Pruritus
Alan B. Fleischer Jr.
Christopher B. Yelverton
Like the sensation of pain, pruritus (itching) can diminish the quality of life in patients with cancer. Because of the distress pruritus may cause, the cancer clinician should be aware of its importance and its management. Pruritus in patients with cancer may be attributable to a primary skin disease, a coexisting medical condition, a medication, or the cancer itself. Indeed, to quote Krajnik and Zylicz, “There is no one cure for all pruritic symptoms. Better understanding of mechanisms of pruritus may help develop better treatments” (1). A number of notable articles, chapters, and texts on itch have been published by leading authorities (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13). This chapter focuses on pruritus in patients with cancer and reviews its etiology, diagnosis, and management. Readers should bear in mind that patients with cancer can be affected by the same pruritic conditions that those without cancer may acquire, in addition to cancer and cancer treatment–associated conditions.
Pruritus Sensations
In simplest terms, pruritus is the sensation that provokes scratching. Like the sensation of pain, objective analysis cannot easily confirm the presence or severity of pruritus. Nevertheless, patients are generally thought to be reliable in their assessment of pruritus severity. Scratch marks (excoriations), skin thickening (lichenification), and visible cutaneous disease support patients’ subjective complaints.
To complicate the issue, some patients with typically itchy diseases, such as scabies, deny that they itch. These patients may complain of burning, stinging, tingling, tickling, or a crawling sensation. These symptoms are closely related to pruritus, have similar pathogenic mechanisms, and are treated identically. Bernhard (14) summarized this notion by stating, “one man’s itch is another man’s tickle … and one man’s stinging itch is another man’s pain.” For most people, itch is readily distinguished from pain, and many patients with severe pruritus would be happy to have pain instead (15).
Pruritus is a distinct, complex sensation that may be considered a primary sensory modality (10). The cutaneous itch response is carried by unique sensory C-fibers (15). Although itch fibers are histologically indistinguishable from pain receptors, they may be distinguished electrophysiologically. These unmyelinated fibers carry sensations to the spinothalamic tract where they are relayed to the thalamus and subthalamus. Experimental injection of histamine into the skin induces itch or pain. This histamine-induced pruritus may be suppressed by systemic antihistamine administration (16).
Because many patients with pruritus show no signs of histamine release (e.g., cutaneous wheal and flare), it is likely that other compounds (e.g., cytokines and neuropeptides) cause most pruritus. Furthermore, the failure of many pruritic conditions to improve with nonsedating antihistamines suggests that histamine is a minor pruritus mediator (17, 18). Studies have revealed that pruritus may be caused by opiates, serotonin, and other neuropeptides, prostaglandins, kinins, proteases, and physical stimuli (10). Each of these agents may induce pruritus primarily or act through secondary mediators.
The sensation of pruritus also may arise within the central nervous system. Systemic opioids are known to induce pruritus, and the opioid-antagonists, including naloxone hydrochloride, naltrexone hydrochloride, and nalmefine hydrochloride, decrease the pruritus of cholestatic and other liver disease (19, 20, 21, 22). Exogenous opioids administered in small quantities to spinal levels in spinal anesthesia relieve pain and can stimulate itching (23). Plasma from patients with cholestatic itching causes facial scratching when introduced into the medullary dorsal horn of monkeys; this scratching is abolished by administering the opioid receptor antagonist naloxone hydrochloride (24). Although opioids may promote histamine release by mast cells (e.g., exacerbating urticarial itch), opioid peptides generally do not cause any release of histamine when injected alone.
Other central nervous system pruritic phenomena include cerebrovascular accident pruritus (25) and phantom limb or phantom breast pruritus (i.e., pruritus in an amputated extremity or removed breast) (26, 27). Therefore, it is clear that pruritus is often not histamine induced and may not arise in the skin.
Dermatologic Diseases and Pruritus
Many skin diseases may contribute to the sensation of pruritus. Dry skin, or xerosis, is commonly seen in patients with cancer who have generalized wasting or have undergone chemotherapy or radiation therapy. Xerosis makes the skin more susceptible to irritation from environmental assault (28).
Many other diseases may present with pruritus, including scabies, atopic dermatitis, dermatitis herpetiformis, bullous pemphigoid, miliaria, pediculosis, and urticaria (29). These cutaneous diseases are often readily diagnosed by careful clinical examination. Signs of dermatologic diseases may be remarkably subtle or nonspecific in any given patient, particularly in the immunocompromised host. There is no substitute for an excellent physical examination of the skin surface (30, 31, 32, 33, 34, 35, 36).
Pruritus and Malignancy
Pruritus may be associated with virtually any malignancy (Table 20.1) (5, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52). Some neoplasms, particularly hematologic malignancies, are more frequently associated with pruritus. Primary polycythemia, for example, has a pruritus prevalence of 30 to 50%, and Hodgkin’s disease has a prevalence of 15%. Cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and other cutaneous lymphomas are notoriously pruritic. Generally, the etiology of the pruritus in these patients is thought to be related to a poorly understood paraneoplastic phenomenon. Pruritus may be a presenting symptom in both solid and hematologic cancers (53, 54). Gobbi et al. (48) reported that severe pruritus in Hodgkin’s disease predicts a poor prognosis. Pruritus may also be a sign of malignant physical obstruction of the biliary system from either a primary or metastatic tumor (50).
Table 20.1 Systemic Conditions Reported to Be Associated With Generalized Pruritus | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Pruritus and Nonmalignant Internal Diseases
Patients with cancer are not exempt from having concurrent medical conditions. There is no question that other internal diseases may be associated with pruritus (Table 20.1). Pruritus has been reported to herald the onset of thyroid disease (55), renal insufficiency (56), liver disease (57), iron deficiency (58), diabetes mellitus (59), paraproteinemia (60), Sjögren’s syndrome (61), and other conditions. Patients with cancer can independently develop other medical conditions, or the cancer itself may cause a systemic condition, such as biliary obstruction, that may cause pruritus. Mechanisms of pruritus induction in most of these diseases are poorly understood. It has been postulated that renal disease may induce a metastatic calcification, hyperphosphatemia, xerosis, mast cell proliferation, and other changes that might be associated with pruritus.
Cancer Therapy
Pruritus may be the result of a chemotherapy reaction, radiation therapy, or medications used for symptom management. Pruritus has been reported as an adverse reaction to chemotherapeutic agents, including those listed in Table 20.2 (62, 63, 64, 65, 66, 67, 68). Adverse effects of some chemotherapeutic agents may include anemia and other metabolic disturbances, which could also lead to pruritus. New combinations of chemotherapeutic agents in ever increasing dosage regimens will undoubtedly be associated with increased cutaneous toxicity. Pruritus caused by opioids, particularly injectible opioids, used for pain control is also possible. Additionally, pruritus may be caused by other chemicals that may be used in the preparation of medications and medication administration tools (69).
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