Mrs S is a 58-year-old female who presented to the nurse practitioner complaining of fatigue and mid-thoracic back pain that had become worse in the last few weeks. She works full time as a fourth-grade teacher and cares for her 3 grandchildren every weekend while her daughter works. The youngest grandchild is 18 months old. Initially, Mrs S attributed the fatigue and back pain to “long hours and not enough rest,” or that she may have “pulled a muscle” when lifting the grandchildren. Now Mrs S rates her back pain a “9/10,” with 10 being the worst pain imaginable, with intermittent “shooting” pains down her right leg. She has no other complaints except for insomnia as a result of the pain. She recalls no trauma. She has no additional health concerns except for controlled, mildly elevated blood pressure over the past 3 years. She takes Norvasc 5 mg po daily but is on no other medications.
On physical examination, Mrs S had point tenderness to her lower thoracic spine on palpation. She had no weakness in her legs, and results from a neurologic examination of the upper and lower extremities were normal. A chemistry panel and complete blood count (CBC) were ordered, as well as a urinalysis to rule out a urinary tract infection as the source of her back pain.
The CBC revealed anemia with hemoglobin 9.8 g/dL (range, 12-15 g/dL). Serum creatinine was 1.2 mg/dL (range, 0.5-1.4 mg/dL), and serum calcium was 11.1 g/dL (range, 8.5-10.2 g/dL). An x-ray revealed compression fractures at T9 and T10 vertebral bodies. Magnetic resonance imaging (MRI) of the thoracic and lumbar spine was planned as she was admitted to the hospital for pain control, evaluation, and management of her hypercalcemia.
Overview of Oncology Pain
Part 2 of the Conquering the Cancer Care Continuum series on Palliation in Cancer Care focuses on pain management in oncology. Cancer pain remains a commonly feared yet widely undertreated aspect of cancer.1 Many definitions of cancer pain exist, including one from the Committee on Taxonomy of the International Association for the Study of Pain, in which pain is defined as “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” The National Comprehensive Cancer Network, World Health Organization (WHO), and several other organizations have logical and systematic ways to diagnose, monitor, and treat cancer pain.2,3 Each entity agrees that cancer pain must be promptly diagnosed for appropriate and rapid intervention. Thus, the importance of diagnosis and practical recommendations will be reviewed as they relate to our case study.
The Etiology of Oncology Pain Is Important
The therapeutic intervention to control cancer pain can only occur after the pain is appropriately classified. Cancer pain can manifest itself as acute or chronic in nature. The onset of acute pain occurs within a relatively short time and is often the result of a traumatic event. Chronic pain develops over a longer period.2 Chronic pain can occur following an initial pain-provoking event such as tumor invasion. Regardless of time and etiology, inadequate pain management remains prevalent, costly, and harmful to patients with cancer.4
Cancer pain can be categorized as nociceptive or neuropathic. Nociceptive pain occurs as a result of ongoing damage or tissue destruction to the somatic and visceral structures. Thermal, mechanical, or chemical processes lead to damaged pain receptors in the skin, muscles, and connective tissues. Nociceptive pain can be acute or chronic. Neuropathic pain results after damage to the nerve fibers that arise from the central and peripheral nervous systems.5 Neuropathic pain can cause a variety of sensations from numbness and tingling to shooting and/or burning.1,2 The treatments of nociceptive and neuropathic pain differ as adjunct medications can be more useful in neuropathic pain control that addresses the nerve damage. Therefore, incorrect diagnosis of the etiology of pain can lead to inadequate pain control.
Assessment of Cancer Pain: History and Physical Examination
Appropriate assessment of the individual’s cancer-related pain can lead to prompt diagnosis, treatment, and improved quality of life. A thorough evaluation of pain begins with taking a pain history. The pain history guides the clinician toward the etiology of the pain. Key considerations when assessing pain are shown in Table 1.
Once the clinician obtains a thorough pain history, a physical examination is then performed. Attention to physical examination findings is critical to provide clues to the etiology of pain. Key components of the physical examination include locating the site of pain, examining the area, and performing a neurologic assessment. In our case study, mid-thoracic back pain was the major complaint. Therefore, percussion of the spine and localization of the pain provided the opportunity to order the appropriate radiologic imaging.
For all individuals with back pain, it is also imperative to determine if signs of spinal cord compression (SCC) are present. These include weakness in the lower extremities, hyperreflexia, falls, incontinence, or loss of sphincter tone. If SCC is suspected on neurologic examination or based on clinical history, further imaging is required to rule out this oncologic emergency because SCC can lead to paralysis.
Laboratory and Radiologic Assessment of Pain
Following the history and physical examination, the clinician considers laboratory and radiologic testing to further elucidate the etiology of the pain. A chemistry panel with serum calcium, alkaline phosphatase, and serum creatinine identifies if hypercalcemia of malignancy and associated renal dysfunction are present. Specific bone and disease markers appropriate to the cancer type can confirm disease progression if a known cancer diagnosis exists. A CBC with differential will identify anemia, thrombocytopenia, or neutropenia. Abnormal CBC findings may suggest tumor invasion within the bone marrow microenvironment.6,7
Metastatic cancer cells produce inflammatory cytokines that lead to osteolysis or bone pain. Treating the cancer itself can lead to a reduction in pain.8,9 In patients with suspected fracture or bone metastasis as the source of cancer pain, radiographic films of the painful area will, in many cases, identify if bone destruction has occurred. Patients with breast or prostate cancer can undergo a technetium bone scan to identify if widespread tumor destruction is present. Patients with multiple myeloma should receive a bone survey. The bone survey includes radiographic images of the skull, long bones, and spine and will identify lytic lesions. However, bone scans will fail to identify lytic lesions due to the pathobiology of the plasma cell tumor.10 It is important to note that a 30% to 40% bone loss is required before bone lesions are visible on plain x-ray films.11
Patients may undergo the above imaging, and the cause of the pain may still not be identified. These individuals may benefit from more sophisticated imaging techniques, which include MRI, computed tomography (CT), and/or positron emission tomography (PET) scans. The benefit of MRI and/or CT scans of the painful area is that the clinician can visualize images within a short period, and they are more sensitive than x-rays to determine if damage to the bones or tissues has occurred. However, the MRI and CT scans are limited by not being able to detect lesions or tumors until the structural changes in the tissue are large enough to be detected. A PET scan can be used in a variety of cancers and is capable of detecting cellular and/or molecular changes that precede structural abnormalities. A limitation of the PET scan is that areas of inflammation and physiologic activity can make it unclear whether cancer is causing the pain.12
Even with the most sophisticated radiologic techniques, there are some individuals with cancer in whom the cause of pain cannot be reliably identified. Therefore, the clinician needs to correlate the information gained from radiologic imaging with clinical examination and laboratory findings to determine the cause of pain.
Additional Types of Oncology Pain
It has been discussed in this article that patients with cancer may experience pain as a result of the diagnosis (such as pain from nerve root compression or tumor), or the treatment itself (damage to the skin from radiation or surgery). It is essential for clinicians to further identify the etiology of cancer pain so treatment can be tailored to the individual. A common type of nociceptive pain is called incident or “functional” pain that usually occurs with voluntary movement. Incident pain is the classic type of pain that occurs as a result of skeletal metastases, but it can be involuntary as a result of a cough or sneeze. Incident pain is difficult to control in patients with cancer because a steady level of opioid medication is required to treat the peaks of pain that occur when patients are moving around performing activities of daily living.
Breakthrough pain occurs when the pain becomes unpredictably worse and requires medication to obtain relief. In patients taking long-acting opioids, additional pain medication is unpredictably required between scheduled doses of medication. In contrast, “end-of-dose failure” is a predictable occurrence of pain in which the pain recurs before the next dose of medication is due.1
The key to treating incident, breakthrough, and end-of-dose pain is to treat the underlying cause of the pain as effectively as possible. Palliative radiation, chemotherapy to control the disease, or adjunct medications if nerves are involved may be warranted.
Recommendations for the Management of Cancer Pain
Analgesic agents are essential to the management of cancer pain. In an effort to identify guidelines to improve the practice of pain management, the WHO developed the analgesic ladder in 1986. The 3-step cancer pain relief ladder suggests a stepwise approach to cancer pain. This includes non-opioid drugs for the first step, mild opioids either with or without non-opioids for the second step, and more potent opioid analgesics for the third step. The guidelines are reasonable but not prescriptive or all inclusive for patients.1,13
Nociceptive and non-nociceptive types of pain can, in most cases, be appropriately managed by a combination of pharmacologic and nonpharmacologic or adjunct therapies. Mild nociceptive pain is often controlled with acetaminophen and/or narcotic and nonnarcotic pain medications. Opioid analgesics are required to control patients with higher pain scores. A list of commonly used medications can be found in Table 2.
Adjunct agents are also used. These include neuroleptic drugs (eg, gabapentin or pregabalin) and antidepressants (eg, duloxetine or sertraline). Nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen can be used in patients with bone pain. However, NSAIDs should be used cautiously in patients with kidney disease and elevated serum creatinine levels. In patients whose pain is not the result of tumor invasion but is musculoskeletal, physical therapy or acupuncture techniques can be used.2
Supportive Care: Bone Metastasis
In patients with cancer that has metastasized to the bone, bisphosphonates and monoclonal antibodies should be used. Bisphosphonates are potent inhibitors of bone resorption and are effective in decreasing pain related to metastatic cancer as well as improving bone quality over time once disease control has been achieved. While the optimal duration of therapy is unknown, in the setting of adequate renal function, monthly bisphosphonates such as pamidronate or zoledronic acid may decrease the risk of skeletal-related events.11
Denosumab is a high-affinity monoclonal antibody approved for the treatment of osteoporosis in postmenopausal women and for the treatment of skeletal metastases in breast and prostate cancer. Denosumab works most notably as a receptor activator of nuclear factor κB ligand (RANKL) inhibitor. Stimulation of osteoclasts (responsible for bone breakdown) and osteoblasts (responsible for bone repair) is controlled in part by the balance between the osteoprotegerin (OPG), RANKL, and RANK (receptor activator of nuclear factor κB) triad. RANKL binds to the RANK receptor found on the surface of osteoclasts. Binding of RANKL results in stimulation of osteoclast activity and leads to bone breakdown. OPG is a decoy receptor produced by osteoblasts. OPG inhibits osteoclastogenesis by binding to RANKL, which inactivates RANKL. RANKL is the key mediator of osteoclastogenesis. Therefore, administering a monoclonal antibody such as denosumab blocks RANKL activity.14
Palliative radiation is administered to tumors with the goal of local pain control. Individuals with bulky abdominal tumors or bone tumors can experience pain relief with single or fractionated doses of radiation. In patients with hematologic malignancies, it is important to spare the bone marrow repeated doses of radiation and treat the disease systemically if possible.
Surgical intervention might be warranted in patients with metastatic cancer. However, the risk-benefit ratio must be considered, depending on how invasive the surgery is. Cancer type, prognosis, general health, and functioning of the individual must be taken into consideration. Debulking of a large tumor followed by radiation or systemic chemotherapy has been shown to improve disease control and quality of life in patients with certain cancers and can be considered on a case-by-case basis.15
When possible, minimally invasive surgeries are recommended, especially if vertebral compression fractures (VCFs) are the source of cancer pain, such as in the case study. Two such procedures are balloon kyphoplasty (BKP) and vertebroplasty. Both are minimally invasive outpatient techniques that form an internal “cast” in the collapsed vertebral body. The goals of the BKP procedure are to reduce the fracture and form an internal cast, and height restoration. In BKP, a bone tamp is used to inflate a balloon and create a cavity for cement to flow. The balloon is deflated but the cavity remains. Under fluoroscopy, cement called polymethylmethacrylate is injected into the collapsed vertebral body. Vertebral height is restored to some degree, and pain is decreased. With the vertebroplasty technique, thinner cement is injected into the collapsed vertebral body using a needle. While height cannot be restored, pain relief is obtained with the procedure.16
In the recent randomized Cancer Patient Fracture Evaluation (CAFE) study, patients with painful VCFs were randomized to receive the BKP procedure or to nonsurgical management. In patients with cancer, BKP was shown to be an effective treatment that rapidly reduces pain and improves function. BKP provided better results than nonsurgical management at 1 month in measures of pain, back function, quality of life, activity, bed rest, and analgesic use, suggesting that an early intervention is better than a delayed procedure.17
Case Study Outcome
Mrs S was diagnosed with metastatic breast cancer. She was given pamidronate 90 mg IV piggyback for hypercalcemia of malignancy and started on morphine 2 to 4 mg IV every 3 hours as needed for pain control via a patient-controlled analgesia pump on day 1 of hospital admission. She began gabapentin to treat the shooting neuropathic pain. However, her back pain persisted and was thought secondary to the vertebral compression fractures at T9 and T10. To treat her painful VCFs, the BKP procedure was performed to the T9 and T10 vertebral bodies and resulted in pain relief by day 4. The clinician calculated the 24-hour dose of IV morphine to a long-acting morphine sulfate continuous release (morphine CR 15 mg po every 12 hours) on day 5. Her pain was adequately controlled, but she was given a prescription for short-acting morphine for breakthrough pain management. A bowel regimen was reviewed to prevent constipation. She was discharged to home on day 6 pain free.
Pain can be a devastating but unnecessary consequence of cancer. Pain as it relates to cancer can also be a complex phenomenon and provide a sequelae of symptoms based on the pathophysiology of the disease. Treatment of cancer pain requires the appropriate diagnosis and management, as well as the expertise of many disciplines, with the overarching goal of controlling the disease and improving quality of life.
1. Aiello-Laws L, Reynolds J, Deizer N, et al. Putting evidence into practice: what are the pharmacologic interventions for nociceptive and neuropathic cancer pain in adults? Clin J Oncol Nurs. 2009;13:649-655.
2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Multiple Myeloma. Version 1.2013. www.nccn.org/professionals/physician_gls/f_guidelines.asp#site. Accessed February 15, 2013.
3. World Health Organization. Pharmacovigilance. www.who.int/medicines/
areas/quality_safety/safety_efficacy/pharmvigi/en/index.html. Accessed February 15, 2013.
4. Sarzi-Puttini P, Vellucci R, Zuccaro SM, et al. The appropriate treatment of chronic pain. Clin Drug Investig. 2012;32(suppl 1):21-33.
5. Rayment C, Hjermstad MJ, Aass N, et al. Neuropathic cancer pain: prevalence, severity, analgesics and impact from the European Palliative Care Research Collaborative – Computerised Symptom Assessment study [published online ahead of print November 21, 2012]. Palliat Med.
6. Riccio A, Wodajo F, Malawer M. Metastatic carcinoma of the long bones. Am Fam Physician. 2007;76:1489-1494.
7. Morgans AK, Smith MR. Bone-targeted agents: preventing skeletal complications in prostate cancer. Urol Clin North Am. 2012;39:533-546.
8. Lipton A, Uzzo R, Amato RJ, et al. The science and practice of bone health in oncology: managing bone loss and metastasis in patients with solid tumors. J Natl Compr Canc Netw. 2009;7(suppl 7):1-29.
9. Raje N, Roodman GD. Advances in the biology and treatment of bone disease in multiple myeloma. Clin Cancer Res. 2011;17:1278-1286.
10. Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.
11. Van Poznak CH, Temin S, Yee GC, et al. American Society of Clinical Oncology executive summary of the clinical practice guideline update on the role of bone-modifying agents in metastatic breast cancer. J Clin Oncol. 2011;29:1221-1227.
12. Debergh I, Vanhove C, Ceelen W. Innovation in cancer imaging. Eur Surg Res. 2012;48:121-130.
13. Gordon DB, Dahl JL, Miaskowski C, et al. American Pain Society recommendations for improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force. Arch Intern Med. 2005;165:1574-1580.
14. Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol. 2011;29:1125-1132.
15. Yu HH, Tsai YY, Hoffe SE. Overview of diagnosis and management of metastatic disease to bone. Cancer Control. 2012;19:84-91.
16. Hussein MA, Vrionis FD, Allison R, et al. The role of vertebral augmentation in multiple myeloma: International Myeloma Working Group Consensus Statement. Leukemia. 2008;22:1479-1484.
17. Berenson J, Pflugmacher R, Jarzem P, et al. Balloon kyphoplasty versus non-surgical fracture management for treatment of painful vertebral body compression fractures in patients with cancer: a multicentre, randomised controlled trial. Lancet Oncol. 2011;12:225-235.