BONE pain is a common problem in the palliative care setting, especially for patients with progressive cancer. Radiation therapy is usually considered for cancer patients when bone pain is focal and poorly controlled by an opioid or is associated with a lesion that appears to be prone to fracture on radiographic examination. Anecdotally, multifocal bone pain has been observed to benefit from treatment with a nonsteroidal antiinflammatory drug (NSAID) or a corticosteroid (Lussier, Huskey, Portenoy, 2004; Lussier Portenoy, 2004; Mercadante, Casuccio, Agnello, et al., 1999). Other adjuvant analgesics that are potentially useful in this setting include calcitonin, bisphosphonate compounds, gallium nitrate, and selected radiopharmaceuticals (Table 29-1). Because there are limited data comparing the advantages and disadvantages of these adjuvant analgesics for bone pain, selection of one agent over another is usually made on the basis of convenience, cost, patient preference, and clinical setting. See Table V-1 for characteristics and dosing of some of the adjuvant analgesics used for persistent bone pain.
Table 29-1
Adjuvant Analgesics Used for Malignant Bone Pain
| Class | Comment |
| Calcitonin | Reduces bone pain; decreases rate of bone turnover; useful in osteoporosis; used most often by subcutaneous injection or nasal spray |
| Bisphosphonates (e.g., pamidronate, clodronate, zolendronate) | Reduces malignant bone pain and risk for skeletal morbidity |
| Radionuclides (e.g., strontium-89, samarium-153, rhenium-186, hydroxyethylene diphosphonic acid, gallium nitrate) | Slow onset; used only if no further chemotherapy is planned |
| Corticosteroids | Anecdotal reports of effectiveness in bone pain |
| NSAIDs | Anecdotal reports of effectiveness in bone pain |
NSAIDs, Nonsteroidal antiinflammatory drugs.
Note: This table lists the classes of adjuvant analgesics for malignant bone pain with comments on their use. See text for discussion and references.
From Pasero, C., & McCaffery, M. Pain assessment and pharmacologic management, p. 734, St. Louis, Mosby. Pasero C, McCaffery M. May be duplicated for use in clinical practice.
Calcitonin has been shown to ameliorate bone pain in some but not all patients with and without cancer. Clinical experience with this drug suggests that it is relatively safe and can produce substantial pain relief for some patients (Lussier, Portenoy, 2004). Optimal doses and dosing frequency for calcitonin remain unknown, and the durability of favorable effects, if they occur, has not been evaluated systematically. For bone pain associated with cancer metastases, a systematic review of two studies showed variable results and emphasized that calcitonin did not slow disease progression in the bone (Martinez-Zapata, Roque, Alonso-Coello, et al., 2006).
More favorable outcomes have been noted in the treatment of osteoporosis. In patients with this disorder, calcitonin may help in maintaining bone density, but its efficacy in fracture prevention is not known (Cranney, Welch, Adachi, et al., 2000; Karsdal, Henriksen, Arnold, et al., 2008). It can provide significant analgesia for acute osteoporotic vertebral compression fractures (Lussier, Portenoy, 2004), and the use of calcitonin in older women with osteoporosis is an acceptable practice with perceived benefits in reducing pain and improving bone health (Mehta, Malootian, Gilligan, 2003; Miller, 2006).
When used for relief of malignant bone pain, calcitonin is administered most often by the intranasal or subcutaneous routes (Lussier, Portenoy, 2004). It is available as a nasal spray (Miacalcin Nasal Spray) with a recommended dose of one puff in one nostril daily, providing 200 IU. If this does not produce adequate results, an increase in dose (400 IU, two sprays/day) can be tried. Subcutaneous therapy is usually initiated with a low dose, such as 25 IU daily. This may reduce the incidence of nausea, the major adverse effect. Skin testing with 1 IU before the start of therapy is sometimes recommended because of the small risk for serious hypersensitivity reactions. After therapy begins, gradual dose escalation may identify a minimal effective dose. The usual maximum dose, which is recommended solely on the basis of clinical experience, is in the range of 100 to 200 IU/day subcutaneously. The dosing frequency is usually daily at the start of therapy, then reduced, if possible, to the fewest weekly doses required to sustain effects. Calcitonin therapy is associated with a relatively high incidence of the most common adverse effects, facial flushing and nausea (Cranney, Welch, Adachi, et al., 2000).
Bisphosphonates (previously known as diphosphonates) are analogs of inorganic pyrophosphate that inhibit osteoclast activity and, consequently, reduce bone resorption in a variety of illnesses causing pathologic effects on bone (Lussier, Portenoy, 2004). Bone metastases cause an imbalance between bone formation and resorption, and this process may be involved in the development of pain (Catala, Martinez, 2006). It is reported that more than half of all cancer pain is caused by metastases to bone (Halvorson, Sevcik, Ghilardi, et al., 2008). Hypercalcemia, caused in part by the release of mediators such as cytokines and prostaglandins, is another common complication of bone metastases and can affect 10% to 20% of patients with these lesions (Mehrotra, 2009).
Bisphosphonates are widely used to prevent and treat the complications of bone metastases (Gainford, Dranitsaris, Clemons, 2005). Although recent concerns about an uncommon toxicity, osteonecrosis of the jaw (see adverse effects) has tempered enthusiasm for long-term or prophylactic use, bisphosphonates continue to be used for symptoms and may provide analgesia and improve function and quality of life (Knotkova, Pappagallo, 2007). The underlying mechanisms of analgesia are not clear but are thought to be related to inhibition of osteoclasts and macrophages (Knotkova, Pappagallo, 2007). Commonly used bisphosphonate agents for cancer-related bone pain include pamidronate (Aredia), clodronate (Bonefos in Canada), zolendronate (Zometa), and the more recent, ibandronate (Boniva). Readers are referred to a 2009 journal supplement devoted to bisphosphonate treatment (J Oral Maxillofac Surg, 67[5, Suppl 1], 1-120).
A systematic review of 95 articles found that bisphosphonates significantly reduced skeletal morbidity except in the outcomes of spinal cord compression and time to first skeletal-related event (Ross, Saunders, Edmonds, et al., 2003). Pain relief was not included in this review but this analysis points to the importance of the role of bisphosphonates in reducing factors that influence the pain experience. A Cochrane Collaboration Review evaluated 30 randomized trials (including open trials) and concluded that bisphosphonates provide some pain relief for bone metastases, but there was insufficient evidence to recommend them as first-line analgesic therapy (Wong, Wiffen, 2002). The researchers generally recommended their use when other analgesics or radiotherapy are inadequate for the management of cancer-related bone pain (Wong, Wiffen, 2002). Concomitant administration of other analgesics with bisphosphonates treatment is recommended (Catala, Martinez, 2006).
A synthesis of findings from 10 randomized controlled trials found that reductions in pain were associated with bisphosphonate therapy in men with bone metastases resulting from advanced prostate cancer, but there was no effect on disease progression or survival rates (Yuen, Shelley, Sze, et al., 2006). There was an increase in nausea with bisphosphonates compared with placebo. Other systematic reviews have demonstrated similar results (Catala, Martinez, 2006; Santangelo, Testai, Barbagallo, et al., 2006).
A 44-week randomized controlled trial administered mitoxantrone chemotherapy and prednisone plus the bisphosphonate clodronate (1500 mg IV every 3 weeks) or mitoxantrone and prednisone plus placebo to men with hormone-resistant prostate cancer and bone metastases (Ernst, Tannock, Winquist, et al., 2003). There were no significant differences in palliative response and overall quality of life; however, subgroup analysis revealed that the best response rate in terms of pain relief was in those who had entered the study with moderate pain. The researchers concluded that clodronate may be beneficial in patients with this level of pain.
Animal research demonstrated rapid attenuation of bone pain both with a single dose and with three consecutive daily doses of ibandronate (Halvorson, Sevcik, Ghilardi, et al., 2008). This research also established that the bisphosphonate prevented bone destruction and produced tumor necrosis. Further, ibandronate treatment attenuated neurochemical reorganization of the peripheral and central nervous systems, a discovery that helps to clarify previously unknown underlying mechanisms of action.
Bisphosphonates may be helpful for other types of pain as well. An open-label pilot study administered 6-mg infusions of ibandronate on 3 consecutive days to patients with complex regional pain syndrome (CRPS) type I (Breuer, Pappagallo, Ongseng, et al., 2008). The treatment was well tolerated and resulted in significant improvements in several of the neuropathic pain qualities (e.g., sensitive, deep, intense, and surface). Results were more impressive in hand than in foot CRPS. Others have found similar results in this painful condition (Knotkova, Pappagallo, 2007).
Several generations of bisphosphonates have evolved over the years, and each new generation seems to provide increased effectiveness (Catala, Martinez, 2006). Etidronate (Didronel), a first-generation bisphosphonate, has no efficacy for bone-related pain treatment. The second-generation agent pamidronate is recommended in doses of 60 to 90 mg IV for 2 hours once a month (Catala, Martinez, 2006). A 2-year study showed that a single 60-mg dose of pamidronate improved pain scores, patients’ global assessments of disease severity, and function scores in patients with CRPS (Robinson, Sandom, Chaptman, 2004). The third-generation bisphosphonates are used more often and include ibandronate and zolendronate. Ibandronate is given in 4 to 6 mg IV doses over a 2-hour period once per month. Zolendronate, which is 100 times more potent than pamidronate, was recommended by the American Society of Clinical Oncology as the bisphosphonate of choice for patients with bone cancer (Berenson, Hillner, Kyle, et al., 2002). Its benefits, when compared to other bisphosphonates, include faster onset, shorter infusion time, and greater efficacy (Maxwell, Swift, Goode, et al., 2003). Dosing is 4 mg IV over 15 minutes once a month (Catala, Martinez, 2006). The IV route is preferred for administration of bisphosphonates because it produces faster onset and better effectiveness. There is evidence of effectiveness with oral clodronate, so its use is justified in countries where it is available (Catala, Martinez, 2006).
The incidence of adverse effects varies among bisphosphonate agents, routes of administration, and lengths of therapy. The most common acute-phase adverse effects are flulike symptoms of nausea and vomiting, fever, and diarrhea (Maxwell, Swift, Goode, et al., 2003). Anemia, myalgia and arthralgia, constipation, headache, and anorexia can also occur during therapy. Gastrointestinal effects occur primarily with oral agents and may be avoided by adhering to dosing instructions. Renal toxicity is a potentially serious event and is more likely with IV administration and when drug delivery is faster than recommended (Catala, Martinez, 2006). Renal function should be checked prior to administration of these drugs and monitored during the course of therapy.
More recently, anecdotal reports and observations in studies of cancer patients have linked long-term bisphosphonate therapy to what is called bisphosphonate-related osteonecrosis of the jaw (BRONJ), a concerning and severe adverse event that can significantly affect quality of life (Adamo, Caristi, Sacca, et al., 2008; Knotkova, Pappagallo, 2007). This has also been a growing problem among noncancer populations treated with bisphosphonates and is more prevalent when IV bisphosphonate is administered (Gutta, Louis, 2007). Although BRONJ is rare, it is important that all patients receiving bisphosphonates be warned of this adverse effect and the need to practice good oral hygiene and preventive dental care. If patients develop BRONJ, they should be referred promptly for dental medicine evaluation.
The United States Food and Drug Administration (U.S. FDA) (2008) issued an informational bulletin to health care professionals regarding the possibility of severe and sometimes incapacitating bone, joint, or muscle pain in patients taking bisphosphonates. Risk factors are unknown, and some patients report complete relief after discontinuing bisphosphonates. The bulletin encourages health care professionals to consider whether bisphosphonate use might be responsible for any reports of severe musculoskeletal pain.
Radionuclides that are absorbed at areas of high bone turnover have been evaluated as potential therapies for metastatic bone disease (Lussier, Portenoy, 2004). The first radionuclide introduced into clinical practice was phosphorus-32 orthophosphate. Early data suggest that treatment with a radiopharmaceutical can yield meaningful pain relief in approximately 80% of patients, and 10% can expect complete relief of pain (Robinson, Preston, Baxter, et al., 1993; Robinson, Preston, Schiefelbein, et al., 1995). A Cochrane Collaboration Review of seven trials concluded that radioisotopes alone provided effective pain relief comparable to external-beam radiotherapy (McQuay, Collins, Carroll, et al., 1999). A later review of four trials reported a small effect on short-term (1 to 6 months) pain control, but treatment was associated with an increased risk of leukocytopenia and thrombocytopenia (Roque, Martinez-Zapata, Alonso-Coello, et al., 2003). Data were insufficient to evaluate long-term effects. A more recent systematic review of trials with single-agent radiopharmaceuticals (strontium-89 and samarium-153) shows that there are benefits to using these agents, and treatment should be considered for the palliation of multiple sites of bone pain resulting from metastatic cancer when pain control cannot be achieved by means of conventional analgesic regimens (Bauman, Charette, Reid, et al., 2005).
The clinical response to a radiopharmaceutical occurs in 7 to 21 days, and peak response may be delayed for a month or more. Approximately 5% to 10% of patients experience a transitory pain flare immediately after treatment. The usual duration of benefit is 3 to 6 months, after which retreatment may regain favorable effects. Leukopenia or thrombocytopenia peaks a few weeks after treatment and occurs to a clinically significant degree in approximately 10% and 33% of patients, respectively (Porter, McEwan, Powe, et al., 1993). Bone marrow effects usually wane by 12 weeks after treatment. Bone marrow suppression is the major toxicity, and the desire for a compound with a better therapeutic index has spurred the development of several new radionuclides.
The newer radionuclides, strontium chloride-89, samarium- 153 ethylenediamine tetramethylene phosphonic acid, rhenium-186, and hydroxyethylene diphosphonic acid, have been most promising thus far (Lussier, Portenoy, 2004). Observational studies of patients with bone metastases resulting from a variety of tumor types have provided strong evidence that these compounds can reduce bone pain without undue risk to bone marrow or other vital structures. A prospective evaluation of 64 patients with breast or prostate cancer who were receiving rhenium-188 hydroxyethylidene diphosphonate (188Re-HEDP); rhenium-186 hydroxyethylidene diphosphonate (186Re-HEDP); or strontium-89 (89Sr) showed that all of the drugs were effective in palliating pain symptoms and improving quality of life, but functional status was significantly better with 188Re-HEDP (Liepe, Runge, Kotzerke, 2005).
Strontium-89 and samarium-153, which are commercially available in the United States, have been most extensively evaluated as treatments for bone pain (Akerley, Butera, Wehbe, et al., 2002; Lussier, Portenoy, 2004; Nilsson, Strang, Ginman, et al., 2005; Porter, McEwan, Powe, et al., 1993; Tripp, Kuettel, 2006). Like other radiopharmaceuticals, they are potentially effective in the treatment of pain due to osteoblastic bone lesions or lesions with osteoblastic components. Prior to treatment, an osteoblastic component should be confirmed by positive bone scintigraphy.
Given the delayed onset and peak effects, treatment with these agents should not be considered unless patients have life expectancies greater than 3 months. The delay also implies that this treatment should not be considered as the sole approach for patients with severe pain. Because of the potential for bone marrow toxicity, treatment should not be considered unless adequate bone marrow reserve has been documented (Lussier, Portenoy, 2004). In the case of strontium-89, this is usually considered to be a platelet count above 60,000 and a white blood cell count above 2400 (Robinson, Preston, Schiefelbein, et al., 1995). Impending pathologic fracture is another contraindication to use of radiopharmaceuticals (Tripp, Kuettel, 2006). Patients who continue to be candidates for myelosuppressive chemotherapy should not be treated because the effects on bone marrow may worsen the toxicity of later cytotoxic therapy or limit the ability to rebound after therapy (Lussier, Portenoy, 2004).
Limited data are available for comparative studies of strontium-89 and samarium-153. Unlike strontium-89, samarium-153 can be imaged and provides a scintigraphic picture of bone metastases at the same time treatment is given. In a small case series of 57 patients with metastatic prostate cancer (38 treated with strontium-89 and 19 with samarium-153), no differences were observed in effects on pain or time to disease progression (Dickie, Macfarlane, 1999). For now, the indications and safety issues should be assumed to be similar for both of these radiopharmaceuticals.
Radiopharmaceuticals are not widely used in the United States because of relatively disappointing results; however, these results may be related to the low maximum allowed dose of 4 mCi in the United States (Tripp, Kuettel, 2006). Trials in other countries that used higher doses (e.g., 10.8 mCi in Canada) have yielded more positive results (Porter, McEwan, Powe, et al., 1993).
Radiation therapy is usually considered for patients with progressive cancer who have bone pain that is focal and poorly controlled by an opioid or is associated with a lesion that appears to be prone to fracture on radiographic examination. Adjuvant analgesics that may be useful in this setting include calcitonin, bisphosphonate compounds, gallium nitrate, and selected radiopharmaceuticals. Because there are limited data comparing the advantages and disadvantages of these adjuvant analgesics for bone pain, selection of one agent over another is usually made on the basis of convenience, cost, patient preference, and clinical setting.