Adjuvant Analgesics in Management of Cancer-Rated Bone Pain

Synonyms

Malignant Bone Pain; boney pain; cancer-related bone pain

Definition

Adjuvant analgesics in the management of cancer-related bone pain are supplemental treatments that are added to the primary analgesics, usually NSAIDs and opioids. These additional analgesic interventions include radiation, using either palliative radiotherapy or radiopharmaceuticals, and two classes of medications, bisphosphonates and steroids.

Characteristics

Normal bone undergoes constant remodeling in which resorption or formation of bone occurs. The cells involved in these processes are osteoblasts and osteoclasts, respectively. These cells respond to signals from several types of mediators, including hormones, prostaglandins, and cytokines. Tumor cells invade bone and interrupt the balance between osteoblastic and osteoclastic activity, alter bone integrity and produce pain (Mercadante 1997).

Boney cancers can be exquisitely painful. The severity of pain does not always correlate with radiographic findings. Primary and metastatic bone tumors produce severe pain in about 90% of patients who develop such tumors. Therefore, aggressive and effective treatment of boney cancer pain is important to maintain patients’ quality of life.

Boney metastases occur in approximately 60–85% of patients who develop metastatic disease from some of the more common cancers, e.g. breast, prostate, and lung. Bone is one of the most common metastatic sites. There are also primary bone cancers, e.g. myeloma, osteosarcoma, Ewing’s sarcoma (Mercadante 1997).

When tumors metastasize to bone, they can either be osteolytic, causing boney destruction, or osteoblastic producing sclerotic boney changes (1). Figure 1 illustrates bone changes in cancer. Examples of these processes are prostatic cancer stimulating osteoblasts to lay down boney material, and breast cancer causing osteolysis from stimulation of osteoclasts. Mixed osteoblastic-osteoclastic states also can occur.

Figure 1

Cancer effects on bone. (a) Normal bone (balance between formation and remodeling). (b) Osteolytic bone (unbalanced – increase in osteoclastic activity). (c) Osteoblastic bone (unbalanced –increase in bone formation).

Chemical mediators, most notably prostaglandins and cytokines, are released in areas of tumor infiltration. These mediators stimulate osteoclasts or osteoblasts and nociceptors (Payne 1997). When tumor invasion occurs, the highly innervated periosteum that surrounds bone is disturbed and microfractures may occur within the trabeculae (Payne 1997). Nerve entrapment can also occur as disease progresses, due either to direct tumor effects or to collapse of the skeletal structure (Mercadante1997; Payne 1997; Benjamin 2002).

Radiopharmaceuticals and bisphosphonates are very effective at treating boney pain; some clinicians consider these first line therapies. The combination of the two may be additive or synergistic in the treatment of bone pain and dose sparing to lessen dose-related complications of opioid therapy (Hoskin 2003).

Radiotherapy and radiopharmaceuticals are often underutilized therapies for treating bone pain. These two methods of delivering radionuclides have comparable efficacy as analgesics. A systematic review of 20 trials (12 using external field radiation and 8 using radioisotopes) showed that 1 in 4 patients received complete pain relief in one month, and 1 in 3 patients achieved at least 50% pain relief. For radiotherapy, no differences in efficacy or adverse events were reported with single or multiple fractional dosing in the external field trials. Radiotherapy has been reported to be up to 80% effective for the treatment of boney pain (McQuay et al. 2000). Radiation can be delivered by localized or widespread external beam radiation that can be localized or widespread, and also by systemic bone-seeking radioisotopes. For widespread painful boney metastases, external hemibody radiation may be administered. With radiation administered above the diaphragm, pneumonitis is a risk (Mercadante 1997). Below the diaphragm administration commonly causes nausea, vomiting, and diarrhea. If whole body radiation is the goal, a period of 4–6 weeks between treatments must occur to allow bone marrow recovery.

An alternative to systemic delivery is the use of radioisotopes that target bone. There are four such agents available: ⁸⁹strontium (⁸⁹Sr), ³²phosphorous (³²P), ¹⁸⁶rhennium (¹⁸⁶Re), and ¹⁵³samarium (¹⁵³Sm). ⁸⁹Sr is the most commonly used due to its greater specificity for bone. All of these agents target osteoblastic activity. They emit beta particles and are associated with less systemic toxicity than hemibody radiation. However, bone marrow suppression is still a risk. Use of these radiopharmaceuticals is limited due to the expense of the drugs and by storage and disposal requirements (Hoskin 2003). Current radioisotope research is focusing on low energy electron emitters over the current energetic β emitters to produce therapeutic benefit without bone marrow suppression (Bouchet et al. 2000).

Local irradiation is the treatment of choice for localized bone pain, because this method is associated with a low incidence of local toxicity and virtually no systemic toxicity. Radiotherapy often provides relatively prompt pain relief, which is probably due to reduced effects of local inflammatory cells responsible for the release of inflammatory mediators, not tumor regression alone.

Bisphosphonates are another form of systemic treatment for bone pain. A recent meta-analysis of 30 randomized controlled trials, to evaluate relief of pain from bone metastases, supports the use of bisphosphonates as adjunct therapy when primary analgesics and/or radiotherapy are inadequate to treat the pain (Wong and Wiffen 2002). Evidence is lacking for the use of bisphosphonates as first line therapy for immediate relief of bone pain.

Two bisphosphonates are currently approved for the treatment of painful boney metastasis in the United States; pamidronate and zoledronic acid. Both are intravenous preparations. Doses of 90 mg pamidronate administered over two to four hours and 4 mg zoledronic acid administered over 15 min every three to four weeks have comparable effectiveness in reducing the need for radiotherapy, decreasing the occurrence of fractures, and reducing pain scores (Lucas and Lipman 2002). The most common adverse effects of both agents include bone pain, anorexia, nausea, myalgia, fever, and injection site reaction. Bisphosphonates have been associated with renal toxicity. Bisphosphonates bind strongly to the bone surface and are taken up by osteoclasts during bone resorption. The osteoclasts are then inhibited and apoptosis is induced. The reduction in the number of osteoclasts inhibits boney metastasis. The bisphosphonates also have an anti-tumor effect, possibly due to drug uptake in tumor cells (Green and Clezardin 2002).

Although NSAIDs are generally considered first-line drugs for mild cancer pain, their specific role in boney pain is currently being investigated. A recent study in mice evaluated a cycloxygenase-2 (COX-2) selective NSAID on movement-evoked cancer bone pain and tumor burden. A decrease of ongoing and movement-evoked pain was seen in acutely treated mice (day 14 post tumor implantation), and the same decrease in pain was expressed as well as decreased tumor burden, osteoclastogenesis, and bone destruction, by 50% of chronically treated mice (day 6 post tumor implantation) (Sabino et al. 2002). Tumors that invade bone express COX-2, possibly as a mechanism for implantation. This work supports the inhibition of prostaglandin synthesis as being the mechanism of action of the drugs in cancer-related bone pain.

Systemic steroids can also be useful adjuvants in cancer-related bone pain due to broad-spectrum anti-inflammatory properties. They are most commonly used for spinal cord compression due to collapse of vertebrae or pressure by the tumor itself. Approximately 90% of prostatic metastases involve the spine, with the lumbar region most commonly affected. Early diagnosis of spinal cord compression is critical. It presents as localized back pain in 90–95% of patients; muscle weakness, autonomic dysfunction and sensory loss will follow if untreated (Benjamin 2002). Intravenous dexamethasone is a steroid of choice due to its high potency, low mineralocorticoid activity and low cost.

When primary analgesics, i.e. nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids, no longer control boney pain adequately, adjuvants should be considered. Local radiation should be used when pain is localized and fractures are ruled out. Pain due to solid tumors tends to respond greater to radiotherapy than bisphosphonates. Generally, as the disease progresses patients will have received both of these modalities. The role of their use together has yet to be evaluated. To forestall neurological complications of spinal cord compression, steroids are indicated and should be started promptly upon suspicion.