Adjuvant Analgesics for Persistent (Chronic) Bone Pain

Chapter 29


Adjuvant Analgesics for Persistent (Chronic) Bone Pain



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.




Calcitonin


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


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).



Dose Selection


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).

< div class='tao-gold-member'>

Related posts:

  1. Perioperative Nonopioid Use
  2. Other Challenges in Pain Assessment
  3. Intravenous Patient-Controlled Analgesia
  4. Switching to Another Opioid or Route of Administration

Stay updated, free articles. Join our Telegram channel
Tags:
Jun 24, 2016 | Posted by in PHARMACY | Comments Off on Adjuvant Analgesics for Persistent (Chronic) Bone Pain

Full access? Get Clinical Tree
Get Clinical Tree app for offline access