Pruritus: Persistent Itching Overview

Pruritus (or itching) is an unpleasant sensation that elicits the desire to scratch. It is a distressing symptom that can cause alterations in comfort and threaten the effectiveness of the skin as a major protective barrier. Because of the subjective nature of pruritus, the lack of a precise definition, and the lack of suitable animal models, pruritus is a disorder that has not been researched adequately.

The skin comprises 15 percent of the body’s total weight, and is the largest organ of the body. The skin has significant psychosocial and physical functions. Its function as a protective mechanism is the skin’s most important role. But skin is also essential to self image and one’s ability to touch and be touched, thereby providing an important component of communication.

Symptoms of generalized itching, without rash or skin lesions, may be related to anything from dry skin to an occult carcinoma, and the etiology of the symptoms should be explored. Common nonmalignant etiologic factors include drug reactions, xerosis, scabies, or primary skin diseases. Pruritus is one of the most common complaints of the elderly patient, but estimates of the significance of pruritic symptoms in the elderly population vary from 10 to 50 percent. The most common diagnosis related to pruritus in this population is simply dry skin.

Generalized pruritus is found in about 13 percent of all individuals with chronic renal disease and about 70 to 90 percent of those undergoing hemodialysis for its treatment. Cholestatic liver disease with intrahepatic or post hepatic obstruction, with or without increased serum levels of bile acids, is often associated with pruritus. Other etiologic factors include (but are not limited to) primary biliary cirrhosis, cholestasis related to phenothiazines or oral contraceptives, intrahepatic cholestasis in pregnancy, and post hepatic obstruction.
Etiology/pathophysiology

Hematologic disorders that cause pruritus include polycythemia vera. Some conditions that cause iron deficiency, including exfoliative skin disorder, also cause pruritus. Diabetes and thyrotoxicosis are endocrine causes of pruritus.

Pruritus is a frequent clinical manifestation of people with AIDS, AIDS-related Kaposi’s sarcoma, and AIDS-related opportunistic infections. Pruritus with or without rash has been reported in approximately 84 percent of people with AIDS and 35.5 percent of those with AIDS-related Kaposi’s sarcoma. The incidence of pruritus associated with AIDS-related opportunistic infections approaches 100 percent.

Various malignant diseases are known to produce pruritus. Hodgkin’s disease causes pruritus in 10 to 25 percent of patients. In some instances, pruritus precedes diagnosis of the lymphoma, and may be an indicator of a less favorable prognosis when associated with significant fever or weight loss (“B” symptoms).

Pruritus associated with Hodgkin’s disease is characterized by symptoms of burning and intense itching occurring on a localized skin area, frequently on the lower legs. Other lymphomas and leukemias have been associated with a less intense but more generalized pruritus. Adenocarcinomas and squamous cell carcinomas of various organs (i.e., stomach, pancreas, lung, colon, brain, breast, and prostate) sometimes produce generalized pruritus that is more pronounced on the legs, upper trunk, and extensor surfaces of the upper extremities.

Pruritus associated with malignant diseases has been observed to diminish or disappear with eradication of the tumor and reappear with recurrence of disease.

Drugs associated with secondary pruritus include opium derivatives (cocaine, morphine, butorphanol), phenothiazines, tolbutamide, erythromycin estolate, anabolic hormones, estrogens, Progestins, testosterone and subsequent cholestasis, aspirin, quinidine and other antimalarials, biologics such as monoclonal antibodies, and vitamin B complex. Subclinical sensitivity to any drug may be related to pruritus.

Hypothesized mechanisms of pruritus have been inferred from studies of pain, since pain and itching share common molecular and neurophysiological mechanisms. Both itch and pain sensations result from the activation of a network of free nerve endings at the dermal-epidermal junction. Activation may be the result of internal or external thermal, mechanical, chemical, or electrical stimulation.

The cutaneous nerve stimulation is activated or mediated by several substances including histamine, vasoactive peptides, enkephalins, substance P (a tachykinin that affects smooth muscle), and prostaglandins. It is believed that non-anatomic factors (such as psychological stress, tolerance, presence and intensity of other sensations and/or distractions) determine itch sensitivity in different regions of the body.

The itch impulse is transmitted along the same neural pathway as pain impulses, i.e., traveling from peripheral nerves to the dorsal horn of the spinal cord, across the cord via the anterior commissure, and ascending along the spinothalamic tract to the laminar nuclei of the contralateral thalamus.

Thalamocortical tracts of tertiary neurons are believed to relay the impulse through the integrating reticular activating system of the thalamus to several areas of the cerebral cortex. Factors that are believed to enhance the sensation of itch include dryness of the epidermis and dermis, anoxia of tissues, dilation of the capillaries, irritating stimuli, and psychological responses.

The motor response of scratching follows the perception of itch. Scratching is modulated at the corticothalamic center and is a spinal reflex. After scratching, itching may be relieved for 15 to 25 minutes.

The mechanism through which the itch is relieved by scratching is unknown. It is hypothesized that scratching generates sensory impulses, which break circuits in the relay areas of the spinal cord. Scratching may actually enhance the sensation of itching, creating a characteristic itch-scratch-itch cycle. Other physical stimuli such as vibration, heat, cold, and ultraviolet radiation diminish itching and increase the release of proteolytic enzymes, potentially eliciting the itch-scratch-itch cycle.

A pinprick near or in the same dermatome as an itchy point will abolish the itch sensation. It is known that hard scratching may substitute pain for the itch, and in some instances, the patient might find pain the more tolerable sensation. It is thought that spinal modulation of afferent stimuli (Gate theory) and central mechanisms may play a role in the relief of itch.

Hypothesized pathogenesis of pruritus associated with underlying disease states are varied. Biliary, hepatic, renal, and malignant diseases are thought to produce pruritus through circulating toxic substances. Histamine released from circulating basophils and the release of leuko peptidase from white blood cells may trigger pruritus associated with lymphomas and leukemias. Elevated blood levels of kininogen in Hodgkin’s disease, release of histamine or bradykinin precursors from solid tumors, and release of serotonin in carcinoid may all be related to pruritus.

People receiving cytotoxic chemotherapy, irradiation, and/or biologic response modifiers for treatment of malignancy are likely to experience pruritus. This same population is quite likely to be exposed to many of the other etiologic factors relating to pruritus ranging from nutritionally related xerosis (dry skin) to radiation desquamation, chemotherapy and biologic agent-induced side effects, antibiotic reactions, and other drug sensitivities.
Cytotoxic Chemotherapy

Each of the major classes of antineoplastic agents (alkylating agents, antimetabolites, antibiotics, plant alkaloids, nitrosoureas, and enzymes) include drugs capable of producing cutaneous reactions including pruritus. Patients receiving antineoplastic drugs frequently report dry skin and scaling, thought to be related to effects on sebaceous and sweat glands. Many problems are self-limiting and require no active intervention. Other problems warrant anticipation and implementation of preventive measures.

Hypersensitivity to cytotoxic agents can be manifested by pruritus, edema, urticaria, and erythema. Hypersensitivity reactions vary in symptomatology and depend on the drug, the dosage, and the allergy history of the patient. The agents most associated with hypersensitivities include doxorubicin, daunorubicin, cytarabine, L-asparaginase, paclitaxel, and cisplatin. In most reports, these reactions have been localized to the area of the vascular access and dissipate within 30 to 90 minutes. More dramatic and even life-threatening reactions can occur, and the development of pruritus may represent an early stage of serious hypersensitivity reactions.
Radiation Therapy

Radiation therapy-related pruritus is usually associated with dry desquamation of skin within the treatment field. Dryness and pruritus may occur at an accumulated dose of 2000 to 2800 cGy, and is caused by obliteration of sebaceous glands within the field. This is an acute phenomenon that correlates with the depletion of actively proliferating basal cells in the epidermal layer of the skin, a fixed percentage of which die with each dose fraction of irradiation.

Remaining basal cells undergo cornification and shed at an increased rate, while non-proliferating basal cells are stimulated and their cell cycle shortened. Subsequent peeling of the skin is defined as dry desquamation. The skin becomes dry and the patient may notice itching and burning sensations. Dry skin is susceptible to further injury through scratching and/or formation of fissures, augmenting the risk of infection and tissue necrosis.

If the desquamation process continues, the dermis will eventually be exposed and moist desquamation results. This side effect increases the risk of infection, discomfort, and pain, possibly necessitating interruption of a treatment plan to allow for healing. This can compromise the final outcome of cancer therapy. For this reason, it is desirable to anticipate and prevent the progression of skin reactions to this stage.

External beam therapy with electrons may elicit sore skin reactions than photon therapy since the depth of penetration and linear energy transfer is closer to the skin surface with electrons. Radiation delivery techniques (bolus doses and tangential fields) also influence the degree of reaction. Fields that include skin folds (i.e., the axilla, breast, perineum, and gluteus) are anticipated to have increased reactions because of friction, higher moisture content, and low aeration.