INTRODUCTION — Pain is an unpleasant sensory and emotional experience that affects most aspects of life, including physical functioning, daily activity, psychologic and emotional status, and social life. Pain is a complex symptom and there is substantial heterogeneity in how it is experienced and in how it is manifested (table 1).
In many cases, the constellation of symptoms and signs can suggest a specific cancer pain syndrome [1]. The identification of such a syndrome may help to elucidate the etiology of the pain, direct the diagnostic evaluation, clarify the prognosis for the pain or the disease itself, and guide therapeutic intervention.
Cancer pain syndromes can be broadly characterized as acute or chronic. Acute pain syndromes usually accompany diagnostic or therapeutic interventions, whereas chronic pain syndromes usually are directly related to the neoplasm itself or to an antineoplastic therapy.
This topic review will provide an overview of acute and chronic cancer pain syndromes. Cancer pain assessment is discussed elsewhere. (See "Assessment of cancer pain".)
ACUTE PAIN SYNDROMES — Most acute cancer pain syndromes are iatrogenic, ie, related to a diagnostic test or treatment (table 2) [1]. However, some are disease-related, such as pain due to acute hemorrhage into a tumor, bone pain from a pathologic fracture, and visceral pain from acute obstruction or perforation of a hollow structure (table 3).
Analgesic management of these acute pain syndromes is discussed in the following topics:
●"Breakthrough pain" is typically defined as a transient flare of moderate to severe pain occurring on a background of chronic pain that is adequately controlled by an opioid regimen [2]; this flare of pain is typically short lived and is usually related directly to the cancer, a cancer treatment, or a diagnostic test. The management of breakthrough pain is discussed elsewhere. (See "Cancer pain management with opioids: Optimizing analgesia", section on 'Management of breakthrough pain'.)
●In patients receiving chronic opioid therapy for persistent cancer pain, the term "breakthrough pain" is not used to describe singular events of acute, severe, and longer lasting pain that occur after surgery or after an injury, whether or not the pain is related to the cancer (eg, pathologic bone fracture). The management of this sort of severe acute pain is similar to that for patients who are receiving long-term opioids for chronic non-cancer pain. (See "Management of acute pain in the patient chronically using opioids for non-cancer pain".)
Directly related to cancer — Acute pain syndromes that are directly related to the tumor may necessitate urgent treatment of the underlying lesion, in addition to aggressive pain control.
●Hemorrhage into a tumor – The prototype for this type of pain is bleeding into a site of hepatocellular carcinoma (HCC). This is typically accompanied by severe right upper quadrant pain, and is a potentially life-threatening complication, if the tumor ruptures. Urgent intervention for control of bleeding may be needed, in addition to transfusion and pain control. If measures such as transarterial embolization are unsuccessful, emergency surgery may be required. (See "Clinical features and diagnosis of hepatocellular carcinoma", section on 'Clinical features'.)
●Pathologic fracture – A pathologic fracture is a bone fracture that occurs within a preexisting lesion such as a skeletal metastasis or a primary bone tumor. (See "Clinical presentation and evaluation of complete and impending pathologic fractures in patients with metastatic bone disease, multiple myeloma, and lymphoma".)
Patients describe the sudden onset of back or limb pain, with or without antecedent trauma. Surgical stabilization of long bone fractures, if feasible and consistent with the overall goals of care, may relieve pain and should be considered. Vertebral collapse may be treated conservatively with analgesics or with an intervention, specifically vertebroplasty or kyphoplasty; surgery is typically considered only rarely and typically to address associated neurologic impairment. Radiation therapy (RT) is usually considered for all pathologic fractures and often augments pain control over a period of weeks or longer. (See "Radiation therapy for the management of painful bone metastases".)
●Obstruction/perforation of a hollow viscus – Obstruction of a bile duct, ureter, or bowel lumen by an intraabdominal or pelvic cancer or retroperitoneal fibrosis can also present with acute severe pain. Relief may be obtained urgently through percutaneous decompression, stenting, or occasionally surgery. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer" and "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis" and "Clinical manifestations and diagnosis of retroperitoneal fibrosis" and "Management of small bowel obstruction in adults".)
●Superior vena cava obstruction – Superior vena cava obstruction due to a tumor in the mediastinum presents with some combination of facial and neck swelling, dyspnea, dilated neck and chest wall veins, neck pain, or headache. Treatment usually involves administration of a glucocorticoid and urgent RT, with or without endovenous recanalization. (See "Malignancy-related superior vena cava syndrome".)
●Pain due to acute thrombosis – Deep venous thrombosis, most often in an extremity, is a relatively common complication of cancer and is usually associated with pain and swelling in the limb. (See "Risk and prevention of venous thromboembolism in adults with cancer" and "Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy".)
Associated with antineoplastic treatments — Acute pain can be associated with all types of antineoplastic therapy, including chemotherapy, hormonal therapy, immunotherapy, and RT (table 4). Pain is highly prevalent during treatment, and the likelihood of significant treatment-associated pain varies with the disease and its treatment. A systematic reviewed not a pooled prevalence rate of 40 percent during cancer treatment across all treatments and conditions [3].
Oral mucositis — The most common acute painful disorder associated with antineoplastic therapy is oral mucositis [4]. Many types of systemic chemotherapy can result in this complication, as can radiation to the head and neck region. Chemotherapy-associated mucositis can affect the mucosa throughout the entire gastrointestinal tract, but pain most often results from oral mucositis (stomatitis). Oral mucositis typically becomes clinically evident during the first week after chemotherapy administration and evolves over weeks after the start of fractionated RT. (See "Oral toxicity associated with systemic anticancer therapy" and "Management and prevention of complications during initial treatment of head and neck cancer".)
The incidence of chemotherapy-induced oral mucositis varies with the drug regimen and dose, the use of concurrent therapies (especially RT), and host factors:
●High doses of chemotherapy that are part of a conditioning regimen for hematopoietic stem cell transplantation cause noninfectious mucositis in approximately 70 percent of patients by killing cells with high mitotic rates. Ulceration of the oropharyngeal mucosa begins several days following initiation of the conditioning regimen. Initial symptoms may consist of mild or moderate burning discomfort, but this often progresses to the point where mucositis interferes with talking, eating, and swallowing. Significant pain requiring opioid use persists in one-half of patients at three weeks after transplant. (See "Early complications of hematopoietic cell transplantation", section on 'Oral mucositis'.)
●Standard doses of many common chemotherapeutic agents can also cause mucositis (table 5). Newer targeted therapies, such as mammalian target of rapamycin (mTOR) inhibitors (eg, everolimus) and small molecule inhibitors of the vascular endothelial growth factor receptor (eg, sorafenib, regorafenib), can also cause painful stomatitis. The frequency and severity are both drug- and dose-dependent. The three most commonly used cytotoxic agents associated with oral mucositis are doxorubicin, fluorouracil (FU), and methotrexate. (See "Oral toxicity associated with systemic anticancer therapy", section on 'Mucositis' and "Toxicity of molecularly targeted antiangiogenic agents: Non-cardiovascular effects", section on 'Oral toxicity'.)
●Mucositis develops in nearly all patients receiving RT to the head and neck region. RT-induced mucositis is similar qualitatively to that induced by chemotherapy. It usually develops two to three weeks after starting treatment. The Incidence and severity of RT-induced mucositis depend on the field, total dose and duration of RT, and the use of concomitant chemotherapy.
Although newer RT approaches such as three-dimensional conformal RT (3D-CRT) and intensity-modulated RT (IMRT) may reduce the incidence, mucositis remains a common problem in patients treated for head and neck cancer. (See "Management of late complications of head and neck cancer and its treatment" and "Management and prevention of complications during initial treatment of head and neck cancer", section on 'Mucositis'.)
●Pain due to mucositis may be more severe or prolonged when the ulcers become superinfected with bacteria or fungus, and in the setting of graft-versus-host disease. (See "Clinical manifestations, diagnosis, and grading of acute graft-versus-host disease".)
Numerous treatment strategies for established mucositis have been studied, as have several preventive strategies.
A year 2020 evidence-based review by the Multinational Association of Supportive Care in Cancer and the International Society of Oral Oncology [5] offers specific guidelines, which are discussed in more detail elsewhere. (See "Oral toxicity associated with systemic anticancer therapy".)
Chemotherapy-induced neuropathy — Many chemotherapeutic agents are neurotoxic. Acute neuropathic pain in patients treated with chemotherapy may manifest as a polyneuropathy, or less commonly, a mononeuropathy.
Chemotherapy-related polyneuropathy was first described in patients treated with the vinca alkaloid vincristine. Other agents with a high incidence of polyneuropathy include cisplatin, paclitaxel, oxaliplatin, thalidomide, and bortezomib [6]. All of these drugs can produce acute paresthesias and dysesthesias. Although they can present acutely (eg, oxaliplatin-induced pharyngolaryngeal spasm), the onset of pain associated with neuropathy in patients treated with these agents is more often insidious. (See "Overview of neurologic complications of conventional non-platinum cancer chemotherapy" and "Overview of neurologic complications of platinum-based chemotherapy", section on 'Acute neurotoxicity'.)
Chemotherapy-induced neuropathic pain usually gradually improves after the treatment is stopped or the dose is reduced; occasionally, neuropathic pain becomes chronic. (See 'Chemotherapy-related neuropathy' below.)
Rare overall, acute chemotherapy-related mononeuropathy is best described with vincristine. Orofacial pain (particularly jaw pain) is the most common manifestation, with multiple sites affected in the distribution of the trigeminal and glossopharyngeal nerves [7]. Other nerves, including the recurrent laryngeal, optic, and auditory nerves, may also be affected.
Other chemotherapy-related acute pain syndromes — Specific chemotherapeutic agents and hormone agents are associated with a variety of other acute pain syndromes, examples of which are provided in the table (table 6). Arthralgia or myalgia often accompanies paclitaxel therapy and may occur with rapid glucocorticoid tapering (a syndrome known as "pseudorheumatism"); bone pain may also occur during treatment with pegfilgrastim.
Painful rash on the palms and soles, a condition known as palmar-plantar erythrodysesthesia syndrome, hand-foot syndrome, acral erythema, toxic erythema of the palms and soles, has been associated with numerous drugs, including continuously infused fluorouracil, capecitabine, vinorelbine, liposomal doxorubicin, docetaxel and paclitaxel, the tyrosine kinase inhibitors sorafenib and sunitinib, high-dose methotrexate, and the mTOR inhibitor everolimus. (See "Cutaneous adverse effects of conventional chemotherapy agents" and "Cutaneous adverse events of molecularly targeted therapy and other biologic agents used for cancer therapy".)
Intrathecal therapy for leptomeningeal metastatic disease, intraperitoneal therapy for gynecologic tumors, intravesical therapy for bladder cancer, and hepatic intraarterial injection of chemotherapy (typically hepatic transarterial chemoembolization) all can be complicated by acute pain. When acute pain is anticipated, patient preparation, education, and reassurance are important. (See "Treatment of leptomeningeal disease from solid tumors" and "Intraperitoneal chemotherapy for treatment of ovarian cancer" and "Treatment of primary non-muscle invasive urothelial bladder cancer", section on 'Intravesical therapy' and "Localized hepatocellular carcinoma: Liver-directed therapies for nonsurgical candidates not eligible for local thermal ablation", section on 'TACE and bland particle embolization'.)
Radiation therapy-induced bone pain — Approximately one-third of patients undergoing RT to a bone metastasis will experience an acute increase in focal bone pain [8]. This pain is transitory, but if severe, it may necessitate treatment with an opioid or a short course of an oral glucocorticoid. (See "Radiation therapy for the management of painful bone metastases", section on 'Time course of relief and incidence of pain flare'.)
Radiation plexopathy — An acute, transient brachial plexopathy can occur after RT that involves a nerve plexus (table 4) [9]. Mimicking the syndrome known as acute brachial plexitis (brachial neuritis), this disorder is characterized by pain, paresthesias, and weakness in the shoulder, arm, and hand. The syndrome is usually self-limited but may cause persistent pain or dysfunction. Newer methods of RT appear to have substantially reduced the incidence of this condition. (See "Brachial plexus syndromes" and "Lumbosacral plexus syndromes".)
Radiation enteritis and proctitis — Patients undergoing abdominal irradiation may experience cramping, nausea, and vomiting (radiation enteritis). The corresponding syndrome in those receiving pelvic irradiation (radiation proctitis) includes painful tenesmus with diarrhea, mucus discharge, and bleeding. Newer RT methods such as 3D-CRT have reduced the incidence and severity of these painful syndromes, but they have not eliminated the risk of bowel toxicity when the RT field includes the intestinal viscera. (See "Overview of gastrointestinal toxicity of radiation therapy", section on 'Enteritis' and "Radiation proctitis: Clinical manifestations, diagnosis, and management".)
Symptoms can occur within hours after the onset of RT, but they more often develop several weeks into therapy. Specific factors that increase the risk for RT-related bowel toxicity include older age, concomitant chemotherapy, and at least in the setting of rectal cancer, the use of postoperative rather than preoperative RT. (See "Neoadjuvant chemoradiotherapy, radiotherapy, and chemotherapy for rectal adenocarcinoma", section on 'Indications for neoadjuvant treatment'.)
CHRONIC PAIN SYNDROMES — Approximately three-fourths of cancer patients who have chronic pain have nociceptive (somatic or visceral) or neuropathic syndromes that represent direct effects of the neoplasm (table 7) [1]. (See "Assessment of cancer pain", section on 'Inferred pathophysiology and treatment implications'.)
Other causes of chronic pain in cancer patients are antineoplastic treatments (table 8) [10], and disorders that are unrelated to the disease or its treatment.
A significant barrier to better understanding chronic cancer pain syndromes, their prevalence, and their consequences, is the lack of consistent diagnostic criteria for specific syndromes. At present, they are classified according to the putative mechanism (ie, tumor related, treatment related) and the underlying pathophysiology (ie, nociceptive [somatic, visceral] or neuropathic). Consensus-based core diagnostic criteria for several cancer-related pain syndromes, specifically bone pain, chemotherapy-induced peripheral neuropathy, and pancreatic cancer-related pain, have been published [11].
Tumor-related somatic pain syndromes — Tumor involvement of bone, joints, muscle, or connective tissue can cause persistent somatic pain (table 7).
Multifocal bone pain — Bone metastases are the most prevalent cause of chronic pain in cancer patients. Skeletal metastases are a common manifestation of distant disease spread from many types of solid cancers, especially those arising in the lung, breast, and prostate. (See "Epidemiology, clinical presentation, and diagnosis of bone metastasis in adults".)
The pain associated with bone metastases may be due to direct invasion, secondary pathologic fracture, or damage to adjacent structures. Although the factors that convert a painless to a painful bone metastasis are not known, it is now well accepted that bone pain, once established, has both inflammatory and neuropathic components [12]. The neuropathic component is presumably induced by direct nerve injury and consequent pathologic sprouting of both sensory and sympathetic nerve fibers [13,14]. Presumably, some combination of these neural changes, the complex perineural release of growth factors and/or chemical mediators, and mechanical distortion related to microfracture culminates in bone pain. Diagnostic criteria for cancer-induced bone pain have been developed (table 9) [11].
Local field external beam radiation therapy (RT) is a well-recognized and effective palliative modality for painful bone metastases; pain relief is seen in 80 to 90 percent of cases. (See "Radiation therapy for the management of painful bone metastases".)
Although the majority of patients with multifocal bone pain have widespread bony metastases, hematologic malignancies can rarely produce painful bone marrow expansion [15]. This is presumably caused by nests of rapidly growing cells in the marrow.
In addition, a rare paraneoplastic form of renal phosphate wasting called oncogenic osteomalacia can cause osteomalacia, multifocal bone pain, and fractures [16]. This rare syndrome is most often associated with mesenchymal neoplasms, and complete tumor removal can lead to rapid correction of the biochemical derangements, remineralization of bone, and symptom improvement. (See "Hereditary hypophosphatemic rickets and tumor-induced osteomalacia", section on 'Tumor-induced osteomalacia'.)
●Vertebral pain syndromes – The most common sites of bone metastases are the vertebrae. Specific syndromes may evolve from lesions involving different spinal levels (table 10). Back pain that develops at any level from vertebral metastases may signal epidural extension, which is associated with the serious complications of spinal cord or cauda equina compression. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression".)
Neoplastic epidural spinal cord compression (ESCC) is a common complication of solid tumors [17]. Most often, ESCC is caused by posterior extension of a vertebral body metastasis into the epidural space (figure 1). ESCC almost always presents initially as back or neck pain. Untreated, tumor growth may eventually cause irreversible loss of neurologic function. Because pain usually precedes neurologic impairment by weeks or months, it is crucial to diagnose epidural disease extension in patients when pain is the sole complaint so that effective treatment may be started to prevent or retard the progression of neurologic impairment. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Clinical features'.)
In patients with metastatic disease, worsening spine pain, pain described as worse when recumbent, pain that develops in a radicular distribution (eg, around the chest wall or into the arm or leg), or pain associated with a neurologic symptom or sign typically indicates the need for magnetic resonance imaging (MRI). Total spine MRI is the preferred approach to evaluate for ESCC in the context of metastatic disease. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Diagnostic evaluation'.)
For most patients, RT represents first-line definitive treatment for ESCC. Although multiple fraction RT has been considered the standard of care, there is no evidence that outcomes are better among those with advanced illness than those obtained with single-fraction therapy [18]; a single palliative dose of RT is an option for patients with limited prognosis. Glucocorticoid treatment also is useful to temporarily improve pain and neurologic functioning, often providing a window of time during which RT can be provided. Surgical decompression is considered if the tumor type is typically radioresistant and the lesion is high grade, if the neurologic status is deteriorating during RT, if ESCC occurs in a previously irradiated field, if the lesion is posterior and can be easily extirpated, or if a tissue diagnosis is needed. (See "Treatment and prognosis of neoplastic epidural spinal cord compression".)
●Pelvic and hip metastases – Pelvic metastases may involve the ilium, ischium, pubis, or sacroiliac areas. In addition to local pain, tumor invasion of the hip joint may present as hip or inguinal pain upon walking or as pain in the knee or thigh. Injury to structures just inside the pelvic ring can result in related syndromes, such as a malignant piriformis syndrome (pain in the buttock and/or sciatic distribution, often with exacerbation during internal rotation of the hip) or a painful plexopathy (table 7). (See "Overview of lower extremity peripheral nerve syndromes", section on 'Compression/trauma in the sciatic notch/gluteal region'.)
Sacral syndrome is associated with the destruction of the sacrum due to neoplastic infiltration. It is characterized by severe focal pain radiating to the buttocks, perineum, and posterior thigh. Involvement of the lateral hip rotators makes movement at the hip painful.
These lesions are typically treated with RT, but interventional pain strategies or surgery may be considered in some cases [19].
●Base of skull metastases – Neoplastic injury to the base of the skull may occur from the local extension of a nasopharyngeal cancer or from skeletal metastases involving this area, usually due to breast, lung or prostate cancers [20-22]. Depending on their location, base of skull metastases may cause specific pain syndromes (table 11). In most situations, the responsible lesion is readily identifiable on axial CT imaging with bone windows or MRI.
Soft tissue pain — Sarcomas can arise in muscle, as can metastases [23]. In either case, pain at the local site of involvement is common.
Muscle pain may also be due to muscular cramps, which in cancer patients can be associated with neural injury (eg, radiculopathy or plexopathy) or caused by a biochemical abnormality [24]. Biochemical abnormalities such as hypercalcemia or hyponatremia may be the result of a paraneoplastic syndrome (see "Causes of hypotonic hyponatremia in adults").
Treatment of cancer-associated muscle cramps is nonspecific and employs the same approaches used to manage cramps in other disorders [25,26].
Somatic chest wall pain is common among patients with lung cancer or mesothelioma, and can be due to direct tumor infiltration of the ribs, intercostal spaces, or parietal pleura (table 7). The pain usually is worsened by deep inspiration or cough. A malignant intercostal mononeuropathy may accompany this lesion and yield a syndrome that has mixed nociceptive and neuropathic features.
Soft tissue pain may also be caused by a paraneoplastic disorder (eg, hypertrophic osteoarthropathy). (See 'Paraneoplastic syndromes' below.)
Tumor-related visceral pain syndromes — Visceral pain can be caused by obstruction of any hollow viscus or injury to another pain-sensitive visceral structure such as the visceral pleura, hepatic capsule, or peritoneum (table 7) [1]. These syndromes are particularly common in patients with gastrointestinal and gynecologic malignancies.
●Hepatic distention syndrome – Pain-sensitive structures in the region of the liver include the hepatic capsule, vessels, and biliary tract. Stretching of the hepatic capsule by a primary hepatoma or intrahepatic metastases can cause chronic cancer pain, which is commonly described as dull, right sided subcostal pain. If the superior aspect of the capsule is involved, diaphragmatic irritation may lead to referred pain to the top of the ipsilateral shoulder.
Pain also may result from injury or invasion of the porta hepatis, with or without biliary duct obstruction. This pain may be referred to the ipsilateral scapular region.
●Midline retroperitoneal syndrome – Tumor invasion of the pancreas or other subdiaphragmatic midline structures (eg, with retroperitoneal lymphadenopathy) may produce pain by injuring the deep somatic tissues of the posterior abdominal wall or by invasion of the celiac plexus [27-29]. Pain is experienced in the epigastrium, low thoracic region of the back, or both. It is often described as a dull ache or a "boring" pain that is worse when lying down and relieved by sitting up.
●Chronic intestinal obstruction – Diffuse abdominal pain may be related to chronic intestinal obstruction from either an abdominal neoplasm or scarring. The common cancers that cause intestinal obstruction are ovarian (up to 42 percent of cases) and colorectal (up to 24 percent of cases) [30,31]. In such cases, pain may be related to distension proximal to an obstructed bowel segment, mural ischemia, or tension on the mesentery.
Pain may be continuous or colicky, and may be referred to the dermatomes represented by the spinal segments supplying the affected viscera. Nausea, vomiting and constipation are important associated symptoms. Abdominal radiographs taken in both the supine and upright positions may demonstrate the presence of air-fluid levels and intestinal distention. CT or MRI usually reveals the extent of the intraabdominal neoplasm. (See "Large bowel obstruction" and "Etiologies, clinical manifestations, and diagnosis of mechanical small bowel obstruction in adults" and "Palliative care of bowel obstruction in cancer patients".)
●Peritoneal carcinomatosis – Carcinomatous seeding of the peritoneum leads to peritoneal inflammation, mesenteric tethering, malignant adhesions, and ascites, all of which can cause pain. Cancers of the ovary, colorectum and stomach are frequent causes of this syndrome. Pain may be diffuse or focal, sharp or crampy, and worse postprandially. Abdominal distention, nausea and constipation are common. CT may reveal evidence of ascites, omental infiltration, and/or peritoneal nodules [32]. (See "Malignancy-related ascites".)
●Malignant perineal pain – Malignancy-related perineal pain is most often associated with tumors of the colon or rectum, female reproductive tract, and distal genitourinary system. The pain may be exacerbated by sitting or standing, and there may be a component of tenesmus or tenesmoid pain, or intermittent severe pain consistent with bladder spasms [33]. Some patients describe a discrete syndrome that is characterized by discomfort or pain that occurs rapidly after standing and disappears in other positions; this symptom complex mimics an idiopathic tension myalgia syndrome. (See "Chronic pelvic pain in nonpregnant adult females: Causes".)
●Adrenal pain syndrome – Adrenal metastases (which are most commonly seen in non-small cell lung cancer) can produce unilateral flank pain which may radiate into the ipsilateral upper and lower quadrants of the abdomen [34]. Severe acute pain may result from adrenal hemorrhage [35]. (See "Clinical presentation and evaluation of adrenocortical tumors".)
●Ureteral obstruction – Gastrointestinal, genitourinary and gynecologic cancers are the most common causes of ureteral obstruction [36]. Although these patients may present acutely, others present subacutely with flank pain which radiates to the inguinal region. Pain is often colicky, ie, intermittent and wave-like. When severe, pain due to ureteric obstruction may be associated with nausea and vomiting. Imaging studies may confirm the nature of the syndrome by demonstrating ipsilateral hydronephrosis. (See 'Directly related to cancer' above and "Clinical manifestations and diagnosis of urinary tract obstruction (UTO) and hydronephrosis".)
Tumor-related neuropathic pain — Neuropathic pain syndromes that are directly caused by neoplastic invasion may involve the spinal cord, nerve roots, plexuses, or peripheral nerves (table 7). Approximately 40 percent of patients with chronic cancer-related pain have a neuropathic pain syndrome.
Leptomeningeal metastases — Any solid or hematologic neoplasm can potentially infiltrate the leptomeninges, but the common tumors are lung and breast cancer, lymphoma and leukemia [37,38]. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors".)
Clinical presentation is variable:
●Some patients have headache, which may or may not have characteristics typical for intracranial hypertension (generalized aching or throbbing that is worse in the morning and with Valsalva maneuvers, and sometimes associated with nausea and vomiting). (See "Evaluation and management of elevated intracranial pressure in adults".)
●Others experience nonspecific back pain, or pain in a radicular distribution that can affect any level of the neuraxis.
●These variable pains may be accompanied by an equally diverse set of neurologic complications, including seizures, cognitive impairment, hemiparesis or hemisensory syndromes, spinal cord syndromes, or any combination of motor or sensory disturbance consistent with a cranial neuropathy or radiculopathy.
Given the variable presentation, leptomeningeal metastases can mimic any type of pain syndrome or neurologic disorder, and should be suspected whenever pain or neurologic impairment progresses and eludes initial diagnosis.
The diagnosis of a leptomeningeal neoplasm is made by the finding of malignant cells on lumbar puncture. T1-weighted, gadolinium-enhanced cranial and spinal cord MRI may identify or raise suspicion for leptomeningeal spread, and can be positive even if the cerebrospinal fluid is initially negative. (See "Clinical features and diagnosis of leptomeningeal disease from solid tumors", section on 'Diagnostic evaluation'.)
Cranial neuralgias — Malignancy-related cranial neuralgias can develop from metastases involving the base of the skull or the leptomeninges, or from cancers that arise in the soft tissue of the head, neck, or sinuses [39].
●Glossopharyngeal neuralgia – Glossopharyngeal neuralgia is characterized by paroxysmal unilateral severe, stabbing or lancinating pain in the throat or neck which may radiate to the ear and mastoid regions. Typical triggers include chewing, swallowing, coughing, speaking, yawning, certain tastes, or touching the neck or external auditory canal. The syndrome can occur in a pattern of episodes lasting weeks to months, alternating with longer periods of remission.
Injury to the ninth cranial nerve is most often caused by leptomeningeal metastases, or from primary tumors or metastatic deposits that involve the jugular foramen. (See "Overview of craniofacial pain", section on 'Glossopharyngeal neuralgia'.)
●Trigeminal neuralgia – A syndrome that mimics idiopathic trigeminal neuralgia may be caused by tumors of the middle or posterior cranial fossa. This pain may be labeled a painful trigeminal neuropathy. However, because it most often presents with "electric shock-like" or stabbing paroxysms that are similar to the symptoms seen in the idiopathic syndrome, it may be called a malignant, or tumor-related, trigeminal neuralgia. If a lesion that involves the trigeminal nerve produces different qualities of pain, such as a constant aching or burning in the face, it is more appropriate to describe the syndrome as a painful trigeminal neuropathy rather than a malignant trigeminal neuralgia. (See "Trigeminal neuralgia", section on 'Clinical features'.)
Many patients with tumor-related trigeminal neuralgia are treated, at least initially, for an idiopathic process. Over time, however, tumor growth leads to symptoms and signs that raise suspicion as to the nature of the disorder (eg, change in the quality of the pain or the development of neurologic deficits on examination) [40]. Imaging of both the brain and skull base may be necessary to characterize or exclude a mass lesion as the cause of the pain and associated features. (See "Trigeminal neuralgia", section on 'Mechanisms'.)
Radiculopathies — Any malignant process that compresses, distorts, or inflames nerve roots may cause a painful radiculopathy. If multiple nerve roots are affected, it is called a polyradiculopathy. A painful radiculopathy may result from leptomeningeal metastases, intradural tumor (particularly meningioma, neurofibroma, and ependymoma) or tumor in the epidural space. The latter situation is most common and may arise via posterior extension of a tumor from a vertebral body metastasis, or growth into the intervertebral foramen from a paraspinal site of disease (figure 1). (See "Acute lumbosacral radiculopathy: Pathophysiology, clinical features, and diagnosis".)
Radicular pain may be continuous or intermittent, aching or sharp, or dysesthetic (eg, burning or electrical-like) in quality; it may or may not be associated with neurologic signs. When located in the thoracic level and bilateral in distribution, the pain may be experienced as a tight band across the chest or abdomen, a presentation that signals a relatively high likelihood of associated epidural disease. (See "Clinical features and diagnosis of neoplastic epidural spinal cord compression", section on 'Pain'.)
A high index of suspicion for a malignant cause of radiculopathy or polyradiculopathy should lead to a spinal MRI. If the patient has known vertebral metastasis or paraspinal disease, this test can be done without contrast enhancement; if infiltration of nerve roots is suspected, then a study with and without the injection of contrast is more informative.
Plexopathies — Tumor-related plexopathies may involve the cervical, brachial, or lumbosacral plexus (table 12) [41]. Pain is the usual presenting symptom.
●Cervical plexopathy – A malignant cervical plexopathy may be due to a head and neck tumor, or to metastatic deposits that originate in the cervical lymph nodes. The pain, which is often described as aching or burning, may be experienced in the periauricular, postauricular, or anterior regions of the neck, or be referred to the lateral aspect of the face, head or shoulder.
If there is involvement of the superior cervical (stellate) ganglion of the sympathetic chain or of the sympathetic nerves adjacent to the carotid artery, Horner syndrome (ipsilateral miosis, ptosis, and anhidrosis) may be present. (See "Horner syndrome".)
●Brachial plexopathy – Brachial plexopathy may present with shoulder, arm or hand pain, with or without neurologic deficits or Horner syndrome.
The usual cause of a malignant brachial plexopathy is local extension of a primary or metastatic tumor; cancers of the lung or breast, and lymphomas are the most common etiology [41]. Primary brachial plexus tumors, such as schwannomas or neurofibromas, are uncommon, and most occur as solitary tumors. These rarely cause symptomatic plexopathies. However, multiple tumors occur in patients with neurofibromatosis type 1, and these are more likely than solitary tumors to present with pain or clinical deficits.
Initial signs and symptoms vary based on anatomic location (see "Brachial plexus syndromes"):
•When the inferior plexus is involved first, as occurs with tumors of the lung arising in the region of the superior sulcus (Pancoast tumors), pain typically begins in the elbow and gradually spreads to involve the medial arm and hand. (See "Superior pulmonary sulcus (Pancoast) tumors".)
•When the superior aspect of the plexus is injured first, as occurs when tumor arises from cervical lymph nodes and grows inferiorly, the pain typically starts in the shoulder.
The pain is classically followed by paresthesias in the distribution innervated by the involved nerves (figure 2). Weakness and sensory loss follow. Ultimately, a panplexopathy may develop, with pain and dysfunction that affects the entire limb.
Among patients who have been previously treated for a malignancy, the differential diagnosis of a new brachial plexopathy includes recurrent tumor and radiation injury. In the setting of a known neoplasm and RT, distinguishing between cancer recurrence and radiation-induced plexopathy can be challenging. (See "Brachial plexus syndromes", section on 'Radiation-induced' and 'Postradiation pain syndromes' below.)
The diagnosis of neoplastic versus radiation-induced brachial plexopathy is suggested by the symptoms and signs, and electrodiagnostic findings, and is confirmed by imaging, or in some cases, by biopsy. In general, radiation-induced plexopathy is less painful than neoplastic brachial plexopathy; the upper plexus is more commonly involved, there often is relatively intense paresthesias, and radiation changes in the skin and other soft tissues are evident (eg, poikiloderma, telangiectasias, atrophy, hyperpigmentation, and lymphedema). Radiation is less likely to be associated with Horner syndrome than plexopathy related to tumor recurrence.
The diagnosis of a radiation-induced rather than neoplastic plexopathy is supported by the presence of so-called myokymic discharges on electromyography. These are relatively specific for radiation-induced injury, but are not a universal feature, and their absence does not exclude the diagnosis.
MRI or CT scan of the plexus can usually establish the diagnosis. Occasionally, biopsy is needed. Because tumors adjacent to the spine may be responsible for a brachial plexopathy, MRI of the epidural space may be needed. Imaging of the chest by CT or MRI is most useful to detect a pulmonary tumor.
●Celiac plexus – Tumor invasion of the celiac plexus, most notably by pancreatic cancer, is commonly associated with intense and often refractory midepigastric pain, which has been labeled the midline retroperitoneal syndrome. Diagnostic criteria for this syndrome have been proposed (table 13) [8]. The pain is often described as gnawing and radiates bilaterally under the ribs and into the midback. This pain is attributed to local tumor growth and the proximity of tumors to the celiac plexus. (See "Supportive care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on 'Pain'.)
●Lumbosacral plexopathy – Malignant lumbosacral plexopathy is primarily associated with colorectal, cervical, and breast cancers, sarcomas, lymphomas, and sacral chordomas. Neoplastic invasion typically presents with severe and progressive pain. The distribution of the pain and associated signs and symptoms depends on the site of anatomic involvement (table 12).
The diagnostic evaluation of a patient with a lumbosacral plexopathy is described in detail elsewhere. (See "Lumbosacral plexus syndromes".)
Peripheral mononeuropathies — Painful peripheral mononeuropathies can result from direct tumor invasion of a peripheral nerve [41]. A classic example is malignant intercostal neuropathy complicating a chest wall tumor.
Paraneoplastic syndromes — Paraneoplastic syndromes are a heterogeneous group of disorders in cancer patients that are caused by substances released by a tumor or produced in reaction to it. These substances can be hormones or other compounds, including antibodies or other compounds produced through immune responses. Paraneoplastic disorders are not caused by direct tumor invasion, metabolic and nutritional deficits, infections, coagulopathy or side effects of cancer treatment.
Paraneoplastic syndromes most commonly affect the nervous system, but they can affect many tissues. Approximately 40 percent of paraneoplastic neuropathies are associated with pain [42]. Some examples of painful paraneoplastic syndromes are outlined in the table (table 14), and two are described in more detail below:
●Subacute sensory neuronopathy – One of the best characterized painful neurologic paraneoplastic syndromes is subacute sensory neuronopathy (sensory ganglionopathy), a rare condition that is related to inflammation of the dorsal root ganglion. Like many other neurologic paraneoplastic syndromes, it is most common in patients with small cell lung cancer.
The sensory deficits typically begin with loss of vibratory sensation and joint position sense following by impairment in pain and temperature sensation. Patients frequently complain of the sensation of "pins and needles" or "electric shocks." The symptoms may initially affect one extremity but, in a few weeks or months, they usually progress to involve other extremities, the face, abdomen, or trunk. A severe sensory ataxia may prevent walking or even self-care. In a subset of patients, hyperalgesia and spontaneous pain remain the prominent symptom, and sensory ataxia is mild or even absent. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Subacute sensory neuronopathy'.)
Other, more prevalent paraneoplastic polyneuropathies comprise axonopathies that may accompany any tumor type but are often associated with plasma cell dyscrasias. The pain associated with these types of neuropathy begins in the feet symmetrically and gradually ascends as the lesion progresses. All of these paraneoplastic neuropathies can be the initial manifestation of an underlying malignancy and their occurrence should prompt a search for an occult cancer. (See "Paraneoplastic syndromes affecting spinal cord, peripheral nerve, and muscle", section on 'Chronic sensorimotor neuropathy'.)
●Hypertrophic osteoarthropathy – Hypertrophic osteoarthropathy is a syndrome characterized by abnormal proliferation of the skin and osseous tissue at the distal parts of the extremities. The secondary form is usually associated with lung cancer. Clinical features include digital clubbing (figure 3), periostosis of tubular bones (image 1 and image 2), and synovial effusions, which are most prominent in the large joints. Periostosis is usually accompanied by pain on palpation of the involved area. Some patients present with a painful arthropathy in advance of clubbing. (See "Malignancy and rheumatic disorders", section on 'Hypertrophic osteoarthropathy'.)
Headache — A new, changed, or progressive headache in a patient with a history of cancer should be evaluated first with a thorough neurologic examination, and then with imaging studies if the diagnosis of an intracranial mass lesion is suspected. (See "Evaluation of headache in adults".)
Chronic pain related to antineoplastic treatments — Chemotherapy (including glucocorticoid therapy, hormonal therapy, cytotoxic therapy, and biologic agents), RT, and surgery each may be associated with a group of chronic pain syndromes (table 8). As a result of these syndromes, chronic pain is one of the most common and troubling conditions among cancer survivors [43-45].
Chemotherapy-related neuropathy — Although painful peripheral neuropathy resulting from cytotoxic therapy usually subsides over time, some patients develop persistent chronic pain (see "Prevention and treatment of chemotherapy-induced peripheral neuropathy", section on 'Chronic neurotoxicity'). Diagnostic criteria for chemotherapy-induced peripheral neuropathic pain have been proposed (table 15).
The pain is similar to other axonopathies, with initial involvement of the feet and distal legs, followed by the hands and arms. The severity of the pain, and the presence and degree of neurologic impairment vary widely depending on the agent to which the patient was exposed and the dose. (See "Overview of neurologic complications of platinum-based chemotherapy" and "Overview of neurologic complications of conventional non-platinum cancer chemotherapy".)
Occasionally, patients develop a persistent Raynaud phenomenon; this has been observed in approximately one-third of cancer patients with testicular tumors treated with regimens containing cisplatin, vincristine, and bleomycin. (See "Treatment-related toxicity in men with testicular germ cell tumors", section on 'Raynaud phenomenon'.)
Bone complications and glucocorticoids — Chronic use of glucocorticoids may cause avascular necrosis of the femoral or humeral head, which is typically heralded by a painful arthropathy. Radiologic changes on MRI or CT studies may not appear for a few months after the initial report of pain.
Steroids also accelerate osteoporosis, which may predispose to vertebral compression fractures associated with acute or chronic back pain. (See "Major side effects of systemic glucocorticoids", section on 'Bone and muscle effects'.)
Antiandrogens and gynecomastia — Painful gynecomastia develops in the majority of males receiving therapy for antiandrogens alone for advanced prostate cancer unless prophylactic RT is administered. (See "Side effects of androgen deprivation therapy", section on 'Gynecomastia'.)
Postsurgical pain syndromes — Well-defined pain syndromes may occur after the surgical excision of cancer. The best characterized include postmastectomy pain syndrome, post-radical neck dissection pain syndrome, post-thoracotomy pain syndrome, postoperative frozen shoulder, postsurgery pelvic floor pain, stump and phantom limb pain following amputation, and phantom breast pain (table 16). These syndromes are predominantly neuropathic and presumably related to nerve injury at the time of surgery. (See "Management of late complications of head and neck cancer and its treatment" and "Mastectomy", section on 'Pain' and "Mastectomy", section on 'Phantom breast syndrome'.)
Pain and phantom sensation after limb amputation — Chronic pain following limb amputation may involve stump pain, phantom pain, or both. Stump pain may be due to neuroma formation several months after amputation, but a poorly fitting prosthesis, recurrent tumor, infection, or ischemia also may contribute [46].
Phantom sensation, the sensory experience that the amputated limb is still present, occurs in most amputees. Phantom pain, which is often paroxysmal and atypical, and described by some as an intense twisting or crushing sensation, is also common [47]. (See "Lower extremity amputation", section on 'Phantom limb pain' and "Upper extremity amputation", section on 'Phantom limb pain'.)
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; this phenomenon may explain the elicitation of phantom pain by sensory stimulation at other sites [48].
There is limited evidence that mirror therapy, motor imagery, and virtual visual feedback reduce phantom limb pain [49]. The evidence in favor of mirror therapy appears to be the strongest [50]. There is also emerging support for the efficacy of transcranial stimulation, in particular transcranial magnetic stimulation [51]. There is only low-quality evidence supporting several drug therapies, including gabapentin, ketamine, and morphine [52].
Postradiation pain syndromes — Chronic pain following RT is a late complication and often must be differentiated from recurrent tumor.
Plexopathies — Radiation-induced cervical, brachial or lumbosacral plexopathies may occur months to many years after RT [41,53]. The usual presenting signs are weakness and sensory changes. Although they cause pain, it is rarely severe. Chronic perineal pain following pelvic RT is often clinically associated with a sacral plexopathy. The pain is burning in nature and may extend anteriorly to the vagina or scrotum [54].
The incidence of these syndromes has declined over the years due to lower-dose regimens and better RT techniques. (See "Brachial plexus syndromes", section on 'Neoplastic and radiation-induced brachial plexopathy' and "Lumbosacral plexus syndromes", section on 'Radiation plexopathy'.)
The main differential is with a plexopathy from recurrent tumor. As noted above, in the setting of a known neoplasm and RT, distinguishing between cancer recurrence and radiation-induced brachial plexopathy can be challenging. These issues are discussed above. (See 'Plexopathies' above.)
Myelopathy — Chronic radiation myelopathy is another late complication which may develop many years following the completion of RT. Sensory symptoms, including pain, typically precede the development of progressive motor and autonomic dysfunction. The pain is usually characterized as a burning dysesthesia and is localized to the area of spinal cord damage or below this region. The neurologic findings may be consistent with a transverse myelopathy, sometimes in a Brown-Sequard pattern. (See "Complications of spinal cord irradiation", section on 'Late radiation-induced myelopathy' and "Anatomy and localization of spinal cord disorders", section on 'Brown-Sequard (hemicord) syndrome'.)
Gastrointestinal tract — Chronic enteritis and proctitis may result from irradiation to the abdomen and pelvis. Small bowel obstruction, strictures, gastroparesis and intestinal pseudo-obstruction (eg, impaired gastrointestinal motility without any anatomical obstruction), fistula formation, gastrointestinal perforation, and bleeding are all late manifestations of radiation toxicity to the gastrointestinal tract, and persistent abdominal pain often complicates these lesions. (See "Diagnosis and management of chronic radiation enteritis" and "Overview of gastrointestinal toxicity of radiation therapy" and "Chronic intestinal pseudo-obstruction: Etiology, clinical manifestations, and diagnosis" and "Gastroparesis: Etiology, clinical manifestations, and diagnosis".)
Lymphedema — Lymphedema may result from RT to the breast or shoulder, or to the pelvis. The most common symptoms are heaviness, changes in skin, and discomfort or pain. The disorder carries a high burden and recent advances present opportunities to improve prevention and management [55]. Some patients with lymphedema develop stretch injuries to the plexus or nerve entrapment syndromes, and as a result, experience neuropathic pain [56]. The new onset of severe or progressive pain in a lymphedematous limb suggests tumor recurrence infection, or a secondary malignancy (eg, Stewart-Treves syndrome) and requires reevaluation. (See "Clinical features and diagnosis of peripheral lymphedema" and "Lower extremity lymphedema" and "Breast cancer-associated lymphedema".)
Osteonecrosis — Radiation can cause osteoradionecrosis as a result of endarteritis obliterans in the bone. Osteoradionecrosis of the jaw may follow RT for head and neck cancers and is associated with pain and mechanical dysfunction. Osteonecrosis of other bones occurs less often but may complicate RT at virtually any site. (See "Management of late complications of head and neck cancer and its treatment", section on 'Osteoradionecrosis and soft tissue necrosis'.)
Medication-related osteonecrosis of the jaw can also occur as an uncommon but potentially serious side effect in patients with metastatic bone disease who are treated with high-potency bisphosphonates or denosumab to prevent skeletal-related events. (See "Medication-related osteonecrosis of the jaw in patients with cancer".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuropathic pain" and "Society guideline links: Cancer pain".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Managing pain when you have cancer (The Basics)" and "Patient education: Mouth sores from cancer treatment (The Basics)")
SUMMARY
●A cancer pain syndrome is defined as a clinically meaningful constellation of symptoms and signs in a patient with cancer. The identification of a specific pain syndrome in cancer patients may help to elucidate the etiology, help direct the diagnostic evaluation, clarify the prognosis for the pain or the disease itself, and guide subsequent therapeutic interventions. (See 'Introduction' above.)
●Cancer pain syndromes may be broadly divided into those that are acute and those that are chronic. Acute pain syndromes usually accompany diagnostic or therapeutic interventions, although some are directly related to the malignancy itself (eg, hemorrhage into a hepatocellular cancer, pathologic fracture, obstruction or perforation of a bile duct, ureter, or bowel lumen). (See 'Acute pain syndromes' above.)
●Chronic pain syndromes are usually directly related to the neoplasm itself (table 7) or to an antineoplastic therapy (including chemotherapy, surgery, or radiation therapy (table 8)). (See 'Chronic pain syndromes' above.)
