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Boneache, Pain in Bone
Bone Pain

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Introduction

Most patients referred for palliation of metastatic bone pain have primary tumors of the highest overall incidence: breast, prostate, or lung. Other neoplasms involving bone, such as myeloma, also respond to radiation. Regular followup should be provided to offer treatment of new symptoms or the use of other palliative techniques such as radiopharmaceuticals.

Plain radiographs are useful in detecting lytic or blastic lesions from bone metastases. Bone scintigraphy, however, is more sensitive than skeletal radiography for the detection of most bone metastases. Although 73 percent of patients in one series were asymptomatic when skeletal metastases were discovered by scintigraphy, 66 percent of these symptom-free patients ultimately experienced moderate to severe bone pain (Sherry, Greco, Johnson, et al., 1986a). In patients who experience bone pain and have normal bone scans, MRI may be a helpful diagnostic tool.

Indications for the radiation of bone metastases include pain relief and the prevention or promotion of healing of pathologic fractures. Spinal cord compression associated with vertebral collapse due to bony or epidural metastases requires emergent radiation therapy, sometimes in coordination with surgical intervention to preserve neurologic integrity (Bates, 1992). Orthopedic complications, including pathologic fracture and spinal cord compression, have been reported in 36 percent of breast cancer patients with skeletal metastases (Sherry, Greco, Johnson, et al., 1986b). Lytic lesions that are 2.5 cm or larger in weight-bearing bones or that cause a more than 50 percent loss of cortical bone place patients at high risk for pathologic fracture (Bates, 1992); patients with such lesions may benefit from prophylactic surgical fixation in conjunction with adjuvant irradiation.

Pain Relief With Localized Radiation Therapy.Radiation is commonly administered to a localized bone metastasis. An analysis of therapeutic results is complicated by variation in the location and extent of bone metastases, primary histology, individual differences (including patients' underlying medical conditions), and co-administered treatments. Concurrent analgesic use is frequently a confounding, poorly quantified variable in many accounts of pain control during local radiation of a metastasis. Most retrospective and prospective studies report that 75 percent or more of patients obtain relief from pain and that about half of those who achieve relief become pain-free (Nielsen, Munro, and Tannock, 1991). However, selection bias cannot be excluded; valid and reliable pain assessment instruments were not commonly used.

The literature is divided on appropriate fractionation (Blitzer, 1985;Hoskin, 1988;Tong, Gillick, and Hendrickson, 1982). Protracted regimens of more than 10 treatments may be more appropriate for patients with life expectancies of longer than 6 months to reduce potential late radiation effects or acute effects such as nausea if critical structures such as the stomach have to be included in the radiation field. For patients with a more limited life expectancy, radiation can be administered in fewer fractions, depending on the patient's clinical status (Lawton and Maher, 1991;Maher, Coia, Duncan, et al., 1992). These later regimens result in effective palliation in over 70 percent of patients at 3-months' followup, with negligible complications when radiation portals are localized (Arcangeli, Micheli, Arcangeli, et al., 1989;Bates, Yarnold, Blitzer, et al., 1992;Blitzer, 1985;Tong, Gillick, and Hendrickson, 1982).

Wide-Field Radiation Therapy.Hemibody irradiation, which can treat multiple disease sites, is particularly appropriate for diffuse bone pain. A single large fraction of 6 Gy to 8 Gy is administered to one half of the body. If necessary, the other half can be treated after a 3-week interval to allow for bone marrow recovery. With antiemetics and partial shielding to reduce lung exposure, toxicity occurs in fewer than 10 percent of patients, and 50 percent experience stabilization of disease at 1-year followup (Poulter, Cosmatos, Rubin, et al., 1992).Salazar, Rubin, Hendrickson, et al. (1986) reported that palliation was achieved in 73 percent of patients treated with hemibody irradiation, and pain recurrence was lower than that reported in an earlier uncontrolled study of the palliative effects of local radiotherapy (Tong, Gillick, and Hendrickson, 1982). This analysis is consistent with other reported studies of hemibody irradiation in which 50 percent of patients report at least partial pain relief within 48 hours of treatment with an eventual total response rate of 55 to 100 percent (Kuban, Schellhammer, and el-Mahdi, 1991;Salazar, Rubin, Hendrickson, et al., 1986).

Radiopharmaceuticals.Several radiopharmaceuticals have been used therapeutically. Iodine-131, used for the treatment of multiple bone metastases from thyroid cancer, results in bone scan evidence of response in 53 percent of patients (Maxon and Smith, 1990). Phosphorus-32-orthophosphate has provided partial or complete relief of pain in about 80 percent of patients with bone metastases from breast and prostate carcinoma ( Silberstein, Elgazzar, and Kapilivsky, 1992). In an analysis of 18 published studies, strontium-89 was found to provide partial to complete pain relief for 65 percent (Silberstein, unpublished manuscript). For example, Silberstein and Williams, (1985)) reported a palliative response of 51 percent of patients, and Robinson, Spicer, Preston, et al. (1987) reported 80 to 89 percent palliative response. In these studies, analgesic use and activities of daily living were used as measures of palliation. Myelosuppression, manifested by approximately a 30 to 50 percent decline in leukocyte and platelet levels within 4 to 6 weeks, generally occurs in patients with either extensive disease or pretreatment peripheral cytopenia (Lewington, McEwan, Ackery, et al., 1991). Rhenium-186 and samarium-153 phosphonate chelates have demonstrated 65 to 80 percent efficacy in international clinical trials, with FDA approval pending (Maxon, Schroder, Thomas, et al., 1990;Turner, Claringbold, Hetherington, et al., 1989). These beta-emitting radiopharmaceuticals, which require only a single intravenous injection, are used to relieve pain from widespread, osteoblastic skeletal metastases visualized with bone scintigraphy. If pain recurs, 50 percent of patients will respond to a second administration.

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Plexopathy

Painful nerve compression or infiltration by a malignant tumor can sometimes be alleviated by radiation therapy. These primary tumors often require fractionated radiation therapy over 5 to 7 weeks in an attempt to secure local or regional control of the disease. Dosage is limited by the proximity of the tumor to radiosensitive structures, such as the spinal cord. Peripheral nerves, however, can tolerate higher doses.

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Other Therapeutic Applications

Palliative radiation can be administered to any location of symptomatic primary or metastatic disease. Aggressive, sometimes protracted multimodality therapy may be given to patients with certain primary tumors, such as soft tissue sarcomas and carcinomas of the breast, lung, and rectum, to relieve both symptoms and to achieve control of advanced disease. Palliative radiation may also be given to metastatic lesions involving the brain, eye, skin, and soft tissue. Localized radiation may be used to treat lymph node involvement causing symptoms due to pressure on adjacent nerve roots and blood vessels. Intra-abdominal tumors may infiltrate the retroperitoneum and adjacent nerve roots or may cause local symptoms such as bowel obstruction. Although limited by the tolerance of the bowel to radiation, some tumor regression and symptomatic relief may be accomplished through fractionated radiation. Because the radiation tolerance of normal liver or kidney is even lower than that of bowel, treatment of pain due to capsular distention of either organ is rarely undertaken. Radiotherapy is generally not administered in these cases unless a trial of analgesic therapy and, when appropriate, chemotherapy has been unsuccessful. Symptomatic bleeding from endobronchial, cervical, and bladder tumors can often be stopped by external beam irradiation.

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Brachytherapy

Brachytherapy involves the placement of a radioactive source within tissue to deliver localized radiation and is frequently applied to treat recurrent disease in an area previously treated by external beam radiation. Advantages include the sparing of critical structures close to the tumor, and brevity of treatment (hours to days). Difficulties primarily involve anatomic constraints on implant placement. Common applications include the endoluminal treatment of recurrent endobronchial and bile duct tumors, the intracavitary treatment of cervical and endometrial cancer, and interstitial implants in unresectable tumors with catheters or radioactive seeds. Occasionally, hyperthermia will be combined with either brachytherapy or external beam irradiation to relieve pain and other symptoms of recurrent disease originating from head and neck or breast cancers.

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Anesthetic Techniques

Nerve Blocks

The possibility of controlling otherwise intractable pain by the relatively brief application of a local anesthetic or neurolytic agent makes neural blockade an attractive approach in selected patients. Published estimates of the percentage of all patients with cancer pain for whom nerve block procedures may appropriately be considered vary greatly. Variability in this estimate reflects evolution of the effectiveness of noninvasive therapies, interinstitutional differences in availability of clinicians with the necessary expertise, and access to alternative options such as spinal opioid therapy or neurosurgery (Bonica, Buckley, Moricca, et al., 1990). Allowing for vagueness in methods of arriving at published estimates, lack of uniformity in clinical conditions treated by neural blockade, and in reported clinical outcomes, it still appears that some 50 to 80 percent of patients who receive nerve blocks for cancer pain may benefit (Cousins and Bridenbaugh, 1987;Patt, 1993;Raj, 1992)(Table 19).

Local anesthetic such as lidocaine or bupivacaine is typically applied at an anatomically defined site to provide diagnostic information (e.g., whether the pain is somatic or visceral; whether it has a sympathetic mechanism). Prognostic injection assesses side effects such as hypotension and subjective sensations, including pain relief or unpleasant numbness, likely to result from a planned neurodestructive procedure. Although the lack of a desirable result from local anesthetic injection after proper needle placement generally predicts the failure of a neurolytic block, a promising result after local anesthetic injection does not guarantee the success of subsequent chemical destruction.

Therapeutic injections of a local anesthetic may provide relief that outlasts its pharmacologic action. Prolonged benefit may follow injection of trigger points for myofascial pain -- a procedure sufficiently simple, safe, and efficacious that it can be accomplished by many primary care providers. The injection of an anti-inflammatory corticoid with a local anesthetic into the spinal space or around nerve roots can reduce edema and irritation produced by tumor compression and provide analgesia for days to weeks. One or more cervical or lumbar sympathetic blocks may result in prolonged relief in patients whose cancer-related pain is sympathetically maintained. Sympathetic block performed during acute herpes zoster infection can immediately decrease pain, hasten resolution, and avert the development of postherpetic neuralgia, and should be considered as preemptive therapy for this debilitating sequel (Ferrer, 1989). The simpler technique of subcutaneous infiltration with local anesthetic and corticoid has also been reported to provide symptomatic relief for herpes zoster. When single sympathetic blocks produce only transient benefit, the placement of a catheter at the sympathetic ganglion (or the corresponding intraspinal segments or interpleural space) to enable continuous sympathetic blockade for days to weeks may produce sustained benefit.

Patient selection and timing of neural destruction for pain relief are based on the exhaustion of more conservative modalities, a lack of available, clinically superior options, and the availability of capable physician and support systems after the procedure. Nondestructive analgesic infusion techniques can preempt the need for neurolytic procedures. Therapeutic choices depend on patient and family preferences and the clinical judgment of their health care providers (Verrill, 1990).

Peripheral nerve destruction can be accomplished by the injection of ethanol, phenol, or other neurolytic agents at sites where a previous test injection of local anesthetic has produced pain relief. Whereas phenol induces warmth and then numbness, alcohol produces intense transient burning after injection and hence should be immediately preceded by local anesthetic injection. Small volumes of alcohol or phenol may be injected intrathecally to destroy nerve root function in a localized distribution. Approximately 60 percent of patients treated with intraspinal alcohol or phenol experience complete or near-complete relief of pain until death (Rodriquez-Bigas, Petrelli, Herrera, et al., 1991). When a patient is painfree after neurolysis, opioids should not be stopped abruptly, lest a withdrawal syndrome be provoked. Complications including paresis, paralysis, and bowel or bladder dysfunction affect 0.5 to 2 percent of patients treated with intraspinal alcohol or phenol ( Gerbershagen, 1981). An epidural injection of phenol (or alcohol, according to some reports) can accomplish the same goal; however, the targeting of the injectate is less precise, the neurolytic effects take place over a more diffuse area than that affected by the intrathecal route, and the technique is less well established than intrathecal injection (Salmon, Finch, Lovegrove, et al., 1992).

Neurolytic sympathetic blockade is useful to relieve pain in the arm, head and neck (stellate ganglion), or leg (lumbar sympathetic block), as well as to interrupt the visceral afferent pain pathways mediating pain in the pancreas and other upper abdominal organs (celiac block) or in the pelvis (hypogastric block). Side effects of celiac block include transient hypotension and diarrhea; complications (less likely with radiologic guidance) include paraplegia or less severe radicular weakness or numbness, intrarenal injection and damage, retroperitoneal hematoma, and failure of ejaculation (Ischia, Ischia, Polati, et al., 1992;van Dongen and Crul, 1991). Four-fifths or more of patients with pancreatic or other abdominal cancers derive pain relief from celiac block, usually lasting until death (Brown, Bulley, and Quiel, 1987;Eisenberg, Carr, and Chalmers, unpublished manuscript;Mercandante, 1993). Even when relief is incomplete, patients may appreciate the ability to lower their opioid dosage and by doing so reduce drowsiness and constipation. It thus appears reasonable to consider early celiac neurolytic block for patients with a short life expectancy and pain from pancreatic cancer (Mercadante, 1993). A recently reported technique for refractory chest wall tumor pain is interpleural blockade, which uses long-term local anesthetic infusion or single-dose phenol (Lema, Myers, de Leon-Casasola, et al., 1992).

Neurolytic blockade of peripheral nerves should be reserved for instances in which other therapies (palliative irradiation, TENS, pharmacotherapy) are ineffective, poorly tolerated, or clinically inappropriate. Suitable targets for this approach include intercostal nerves at the site of painful tumor, after maximal doses of radiation and systemic analgesics, or nerves of the head and neck (e.g., gasserian ganglion). Pain recurrence due to neuritis is common because an alcohol-damaged nerve regenerates over weeks to months. If the mechanism of pain is partial or complete denervation, this will not be corrected (and may potentially be worsened) by further chemical damage to the nerve.

Pain that is diffuse (e.g., from multiple bony metastases) may respond to chemical ablation of the pituitary, which is accomplished by alcohol administered through a needle advanced transnasally until its tip rests in the pituitary fossa (see also Neurosurgery, below). Pain relief by this intervention may be rapid and striking, while ascending nociceptive pathways remain unharmed. Pain relief has been reported in about two-thirds of patients, whether or not the primary tumor is hormone dependent (Takeda, Fujii, Uki, et al., 1983). Complications include headache, persistent leakage of CSF, coma, and cranial nerve palsies, all of which occur at a frequency of 5 percent or less (Cook, Campbell, and Puddy, 1984). Diabetes insipidus is a predictable side effect of complete pituitary ablation.

Technical aspects of the above procedures are beyond the scope of this guideline and are well described in a number of recent monographs (Abram, 1989;Charlton, 1986;Cousins and Bridenbaugh, 1987;Swerdlow, 1987). Complications associated with local anesthetic nerve blocks, catheter implants, neurostimulator implants, thermal ablations, and neurolytic injection have been reported (Cousins and Bridenbaugh, 1987;Melzack and Wall, 1990;Raj, 1992). Serious side effects including hemorrhage, infection, unexpected nerve damage, pneumothorax, and cardiorespiratory arrest are rare but nonetheless mandate resuscitative skills and close short-term followup.

Because of the appeal of nerve blocks for use in intractable pain and their potential for harm as well as benefit, clinicians should:

Assess thoroughly each patient's pain mechanism, in order to apply the most appropriate block.
Screen patients according to coexistent medical conditions (e.g., coagulopathy); ability to understand risks of the proposed procedure (e. g., paresis or incontinence); and ability to cooperate during the procedure (e.g., not move).
Consider a block only if the person planning to do it is experienced and skillful; prepared to deal with its immediate effects and side effects (e.g., hypotension, respiratory depression, or paralysis); and able to provide followup assessment and treatment.
Use radiographic control for blocks when ease and safety depend on the precise identification of landmarks.

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Bone Pain