Chronic Pruritis

Chronic pruritus is defined as a generalized itching sensation lasting ≥6 wk in duration.

Epidemiology & Demographics

Incidence

Symptoms of itch are common accounting for about 7 million, or about 1%, of all outpatient office visits in the U.S. per year.

Prevalence

Estimates of prevalence within the general population range from 8% to 17%. Reported prevalence between 7% to 60% of geriatric populations.

Predominant Sex & Age

More common in women and older adults.

Risk Factors

Asthma, xerosis (dry skin), elevated body mass index, anxiety, and liver disease are associated with increased risk for chronic pruritus.

Genetics

Unknown.

Physical Findings & Clinical Presentation

•Chief concern is typically an itch lasting longer than 6 wk.
•History should be taken including questions about:
- 1.Duration, quality, and localization of itch
- 2.Presence of skin lesions preceding the itch
- 3.Associated skin symptoms
- 4.Possible allergies or medication changes
- 5.Signs or symptoms of pregnancy, liver disease, gastrointestinal disease, renal disease, neurologic, or psychiatric conditions
- 6.Constitutional symptoms indicating underlying systemic illness
- 7.Itching or new lesions in family members or close contacts
- 8.New sexual contacts
- 9.Descriptive features of the pruritus and additional patient history are summarized in the below table.

TABLE

TABLE 1

Descriptive Features of the Pruritus and Additional Patient History

From Bolognia J: Dermatology, ed 4, 2018, Elsevier.

Descriptive Features of the Pruritus and Additional Patient History

Questions to ask regarding the pruritus

•WHEN did it start? Duration: Days, weeks, months, years•WHERE did it start? WHERE is it now? Location: Localized or generalized, unilateral or bilateral•HOW did it start? Onset: Abrupt, gradual, prior history of pruritic episodes•HOW does it feel? Nature: Prickling, crawling, burning, stinging•HOW intense is it? Severity: Mild, moderate, severe; interference with normal activities or sleep•HOW often do you feel it? Time course: Intermittent, continuous, cyclical, nocturnal•WHAT makes it worse? Provoking/aggravating factors: Heat, cold, water, air, exercise, occupation, hobbies•WHAT makes it better? Itch relief: Cold, heat, scratching/rubbing/hurting, cool/hot showering•WHAT do you think is the cause? Patient’s theory of pruritus etiology

Additional patient history

•Skin care, bathing habits, exposure to irritants•Medications (including topical agents): Prescribed, over-the-counter; duration of use and relationship to onset of pruritus•Use of nicotine, alcohol, and recreational/illicit drugs•Allergies (known and suspected): Drugs, airborne, food, contact•Atopic history: Atopic dermatitis, allergic rhinoconjunctivitis, asthma•Past and present medical history: Thyroid, liver, or renal dysfunction; other systemic diseases; psychologic disease; surgeries or accidents•Family history: Atopy, skin disease, similar pruritic conditions•Occupation, hobbies, personal stress•Household and personal contacts; pets and their care•Dietary habits•Sexual history•Travel history•Prior diagnoses made by physician or patient

Primary skin lesions may be primary due to an underlying skin condition or secondary changes due to persistent scratching.
•Primary lesions may include:
- 1.Bullae
- 2.Ichthyosis (dry, thickened, scaly skin)
- 3.Macular erythema
- 4.Papules
- 5.Vesicles
- 6.Wheals
- 7.Xerosis
•Secondary skin changes may include:
- 1.Atrophy
- 2.Crusting
- 3.Excoriation
- 4.Hyperpigmentation or hypopigmentation
- 5.Lichenification
- 6.Necrosis
- 7.Nodules
- 8.Papules
- 9.Prurigo nodules
- 10.Scars
- 11.Ulcerations

Etiology

•Dermatologic etiologies for pruritus include allergic contact dermatitis, atopic dermatitis, bullous pemphigoid, cutaneous T-cell lymphoma, dermatitis herpetiformis, dermatophyte infection, folliculitis, lichen planus, lichen simplex chronicus, pediculosis, psoriasis, scabies, sunburn, urticarial, and xerosis. Primary dermatologic conditions associated with pruritus are summarized in the below table.

TABLE

TABLE 2

Primary Dermatologic Conditions Associated with Pruritus

From Bolognia J: Dermatology, ed 4, 2018, Elsevier.

Primary Dermatologic Conditions Associated With Pruritus
Cause	Dermatologic disease
Inflammation	•Atopic dermatitis•Allergic or irritant contact dermatitis•Seborrheic dermatitis, especially of the scalp•Stasis dermatitis•Psoriasis•Parapsoriasis•Pityriasis rubra pilaris•Lichen planus•Urticaria, dermographism•Mastocytosis•Papular urticaria, urticarial dermatitis•Drug eruptions, e.g., morbilliform•Polymorphous light eruption, actinic prurigo, chronic actinic dermatitis•Bullous diseases, e.g., DH, BP•Polymorphic eruption of pregnancy (PEP)•Eosinophilic folliculitis•Dermatomyositis•Prurigo pigmentosa•Lichen sclerosis•Graft-versus-host disease
Infestation/bites & stings	•Scabies•Pediculosis•Arthropod bites
Infections	•Bacterial infections, e.g., folliculitis•Viral infections, e.g., varicella•Fungal infections, e.g., inflammatory tinea•Parasitic infections, e.g., schistosomal cercarial dermatitis
Neoplastic	•Cutaneous T-cell lymphoma, e.g., mycosis fungoides, Sézary syndrome
Genetic/nevoid	•Darier disease and Hailey–Hailey disease•Ichthyoses, e.g., Netherton, Sjögren–Larsson, and peeling skin syndromes•Pruriginosa subtype of dominant dystrophic EB•Porphyrias, e.g., porphyria cutanea tarda and erythropoietic protoporphyria•Inflammatory linear verrucous epidermal nevus (ILVEN)•Large/giant congenital melanocytic nevi, occasionally, especially in bulky lesions with neural differentiation
Other	•Xerosis, eczema craquelé•Primary cutaneous amyloidosis (macular, lichenoid)•Postburn pruritus•Scar-associated pruritus•Fiberglass dermatitis

BP, Bullous pemphigoid; DH, dermatitis herpetiformis; EB, epidermolysis bullosa.

Systemic etiologies for pruritus include:
- 1.Autoimmune
  - a.Dermatitis herpetiformis
  - b.Dermatomyositis
  - c.Linear immunoglobulin A disease
  - d.Scleroderma
  - e.Sjogren syndrome
- 2.Hematologic
  - a.Hemochromatosis
  - b.Iron deficiency anemia
  - c.Mastocytosis
  - d.Plasma cell dyscrasias
  - e.Polycythemia rubra vera
- 3.Hepatobiliary
  - a.Primry biliary cirrhosis
  - b.Chronic pancreatitis
  - c.Drug-induced cholestasis
  - d.Hepatitis
  - e.Sclerosing cholangitis
- 4.Infectious disease
  - a.Human Immunodeficiency Virus infection
  - b.Parasitic disease
  - c.Prion disease
- 5.Malignancy
  - a.Leukemia
  - b.Lymphoma
  - c.Multiple myeloma
  - d.Paraneoplastic syndrome
- 6.Endocrine
  - a.Carcinoid syndrome
  - b.Diabetes mellitus
  - c.Hyperthyroidism
  - d.Hypothyroidism
  - e.Hyperparathyroidism
- 7.Neurologic
  - a.Cerebral abscess
  - b.Cerebral tumor
  - c.Peripheral neuropathy

Diagnosis

Differential Diagnosis

•Liver disease (primary biliary cirrhosis, hepatitis)
•Multiple myeloma
•Lymphoma
•Leukemia
•Xerosis (dry skin)
•Allergic reaction
•Renal disease (uremia)
•Diabetes mellitus
•Medication side effect
•Atopic dermatitis
•Dermatitis herpetiformis (associated with gluten sensitivity)
•Insect bite and scabies
•Anxiety
•Pregnancy
•Pruritis of elderly skin
•Lichen Simplex Chronicus

Workup

Diagnostic testing should be guided by clinical suspicion of underlying causes such as liver disease, HIV, lymphoma, hypothyroidism, renal failure, and polycythemia vera.

Laboratory Tests

•Complete blood count with differential, glucose, creatinine, liver function tests, serum protein electrophoresis, hepatitis serologies, HIV testing, and ferritin can be considered. If diagnosis remains uncertain, skin biopsy should be performed.
•Laboratory and radiographic evaluation in patients with pruritus of unknown etiology are summarized in the below table.

TABLE

TABLE 3

Laboratory and Radiographic Evaluation in Patients with Pruritus of Unknown Etiology. A general physical examination should also be performed by the patient’s primary care physician. Selection of particular tests beyond the basic initial evaluation is based upon the patient’s history, physical examination findings, and pruritus severity. The results of initial testing can also help to direct further evaluation.

From Bolognia J: Dermatology, ed 4, 2018, Elsevier.

Laboratory and Radiographic Evaluation in Patients with Pruritus of Unknown Etiology

Basic initial evaluation

•Complete blood cell count (CBC) with differential and platelet count•Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)•Creatinine, blood urea nitrogen, electrolytes•Liver transaminases, alkaline phosphatase, bilirubin•Lactate dehydrogenase (LDH)•Fasting glucose•Thyroid stimulating hormone (TSH) ± free thyroxine

Possible additional evaluation

Skin biopsy•Routine histology (if skin lesions are present)•Direct immunofluorescence studies ∗Other laboratory tests•Serum total and/or allergen-specific IgE•Serum ferritin, iron, total iron binding capacity•Hemoglobin A1c•Parathyroid function (calcium, phosphate, and parathyroid hormone levels)•Stool for ova/parasites and/or occult blood•Viral hepatitis panel (including hepatitis B and C viruses)•HIV testing•Anti-tissue transglutaminase ± epidermal transglutaminase IgA antibodies ∗∗•Anti-BP180 and anti-BP230 bullous pemphigoid IgG antibodies•Anti-mitochondrial and anti-smooth muscle antibodies•Serum tryptase, histamine, and/or chromogranin-A levels•Urinalysis with sediment evaluation•24-hour urine collection for 5-hydroxyindoleacetic acid (5-HIAA; a serotonin metabolite) and porphyrins•Serum protein electrophoresis, serum immunofixation electrophoresisRadiographic studies•Chest x-ray or CT scan•Abdominal and pelvic ultrasonography or CT scan•Lymph node ultrasonography•Spinal x-ray or MRI (for regional pruritus)Other investigations•Patch testing•Prick testing for major atopy and relevant occupational allergens•Age-appropriate cancer screening (in conjunction with primary care physician)•If hydroxyethyl starch (HES)-induced pruritus is suspected, electron microscopy of a biopsy sample from normal-appearing skin

∗ Biopsy perilesional skin or normal-appearing skin (in vicinity of lesions if present) to assess for bullous pemphigoid and dermatitis herpetiformis, respectively.

∗∗ Often performed in conjunction with serum total IgA; in patients with IgA deficiency, anti-tissue transglutaminase IgG antibodies should be assessed.

Imaging Studies

Chest x-ray if diagnosis remains uncertain and concern for underlying pathology.

Treatment

Keeping skin cool, using emollients, taking short tepid showers, and avoiding soaking may help symptoms. Moisturizing soaps without fragrance and avoiding antibacterial soaps may help as well.

Nonpharmacologic Therapy

•Avoid excessive bathing, frequent use of soap, dry environments, topical irritants or vasodilators such as caffeine, alcohol, and exposure to warm water. Apply emollients liberally after bathing and use fragrance-free soaps. Humidifiers may be used in dry indoor environments, particularly during the winter months. Keeping fingernails short and clean may prevent complications of repetitive scratching.

Acute General Rx

•Antihistamines are usually recommended. H1 blocker diphenhydramine may be sedating. Non-sedating H1 blockers such as cetirizine, fexofenadine, and loratadine are also effective.
•The addition of an H2 blocker (cimetidine, famotidine, ranitidine, nizatidine) should be considered if H1 blockers alone are ineffective.
•Montelukast inhibitors may also be effective when adding to an H1 blocker for symptom control.

Chronic Rx

•The management of pruritus should focus on the underlying cause. If patients have pruritus with a systemic cause, itching may slowly improve as the primary disease improves.
•Topical naltrexone and topical or oral doxepin may benefit patients with persistent symptoms.
•The below table summarizes drug treatment of pruritus.

TABLE

TABLE 4

Drug Treatment of Pruritus. Topical naltrexone, aspirin, and cannabinoids may also have antipruritic effects, and injections of botulinum toxin type A have been used to treat neuropathic itch. In the future, topical anti-itch medications may target serine proteases (e.g., cathepsin S), nerve growth factor, or neurotrophin 4

From Bolognia J: Dermatology, ed 4, 2018, Elsevier.

Drug Treatment of Pruritus
Medication	Mechanism(s) of Action	Uses and Efficacy	Major Adverse Effects
Topical agents
Capsaicin (active component in hot chili peppers)	•Activates and subsequently desensitizes TRPV1, a vanilloid TRP receptor•Causes release from C neurons and (eventually) depleted stores of neuropeptides (e.g., substance P, CGRP, somatostatin)•Prolonged use leads to neuronal degeneration at sites of application, which can result in a reversible decrease in epidermal nerve fiber density	•Used primarily for localized, chronic pruritic disorders, especially those of neuropathic origin•Controlled studies support use for:•Notalgia paresthetica•Brachioradial pruritus•Hemodialysis-associated pruritus•Postherpetic neuralgia, with a transdermal patch FDA-approved for this indication	•Transient burning sensation, which usually resolves after several days of consistent use; application of topical lidocaine or EMLA may be helpful
Doxepin	•Tricyclic compound with potent antihistamine effects (H₁and H₂); also anticholinergic properties	•Shown to relieve pruritus in patients with atopic dermatitis	•Drowsiness in ∼25% of patients due to percutaneous absorption•Allergic contact dermatitis
Menthol	•Activates TRPM8 and TRPA1, producing a cool sensation	•Inconsistent results in controlled studies•May be especially beneficial for patients whose itch is relieved by cold showers	•Skin irritation
Pramoxine	•Anesthetic (blocks transmission of nerve impulses)	•Beneficial for histamine-induced itch and uremic pruritus in end-stage renal disease	•Allergic contact dermatitis (uncommon)
Tacrolimus, pimecrolimus	•Calcineurin inhibitors that block production of multiple proinflammatory cytokines•May initially activate and subsequently desensitize TRPV1	•Can decrease itch related to the inflammation of atopic dermatitis	•Transient burning sensation
“Barrier repair” creams, other emollients and humectants	•Diminish transepidermal water loss and decrease flux between a distended and desiccated state•Minimize microfissures that expose C nerve fibers•Agents that acidify the stratum corneum may reduce itch, as alkaline agents (e.g., bar soaps) can activate proteases and increase lipid rigidity	•Decrease itch in patients with atopic dermatitis	None
Strontium	•Calcimimetic thought to inhibit ion channels in nerve fibers	•Strontium 4% hydrogel was shown to relieve localized cowage-induced itch	None identified
Ketamine-amitriptyline-lidocaine (10%-5%-5% compounded cream)	•Anaesthetic effect; targets ion channels in peripheral nerves and NMDA receptors	•May decrease neuropathic itch and other forms of pruritus, including the itch of prurigo nodularis	•Mild burning sensation•Potential systemic absorption
Systemic agents
Antihistamines (especially doxepin)	•Doxepin is a tricyclic compound with potent antihistamine effects (H₁and H₂) and anticholinergic properties; first-generation, sedating antihistamine	•Decrease wheal formation as well as pruritus in patients with urticaria	•Sedation•Anticholinergic effects•Interaction with MAO inhibitors (for doxepin)
Naloxone, naltrexone	•μ-Opioid receptor antagonists ∗	•Controlled trials show efficacy for cholestatic and renal pruritus•May be of benefit for severe pruritus of other etiologies	•Hepatotoxicity•Nausea/vomiting•Insomnia•Reversal of analgesia
Nalfurafine ^†	•κ-Opioid receptor agonist ∗	•Controlled trials show efficacy for renal pruritus	•Insomnia
Butorphanol	•κ-Opioid receptor agonist and μ-opioid receptor antagonist ∗	•Relieves pruritus associated with morphine with epidural administration of both agents•May reduce severe pruritus associated with systemic disease or inflammatory skin conditions ^‡	•Nausea/vomiting•Sedation•Dependence (rare)
Mirtazapine	•Serotonin and norepinephrine inverse agonist that reduces central itch perception	•May reduce nocturnal pruritus (at low doses, e.g., 15 mg nightly)	•Sedation•Weight gain
Paroxetine	•Selective serotonin reuptake inhibitor (SSRI)	•A controlled study showed benefit for pruritus related to systemic disease	•Sexual dysfunction•Sedation•Insomnia•Weight gain
Thalidomide	•Blocks neuropathic afferent pathways (peripherally and centrally)•Inhibits TNF synthesis	•May be helpful for prurigo nodularis, actinic prurigo and, pruritus of advanced age	•Teratogenicity•Peripheral neuropathy
Gabapentin, pregabalin	•Structural analogues of the neurotransmitter GABA•Thought to inhibit central itch pathways	•Beneficial for neuropathic itch (e.g., brachioradial pruritus), post-burn pruritus and postherpetic neuralgia	•Peripheral edema•Sedation•Abdominal pain
Aprepitant	•Antagonist of the neurokinin-1 receptor, which is activated by substance P	•Primarily used as an antiemetic in oncology patients; reports of reduced pruritus in patients with atopic dermatitis, Sézary syndrome, and other forms of CTCL as well as decreases in pruritus induced by anti-EGFR antibodies or tyrosine kinase inhibitors	•Fatigue•Hiccups

CGRP, Calcitonin gene-related polypeptide; EMLA, eutectic mixture of local anesthetics (lidocaine + prilocaine); FDA, U.S. Food and Drug Administration; MAO, monoamine oxidase; TRP, transient receptor potential ion channel family; CTCL, cutaneous T-cell lymphoma; EGFR, epidermal growth factor receptor; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate; TNF, tumor necrosis factor.

∗ Inhibit itch transmission within the central nervous system.

† Currently not commercially available in the U.S.

‡ An intranasal spray is currently available.

Complementary & Alternative Medicine

Natural supplements for atopic eczema include fish oil, and vitamin D plus vitamin E have demonstrated limited benefit.

Disposition

Overall prognosis depends on the underlying cause of pruritus.

Referral

Patients with psychogenic pruritus may benefit from a referral to a psychologist or psychiatrist.

Pearls & Considerations

Comments

In patients with an identified underlying cause, the mainstay of treatment is treating the underlying condition.

Prevention

Avoid excessive bathing. Avoid frequent use of drying soaps, dry environments, topical irritants, or vasodilators such as caffeine, alcohol, and exposure to warm water. Apply emollients liberally after bathing. Use unscented soaps. A humidifier may be used in dry indoor environments, particularly during the winter months. Keeping fingernails short and clean may prevent complications of repetitive scratching.

Patient & Family Education

Medline: https://medlineplus.gov/itching.html
American Academy of Family Physicians: https://www.aafp.org/afp/2011/0715/p203.html
DermNetNZ: https://dermnetnz.org/topics/pruritus/

Chronic Pruritis