A. Introduction

1. Definition of an itch is a skin sensation leading to desire to scratch
2. Distinct sensation from pain and touch
3. Types of Pruritus
   1. Pruritoceptive - urticarial diseases and dry skin
   2. Neuropathic
   3. Neurogenic
   4. Psychogenic - as in delusional stqate of parasitophobial

B. Pathophysiology

1. Central nervous system (CNS) "itch center" may be diffuse based on functional MRI studies
2. Etiology best studied for urticarial diseases
3. Mechanism of Pruritoceptive Itch
   1. Occurs in inflamed or dry skin
   2. Occurs in atopy, urticaria, scabies, insect bite reaction, psoriasis, others
   3. Transmitted by C nerve fibers
   4. Interaction of dermal mast cells and afferent C neurons in skin
4. Mast Cell Role
   1. Activation of mast cells triggers proteases tryptase and chymase production
   2. These Activate proteinase activated receptor-s (PAR-2) localized on C-fiber terminals
   3. Activated C fibers transmit signal to CNS which produces itch sensation
   4. Neuropeptides including substance P are released
5. Substance P (SP)
   1. Low concentrations of SP activate neurokinin 1 (NK1) receptors on mast cells
   2. This leads to increased production of mast cell inflammatory mediators including TNFa
   3. SP also directly activates vanilloid receptors (VR1) on C-terminal fibers
   4. Depletion of SP with capsaicin can alleviate itching
6. Other Vasoactive Substances
   1. Histamine - particularly through H1 and some H2 receptors
   2. Prostaglandins - particularly E2 type, may potentiate histamine
   3. Other Neuropeptides - CGRP (calcitonin gene related peptide) and VIP
   4. Serotonin (5-hydroxytryptamine, 5-HT) - mainly through HT3 receptors
7. Inflammatory mediators probably stimulate vasoactive substance production
8. Interleukins - IL2 infusions induced erythema and pruritus, may play a role
9. Neuropathic
   1. Itch arising due to disease anywhere along afferent pathway
   2. Most commonly with post-herpes zoster neuralgia
   3. Also occasionally with multiple sclerosis, brain tumors
10. Neurogenic
    1. Systemic Illness - cholestatic liver disease and chronic renal failure
    2. Originates centrally without evidence of peripheral neural pathology
    3. Usually due to opioid neuropeptides on mu (µ) opioid receptors
    4. Itch inhibitor signals may not be functional

C. Treatment

1. Dry Skin
   1. Moisturizing lotion and exfoliatives may be efficacious
   2. Diseases like psoriasis may require more aggressive therapy
2. Urticarial Disease
   1. Antihistamines
   2. Glucocorticoids
   3. Topical tacrolimus very effective in resistant atopic dermatitis
3. Cholestatic Disease
   1. Jaundice often accompanied by pruritus
   2. PBC - pruritus is major symptom
   3. Cholestyramine (Questran®) may improve symptoms by binding bilirubin
   4. Ursodiol (ursodeoxycholic acid, Actigal®) may be effective, particularly in PBC
   5. Naloxone (Narcan®), an opiate antagonist, can relieve itching in cholestasis
   6. Phenobarbital, 60-120mg po qd, may be tried as well
4. Chronic Renal Failure
   1. Azotemia associated with pruritus
   2. Increasing dialysis frequency usually improve symptoms
   3. Naltrexone 50mg/kd, a mu-opioid antagonist, can improve symptoms of uremic pruritus [2]
   4. Kappa opioid agonists appear to be more effective than mu antagonists

References

1. Yosipovitch G, Greaves MW, Schmetz M. 2003. Lancet. 361(9358):690
2. Peer G, Kivity S, Agami O, et al. 1996. Lancet. 348:1552