Diagnosis and Management of Chronic Pruritus: An Expert Consensus Review.

What was known?

The recommendations for the management presented in this paper are the result of a panel consensus meeting held in March 2014 in Mumbai. The aim of these recommendations is to improve the diagnosis and management of Indian patients with pruritus.

Introduction

Pruritus is an unpleasant sensation on the skin eliciting the desire to scratch. Chronic pruritus (CP) refers to daily/almost daily itching, lasting more than 6 weeks.[ 1 ] Clinically, pruritus has been described as the most frequent symptom in dermatological condition. It has demonstrated a significant impact on patient's quality of life (QoL) that causes various problems related to sleep, anxiety, attention, and sexual function. Moreover, CP poses a significant burden on the society in terms of health-care cost and treatment challenges.[ 1 ] In addition, many systemic diseases are also known to be associated with pruritus and further incapacitating nature of this condition.[ 2 ] Insufficient data have been reported on the prevalence of CP. It has been suggested that there is an increase in the prevalence of CP with advancing age.[ 3 ] Moderate-to-severe pruritus is known to affect 60% of the elderly individuals (≥65 years of age).[ 4 ] Recent studies have suggested a point prevalence of CP to be approximately 13.5% in the general adult population and 16.8% in those undergoing cancer screening.[ 5 6 ] In addition, a German population-based cross-sectional study reported a 12-month prevalence and lifetime prevalence of CP to be approximately 16.4% and 22.0%, respectively.[ 5 ]

Current Challenges in Management of Chronic Pruritus

In dermatologic practice, CP is the most troublesome symptom. It has a major impact on QoL score and also has severe psychological implications. Treatment of CP remains a challenge when it is not associated with a skin lesion or it is not of systemic origin.[ 7 ] Anti-inflammatory agents including steroids and antihistamines help in managing pruritus in case of cutaneous inflammatory disorders and allergic disorders, respectively. Systemic disorders associated with pruritus include uremic pruritus, hepatobiliary pruritus, pruritus due to hematological causes such as polycythemia vera, leukemia, lymphomas (especially Hodgkin's disease), multiple myeloma, pruritus due to endocrine disorders, and multiple sclerosis. In recent times, understanding the pathomechanism of pruritus of systemic origin has improved considerably.[ 7 ] Clinicians must offer individualized therapy in the management of pruritus. However, lack of randomized controlled trials has been reported due to the diversity and complexity of the symptom, multifactorial etiologies, and lack of well-defined outcome measures. In addition, for documenting CP, no standardized method has been reported. There is lack of guidelines suggesting apt diagnostic modalities for the management of CP. This is suggestive of the dire need for comprehensive consensus discussing diagnosis and management of CP. Therefore, the current discussion will mainly focus on expert commentaries for the diagnosis and management of CP.

Methods

We screened 87 of 95 studies that contained qualitative data. We searched PubMed, EMBASE, Scopus, Web of Science, and the WHO's regional databases, for studies on “Diagnosis and management of chronic pruritus” from January 1, 2014, to July 31, 2015. We included programmatic reports and hand-searched references of published reviews and articles. Two independent reviewers screened articles and extracted data.

Figure 1 depicts the clinical classification for the management of patients with CP.[ 8 ] Pruritus and itch are considered to be synonymous. The term “pruritus of unknown origin” or “pruritus of undetermined origin” has been commonly specified in patients with no identified underlying disease. Although Groups I and II may already suggest a category, the classification of the patient is performed in the second step based on histological, laboratory, and radiological investigations. If no category fits or several diseases are found (green arrows), the patients are classified into “mixed” or “others.”

Table 1 shows etiological classification of CP.

Dermatological origin of chronic pruritus [ Table 2 ]

Pruritus due to dermatological diseases with/without primary skin lesions (rash)

Dermatoses induce pruritus locally or generalized and present with primary skin lesions.[ 10 ]

Systemic origin of chronic pruritus [ Table 3 ]

Renal/uremic itch

Patients with uremia suffer from continuous itch while others experience it in episodes or exacerbations.[ 11 ]

Hepatic itch

Any liver disease with cholestasis can give rise to the development of pruritus which is generalized and without rash.[ 12 13 ]

Diabetes mellitus

Generalized pruritus has been documented in diabetics; however, its frequency is unknown. Localized pruritus along with infection (around anus, genitals) is more common in DM caused due to candidiasis.[ 14 ] Neuropathic itch of the scalp has been reported in patients with DM. It must be noted that controlling diabetes mainly aid for complete relief of pruritus.[ 15 ]

Thyroid diseases

Pruritus-associated hypothyroidism and hyperthyroidism has been reported in patients.[ 16 ]

Parathyroid diseases

Pruritus is also reported in patients presenting with abnormal parathyroid gland activity. Secondary hyperparathyroidism associated with chronic renal diseases may essentially account for uremic itch. Further, in patients with primary hypoparathyroidism, pruritus is caused due to dry skin and cutaneous candidiasis.[ 16 17 ]

Premenstrual or perimenstrual pruritus

CP can be due to oral contraceptive pill-induced cholestasis. Generalized pruritus can be related to intradermal estrogen administration. Hormone replacement therapy is a viable option in treatment of episodic pruritus in perimenopausal women.[ 18 19 ]

Pruritus and malignancy

Generalized pruritus has been documented in cases of carcinoma of the lung, stomach, colon, prostate, breast, and pancreas. Surgical removal of the tumor and use of serotonin re-uptake inhibitors or serotonin antagonists in inoperable cases are usually the recommended treatments. Different forms of mastocytosis, i.e., solitary mastocytoma, urticaria pigmentosa, telangiectasia macularis eruptiva perstans, and systemic mastocytosis are also significantly associated with symptoms of pruritus. In addition, pruritus may be associated with flushing in patients with carcinoid syndrome. In such cases, serotonin, produced in the enterochromaffin cells of the tumor, is responsible for eliciting pruritus. The use of antiserotonin drugs is usually considered to alleviate this symptom. Frequently, brain tumors are reported to be associated with pruritus. Importantly, 50% of these cases have reported nasal pruritus. However, exact mechanism for this association has not been fully understood. It has been postulated that immunological mechanisms, toxic metabolites, iron deficiency, and dry skin may trigger pruritus in such patients. Commonly, antihistamines are not considered to be helpful for relieving itch. However, eradication of the tumor can help diminish or abolish itch. Unilateral pruritus over the scapular region has been documented in patients with multiple endocrine neoplasms syndrome and is reported to be associated with deposition of amyloid. Pruritus can also be caused due to drugs given for chemotherapy such as antimetabolites, alkaloids, alkylating agents, and irradiation.[ 16 ]

Hematologic diseases and pruritus

Several hematological diseases are linked to cause pruritus. Itching may appear following contact with water or after a hot bath in patients with polycythemia vera. Symptom of aquagenic pruritus may be reported before the development of polycythemia vera. The use of salicylates, photochemotherapy, or interferon-α can be considered for treating such cases. In addition, pruritus is often reported in patients with iron deficiency, even in absence of anemia. Iron supplementation often alleviates this symptom. Patients with hemochromatosis may also report pruritus where they demonstrate elevated levels of iron in blood and tissues. Itchiness is also reported in about 30% of patients with Hodgkin's disease. Radiation therapy or chemotherapy improves the symptoms of pruritus in Hodgkin's disease. Patients with host reactions after bone marrow transplantation may also report pruritus.[ 16 ]

Pruritus in infectious diseases

Pruritus may be reported in some generalized infections. Furthermore, pruritic papular eruption or eosinophilic folliculitis has been documented in patients infected with HIV.[ 19 20 ]

Neurological and somatoform origin of chronic pruritus [ Table 4 ]

Localized neuropathic pruritus

Neuropathic itch of the scalp has been reported in patients with herpes zoster. In addition, localized neuropathic pruritus suggesting a compression of peripheral or brachioradial pruritus is found in postzosteric pruritus, notalgia paresthetica, and brachioradial pruritus.[ 15 21 ]

Systemic neurological pruritus

Such patients present with hypo/hyperesthesia with itching and have localized, dermatomal involvement.

Syringomyelia

It is characterized by chronic lichenoid rash secondary to scratching.[ 22 ]

Neurofibromatosis

Pruritus is commonly reported in patients with neurofibromatosis. Patients generally demonstrate widespread cutaneous phenomenon. Mast cells found in neurofibromas account for the release of histamine, which leads to itching. Furthermore, the presence of localized pruritus may aid for suspicion of an underlying spinal cord or central nervous tumor.[ 1 ]

Transverse myelitis

Transverse myelitis is seen mostly in the neurology or orthopedic inpatients. A case reported in 2003 stated the development of severe pruritus and hyperesthesia due to transverse myelitis. Usually, patients complain of pain in legs followed by severe pruritus and hyperesthesia. Patients with transverse myelitis may also show lichenoid plaques and excoriations over affected area. It is mostly treatable by surgical methods. Medically sedative antihistamines are helpful than nonsedative antihistamines.[ 23 ]

Cerebral lesions

Cerebrovascular accidents (CVA) may be responsible for neuropathic itch. Patients suffering from CVA have reported to develop poststroke pruritus in a few days or weeks. Patients with CVA may report excessive localized or generalized pruritus but primarily involves skin contralateral to the stroke lesion.[ 24 ]

Notalgia paresthetica

It is characterized by unilateral pruritus located medial or inferior to the scapula in the T2–T6 dermatomal region. It is commonly reported in middle-aged women and is known to last for months or years. It may also be associated with pain, paresthesias, numbness, or hypersensitivity.[ 25 ]

Drug-induced pruritus

Most of the medications including angiotensin-converting enzyme inhibitors, antibiotics, antidepressants, antidiabetics, and drugs are likely to cause generalized pruritus.[ 26 ] CP may develop due to drug-induced hepatotoxicity or cholestasis as well as drugs leading to xerosis or phototoxicity.[ 27 ] Hydroxyethyl starch used for restoration of fluids may be associated with generalized or localized pruritus.[ 28 ]

Chronic pruritus in special population

Elderly patients

Pathological mechanism of pruritus in elderly patients is still unclear. However, associated etiological factors that are known to contribute for developing pruritus may include pathophysiological changes of the aged skin, decreased function of the stratum corneum, xerosis cutis, comorbid conditions, and multiple-drug use.[ 29 ] Studies conducted in elderly patients reported pruritus as the most common symptom in 11.5% of 4099 patients.[ 30 ] Moreover, an American study and a Thailand study reported occurrence of pruritus as the common symptom among 29% and 41% elderly patients, respectively.[ 31 32 ] A prevalence of about 12.8% for pruritus was observed among patients aged >85 years.[ 30 ]

Pregnant women

Estimated occurrence of pruritus in pregnancy is 18%.[ 33 ] Polymorphic eruption of pregnancy, pemphigoid gestation, intrahepatic cholestasis of pregnancy (ICP), and atopic eruption of pregnancy are specific dermatoses associated with pruritus.[ 34 35 36 ] ICP is characterized by severe pruritus without any primary skin lesions, and it is more commonly reported in women of advanced maternal age, multiple gestations, history of cholestasis on oral contraceptives, and during winter months.[ 37 38 39 ] Recognizing ICP is important because it is associated with increased fetal mortality. The only recognizable sign would be pruritus.

Children

A Norwegian cross-sectional questionnaire-based population study in adolescents revealed a pruritus prevalence of 8.8%. In this study, mental distress, gender, sociodemographic factors, asthma, rhinoconjunctivitis, and eczema were associated with pruritus.[ 40 ] No evident epidemiological studies have been conducted for advocating the prevalence of CP in children.[ 33 41 ]

Diagnostic criteria for chronic pruritus

Figure 2 illustrates the diagnostic approach for CP.[ 10 ] Detailed history of the patient should be taken:[ 42 ] Onset (drugs, winter itch), duration of itch, quality, time course (scabies), localization (notalgia paresthetica), preceding skin changes, relieving factors (atopic atmokinesis occurs while changing clothes), exacerbating factors (scratching with brushes, combs, knitting needles), atopic diathesis, drug history, history of allergies, weight loss, fever, fatigue, emotional stress, and other symptoms indicating underlying disease have to be reviewed. Other important symptoms in diagnosing etiology of pruritus include history of infection in family members: Scabies and other parasites infection among family members. Pruritus during physical activity: Cholinergic pruritus, which is often reported to be atopic Aquagenic pruritus provoked by skin cooling/bathing, Nocturnal pruritus with chills, fatigue, sweating, weight loss reported in lymphoma, sleep disturbance are rare with psychogenic pruritus, whereas most types cause wakening, seasonal variations cause asteatotic/xerotic, atopic, solar urticarial and textile dermatitis.

Clinical examination [ Table 5 ][ 42 ]

Search for primary skin lesions: A thorough inspection of the entire skin including mucous membranes, scalp, hair, nails, and anogenital region. Look for lesions in the interscapular regions, nondominant hand site or areas not normally assessable to hand. The distribution of primary and secondary skin lesions should be recorded together with skin signs of systemic disease General physical examination should include palpation of the liver, kidneys, spleen, and lymph nodes A solely psychological cause of pruritus should not be diagnosed without psychiatric examination.

Screening tests

Fasting blood sugar, postprandial blood sugar, complete blood count, erythrocyte sedimentation rate, absolute eosinophil count, peripheral smear, serum IgE, urinalysis, stool routine and occult blood, thyroid-stimulating hormone (TSH) free T4, blood urea creatinine, liver function test, X-ray chest (radiologist to report), ultrasonography abdomen, Vitamin D, skin biopsy for direct immunofluorescence, serum protein electrophoresis.

Investigations[ 10 ]

Baseline screening: Creatinine, aspartate aminotransferase (AST), alanine transaminase (ALT), alkaline phosphatase, bilirubin, TSH, complete blood count, glucose, chest X-ray and in case of genitoanal pruritus calcium (Ca), gamma-glutamyl transpeptidase (γ-GT), and Stool test for parasites in genitoanal pruritus Renal insufficiency: Creatinine (and urea for elderly), phosphate, parathyroid hormone (PTH), bicarbonate, urinalysis, urine protein concentration and sonography, computed tomography (CT) or magnetic resonance imaging (MRI) of the kidneys Liver diseases with or without cholestasis: γ-GT, arterial pressure (AP), bilirubin, AST, ALT (and hepatitis B-, hepatitis C-antibodies, if a risk-patient), lactate dehydrogenase (LDH), antimitochondrial antibodies (AMAs), antinuclear antibody, anti-hepatitis B core antibody, hepatitis B surface antigen, anti-hepatitis C virus-antibody, anti-smooth muscle antibody, antiactin antibody, sonography of the liver, CT or MRT, magnetic resonance cholangiogram or endoscopic retrograde to rule out primary sclerosing cholangitis Hyperparathyroidism: PTH, calcium (only, if symptoms or signs of hyperparathyroidism [“stones, bones, moans and abdominal groans and psychiatric overtones”]), phosphate, Vitamin D (1,25-Vitamin D, 25-Vitamin D) and sonography of the parathyroid glands, scintigraphy, MRI Hyper- and hypo-thyroidism: TSH, T3, T4, Human assay for microsomal thyroid antibodies (MAKs) and Human assay for thyrotropin receptor antibodies (TRAKs), sonography of the thyroid glands and iodine-scintigraphy Anemia: Complete blood count including mean corpuscular volume and mean corpuscular hemoglobin concentration, LDH, ferritin, transferrin saturation (TSAT) and bone marrow aspiration with iron staining Iron deficiency: Ferritin and TSAT Malabsorption: Serum protein, serum albumin, calcium, blood count, gliadin-antibody, Vitamin A (hyperkeratosis by Vitamin A deficiency), Vitamin B12 (neuropathy by Vitamin B deficiency) and endoscopy with biopsy Pruritus of the elderly: Serum creatinine, ALT, AST, alkaline phosphatase, bilirubin, TSH, full blood count and blood urea nitrogen (+estimated creatinine clearance) Infective diseases: HIV-antibodies, Western blot Parasitoses including helminthosis, Giardia lamblia (rare): Stool culture and microscopic examination Hematological disorders: Polycythemia vera – Blood count, thrombocytes, sedimentation rate. To rule out secondary erythrocytosis: O 2 saturation, erythropoietin level (renal cell carcinoma or polycystic kidneys), bone marrow with chromosomal aberrations and sonography, CT or MRI of the spleen. Lymphoma – Blood count, blood smear, thrombocytes, sedimentation rate, bone marrow with chromosomal aberrations, sonography, CT or MRI of the abdomen, thorax and additional affected areas (positron emission tomography) Neurological diseases: Multiple sclerosis – Cerebrospinal fluid analysis, electroencephalography (EEG), MRI and CT of the brain und functional tests. Brain tumors – Cerebrospinal fluid analysis with histopathology and EEG, MRI, CT of the brain. Notalgia paresthetica – MRI of the thoracic spine. Brachioradial pruritus – MRI of the thoracic and cervical spine Psychiatric or psychosomatic diseases: Psychiatric and psychosomatic exploration, psychiatric short questionnaire for depressive and anxiety disorder Pregnancy with or without cholestasis: γ-GT, AP, bilirubin, AST, ALT, bile acids, hepatitis A, B, C, Epstein–Barr and cytomegalovirus, liver autoimmune screen for chronic, active hepatitis, and primary biliary cirrhosis (anti-smooth muscle and AMAs) and liver ultrasound Drug-induced pruritus: γ-GT, AP, bilirubin, AST, ALT, LDH, and skin biopsy in case of Hydroxy ethyl starch (HES) exposition.

Management of chronic pruritus[ 42 ]

To improve the management of CP adherence following measures to be taken:

Develop a usable document or intake sheet Form a decision tree Prepare a list of basic investigations Produce guidelines for usage of drugs Prepare a patient education pamphlet.

Grading for the management of chronic pruritus[ 42 ]

No itch (Grade 0) Itch with no need to scratch (Grade 1) Itch with need to scratch (Grade 2) Itch with need to scratch requiring treatment (Grade 3).

General approach

Individualized treatment approach should be considered for patients with CP depending on their age, comorbid conditions, medications, quality, and intensity of pruritus. Medical care may extend for longer duration due to failure of previous therapies, psychological stress, and uncertainty of origin of pruritus. General measures for managing CP are shown in Table 1 . Further, appropriate clinical and diagnostic evaluation may be required prior initiation of symptomatic treatment.

Stepwise approach to chronic pruritus

Overall stepwise approach for managing CP is shown in Figure 3 .[ 10 ]

Consensual Therapeutic Recommendations of Chronic Pruritus[ 10 42 ]

Topical applications or treatments [ Table 6 ]

Local anesthetics[ 43 ]

These drugs are considered effective for short treatment of mixed pain, dysesthesia, and itch over localized areas.

Capsaicin[ 44 45 ]

Similar to local anesthetics, it is used for managing CP, but it is not considered suitable for facial and periorificial skin. Further, capsaicin requires frequent reapplication. Moreover, its preparations with nonsteroidal anti-inflammatory drugs (NSAIDs) have demonstrated better tolerability (personal observation).

Topical corticosteroids[ 46 47 ]

Topical corticosteroids are considered very effective, only in cases of inflammatory dermatoses.

Calcineurin inhibitors[ 48 ]

These drugs are effective for medium to long-term treatment of localized pruritus of any etiology. These drugs have demonstrated good evidence mainly for all types of eczemas, Lichen sclerosus et atrophicus (LSA), Lupus erythematosus (LE). However, with its treatment, 25% patients may report initial itch and burning sensation.

Menthol, camphor, and zinc[ 49 ]

Menthol, camphor, and zinc have demonstrated rapid onset of action and short duration of relief. These drugs can be applied on widespread areas with no significant risk of systemic toxicity.

Opioid agonists[ 50 ]

Significant antipruritic activity has been demonstrated by N-palmitoylethanolamine containing product among patients with atopic dermatitis (AD). Naltrexone[ 51 52 ] is considered to be effective in cholestatic pruritus. It is also observed to be effective in renal itch.

Systemic therapy [Tables 7 and 8 ]

Antihistamines[ 71 72 73 74 ]

H1-type antihistamines are the most clinically investigated drug for managing pruritus. Sedative first-generation antihistamines are considered to be highly effective where hydroxyzine is considered to be the most potent antihistamine in managing CP which has been demonstrated in vivo studies[ 10 ] Nonsedating second-generation antihistamines are long acting, less sedating, and have documented anti-inflammatory activity; however, they are considered to be less effective than sedative first-generation molecules for the relief from CP. Antihistamines have also been considered suitable for urticaria, mastocytosis, and allergic reactions. However, these are frequently administered and considered effective for itch of other etiologies. It is also not effective in standard doses for itch due to internal diseases. Antihistamines are the most commonly prescribed systemic antipruritic drug by the dermatologists. First-generation antihistamines such as hydroxyzine, chlorpheniramine, clemastine, cyproheptadine, diphenhydramine, and promethazine effectively bind to H1-receptors and also to muscarinic, α-receptors, dopamine, and serotonin receptors and demonstrate central sedative effect. Systemic H1-antihistamines are usually used to treat pruritus associated with AD. However, only sedative antihistamines have shown beneficial effects, mainly by improving sleep which is significantly affected leading to QoL impairments. Hydroxyzine in the dose of 75–100 mg/day and 1–2.5 mg/kg/day is recommended as an effective agent in the treatment of CP for adults and children, respectively. A controlled study reported that there was 750-fold increase in the dose of histamine that is required to elicit itch with the addition of hydroxyzine. Hydroxyzine was reported to be more efficacious in treating histamine-induced pruritus compared to neuroleptics such as thiothixene, chlorpromazine, and thioridazine. Antihistamines have demonstrated added efficacy when administered with leukotriene antagonists in physical and NSAID-aggravated urticarial.[ 10 ] However, addition of H2 antagonists has shown poor.

Gabapentin and pregabalin[ 75 ]

Gabapentin and pregabalin are effective in all types of neuropathic itch and intractable itch of other etiologies as well. It can be a good evidence for renal and hepatic itch. Serotonin-specific reuptake inhibitors (SSRIs)[ 64 ] are considered effective for neurologic, psychogenic, or paraneoplastic itch. It can be considered as the second-line treatment for intractable itch of any type.

Tricyclic antidepressants[ 75 ]

It is similar to SSRIs and has also been considered in AD other than pruritus.

Cyclosporine

Cyclosporine is reported to be effective in managing pruritus associated with AD and its variants, such as chronic urticaria.

Thalidomide[ 56 70 ]

Thalidomide has reported its effectiveness in managing prurigo nodularis and pruritus associated with HIV infection.

Ultraviolet rays[ 54 77 ]

Narrow-band ultraviolet (UV) B, psoralen plus UV A, and UVA1 are considered to be effective in itch of primary dermatologic conditions. In addition, they have been observed to be effective in renal, hepatic, polycythemia vera, and paraneoplastic itch. Table 9 illustrates antipruritic agents using during pregnancy.[ 87 ]

Summary

CP is quite frequent finding associated with skin and systemic diseases in the overall population. It is known to significantly affect quality life score of an individual and also adds burden on the healthcare cost. Sedative H1 antihistamines are first-choice therapy in CP to improve night time sleep. Studies on application of higher doses are yet to be conducted. UV phototherapy is recommended for generalized pruritus, especially in the elderly pruritus patients or in case of contraindications for systemic therapy. Anticonvulsants/pain modulators are recommended in neuropathic pruritus. Antidepressants are recommended in forms of CP not responding to other therapies. Systemic glucocorticoids are not recommended for the treatment of CP except of very severe and desperate cases. Serotonin receptor antagonists and thalidomide are not recommended for treatment.

Financial support and sponsorship

Moral support and financial support provided by advisory board meeting conducted by UCB India Private Limited.

Conflicts of interest

There are no conflicts of interest.

What is new?

Chronic pruritus is quite frequent finding associated with skin and systemic diseases in the overall population. It is known to significantly affect quality life score of an individual and also adds burden on the healthcare cost. A specific recommendation for treatment of CP is difficult as a result of varied and diverse possibility of underlying diseases associated with CP. The recommendations in this guideline are offered with a view to reduce the burden on the physicians and assist in effective management of CP.

Acknowledgment

We express our sincere gratitude to all my contributors Dr. Abir Saraswat Consultant Dermatologist, Indushree Skin Clinic, Lucknow; Dr. Kiran Godse Professor of Dermatology, Department of Dermatology, D. Y. Patil Hospital and School of Medicine, Navi Mumbai; Dr. D S Krupa Shankar Consultant Dermatologist, Mallige Medical Centre, Bengaluru; Dr. S Sanjay Kandhari Consultant Dermatologist, Dr. Kandhari's Skin Clinic, 11 Munirka Marg, New Delhi; Dr. Shrutakirthi D Shenoi Professor, Department of Dermatology, Kasturba Medical College Hospital, Manipal - 576 104; Dr. Sushil Tahiliani Visiting Dermatologist, Hinduja Healthcare Surgical Hospital, Mumbai; and Dr. V Vijay Zawar Consultant Dermatologist, Skin Diseases Center, Nashik.

1 Patel T Yosipovitch G Therapy of pruritus Expert Opin Pharmacother 2010 11 1673 82 20426711 10.1517/14656566.2010.484420 PMC2885583

2 Tivoli YA Rubenstein RM Pruritus: An updated look at an old problem J Clin Aesthet Dermatol 2009 2 30 6 PMC2924137 20729968

3 Rea JN Newhouse ML Halil T Skin disease in Lambeth. A community study of prevalence and use of medical care Br J Prev Soc Med 1976 30 107 14 133742 10.1136/jech.30.2.107 PMC478948

4 Zylicz Z Twycross R Jones EA Pruritus in Advanced Disease 2004 Oxford Oxford University Press

5 Matterne U Apfelbacher CJ Loerbroks A Schwarzer T Büttner M Ofenloch R Prevalence, correlates and characteristics of chronic pruritus: A population-based cross-sectional study Acta Derm Venereol 2011 91 674 9 21879245 10.2340/00015555-1159

6 Ständer S Schäfer I Phan NQ Blome C Herberger K Heigel H Prevalence of chronic pruritus in Germany: Results of a cross-sectional study in a sample working population of 11,730 Dermatology 2010 221 229 35 20924157 10.1159/000319862

7 Khopkar U Pande S Etiopathogenesis of pruritus due to systemic causes: Implications for treatment Indian J Dermatol Venereol Leprol 2007 73 215 7 17675726 10.4103/0378-6323.33632

8 Ständer S Weisshaar E Mettang T Szepietowski JC Carstens E Ikoma A Clinical classification of itch: A position paper of the International Forum for the Study of Itch Acta Derm Venereol 2007 87 291 4 17598029 10.2340/00015555-0305

9 Boyd KP Korf BR Theos A Neurofibromatosis type 1 J Am Acad Dermatol 2009 61 1 14 19539839 10.1016/j.jaad.2008.12.051 PMC2716546

10 Weisshaar E Szepietowski JC Darsow U Misery L Wallengren J Mettang T European guideline on chronic pruritus Acta Derm Venereol 2012 92 563 81 22790094 10.2340/00015555-1400

11 Berger TG Steinhoff M Pruritus and renal failure Semin Cutan Med Surg 2011 30 99 100 21767770 10.1016/j.sder.2011.04.005 PMC3692272

12 Cacoub P Poynard T Ghillani P Charlotte F Olivi M Piette JC Extrahepatic manifestations of chronic hepatitis C. MULTIVIRC Group. Multidepartment Virus C Arthritis Rheum 1999 42 2204 12 10524695 10.1002/1529-0131(199910)42:10<2204::AID-ANR24>3.0.CO;2-D

13 Kremer AE van Dijk R Leckie P Schaap FG Kuiper EM Mettang T Serum autotaxin is increased in pruritus of cholestasis, but not of other origin, and responds to therapeutic interventions Hepatology 2012 56 1391 400 22473838 10.1002/hep.25748

14 Sreedevi C Car N Pavlic-Renar I Dermatologic lesions in diabetes mellitus Diabetol Croat 2002 31 147 59

15 Bin Saif GA Ericson ME Yosipovitch G The itchy scalp – Scratching for an explanation Exp Dermatol 2011 20 959 68 22092575 10.1111/j.1600-0625.2011.01389.x PMC3233984

16 Yonova D Pruritus in certain internal diseases Hippokratia 2007 11 67 71 19582180 PMC2464269

17 Dahl MG Premenstrual pruritus due to recurrent cholestasis Trans St Johns Hosp Dermatol Soc 1970 56 11 3 5485624

18 Stephens CJ Black MM Perimenstrual eruptions: Autoimmune progesterone dermatitis Semin Dermatol 1989 8 26 9 2701706

19 Gelfand JM Rudikoff D Evaluation and treatment of itching in HIV-infected patients Mt Sinai J Med 2001 68 298 308 11514917

20 Eisman S Pruritic papular eruption in HIV Dermatol Clin 2006 24 449 57 vi 17010775 10.1016/j.det.2006.06.005

21 Marziniak M Phan NQ Raap U Siepmann D Schürmeyer-Horst F Pogatzki-Zahn E Brachioradial pruritus as a result of cervical spine pathology: The results of a magnetic resonance tomography study J Am Acad Dermatol 2011 65 756 62 21641675 10.1016/j.jaad.2010.07.036

22 Kinsella LJ Carney-Godley K Feldmann E Lichen simplex chronicus as the initial manifestation of intramedullary neoplasm and syringomyelia Neurosurgery 1992 30 418 21 1620308 10.1227/00006123-199203000-00019

23 Bond LD Jr Keough GC Neurogenic pruritus: A case of pruritus induced by transverse myelitis Br J Dermatol 2003 149 204 5 12890224 10.1046/j.1365-2133.2003.05388.x

24 Garibyan L Chiou AS Elmariah SB Advanced aging skin and itch: Addressing an unmet need Dermatol Ther 2013 26 92 103 23551366 10.1111/dth.12029 PMC4051285

25 Ellis C Notalgia paresthetica: The unreachable itch Dermatol Pract Concept 2013 3 3 6 10.5826/dpc.0301a02 PMC3663387 23785628

26 Reich A Ständer S Szepietowski JC Drug-induced pruritus: A review Acta Derm Venereol 2009 89 236 44 19479118 10.2340/00015555-0650

27 Kaplan AP Drug-induced skin disease J Allergy Clin Immunol 1984 74 4 Pt 2 573 9 6238077 10.1016/0091-6749(84)90109-x

28 Metze D Reimann S Szepfalusi Z Bohle B Kraft D Luger TA Persistent pruritus after hydroxyethyl starch infusion therapy: A result of long-term storage in cutaneous nerves Br J Dermatol 1997 136 553 9 9155957

29 Sommer F Hensen P Böckenholt B Metze D Luger TA Ständer S Underlying diseases and co-factors in patients with severe chronic pruritus: A 3-year retrospective study Acta Derm Venereol 2007 87 510 6 17989889 10.2340/00015555-0320

30 Yalçin B Tamer E Toy GG Oztas P Hayran M Alli N The prevalence of skin diseases in the elderly: Analysis of 4099 geriatric patients Int J Dermatol 2006 45 672 6 16796625 10.1111/j.1365-4632.2005.02607.x

31 Beauregard S Gilchrest BA A survey of skin problems and skin care regimens in the elderly Arch Dermatol 1987 123 1638 43 3688904

32 Thaipisuttikul Y Pruritic skin diseases in the elderly J Dermatol 1998 25 153 7 9575676 10.1111/j.1346-8138.1998.tb02371.x

33 Weisshaar E Diepgen TL Luger TA Seeliger S Witteler R Ständer S Pruritus in pregnancy and childhood – Do we really consider all relevant differential diagnoses? Eur J Dermatol 2005 15 320 31 16172038

34 Ambros-Rudolph CM Müllegger RR Vaughan-Jones SA Kerl H Black MM The specific dermatoses of pregnancy revisited and reclassified: Results of a retrospective two-center study on 505 pregnant patients J Am Acad Dermatol 2006 54 395 404 16488288 10.1016/j.jaad.2005.12.012

35 Charles-Holmes R Polymorphic eruption of pregnancy Semin Dermatol 1989 8 18 22 2701704

36 Girling JC Obstetric cholestasis. Guideline No. 43 2006 London Royal College of Obstetricians and Gynaecologists (RCOG)

37 Reyes H Gonzalez MC Ribalta J Aburto H Matus C Schramm G Prevalence of intrahepatic cholestasis of pregnancy in Chile Ann Intern Med 1978 88 487 93 637428 10.7326/0003-4819-88-4-487

38 Reyes H Taboada G Ribalta J Prevalence of intrahepatic cholestasis of pregnancy in La Paz, Bolivia J Chronic Dis 1979 32 499 504 457835 10.1016/0021-9681(79)90111-5

39 Clark TJ Dwarakanath L Weaver JB Pruritus in pregnancy and obstetric cholestasis Hosp Med 1999 60 254 60 10396430 10.12968/hosp.1999.60.4.1091

40 Halvorsen JA Dalgard F Thoresen M Thoresen M Bjertness E Lien L Itch and mental distress: A cross-sectional study among late adolescents Acta Derm Venereol 2009 89 39 44 19197540 10.2340/00015555-0554

41 Weisshaar E Dalgard F Epidemiology of itch: Adding to the burden of skin morbidity Acta Derm Venereol 2009 89 339 50 19688144 10.2340/00015555-0662

42 Excerpts from the Steering Committee Meeting – Chronic Pruritus, Hotel Orchid, Mumbai; 14 March 2014

43 Bernhard JD Itch: Mechanisms and Management of Pruritus 1994 New York McGraw-Hill

44 Breneman DL Cardone JS Blumsack RF Lather RM Searle EA Pollack VE Topical capsaicin for treatment of hemodialysis-related pruritus J Am Acad Dermatol 1992 26 91 4 1732343 10.1016/0190-9622(92)70013-6

45 Tarng DC Cho YL Liu HN Huang TP Hemodialysis-related pruritus: A double-blind, placebo-controlled, crossover study of capsaicin 0.025% cream Nephron 1996 72 617 22 8730431 10.1159/000188949

46 Pauli-Magnus C Klumpp S Alscher DM Kuhlmann U Mettang T Short-term efficacy of tacrolimus ointment in severe uremic pruritus Perit Dial Int 2000 20 802 3 11216583

47 Kuypers DR Claes K Evenepoel P Maes B Vanrenterghem Y A prospective proof of concept study of the efficacy of tacrolimus ointment on uraemic pruritus (UP) in patients on chronic dialysis therapy Nephrol Dial Transplant 2004 19 1895 901 15150348 10.1093/ndt/gfh202

48 Chen YC Chiu WT Wu MS Therapeutic effect of topical gamma-linolenic acid on refractory uremic pruritus Am J Kidney Dis 2006 48 69 76 16797388 10.1053/j.ajkd.2006.03.082

49 Rosner MH Cromolyn sodium: A potential therapy for uremic pruritus? Hemodial Int 2006 10 189 92 16623673 10.1111/j.1542-4758.2006.00093.x

50 Szepietowski JC Szepietowski T Reich A Efficacy and tolerance of the cream containing structured physiological lipids with endocannabinoids in the treatment of uremic pruritus: A preliminary study Acta Dermatovenerol Croat 2005 13 97 103 16324422

51 Peer G Kivity S Agami O Fireman E Silverberg D Blum M Randomised crossover trial of naltrexone in uraemic pruritus Lancet 1996 348 1552 4 8950882 10.1016/s0140-6736(96)04176-1

52 Pauli-Magnus C Mikus G Alscher DM Kirschner T Nagel W Gugeler N Naltrexone does not relieve uremic pruritus: Results of a randomized, double-blind, placebo-controlled crossover study J Am Soc Nephrol 2000 11 514 9 10703675 10.1681/ASN.V113514

53 Gunal AI Ozalp G Yoldas TK Gunal SY Kirciman E Celiker H Gabapentin therapy for pruritus in haemodialysis patients: A randomized, placebo-controlled, double-blind trial Nephrol Dial Transplant 2004 19 3137 9 15575002 10.1093/ndt/gfh496

54 Gilchrest BA Rowe JW Brown RS Steinman TI Arndt KA Ultraviolet phototherapy of uremic pruritus. Long-term results and possible mechanism of action Ann Intern Med 1979 91 17 21 464448 10.7326/0003-4819-91-1-17

55 Che-Yi C Wen CY Min-Tsung K Chiu-Ching H Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus Nephrol Dial Transplant 2005 20 1912 5 15985509 10.1093/ndt/gfh955

56 Silva SR Viana PC Lugon NV Hoette M Ruzany F Lugon JR Thalidomide for the treatment of uremic pruritus: A crossover randomized double-blind trial Nephron 1994 67 270 3 7936015 10.1159/000187978

57 Ashmore SD Jones CH Newstead CG Daly MJ Chrystyn H Ondansetron therapy for uremic pruritus in hemodialysis patients Am J Kidney Dis 2000 35 827 31 10793015 10.1016/s0272-6386(00)70251-4

58 Murphy M Reaich D Pai P Finn P Carmichael AJ A randomized, placebo-controlled, double-blind trial of ondansetron in renal itch Br J Dermatol 2003 148 314 7 12588385 10.1046/j.1365-2133.2003.05172.x

59 Davis MP Frandsen JL Walsh D Andresen S Taylor S Mirtazapine for pruritus J Pain Symptom Manage 2003 25 288 91 12614964 10.1016/s0885-3924(02)00645-0

60 De Marchi S Cecchin E Villalta D Sepiacci G Santini G Bartoli E Relief of pruritus and decreases in plasma histamine concentrations during erythropoietin therapy in patients with uremia N Engl J Med 1992 326 969 74 1545849 10.1056/NEJM199204093261501

61 Francos GC Kauh YC Gittlen SD Schulman ES Besarab A Goyal S Elevated plasma histamine in chronic uremia. Effects of ketotifen on pruritus Int J Dermatol 1991 30 884 9 1816135 10.1111/j.1365-4362.1991.tb04360.x

62 Bergasa NV Mehlman JK Jones EA Pruritus and fatigue in primary biliary cirrhosis Baillieres Best Pract Res Clin Gastroenterol 2000 14 643 55 10976020 10.1053/bega.2000.0109

63 Goulis J Leandro G Burroughs AK Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: A meta-analysis Lancet 1999 354 1053 60 10509495 10.1016/S0140-6736(98)11293-X

64 Mayo MJ Handem I Saldana S Jacobe H Getachew Y Rush AJ Sertraline as a first-line treatment for cholestatic pruritus Hepatology 2007 45 666 74 17326161 10.1002/hep.21553

65 Ghent CN Carruthers SG Treatment of pruritus in primary biliary cirrhosis with rifampin. Results of a double-blind, crossover, randomized trial Gastroenterology 1988 94 488 93 3275568 10.1016/0016-5085(88)90442-8

66 Wolfhagen FH Sternieri E Hop WC Vitale G Bertolotti M Van Buuren HR Oral naltrexone treatment for cholestatic pruritus: A double-blind, placebo-controlled study Gastroenterology 1997 113 1264 9 9322521 10.1053/gast.1997.v113.pm9322521

67 Terg R Coronel E Sordá J Muñoz AE Findor J Efficacy and safety of oral naltrexone treatment for pruritus of cholestasis, a crossover, double blind, placebo-controlled study J Hepatol 2002 37 717 22 12445410 10.1016/s0168-8278(02)00318-5

68 Bergasa NV Alling DW Talbot TL Swain MG Yurdaydin C Turner ML Effects of naloxone infusions in patients with the pruritus of cholestasis. A double-blind, randomized, controlled trial Ann Intern Med 1995 123 161 7 7598296 10.7326/0003-4819-123-3-199508010-00001

69 Shohrati M Tajik A Harandi AA Davoodi SM Akmasi M Comparison of hydroxyzine and doxepin in treatment of pruritus due to sulfur mustard Skinmed 2007 6 70 2 17361495 10.1111/j.1540-9740.2007.05880.x

70 Schwörer H Ramadori G Treatment of pruritus: A new indication for serotonin type 3 receptor antagonists Clin Investig 1993 71 659 62 10.1007/BF00184497 8219665

71 Müller C Pongratz S Pidlich J Penner E Kaider A Schemper M Treatment of pruritus in chronic liver disease with the 5-hydroxytryptamine receptor type 3 antagonist ondansetron: A randomized, placebo-controlled, double-blind cross-over trial Eur J Gastroenterol Hepatol 1998 0 865 70 10.1097/00042737-199810000-00010 9831410

72 O’Donohue JW Haigh C Williams R Ondansetron in the treatment of cholestasis: A randomised controlled trial Gastroenterology 1997 112 A1349

73 McCormick PA Scott F Epstein O Burroughs AK Scheuer PJ McIntyre N Thalidomide as therapy for primary biliary cirrhosis: A double-blind placebo controlled pilot study J Hepatol 1994 21 496 9 7814794 10.1016/s0168-8278(94)80092-8

74 Schwörer H Ramadori G Improvement of cholestatic pruritus by ondansetron Lancet 1993 341 1277 10.1016/0140-6736(93)91178-o 8098410

75 Raiford DS Pruritus of chronic cholestasis QJM 1995 88 603 7 7583073

76 Walt RP Daneshmend TK Fellows IW Toghill PJ Effect of stanozolol on itching in primary biliary cirrhosis Br Med J (Clin Res Ed) 1988 296 607 10.1136/bmj.296.6622.607 PMC2545238 3126923

77 Fleischer AB Jr The Clinical Management of Itching 2000 New York, London Parthenon Publishing

78 Bergasa NV Link MJ Keogh M Yaroslavsky G Rosenthal RN McGee M Pilot study of bright-light therapy reflected toward the eyes for the pruritus of chronic liver disease Am J Gastroenterol 2001 96 1563 70 11374700 10.1111/j.1572-0241.2001.03778.x

79 Epstein MP Kaplan MM A pilot study of etanercept in the treatment of primary sclerosing cholangitis Dig Dis Sci 2004 49 1 4 14992426 10.1023/b:ddas.0000011827.87103.2e

80 Doria C Mandalá L Smith J Vitale CH Lauro A Gruttadauria S Effect of molecular adsorbent recirculating system in hepatitis C virus-related intractable pruritus Liver Transpl 2003 9 437 43 12682899 10.1053/jlts.2003.50055

81 Mullhaupt B Kullak-Ublick GA Ambühl PM Stocker R Renner EL Successful use of the Molecular Adsorbent Recirculating System (MARS) in a patient with primary biliary cirrhosis (PBC) and treatment refractory pruritus Hepatol Res 2003 25 442 6 12699855 10.1016/s1386-6346(02)00310-8

82 Bellmann R Graziadei IW Feistritzer C Schwaighofer H Stellaard F Sturm E Treatment of refractory cholestatic pruritus after liver transplantation with albumin dialysis Liver Transpl 2004 10 107 14 14755786 10.1002/lt.20001

83 Bellmann R Feistritzer C Zoller H Graziadei IW Schwaighofer H Propst A Treatment of intractable pruritus in drug induced cholestasis with albumin dialysis: A report of two cases ASAIO J 2004 50 387 91 15307554 10.1097/01.mat.0000132552.58214.00

84 Acevedo Ribó M Moreno Planas JM Sanz Moreno C Rubio González EE Rubio González E Boullosa Graña E Therapy of intrac’table pruritus with MARS Transplant Proc 2005 37 1480 1 15866646 10.1016/j.transproceed.2005.02.002

85 Montero JL Pozo JC Barrera P Fraga E Costán G Domínguez JL Treatment of refractory cholestatic pruritus with molecular adsorbent recirculating system (MARS) Transplant Proc 2006 38 2511 3 17097984 10.1016/j.transproceed.2006.08.052

86 Neuberger J Liver transplantation for cholestatic liver disease Curr Treat Options Gastroenterol 2003 6 113 21 12628070 10.1007/s11938-003-0012-y

87 Wolverton SE Comprehensive Dermatologic Drug Therapy 2012 USA Elsevier Health Sciences