Mechanisms and management of bone pain (1997)

Acute and chronic pain is a public health problem as measured by its prevalence in the society, as well as the direct and indirect costs associated with it, including the substantial loss in productivity.1, 2 Pain also is the most common symptom for which patients seek medical attention.3 The prevalence of pain from cancer was shown to be 55% in a recent study of ambulatory patients, and 46% of those patients reporting pain received inadequate analgesics.4 Metastatic bone pain is the most common pain syndrome encountered in cancer patients.5 Despite the high prevalence of unrelieved pain in the general population, there have been major strides in understanding basic neurobiologic mechanisms of acute and chronic pain, including cancer pain, that have direct treatment implications.6-8 This article will review the mechanisms of bone and joint pain and the manner in which the nervous system encodes nociceptive information. The clinical anatomy of ascending nociceptive and descending pain suppression pathways will be discussed, with an emphasis on treatment approaches for bone and joint pain. Sensory receptors that are preferentially sensitive to noxious (tissue damaging) or potentially noxious stimuli are prevalent in skin, muscle, joint and bones, other connective tissues, and viscera.6-8 Nociceptors are defined morphologically and physiologically by their patterns of response to mechanical, thermal, and chemical cutaneous stimuli (Fig. 1 (4K)). Once activated, nociceptors conduct impulses via lightly myelinated afferent fibers (A-δ) or unmyelinated (C) afferent fibers and increase their rate of action potential production in direction correlation with the intensity of the stimulus. In this way they differ from simple thermal or mechanoreceptors. In cutaneous nerves in humans, 10% of all myelinated fibers carry nociceptive information; >90% of all unmyelinated fibers are nociceptive.9 Nociceptors are defined by their patterns of response to stimuli. Reprinted from Pain, Vol. 63. Watkins LR, Maier SF, Goehler LE. Immune activation: the role of pro-inflammatory cytokines in inflammation, illness responses and pathological pain states, pages 289-302, with kind permission from Elsevier Science-NL, Sara Burgerharrstraat 25, 1055 KV Amsterdam, The Netherlands. The technique of microneurography, in which single afferent or efferent fibers can be stimulated in and/or recorded from awake patients or volunteers, has allowed the correlation of electrical activity in afferent nociceptive fibers with verbal patient reports of pain.10 Nociceptors are not spontaneously active, but may show sensitization, particularly after thermal injury to the skin. Sensitization is manifested as a decreased threshold of activation after injury, increased intensity of a response to a noxious injury, and the emergence of spontaneous activity.11 Sensitization of nociceptors may occur within minutes after a thermal injury, and may last for hours. It is believed that nociceptor sensitization is a physiologic mechanism of persistent pain in humans.11 Sensitization of nociceptors has been produced by efferent sympathetic activity,12 and also may occur as a result of chemical stimulation by endogenous substances such as potassium, adenosine triphosphate, bradykinin, prostaglandins, and a host of cytokines such as interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF) released in response to tissue injury or as a result of immune-mediated mechanisms of tissue repair.7, 13 Pain originating from skeletal muscle or bone, as well as thoracic, abdominal, and pelvic viscera is much more common than cutaneous pain, although the latter has been studied more frequently in animal models of pain until recently. A-δ mechanoreceptors and C-nociceptors appear to be localized to connective tissue between muscle fibers and in blood vessel walls or tendons, and in the joint capsule and periosteum.14 Tumor metastasis to bone is associated with bone destruction and new bone formation, and prostaglandin biosynthesis appears to be an integral part of this process.15 For example, prostaglandins in the E series mediate osteoclastic bone resorption, and play a part in the IL-1 enhancement of bone metastasis.15 Prostaglandins in the A and E series may stimulate metastatic tumor cells directly. The link between osteolytic bone metastasis and pain is provided by the concomitant activation of osteoclasts and nociceptors by prostaglandins and cytokines.13 In fact, osteolytic destruction of bone is mediated by several humoral mechanisms in addition to prostaglandins and include parathormone, cytokines, and growth factors that stimulate osteoclast activity.16 There is sound experimental evidence for IL-1, IL-6, and TNF activation of nociceptors as well.13 Thus, many of the chemical mediators of osteolysis also have been shown to activate nociceptors (Fig. 2 (6K)). This diagram illustrates the chemical mediators which act on the peripheral nerve or nociceptor terminal. Note that interleukins 1 and 6 (IL-1, IL-6) are in the osteolytic destruction of bone as well as nociceptor activation. Reprinted from Fields H. Pain. © 1987, McGraw-Hill, with permission of the publisher. In the presence of inflammation, peripheral opioid receptors are exposed on primary afferent nociceptive fibers.17 Opioid receptors also are present on immune system cells that migrate to inflamed tissue.18 Local application of opioids that are polar and that do not cross the blood-brain barrier would be advantageous to avoid adverse central nervous system effects.19 In fact, recent clinical studies have demonstrated an analgesic effect of direct intraarticular injection of opioids after knee surgery.17 Pain originating from visceral tissues also is mediated through nociceptors.20 Silent nociceptors have been identified that are sensitized by inflammatory changes in visceral tissues.21 Visceral pain often is poorly localized and referred to cutaneous sites. These clinical properties may reflect the convergence of visceral afferent input into the same neuronal pool-mediated cutaneous somatosensory sensation.7 Nociceptor activation from visceral and musculoskeletal tissues may produce muscle spasms through reflex circuits from afferent noxious input onto efferent gamma motor neuron output.7 Neuropathic pain can occur by many mechanisms, but generally does not involve nociceptor activation.8, 22 Pain is accompanied by allodynia (pain that occurs from a usually innocuous stimulus applied to the skin) and hyperalgesia (increased pain to a normally mildly painful stimulus). Allodynia and hyperalgesia may reflect secondary central nervous system changes induced by nociceptive processes as a result of activation of N-methyl-d-aspartate (NMDA) receptors. In addition, neuropathic pain often is experienced in an area of sensory loss, which is an apparent paradox to most patients and inexperienced clinicians. A full discussion of neuropathic pain is beyond the scope of this article; however, neuropathic and bone pain frequently coexist when spinal pathology expands to compress or invade nerve roots or the spinal cord, such as occurs with epidural spinal cord compression complicating vertebral body metastasis or osteophytic compression of spinal nerve roots. Once activated, nociceptors transduce chemical, mechanical, or thermal stimuli into afferent impulses that enter the nervous system through the dorsal and ventral roots23 and synapses in the dorsal horn of the spinal cord. In the dorsal horn, substantial modulation of the nociceptive signal can occur as a result of complex interaction between intrinsic cells in the substantia gelantinosa and descending projections from the brainstem.24, 25 Second-order neurons, which have cell bodies in lamina V of the dorsal horn, respond in a quantal (all of none or nociceptive specific pattern) or in a graded fashion to increasing stimulus intensity, the so-called wide-dynamic range response.6 These cells send axons across the midline to ascend in the contralateral anterolateral quadrant of the spinal cord as the spinothalamic tract. The spinothalamic tract, and other ascending tracts, input sensory information to the thalamus and the cortex to mediate the conscious perception of pain.26 The thalamus and cortex are critical to the conscious perception of pain.22 Recent neuroimaging studies utilizing positron emission tomography scanning and functional magnetic resonance imaging have documented activation of the thalamus, primary and secondary somatosensory cortex, and cingulate and insular cortex after the application of experimental pain stimuli.27, 28 Activation of the association cortex, especially that traditionally associated with the limbic system (cingulate cortex, insula), is consistent with the need for complex temporal-spatial summation to occur and the need for integration of the nociceptive stimulus with other pathways associated with memory and emotion to fully perceive a nociceptive stimulus as "pain." Important neuroanatomic pathways descend from the brainstem into the spinal cord through the dorsal longitudinal fasiculus to modulate the ascending nociceptive information.25 Analgesic drugs that act on the central nervous system, such as opioids and tricyclic antidepressants, are believed to activate this inhibitory pathway.7, 29 Recently, the role of excitatory amino acids such as glutamate has been shown to have important consequences in nociception.30 Glutamate acts through the NMDA receptors; activation of this receptor is known to produce long-acting postsynaptic changes in the nervous system, and has been implicated in the development of chronic pain.30 For example, pharmacologic agents that block NMDA receptor activation, such as ketamine hydrochloride or dextromethorphan, may relieve or prevent pain from occurring in some circumstances.31 The inhibition of NMDA receptors also has been implicated in the reversal of morphine tolerance in animals.32 Thus conventional analgesic agents used to manage bone pain (such as nonsteroidal antiinflammatory drugs [NSAIDs]), act on the peripheral nociceptive primary afferents and opioids act in the central nervous systems (in the descending inhibitory pathways), respectively. However, recent evidence also indicate that NSAIDs may have important central actions33 and opioids may have peripheral actions.14 The mechanism of action of other agents or modalities used to treat bone pain such as bisphosphonates, calcitonin, corticosteroids, external beam radiation, and radiopharmaceuticals, most likely have direct effects on osteoclasts, or reduce edema and inflammation and reduce pain by a secondary effect to diminish nociceptor activation. A full discussion of principles necessary for pain assessment and management is beyond the scope of this article, but has been reviewed in recent monographs or articles, and is summarized in Table 1.34-36 In addition, Tables 2, 3, and 4 list the commonly used analgesics for the management of acute and chronic pain, including pain of musculoskeletal origin. Bone can be imaged by a number of modalities, including conventional roentgenography, bone scintigraphy, computed tomography, and magnetic resonance imaging. It is important to define the areas of bone pathology by the appropriate imaging modality to appropriately assess pain and to provide a comprehensive treatment plan. Codeine (with APAP or ASA) Tylenol #2 (15 mg codeine) Tylenol #3 (30 mg codeine) Tylenol #4 (60 mg codeine) Hydrocodone (with APAP or ASA) Lorcet, Lortab, Vicodin, others Oxycodone hydrochloride Roxicodone (single entity) Percocet, Percodan, Tylox, others 30 mg every 3-4 hours orally 10 mg every 3-4 hours intravenously Sustained release MS Contin, Oramorph SR Morphine is also available as suppository MSIR is preferred rescue analgesic for controlled-release preparations Hydromorphone Dilaudid, others Sustained-release formulation in clinical development Comes in 2-, 4-, and 8-mg tablets Available as a suppository (4 mg?) Duragesic (transdermal) Sublimaze, others 50 μg/hour every 72 hours 50 μ/hour via continuous infusion The only opioid available for transdermal administration. Potency relative to morphine close to 100:1. Many patients require oral rescue doses. Methadone Dolophine, others 20 mg every 6-8 hours intravenously 10 mg every 6-8 hours intravenously Levorphanol Levo-Dromoran Amitriptyline, 10-25 mg orally at bedtime → 150 mg/day Nortriptyline, 25 mg orally at bedtime → 100-150 mg/day Dexamethasone, 4-16 mg/day orally (2-4 divided doses) Prednisone, 60-80 mg/day orally (2-4 divided doses) Methylphenidate, 5-20 mg/day orally Dextroamphetamine sulfate, 5-15 mg/day orally In patients with metastatic disease in weight-bearing bones, appropriate referrals to orthopedic surgery and physical medicine and rehabilitation services obviously are essential to avoid pathologic fracture. Because it is always preferable to treat the cause of pain whenever possible, patients with metastatic bone disease and pain should be considered for trials of radiotherapy or radiopharmaceutical treatments,37 "palliative chemotherapy,"38 and bisphosphonates39 as their pain is treated with analgesics. Patients with skeletal abnormalities in weight-bearing bones often have movement-related pain (so-called incident pain), and require "rescue analgesics"--quick-acting drugs, usually opioids, to provide pain relief that breakthrough the chronic daily pain.40 New formulations of analgesics, such as an oral transmucosal fentanyl citrate, that can produce analgesic blood concentrations of fentanyl within 5 minutes of placement in the oral mucosa may have a major role in treating patients with severe incident-related breakthrough pain.41