Background:  Cancer-related incident bone pain is a form of breakthrough pain caused by movement and is most commonly associated with bone metastases.It is often distinguished from other common forms of bone pain like arthritis or the pain associated from the administration of filgastrim-like products which are usually constant in nature and worse at night. Management of incident bone pain often requires a multimodal approach as the onset of oral immediate release (IR) opioidsmay be too slow to address a rapid-onset pain elicited by activity (1). Cancer-related incident bone pain is correlated with a decreased patient-reported quality of life, a reduced functional capacity, as well as increased psychological distress (2). Although there isn’t a clear association with the size, location, or number of bone metastasis (2,3), approximately 70% of patients with bone metastases will develop pain (4). 

Pathophysiology: Bone metastases occur in up to 70% of those with prostate and breast cancer and up to 30% of those with cancers of the lung, bladder and thyroid (5). Osteolytic lesions (associated with multiple myeloma, lung, thyroid, kidney and breast cancer), osteoblastic lesions (usually associated with prostate cancer), and mixed lesions (associated with lymphoma, breast and lung cancer) all can cause pain via increased bone destruction, bone remodeling, and the loss of bone integrity (2).  This process causes pain via the production of inflammatory by-products such as prostacyclins and cytokines which activate sensory nerves to transmit painful stimuli to the central nervous system (2,6). The pain is usually intense, easy to localize, and sudden in onset (1). Maximal pain usually occurs in 3 minutes and lasts 30 minutes after movement (1,7,8).  

Diagnostics:  Depending on the oncologic situation, plain radiography, skeletal scintigraphy (aka bone scans for osteolytic lesions), computed tomography, magnetic resonance imaging, and positron emission tomography can identify if bone metastases match up with the site of pain (9). Oncologists can help in determining the appropriate radiologic study. 

Analgesic Options: For ambulatory patients, many experts recommend a multi-modal analgesic approach in which all the following analgesic options, including interventional ones, are considered simultaneously in the hopes of maximizing analgesia and functional capacity. As patients become moribund and less ambulatory from the dying process, cancer-related bone pain often diminishes. 

Opioids:There are several challenges in determining the best opioid dose, regimen, and timing for incident bone pain. First, many oral IR opioids have an onset of action around 20-40 minutes, which is often too delayed to manage bone pain brought on by activity. Furthermore, if scheduled opioids are dosed to manage pain at rest, they often are under-dosed for ambulation. Conversely, if scheduled opioids are based on ambulation pain requirements, patients may feel over-sedated at rest.  

• The limited data available suggest that regularly scheduled long-acting opioids or basal opioid infusions provide better symptom relief, compared with only as needed fast acting opioids, even at initial doses and even for patients with little to no pain at rest (1). 
• For activities that reliably incite pain (e.g. a physical therapy session), some experts suggest a trial dose of a prophylactic IR opioid given 20-30 minutes prior to the activity.  
• A few industry-supported studies suggest that trans-mucosal fentanyl may have a quicker onset of analgesia (5-15 minutes) and superior analgesia compared with IR morphine for incident-bone pain (see Fast Facts#103 and #331) (7,8). Potential benefits of transmucosal fentanyl must be weighed against their considerable cost and regulatory and accessibility issues (7,8).

External Beam Radiotherapy (EBR): Single fraction radiotherapy can offer analgesia in 24-48 hours for many patients with incident bone pain with similar efficacy as multi-fraction radiotherapy (see Fast Fact#335) (10). Despite its effectiveness, 20-30% of patients treated with EBR still experience refractory bone pain and may require additional analgesic modalities (11).

Anti-inflammatories:Despite their widespread use, data supporting the use of NSAIDs and corticosteroids for bone metastases pain remain limited (12,13). Surveys of palliative medicine providers show that dexamethasone 4-8 mg by mouth daily is the most commonly used corticosteroid for metastatic bone pain (13). No NSAID is proven to be superior over any other, but some experts suggest a 3-day course of parenteral ketorolac 30 mg q8 in the inpatient setting for patients under 65 without a history of thrombocytopenia, renal failure, or gastrointestinal toxicities (14). Co-prescription of a H2 blocker (e.g. famotidine) or a proton pump inhibitor is often advised with NSAIDs (14).

Bisphosphonatesare associated with bone stabilization and analgesia via bone resorption and increasing the pH of the tumor environment (see Fast Fact#113) (9).  Analgesia typically begins within a week and lasts 12 weeks. Zoledronic acid and pamidronate have the best supporting evidence in this medication class and are usually prescribed by the treating oncologist (11,15). 
Radiopharmaceuticals:See Fast Fact#116. In patients with widespread painful bone metastases, the use of an injected intravenous radioactive isotopes like ⁸⁹Sr (strontium), ¹⁵³Sm (samarium), or ²²³R (radium, which is commonly utilized for prostate cancer) can target radiation to all metastatic skeletal sites and provide significant analgesia in up to 75% of selected patients (5). Onset of pain relief is usually 1-3 weeks and may last 6 months. Myelosuppression and renal insufficiency are relative contraindications.Cryoablation and Radiofrequency Ablation:These minimally invasive procedures are usually performed by interventional radiologists to direct either localized cold (cryoablation) or heat (radiofrequency ablation) to destroy metastatic lesions. They have been associated with improved analgesia of incident-bone pain (16,17). General anesthesia, conscious sedation or short post-procedure hospitalization may be required. Adjuvant Therapies:Animal model studies suggest that carbenoxolone may become a promising analgesic for cancer-induced bone pain (18). Although commonly prescribed, there is insufficient evidence to strongly recommend anti-depressants, scheduled acetaminophen, ketamine, topical lidocaine, acupuncture, or massage for the treatment of incident bone pain (12,19,20).   

References:

1. Mercadante S, Villari P,Ferrera P, Casuccio A. “Optimization of opioid therapy for preventing incident pain associated with bone metastases.” Journal of Pain and Symptom Management, vol. 28, no. 5, November 2004, pp. 505-510.
2. Middlemiss T, Laird B.J.A, Fallon M.T. “Mechanisms of Cancer-induced Bone Pain.” Clinical Oncology, vol. 23, no. 6, August 2011, pp. 387-392.
3. Clare, C, et al. “Painful bone metastases: a prospective observational cohort study.” Palliative Medicine, vol. 19, no. 7, October 2005, pp 521-525.
4. Biermann, S, et al. “Metastatic Bone Disease: Diagnosis, Evaluation, and Treatment.” The Journal of Bone and Joint Surgery, vol. 91-A, no. 6, JUNE 2009, pp. 1518-1530. 
5. Guerra, F, Adriana, L, Tavares, A, Tavares J. “Palliative treatment of metastatic bone pain with radiopharmaceuticals: A perspective beyond Strontium-89 and Samarium-153.” Applied Radiation and Isotopes, vol. 110, April 2016, pp. 87-99. 
6. Callstrom, M, et al. “Percutaneous image‐guided cryoablation of painful metastases involving bone.” Cancer, vol. 119, no. 5, March 2013, pp.1033-1041.
7. Überall MA, Müller-Schwefe GH. “Sublingual fentanyl orally disintegrating tablet in daily practice: efficacy, safety and tolerability in patients with breakthrough cancer pain.” Curr Med Res Opin. Vol 27, no. 7, July 2011, pp. 1385-94. 
8. Rivera, I, et al. “Efficacy of Sublingual Fentanyl vs. Oral Morphine for Cancer-Related Breakthrough Pain.” Advances in Therapy, vol. 31, no. 1, January 2014, pp. 107–117. 
9. von Moos R, Strasser F, Gillessen S, Gillessen S, Zaugg K. “Metastatic bone pain: Treatment options with an emphasis on bisphosphonates.” Supportive Care in Cancer, vol. 16, no. 10, pp. 1105-15. 
10. Sze WM, Shelley M, Held I, Mason M. “Palliation of metastatic bone pain: single fraction versus multifraction radiotherapy.” Cochrane Database of Systematic Reviews, no 2, 2004. 
11. Palmieri C, Fullarton J, Brown J. “Comparative efficacy of bisphosphonates in metastatic breast and prostate cancer and multiple myeloma:  A mixed-treatment meta-analysis.”  Cancer Res2013; 19(24): 6863-72. 
12. Afsharimani, B; Kindl, K; Good, P; Hardy, J. “Pharmacological options for the management of refractory cancer pain–what is the evidence?” Supportive Care in Cancer, vol. 23, no. 5, May 2015, pp. 1473-1481.
13. White, P, Arnold, R, Bull, J. “The Use of Corticosteroids as Adjuvant Therapy for Painful Bone Metastases: A Large Cross-Sectional Survey of Palliative Care Providers.” American Journal of Hospice and Palliative Medicine, vol. 35, no. 1, December 2016, pp. 151-158.
14. National Comprehensive Cancer Network. Nccn Clinical Practice Guidelines in Oncology: Palliative Care, Version 2.2011. http://www.nccn.org/professionals/physician_gls/pdf/pain.pdf; 2011.  Accessed May 28, 2019.
15. Liptona, Allan. “Treatment of Bone Metastases and Bone Pain with Bisphosphonates.” Supportive Cancer Therapy, vol. 4, no. 2, January 2007, pp. 92-100.
16. Callstrom, M, et al. “Percutaneous Image-Guided Radiofrequency Ablation of Painful Metastases Involving Bone: A Multicenter Study.” Journal of Clinical Oncology, vol. 22, no. 2, January 2004, pp. 300-306.
17. Li, F, et al. “An Effective Therapy to Painful Bone Metastases: Cryoablation Combined with Zoledronic Acid.” Pathology & Oncology Research, vol 20, no. 4, October 2014, pp. 885–891.
18. Falk, S. “Carbenoxolone as a novel therapy for attenuation of cancer-induced bone pain.” Pain vol. 159, no. 6, June 2018, pp. 1127-1136. 
19. Paley C, Bennett M, Johnson M. “Acupuncture for Cancer-Induced Bone Pain?” Evidence-Based Complementary and Alternative Medicine, vol. 2011, art. 671043. February 2010; pp. 1-8.
20. Cassileth B, Deng G. “Complementary and Alternative Therapies for Cancer.” The Oncologist, vol. 9, no.1, February 2004, pp. 80-89.

Conflicts of Interest: None

Authors’ Affiliations:  University of Nevada, Reno Nevada; VA Sierra Nevada Health Care System

Version History:  first electronically published in July 2019; originally edited by Sean Marks MD.

Fast Facts and Conceptsare edited by Sean Marks MD (Medical College of Wisconsin) and associate editor Drew A Rosielle MD (University of Minnesota Medical School), with the generous support of a volunteer peer-review editorial board, and are made available online by the Palliative Care Network of Wisconsin(PCNOW); the authors of each individual Fast Fact are solely responsible for that Fast Fact’scontent. The full set of Fast Facts are available at Palliative Care Network of Wisconsinwith contact information, and how to reference Fast Facts.

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