Pruritis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Ammu Susheela, M.D. [2] Kiran Singh, M.D. [3] Luke Rusowicz-Orazem, B.S.

Overview

Itch (Latin: pruritus) is defined as an unpleasant sensation that evokes the desire or reflex to scratch. Itch has many similarities to pain and both are unpleasant sensory experiences but their behavioral response patterns are different. Pain creates a reflex withdrawal while itch leads to a scratch reflex.[1] Unmyelinated nerve fibers for itch and pain both originate in the skin, however information for them are conveyed centrally in two distinct systems that both use the same peripheral nerve bundle and spinothalamic tract.[2]

Historically, the sensations of itch and pain have not been considered to be independent of each other until recently where it was found that itch has several features in common with pain but exhibits notable differences.[3] The physiological mechanisms of itch are currently poorly understood and this is mainly due to the lack of animal models of itch. Pruritic stimuli mostly create the same reactions as noxious stimuli in experimental animals, but humans are capable of discerning the distinct features of itch and pain. Therefore human studies have provided most of the information regarding the processing of pruritic stimuli.[4]

Mechanism

Itch can originate in the peripheral nervous system (dermal or neuropathic) or in the central nervous system (neuropathic, neurogenic, or psychogenic).[5]

Dermal/Pruritoceptive

Itch originating in the skin is considered pruritoceptive and can be induced by a variety of stimuli, including mechanical, chemical, thermal, and electrical stimulation. The primary afferent neurons responsible for histamine induced itch are unmyelinated C-fibers. In human C-fiber nociceptors, two major classes exist: mechano-responsive nociceptors and mechano-insensitive nociceptors. Mechano-responsive nociceptors have been in shown in studies to respond to mostly pain and mechano-insensitive receptors respond mostly to itch induced by histamine. However it does not explain mechanically induced itch or when itch is produced without a flare reaction which involves no histamine. Therefore it is possible that pruritoceptive nerve fibers have different classes of fibers, which is currently unclear in current research.[1]

Studies have been done to show that itch receptors are only found on the top two skin layers, the epidermis and the epidermal/dermal transition layers. Shelley and Arthur had verified the depth by injecting individual itch powder spicules (Mucuna pruriens) and found that maximal sensitivity was found at the basal cell layer or the innermost layer of the epidermis. Surgical removal of those skin layers removed the ability for a patient to perceive itch. Itch is never felt in muscle, joints, or inner organs, which show that deep tissue does not contain itch signaling apparatuses.[3]

Sensitivity to puritic stimuli is not even across the skin and has a random spot distribution with similar density to that of pain. The same substances that elicit itch upon intracutaneous injection (injection within the skin) elicit only pain when injected subcutaneously (beneath the skin). Itch is readily abolished in skin areas treated with nociceptor excitotoxin capsaicin but remains unchanged in skin areas which were rendered touch-insensitive by pretreatment with saponins, an anti-inflammatory agent. Although experimentally induced itch can still be perceived under a complete A-fiber conduction block, it is significantly diminished. Overall, itch sensation is mediated by A-delta and C nociceptors located in the uppermost layer of the skin.[6]

Neuropathic

Neuropathic itch can originate at any point along the afferent pathway as a result of damage of the nervous system. They could include diseases or disorders in the central nervous system or peripheral nervous system.[3] Examples of neuropathic itch in origin are nostalgia paresthetica, brachioradial pruritus, brain tumors, multiple sclerosis, peripheral neuropathy, and nerve irritation.[7]

Neurogenic

Neurogenic itch, which is itch induced centrally but with no neural damage, is often associated with increased accumulation of endogenous opioids and possibly synethetic opioids.[3]

Psychogenic

Itch is also associated with some psychiatric disorders such as delusions of parasitosis or related obsessive-compulsive disorders, for example neurotic scratching.[3]

Interactions between Itch and Pain

Pain Inhibits Itch

The sensation of itch can be reduced by many painful sensations. Many studies done in the last decade have shown that itch can be inhibited by many other forms of painful stimuli, such as noxious heat, physical rubbing/scratching, noxious chemicals, and electric shock. Any stimuli that causes pain will inhibit itching.

The inhibition of itch by painful stimuli, including heat, physical stimulus, and chemical stimulus, has been shown experimentally. In an article written by Louise Ward and others, they studied the effects of noxious and non-noxious counterstimuli, such as heat, physical vibration, or chemical stimulation on skin, in healthy adults after they had experimentally induced itch (transdermal iontophoresis of histamine) and pain (with topical mustard oil) in their skin. They found that when they induced non-noxious counterstimuli, the reduction of pain and itch was reduced only for up to 20 seconds. However when they induced noxious counterstimuli, there was a significant inhibition of itch for an extended period of time but no inhibition of pain. In addition, it was found that brief noxious stimuli created an anti-itch state for more than 30 minutes. These findings show that itch is not a subliminal form of pain and that noxious counterstimulus is likely to act through a central instead of a peripheral mechanism.[4]

Painful electrical stimulation reduced histamine-induced itch for several hours at a distance up to 10 cm from the stimulated site, which suggests a central mode of action. A new method had been recently found, by Hans-Jorgen Nilsson and others, that is able to relieve itch without damaging the skin called cutaneous field stimulation (CFS). CFS consists of a flexible rubber plate with 16 needle-like electrodes placed regularly at 2-centimeter intervals in a 4 by 4 matrix used to electrically stimulate nerve fibers in the surface of the skin. The electrodes were stimulated continuously at 4 Hertz per electrode, pulse duration of 1 millisecond, intensity 0.4-0.8 milliamperes, and for 25 minutes. CFS resulted in a pricking and burning sensation that usually faded away very quickly. The burning sensation was still present during a selective block of impulse conduction of A-fibers in myelinated fibers indicating that nociceptive C-fibers are activated by CFS. In addition, a flare reaction had been noted to develop around the CFS electrodes which indicate activation of axon reflexes in nociceptive C-fibers. Itch, which was induced by transdermal iontophoresis of histamine, was inhibited within the skin area treated with CFS, and it was reduced 10 cm distally to a significant amount. CFS proves to offer a new method of combating itch by using painful electrical stimulation as it creates a long lasting inhibitory effect, does not create any significant skin injuries, and is simple to manage. It is able to activate powerful itch inhibitory mechanisms possibly routed through central mechanisms, which could normally be activated by scratching of the skin.[8]

A study done by Gil Yosipovitch, Katharine Fast, and Jeffrey Bernhard showed that noxious heat and scratching was able to inhibit or decrease itch induced by transdermal iontophoresis of histamine and most interestingly, decrease skin blood flow. Twenty-one healthy volunteers participated in their study. Baseline measurements of skin blood flow were obtained on the flexor part of the forearm and then compared with skin blood flow after various stimuli. Then transdermal iontophoresis of histamine was performed and tested with various stimuli. It is well known that skin blood flow is significantly increased during mechanical scratching, warming, and noxious heat. However it is quite interesting that this study is the first to examine the changes of blood flow by stimuli during iontophoresis of histamine and how itch is perceived in those conditions. Its examination provided an unexpected result that noxious heat and scratching has an inhibitory effect.[9]

A negative correlation was found between pain sensitivity and itch sensitivity. In a study done by Amanda Green and others, they aimed to determine itch-related genetic factors, and establish a more useful animal model for itch. They looked at 11 different inbred mouse strains and compared their scratching behavior in response to two itch inducing agents, histamine and chloroquine. Every strain revealed an inverted-U shape dose response relationship from chloroquine, indicating that moderate dosages produced more scratching than at higher dosages. An explanation is that higher dosage produces more pain and the presence of pain inhibits pain thereby lowering the amount of overall scratching. Another notable result was that histamine induced scratching occurred in female mice on average 23% more than males. Finally, it was found that mice having strains sensitive to pain were resistant to itch and vice versa.[10]

Peripheral Sensitization

Inflammatory mediators such as bradykinin, serotonin (5-HT) and prostaglandins, released during a painful or pruritic inflammatory condition not only activates pruriceptors but also causes acute sensitization of the nociceptors. In addition, expression of neuro growth factors (NGF) can cause structural changes in of nociceptors such as sprouting. NGF is high in injured or inflamed tissue. Increased NGF is also found in atopic dermatitis, a hereditary and non-contagious skin disease with chronic inflammation.[11] NGF is known to up-regulate neuropeptides, especially substance P. Substance P has been found to have an important role in inducing pain however there is no confirmation that substance P directly causes acute sensitization. Instead substance P may contribute to itch by increasing neuronal sensitization and may the affect release of mast cells, which contain many granules rich in histamine, during long-term interaction.[1]

Central Sensitization

Noxious input to the spinal cord is known to produce central sensitization, which consists of allodynia, exaggeration of pain, and punctuate hyperalgesia, extreme sensitivity to pain. Two types of mechanical hyperalgesia can occur: 1) touch that is normally painless in the uninjured surroundings of a cut or tear can trigger painful sensations (touch-evoked hyperalgesia), and 2) a slightly painful pin prick stimulation is perceived as more painful around a focused area of inflammation (punctuate hyperalgesia). Touch-evoked hyperalgesia requires continuous firing of primary afferent nociceptors, and punctuate hyperalgesia does not require continuous firing which means it can persist for hours after a trauma and can be stronger than normally experienced. In addition, it was found that patients with neuropathic pain, histamine ionophoresis resulted in a sensation of burning pain rather than itch, which would be induced in normal healthy patients. This shows that there is spinal hypersensitivity to C-fiber input in chronic pain.[1]

Causes

Common Causes

Causes by Organ System

Cardiovascular Angioedema , Cerebrovascular accidents, Portal hypertension , Urticaria , Vasculitis, Vibratory angioedema 
Chemical/Poisoning Gold salts, Insect bites, Mercury , Obeticholic acid, Urushiol
Dental No underlying causes
Dermatologic Acrodermatitis chronica atrophicans, Acrokeratosis paraneoplastica of bazex, Acropustulosis of infancy, Actinic granuloma, Allergic conjunctivitis, Athlete's foot, Atopic dermatitis, Bacterial conjunctivitis, Bullous pemphigoid, Burn wounds, Chilblains, Conjunctivitis, Contact dermatitis, Cutaneous larva migrans, Dandruff , Dermatitis artefacta, Dermatitis herpetiformis, Dermatomyositis, Dermatophytosis, Diffuse systemic sclerosi , Eczema, Erythema annulare centrifugum, Erythroderma, Fox-fordyce disease, Gestational pemphigoid, Hidradenitis suppurativa, Id reaction, Inflammatory linear verrucous epidermal nevus, Jaundice, Kerion, Kraurosis vulvae, Lamellar ichthyosis , Melanoma, Miliaria rubra, Nephrogenic fibrosing dermopathy, Nummular dermatitis, Papilloma , Paraneoplastic syndrome, Photodermatitis , Polymorphic eruption of pregnancy, Polymorphic light eruption, Pompholyx, Primary cutaneous amyloidosis, Psoriasis, Sarcoidosis, Scars, Scleroderma, Skin allergies , Skin conditions , Skin rash , Sunburn, Swimmer's itch, Symptomatic dermatographism, Transient acantholytic dermatosis, Trigeminal trophic syndrome, Urticaria , Vernal keratoconjunctivitis , Xerosis, X-linked ichthyosis 
Drug Side Effect Acamprosate, Acipimox, Alfentanil, Allopurinol, Altretamine, Amphetamine, Carbimazole, Chloroquine, Cilostazol, Cimex lectularius , Ciprofloxacin, Diamino diphenylmethane, Drug side effect, Drug-induced liver disease , Fixed drug eruption, Imipenem, Ketoconazole, Medication side effects, Mefloquine, Meropenem, Methimazole, Methionine, Morphine, Necitumumab, Niacin, Niclosamide, Nicotinic acid, Norfloxacin, Opioid use, Palifermin, Pellagra, Permethrin, Polycythemiaistamine, Propylthiouracil, Prurigo nodularis, Remifentanil, Schamberg's disease, Siltuximab, Simeprevir, Simvastatin, Sufentanil, Trametinib, Trimethoprim
Ear Nose Throat No underlying causes
Endocrine Aging, Hyperparathyroidism, Hyperthyroidism, Hypoparathyroidism, Hypothyroidism, Multiple endocrine neoplasia, Thyroid disease
Environmental Occupational cancer , Photodermatitis , Sunburn
Gastroenterologic Bile acid synthesis defects , Cholestasis, Cholestatic jaundice, Drug-induced liver disease , Dumping syndrome, Hepatobiliary disease, Hepatoma , Intrahepatic cholestasis of pregnancy, Liver cancer , Liver failure , Metastatic liver cancer , Pancreatic islet cell cancer , Pfic , Primary sclerosing cholangitis
Genetic Erythropoietic protoporphyria, Fabry disease, Familial cold urticaria, Lamellar ichthyosis , Wells syndrome , Wiskott-aldrich syndrome, X-linked ichthyosis 
Hematologic Blood transfusion and complications, Chronic eosinophilic leukemia, Chronic lymphocytic leukemia, Diabetes mellitus, Essential thrombocythemia, Hemochromatosis, Hepatoma , Hodgkin's disease, Hodgkin's lymphoma, Hypereosinophilic syndrome, Hyperimmunoglobulin e (ige) syndrome, Interleukin 2, Iron deficiency, Jaundice, Leukemia, Myelodysplastic syndrome, Non-hodgkin's lymphoma, Polycythemia rubra vera, Pulex irritans, Rhesus isoimmunisation , Vitamin a
Iatrogenic Blood transfusion and complications, Dumping syndrome, Symptomatic dermatographism
Infectious Disease Acanthocheilonemiasis , Aids, Ancylostoma duodenale, Ascariasis, Athlete's foot, Bacterial conjunctivitis, Brachioradial pruritus, Candida albicans, Chronic hepatitis , Chronic myringitis, Connective tissue diseases, Creutzfeldt-jakob disease, Cutaneous larva migrans, Delusional parasitosis, Dermatitis herpetiformis, Dracunculiasis, Elastosis perforans serpiginosa, Gnathostomiasis, Hepatitic c, Herpes simplex, Herpes virus 2, Herpes zoster, Hidradenitis suppurativa, Hiv , Hookworms, Hymenolepiasis, Leptospirosis, Lice, Lichen aureus, Lichen planus, Lichen sclerosus et atrophicus, Lichen simplex chronicus, Lichen striatus, Louse-borne diseases , Lymphatic filariasis, Malassezia furfur, Mansonelliasis, Miliaria rubra, Mite conditions , Morphoea, Necator americanus , Onchocerciasis, Parvoviral infection, Pediculosis, Pediculus humanus capitis , Pediculus humanus corporis , Pemphigoid gestationis, Pemphigus foliaceus , Phaeohyphomycosis , Phthiriasis, Pinworms, Pityriasis alba, Pityriasis rosea, Postherpetic neuralgia, Pulex irritans, Rabies, Rhabditida infections , Rhesus isoimmunisation , Sarcoptes scabiei, Scabies, Secernentea infections , Shingles, Strongyloidiasis, Swimmer's itch, Taeniasis , Terbinafine, Threadworm, Tinea capitis, Tinea corporis, Tinea pedis, Treponema pallidum, Trichinosis, Trichomoniasis , Trypanosomiasis , Tungiasis, Uveitis , West african trypanosomiasis 
Musculoskeletal/Orthopedic Fibromyalgia
Neurologic Brain abscess, Chronic fatigue syndrome, Creutzfeldt-jakob disease, Functional disorders, Multiple sclerosis, Neurofibromatosis, Notalgia paraesthetica, Postherpetic neuralgia, Psychogenic excoriation, Sleeping sickness , Small-fiber neuropathies
Nutritional/Metabolic Diabetes mellitus, Starvation, Vitamin a
Obstetric/Gynecologic Gestational pemphigoid, Herpes gestationis, Intrahepatic cholestasis of pregnancy, Kraurosis vulvae, Polymorphic eruption of pregnancy, Pregnancy, Vaginitis, Vulvar cancer 
Oncologic Carcinoid syndrome, Chronic eosinophilic leukemia, Chronic lymphocytic leukemia, Cutaneous t-cell lymphoma, Hodgkin's disease, Hodgkin's lymphoma, Leukemia, Liver cancer , Malignancy, Mastocytosis, Melanoma, Metastatic liver cancer , Multiple endocrine neoplasia, Myelodysplastic syndrome, Non-hodgkin's lymphoma, Occupational cancer , Pancreatic islet cell cancer , Paraneoplastic syndrome, Polycythemia rubra vera, Uveal melanoma , Vulvar cancer 
Ophthalmologic Connective tissue diseases, Uveal diseases , Uveal melanoma , Uveitis , Vernal keratoconjunctivitis 
Overdose/Toxicity Cocaine use, Opioid use
Psychiatric Parasitophobia, Psychogenic excoriation
Pulmonary Amyloidosis
Renal/Electrolyte Nephrogenic fibrosing dermopathy, Renal disease, Renal failure
Rheumatology/Immunology/Allergy Adrenergic conditions , Allergies, Amyloidosis, Cholinergic conditions , Decompression sickness, Dermatophytosis, Eosinophilia-myalgia syndrome, Fibromyalgia, Id reaction, Latex allergies , Macrophage activation syndrome, Mastocytosis, Neurofibromatosis, Peanut allergies , Penicillin allergy , Pollen allergy , Primary cutaneous amyloidosis, Psoriasis, Sarcoidosis, Sjögren syndrome, Skin allergies , Systemic lupus erythematosus
Sexual Aids, Hepatitic c, Herpes gestationis, Herpes simplex, Herpes virus 2, Herpes zoster, Hiv
Trauma Burn wounds, Insect bites, Shaving
Urologic Xanthogranulomatous cholecystitis
Miscellaneous No underlying causes

Causes in Alphabetical Order

History and Symptoms

  • Include medical and family history, exposure history, sexual history

Physical Examination

  • Complete system evaluation can detect underlying diseases

Abdomen

  • Stool exam (blood)
  • Pap smear & pelvic

Laboratory Findings

  • Labs include

Treatment

Main article: Antipruritic

A variety of over-the-counter and prescription anti-itch drugs are available. Some plant products have been found to be effective anti-pruritics, others not. Non-chemical remedies include cooling, warming, soft stimulation.

Sometimes scratching relieves isolated itches, hence the existence of devices such as the back scratcher. Often, however, scratching can intensify itching and even cause further damage to the skin, dubbed the "itch-scratch-itch cycle".

The mainstay of therapy for dry skin is maintaining adequate skin moisture and topical emollients.

Sensations Associated with Scratching

Pain and itch have very different behavioral response patterns. Pain evokes a withdrawal reflex which leads to retraction and therefore a reaction trying to protect an endangered part of the body. Itch creates a scratching reflex which draws one to the affected skin site. For example, responding to a local itch sensation is an effective way to remove insects on the skin. Scratching has traditionally been regarded as a way to relieve one self by reducing the annoying itch sensation. However there are hedonic aspects of scratching as one would find noxious scratching highly pleasurable.[1] This can be problematic with chronic itch patients, such as ones with atopic dermatitis, who may scratch affected spots until it no longer produces a pleasant or painful sensation instead of when the itch sensation disappears.[12] It has been hypothesized that motivational aspects of scratching include the frontal brain areas of reward and decision making. These aspects might therefore contribute to the compulsive nature of itch and scratching.[1]

Contagious Itch

Events of “contagious itch” are very common occurrences. Even a discussion on the topic of itch can give one the desire to scratch. Itch is likely more than a localized phenomenon in the place we scratch. Results from a recent study showed that itching and scratching were induced purely by visual stimuli in a public lecture on itching. There is currently little detailed data on central activation for contagious itching but it is hypothesized that a human mirror neuron system exists in which we imitate certain motor actions when we view others performing the same action. A similar phenomenon in which mirror neurons are used to explain the cause is contagious yawning.[1]

See also

References

  • Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:138
  • Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:300-301
  • Andrew D, Craig AD (2001). Spinothalamic lamina I neurons selectively sensitive to histamine: a central neural pathway for itch. Nature Neuroscience Jan;4(1):9-10.
  • National Cancer Institute (2003) "Pruritus" Retrieved Aug. 22, 2005.==External links==
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  1. ↑ 1.0 1.1 1.2 1.3 1.4 1.5 1.6 Ikoma, A., Steinhoff, M., Stander, S., Yosipovitch, G., Schmelz, M. (2006). The neurobiology of itch. Nature Reviews Neuroscience, 7(7), 535-547.
  2. ↑ Greaves, M.W., Khalifa, N. (2004). Itch: More than skin deep. Int Arch Allergy Immunol, 135, 166-172.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Twycross, R., Greaves, M.W., Handwerker, H., Jones, E.A., Libretto, S.E., Szepietowski, J.C., Zylicz, Z. (2003). Itch: scratching more than the surface. Q J Med, 96, 7-26.
  4. ↑ 4.0 4.1 Ward, L., Wright E., McMahon S.B. (1996). A comparison of the effects of noxious and innocuous counterstimuli on experimentally induced itch and pain. Pain, 64, 129-138.
  5. ↑ Yosipovitch, G., Greaves, M.W., Schmelz, M. (2003). Itch. The Lancet, 361(9358), 690-694.
  6. ↑ Schmelz, M., Schmidt, R., Bickel, A., Handwerker, H.O., Torebjork, H.E. (1997). Specific C-Receptors for Itch in Human Skin. The Journal of Neuroscience, 17(20), 8003-8008.
  7. ↑ Bernhard, J.D. (2005). Itch and pruritus: what are they, and how should itches be classified? Dermatologic Therapy, 18, 288-291.
  8. ↑ Nilsson, H., Levinsson, A., Schouenborg, J. (1997). Cutaneous field stimulation (CFS): a new powerful method to combat itch. Pain, 71, 49-55.
  9. ↑ Yosipovitch, G., Fast, K., Bernhard, J.D. (2005). Noxious Heat and Scratching Decrease Histamine-Induced Itch and Skin Blood Flow. Journal of Investigative Dermatology, 125, 1268-1272.
  10. ↑ Green, A.D., Young, K.K., Lehto, S.G., Smith, S.B., Mogil, J.S. (2006). Influence of genotype, dose and sex on pruritogen-induced scratching behavior in the mouse. Pain, 124, 50-58.
  11. ↑ Rukweid, R., Lischetzki, G., Mcglone, F., Heyer, G., Schmelz, M. (2000). Mast cell mediators other than histamine induce pruritus in atopic dermatitis patients: a dermal microdialysis study. British Journal of Dermatology, 142(6), 1114-1120.
  12. ↑ Karsak, et. al. (2007). Attenuation of Allergic Contact Dermatitis Through the Endocannabinoid System. Science, 316, 1494-1497.
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