Manual of Dermatologic Therapeutics
7th Edition
© 2007 Lippincott Williams & Wilkins
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26
Pruritus
Kira R. Giovanielli
I. Definition and Pathophysiology
Pruritus is defined as the cutaneous sensation that elicits the desire to scratch. Itching may be localized, generalized, paroxysmal, or unremitting and may be further qualified as burning, tingling, or pricking. Pruritus is almost always an unpleasant sensation and is the most common dermatologic symptom. Like pain, touch, heat, and vibratory sensation, it serves as a protective mechanism against external agents such as plants and parasites. It may be caused by a primary cutaneous disorder, but in 10% to 50% of patients, it may signal an underlying systemic disease.
The neurophysiology of pruritus is becoming better understood. Itching does not occur in an area insensitive to pain nor can it be elicited in patients with congenital absence of cutaneous pain sensation. Therefore, itching was historically believed to be a subset of pain and carried on the same unmyelinated C fibers to the dorsal root ganglia and spinothalamic tract. However, through the use of microneurography, a technique that involves the insertion of fine glass electrodes into C fibers, a subpopulation of exceptionally slow-conducting neurons has been identified. These account for only 10% to 15% of total C fibers, respond to both pruritogenic and thermal stimuli, and have extremely wide innervation territories. Interestingly, increasing temperature lowers the threshold of these receptors to pruritogenic stimuli, corresponding to the frequent patient complaint of increasing itch with higher temperature.
The specialized C fibers may be stimulated by an array of chemical mediators. Histamine is the main peripheral mediator of pruritus, but is not believed to play a significant role in most cases of pruritus secondary to systemic disease. Serotonin, which is contained in platelets, is a less potent pruritogen but can be potentiated by prostaglandin E2. Serotonin antagonists and aspirin, which inhibits prostaglandin synthesis and aggregation, have been found to relieve the itch of polycythemia vera and uremic pruritus. Multiple neuropeptides including substance P, neurotensin, somatostatin, and melanocyte-stimulating hormone may also play a role in pruritus by mediating release of histamine. Opiates exert central regulation of itching through the central nervous system (CNS) but also act peripherally by potentiating histamine-induced itch.
Once stimulated, the specialized C fibers transmit impulses to the ipsilateral dorsal root ganglia where they synapse with itch-specific secondary neurons (1). These secondary neurons cross over and continue to the somatosensory cortex of the postcentral gyrus (2). Recent positron emission tomography (PET) scans suggest that histamine-induced itch activated both the anterior cingulate cortex, which processes the sensory and emotional aspects of itch, as well as the supplemental motor area (1). This explains the traditional observation that itch leads to an inevitable urge to scratch. Central processing of pruritus may also explain variations in the perception of itch (e.g., itching is usually worse at bedtime when there are fewer “distractions”). Psychogenic itching occurs when a psychological or psychiatric state, such as depression, causes either the itch sensation or a lowered threshold for itching (3). CNS pruritus or neurogenic itching presents with intermittent intense “seizures” of itching that cannot be ignored. This may be due to a cerebral stroke, tumor, abscess, or multiple sclerosis or be idiopathic in nature.
Seventy percent of elderly patients are affected by pruritus that may or may not be associated with a dermatologic disease. The presence of serum antibasement membrane zone antibodies has been hypothesized as one cause of senile pruritus (4). Direct and indirect immunofluorescence may be needed to exclude subclinical bullous pemphigoid in elderly patients with severe or unexplained pruritus. This testing would
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also exclude dermatitis herpetiformis, an autoimmune disease associated with gluten-sensitive enteropathy and characterized by deposition of immunoglobulin A (IgA) at the dermal papillae and intractable pruritus over elbows, knees, and the base of the scalp.
Itching is the cardinal symptom of most dermatologic disorders. Although scrupulous examination may be necessary to detect subtle evidence of certain pruritic dermatoses (e.g., mild atopic dermatitis, scabies, and asteatotic eczema), it is the patient who presents with itching but without rash who can pose a particularly challenging diagnostic and therapeutic dilemma. The remainder of this chapter will be devoted to such cases.
II. General Considerations
Pruritus accompanied by no visible skin alterations, other than those produced by scratching, may be a manifestation of numerous systemic disorders (Table 26.1). The evaluation of such patients must be open-minded yet orderly. A detailed history and physical examination, with particular attention to features such as pallor, icterus, adenopathy, or organomegaly, are crucial. Those diseases in which pruritus is a particularly common complaint will be discussed individually.
  • Uremic pruritus. Chronic renal failure is currently the most prevalent of all systemic diseases associated with pruritus. One fourth to one third of uremic patients treated without dialysis exhibit pruritus, and with maintenance hemodialysis this number increases to 70% to 80%. Many patients find that their itching is most severe during or immediately after dialysis treatments, and recent evidence suggests that this may be due to an accumulation of pruritogenic metabolites rather than a hypersensitivity reaction to the products from the dialysis equipment (2).
    The etiology of uremic pruritus is unclear but is likely multifactorial, including xerosis, secondary hyperparathyroidism, abnormal mast cell proliferation, changes in endogenous opioid production, abnormal cutaneous innervation, and increased histamine concentrations.
    TABLE 26-1 Systemic Disorders Associated with Pruritus
    Drug reactions or drug effects (e.g., opiates)
    Endocrine
          Carcinoid syndrome
          Hyperthyroidism
          Hypothyroidism
          Diabetes mellitus
    Hepatitis C
    HIV infection
    Hypereosinophilic syndrome
    Iron deficiency
    Mastocytosis
    Myeloproliferative disorders (e.g., polycythemia vera, Hodgkin’s disease, myelodysplastic syndrome)
    Neurologic disorders (e.g., brain abscess, multiple sclerosis, brain infarct, tumor)
    Obstructive biliary disease (e.g., primary biliary cirrhosis)
    Paraproteinemia/myeloma
    Parasitic infections
    Pregnancy
    Uremia
    Visceral malignancies
    HIV, human immunodeficiency virus.
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    Increased levels of magnesium and vitamin A within the skin have also been postulated to contribute to itching.
  • Hepatogenic pruritus occurs in 20% to 25% of patients with jaundice, but is rare in those lacking cholestasis. Only 4% of patients with Hepatitis C without jaundice exhibit pruritus, although 100% of patients with primary biliary cirrhosis suffer from pruritus and it is the initial symptom in almost half the patients presenting with this disease. Although purified bile salts applied to the skin are pruritogenic and lowering the serum bile concentration usually ameliorates cholestatic pruritus, no convincing evidence has been found that total or individual levels of bile salts, either circulating or within the skin, correlate with the presence or absence of itching. Additional theories propose a role for an accumulated pruritogenic intermediary in bile salt synthesis, bile salt toxicity to hepatic membranes with release of a pruritogen, mast cell activation with histamine release, and centrally acting endogenous opioids accumulating as a result of hepatic failure.
  • Hematologic disorders. Between 30% and 50% of patients with polycythemia vera have pruritus, which often has a prickling sensation and may be evoked by a sudden decrease in temperature, such as when a person gets out of a hot shower. The pruritus may precede the development of the disease by several years, and successful treatment of the disease usually relieves pruritus. Although elevated plasma and urine histamine levels, correlating with an increased number of basophils, have been found in two thirds of patients with polycythemia vera, antihistamines are usually ineffective in controlling their pruritus. Iron deficiency, with or without anemia, may also be associated with pruritus, and in some patients with controlled polycythemia vera and iron deficiency, iron replacement has been shown to abolish the pruritus. However, the risks of iron therapy in polycythemia vera are significant and, in general, preclude its use.
    Pruritus is seen in approximately 30% of patients with Hodgkin’s disease, often many years before the correct diagnosis is evident. It is frequently most severe at night, starting with the legs and later involving the whole body. In localized disease, pruritus may localize to areas of lymphatic drainage from diseased areas, whereas generalized pruritus is seen more often in the nodular sclerosis type of Hodgkin’s disease with mediastinal mass. Severe, generalized pruritus may indicate a worse prognosis.
  • Aquagenic pruritus occurs 1 to 5 minutes after water contact, regardless of temperature, and may last as long as 2 hours. Patients experience itching, tingling, or stinging sensations. No visible skin changes are seen. Polycythemia rubra vera and other myeloproliferative disorders must be excluded. Elevated acetylcholinesterase levels have been detected after water exposure in these patients.
  • Notalgia paresthetica is a sensory neuropathy in which patients present with localized pruritus of the back occasionally accompanied by pain or paresthesia in the T2-T6 distribution. Although the exact pathogenesis of the disease is not known, there is a striking correlation of nostalgia paresthetica with degenerative changes of the spine, suggesting that spinal nerve impingement may play a role (5).
  • Brachioradial pruritus is a condition with localized, intense pruritus over the distribution of the brachioradial nerve on the lateral forearm(s). The primary etiology is presumed to be a solar dermopathy as most patients have a history of excessive ultraviolet exposure, although nerve root impingement has also been hypothesized (6).
  • Scalp dysesthesia or pruritus is characterized by debilitating scalp pain and/or pruritus. Most of these patients are women, and there is no evidence of scalp disease except possibly mild erythema. The symptoms usually intensify with psychological stress, and a subset of these patients will have an associated psychiatric disorder.
  • Pruritus occurs frequently in patients with HIV and may be the presenting sign of acquired immunodeficiency syndrome (AIDS). With advancing HIV disease, there is a switch from Th1 to Th2 cytokines and an associated immune dysregulation (7). Basophils and mast cells from patients infected with HIV demonstrate enhanced degranulation. Additionally, peripheral neuropathy may also contribute to pruritus in this population.
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III. Subjective Data
The history should include the nature, onset, and duration of the pruritus. A thorough history of medication use should be taken including prescription, over-the-counter, and alternative therapies. A detailed review of systems should be undertaken to try to establish any underlying medical problems. Occasionally, one may obtain clues to a particular underlying illness by features such as the relationship to temperature change noted previously for polycythemia vera. More extraordinary are those cases in which the discrete localization of the pruritus suggests the cause (e.g., nasal pruritus as a manifestation of a brain tumor or atypical angina). Psychogenic pruritus does not usually disturb sleep.
IV. Objective Data
A thorough physical examination should be undertaken, including evaluation of the liver, spleen, thyroid gland, and lymph nodes. Primary and secondary lesions, morphology, distribution, and the presence of lichenification are all important clues. In evaluating the upper back, look for sparing of this area (“butterfly sign”), indicating that the pruritus is not related to an underlying dermatologic disease.
In the case of generalized, persistent pruritus of unknown etiology, two levels of screening laboratory tests are recommended:
  • Initial screening (2)
    • Complete blood count (CBC) with differential
    • Chemistry profile including liver and renal function
    • Hepatitis C screen
    • Thyroid panel
    • Urinalysis
    • Occult blood in stool for patients over 40 years
    • HIV testing
    • Chest x-ray
    • Referral to their primary care physician for complete physical examination to detect any possible underlying malignancy/disease not detected with the above measures
    • Consider skin biopsy for routine histology and special stains for mast cells and a second specimen for immunofluorescence.
  • Second-level screening (8)
    • Serum protein electrophoresis
    • Ferritin level
    • Ova and parasite evaluation of stool
    • 5-Hydroxcyindoleacetic acid and mast cell metabolites in the urine
    • Additional radiologic studies as necessary.
V. Therapy
  • Specific measures
    • Uremic pruritus
      • Naltrexone (50 mg PO daily), an opiate antagonist, has been effective in relieving the pruritus associated with hemodialysis, supporting the role of opioids in renal itch. It has shown short-term benefits with few side effects (9).
      • Activated charcoal (6 g daily) has been found in two controlled trials to be effective in some patients on dialysis (9). Charcoal may nonspecifically bind other oral drugs that patients are receiving. It is cost-effective and has a favorable side-effect profile.
      • Ultraviolet B (UVB) phototherapy has shown effectiveness in double-blind trials, but similar effects are not seen with UVA (9). The potential carcinogenic risk in a group of patients who may later receive transplants should not be overlooked. Additionally, the psychological effects of becoming dependent on another machine should not be underestimated.
      • Ondansetron (4 mg twice daily), a potent and selective serotonin antagonist has been reported to be effective in patients on continuous ambulatory peritoneal dialysis (9). In these patients, ondansetron reduced the plasma levels of both histamine and serotonin.
      • Topical capsaicin 0.025% cream application has improved localized pruritus related to hemodialysis.
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      • Parathyroidectomy may result in a dramatic relief from itching within 24 to 48 hours in patients with secondary hyperparathyroidism. The response is not invariable, and if patients become hypercalcemic postoperatively, the pruritus can recur.
      • Cholestyramine has been tried with some success, but often has varied results.
      • Erythropoietin therapy lowers plasma histamine levels and can reduce the symptoms of pruritus in patients with uremia on hemodialysis.
    • Cholestatic pruritus
      • Cholestyramine (4 g one to three times daily), an anion exchange resin, is frequently effective, although, as mentioned earlier, its antipruritic effect seems separate from its ability to normalize bile salt levels. Cholestyramine is a powder that is mixed with water or another fluid before ingesting. Colestipol (Colestid) is another ion exchange resin that may be substituted in patients who find cholestyramine too constipating. Like charcoal, ion exchange resins may bind other orally administered drugs. Oral vitamin K supplements (10 mg/week) should be given concurrently.
      • Phenobarbital (3 to 4 mg/kg/day PO) can reduce cholestatic pruritus, possibly by enhancing hepatic microsomal function (1). Phenobarbital is sedating and may interfere with the metabolism of many drugs.
      • Phototherapy using UVB or continuous-spectrum fluorescent bulbs (Daylite, 360 to 700 nm) may be helpful in individual patients, although seemingly not as often as for uremic pruritus.
      • Rifampin (300 to 450 mg daily) is very effective in relieving the pruritus of primary biliary cirrhosis, by inhibiting hepatic bile uptake and stimulating mixed-function oxidases. Liver enzymes should be monitored to detect drug-induced hepatitis. Children with pruritus and cholestatic liver disease have also been reported to improve with this drug.
      • Plasma perfusion through a column of charcoal-coated beads was effective in relieving pruritus in a study of eight patients. The duration of response ranged from 1 day to 5 months (1).
      • Naltrexone (50 mg daily), an oral opioid antagonist, has demonstrated effectiveness with fewer side effects than the parenterally administered nalmefene.
      • Danazol, a synthetic androgen, has been used to treat the pruritus of primary biliary cirrhosis, urticaria, and also idiopathic pruritus.
    • Hematologic diseases
      • Cimetidine, an H2 blocker (see Chap. 40, Antihistamines), and cyproheptadine, an antihistamine and antiserotonin agent (see Chap. 40, Antihistamines), have been anecdotally reported to be effective in reducing the pruritus caused by polycythemia vera, as well as Hodgkin’s disease (1).
      • Pizotifen (0.5 mg three times daily), a potent antihistamine and antiserotonin agent usually prescribed for migraine prophylaxis, has had reported success in patients with polycythemia vera (1).
      • Interferon-α-2b and psoralens plus ultraviolet A (PUVA) have both been used successfully in treating the pruritus of polycythemia vera.
      • Danazol has been used for treatment of pruritus associated with polycythemia vera and systemic lupus erythematosus. The exact mechanism of action is unknown.
      • Iron replacement will abolish pruritus due to iron deficiency, often before any measurable change occurs in the hematologic status. However, care should be taken in patients with polycythemia vera, whose underlying disease can be exacerbated by iron supplementation.
  • General measures
    • Oral antihistamines are usually ineffective for pruritus caused by systemic illness. Agents such as hydroxyzine, diphenhydramine, and cyproheptadine and may be helpful because of their sedative effect, not their primary antihistamine properties. Doxepin, a tricyclic antidepressant with antihistamine activity, is highly recommended both for its antipruritic and sedating qualities as well as mild antidepressant effects.
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    • Topical antihistamines have been shown effective in decreasing pruritus in various types of dermatitis (atopic, lichen simplex chronicus) and may be helpful in other pruritic conditions. A risk for contact sensitization exists with topical antihistamines. Doxepin (Zonalon) cream is applied twice daily to localized areas or “hot spots”; there is systemic absorption, precluding its application to large body surface areas. Drowsiness may be a problem if applied to >10% of the body surface. Topical pramoxine, a topical anesthetic and antihistamine, can be useful in pruritus with low risk of contact sensitization, but with a short duration of action.
    • Coexisting conditions that may aggravate the pruritus, particularly xerosis, as is frequently observed in chronic renal failure, should be managed appropriately. Discontinuation of antistatic sheets in the dryer is sometimes helpful. The use of too many blankets or keeping the temperature of the house too high should be discouraged.
    • Dietary manipulation occasionally may be helpful—low-protein diets have been successful for uremic pruritus, whereas diets rich in polyunsaturated fatty acids may help cholestatic pruritus.
    • Topical lidocaine or topical capsaicin (Zostrix) can be effective for localized pruritus such as notalgia paraesthetica. Patients should be warned about the burning sensation associated with application of capsaicin.
    • Phototherapy with PUVA or UVB can be helpful in pruritus in general. In HIV-associated pruritus, there is theoretical evidence that ultraviolet radiation can be associated with viral activation, although no consistent alteration in CD4-positive cell counts or viral load have been determined (10).
    • Naltrexone, an oral opiate receptor antagonist, has been found to be helpful in patients with a variety of skin disorders, with a single daily dose of 50 mg. Further double-blind studies are necessary, and the issue of tolerance and withdrawal symptoms with this group of drugs needs to be taken into account.
    • Transcutaneous electronic nerve stimulation (TENS) and cutaneous field stimulation (CFS) may be helpful in generalized and localized pruritus (11,12).
    • Herbal remedies such as oatmeal baths, chamomile compresses, and aloe vera cream may provide relief with few side effects (13).
    • Occasionally, a referral to a neurologist may be helpful in detecting an underlying neurologic disorder.
References
1. Etter L, Myers SA. Pruritus in systemic disease: mechanisms and management. Dermatol Clin 2002;20:459–472.
2. Krajnik M, Zylicz Z. Understanding pruritus in systemic disease. J Pain Symptom Manage 2001;21:151–168.
3. Gupta MA, Gupta AK. Depression modulates pruritus perception: a study of pruritus in psoriasis, atopic dermatitis, and chronic idiopathic urticaria. Psych Med 1994;56:36–40.
4. Hachisuka H, Kurose K, Karashima T, et al. Serum from normal elderly individuals contains anti-basement membrane zone antibodies. Arch Dermatol 1996;132:1201–1205.
5. Savk E, Savk O, Bolukbasi O, Notalgia paresthetica: a study on pathogenesis. Int J Derm 2000;39:754–659.
6. Wallengren J. Brachioradial pruritus: a recent solar dermopathy. J Am Acad Dermatol 1998;39:803–806.
7. Smith KJ, Skelton HG, Yeager J, et al. Pruritus in HIV-1 disease: therapy with drugs which may modulate the pattern of immune dysregulation. Dermatology 1997;195:353–358.
8. Woodall TG. Pruritus. Curr Probl Dermatol 112:2000;P14–P16.
9. Murphy M, Carmichael AJ. Renal itch. Clin Exp Dermatol 2000;25:103–106.
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10. Lim HW, Vallurupalli S, Meola T, et al. UVB phototherapy is an effective treatment for pruritus in patients infected with HIV. J Am Acad Dermatol 1997;37:414–417.
11. Monk BE. Transcutaneous electronic nerve stimulation in the treatment of generalized pruritus. Clin Exp Dermatol 1993;18:67–68.
12. Nilsson H, Levinsson A, Schouenborg J. Cutaneous field stimulation (CFS): a powerful new method to combat itch. Pain 1997;71:49–55.
13. Millikan LE. Alternative therapy in pruritus. Dermatol Ther 2003;16:175–180.
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