Just an Itch? Beyond Benadryl ™ Michael Greenwald, MD Assistant Professor, Pediatrics Emory University Children’s Healthcare of Atlanta

Objectives Understand the relationship between pain (sensation and treatment) and pruritis Understand basic pathophysiologic mechanisms for itching Identify effective treatments for various causes of itching Psychologically induce everyone here to scratch themselves at least once

#1 Help this patient A 12 y/o with Sickle Cell Disease presents to the ED with an acute vaso-occlusive crisis. After his first dose of morphine he experiences generalized intense itching. His pain is still high (7/10). So now you have 2 problems - what do you recommend?

#2 Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron Diphenhydramine Topical Steroids

Part I: Understanding the Itch Definition Epidemiology Pathophysiology Why We Scratch

Part II: How to treat an Itch (Understand the Cause!) Inhibit mediators of itch Block chemicals that induce pruritis Treat effects of diseases which induce itching

Defining Pruritis An unpleasant localized or generalized sensation on the skin, mucus membranes or conjunctivae which the patient instinctively attempts to relieve by scratching or rubbing

Diversity of Causes and Presentation Many Causes, Many Treatments to Trivial to Life threatening (mosquito bite) (malignancy) 10-50% of cases with generalized itching have systemic disease

Diseases & Itching Infections Infestations (scabies) Inflammatory skin conditions (eczema, contact derm, psoriasis) Chronic Renal Failure Cholestatic liver disease Depression/anxiety

Assessment Challenges No assessment tool validated to study levels of distress from itching Most rely on 0-10 VAS similar to pain scores

Poorly Understood & Managed Relies on similar components of the pain system: receptors, neurotransmitters, spinal pathways and centers in the brain Stimulating pain can relief itching Treating pain with some analgesics relieves itching, others trigger itching Pruritis is a common side-effect of opioid administration, sometimes worse than the pain

Pruritogenic Stimuli Pressure Low-intensity electrical or punctate stimuli (TENS) Histamine: acts directly on free nerve endings in skin

Itch Pathways Cutaneous (pruritoceptive) Neurogenic Neuropathic Mixed Psychogenic

Pain vs Itch Nerves Itch transmitted from specialized pain receptors: a subclass of C-nociceptors –Mechano-insensitive –Histamine sensitive Nerve endings cluster around “itch points” which correspond to areas very sensitive to pruritogenic stimuli

Itch pathways Fibers dermal/epidermal jxn  Thin unmyelinated axons, lots of branching  Ipsilateral dorsal horn of spinal cord  Synapse with itch-specific secondary neurons Cross to opposite anterolateral spinothalamic tract to thalamus  Somatosensory cortex of postcentral gyrus  SLOW transmission and BROAD receptor field

Itch Mediators Histamine Prostaglandins Leukotrienes Serotonin Acetylcholine Substance P Proteases Peptides Enzymes Cytokines

Why do you scratch? Histamine activates both the anterior cingulate cortex (sensory, emotions) and the supplemental motor area

Lateral Inhibition: “Gate Theory” Noxious stimuli of skin adjacent to pruritic trigger attenuates initial itch sensation Scratching stimulates large fast- conducting A-fibers adjacent to slow unmyelinated C fibers A-fibers synapse with inhibitory interneurons and inhibit C-fibers

Pain & Itch Painful stimuli (thermal, mechanical, chemical) can inhibit itching Inhibition of pain (opioids) may enhance itching

Part II: How to Treat an Itch (Understand the Cause!)  Inhibit mediators of itch: histamine, prostaglandins, substance P, serotonin, cytokines  Block chemicals that induce pruritis: opioids, antimicrobials  Treat effects of diseases which induce itching: eczema, CRF, LF, heme, neuro, endo

Itch Mediators: Histamine Different effects on different H receptors applied into epidermis  itch applied into dermis  pain Only a few types of itch relieved by anti-histamines (i.e. those caused by histamine release in the skin): insect bites, allergic skin reactions, cutaneous mastocytosis 85% H receptors in skin are H1 15% H receptors are H2

NSAIDs for itching? Prostaglandins cause itch directly on conjunctiva (but no effect when directly applied to skin) Potentiates histamine elicited itch  Ketorolac eases itch in conjunctiva

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron Diphenhydramine Topical Steroids

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine  Toradol Odansetron Diphenhydramine Topical Steroids

Substance “P” (“P” for pain and pruritis?) Neuropeptide synthesized in DRG Transmitted to free nerve endings to modulate pain and pruritis Substance P containing C-fibers most abundant near junction b/epidermis & dermis (esp in lips, fingertips, prepuce and breast) Induces pruritis directly & indirectly by releasing histamine from mast cells –Hemodialysis-associated itch –Atopic dermatitis –Psoriasis

Substance P Depletion Capsaicin cream: excites C-fibers  release substance P & calcitonin gene- related peptide  depletion of both –.025% 5 times a day for notalgia paraesthetica

Other Peptides Bradykinin: pain, inflammation & itch Neurotension, Vasoactive Intestinal Peptide, Somatostatin, Melanocyte-stimulating hormone:  histamine release from dermal mast cells

Acetylcholine Intra-dermal injection usually  burning In eczema  itching  Independent of histamine

Serotonin Some patients with refractory itch have been relieved by serotonin antagonist odansetron (Zofran)

Itch & Inflammation Cytokines: LMW mediators of inflammatory signals b/cells (e.g. TNF) Induce cells to secrete chemokines which cause migration of inflammatory cells from vascular space to inflammatory site

Chemically induced itching: Systemic Opioids Usually face (trigem. nerve), neck, upper thorax 0-90% Not necessarily related to dose  incidence during pregnancy (interaction b/ estrogen & opiate receptors) Morphine, sufentanil > fentanyl > butorphenol Histamine is released, but not the main cause of itching Site of injection vs distal to injection

Opioid induced itching: Systemic vs Local Nonimmunologic release of histamine from morphine, codeine, meperidine  Attentuated by opioid receptor antagonists Intradermal morphine reduced by H1 antihistamines but not naloxone H2 blockers alone not effective but enhance H1 blockers

Help this patient A 12 y/o with Sickle Cell Disease presents to the ED with an acute vaso-occlusive crisis. After his first dose of morphine he experiences generalized intense itching. His pain is still high (7/10). So now you have 2 problems - what do you recommend?

Help this patient A 12 y/o with Sickle Cell Disease presents to the ED with an acute vaso-occlusive crisis. After his first dose of morphine he experiences intense itching. His pain is still high (7/10). So now you have 2 problems - what do you recommend?  Nubain

Chemically induced itching: Neuroaxial Intrathecal, epidural opioids commonly complicated by pruritis Direct action on medullary dorsal horn and trigeminal nucleus of medulla – not t/histamine release Blocked by naloxone (therefore opioid receptor mediated) Also possibly related to antagonism to inhibitory neurotransmitters GABA and Glycine and 5-HT receptors (ondansteron effective)

Chemically induced itching: Neuroaxial Spinal anesthesia with lidocaine: % pruritis Fentanyl: –Intrathecal % –Epidural 67% Morphine –Intrathecal 62-82% –Epidural 65-70%

Treatments: opioid related pruritis Diphenhydramine – for systemic opioids For Neuraxial Opioids: –Ondansteron –Naloxone (1-2mcg/kg/hr) –Nalbuphine (10-20 mcg/kg/hr) –Propofol (.5-1mg/kg/hr) –Lidocaine (2mg/kg/hr) –NSAIDs (diclofenac, tenoxicam) –Droperidol

Chemically induced itching: Antibiotics Penicillin: immediate type I hypersensitivity reaction Vancomycin: massive nonimmunologic release of histamine  “Red Man Syndrome” –(flushing CP, pruritis, muscle spasms, hypotension) –Related to rate of infusion –Potentiated by muscle relaxants and opioids –Attenuated by H1 blockers Rifampin

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron Diphenhydramine Topical Steroids

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron  Diphenhydramine Topical Steroids

Chemically induced itching: Other drugs Fentanyl: itching decreased when mixed with bupivicane, increased when mixed with procaine Drug induced cholestasis –esp phenothiazenes, estrogens, tolbutamide, anabolic steroids

Diseases Associated with Itching Renal Hepatic H Pylori Infection Hematologic d/o Metabolic/Endocrine Neurologic HIV Skin Diseases

Eczema & Itching Hallmark of atopic dermatitis >80% pts recognize stress as a trigger for increased itching Alexithyma: Patients with chronic dermatosis who develop abnormal language development as a result of the perception that touch is noxious

Eczema & Itching: Treatment  cool compresses  emollients  topical steroids  antidepressants  anxiolytics  antibiotics

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron Diphenhydramine Topical Steroids

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron Diphenhydramine  Topical Steroids

Systemic Treatment: Histamine blockers H1-receptor antagonists: diphenhydramine Side effects: anticholinergic effects, paradoxical agitation, excessive sedation H2-antagonists may enhance H1-blockers No quality studies demonstrating efficacy of oral antihistamines for atopic dermatitis!

Renal Diseases and Itching Chronic Renal Failure: 25-86% itching (not in acute renal failure) Attrib to accumulation of pruritogens:  histamine (  mast cells), serotonin   Ca, Phos, Mg, Al, vit A also implicated 1/3 uremic patients not on dialysis Maintenance hemodialysis: 70-80%

Renal Diseases and Itching Tx for uremic itching: renal transplant –Effective even when transplant is failing as long as immunosuppresants are given –Antihistamines not effective Also effective: moisturizers, UV-B tx (  vit A in skin), oral activated charcoal, cholstyramine, naltrexone, ondansterone, topical capsaicin, azelastin, thalidomide, IV lidocaine, erythropoetin, electric needle stim

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction  Activated Charcoal Cimetidine Toradol  Odansetron Diphenhydramine Topical Steroids

Hepatic Diseases & Itching 20-25% janudiced patients with hepatobiliary disease associated with cholestasis –100% primary biliary cirrhosis –Viral hepatitis Attrib to bile salts in serum and tissues Begins palms and soles & spreads inward

Hepatic Diseases & Itching Tx: reverse cholestatis, liver transplant Also helpful: oral guar gum (dietary fiber) binds bile acids; cholestyramine; rifampin! (inhibits bile uptake), opioid antagonists, codeine, propofol, ondansetron Not helpful: scratching

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol  Odansetron Diphenhydramine Topical Steroids

Hematologic Disease & Itching Polycythemia vera (50%) hydroxyurea tx iron def anemia, lymphomas (Tx: cimetidine) –Hodgkins – 30% – T-cell: almost all leukemias, plasma cell dyscrasias, mastocytosis

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal Cimetidine Toradol Odansetron Diphenhydramine Topical Steroids

Match D/O with Antipruritic  Lymphoma  Chronic Renal Failure  Liver Failure  Conjunctivitis  Eczema  Penicillin Reaction Activated Charcoal  Cimetidine Toradol Odansetron Diphenhydramine Topical Steroids

Neurologic Disorders & Itching Central: MS, CNS abscess, spinal and cerebral tumors (17%), CVAs –Attrib to effects on descending pathways which  itching Neurogenic –Shingles (10-15% in US) –Notalgia paresthetica: sensory entrapment syndrome causing neuropathy of T2-6 dorsal spinal nerves

Endocrine D/O & Itching Diabetes Thyrotoxicosis Myxodema Postmenopausal syndrome  Most common trigger: mucocutanious candidiasis

What to Ask of the Itchy Patient Local vs generalized? Sequence of events: itch vs rash Description of sensation Timing & severity

General Approach to Itching  Treat the Cause  Treat the Co-morbidities

Conclusions Pruritis is common and often disabling Pruritis has many similarities to pain Pruritis is related but not identical to pain Effective interventions are possible Antihistamines are not always the most effective treatment

Questions?

Systemic Treatment: Opioids Naloxone (.8mg) for biliary cirrhosis Nalmefene (5mg BID): –more potent and longer duration (12-48hrs) –May induce w/drawl sx if stopped abruptly

Take Home Points  Pain and Itching are intimately related –Cause/Triggers –Patho-physiology –Treatment  Different mechanisms for itching call for different treatments  Antihistamines are effective for a select few causes of itching

Treatment Cooling skin (eczema and other dermatoses) Vibration, TENS for localized and generalized pruritis (effectiveness dissipates w/use) UV therapy for chronic renal failure –Inhibits release of histamine and proliferation of dermal mast cells

Treatment: Topicals Moisturizers, calamine, antihistamines, corticosteroids, EMLA Capsaicin cream: excites C-fibers  release substance P & calcitonin gene- related peptide  depletion of both –.025% 5 times a day for notalgia paraesthetica