Chronic Pruritus in the Absence of Specific Skin Disease: An Update on Pathophysiology, Diagnosis, and Therapy

Nicoletta Cassano; Gianpaolo Tessari; Gino A. Vena; Giampiero Girolomoni

Disclosures

Am J Clin Dermatol. 2010;11(6):399-411. 

In This Article

Relevant Clinical Examples of Pruritus Associated with Systemic Diseases

Uremic Pruritus

Pruritus is present in 15–49% of patients with chronic renal failure and in up to 90% of patients receiving dialysis.[32] The pathogenesis is still obscure but present data point toward a central role of the immune and opioidergic systems. Hemodialysis-related pruritus seems to be induced by an immune system derangement, resulting in a proinflammatory state.[33] An imbalance in the opioidergic system, with hyperactivity of μ-opioid receptors, has also been observed.[1,2,33] Other factors may include calcium-phosphate imbalance, hyperparathyroidism, anemia, higher serum levels of histamine, and peripheral neuropathy.[32,33] In two-thirds of patients, pruritus is generalized, while in the others it is localized, particularly on the back. In nearly half of patients it appears on a daily basis, whereas in the other half it occurs more rarely. Some patients report pruritus during or soon after dialysis.[33] Pruritus and its severity seem to correlate with duration of dialysis and skin dryness, but without general agreement.[32,33] Chronic pruritus is a strong independent predictor of poor quality of life and of severe sleep disturbances in dialysis patients.[34,35]

Many attempts have been made to relieve this bothersome symptom; however, with generally limited success.[36] Patients may benefit from the regular use of emollients to control skin xerosis.[33] Sedating antihistamines may be helpful, but no randomized controlled trials (RCTs) support their use.[33] Thalidomide, gabapentin, and nalfurafine, a κ-opioid receptor agonist, have proven to be effective in RCTs, but the potential toxicity associated with these drugs limits their use.[37–39] Some studies demonstrated that UVBis still the treatment of choice in moderate to severe pruritus, but the need for regular sessions of therapy over the dialysis treatment may be impractical for many patients.[40,41] General considerations regarding treatment of uremic pruritus are reported in table IV .

Cholestatic Pruritus

Cholestasis refers to a reduction in bile flow, which may be due to extra-hepatic (usually obstructive) or intra-hepatic causes (e.g. primary sclerosing cholangitis, primary biliary cirrhosis, chronic hepatitis, malignant tumors, pregnancy).[42] A large number of drugs may induce cholestasis, with or without liver injury, after weeks to months from the start of treatment.[43] Pruritus can occur in up to 80%of patients with primary biliary cirrhosis.[44] The pathogenesis of cholestasis-associated pruritus remains poorly understood, and may be multifactorial. Peripherally acting pruritogens (bile acids) and altered central neurotransmission have been implicated.[43,44]

The management of cholestatic pruritus has been extensively reviewed, and current recommendations are summarized in table V .[44,47] Naloxone, naltrexone, rifampin (rifampicin), colestyramine (cholestyramine), and phenobarbital (phenobarbitone) are recommended as agents of choice by the American guidelines for the treatment of pruritus in primary biliary cirrhosis.[44] However, the available RCTs have been conducted in small numbers of patients, are few in number, and have used heterogeneous methods. Cumulative evidence from pooled RCTs suggests that rifampin and opioid antagonists demonstrate a reduction in pruritus, whereas there are insufficient data to judge the efficacy of colestyramine.[45] Some evidence also supports the use of the serotonin reuptake inhibitor sertaline[46] and ursodeoxycholic acid,[47] with the latter drug being the mainstay of therapy in primary biliary cirrhosis.

Pruritus Accompanying Systemic Infections Including HIV Infection

Pruritus may be a symptom of cutaneous and extracutaneous infection, as well as of intestinal parasitic infestation. In particular, certain viral infections may have a prominent role in chronic pruritus.

Pruritus is one of the most frequent symptoms encountered in HIV infection and can even be the first clinical symptom. It can be isolated or associated with different skin diseases (such as seborrheic dermatitis, atopic dermatitis, psoriasis, eosinophilic folliculitis) or may result from the release of pruritogenic mediators, neurologic disturbances, drug intake, or systemic disorders (lymphoma, infections, infestations).[48] The immune dysregulation can cause the perturbation of cytokine milieu, with a trend towards a predominant T helper-2 response. For this reason, eosinophilia is not an uncommon finding. An important skin rash is the pruritic papular eruption, which is correlated with the magnitude of immunodeficiency.[49] Some case series showed that the prevalence of prurigo nodularis was higher in patients with CD4-positive cell counts of <200 cells/mm3 and among patients not receiving highly active antiretroviral therapy (HAART), whereas patients with HIV viral loads >55 000 copies/mL had a higher prevalence of 'idiopathic' pruritus.[50] Some HIV-associated pruritic skin diseases may be ameliorated by HAART. Both psoralen plus UVA (PUVA) and UVB have proven to be successful in HIV-associated pruritus, with UVB preferred overPUVAdue to safety reasons.[40,48,49] Other symptomatic treatments have mostly been used in small case series or uncontrolled studies.[48] Some reports support the efficacy of thalidomide for the treatment of prurigo nodularis in HIV-infected patients, who appear, however, particularly prone to developing peripheral neuropathy.[51]

Pruritus has been reported in up to 15% of patients with chronic HCV infection, and may be a presenting symptom. The pathogenesis of HCV-related itch is still obscure. Chronic hepatitis with moderate to severe fibrosis has been suggested to result in low-grade cholestasis, with pruritus resulting from the disappearance of the bile duct. In the absence of cholestasis, itch may be an adverse effect of antiviral therapy, as it happens in up to 29% of patients treated with interferon-α plus ribavirin.[52] Both HIV and HCV infection are associated with prurigo nodularis.[18]

Malignancy-related Pruritus

Pruritus can be present as a part of a paraneoplastic syndrome in association with some solid tumors including lung, colon, breast, stomach, and prostate. In the palliative care setting, pruritus has been estimated to affect 5–27% of patients.[53] The pathogenesis is complex and may involve central and peripheral mechanisms, including the production of pruritogenic substances by the tumor or itch induced by drugs used in palliative care (opioids).[54] Malignancy-related pruritus is usually generalized. In some patients, localization of pruritus correlates with the site of the tumor: carcinomas of the cervix, rectum/sigmoid colon, and prostate may present with pruritus of the vulva, anus, and scrotum, respectively.[55] In these cases, pruritus may derive from direct activation of peripheral nerve fibers at tumor sites.[56] Brain or spinal tumors may manifest with facial or nasal itch, and dermatomal itch, respectively.[57,58]

Pruritus is common in patients with hematologic malignancies. Itch is reported by about 30%of patients with Hodgkin disease, especially those with the nodular sclerosing subtype. It is considered a B symptom, and can precede any identifiable sign of the tumor by up to 5 years.[55] Nearly half of patients with polycythemia vera have pruritus, either spontaneous or soon after contact with water (aquagenic pruritus), especially at high temperature; and in more than 20% of patients it can persist despite adequate disease control. Other than true itch sensation, aquagenic pruritus is accompanied by stinging or pin-point sensations lasting 10–30 minutes after contact with water, and in most cases is a transient benign disorder. Aquagenic pruritus, which seems to be more common among polycythemia vera JAK2 617V>F homozygous patients, may be the sole marker of the disease and can appear as many as 3–5 years before the true onset of the disease.[59,60] Aquagenic pruritus has also been described in patients with acute lymphoblastic leukemia, and myelodysplastic syndrome alone or in association with T-cell non-Hodgkin lymphoma.[60] Generalized pruritus has also been reported in patients with other hematologic malignancies, such as chronic lymphocytic leukemia, non-Hodgkin lymphoma, and multiple myeloma.[61,62]

Endocrine Disorders and Iron Deficiency

Pruritus can be associated with thyroid abnormalities (hyperthyroidism more frequently) and with diabetes mellitus. Hypothyroidism, hypoparathyroidism, and pseudohypoparathyroidism can cause pruritus secondary to severe skin dryness.[63] Although the relationship between diabetes and pruritus is still controversial, some reports suggest an increased frequency of vulvar pruritus only in women with poorly controlled diabetes.[63] However, diabetes may cause neuropathy, and consequently can be implicated in neuropathic itch.

Iron deficiency is another well known cause of chronic pruritus. High rates of this association have been recently reported, suggesting the opportunity to include ferritin and iron studies among the routine examinations of patients with chronic pruritus of apparently unknown origin.[64] Pathogenic mechanisms remain unknown. Restoring the serum ferritin within the normal range through iron supplementation has been reported to be helpful. In any case, the presence of iron deficiency should lead to the exclusion of any condition responsible for such a deficiency, including malignancies.[64]

Drug-Induced Pruritus

Pruritus occurs in 10–50% of patients receiving intravenous administration of opioids, and in 20–100% of patients when opioids are given by epidural or intraspinal injections. Postulated mechanisms include a direct central effect, as well as histamine and serotonin release.[65] An extensive review of numerous RCTs investigating the therapeutic approach to opioid-induced itch has been recently published.[65] Few drugs can be used to treat established opioid-induced pruritus. Histamine H1 receptor antagonists have little effect.[65] Intravenous nalbuphine and propofol significantly reduced opioid-induced itch in adults undergoing surgery (RCTs).[66] Nalbuphine seems to be more effective than propofol (RCT).[67] Ondansetron diminished postoperative itch and vomiting after opioid administration[68] and was also found to attenuate intrathecal fentanyl-induced pruritus.[65] Prevention of opioid-induced itch can also be obtained with low doses of opioid antagonists (naloxone, naltrexone, and nalmefene), but they may reverse the analgesic effects.[66,69,70] An agonist/antagonist drug such as nalbuphine can reduce pruritus without compromising analgesia.[71] Of note, recent RCTs have shown that premedication with either mirtazapine or gabapentin is capable of preventing pruritus caused by intrathecal morphine.[72,73]

Essentially any other drug may cause an adverse reaction in the skin, which can be associated with pruritus. Pruritic reactions are usually morbilliform or urticarial; however, a growing number of drugs can induce pruritus without any skin rash.[74,75] No universally accepted method for assessing the causality of an adverse drug reaction has been approved.[76] A congruous temporal sequence between the beginning of drug therapy and onset of itch, improvement after drug withdrawal, and recurrence after drug rechallenge are useful elements.[74,76] Drug-induced pruritus is likely to be underestimated in the general population, and especially in elderly patients, and it can be misdiagnosed as senile 'idiopathic' pruritus.[75,76] Antihypertensive drugs, especially angiotensin converting enzyme inhibitors, can induce pruritus alone, or pruritus associated with angioedema and other pruritic cutaneous disorders (i.e. urticaria, maculopapular and lichenoid eruptions).[77] In the elderly, drug-induced pruritus is frequently observed in patients taking multiple medications, which may more easily induce adverse effects because of impaired metabolism and/or pharmacologic interactions. Alist of the principal drugs able to induce pruritus without skin changes is given in table VI .

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