1. PRURITUS Catriona Mayland July 2002

2. Topics Definition Neuroanatomy Mediators Evaluation General treatment Systemic disorders Specific treatment

3. Definition Unpleasant sensation causing desire to scratch Normally protective function Sensation arises from superficial skin, mucous membranes, conjunctiva

4. Neuroanatomy Nerve endings – dermo-epidermal junction Impulses – dorsal root ganglion Synapse in dorsal horn Efferents – contralateral spinothalamic tract Somatosensory cortex New concepts – peripheral & central mechanisms

5. Mediators Physical stimulation Chemical mediators –Amines e.g. histamine, serotonin, dopamine –Opiods e.g. met-enkephalin, -endorphin –Eicosanoids –Cytokines e.g. IL-1 to 11, TNF

6. And there’s more… Proteases e.g. tryptases, papain, kallikrein Growth Factor Neuropeptides –Substance P –CGRP, VIP, CCK –Bradykinin –Somatostatin, endothelin, neurokinin

7. Histamine Itching if applied to superficial damaged skin or injected intradermally Dermal mast cells Skin blood vessels, eccrine glands, basophils, hair follicles

8. Action Direct stimulation H receptors ? stimulation formulation other mediators Repeated injection – response decreases ? role in chronic itch

9. Serotonin Action –Direct on peripheral serotoninergic receptors –C-fibres via 5-HT3 receptors

10. Central Transmitters Endogenous opiods –Regulatory action –Both excitatory and modulatory effects –Inhibit presynaptic signals – modulate secondary transmission –Abnormal central settings – directly trigger itch despite no peripheral input

11. Other Mediators Exacerbate –Heat –Anxiety –Boredom –Poor coping strategies Reduce –Cold –Relaxation –Distraction –Good coping stategies

12. Evaluation Primary dermatological disease Systemic disease History and examination Drugs, onset, localised or systemic

13. Non-drug Treatments Discourage scratching – short nails Avoid hot baths, overheating and sweating Pat skin dry! Cool cotton clothes! Avoid alcohol and spicy foods

14. Skin Care Emollient – aqueous cream & menthol Calamine lotion - ?still recommended Barrier cream Consider hydrocortisone NB Eurax and topical antihistamines

15. Systemic Disorders Renal failure Hepatogenic Haematopoietic Endocrine Solid tumours HIV Opiod induced Neurogenic Aquagenic Inatrogenic Senile Psychogenic

16. Chronic Renal Failure Aetiology –Dry skin –Hyperparathyroidism –Mast cell proliferation –Loss opiod receptors and increased endogenous opiods

17. Peripheral neuropathy Increased –Histamine –Vitamin A –Magnesium, phosphate, aluminium –Serotonin –Substance P

18. Hepatogenic Pruritus PBC drug induced cholestasis –Oral contraceptive, phenothiazines Biliary obstruction

19. Aetiology ? Bile acids ? Accumulation pruritogen intermediary ? Histamine induced ? Centrally activated pruritogenic opiod ? Increased serotonin

20. Haematopoietic Disorders PCV –Increased histamine Hodgkins Others –? Histamine –? Autoimmune response –? Infiltration –? Release of leukopeptidase

21. Endocrine Disorders Thyrotoxicosis –? Activate kinins –? Reduced itch threshold Hypothyroidism –xerosis Diabetes mellitus –candida

22. Solid Tumours Paraneoplastic ? Allergic reaction to Ag ? Toxic products of necrotic tumour cells Breast, stomach, lung, prostrate, colon

23. Opiod Induced Pruritus Spinal > systemic Peripheral – stimulate release histamine Central – cephalad spread in CSF Bupivicaine given ? Role serotoninergic pathways ? Antagonism of inhibitory transmitters Opiod rotation

24. Inatrogenic Pruritus Aspirin Hydroxyurea Captopril Antibiotics Phenytoin Allopurinol

25. Neurogenic Neuropathies –E.g. multiple sclerosis –Activation artificial synapses Unilateral cerebral lesions –Effects on descending pathways Post-herpetic neuralgia

26. Senile Pruritus Xerosis Skin atropy ? Age associated degeneration in nerve endings ? Postmenopausal syndrome

27. Psychogenic Pruritus Feelings of hopelessness / helplessness Secretion serotonin, dopamine Elevated endogenous opiods ? ‘depressive equivalent’

28. Others HIV High prevalence skin disorders Abnormal levels cytokines Hypereosinophilia Peripheral neuropathy AQUAGENIC Contact with water Pathogenesis unknown

29. Specific Treatments Anti-inflammatory agents –Antihistamines (cimetidine) –Steroids –Salicylates (capsacin) –Thalidomide Central / peripheral nervous system agents –Antidepressants –Anaesthetic agents –Opiod antagonists –Serotonin antagonists –Neuroleptic agents –Tranquillizers

30. Specific treatments Sequestrants –Cholestyramine –Charcoal –Heparin Vaso-active drugs –Alpha blockers –Beta blockers

31. Disease Specific Interventions Cholestatic disease –Rifampicin –Androgens –Urso –Stenting Uraemia –Erythropoitin –UVB phototherapy –Parathyroidectomy –Transplantation

32. Disease Specific Interventions PCV – alpha interferon Fe deficiency – iron Thyroid disorder

33. Miscellaneous Phototherapy TENS Acupuncture Psychotherapy Relaxation

34. Problems in Palliative Medicine Most terminal phase Changing organ function Systemic treatment may be toxic, impractical

35. Conclusions Pathophysiology not fully understood Peripheral and central mechanisms Often associated with systemic diseases

36. Conclusions Importance of non-pharmacological treatment Treat what is treatable Rare problem but impact on quality of life Likely that older drugs will be used Await our protocol review!

37. References Understanding pruritus in systemic disease –Journal Pain & Symptom Management 2001 Pathophysiology of itching –Lancet 1996 Oxford textbook of Palliative Medicine, Symptom Management in Advanced Cancer,Advanced Course in Pain & Symptom Management

38. Antihistamines Useful where histamine release has role E.g. allergic rhinoconjunctivitis Lack activity in CRF, haematopoitic disorders, opiod induced Pizotifen (antiserotoninergic action) Sedating doses e.g. hydroxyzine

39. Capsaicin Anti-inflammatory Reduces substance P from nerve endings Inhibits itch transmission Use : localised pruritus e.g. uraemia

40. Thalidomide Reduce TNF synthesis Anti-inflammatory ? Interfere with cytokine production Use : uraemia

41. Cimetidine Role not established Enhance effect anti-histamines Use : uraemia haematological malignancies

42. Antidepressants Signs depression / anxiety Failure to respond to standard therapy Tricyclics (doxepin) –Antidepressant, antihistamine, sedative SSRI (paroxetine) –Down-regulation post-synaptic receptors –Reduce serotonin – receptor interaction

43. Role CRF Haematological malignancies Depressive disorders Neuroleptics / benzodiazepine use

44. 5-HT3 Antagonists Ondansetron Serotonin mediator of itch Use : cholestasis, uraemia, spinal opiods Expensive Often IV use

45. Opiod Antagonists Counteract endogenous opiods Can be impractical Naltrexone (oral preparation) Use : CRF, hepatogenic & haematological pruritus ‘opiod abstinence syndrome’

46. Buprenorphine Partial agonist Nalbuphine Mixed agonist-antagonist Needs further evaluation Opiod rotation

47. Anaesthetic Agents Lignocaine Abnormal pattern cutaneous innervation Associated peripheral neuropathy Use : uraemia Toxic adverse effects

48. Propofol Subhypnotic doses in hepatogenic pruritus Opiod induced –? Inhibit dorsal root transmission –? Blocks

49. Sequestrants Cholestyramine Reduce bile acids Remove other pruritogens Use : cholestasis Unpalatable Diarrhoea

50. Charcoal Use : uraemia ?chelates metabolites Heparin

51. Disease Specific Drugs Uraemia Erythropoietin UVB phototherapy Parathyroidectomy Transplantation

52. Disease Specific Drugs Cholestatic disease Androgens –Stanazol, methytestosterone Rifampicin Biliary stenting definitive treatment

53. Ultraviolet Light UVB Reduce content vitamin A Inhibit release histamine & proliferation mast cells Use : renal and liver disease, AIDS

54. PUVA Ultrastructural changes in nerves Increase sensory thresholds Reduce end-organ responsiveness ? Stabilise mast cells Use : pruritic dermatoses

55. Others TENS –Induction on ‘lateral inhibition’ in spinal cord Acupuncture Plasma exchange Psychotherapy Relaxation