Chinese Guidelines for the Management of Chronic Pruritus (2018)#

The Allergic Disease Committee of Chinese Dermatologist Association∗

Abstract Chronic pruritus is a very common clinical symptom that seriously affects people’s quality of life.Pruritus is associated not only with skin diseases but also with a variety of systemic diseases. It brings great challenges to clinical management. To standardize the management of chronic pruritus, experts of the Allergic Disease Committee of Chinese Dermatologist Association discussed many times and finally formed this guideline to provide reference and guidance for the clinical work of dermatologists and other physicians at all levels.

Keywords: Chinese, chronic pruritus, guidelines, treatment

Introduction

Pruritus or itching is a sensation that stimulates the desire to scratch, and the one lasting more than six weeks is usually defined as chronic pruritus.2Pruritus is no longer used as a diagnostic term if a clear cause is idenified.However, the cause cannot be determined in a small number of patients, who are thus considered to have pruritus of unknown origin.3

Pruritus can be classified by various methods according to its origin,pathogenesis,and appearance of skin lesions.4The current recommendation is to classify pruritus as follows (1) Dermatological pruritus is caused by skin diseases, especially inflammatory skin diseases; (2) Systemic pruritus is caused by systemic diseases such as liver and kidney diseases,infections,or tumors;(3)Neurogenic pruritus is caused by central or peripheral neuropathy;(4)Psychological/psychosomatic pruritus is caused by neurological dysfunction;(5)Mixed pruritus is a combination of two or more of the above types of pruritus;and(6)Other types of pruritus are those that cannot be classified as any of the above types.

Etiology and epidemiology

The epidemiological data of pruritus are very limited,and relevant data are still lacking in China.The occurrence of pruritus is influenced by region, race, age, occupation,disease, subjects and methods of investigation, and other factors. The data also vary from country to country. The incidence of chronic pruritus exceeds 10% in adults and may reach 60% in the aged.5The incidence of chronic pruritus also varies greatly among patients with different illnesses.6For example, pruritus occurs in almost all patients with atopic dermatitis7and urticaria, the incidence of pruritus in patients with psoriasis is about 80%,8that in patients with primary biliary cirrhosis ranges from 80% to 100%, and that in patients with chronic kidney disease and Hodgkin lymphoma is 40%-70%and 30%,respectively.9In some cases,pruritus is the only early manifestation of these diseases.

Pruritus can occur in association with many systemic diseases.10Common diseases include (1) primary or secondary metabolic or endocrine diseases,such as chronic renal failure, diabetes, hyperparathyroidism, hyperthyroidism, or hypothyroidism; (2) hematological diseases,such as erythrocytosis, multiple myeloma, lymphoma, or iron deficiency anemia; (3) digestive diseases, such as primary biliary cirrhosis; (4) systemic infections (eg,human immunodeficiency virus infection) or parasitic infestations, especially helminth infestations; (5) neurological diseases, including multiple sclerosis, intracranial tumors, abnormal back pain, pruritus in the radial arm,and pruritus after herpes zoster; and (6) mental disorders or psychosomatic diseases, such as depression, hallucination, obsessive-compulsive disorder, affective disorder,schizophrenia, and others.

Drugs can also cause pruritus, including antihypertensive drugs, antiarrhythmic drugs, antibiotics, antidepressants, hypoglycemic drugs, anticonvulsants, nonsteroidal anti-inflammatory drugs, diuretics, immunosuppressants,antilipemic agents, psychotropic drugs, sedatives, uric acid-lowering drugs,and tumor-targeting drugs,etc.11The cause of pruritus in 8%-15%of patients cannot be clearly defined; such patients are considered to have pruritus of unknown origin.

Pathogenesis and mechanism

The mechanism of pruritus remains unclear. Initiation of pruritus depends on the interaction between skin cells and nerve fibers. This process involves many cells, mediators,and receptors. The ultimate process of pruritus is the transmission of pruritus signals through the central nervous system. Both histamine-dependent and nonhistamine-dependent pathways transfer peripheral pruritus signals into the central nervous system.12

The development of chronic pruritus is related to sensitization of neural pathways,malfunction of regulation,and changes in neuroplasticity. Peripheral sensitization is characterized by a decreased threshold of pruritus and an increased response to various stimuli.13Nerve growth factor can promote both growth and increased numbers of peripheral nerves as well as upregulate the expression of neuropeptide-like substance P,transient receptor potential vanillin receptor 1, and transient receptor positive ion channel A1 if it enters the spinal dorsal horn ganglion,14which is an important basis for peripheral sensitization.Central sensitization manifests as hypersensitivity to pruritus and an abnormal itch sensation. It is similar to the central sensitization of pain. The exact mechanism is unclear.The central nervous system has many components that regulate pruritus.For example,two kinds of receptors,μ-receptors and κ-receptors,are present on the membrane after the spinal dorsal horn synapse. Activation of the former promotes the development of pruritus, while activation of the latter suppresses pruritus.15These receptors interact with each other to regulate pruritus.Various external factors affect the structure and media of neurons, which leads to changes in neuroplasticity that promote the development of pruritus.

Clinical manifestations

Pruritus manifests in many forms have specific characteristics depending on its cause.

Cutaneous pruritus

Various skin diseases are often accompanied by pruritus,especially atopic dermatitis, psoriasis, and other inflammatory skin diseases.16Cutaneous pruritus usually has the following characteristics:(1)Primary skin lesions exist;(2)The pruritic area is often also the area affected by skin lesions;(3)The degree of pruritus is related to the severity and state of the skin disease. The pruritus is often more severe during the active period of the disease and gradually decreases or disappears as the condition improves (4)Pruritus has specific characteristics depending on the underlying skin disease.

Systemic pruritus

Pruritus associated with systemic disease has the following features:(1)Primary skin lesions are absent,but secondary prurigo or lichen simplex chronicus may exist;4(2)Pruritus can occur at any stage of the disease and may even be the only clue for early diagnosis of the disease;(3)The mechanisms and causes of pruritus in different diseases are complex and variable, and the clinical manifestations generally lack specific characteristics;17(4)The incidence and degree of pruritus do not correspond to the severity of primary diseases;and(5)The pruritus is often stubborn, and routine treatment is usually ineffective. Active treatment of the primary disease can alleviate the pruritus, but it may not be effective.

Neurogenic pruritus

Neurogenic pruritus has the following features18: (1) It is usually localized; (2) It usually manifests as intermittent attacks of pruritus; (3) It is often accompanied by paresthesia or hypoesthesia; and (4) It may be associated with pathological pain. Pruritus caused by peripheral neuropathy is significantly more common than that caused by central nervous disease.

Psychological/psychosomatic pruritus

This type of pruritus has the following features19:(1)The degree of pruritus corresponds to the emotional state; (2)Primary skin lesions are usually absent, but neurogenic epidermal exfoliation and other secondary damage can be seen; and (3) Sleep is not usually interrupted by pruritus;(4) Topical medication is usually ineffective.

Drug-induced pruritus

This term mainly refers to drug-induced pruritus without primary skin or mucosal lesions. Pruritus caused by drug eruption is not included. Secondary skin lesions, such as exfoliation and scaly,lichen-like lesions,can be observed.Almost any medication can cause pruritus. Drug-induced pruritus is diagnosed according to a history of drug use and its relationship with pruritus, disappearance of the symptoms after discontinuation of the medication, recurrence of the pruritus with repeated administration of the suspected drug,and elimination of the possibility that the underlying disease itself is causing the itching.11

Pruritus in special groups

Pruritus in the aged

This refers to pruritus in older patients with an unexplained cause and absence of a primary rash. Its occurrence is closely related to deterioration of the skin barrier function; nerve aging and immune imbalance also play important roles in the pathogenesis.20More than half of cases occur in the legs,followed by the back,scalp,and arms, and the pruritus is usually symmetrical. In most patients,the pruritus occurs every day,especially at night.Complications and drug factors must be ruled out when diagnosing this type of pruritus.21

Pruritus of pregnancy

Several unique skin diseases may develop during pregnancy because of the metabolic, immune, and endocrine changes that occur in the body during this time.Such skin diseases include intrahepatic cholestasis of pregnancy,prurigo gestationis, polymorphic eruption of pregnancy,pemphigoid gestationis, and others. These diseases are accompanied by pruritus. Exacerbation of preconception skin diseases can also appear as pruritus during pregnancy.22-23

Pruritus in children

Pruritus in children is mainly seen in association with atopic dermatitis, but it may also occur in some genetic diseases such as congenital biliary atresia, familial hyperbilirubinemia syndrome, polycystic kidney disease, and others.24The incidence of drug-induced pruritus in children is low,possibly because fewer types of medication are used in children than in adults.

Diagnosis

Medical history

An accurate medical history can provide basic diagnostic clues. Medical history inquiries include the following elements:(1)Was the onset of pruritus sudden or gradual?(2)Is the progression of pruritus persistent,intermittent,or periodic, and are diurnal changes present? (3) Are any concomitant sensations present, such as a sense of acupuncture, creeping insects, burning, hypoesthesia, or others? (4) What is the duration of the pruritus (days,weeks, months, or years)? (5) What is the severity of the pruritus;for example,does it affect daily life and sleep?(6)Is the pruritus localized or extensive? Is it unilateral or bilateral? (7) Are any inducing factors present, such as water, dampness, air exposure, exercise, or others? (8) Is the pruritus related to social activities,such as the patient’s occupation,working environment,tourism,or others?(9)What is the patient’s medication history? This should include medications for external use, prescription drugs,nonprescription drugs, traditional Chinese medicine, and drug abuse.(10)What is the patient’s medical history?Any history of thyroid, liver, or kidney diseases as well as allergic diseases should be given of special concern.

Physical examination

The clinician should pay attention not only to the skin condition but also to any other signs related to systemic diseases such as abnormalities of the lymph nodes, liver,and spleen;this will help to identify systemic diseases that cannot be identified by the history. During the skin examination,the clinician should assess whether the lesion is primary or secondary,and attention should be given to the skin dryness and the appearance and distribution of skin lesions.Preexisting skin conditions such as dermatitis,eczema,or psoriasis should be identified.Special attention should be paid to dermal signs of systemic diseases such as spider nevi, palmar erythema, and mucus edema, etc.

Laboratory examination

For patients with generalized pruritus of unknown etiology, laboratory examinations should be performed based on the medical history and physical signs.

Assessment of severity

The severity of pruritus is an important basis for guiding clinical treatment and evaluating its efficacy.The use of a numerical rating scale (Fig. 1A) and visual analog scale(Fig. 1B) is recommended. The patient may indicate the severity of pruritus on the corresponding scale.25

Diagnostic approach and procedures

According to the medical history, physical signs, and laboratory examination results, complex and variable pruritus can be divided into two forms:one with a primary skin disease and the other with no primary skin disease.The corresponding disease or possible causes are then further identified, and selected examinations are carried out.26Basic diagnostic clues can be obtained according to the patient’s physical characteristics and medical history:(1)Pruritus with an acute onset,short course,and lack of primary skin lesions is unlikely to be associated with a systemic disease; (2) Because the upper back is usually inaccessible to the hand (except with the aid of a tool), a“butterfly sign” often manifests in the unaffected area,which is more common in pruritus secondary to mental disorders and systemic diseases; (3) Parasitic infestations such as scabies should be highly suspected if more than one member of a household or people living in close proximity develop pruritus and rashes at the same time; (4) Pruritic disease often wakes patients at night, but pruritus caused by mental disorders often does not affect sleep;(5)Itching induced by non-skin disease must be excluded if it only appears as secondary skin damages like skin scratch or mossy;(6)Pruritus induced by systemic disease often lacks specificity,but if generalized pruritus occurs at night and is accompanied by chills, sweating, and fever, it may be an early manifestation of Hodgkin lymphoma; and (7)Pruritus that appears after a bath might be aquagenic pruritus caused by polycythemia vera and other diseases.

Management

General principles

There is a need to strengthen patient education, identify and remove the causes ensure a high quality of standard basic treatment, and choose targeted intervention for the pathophysiological mechanism of pruritus.27Individualized treatment should be carried out according to the patient’s age, severity of itching, and complications, and the balance between the curative effect and treatment cost should be considered. Patient education, avoidance of factors that induce or aggravate pruritus, control of scratching behavior, and local or systemic use of sleeppromoting drugs as appropriate are basic considerations throughout the whole process of management. On this basis, the following step-by-step treatment has been developed28: Step 1: Remove the cause or treat the underlying disease. Step 2: Use topical moisturizers, oral antihistamines, and topical glucocorticoids. Step 3:Systematically administer glucocorticoid or nonglucocorticoid anti-inflammatory agents, central nervous system inhibitors, anti-itch mediators, biological agents, or acupuncture and moxibustion of traditional Chinese medicine according to the mechanism of the pruritus.

Patient education

Patients should be guided to avoid factors that induce or aggravate pruritus, mainly in the following aspects: (1)Patients should avoid dry climates, heat environments,drinking,excessive bathing,contact with various irritants or allergens,nervous anxiety,and other factors(2)Patients should be educated on optimal lifestyle measures,including the use of nonalkaline soap, the correct use of moisturizers,bathing for no longer than 20 minutes,gentle drying of the skin after bathing, and wearing soft cotton clothes (3) Patients should be advised to reduce or avoid scratching, informed of the harm caused by scratching in the occurrence and development of diseases,and educated about how to control the itch-scratch cycle.

Topical medication

Antihistamines

Topical first-generation antihistamines are effective in the treatment of atopic dermatitis, discoid eczema, lichen sclerosus, lichen simplex chronicus, and other local or generalized pruritic diseases.29Such drugs include doxepin cream and diphenhydramine cream.Five percent doxepin cream has a local antipruritic effect after topical application30and can have a central sedative and antipruritic effect after percutaneous absorption. It is suitable in combination with all kinds of oral sedative antihistamines or antidepressants in patients with pruritus. Notably, a small number of patients develop local stimulation with the use of doxepin cream, and topical use covering more than 5% of the body surface area can cause central sedative toxicity.

Glucocorticoids

The principles of topical glucocorticoid therapy should be followed topical use of glucocorticoids is an important option for the pruritus caused by inflammatory skin diseases such as atopic dermatitis31and psoriasis.Glucocorticoids with a mild or moderate effect are usually selected for nonhypertrophic lesions or lesions on the thin,tender parts of the body. These include creams such as desonide,fluticasone propionate,hydrocortisone butyrate,clobetasone butyrate, and others. Moderate or strong glucocorticoids, including mometasone furoate, betamethasone dipropionate, and halometasone, can be selected for localized hypertrophic skin lesions.32Moderate or strong glucocorticoids may also be selected for lichenification and rashes secondary to pruritus caused by noninflammatory skin diseases or systemic diseases,aiming to reduce the effect of skin pruritus sensitization on the process of chronic pruritus. To avoid the adverse effects of long-term use of hormones on the skin barrier and the adverse effects of glucocorticoid absorption on the whole body, the course of treatment with topical glucocorticoids should not exceed two to four weeks.

Anesthetics

Figure 1. Scale for measuring pruritus. (A) Numerical rating scale (NRS). (B) Visual analogue scale (VAS).

These drugs can effectively control pruritus, including localized pruritus on the face or anus, pruritus caused by chronic kidney disease, and neuropathic itching such as post-herpes zoster pruritus.33However, the effect of anesthetics on pruritus caused by inflammatory skin diseases is poor.These drugs include 1%or 2.5%procaine cream and 2.5% lidocaine+2.5% prilocaine cream.34These drugs are less irritating when applied topically.Their use is recommended for only a short period of one to two weeks, and insufficient research-based data are available on the safety of their long-term use.

Capsaicin

Capsaicin relieves pruritus by inducing C nerve fibers to release neurotransmitters that cause red spots and heat.Topical use of capsaicin can effectively control local pruritus. This medication is suitable for paresthesia and pain in the back, radial arm itch, post-herpes zoster itch,dialysis-induced itch in patients with nephrotic syndrome,psoriatic itch,and postphototherapy itch.35Topical use of capsaicin may cause a burning sensation. A higher initial concentration and more frequent use are usually associated with a better antipruritic effect with faster onset;however,the local burning feeling is also serious,so its use is limited.The 0.025%concentration is usually only a mild irritant,36but if the patient cannot tolerate it, the matrix can be diluted to a lower concentration, especially for perianal pruritus.

Calcineurin inhibitors

Tacrolimus ointment and pimecrolimus cream have certain antipruritic effects in the treatment of inflammatory skin diseases. These drugs can be used for the treatment of pruritus caused by atopic dermatitis,seborrheic dermatitis,psoriasis,and other diseases37as well as refractory anal and external genital itching.Patients may experience a burning sensation in the first few days of topical use, but this sensation usually disappears after continuing use.

Others

Zinc oxide, mint, camphor, and other preparations used topically also have a certain antipruritic effect. In particular, menthol activates channels such as transient receptor potential channel m-8 to relieve pruritus.38

Systemic pharmacotherapy

Antihistamines

Antihistamines are effective in treating histamine-dependent pruritus such as urticaria.However,there is a lack of evidence regarding the effect of antihistamines on nonhistamine-dependent pruritus.12First-generation antihistamines such as chlorpheniramine and diphenhydramine have a definite sedative adverse effect. It is recommended to take these antihistamines at night to promote sleep;however, they can also interfere with sleep quality. Firstgeneration antihistamines should be avoided in patients with glaucoma and prostatic hypertrophy. In addition to its antihistamine effect, ketotifen has a clear stabilizing effect on hypertrophic cell membranes and can be used in some patients with chronic pruritus.39Second-generation

antihistamines, such as avastin, levocetirizine, olopatadine,epinastine,and benzostatins,have anti-inflammatory effects.40Clinical application of these drugs shows positive effects on various types of chronic inflammatory pruritus.The effects are more obvious when using 2-4 times of the standard dose of antihistamines,and the adverse reactions do not substantially increase. However, full communication and informed consent are required.

Glucocorticoids

Systemic application of glucocorticoids in the treatment of pruritus caused by inflammatory skin diseases has a rapid onset and good effect and plays an important role in timely control of the disease.41Because glucocorticoids have many adverse effects and the disease is prone to rebound after withdrawal, drug indications should be strictly controlled, especially in children and elder patients.

Opioid agonists and antagonists

Studies have shown that endogenous or exogenous endorphins are involved in the development of pruritus.Application of an opioid μ-receptor antagonist or κ-receptor agonist can effectively suppress pruritus.42Treatment of chronic urticaria, atopic dermatitis, cholestatic pruritus, and chronic nephropathy-related intractable pruritus with opioid μ-receptor antagonists,including nalmefene (10mg twice daily), naloxone (400-800μg/day), or naltrexone (50-100mg/day), is effective; the κ-receptor agonist nalfurafine (2.5-5.0μg/day) also has a positive effect. Adverse reactions to these drugs are common and include increased or decreased blood pressure, tachycardia, liver damage, and rash. They should be used carefully, starting at a small dose, etc.

Antiepileptics

The main antiepileptics used for pruritus are gabapentin and pregabalin.43The mechanism of their action is not entirely clear.Studies have shown that they have a positive effect on pruritus related to chronic kidney disease,cholestatic pruritus,scar-related pruritus,and neuropathic pruritus such as post-herpes zoster pruritus, with good drug safety.Gabapentin should be started at a small dose that can be increased according to the severity of pruritus,with the maximum dose not exceeding 1,800mg/day.The dose of pregabalin ranges from 75 to 300mg/day. The whole duration of treatment is two to four weeks;it may be extended according to the specific condition being treated.44

Antidepressants

Psychological and emotional factors can reduce the itch threshold and promote pruritus.Antidepressants work by targeting serotonin and histamine to fight pruritus.45Mirtazapine (7.5-30mg/day), doxepin (25-50mg/day),and paroxetine (20mg/day) can effectively relieve mental itching, parasitic delusions, and other unexplained pruritus. Adverse reactions include mental disorders, lethargy,irritability,dry mouth,increased pruritus,atrioventricular block,and even death.Patients of advanced age need to be particularly careful with these drugs. Mirtazapine and doxepin should usually be taken before bed, while paroxetine should be taken in the morning.

Serotonin receptor antagonists

Serotonin is involved in multiple causes of pruritus. The use of serotonin receptor antagonists such as ondansetron(8-24mg/day),tropisetron(5mg/day),and granisetron(1 mg/day)can effectively treat multiple causes of pruritus.46However,other studies have found no effect.These drugs may be tried in patients with intractable pruritus; if no effect is observed after two weeks, they should be discontinued. Adverse reactions include headache, dizziness, and constipation, among others.

Thalidomide

Thalidomide can relieve pruritus through central sedation,inhibiting local nerve growth factor and antagonizing tumor necrosis factor alpha. It is mainly used for prurigo nodularis and refractory pruritus that do not respond to conventional treatment.47The main adverse reactions include teratogenic effects and dose-dependent neuropathy.

Immunosuppressants

Immunosuppressants used for pruritus include cyclosporine,azathioprine,methotrexate,and others,which can be used to treat pruritus caused by inflammatory skin diseases. Among them, cyclosporine may have a role in reducing excitability of peripheral nerve endings and is used in noninflammatory pruritus, including that associated with chronic kidney disease.48The main adverse reactions of these drugs are immunosuppression,leukopenia, and liver and kidney function damage.

Biological agents

While controlling the primary disease,anti-interleukin-31 monoclonal antibody and tumor necrosis factor alpha antagonist can effectively relieve pruritus.49

Ultraviolet phototherapy

Ultraviolet(UV) phototherapy can be effective in treating pruritus caused by many causes.50Available UV sources include broad-spectrum UVB (290-320nm), narrowspectrum UVB (311nm), long-wave length UVA (320-400nm), and UVA1 (340-400nm). Phototherapy can inhibit the function of inflammatory cells and reduce the number of nerve endings associated with the immune response of procalcitonin gene-related peptides in the skin.The penetration depth of UVB is shallow, and it mainly affects keratinocytes and Langerhans cells. UVA1 can reach the dermis and inhibit T cells,mast cells,and dermal dendritic cells, and it plays a greater role in relieving pruritus.Broad-spectrum UVB and narrow-spectrum UVB can achieve satisfactory effects in the treatment of pruritus accompanied by atopic dermatitis or psoriasis. UVA1 is more effective than UVB in the treatment of prurigo.Phototherapy is usually combined with topical or systemic medication. However, it should not be combined with topical use of calcineurin inhibitors or systemic use of immunosuppressants because of the increased risk of immunosuppression and tumors.In addition,UVB should be used with caution in children under 12 years of age,and UVA1 should be used with caution in children under 18 years of age.51

Traditional Chinese medicine

According to clinical syndrome differentiation, pruritus can be treated with the methods of expelling wind,desiccant,heat,detoxification,and insecticide and activating blood circulation and raising blood, Wen Yang, and Qi. Also frequently used are Xiao Feng San, Longdan Xiegan decoction, desiccant stomach herb soup, Xijiao Dihuang, Taohong Siwu decoction, Angelica decoction,and Guifu Bawei pills, with addition or subtraction of these prescriptions. Well-known old Chinese medicines such as Jingfang prescription, nourishing blood and skin soup, relieving itching and wind soup, and invigorating blood and dispelling wind soup can also be used.Hundreds of medicines are often used for topical treatment, including realgar, cnidium, earth hibiscus, big maple, sulfur, dry alum, and other insecticidal antipruritics.

Authors list

Fei Hao, The Third Affiliated Hospital of Chongqing Medical University; Qi-Quan Chen, Southwest Hospital,Army Medical University(Third Military Medical University;Heng Gu,Chinese Academy of Medical Sciences and Peking Union Medical College; Gang Wang, Xijing Hospital, Fourth Military Medical University; Tie-Nan Li, Shenyang Seventh People’s Hospital; Zhi-Qiang Xie,Peking University Third Hospital; Hong Fang, First Affiliated Hospital of Medical School of Zhejiang University; Dong-Mei Zhang, Southwest Hospital, Army Medical University (Third Military Medical University);Ruo-Yu Li, Peking University First Hospital, Research Center for Medical Mycology, Peking University; Heng-Jin Li,Chinese PLA General Hospital;Lin-Feng Li,Beijing Friendship Hospital, Capital Medical University, Beijing,China; Zhi-Qiang Song, Southwest Hospital, Army Medical University (Third Military Medical University);Bin Yang, Dermatology Hospital of Southern Medical University, Southern Medical University; Qian-Jin Lu,Hunan Key Laboratory of Medical Epigenomics, The Second Xiangya Hospital of Central South University;Xu Yao, Chinese Academy of Medical Sciences and Peking Union Medical College; Hong-Zhong Jin, Peking Union Medical College Hospital;Jin-Hua Xu,Huashan Hospital Affiliated with Fudan University; Bo Cheng, The First Affiliated Hospital of Fujian Medical University; Tian Qian,The Third Affiliated Hospital of Chongqing Medical University.