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

Abstract and Introduction

Abstract

Background: Metastatic bone disease is a common cause of pain in cancer patients. A multidisciplinary approach to treatment is often necessary because simplified analgesic regimens may fail in the face of complex pain generators, especially those involved in the genesis of neuropathic pain. From the origins of formalized guidelines by the World Health Organization (WHO) to recent developments in implantable therapies, great strides have been made to meet the needs of these patients.
Methods: The authors review the existing literature on the pathophysiology and treatment options for pain generated by metastatic bone disease and summarize classic and new approaches.
Results: Relatively recent animal models of malignant bone disease have allowed a better understanding of the intimate mechanisms involved in the genesis of pain, resulting in a mechanistic approach to its treatment. Analgesic strategies can be developed with specific targets in mind to complement the classic, opioid-centered WHO analgesic ladder obtaining improved outcomes and quality of life. Unfortunately, high-quality evidence is difficult to produce in pain medicine, and these concepts are evolving slowly.
Conclusions: Treatment options are expanding for the challenging clinical problem of painful metastatic bone disease. Efforts are concentrated on developing alternative nonopioid approaches that appear to increase the success rate and improve patients' quality of life.

Introduction

Metastatic bone disease is among the most common causes of cancer pain.[1,2] However, a significant number of these lesions cause no pain or the incidence of pain is unrelated to the size of the tumor.[3] The causes leading to the development of pain within a bone tumor have been difficult to investigate, mainly because for many years, a suitable animal model of cancer pain did not exist. Injection of mouse osteolytic sarcoma cells into the intramedullary space of the mouse femur was the first model created in 1999.[4] This and newer models have provided advanced insight into the intimate mechanisms of cancer pain.

Primary peripheral nociceptor afferents express a wide variety of receptors that detect noxious stimuli. This is in contrast to most other sensory modalities for which peripheral terminals typically respond to one type of stimulus. The vanilloid receptor-1 (VR1) detects heat, protons (acidity), and lipid metabolites; mechanically gated ion channels respond to mechanical stimuli; purinergic receptors react to adenosine trisphosphate (ATP) and adenosine diphosphate (ADP); and a growing number of other receptors respond to molecules of the "inflammatory soup" such as cytokines, histamine, serotonin, nerve growth factors, prostaglandins, and endothelins.[5] Sustained stimulation of these nerve fibers produces plastic changes that contribute to lowering the threshold level of activation. This process is known as peripheral sensitization, the underlying cause of the clinical phenomena of hyperalgesia (mild noxious stimulus is perceived as highly painful) and allodynia (stimulus that would normally be perceived as non-noxious is perceived as noxious), which are hallmarks of neuropathic pain (Fig 1).

Figure 1.

Detection by sensory neurons of noxious stimuli produced by tumors. Nociceptors (pink) use several different types of receptor to detect and transmit signals about noxious stimuli that are produced by cancer cells (yellow) or other aspects of the tumor microenvironment. The vanilloid receptor-1 (VR1) detects extracellular protons (H+) that are produced by cancer cells, whereas endothelin-A receptors (ETAR) detect endothelins (ET) that are released by cancer cells. The dorsal-root acid-sensing ion channel (DRASIC) detects mechanical stimuli as tumor growth mechanically distends sensory fibers. Other receptors that are expressed by sensory neurons include prostaglandin receptors (EP), which detect prostaglandin E2 (PGE2) that is produced by cancer and inflammatory cells (macrophages). Nerve growth factor (NGF) released by macrophages binds to the tyrosine kinase receptor TrkA, whereas extracellular ATP binds to the purinergic P2X3 receptor. Activation of these receptors increases the excitability of the nociceptor, inducing the phosphorylation of the 1.8 and/or 1.9 sodium channels (Na+ channel) and decreasing the threshold required for nociceptor excitation. From Mantyh PW, Clohisy DR, Koltzenburg M, et al. Molecular mechanisms of cancer pain. Nat Rev Cancer. 2002; 2(3):201–209. Reprinted by permission from Macmillan Publishers Ltd.

Tumors are composed of many types of cells other than malignant ones, including inflammatory mediating immune cells such as macrophages and lymphocytes, and every drug generated to antagonize the products of inflammation, whether recently developed or relied on over the years, has a place in the treatment of pain generated at these sites. Tumors are also acidic, particularly osteoclast-activated osteolytic tumors.[6] Bisphosphonates induce osteoclast apoptosis and are now used as agents for management of painful bone metastases, as discussed below. Tumor growth activates mechanically sensitive ion channels by distension of nerve fibers, frequently entrapping them and possibly causing aberrant regeneration, a common pathway to neuropathic transformation, which is another process susceptible to modulation by an increasing number of drugs.

Another phenomenon observed in the cancer pain animal models is the extensive neurochemical reorganization in the spinal cord segments that receive input from primary afferent neurons. These innervate the tumor-bearing bone, demonstrating further means of amplification and perpetuation of the perception of pain or "central sensitization,"[7] an event also susceptible to neuromodulating drugs.

With expanded understanding of the neurophysiology and related pharmacology of cancer bone pain, we can continue refining the clinical approach to alleviate pain and suffering in these patients, which is the original and possibly most important duty of the medical profession.

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