.
    Miaskowski C (2004) Gender differences in pain, fatigue, and depression in patients with cancer. J Natl Cancer Inst Monogr 2004:139–143CrossRefGoogle Scholar
  31. 31.
    Middlemiss T, Laird BJ, Fallon MT (2011) Mechanisms of cancer-induced bone pain. Clin Oncol 23:387–392CrossRefGoogle Scholar
  32. 32.
    Nekolaichuk CL, Fainsinger RL, Lawlor PG (2005) A validation study of a pain classification system for advanced cancer patients using content experts: the Edmonton Classification System for Cancer Pain. Palliat Med 19:466–476CrossRefPubMedGoogle Scholar
  33. 33.
    Nekolaichuk CL, Fainsinger RL, Aass N, Hjermstad MJ, Knudsen AK, Klepstad P, Currow DC, Kaasa S, European Palliative Care Research C (2013) The Edmonton Classification System for Cancer Pain: comparison of pain classification features and pain intensity across diverse palliative care settings in eight countries. J Palliat Med 16:516–523CrossRefPubMedGoogle Scholar
  34. 34.
    Oh SY, Shin SW, Koh SJ, Bae SB, Chang H, Kim JH, Kim HJ, Hong YS, Park KU, Park J, Lee KH, Lee NR, Lee JL, Jang JS, Hong DS, Lee SS, Baek SK, Choi DR, Chung J, Oh SC, Han HS, Yun HJ, Sym SJ, Yoon SY, Choi IS, Shim BY, Kang SY, Kim SR, Kim HJ (2017) Multicenter, cross-sectional observational study of the impact of neuropathic pain on quality of life in cancer patients. Support Care Cancer 25(12):3759–3767CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Pan W (2001) Akaike’s information criterion in generalized estimating equations. Biometrics 57:120–125CrossRefPubMedGoogle Scholar
  36. 36.
    Pina P, Sabri E, Lawlor PG (2015) Characteristics and associations of pain intensity in patients referred to a specialist cancer pain clinic. Pain Res Manag 20:249–254CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Roodman GD (2012) Genes associate with abnormal bone cell activity in bone metastasis. Cancer Metastasis Rev 31:569–578CrossRefPubMedGoogle Scholar
  38. 38.
    Scarpi E, Calistri D, Klepstad P, Kaasa S, Skorpen F, Habberstad R, Nanni O, Amadori D, Maltoni M (2014) Clinical and genetic factors related to cancer-induced bone pain and bone pain relief. Oncologist 19:1276–1283CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    van den Beuken-van Everdingen MH, Hochstenbach LM, Joosten EA, Tjan-Heijnen VC, Janssen DJ (2016) Update on prevalence of pain in patients with cancer: systematic review and meta-analysis. J Pain Symptom Manag 51(1070–1090):e1079Google Scholar
  40. 40.
    van der Vliet QM, Paulino Pereira NR, Janssen SJ, Hornicek FJ, Ferrone ML, Bramer JA, van Dijk CN, Schwab JH (2017) What factors are associated with quality of life, pain interference, anxiety, and depression in patients with metastatic bone disease? Clin Orthop Relat Res 475:498–507CrossRefPubMedGoogle Scholar
  41. 41.
    von Moos R, Costa L, Ripamonti CI, Niepel D, Santini D (2017) Improving quality of life in patients with advanced cancer: targeting metastatic bone pain. Eur J Cancer 71:80–94CrossRefGoogle Scholar
  42. 42.
    Winters-Stone KM, Schwartz A, Nail LM (2010) A review of exercise interventions to improve bone health in adult cancer survivors. J Cancer Surviv 4:187–201CrossRefPubMedGoogle Scholar
  43. 43.
    Wu JS, Beaton D, Smith PM, Hagen NA (2010) Patterns of pain and interference in patients with painful bone metastases: a brief pain inventory validation study. J Pain Symptom Manag 39:230–240CrossRefGoogle Scholar
  44. 44.
    Wu JS, Wong R, Johnston M, Bezjak A, Whelan T, Cancer Care Ontario Practice Guidelines Initiative Supportive Care G (2003) Meta-analysis of dose-fractionation radiotherapy trials for the palliation of painful bone metastases. Int J Radiat Oncol Biol Phys 55:594–605CrossRefPubMedGoogle Scholar
  45. 45.
    Zeger SL, Liang KY (1986) Longitudinal data analysis for discrete and continuous outcomes. Biometrics 42:121–130CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.European Palliative Care Research Centre (PRC), Department of Clinical and Molecular Medicine, Faculty of Medicine and Health Sciences, NTNUNorwegian University of Science and Technology and St. Olavs hospital, Trondheim University HospitalTrondheimNorway
  2. 2.Cancer Clinic, St. Olavs hospitalTrondheim University HospitalTrondheimNorway
  3. 3.European Palliative Care Research Centre (PRC), Department of OncologyOslo University Hospital and Institute of Clinical Medicine, University of OsloOsloNorway
  4. 4.Palliative Care, Pain Therapy and Rehabilitation UnitFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  5. 5.Department of OncologyOslo University Hospital and University of OsloOsloNorway
  6. 6.Academic Unit of Palliative Care, Faculty of Medicine and HealthUniversity of LeedsLeedsUK
  7. 7.End-of-life Care Research GroupVrije Universiteit Brussel (VUB) & Ghent UniversityBrusselsBelgium
  8. 8.Department of Circulation and Medical Imaging, Faculty of Medicine and Health Sciences, NTNUNorwegian University of Science and TechnologyTrondheimNorway
  9. 9.Department of Anaesthesiology and Intensive Care Medicine, St. Olavs HospitalTrondheim University HospitalTrondheimNorway

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