The Management of Pain in Metastatic Bone Disease

Sorin Buga, MD; Jose E. Sarria, MD

Disclosures

Cancer Control. 2012;19(2):154-166. 

In This Article

Medical Management

Calcitonin

Calcitonin acts by inhibiting sodium and calcium resorption by the renal tubule and by reducing osteoclastic bone resorption. However, the role of calcitonin appears to be limited by its short duration of action and rapid development of tachyphylaxis.

Two double-blind clinical trials of patients with metastatic bone pain treated with calcitonin were conducted to study pain relief as the major outcome measure, assessed at 4 weeks or longer.[15] Both studies, which included 90 participants in total, showed no evidence that calcitonin was effective in controlling complications due to bone metastases, improving quality of life, or prolonging patient survival. Calcitonin did provide some relief of neuropathic pain, although its mechanism of action is uncertain, possibly via the serotoninergic system in the hypothalamus and limbic system.

Bisphosphonates

Bisphosphonates bind to the surface of the bone, have a direct apoptotic effect on osteoclasts, impair osteoclastmediated bone resorption, and reduce the tumor-associated osteolysis that is initiated by the development of skeletal metastases. However, their role in pain relief for bone metastases remains uncertain even though they are part of standard therapy for hypercalcemia of malignancy.

There are two classes of bisphosphonates: (1) non-nitrogen containing, such as etidronate, clodronate and tiludronate, and (2) nitrogen containing, such as pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid, which are more potent osteoclast inhibitors.

A Cochrane review of 30 randomized controlled studies (21 blinded, 4 open, and 5 active control) including 3,682 subjects showed that the results did not provide sufficient evidence to recommend bisphosphonates for an immediate effect as first-line therapy for painful bone metastases.[16] Moreover, a retrospective Turkish study on 372 patients that compared different radiotherapy protocols (30 Gy in 10 fractions, 20 Gy in 5 fractions, and 8 Gy in a single fraction) with or without bisphosphonates showed that when combined with palliative radiotherapy, bisphosphonates did not have any additive effects on pain palliation in the management of painful bone metastases. Results from another study that included 372 cancer patients showed that, when combined with palliative radiotherapy, bisphosphonates did not have any additive effects on pain palliation in the management of painful bone metastases.[17] In addition, a single radiotherapy fraction provided equal pain palliation as multiple fractions.[27]

Conversely, a study conducted in Greece[18] and another in Canada[19] showed that zoledronic acid is the only bisphosphonate that has demonstrated statistically significant, long-term clinical benefits through the prevention and delay of skeletal-related events (SREs) in patients with metastatic lung cancer and prostate/renal cancer, respectively. Also, these studies suggested that the longer a patient receives zoledronic acid, the better its effect on survival and time to progression.

Denosumab

Denosumab is a monoclonal antibody with affinity for receptor activator of nuclear factor κB ligand (RANKL), which is secreted by osteoblasts. By binding to RANKL, denosumab prevents osteoclast formation, leading to decreased bone resorption and increased bone mass and thus preventing SREs.

Several studies have shown promising results when comparing denosumab to zoledronic acid. A recently published study enrolled patients with castration-resistant prostate cancer from 342 centers in 39 countries. A total of 950 men were randomly assigned to receive 120 mg subcutaneous denosumab plus intravenous placebo, and 951 men received 4 mg intravenous zoledronic acid plus subcutaneous placebo, every 4 weeks until the primary analysis cutoff date. The median time to the first on-study SRE was 20.7 months (95% confidence interval [CI], 18.8–24.9) with denosumab compared with 17.1 months (95% CI, 15.0–19.4) with zoledronic acid (hazard ratio = 0.82; 95% CI, 0.71–0.95; P = .0002 for non-inferiority; P = .008 for superiority). denosumab was superior to zoledronic acid in preventing SREs.[20]

A similar study that included patients with advanced breast cancer showed that denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio = 0.82; 95% CI, 0.71–0.95; P = .01 for superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio = 0.77; 95% CI, 0.66–0.89; P = .001). Overall survival, disease progression, and rates of adverse events and serious adverse events were similar between the two groups.[21]

Finally, a study comparing denosumab with zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) showed that denosumab was non-inferior (trending to superiority) to zoledronic acid in preventing or delaying first on-study SRE.[22]

Corticosteroids

The mechanism of action of corticosteroids is blocking the synthesis of cytokines that contribute to both nociception and inflammation. The role of corticosteroids in treating spinal cord compression is well known. When spinal cord compression is suspected, patients should be treated with corticosteroids and evaluated with whole-spine MRI or myelography within 24 hours. Providers should initiate definitive treatment (radiotherapy or surgical decompression) within 24 hours of diagnosing cord compression.

A Canadian study involving 41 patients indicated that 8 mg dexamethasone given just before palliative radiotherapy can significantly decrease the incidence of pain flare during the first 2 days immediately after radiotherapy.[23]

Analgesics

The World Health Organization (WHO) analgesic ladder is the most widely used guideline for the medical treatment of cancer pain. Many studies have contributed to its validation.[24,25] It advocates 3 basic steps according to the severity of symptoms (Fig 2A).

Figure 2.

(A) The 3-step analgesic ladder developed by the World Health Organization. Reproduced by permission of WHO. Cancer Pain Relief. Geneva: WHO; 1986. http://www.who.int/cancer/palliative/painladder/en/. (B) The proposed fourth step. From Miguel R. Interventional treatment of cancer pain: the fourth step in the World Health Organization analgesic ladder? Cancer Control. 2000;7(2):149–156. Reproduced by permission of Cancer Control: Journal of the Moffitt Cancer Center.

Step 1 consists of nonopioid analgesics when pain is mild. Nonsteroidal anti-inflammatory drugs (NSAIDs) and COX-2 inhibitors, acetaminophen, adjuvants, and topical analgesic compounds comprise this group. Much controversy has revolved around the safety of NSAIDs; currently, their use is advised with caution, particularly in the elderly.[26] Adjuvants typically refer to drugs that, although are not analgesics per se, can be used for this indication in special circumstances. Several antiepileptics and antidepressants are first-line therapies in the management of neuropathic pain. The most commonly used agents include gabapentin, pregabalin, and tricyclic antidepressants (eg, amitriptyline, nortriptyline).

Step 2 introduces weak opioids such as hydrocodone, codeine, and low-dose oxycodone for pain that is mild to moderate. Other μ receptor agonists with dual mechanisms of action include tramadol and, most recently, tapentadol. These drugs reduce much of the side effects profile of pure opioids and have added effects on neuropathic pain. Propoxyphene (Darvocet, Darvon) has been taken off the market due to concerns of cardiac arrhythmias.

Step 3 consists of stronger opioids such as morphine, hydromorphone, fentanyl, high-dose oxycodone, meperidine, and methadone.

For patients with chronic cancer pain, a combination of long- and short-acting opioids is recommended. The long-acting opioids, whether they are pharmacologically long-acting (such as methadone or levorphanol) or pharmaceutically long-acting (a slow-release delivery system such as extended-release morphine, oxycodone, oxymorphone or hydromorphone), are used for the chronic baseline cancer pain. The shortacting opioids that require repetitive dosing are used for the acute pain.

Regarding breakthrough pain, which is defined as an abrupt, short-lived, and intense flare of pain in the setting of chronic stable pain managed with opioids,[27] there is an increasing trend to the use of transmucosal lipophilic drugs (eg, oral transmucosal fentanyl citrate, fentanyl buccal tablets, sublingual fentanyl, intranasal fentanyl spray, fentanyl pectin nasal spray, fentanyl buccal soluble film) due to the rapid effect of these drugs, which is clinically observable 10 to 15 minutes after administration.[28,29] Breakthrough pain has been reported to occur in 50% to 70% of cancer patients.[30] Patients with pain located in the spine, back, and pelvis may be at risk for resistant breakthrough pain.[31] Breakthrough pain can be categorized as somatic, visceral, or mixed, and also as idiopathic (spontaneous), incidental, and end-of-dose failure (when the pharmacokinetics of the analgesic do not match the patient's dosing schedule).[32]

Ketamine, an N-methyl D-aspartate (NMDA) receptor antagonist, is a less commonly known analgesic. It is effective in treating intractable severe pain caused by metastasis, trauma, chronic ischemia, or central neuropathic pain. Ketamine is effective even when megadoses of intravenous, epidural, or oral opioids prove ineffective or when opioid tolerance has developed.

A recent Italian study[33] investigated the use of ketamine 100 mg daily for 2 consecutive days along with methadone in patients with increased incidental pain and adverse effects from opioids. The results were encouraging, but further research is needed. Another study from Israel examined the benefits of using ketamine in patients with severe bone pain in whom high intravenous doses of morphine, meperidine, or fentanyl and patient-controlled intravenous and epidural analgesia were insufficient.[34] Within 5 to 10 days of ketamine and opioid protocols, pain was controlled and after an additional 5 to 7 days, ketamine could be discontinued and pain was controlled on oral regimens compatible with outpatient care.

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