Just an Itch? Beyond Benadryl ™

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

6. 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

7. #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?

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

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

10. 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

12. 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

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

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

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

16. 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

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

18. Itch Pathways • Cutaneous (pruritoceptive) • Neurogenic • Neuropathic • Mixed Psychogenic

19. 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

20. Itch pathways • Fibers originate @ 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

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

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

25. 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

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

28. 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

29. 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

30. 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

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

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

33. Substance “P” (“P” for pain and pruritis?) • Neuropeptide synthesized in C-fibers @ 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

34. 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

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

36. Acetylcholine • Intra-dermal injection usually  burning • In eczema  itching • Independent of histamine

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

38. 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

39. 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

40. 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 Opioid induced itching:Systemic vs Local

41. 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?

42. 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

43. 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)

44. Chemically induced itching:Neuroaxial • Spinal anesthesia with lidocaine: 30-100% pruritis • Fentanyl: • Intrathecal 67-100% • Epidural 67% • Morphine • Intrathecal 62-82% • Epidural 65-70%

45. 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

46. 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

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

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

49. 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

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