Pruritus (overview) L29.8

Frequently occurring, highly differentiated (polyetiologic) symptom in numerous skin diseases or also in diseases of internal organs or systems.

However, it can also occur without a visible cause (old term: pruritus sine materia) or as a somatoform disorder.

A distinction is made between:

• localized (sometimes also punctiform) or diffuse, possibly generalized pruritus
• acute or chronic pruritus (chronic pruritus = > 6 weeks)
• pruritus caused by external or internal influences.

Pruritus is often perceived as different sensations of the skin and/or semi-mucous membranes (tingling, stinging, burning, biting). Depending on its quality, it is responded to reflexively by squeezing, scratching, rubbing or chafing.

Itching can also be associated with small fiber neuropathy.

Several measurement methods and procedures exist for the subjective assessment of pruritus intensity, such as the "Itch Severity Scale" or the Virtual Analog Scale (VAS), which differentiates between 5 qualities (analog scale from 0-10), which for the sake of simplicity are listed here:

• 0 = no pruritus
• 0.1-2.9 = low/mild pruritus
• 3.0-6.9 = moderate/moderately severe pruritus
• 7.0-8.9 = severe pruritus
• 9.0-10.0 = very severe pruritus

A basic distinction should be made as to whether pruritus develops in normal skin or skin with inflammatory changes.

Pruritus on primarily unchanged skin (outdated term: pruritus sine materia):

• Endocrine and metabolic disorders:
  • Uremic pruritus (pure itching, occasionally attack-like, regularly very severe)
  • Cholestatic pruritus (hepatopathies with cholestasis: occlusive jaundice, drug-induced cholestasis, primary biliary cirrhosis, hepatitis, primary sclerosing cholangitis: pure itching, mechanically inducible, cannot be reduced by scratching) - see also liver diseases, skin changes.
  • Diabetes mellitus (neuropathic itching, painful qualities such as burning, stinging, tearing, intensity mild to severe depending on duration of diabetes)
  • Hyper- or hypothyroidism (rather mild)
  • Hyperparathyroidism
  • Malabsorption (gluten-sensitive enteropathy, eating disorders)
  • Perimenopausal pruritus
• Infections:
  • Intestinal parasitoses (worm diseases, Gardia lamblia)
  • Onchocerciasis
  • HIV infection
  • Epizoonoses.
• Hematologic and lymphoproliferative diseases:
  • Iron deficiency (determination of the storage iron indices -ferritin/transferrin saturation)
  • Hemochromatosis
  • Polycythemia vera
  • Myelodysplastic syndrome
  • M. Hodgkin's disease (pure itching)
  • Cutaneous T-cell lymphoma (pure itching)
  • Plasmacytoma (pure itching)
    
• Solid malignancies:
  • Cervical, prostate, colon carcinoma, pancreatic carcinoma, bile duct and gallbladder carcinoma
• Neurological diseases:
  • Brachioradial pruritus (neuropathic, painful itching)
  • Notalgia paresthetica (neuropathic, painful itching)
  • Zoster neuralgia (itching, pain)
  • "Small-fiber" neuropathies (vulvodynia, glossodynia, restless legs syndrome)
  • Multiple sclerosis (5% pruritus)
  • Neuropathies of various origins (infarcts of the CNS).
• Mental illnesses:
  • Somatoform disorders
  • Schizophrenic psychoses
  • Tactile hallucinosis
  • Pseudo-itching with artifacts.
• Drug-induced (see drug-induced pruritus):
  • e.g. due to ACE inhibitors or fumarates (bright, agonizing itching, relieved by rubbing)

Pruritus on primarily altered skin (pruritus cum materia):

• Autoimmune dermatoses:
  • Bullous autoimmune dermatoses(bullous pemphigoid, paraneoplastic pemphigus, pemphigus vulgaris)
  • IgA linear dermatosis
  • Dermatitis herpetiformis.
• Neoplasms (with direct skin involvement):
  • Cutaneous T-cell lymphoma
  • Leukemic infiltrates of the skin.
• Infections of the skin:
  • Mycoses of the skin
  • Zoster (also post-zosteric)
  • Herpes simplex recidivans
  • Pyoderma
  • Infectious exanthema (e.g. scarlet fever in healing).
• Epizoonoses:
  • Scabies
  • Cheyletiellosis
  • Trombidiosis (cereal scabies)
  • loiasis
  • oxyuriasis
  • Pediculosis
  • Pulicosis
  • Tungiasis
  • insect bites
  • Cercarial dermatitis.

Inflammatory/neoplastic skin diseases of various origins characterized by relevant itching:

• Xerosis cutis
• Atopic eczema
• Contact allergic eczema
• Exfoliative dermatitis (e.g. healing dermatitis solaris)
• Acanthosis nigricans
• Epidermolysis bullosa diseases
• Erythroderma of various origins
• Haemorrhoidal disease
• Hyper-IgE syndrome
• Hypereosinophilia syndrome
• Lichen amyloidosus
• Lichen simplex chronicus (Vidal)
• Lichen sclerosus et atrophicus (burning, stinging, better after rubbing)
• Polymorphic light dermatosis (pure itching, burning)
• Cutaneous mastocytomas (after irritation)
• Pernions (painful, less itchy)
• Pityriasis lichenoides chronica
• Prurigo diseases
• psoriasis
• Pregnancy dermatoses (e.g. PUPPP)
• Seborrhoeic eczema of the infant
• Adverse drug reactions (especially urticarial or lichenoid drug exanthema; pruritus after HAES infusions)
• Urticaria pigmentosa (after irritation)
• Urticaria (light itching, no scratching, better after rubbing)

Pruritus is the most frequently complained symptom in dermatology and yet, to date, only a few reliable scientific studies exist on the pathophysiology, incidence and prevalence of pruritus. The incidence of chronic pruritus in general medical patients is estimated to be about 8%, other studies speak up to 20%.

It is now known that the nerve fibers that conduct itching are free unmyelinated nerve endings that occur with particularly dense branching in the epidermis of the skin, mucous membranes and cornea. The information received there is carried on with the signals for pain and thermal sensations first in the ipsilateral, after synaptic connection in the contralateral tractus spinothalamicus lateralis. Divergent information currently exists about processing in the brain. Activity has been found in both motor and sensory areas of the cortex. Thus, although pain and itch seem to use the same pathways, no subcortical activation has yet been found in itch, unlike pain.

So far, numerous potential chemical mediators of pruritus have been identified:

• Histamine from mast cells and keratinocytes binds to H1 and H2 receptors on peripheral nerve endings. This results in depolarization of the nerve and release of the neuropeptide substance P. Histamine can inhibit SP release via H3 receptors.
• Neurotransmitter of the autonomic nervous system (acetylcholine): Release is also possible from keratinocytes. Binding to muscarinergic (M1-M5) and nicotinergic acetylcholine receptors. Functionally it mediates mainly pain (nociception). Stimulation of the M3-receptors and the nicotinergic receptors mediates itching, e.g. in atopic eczema.
• Bradykinin causes pain in the skin mainly via the B2 receptor, but also causes a degranulation of mast cells and increases e.g. the histamine effect at the nerve fibre, the release of substance P and prostaglandin E.
• Serotonin acts via serotonin 3 receptors to promote itching. However, serotonin 3-receptor antagonists do not show any effect on nephrogenic itching.
• Endothelin is produced by endothelial cells and causes a neurogenic inflammatory response associated with burning itching by stimulating nerve fibres and releasing NO.
• Vanilloid receptors on sensitive skin nerves are cation channels that bind vanilloids and are also activated by capsaicin and heat. They mediate burning pain and itching. Repeated capsaicin application leads to desensitization of the nerve fiber and suppression of itching.
• Proteinases such as trypsin, chymotrypsin and papain also appear to trigger itching, which can be blocked by antihistamine administration. Trypsin from mast cells activates PAR-2 (proteinase activated receptor 2), which is expressed on peripheral nerve fibres. Elevated concentrations of trypsin and PAR-2 have been found in patients with atopic dermatitis.
• Autotaxin (ATX), also known as ectonucleotide pyrophosphatase / phosphodiesterase 2 (NPP2 or ENPP2), is a membrane ectoenzyme that is active as phosphodiesterase and phospholipase. Autotaxin in humans is encoded by the ENPP2 gene located on chromosomes 8q24.12. Autotaxin is important for the formation of the lipid signal molecule lysophosphatidic acid (LPA). Autotaxin has lysophospholipase D activity and cleaves lysophosphatidylcholine into the signal lipid lysophosphatidic acid (LPA). ATX plays an essential role in all forms of cholestatic itching (Ständer S 2018).

Sensitivity modulation:

• Prostaglandins potentiate histamine-induced pruritus and are also able to trigger mild itching themselves.
• Interleukins: IL-2 causes itching by activating C-nerve fibres. IL4 can cause atopic eczema-like skin changes in mice. IL-6 and the IL-6 receptor are expressed in nerve cells and are found in increased amounts e.g. in prurigo papules.
• Neurotrophins and Nerve Growth Factor (NGF) cause nerve growth. NGF and neurotrophin-4 from keratinocytes are overexpressed in Prurigo nodularis and in atopic dermatitis.
• Opioids (e.g. β-endorphin, enkephalins and endomorphins) seem to reduce the sensitivity of peripheral nerve endings via various opioid receptors by inhibiting e.g. substance P release. However, systemically administered opioids can induce itching.
• Cannabinoids reduce histamine-induced itching via CB1 and CB2 receptors. For the treatment of chronic pruritus, cannabinoid agonists were used topically in one study. In 86.4% of the test persons a significant reduction of itching occurred after several weeks of therapy.
• The activation of the cold receptors CMR1 and ANKTM1 (ion channels) by cooling of the skin surface leads to a reduction of itching.

Eosinophil granulocytes:

• In the skin, eosinophilic granulocytes are often found near peripheral nerve fibres in inflammatory allergic diseases. For example, eosinophilic granulocytes are found in direct contact with peripheral nerves in prurigo nodularis . EDN and ECP have neurotoxic effects. EDN can be detected in lesions of patients with Prurigo nodularis. Eosinophil granulocytes can release neurotrophins such as NGF (nerve growth factor) and BDNF (brain-derived neurotrophic factor). BDNF prevents the apoptosis of eosinophilic granulocytes. Neurotrophins are known for their neurotrophic and neuroprotective activity. Furthermore, neurotrophins induce chemotaxis of eosinophilic granulocytes. They are therefore important mediators for the influence of cutaneous inflammation. They play an important role in the process of sensitization and in the development of pruritus. Besides neurotrophins, eosinophil granulocytes can also release neuropeptides such as substance P, VIP (vasoactive intestinal peptide). Both mediators are involved in the mediation of pruritus.

Mast cells:

• Vasoactive intestinal peptide, neurotensin, somatostatin, secretin as well as substance P and corticotropin-releasing hormones (CRH) induce itching, wheals and erythema by degranulation of mast cells.
• Substance P acts via neurokinin receptors on mast cells and the release of NO. Stress leads to increased substance P and CRH concentrations in the skin and thus to mast cell degranulation.
• Together with substance P, the neuropeptide calcitonine-gene-related peptide (CGRP) is frequently found, which possibly has an inhibitory effect on substance P.

Leukotrienes:

• The role of leukotrienes (see below eicosanoids) in the development of itching is unclear. Leukotriene B4 causes itching in mice; nocturnal leukotriene B4 excretion in urine correlates with the intensity of itching in atopic dermatitis. Substance P, a potent pruritic mediator, initiates the arachidonic acid cascade for the production of prostaglandins and leukotrienes; leukotriene antagonists therefore have an antipruritic effect.

Haes:

• Deposits of HAES or polyvinylpyrrolidone in the peripheral nerve endings can also cause massive itching.

Laboratory tests that may lead to clarification of the symptom prurigo:

• ESR, differential blood count, uric acid, urea, creatinine, transaminases, alkaline phosphatase, bilirubin, glucose, HbA1c thyroid function test (TSH, T3, T4), parathyroid function (calcium, phosphate), Serum iron, ferritin, Serum protein electrophoresis, Serum immunoelectrophoresis, Antinuclear antibodies (ANA), Extranuclear antibodies (ENA), Thyroid antibodies, HIV diagnostics (ELISA, PCR), Tryptase (in V.a. mastocytosis)
• X-ray of the thorax
• Stool examination for eggs, parasites, occult blood
• Allergy diagnostics: total IgE, histamine, serotonin, prick test (main allergens), epicutaneous test, urine diagnostics (sediment, 5-hydroxyindolacetic acid, mast cell metabolites).

Pruritus is a subjectively perceived symptom that cannot be measured using physical or biophysical methods. Therefore, various scales (categorical scales, interval scales, continuous scales) and questionnaires (Worchester Itch Index, Eppendorf Itch Questionnaire, s.a. Itchyquol) have been developed for direct or indirect (via scratching behavior) evaluation of itching. In the indirect assessment of itching via scratching behavior, it should be noted that severely itchy diseases such as urticaria and mastocytosis rarely lead to scratching, but rather to rubbing and pressing.

Important anamnestic factors that can lead to clarification of the symptom:

• Onset (e.g. abrupt, gradual, previous itching episodes)
• Time course (e.g. continuous, intermittent, cyclical, nocturnal)
• Duration (e.g. days, weeks, months, years)
• Character of the itching (e.g. tingling, burning, stinging)
• Severity (e.g. interferes with daily life or sleep)
• Localization (e.g. generalized, localized, unilateral, bilateral)
  • localized on the sides of the arm: brachioradial pruritus shoulder blades
  • localized between the shoulder blades(notalgia paraesthetica)
  • localized in the neck area (type labeling of T-shirts)
• Relationship to certain activities (e.g. profession, hobbies)
• Provoking factors (e.g. water, skin cooling, air, physical exertion)
• Does scratching, rubbing or pressure already trigger itching?
• The patient's theory about the cause of the pruritus (dosage, duration and frequency of application or use of topical or systemic medication)
• Targeted questioning after HAES infusions (see below pruritus after HAES infusions) or dialysis
• Known local or systemic allergies
• Atopic diathesis (eczema, allergic rhinitis, allergic asthma)
• Pre-existing conditions (thyroid, liver, kidney or other systemic diseases)
• Family history of atopy, skin diseases and itching
• Occupation
• Hobbies
• Social environment (home environment, personal contacts, diet, stress factors)
• Drugs (nicotine, alcohol, intravenous drugs)
• Skin care habits, use of cosmetics
• Pets (type I sensitization)
• Sexual history (for genital pruritus)
• Travel history (exclusion of epizoonoses or zoonoses)
• Suspected diagnoses already made.

Recording and documentation of pruritus intensity - also for therapy control by means of visual analog scale (VAS) or numerical rating scale with indication of the intensity of itching from 0 to 10.

Up to now there is no antipruritic drug whose efficacy could be equated with the success of aspirin in pain therapy. Therefore, the therapy has to be composed individually depending on patient and disease.

• General:
  • Wear comfortable clothing (no wool or synthetic fibres, cotton clothing instead)
  • Avoid excessive extreme temperature baths. Warm water or a short shower without drying detergents is better.
  • Regular moisturizing of the skin with basic care products (basodexan, optiderm) according to the individual tolerance (rich emmolients for the night, creams for the day).
  • Follow advice to interrupt the itch-scratch cycle (e.g. put on cold washcloth, apply light pressure).
  • Moderate physical activity.
  • Avoid stress and anxiety.
  • Avoid contact with dust and dust mites.
  • Avoid hot food, drinks or other hot liquids.
  • Participation in relaxation therapy.
• Topical therapy:
  • Individually adapted skin care
  • Topical glucocorticoids
  • Cannabinoid agonists
  • Cooling agents: shaking mixtures (e.g. ethanolic zinc oxide shaking mixture NRF)
  • Local anaesthetics (e.g. Optiderm, lidocaine gel)
  • Antihistamines: e.g. diphenhydramine, dimetindene, promethazine
  • Various: Capsaicin, camphor, menthol cream 1%, tacrolimus, pimecrolimus, crotamiton, etc.
• system therapy:
  • Antihistamines (also as high-dose therapy in mono- or multiple therapy)
  • Doxepin
  • Systemic glucocorticoids
  • Ciclosporin A
  • Ondansetron
  • Paroxetine
  • Thalidomide
  • Opioid antagonists (e.g. naloxone, naltrexone, nalmefene)
  • neurokinin receptor 1(NKR1) antagonists, e.g. aprepitant. The primary indication of aprepitant is chemotherapeutic vomiting (e.g. Emend 80 mg p.o./day).
• physical therapy:
  • Cutaneous field stimulation
  • Acupuncture.
• UV-irradiation:
  • Phototherapy
  • PUVA therapy.
• psychotherapy:
  • Group therapy
  • Behavioural Therapy
  • Biofeedback
  • Support groups.

Pruritus in diseases

Drugs that can induce pruritus

Cooling moist compresses, menthol-containing externa (cooling), capsaicin preparationsm these lead to an emptying of the synapses of the peripheral nerves, Cave with open skin areas, with eczema capsaicin is poorly tolerated!

Peppermint oil and mint oil: Either give 1-2 drops directly on the skin, or as a bath 2-4 drops per liter.

Externals with balloon vine her b - Cardiosperma herba are also helpful.

Studies indicate the efficacy of CBD cream and drops, see under Ethiopathogenesis, see under Cannabinoids.

Cannabidiol.

Lavender oil, positive monograph by Commission E, has a simultaneous sedative and local anesthetic effect and can be used as an additive for pruritus. Either as an essential oil (vaporized in the room, or a few drops applied to a cloth) or systemically in capsule form (e.g. Lasea), lavender oil has an emotionally balancing and equalizing effect directly on the limbic system, making it easier to fall asleep.

Systemic therapeutic agents with a sedative effect can be used as support: valerian and hops in combination have a sedative effect (positive monograph of Commission E), preparations e.g. Selon, Kytta-Sedativum f, Ardeysedon, Sensinerv f, Dormoverlan, Vivinox. It should be noted that valerian only develops its full effect after 14 days.

Severe pruritus usually leads to sleep disorders, which is rarely observed in psychogenic pruritus.

Psychiatric comorbidity with chronic pruritus was considered significantly high in a study of 109 subjects. Therefore, psychotherapeutic care (see below somatoform disorders) is additionally recommended.

Nocturnal, generalized pruritus in combination with B-symptoms (fever, night sweats, weight loss) can indicate the presence of a malignant disease!

The older, unclearly defined term"Pruritus sine materia" should be avoided.

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