Cancer Pain Assessment and Syndromes

SUMMARY

Surveys indicate that pain is experienced by 30–60% of cancer patients during active therapy and by more than two-thirds of those with advanced disease ( , ). Unrelieved pain is incapacitating and precludes a satisfying quality of life; it interferes with physical functioning and social interaction and is strongly associated with heightened psychological distress. It can provoke or exacerbate existential distress, disturb normal processes of coping and adjustment, and augment a sense of vulnerability, thereby contributing to preoccupation with the potential for catastrophic outcomes. Persistent pain interferes with the ability to eat, sleep, think, and interact with others and is correlated with fatigue in cancer patients.

The high prevalence of chronic pain in cancer patients and the profound psychological and physical burdens engendered by this symptom oblige all treating clinicians to be skilled in pain management. Relief of pain in cancer patients is an ethical imperative, and it is incumbent on clinicians to maximize the knowledge, skill, and diligence needed to attend to this task.

Undertreatment of cancer pain has many causes, among the most important of which is inadequate assessment ( ).

Approach to Cancer Pain Assessment

Assessment is an ongoing and dynamic process that includes evaluation of the patient’s problems, elucidation of pain syndromes and pathophysiology, and formulation of a comprehensive plan for continuing care. The objectives of cancer pain assessment include (1) accurate characterization of the pain, including the pain syndrome and inferred pathophysiology, and (2) evaluation of the impact of the pain and the role that it plays in the overall suffering of the patient.

Such assessment is predicated on establishment of a trusting relationship with the patient in which the clinician emphasizes relief of pain and suffering as being central to the goal of therapy and encourages open communication about symptoms. Clinicians should not be cavalier about the potential for under-reporting of symptoms; they are frequently described as complaints, and there is a common perception that a “good patient” refrains from complaining ( ). The prevalence of pain is so great that an open-ended question about the presence of pain should be included at each patient visit in routine oncological practice. If the patient is either unable or unwilling to describe the pain, a family member may need to be questioned to assess the distress or disability of the patient.

Pain Syndromes

Cancer pain syndromes are defined by the association of particular pain characteristics and physical signs with specific consequences of the underlying disease or its treatment. Syndromes are associated with distinct causes and pathophysiologies and have important prognostic and therapeutic implications. Pain syndromes associated with cancer can be either acute or chronic. Whereas the acute pains experienced by cancer patients are usually related to diagnostic and therapeutic interventions, chronic pains are most commonly caused by direct tumor infiltration. Adverse consequences of cancer therapy, including surgery, chemotherapy, and radiation therapy, account for 15–25% of chronic cancer pain problems, and a small proportion of the chronic pain experienced by cancer patients is caused by pathology unrelated to either the cancer or therapy for the cancer.

Pain Characteristics

Evaluation of the characteristics of the pain provides some of the data essential for identification of the syndrome. These characteristics include intensity, quality, distribution, and temporal relationships.

Intensity

Evaluation of pain intensity is pivotal to therapeutic decision making. It indicates the urgency with which relief is needed and influences the selection of analgesic drugs, route of administration, and rate of dose titration ( ). Furthermore, assessment of pain intensity may help characterize the pain mechanism and underlying syndrome. For example, the pain associated with radiation-induced nerve injury is rarely severe; the occurrence of severe pain in a previously irradiated region therefore suggests the existence of recurrent neoplasm or a radiation-induced second primary neoplasm.

Quality

The quality of the pain often suggests its pathophysiology. Somatic nociceptive pain is usually well localized and described as sharp, aching, throbbing, or pressure-like. Visceral nociceptive pain is generally diffuse and may be gnawing or crampy when caused by obstruction of a hollow viscus or may be aching, sharp, or throbbing when caused by involvement of organ capsules or mesentery. Neuropathic pain may be described as burning, tingling, or shock-like (lancinating).

Distribution

Patients with cancer pain commonly experience pain at more than one site. Distinction between focal, multifocal, and generalized pain may be important in the selection of therapy, such as nerve blocks, radiotherapy, or surgical approaches. The term “focal” pain, which is used to denote a single site, has also been used to depict pain that is experienced in the region of the underlying lesion. Focal pain can be distinguished from pain referred to a site remote from the lesion. Familiarity with pain referral patterns is essential to target appropriate diagnostic and therapeutic maneuvers ( Table 73-1 ). For example, a patient in whom progressive shoulder pain develops without evidence of focal pathology needs to undergo evaluation of the regions above and below the diaphragm to exclude the possibility of referred pain from diaphragmatic irritation.

Table 73-1

Common Patterns of Pain Referral

PAIN MECHANISM	SITE OF LESION	REFERRAL SITE
Visceral	Diaphragmatic irritation	Shoulder
Visceral	Urothelial tract	Inguinal region and genitalia
Somatic	C7–T1 vertebrae	Interscapular
	L1–2	Sacroiliac joint and hip
	Hip joint	Knee
	Pharynx	Ipsilateral ear
Neuropathic	Nerve or plexus	Anywhere in the distribution of a peripheral nerve
	Nerve root	Anywhere in the corresponding dermatome
	Central nervous system	Anywhere in the region of the body innervated by the damaged structure

Temporal Relationships

Cancer-related pain may be acute or chronic. Acute pain is defined by recent onset and a natural history characterized by transience. The pain is often associated with overt pain behavior (such as moaning, grimacing, and splinting), anxiety, or signs of generalized sympathetic hyperactivity, including diaphoresis, hypertension, and tachycardia. Chronic pain has been defined by persistence for 3 or more months beyond the usual course of an acute illness or injury, by a pattern of recurrence at intervals over months or years, or by association with a chronic pathological process. Chronic tumor-related pain is usually insidious in onset, often increases progressively with tumor growth, and may regress with tumor shrinkage. Overt pain behavior and sympathetic hyperactivity are often absent, and the pain may be associated with affective disturbances (anxiety and/or depression) and vegetative symptoms, such as asthenia, anorexia, and sleep disturbance.

Transitory exacerbations of severe pain over a baseline of moderate pain or less may be described as “breakthrough pain” ( ). Breakthrough pain is common in both acute and chronic pain states. These exacerbations may be precipitated by volitional actions of the patient (so-called incident pains), such as movement, micturition, coughing, or defecation, or by non-volitional events, such as bowel distention. Spontaneous fluctuations in pain intensity can also occur without an identifiable precipitant.

Inferred Pain Mechanisms

It is increasingly becoming clear that the physiology of neuropathic and nociceptive pain may share common features of peripheral and central sensitization. Nonetheless, clinical inference about the predominant mechanisms that may be responsible for the pain continues to be helpful in evaluation of the pain syndrome and management of cancer pain. The assessment process usually provides the clinical data necessary to infer a predominant pathophysiology. Nociceptive pain, neuropathic pain, and idiopathic pain may be recognized. The basis of these types of pain is described in earlier chapters in this book.

Stepwise Approach to the Evaluation of Cancer Pain

A practical approach to assessment of cancer pain incorporates a stepwise approach that begins with data collection and ends with a clinically relevant formulation.

Data Collection

History

Careful review of the patient’s past medical history and chronology of the cancer is important to place the pain complaint in context. The pain-related history must elucidate the relevant pain characteristics, as well as the responses of the patient to previous disease-modifying and analgesic therapies. The presence of multiple pain problems is common, and if more than one is reported, each must be assessed independently. Validated pain assessment instruments can provide a format for communication between the patient and health care professionals and can also be used to monitor the adequacy of therapy (see below).

The clinician should assess the consequences of the pain, including impairment in activities of daily living; psychological, familial, and professional dysfunction; disturbed sleep, appetite, and vitality; and financial concerns. The patient’s psychological status, including current level of anxiety or depression, suicidal ideation, and the perceived meaning of the pain, is similarly relevant. Pervasive dysfunctional attitudes, such as pessimism, idiosyncratic interpretation of pain, self-blame, catastrophizing, and perceived loss of personal control, can usually be detected through careful questioning. It is important to assess the patient–family interaction and to note both the type and frequency of pain behavior and the nature of the family response.

Most patients with cancer pain have multiple other symptoms, and the clinician should evaluate the severity and distress caused by each of these symptoms. Symptom checklists and quality-of-life measures may contribute to this comprehensive evaluation ( , ).

Examination

Physical examination, including neurological evaluation, is a necessary part of the initial pain assessment. The need for a thorough neurological assessment is justified by the high prevalence of painful neurological conditions in this population ( , ). The physical examination should attempt to identify the underlying etiology of the pain problem, clarify the extent of the underlying disease, and discern the relationship of the pain complaint to the disease.

Review of Previous Investigations

Careful review of previous laboratory and imaging studies can provide important information about the cause of the pain and the extent of the underlying disease.

Provisional Assessment

The information derived from these investigations provides the basis for a provisional pain diagnosis, an understanding of the patient’s disease status, and identification of other concurrent concerns. This provisional diagnosis includes inferences about the pathophysiology of the pain and an assessment of the pain syndrome.

Additional investigations are often required to clarify areas of uncertainty in the provisional assessment. The extent of diagnostic investigation must be appropriate to the patient’s general status and the overall goals of care. For some patients, comprehensive evaluation may require numerous investigations, some targeted at the specific pain problem and others needed to clarify the extent of disease or concurrent symptoms.

The lack of a definitive finding on an investigation should not be used to override a compelling clinical diagnosis. In the assessment of bone pain, for example, plain radiographs provide only a crude assessment of bony lesions, and further investigation with bone scintigraphy, computed tomography (CT), or magnetic resonance imaging (MRI) may be indicated. To minimize the risk for error, the physician ordering the diagnostic procedures should personally review them with the radiologist to correlate the pathological changes detected with the clinical findings.

Pain should be managed during the diagnostic evaluation. Comfort will improve compliance and reduce the distress associated with procedures. No patient should be inadequately evaluated because of poorly controlled pain.

Comprehensive assessment may also require additional evaluation of other physical or psychosocial problems identified during the initial assessment. Expert assistance from other physicians, nurses, social workers, or others may be essential.

Formulation and Therapeutic Planning

The evaluation should enable the clinician to appreciate the nature of the pain, its impact, and concurrent concerns that further undermine quality of life. The findings of this evaluation should be reviewed with the patient and appropriate others. Through candid discussion, current problems can be prioritized to reflect their importance to the patient.

This evaluation may also identify potential outcomes that would benefit from contingency planning. Examples include evaluation of resources for home care, pre-bereavement interventions with the family, and provision of assistive devices in anticipation of compromised ambulation.

Measurement of Pain and Its Impact on Patient Well-being

Pain measurement has an important role in the routine monitoring of cancer patients in treatment settings ( , ). Since observer ratings of symptom severity correlate poorly with patient ratings and are generally an inadequate substitute for patient reporting ( ), patient self-report is the primary source of information for the measurement of pain.

Pain Measures in Routine Clinical Management

Guidelines from the , , , and the recommend the regular use of rating scales to assess pain severity and relief in all patients who commence or change treatments. These recommendations also suggest that clinicians teach patients and families to use assessment tools in the home to promote continuity of pain management in all settings.

The two most commonly used scales for adults are a verbal descriptor scale (i.e., “Which word best describes your pain: none, mild, moderate, severe, or excruciating?”) or a numerical scale (i.e., “On a scale from 0 to 10, where 0 indicates no pain and 10 indicates the worst pain you can imagine, how would you rate your pain?”) ( , ).

demonstrated that use of a simple verbal pain assessment tool improved the caregiver’s understanding of pain status in hospitalized patients. Routinely measuring pain intensity as a fifth vital sign by using a pain scale incorporated into the bedside chart can help make pain a visible parameter that is monitored dynamically ( ).

Acute Pain Syndromes

Cancer-related acute pain syndromes are most commonly due to diagnostic or therapeutic interventions ( ) and generally pose little diagnostic difficulty. Although some tumor-related pain has an acute onset (such as pain from a pathological fracture), most such pain will persist unless effective treatment of the underlying lesion is provided.

Acute Pain Associated with Diagnostic and Therapeutic Interventions

Many investigations and treatments are associated with predictable, transient pain. In patients with a pre-existing pain syndrome, otherwise innocuous manipulations can also precipitate incident pain.

Acute Pain Associated With Diagnostic Interventions

Lumbar Puncture Headache

Lumbar puncture (LP)-related headache is the best characterized acute pain syndrome associated with a diagnostic intervention. This syndrome is typified by the delayed development of a positional headache that is precipitated or markedly exacerbated by an upright posture. Less commonly, dural puncture may also cause back pain, arm pain, thoracic pain, and bowel and bladder dysfunction. The pain is believed to be related to a reduction in cerebrospinal fluid (CSF) volume as a result of ongoing leakage through the defect in the dural sheath and compensatory expansion of the pain-sensitive intracerebral veins ( ). The incidence of headache is related to the caliber of the LP needle. Risk for LP headache can be reduced by several strategies: when using a regular beveled needle, longitudinal insertion of the needle bevel, which causes less trauma on the longitudinal elastic fibers in the dura, may reduce the incidence of headache ( ).

Non-traumatic, conically tipped needles with a lateral opening are associated with substantially lower risk for post-LP headaches than regular cannulas are ( , ). The evidence that recumbency after LP reduces the incidence of this syndrome is controversial ( , ).

LP headache, which usually develops hours to several days after the procedure, is typically described as a dull occipital discomfort that may radiate to the frontal region or to the shoulders. The pain is commonly associated with nausea and dizziness. The duration of the headache is usually 1–7 days, and routine management relies on rest, hydration, and analgesics. Persistent headache may necessitate the application of an epidural blood patch. Although a controlled study suggested that prophylactic administration of a blood patch may reduce this complication ( ), the incidence and severity of the syndrome do not warrant such treatment. Severe headache has also been reported to respond to treatment with intravenous or oral caffeine ( ).

Transthoracic Needle Biopsy

Transthoracic fine-needle aspiration of an intrathoracic mass is generally a non-noxious procedure. Severe pain has, however, been associated with this procedure when the underlying diagnosis was a neurogenic tumor ( ).

Transrectal Prostatic Biopsy

Transrectal ultrasound-guided prostate biopsy is an essential procedure in the diagnosis and management of prostate cancer. In a prospective study, 16% of patients reported pain of moderate or greater severity and 19% would not agree to undergo the procedure again without anesthesia ( ). Subsequent studies have demonstrated a low rate of severe pain ( ). When present, pain may persist up to 4 weeks after the biopsy ( ). Periprostatic lidocaine infiltration ( ), intrarectal introduction of 2% lidocaine cream ( ), and a unilateral pudendal nerve block ( ) substantially reduce the pain associated with this procedure.

Mammography Pain

The breast compression associated with mammography can cause moderate and, rarely, severe pain ( ). The duration of the pain is generally short ( ). Unless patients are adequately counseled and treated, occasional patients will refuse repeat mammograms because of pain ( ). Pain may be reduced by using a lower level of compression, and in a systematic review the only intervention found to significantly reduce the pain was patient-controlled compression ( ).

Acute Pain Associated with Therapeutic Interventions

Postoperative Pain

Acute postoperative pain is universal unless adequately treated. Unfortunately, undertreatment is endemic despite the availability of adequate analgesic and anesthetic techniques ( ). Guidelines for management have been reviewed ( , ). Postoperative pain that exceeds the normal duration or severity should prompt careful evaluation for the possibility of infection or other complications.

Radiofrequency Tumor Ablation

Radiofrequency tumor ablation is commonly used for the management of liver metastases. It is also increasingly being used in other settings, including adrenal metastases and renal tumors, as well as for lung, breast, and bone tumors. Percutaneous ablation of liver tumors may be associated with severe right upper quadrant abdominal pain or pain radiating to the right shoulder ( ) in 5–10% of patients. Pain has also been reported after radiofrequency ablation of renal lesions ( ), and it is presumably possible with the use of this approach in other sites.

Cryosurgery

Cryotherapy is commonly used for the management of skin, cervical, and prostatic tumors. Cutaneous cryotherapy typically causes a local painful reaction that decreases in severity over a period of 2–7 days ( ). Cryosurgery of the cervix for the treatment of an intraepithelial neoplasm frequently produces an acute cramping pain syndrome. The severity of the pain is related to the duration of the freeze period and is not diminished with the administration of prophylactic non-steroidal anti-inflammatory drugs (NSAIDs) ( ).

Other Interventions

Invasive interventions other than surgery are commonly used in cancer therapy and may also result in predictable acute pain syndromes. Examples include the pain associated with tumor embolization techniques ( ), radio-embolization of liver tumors ( ), and chemical pleurodesis ( ).

Acute Pain Associated with Analgesic Techniques

Local Anesthetic Infiltration Pain

Intradermal and subcutaneous infiltration of lidocaine produces a transient burning sensation before the onset of analgesia. This can be modified with the use of buffered solutions ( ). Other maneuvers, including warming the solution ( ) and slowing the rate of injection, ( ) do not diminish injection pain.

Opioid Injection Pain

Intramuscular and subcutaneous injections are painful. When repetitive dosing is required, the intramuscular route of administration is not recommended ( , ). The pain associated with subcutaneous injection is influenced by the volume injected and the chemical characteristics of the injectant.

Opioid Headache

Rarely, a reproducible generalized headache develops after opioid administration. Although its cause is not known, speculation suggests that it may be due to opioid-induced release of histamine.

Spinal Opioid Hyperalgesia Syndrome

Intrathecal and epidural injection of high opioid doses is occasionally complicated by pain (typically perineal, buttock, or leg pain), hyperalgesia, and associated manifestations, including segmental myoclonus, piloerection, and priapism. This is an uncommon phenomenon that remits after discontinuation of the infusion ( ).

Spinal Injection Pain

Back, pelvic, or leg pain may be precipitated by an epidural injection or infusion. The incidence of this problem has been estimated to be approximately 20% ( , ). It is speculated that it may be caused by compression of an adjacent nerve root by the injected fluid ( ). Similar problems have been described with intrathecal injections associated with pericatheter fibrosis ( ).

Acute Pain Associated with Anticancer Therapies

Acute Pain Related to Chemotherapy Infusion Techniques

Intravenous Infusion Pain

Pain at the site of infusion of a cytotoxic substance is a common problem. Four pain syndromes related to the intravenous infusion of chemotherapeutic agents are recognized: venous spasm, chemical phlebitis, vesicant extravasation, and anthracycline-associated flare. Venous spasm causes pain that is not associated with inflammation or phlebitis and may be modified by the application of a warm compress or reduction of the rate of infusion. Chemical phlebitis can be caused by cytotoxic medications, including amsacrine, dacarbazine, carmustine, and vinorelbine, as well as the infusion of potassium chloride and hyperosmolar solutions ( ). The pain and linear erythema associated with chemical phlebitis must be distinguished from the more serious complication of vesicant cytotoxic extravasation ( ). Extravasation of vesicant may produce intense pain followed by desquamation and ulceration. Finally, a brief venous flare reaction is often associated with intravenous administration of the anthracycline doxorubicin. The flare is typically accompanied by local urticaria, and occasional patients report pain or stinging ( , ).

Hepatic Artery Infusion Pain

Cytotoxic infusions into the hepatic artery (for patients with hepatic metastases) are frequently associated with the development of diffuse abdominal pain ( , ). Continuous infusions can lead to persistent pain. In some patients the pain is due to the development of gastric ulceration or erosions ( ) or cholangitis ( ). If the latter complications do not occur, the pain usually resolves with discontinuation of the infusion. A dose relationship is suggested by the observation that some patients will comfortably tolerate re-initiation of the infusion at a lower dose ( ).

Intraperitoneal Chemotherapy Pain

Transient mild abdominal pain associated with sensations of fullness or bloating is reported by approximately 25% of patients after intraperitoneal chemotherapy ( ). A further 25% of patients reports moderate or severe pain necessitating opioid analgesia or discontinuation of therapy ( ). Moderate or severe pain is generally caused by chemical serositis or infection ( ). Chemical serositis is a common complication of intraperitoneal administration of the anthracycline agents mitoxantrone and doxorubicin and with paclitaxel (Taxol), but it is relatively infrequent with 5-fluorouracil (5-FU) or cisplatin. Pain may indicate suboptimal drug distribution within the abdominal cavity. Some patients experience discomfort related to sensing abdominal distention or from intercostal nerve irritation. Abdominal pain associated with fever and leukocytosis in blood and peritoneal fluid is suggestive of infectious peritonitis.

Intravesical Chemotherapy or Immunotherapy

Intravesical bacille Calmette-Guérin (BCG) therapy for transitional cell carcinoma of the urinary bladder usually causes a transient bladder irritability syndrome characterized by frequency and/or micturition pain ( ). Similarly, intravesical doxorubicin ( ), mitomycin C ( ), and thiotepa ( ) can also cause a painful chemical cystitis. Rarely, intravesical BCG treatment may trigger a painful polyarthritis, sometimes associated will full-blown Reiter’s syndrome ( ) or localized regional or systemic infections with abscess formation ( ).

Acute Pain Associated with Chemotherapy Toxicity

Mucositis

Severe mucositis is an almost invariable consequence of the myeloablative chemotherapy and radiotherapy that precede bone marrow transplantation, but it is less common with standard-intensity therapy ( ). The cytotoxic agents most commonly associated with mucositis are cytarabine, doxorubicin, etoposide, 5-FU, and methotrexate. Pretreatment oral pathology and poor dental hygiene increase the risk for chemotherapy-induced mucositis. Younger patients have a relatively greater risk for chemotherapy-induced stomatitis, perhaps related to a higher epithelial mitotic rate. Damaged mucosal surfaces may become superinfected with microorganisms such as Candida albicans and herpes simplex virus ( ). The latter complication is most likely to occur in neutropenic patients, who are also predisposed to systemic sepsis arising from local invasion by aerobic and anaerobic oral flora.

Corticosteroid-Induced Perineal Discomfort

A transient burning sensation in the perineum is described by some patients following the rapid infusion of large doses (20–100 mg) of dexamethasone ( ). Clinical severity is variable and the burning may be severe. Experience suggests that this syndrome can be prevented by slow infusion.

Steroid Withdrawal Pseudorheumatism

Withdrawal of corticosteroids may produce a pain syndrome manifested as diffuse myalgias, arthralgias, and tenderness of muscles and joints. These symptoms occur with rapid or slow withdrawal and may develop in patients taking these drugs for a long or short period. Treatment consists of reinstituting the steroids at a higher dose and withdrawing them more slowly ( ).

Painful Peripheral Neuropathy

Chemotherapy-induced painful peripheral neuropathy, which is usually associated with vinca alkaloids, cisplatin, oxaliplatin, and paclitaxel, can have an acute course. The vinca alkaloids (particularly vincristine) are also associated with other, presumably neuropathic acute pain syndromes, including pain in the jaw, legs, arms, or abdomen that may last from hours to days ( ). Vincristine-induced orofacial pain in the distribution of the trigeminal and glossopharyngeal nerves occurs in approximately 50% of patients at the onset of vincristine treatment ( ). The pain, which is severe in about half of those affected, generally begins 2–3 days after vincristine administration and lasts for 1–3 days. It is usually self-limited, and if recurrence occurs, it is generally mild ( ). Vinorelbine is associated with mild paresthesias in about 20% of patients, but severe neuropathy is rare ( ). The neuropathy associated with paclitaxel is dose related and generally subacute in onset with resolution after completion of therapy ( ); however, in a proportion of patients it can be severe and persistent ( ).

Headache

Intrathecal methotrexate for the treatment of leukemia or leptomeningeal metastases produces an acute meningitis syndrome in 5–50% of patients ( ). Headache is the prominent symptom but may be accompanied by vomiting, nuchal rigidity, fever, irritability, and lethargy. Rarely, it may be manifested as a polyradiculopathy ( ). Symptoms usually begin hours after intrathecal treatment and persist for several days. CSF examination reveals a pleocytosis that may mimic bacterial meningitis. Patients at increased risk for the development of this syndrome include those who have received multiple intrathecal injections and patients undergoing treatment for proven leptomeningeal metastases ( ). The syndrome tends to not recur with subsequent injections.

Systemic administration of l -asparaginase for the treatment of acute lymphoblastic leukemia produces thrombosis of the cerebral veins or dural sinuses in 1–2% of patients ( ). This complication typically occurs after a few weeks of therapy, but its onset may be delayed until after the completion of treatment. Headache is the most common initial symptom, but seizures, hemiparesis, delirium, vomiting, or cranial nerve palsies may also occur. The diagnosis is established by MRI ( ).

Trans -retinoic acid therapy, which may be used for the treatment of acute promyelocytic leukemia (APML), can cause a transient severe headache ( ). The mechanism may be related to pseudotumor cerebri induced by hypervitaminosis A.

Diffuse Bone Pain

Trans -retinoic acid therapy in patients with APML often produces a syndrome of diffuse bone pain ( ). The pain is generalized, of variable intensity, and closely associated with transient neutrophilia. The latter observation suggests that the pain may be due to marrow expansion.

Taxol-Induced Arthralgia and Myalgia

Administration of paclitaxel generates a syndrome of diffuse arthralgia and myalgia in 10–20% of patients ( ). These symptoms are related to individual doses; associations with the cumulative dose and duration of infusion are less clear. Diffuse joint and muscle pain generally appears 1–2 days after the infusion and lasts for a median of 4–5 days. Pain is commonly located in the back, hips, shoulders, thighs, legs, and feet. The pain is often exacerbated by weight bearing, walking, or tactile contact. Steroids may reduce the tendency for the development of myalgia and arthralgia ( ).

5-Fluorouracil–Induced Anginal Chest Pain

Ischemic chest pain may develop in patients receiving 5-FU ( ). Although the overall risk is generally considered to be low (1–2%), this is debated and some evidence suggests that the risk is as high as 20% ( ). Overall, the risk is higher in patients treated with a continuous infusion than in those receiving bolus therapy and higher in patients with pre-existing ischemic heart disease ( ). It is widely speculated that coronary vasospasm may be the underlying mechanism ( ). Similar ischemic cardiotoxicity may occur in patients receiving the 5-FU prodrug capecitabine ( ).

Palmar–Plantar Erythrodysesthesia Syndrome

Also called acral erythema, hand–foot syndrome, toxic erythema of the palms and soles, and Burgdorf’s syndrome, this painful rash is seen in association with continuously infused 5-FU, capecitabine ( ), and liposomal doxorubicin ( ). It has also been reported with paclitaxel ( ) and the tyrosine kinase inhibitors sorafenib and sunitinib ( ). It is characterized by the development of a tingling or burning sensation in the palms and soles followed by the development of an erythematous rash. Its pathogenesis is unknown. Management often requires discontinuation of therapy, and symptoms may be more manageable with lower doses of therapy. Symptomatic measures are frequently required ( ), and treatment with pyridoxine has been reported to induce resolution of the lesions ( ).

Post-chemotherapy Gynecomastia

Painful gynecomastia can occur as a delayed complication of chemotherapy. Testis cancer is the most common underlying disorder ( ), but it has been reported after therapy for other types of cancers as well ( , ). Gynecomastia typically develops after a latency of 2–9 months and resolves spontaneously within a few months. Persistent gynecomastia is occasionally observed ( ).

Chemotherapy-Induced Acute Digital Ischemia

Raynaud’s phenomenon, or transient ischemia of the toes, is a common complication of cis-platinum, vinblastine, and bleomycin (PVB) treatment of testicular cancer ( ). Rarely, irreversible digital ischemia leading to gangrene has been reported after bleomycin ( ). Capecitabine and vincristine have been implicated in case reports ( , ).

Chemotherapy-Induced Tumor Pain

Pain at the site of tumor is reported to occur in some patients (7%) after treatment with vinorelbine. Typically, the pain begins within a few minutes of the vinorelbine infusion, is moderate to severe in intensity, and requires analgesic therapy. Premedication with ketorolac may prevent recurrence in some cases ( ).

Acute Pain Associated with Hormonal Therapy

Luteinizing Hormone–Releasing Factor Tumor Flare in Prostate Cancer

Initiation of luteinizing hormone–releasing factor (LHRF) hormonal therapy for prostate cancer produces a transient symptom flare in 5–25% of patients ( ). The flare is presumably caused by an initial stimulation of release of luteinizing hormone before suppression is achieved. The syndrome is typically manifested as an exacerbation of bone pain or urinary retention; spinal cord compression and sudden death have been reported ( ). Symptom flare is usually observed within the first week of therapy and lasts 1–3 weeks in the absence of androgen antagonist therapy. Co-administration of an androgen antagonist during the initiation of LHRF agonist therapy can prevent this phenomenon ( ).

Hormone-Induced Pain Flare in Breast Cancer

Any hormonal therapy for metastatic breast cancer can be complicated by the sudden onset of diffuse musculoskeletal pain commencing within hours to weeks of initiation of therapy ( ). Other manifestations of this syndrome include erythema around cutaneous metastases, changes in liver function study results, and hypercalcemia. It may be associated with increased metabolic activity at tumor sites, which can be detected with positron emission tomography (PET) ( ). The underlying mechanism is not understood. and the flare reaction is often predictive of later tumor response to the hormonal therapy.

Aromatase Inhibitor–Induced Arthralgia

The aromatase inhibitor medications used in hormonal therapy for breast cancer may cause a multifocal arthralgia syndrome in 10–20% of patients ( ). It is most commonly manifested as early morning stiffness and hand/wrist pain. Pain intensity is variable and in some patients it precludes or interferes in daily activities. Occasionally, it is reason to discontinue treatment because of severe symptoms ( ). The possible mechanisms are unclear, but an association with the development of osteoporosis has been noted ( ). Treatment options for arthralgia (primarily NSAIDs) are often inadequate, and areas of active research include high-dose vitamin D and new targeted therapies to inhibit bone loss.

Acute Pain Associated with Immunotherapy

Interferon-Induced Acute Pain

Virtually all patients treated with interferon experience an acute syndrome consisting of fever, chills, myalgias, arthralgias, and headache ( ). The syndrome usually begins shortly after initial dosing and frequently improves with continued administration of the drug ( ). Doses of 1–9 million units of interferon alfa are generally tolerated, but doses of 18 million units or higher usually produce moderate to severe toxicity ( ). Acetaminophen pretreatment is often useful in ameliorating these symptoms.

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