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Objectives. Understand the relationship between pain (sensation and treatment) and pruritisUnderstand basic pathophysiologic mechanisms for itchingIdentify effective treatments for various causes of itchingPsychologically induce everyone here to scratch themselves at least once.
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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. #2 Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
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. Diseases & Itching Infections
Infestations (scabies)
Inflammatory skin conditions (eczema, contact derm, psoriasis)
Chronic Renal Failure
Cholestatic liver disease
Depression/anxiety
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. Itch Mediators Histamine
Prostaglandins
Leukotrienes
Serotonin
Acetylcholine Substance P
Proteases
Peptides
Enzymes
Cytokines
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. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
32. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
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. 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
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. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
48. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
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. Diseases Associated with Itching Renal
Hepatic
H Pylori Infection
Hematologic d/o
Metabolic/Endocrine
Neurologic
HIV
Skin Diseases
51. 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
52. Eczema & Itching: Treatment cool compresses
emollients
topical steroids
antidepressants
anxiolytics
antibiotics
53. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
54. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
55. 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!
56. 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%
57. 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
58. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
59. 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
60. 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
61. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
62. 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
63. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
64. Match D/O with Antipruritic Lymphoma
Chronic Renal Failure
Liver Failure
Conjunctivitis
Eczema
Penicillin Reaction
Activated Charcoal
Cimetidine
Toradol
Odansetron
Diphenhydramine
Topical Steroids
65. 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
66. Endocrine D/O & Itching Diabetes
Thyrotoxicosis
Myxodema
Postmenopausal syndrome
Most common trigger: mucocutanious candidiasis
67. What to Ask of the Itchy Patient Local vs generalized?
Sequence of events: itch vs rash
Description of sensation
Timing & severity
68. General Approach to Itching Treat the Cause
Treat the Co-morbidities
69. 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
70. Questions?
72. 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
73. 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
75. 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
76. 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