Chapter 44. Cancer Pain Syndromes

Pain in cancer patients has numerous possible causes. The vast majority of pain syndromes are caused by direct tumor involvement of pain-sensitive structures, a smaller number are treatment-related, and fewer than 10% are unrelated to the cancer. Metastatic disease may invade bone, obstruct a hollow viscus, and compress nerve or spinal cord. Radiation treatment may cause fibrosis of nerve or spinal cord. Chemotherapeutic agents may cause peripheral neuropathy, aseptic bone necrosis, and predispose to painful opportunistic infections. Surgical treatment leads to acute postoperative pain, and may cause deafferentation pain if major nerves or nerve plexi are cut. In any given patient, one or more of these factors may be in play, and more than 50% of cancer patients with pain have more than one source of pain.1

Primary care physicians and oncologists should be able to recognize and treat most of cancer-related pain. They should be able to initiate treatment for the more common causes with opioids and non-opioid analgesics. More than 70% of patients can be treated effectively with simple analgesics and adjuvant drugs. Effective pain relief, without intolerable side effects, is occasionally difficult to obtain with the use of conventional analgesics. When this occurs, consultation with a specialist in pain management may be necessary.

Daut and Cleeland found that while 36% of 286 patients with nonmetastatic cancer reported pain, 59% of 381 with metastatic disease did.2 Cleeland and colleagues found that 67% of 1308 outpatients with metastatic cancer had pain, and 62% of those had severe pain. Thirty-six percent reported disability due to pain, and 42% of those with pain reported inadequate analgesia.3 Terminal pain, refractory to escalating opioid administration, is a more challenging problem. Depression, uncontrolled pain, the adverse effects of opioids, and fear of pain may precipitate suicidal thoughts or requests for aid in dying.4,5 Pain also adds to the discomfort experienced by those caring for the dying patient.

The likelihood of pain associated with cancer depends on the type and stage of disease. Foley, in a 1-week survey of 540 patients hospitalized at Memorial Sloan-Kettering Cancer Center, showed that the prevalence of pain requiring analgesic drugs varies by cancer type (Table 44-1).6 In contrast, among 1308 outpatients with metastatic cancer, Cleeland and colleagues did not find variation in pain prevalence according to cancer type.3

Pain can be divided into three pathophysiologic categories: somatic nociceptive, visceral nociceptive, and neuropathic, on the basis of the inferred mechanisms of pain (See Chapter 3, Pathophysiology of Pain). It is useful to characterize pain in this way, because the approach to treating each type is somewhat different. However, they are not mutually exclusive, and cancer patients, in particular, may have pain with multiple causes. The mechanisms of each type are the subject of considerable ongoing research.

Somatic Nociceptive Pain

This is the typical pain that we all have experienced acutely or chronically: the cutaneous burn and arthritic joint are examples. The painful site is tender and corresponds to the site of tissue damage. Somatic pain is described as constant, and sometimes throbbing or aching. Bone metastases are the most common malignant cause of somatic pain and, in fact, are the most common source of pain in cancer.7

Noxious (potentially tissue-damaging) mechanical, thermal, and chemical stimuli trigger nociceptive ischemia, inflammation, and perhaps substances produced by a nearby tumor may sensitize nociceptors to ordinarily non-noxious stimuli. Pain signals are carried by small, myelinated Aδ fibers (mechanical and thermal stimuli) and unmyelinated C fibers (all three stimulus types) to the dorsal horn of the spinal cord. From there, they ascend in the contralateral spinothalamic and spinoreticular tracts to the thalamus and reticular formation, respectively (See Chapter 2, Anatomy and Physiology of Pain). Although most research into nociceptive mechanisms has focused on cutaneous pain, nociceptors exist in most tissues to varying degrees.

Visceral Pain

Pain originating from the viscera is familiar to many of us: abdominal cramps and the pain of passing a renal stone are examples. It may be less constant than somatic pain, occurring in dull, colicky waves. Visceral pain is poorly localized, and often referred to a distant cutaneous site, which may be tender. Unlike somatic pain it is often associated with nausea and diaphoresis. Cancer patients experience primary and referred visceral pain from pancreatic cancer, bowel obstruction, and other causes.

The mechanisms of visceral pain transduction and transmission are not well characterized. Visceral autonomic afferents may by involved.8 The noxious stimuli required to trigger visceral pain include ischemia, inflammation, torsion, traction, distension, and impaction. In fact, cutting, crushing, and burning may not be felt as painful.9 Pain referral is poorly understood, but may involve convergent somatic and visceral nociceptive input in the dorsal horn.10 This hypothesis explains the cutaneous sensation of visceral pain in a dermatome corresponding to the innervation of the affected organ, for example, diaphragmatic irritation felt in the shoulder.

Neuropathic Pain

In everyday life, chronic neuropathic pain is uncommon. However, acute and transient neuropathic pain is felt whenever the “funny bone” is struck, or an extremity “falls asleep” from pressure. Perhaps the most frequent nonmalignant chronic neuropathic pain is that produced by nerve root compression from a herniated intervertebral disk. Neuropathic pain is often described as prolonged, severe, burning, lancinating, squeezing, and is often associated with focal neurologic deficits. It is usually constant, but may be interrupted by paroxysms of dramatically increased pain. There may be no area of tenderness, or areas of exquisite sensitivity to normally innocuous stimuli (allodynia). Symptoms and signs of autonomic instability may accompany neuropathic pain. The clinical hallmarks of neuropathic pain are spontaneous pains and painful responses to non-noxious stimuli. Neuropathic pain is also characterized by its relative resistance to opioids, making it the most challenging of pain conditions to treat.11 Cancer patients experience neuropathic pain from a variety of causes. Direct infiltration of neural structures by tumor is the most common, but iatrogenic causes, such as radiation fibrosis and surgical injury, also occur.

Injury to any part of the nervous system, whether central or peripheral, may result in neuropathic pain. A number of theories have been advanced to explain both peripheral and central mechanisms for maintaining the perceived pain. In the periphery, C fibers may become sensitized by direct injury or by ongoing nociception from injured tissues. This sensitization would make them susceptible to stimuli that are not normally perceived as painful, including sympathetic discharges.12,13 Two other peripheral mechanisms include neuroma formation (in which an injured nerve’s attempt to regrow results in an overly sensitive, disordered jumble of fibers), and abnormal foci of sensitivity along the course of a nerve, resulting in ephaptic transmission (cross talk) or ectopic discharges.14,15

Regardless of the initial site of neurologic injury, the central nervous system probably plays a significant role in maintaining the pain syndrome. Increased sensitivity to peripheral stimuli can be demonstrated in the dorsal horn of the spinal cord, as can spontaneous activity. This spinal cord hypersensitivity could explain both the spontaneous pain and the allodynia felt in neuropathic pain syndromes.

Most pain syndromes in patients with advanced cancer are caused by direct tumor invasion of pain-sensitive structures. The specific pain syndrome depends more on the type of structure involved (e.g., bone pain, visceral pain, mucosal irritation) than on the causative tumor. Similarly, though less commonly, the injury is iatrogenic from diagnostic, surgical, chemotherapeutic, and radiotherapeutic interventions. In many patients, pain has multiple causes. Since increasing pain may signal advancing disease, determining its cause is important.16 In addition, knowing the cause of pain assists in selecting the most appropriate analgesic approach. The following are several common, recognizable painful conditions that occur in cancer patients. They are grouped according to the type or location of pain.

Bone Pain

Tumor involvement of bone is the most common cause of cancer pain.7 Any tumor may involve bone, but the most common include metastatic cancer of the breast, lung, prostate, and thyroid, and multiple myeloma.1 This is purely somatic pain, unless pathologic fracture or tumor extension disrupts nerve. As such, pain is usually described as focal and constant, but may be referred. Typically, patients experience several days or weeks of increasing pain. Acutely increased bone pain may signal fracture or neural impingement. Tumors may activate nociceptors by pressure, ischemia, or secretion of algesic substances (e.g., prostaglandin E2, osteoclast activating factor).17 Most pain is probably sensed in periosteum and synovium; these are quite sensitive to surgical manipulation. Common sites of bony metastasis are the vertebral column, skull, humerus, ribs, pelvis, and femur.6

Diagnosis of bony metastases in known cancer patients may be made by plain x-ray when tumor involves the cortex. A computed tomography (CT) scan further defines the morphology of bone lesions that are seen on x-ray films. When the radiography is normal, radionuclide scintigraphy (bone scan) may identify osteoid formation in the marrow, before cortical destruction has occurred. Even in predominantly osteolytic tumors, some reactive osteoid formation usually occurs, and the bone scan is positive (Table 44-2).18 A bone scan, however, is often normal in purely lytic tumors, such as multiple myeloma, and in previously irradiated bone. Furthermore, it lacks the anatomic detail of x-ray film. Magnetic resonance imaging (MRI) is more sensitive than x-ray and bone scan, and can identify bony metastases in previously irradiated bone.6 MRI is not used as the initial diagnostic tool because it is expensive, time-consuming, and often not immediately available.

Other forms of bone pain in cancer are iatrogenic: avascular necrosis of the femoral and humeral heads from steroid treatment, osteoradionecrosis following radiation treatment, and pseudorheumatism from steroid withdrawal. X-ray films do not confirm avascular necrosis for several weeks or months after the onset of pain, whereas a bone scan is more sensitive.6 Osteoradionecrosis usually occurs in the mandible, and may develop months or years after irradiation. It must always be distinguished from recurrent tumor, radiation-induced sarcoma, and osteomyelitis.19 Reinstitution of steroid treatment, followed by slow withdrawal, confirms the diagnosis of pseudorheumatism by relieving the arthralgias and myalgias.6

Back Pain

The vertebral column (particularly the thoracic spine) is the most common site of bony metastasis.20 Although cancer causes less than 1% of back pain in the general population, 98% of known cancer patients who present with back pain have underlying malignancy.21 Up to one third of cancer patients develop metastases to the spine, with prostate, breast, thyroid, and lung cancers being most common.20,22 Because back pain in cancer patients usually signifies bone or epidural metastasis, aggressive investigation to define the presence and extent of tumor is necessary. Left untreated, metastases destabilize the axial skeleton and encroach on the spinal cord or cauda equina.

Investigation of back pain should begin with a detailed history and physical examination, attending to the presence of rapid pain progression, referral patterns, and neurologic symptoms and findings. Points that should raise the suspicion of epidural disease include failure of pain to resolve with recumbency, point tenderness of the spine on examination, and, of course, any history of bowel or bladder dysfunction or focal neurologic deficit.

Vertebral disease at certain levels of the spine may initially have a confusing presentation. High cervical spine metastases may produce only posterior headache, which could be mistaken for tension headache. Involvement of C7-T1 causes pain in the interscapular region. Lesions of T12 or L1 may refer pain to the flank, iliac crest, or sacroiliac joint. Sacral destruction may refer pain in a saddle pattern.1 Radiation myelopathy causes local burning pain, which radiates bilaterally, and progressive neurologic deficits.23

Stable back pain in cancer patients, without neurologic symptoms or signs, warrants nonurgent x-ray films of the affected area. Radiographs will detect approximately 70% of vertebral tumors.21 If plain films are normal, radionuclide bone scan is indicated, because it has a higher sensitivity than radiography for early osteoblastic lesions, fractures, and infection. If x-ray or bone scan is positive or equivocal, MRI should be performed to detect or define the extent of disease, especially that involving soft tissue.18 If both x-ray and bone scan are normal, CT or MRI of the paraspinal and retroperitoneal areas is warranted to detect a source of referred or extraaxial soft tissue pain.

MRI is always the test of first choice when there is evidence of neural compression, and should be completed urgently if cord compression is suspected. MRI is sensitive for early metastases, easily images the entire spine in one scan (unlike CT), and accurately defines the extent of adjacent soft tissue disease.18 CT with myelography may be used when MRI is not available.

Even when there is no evidence of neural compression by history or physical examination, radiologic evaluation should not be delayed for more than several days if back pain is positional or progressing. Unstable vertebral fractures may lead to acute cord compression and may require prophylactic stabilization or irradiation.24

Some patients with back pain due to epidural malignancy do not have vertebral metastases. Tumor may reach the epidural space by hematogenous spread or by direct extension along nerves, through the intervertebral foramina. MRI should be completed when radiologic evaluation and bone scan are negative if radiculopathy, plexopathy, or myelopathy develops.22,25 Other patients with back pain in the absence of vertebral disease may have leptomeningeal carcinomatosis (LM). They have signs of neurologic dysfunction at several levels, and usually complain of headache, nausea, and nuchal rigidity, but may also have lumbar radicular pain.23 Contrast-enhanced MRI of the entire spine and head, followed by lumbar puncture, is appropriate when LM is detected. LM may require treatment with radiation, steroids, or intrathecal chemotherapy.

Loss of motor function, hyper- or hyporeflexia and bowel or bladder disturbances are suggestive of myelopathy. Their presence should prompt immediate intervention, even before diagnostic imaging has been obtained, to prevent permanent neurological impairment (Fig. 44-1). Even in the absence of myelopathy, certain situations require urgent radiologic evaluation. Rapidly progressing pain is highly suspect for tumor, and should be investigated until the extent of disease is known. Increased pain when supine or erect may signal positional cord compression, which will progress to overt myelopathy unless treated. In these situations, MRI of the entire spine should be performed to define the extent of disease and the threat to neural tissue.26

Brachial Plexopathy

Brachial plexopathy is a common neurologic complication of cancer.23 Metastatic brachial plexopathy (MBP) and radiation-induced brachial plexopathy (RBP) are the most likely culprits when shoulder and arm pain are present in the cancer patient. The differential for arm pain includes cervical radiculopathy, osteoarthritis, bursitis of the shoulder, and myofascial pain. Less common cancer-related causes are iatrogenic plexus injury during surgery or central venous catheter placement, chemotherapeutic neurotoxicity, and secondary plexus tumors following radiation.27

MBP, also called Pancoast syndrome and thoracic inlet syndrome, presents in 2% to 9% of patients with lung and breast cancer,28,29 and is also seen in lymphoma, thyroid cancer, and others.27 Tumor may spread to the plexus from the apex of the lung or from nearby lymph nodes. Differentiating MBP from RBP may be difficult when a patient has received radiation (Table 44-3). MBP typically presents with neuropathic pain in the ipsilateral shoulder or arm, which is rapidly progressive. Although both conditions may eventually involve the entire plexus, selective lower plexus involvement implies MBP, and upper plexus involvement occurs with RBP. The time from cancer diagnosis to presentation (3 to 6 years) is similar for MBP and RBP in patients who have received radiation.27 Horner’s syndrome is much more likely in MBP than RBP, and is highly associated with epidural tumor spread, which occurs in 25% of MBP patients, often without abnormalities on x-ray film, bone scan, or myelogram.30 MRI is more sensitive than myelography for epidural disease, and should be used in the evaluation of patients with cancer and brachial plexopathy (Fig. 44-1).25,31

Olsen and colleagues found that 14% of 128 breast cancer patients receiving surgery and radiation developed RBP. The addition of cytotoxic chemotherapy increased the likelihood of RBP. Forty-seven percent of the RBP patients had pain.32 The dose of radiation may also affect the incidence of RBP, as does treatment technique. RBP is associated with progressive fibrous constriction of nerve bundles, thickening of endoneurium, loss of myelin, and obliteration of small blood vessels. Initial symptoms of RBP are paresthesiae, numbness, heaviness, weakness, and swelling. Pain is a presenting symptom in 18%, and becomes a major symptom in 35%. Sensory and motor loss progress gradually, eventually rendering the arm useless. Reversible radiation-induced plexopathy has been reported in conjunction with chemotherapy for breast cancer. This entity presents earlier than RBP, rarely causes pain or weakness, and resolves in time.33

MRI is the best imaging modality to differentiate MBP from RBP.31 If MRI is not available, however, computed tomography should be performed with intravenous contrast. An electromylogram (EMG) of the affected arm and shoulder muscles shows fibrillation potentials and myokymia in RBP, but not in pure MBP. However, patients with brachial plexus tumor may also have some radiation fibrosis, so EMG cannot rule out MBP. Biopsy also may confirm fibrosis or tumor, but cannot rule out either one. When pain presents many years following radiation in a patient who was thought to be free of cancer, MRI and biopsy should be utilized to rule out radiation-induced secondary neoplasm.1

Lumbosacral Plexopathy

Pelvic tumors may invade or compress the lumbar and sacral plexuses to produce pain, bowel and bladder dysfunction, and leg weakness. Jaeckle and colleagues studied 85 patients with pelvic tumor and low back or leg pain.34 The most common primary tumors were colorectal, uterine, cervical, breast, sarcoma, and lymphoma. Seventy percent presented with pain, and 98% eventually developed pain, which was aching and pressure-like. Pain was local, radicular, or referred, and a combination of local and radicular was common. Two thirds developed weakness, and one half developed sensory symptoms. Twenty-seven percent had bilateral plexopathy. Epidural extension was detected in 35% of patients. Radiation-induced lumbrosacral plexopathy (LP) is rare, and, as in RBP, sensory and motor symptoms commonly precede pain; approximately one half of patients never develop pain. Plexopathy follows radiation by an average of 5 years, but there is a considerable range. Symptoms are usually bilateral, but asymmetric.35

Diagnosis of LP starts with a history of unilateral or bilateral pain or weakness in the low back, abdomen, perineum, or leg. Bowel and bladder function may be spared when only the upper plexus is involved. Involvement of the lower lumbosacral plexus (sciatic nerve), occurring in one half of patients resembles sciatica from a herniated intervertebral disk, with a positive straight leg raising test and tenderness in the sciatic notch. Upper plexus involvement, occurring in one third of patients, produces tenderness in the lumbar region.34 Lower (sacral) plexopathy results in urinary incontinence, sexual impotence, and neuropathic perineal and genital pain. Radiologic evaluation of LP begins with MRI or contrast-enhanced CT of the lumbosacral spine. If these are negative, an extraaxial pain source is sought (see Fig. 44-1). If the history suggests radiation fibrosis of the plexus, EMG to detect fibrillation potentials and myokymic discharges is useful but does not rule out tumor as the cause of LP.35

Cervical Plexopathy

Injury to the cervical plexus, whether from tumor or surgery, causes pain in and around the ear or in the anterior neck to the clavicle. The phrenic nerve may also be paralyzed. Horner’s syndrome is seen if the superior cervical ganglion is affected. The differential includes disease of the upper cervical spine and the base of the skull.23 In a patient who has had surgery in the area, Horner’s syndrome, phrenic nerve paralysis, and signs of cervical myelopathy or contralateral radiculopathy should suggest recurrent tumor. In such patients, and in those who have not had neck surgery, MRI with contrast is indicated to define the extent of disease.

Headache and Facial Pain

Headache occurs in about 60% of patients presenting with primary brain tumors, and is the presenting symptom in 50% of patients with cerebral metastases (See also Chapter 19, Pathophysiology of Headaches). It is usually of mild or moderate intensity, similar to a tension-type headache. Only 25% of patients have awakening or morning headaches. Cancer patients with new headaches or a change in headache pattern should be investigated for cerebral metastases. Neurologic signs are more common than neurologic symptoms in these patients. Weakness is a presenting symptom in approximately 30%, but a hemiparesis can be found in about 60%.36 Papilledema is surprisingly uncommon, appearing in only 25%, so its absence should not be taken as reassuring. Investigation of the suspicious headache should include MRI or CT, both with intravenous contrast. MRI is more sensitive, especially for skull base and posterior fossa tumors, and delineates the extent of disease more precisely than CT. Initial management is with corticosteroids, followed by antitumor therapy and/or symptomatic treatment.37 Brain tumor headache characteristically responds rapidly to the administration of corticosteroids.

Not all headaches in patients with cancer are due to cerebral metastases. Leptomeningeal metastases cause headaches that are commonly associated with radicular or cranial nerve findings. Multiple metastases, posterior fossa metastases, and leptomeningeal carcinomatosis are the most frequent intracranial causes of head pain. Other cancer-related causes include ischemic or hemorrhagic stroke, pseudotumor cerebri from superior vena cava syndrome, and sagittal sinus occlusion by tumor or thrombus.23 Fever and migraine are the most common noncancer causes of headaches in patients with cancer.

Cancer is a rare cause of facial pain. Extracranial bony or soft tissue metastases may impinge on cranial and upper cervical nerves, causing headache or facial pain. Pain in these cases is usually unilateral, and may be accompanied by focal tenderness. Glossopharyngeal neuralgia may be seen in patients with leptomeningeal metastases, jugular foramen invasion, or more peripheral primary head or neck malignancies. Pain occurs in the pharynx and base of the tongue, and sometimes around the ear. Pain in the trigeminal distribution has been described with middle and posterior fossa tumors, skull base metastases, and with lymphomatous meningitis.23 Of 2,972 patients with a diagnosis of trigeminal neuralgia at the Mayo Clinic, 10% were found to have tumors, the majority of which were benign.38 Unilateral facial pain has been described as a presenting symptom of ipsilateral nonmetastatic lung cancer. It is typically severe, around the ear and temple, and resolves with radiation of the tumor. It probably occurs when tumor invades the vagus nerve.39

Metastases to the base of the skull produce distinct patterns of head and facial pain.23,37 Breast, lung, prostate, and nasopharyngeal tumors are common primaries. A tumor in the orbit produces progressive pain in the supraorbital area, proptosis, and external ophthalmoplegia. A parasellar tumor may present with unilateral supraorbital and frontal headache with diplopia. Middle fossa tumors often present with pain and sensory changes in the mandibular and maxillary trigeminal distributions, which may be followed by headache, diplopia, dysarthria, and dysphagia. Tumor invading the jugular foramen affects the glossopharyngeal, vagus, and accessory nerves to cause throat pain, hoarseness, dysphagia, and weakness of the sternocleidomastoid and trapezius muscles. Involvement of the occipital condyle causes occipital pain and neck stiffness with associated hypoglossal nerve paralysis. Metastasis to the clivus presents with vertex headache, worse with neck flexion, and eventual lower cranial nerve dysfunction. Sphenoid sinus tumor may cause bifrontal headache radiating to the temples and retro-orbital areas, sometimes with abducens nerve palsy. Fracture of the odontoid process (dens), pathologic or not, causes posterior headache with increased pain on neck flexion. The resulting cervical spine instability or mass effect from such a tumor may cause spinal cord or brain stem compression.

Peripheral Neuropathies

Peripheral neuropathies in cancer can be divided into mononeuropathies and more symmetric polyneuropathies. Any nerve may be directly affected by tumor, but radicular pain and intercostal entrapment from rib metastasis are the most common.23

The most common symmetric polyneuropathies are paraneoplastic syndromes and those resulting from chemotherapy. One paraneoplastic syndrome associated with oat-cell lung cancer, breast, colon, and ovarian cancers is a painful sensory neuropathy. It is characterized clinically by tingling, burning, and lancinating pains in the extremities. Pathologic examination reveals an inflammatory process in the dorsal root ganglia, followed by loss of peripheral myelinated and unmyelinated fibers.40 This syndrome may be a presenting feature of the cancer. Multiple myeloma is commonly associated with a painful sensorimotor neuropathy that responds to tumor therapy.23 Ovarian, lung, and breast cancer may also cause sensorimotor neuropathy as they progress.41,42 In these cases, segmental demyelination and axonal degeneration are seen histologically.40

Chemotherapy often produces a painful peripheral neuropathy with dysesthesias. The vinca alkaloids and cisplatinum are most commonly to blame, and symptoms are dose-related and often irreversible. Burning in the feet and hands and vibratory and proprioceptive deficits are characteristic.23,43

Painful varicella-zoster reactivation causes a dermatomal rash and neuropathic pain. It occurs two to three times as frequently in cancer patients as in the general population. Lymphoma and breast cancers cause a disproportionate number of cases. The dermatome involved is likely to correlate with the site of primary tumor in breast, lung, and gynecologic cancer.44 Advancing age, the severity of the initial rash and pain, and an ophthalmic distribution predispose to the later development of postherpetic neuralgia. Cancer does not appear to increase the likelihood of postherpetic neuralgia when age is accounted for.45 A thorough review of zoster and related pain is provided in another chapter (See Chapter 40, Acute Herpes Zoster and Postherpetic Neuralgia).

Abdominal and Pelvic Pain

In a review of 5675 patients presenting with acute abdominal pain to a group of five European hospitals, 106 (1.9%) were eventually found to have intraabdominal cancer. The risk of cancer for those over 50 years old was 10%.46 Abdominal pain from cancer is typically visceral in nature. As such, it is poorly localized and often referred to distant sites, and often accompanied by nausea and vomiting. Diaphragmatic irritation and distension of the hepatic capsule produce ipsilateral shoulder pain, retroperitoneal tumor may cause back pain, and pelvic tumor may cause perineal pain. Viscus or duct blockage and distension, peritoneal inflammation or tension, mesenteric torsion, and vascular or lymphatic obstruction typically produce pain. Pelvic cancer pain occurs primarily in patients with malignancies of the rectum and genitourinary tracts. Extra-abdominal cancers also often metastasize to the sacrum and pelvis.

Abdominal pain not directly caused by intraperitoneal or retroperitoneal malignancy is also common. Radiation-induced enteritis occurs in acute and chronic forms. Acute injury manifests as abdominal or pelvic pain, diarrhea, or tenesmus in up to one half of patients. Chronic injury, occurring in 2% to 5% of patients, presents as stricture, bleeding, perforation, or fistula 6 to 24 months after radiation. Pain may be associated with bowel ischemia, obstruction, or intraabdominal infection in patients with chronic enteritis.47 Pain may radiate or refer to the abdomen from destructive low thoracic and high lumbar spine disease and nerve root compression. Following abdominal surgery for cancer, adhesions may form and cause painful bowel obstruction.

Pain from pancreatic cancer is of particular interest because of its frequency, severity, and amenability to celiac plexus block. Up to 80% of patients with this disease present with significant pain. With advanced disease, the figure rises to 90%, and probably represents gastric or retroperitoneal invasion. Most tumors are at the head of the gland, and may cause bile duct obstruction early in the disease. Pain from the pancreatic head localizes to the right epigastrium, whereas that from the body is felt in the mid-epigastrium, and tumor in the tail produces pain in the left epigastrium and posterior intercostal space.48

Mucositis

In about 70% of patients, chemoradiotherapeutic conditioning for bone marrow or stem cell transplantation causes noninfectious mucositis (stomatitis) by killing cells with high mitotic rates.49 Several days following conditioning, hemorrhagic degradation and ulceration of the oropharyngeal mucosa begins. While initially causing constant mild or moderate burning discomfort, the condition progresses to preclude talking, eating, or swallowing. Significant pain requiring opioid use persists in one half of patients at 3 weeks after transplant.50 Mucositis from head and neck radiation usually develops in the second or third week of therapy, affects almost all patients, and is otherwise similar to that from bone marrow conditioning. Normal doses of chemotherapeutic agents also cause mucositis in about 40% of patients.49 Pain may be more severe or prolonged when mucosal ulcers become superinfected with bacteria or fungus, and when graft-versus-host disease occurs. Reactivation of herpes simplex, cytomegalovirus, or varicella-zoster infections in the immunocompromised cancer patient may present with vesiculo-ulcerative mucositis.

Chronic Postsurgical Pain

Four postsurgical chronic pain syndromes have been identified. They result from injury to nerve or plexus, so the pain is neuropathic in nature.

Mastectomy

Burning, aching, and tight constriction of the axilla, medial upper arm, and chest with superimposed lancinations and scar sensitivity are characteristic of postmastectomy pain. Phantom breast pain is also described, and uncomfortable lymphedema of the arm is common. Whereas previously less than 10% of mastectomy patients were said to develop chronic pain,23 one half of 467 mastectomy patients recently surveyed went on to develop pain, paresthesias, and phantom sensations.51 Less extensive surgery was more often associated with pain in the ipsilateral arm. In fact, the radiation and chemotherapy that followed less extensive surgery were probably responsible for much of the arm pain. Progressive pain was more common in patients with recurrent disease.

Maunsell and colleagues studied arm symptoms in 223 women who underwent breast surgery with or without axillary dissection.52 About one half complained of arm pain at 3 months postoperatively, and a similar proportion at 15 months. Patients who had axillary dissection were more likely to have arm pain, although this result did not reach statistical significance. Wallace and colleagues also found that breast reconstruction with implants after mastectomy increases the likelihood of chronic pain from about 30% (mastectomy alone or with simple reconstruction) to 50%.53 Submuscular implant placement may injure the long thoracic, thoracodorsal, lateral pectoral, and medial pectoral nerves. Capsule formation around the implant may entrap the long thoracic and the two pectoral nerves.

Evaluation of chest and arm pain after mastectomy should focus on the nature of the pain and its location, as well as neurologic examination to define the areas of sensory loss and hypersensitivity. A neuroma is sought in the chest wall and axilla. Autonomic changes and limited shoulder motion may be present in the “frozen shoulder” syndrome. Scapular winging is seen when the long thoracic nerve has been disrupted. Pain that is not typical of postmastectomy pain syndrome should prompt evaluation for infection and tumor recurrence.

Neck Dissection

During radical neck dissection, the superficial cervical plexus is dissected out. The result is often neuropathic pain and sensory loss in the anterolateral neck and extending to the shoulder. Division of the accessory nerve and removal of the sternocleidomastoid muscle may also lead to chronic pain via postural changes that affect the shoulder girdle and entrap the upper brachial plexus.23 Loss of trapezius function leads to drooping of the shoulder, mild scapular winging, inability to abduct the shoulder above 90°, and forward rotation of the scapula, often with sternoclavicular subluxation (Fig. 44-2).54 Frozen shoulder often develops as a result of weakness and pain.55

Ewing and Martin described 100 radical neck dissection patients in 1952.54 Of 89 with unilateral operations, 42 patients had persistent shoulder pain. In two more recent studies, 76 of 100 radical neck dissection patients had shoulder pain and dysfunction when evaluated at least 6 months after surgery.57,58 In 31, the pain was severe. The deep cervical plexus innervates enough of the trapezius muscle to maintain shoulder mobility and prevent shoulder-arm pain in some patients.58 Any patient who has increasing pain following neck dissection should be evaluated for infection and tumor recurrence.

Thoracotomy

Chronic chest pain after thoracotomy affects up to 55% of patients followed for more than 1 year.59 Keller and colleagues reviewed the records of 238 consecutive thoracotomy patients.60 Post-thoracotomy pain was defined as that requiring regular use of analgesics beyond 3 months from surgery. Eleven percent of patients met this definition, but one half of these used opioid analgesics preoperatively. Chest wall resection and pleurectomy increased the likelihood of chronic pain when compared with pulmonary resection. Importantly, all 20 patients with recurrence of pain after initial control were found to have tumor regrowth. The use of video-assisted thoracic surgery (VATS) for pulmonary resection may decrease the incidence of chronic pain and disability when compared with thoracotomy.61

Mechanisms for chronic pain after thoracotomy are several. The intercostal nerves may be injured during rib resection, or compressed with a retractor. Incidental rib fractures may entrap an intercostal nerve during healing. These patients may develop dermatomal chest wall numbness and neuropathic pain complaints, including point tenderness from neuroma formation. Severe rib retraction may also disarticulate the costochondral and costovertebral junctions, resulting in somatic pain and tenderness. Because the latissimus dorsi and serratus anterior muscles are often cut during thoracotomy, ipsilateral shoulder disability is also common. Untreated thoracotomy pain and inadequate rehabilitation may lead to frozen shoulder. Symptomatic myofascial trigger points often develop in chest wall muscles. All patients with increasing or recurrent pain after thoracotomy should be evaluated for tumor and infection.60

Amputation

Chronic pain following limb amputation is either stump pain or phantom pain or both. Wartan and colleagues surveyed 590 war-related amputees in England to assess the prevalence of chronic pain.62 Of these, 55% reported phantom pain, and 56% had stump pain. Sherman and colleagues surveyed 5000 American veterans with amputations.63 Fifty-five percent responded, and 78% of those reported phantom pain. Stump pain is due to local disease, most commonly infection or neuroma formation. Neuroma formation several weeks after amputation produces exquisite stump tenderness and pain that is either constant or elicited by palpation or movement. An ill-fitting prosthesis, recurrent tumor, infection, or ischemia may also cause local pain and tenderness.64

Phantom sensation, the sensory experience that the amputated limb is still present, occurs in most amputees. Phantom pain is often described as a paroxysmal burning, crushing, and twisting in the missing part. Phantom pain peaks in the first month after surgery and may fade slowly as it “telescopes” toward the stump.63 It is more common after more proximal amputations.65 Patients with extremity pain prior to amputation are more likely to develop immediate postamputation phantom pain,66 and preemptive analgesia with lumbar epidural blockade may reduce the incidence of phantom pain.67

Numerous neurophysiologic explanations for phantom pain have been advanced, from changes at the stump to functional cortical changes. Sensory deafferentation in primates and arm amputation in humans causes cortical somatosensory reorganization.68 This may explain the elicitation of phantom pain by sensory stimulation at other sites. As with the other postsurgical pain syndromes, an unexpected increase in or recurrence of pain should prompt evaluation for infection, ischemia, or tumor recurrence.64,65

It is important to recognize that the experience of cancer pain is not merely physical. Cancer patients and those close to them suffer emotionally as well as physically. The way in which a patient and his or her family adjust to the experience of pain and dying markedly influences their perception of physical pain. Conversely, uncontrolled pain causes or contributes to anxiety, depression, and delirium in many cancer patients.69 Derogatis and colleagues evaluated 215 unselected cancer patients for psychiatric disorders. Forty-seven percent had a DSM-defined (Diagnostic and Statistical Manual of Mental Disorders) psychiatric disorder (Table 44-4).70

Suicide is only slightly more common in cancer patients than the general population, but suicidal ideation is frequent, and strongly associated with mood disturbance. Successful suicide typically occurs in patients with uncontrolled pain. Self-destructive personality traits and delirium also contribute to suicide attempts. The degree to which noncompliance and refusal of life-extending treatment represent suicide is not known.71

Fear of opioid addiction and abuse in cancer patients is a factor in the ongoing underuse of these medications for cancer pain. Tolerance (the need for increasing doses to achieve the same effect) and physical dependence (the occurrence of withdrawal symptoms when stopping or reducing opioid dosage) are expected with chronic opioid use. Addiction (a behavioral pattern of compulsive drug procurement and use for nonmedical reasons) is quite rare in cancer pain patients, and may be less common than in those with nonmalignant pain.72 Given their utility and safety, the sparing use of opioid analgesics in cancer pain is inappropriate.