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PRURITUS Catriona Mayland July 2002 Topics • Definition • General treatment • Neuroanatomy • Systemic disorders • Mediators • Specific treatment • Evaluation Definition • Unpleasant sensation causing desire to scratch • Normally protective function • Sensation arises from superficial skin, mucous membranes, conjunctiva 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 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 And there’s more… • Proteases e.g. tryptases, papain, kallikrein • Growth Factor • Neuropeptides – – – – Substance P CGRP, VIP, CCK Bradykinin Somatostatin, endothelin, neurokinin Histamine • Itching if applied to superficial damaged skin or injected intradermally • Dermal mast cells • Skin blood vessels, eccrine glands, basophils, hair follicles Action • Direct stimulation H receptors • ? stimulation formulation other mediators • Repeated injection – response decreases • ? role in chronic itch Serotonin • Action – Direct on peripheral serotoninergic receptors – C-fibres via 5-HT3 receptors 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 Other Mediators • Exacerbate – – – – Heat Anxiety Boredom Poor coping strategies • Reduce – – – – Cold Relaxation Distraction Good coping stategies Evaluation • Primary dermatological disease • Systemic disease • History and examination • Drugs, onset, localised or systemic Non-drug Treatments • • • • Discourage scratching – short nails Avoid hot baths, overheating and sweating Pat skin dry! Cool cotton clothes! Avoid alcohol and spicy foods Skin Care • Emollient – aqueous cream & menthol • Calamine lotion - ?still recommended • Barrier cream • Consider hydrocortisone • NB Eurax and topical antihistamines Systemic Disorders • • • • • • Renal failure Hepatogenic Haematopoietic Endocrine Solid tumours HIV • • • • • • Opiod induced Neurogenic Aquagenic Inatrogenic Senile Psychogenic Chronic Renal Failure • Aetiology – – – – Dry skin Hyperparathyroidism Mast cell proliferation Loss opiod receptors and increased endogenous opiods • Peripheral neuropathy • Increased – – – – – Histamine Vitamin A Magnesium, phosphate, aluminium Serotonin Substance P Hepatogenic Pruritus • PBC • drug induced cholestasis – Oral contraceptive, phenothiazines • Biliary obstruction Aetiology • • • • • ? Bile acids ? Accumulation pruritogen intermediary ? Histamine induced ? Centrally activated pruritogenic opiod ? Increased serotonin Haematopoietic Disorders • PCV – Increased histamine • Hodgkins • Others – – – – ? Histamine ? Autoimmune response ? Infiltration ? Release of leukopeptidase Endocrine Disorders • Thyrotoxicosis – ? Activate kinins – ? Reduced itch threshold • Hypothyroidism – xerosis • Diabetes mellitus – candida Solid Tumours • • • • Paraneoplastic ? Allergic reaction to Ag ? Toxic products of necrotic tumour cells Breast, stomach, lung, prostrate, colon 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 Inatrogenic Pruritus • • • • • • Aspirin Hydroxyurea Captopril Antibiotics Phenytoin Allopurinol Neurogenic • Neuropathies – E.g. multiple sclerosis – Activation artificial synapses • Unilateral cerebral lesions – Effects on descending pathways • Post-herpetic neuralgia Senile Pruritus • Xerosis • Skin atropy • ? Age associated degeneration in nerve endings • ? Postmenopausal syndrome Psychogenic Pruritus • • • • Feelings of hopelessness / helplessness Secretion serotonin, dopamine Elevated endogenous opiods ? ‘depressive equivalent’ Others • HIV • High prevalence skin disorders • Abnormal levels cytokines • Hypereosinophilia • Peripheral neuropathy • AQUAGENIC • Contact with water • Pathogenesis unknown 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 Specific treatments • Sequestrants – Cholestyramine – Charcoal – Heparin • Vaso-active drugs – Alpha blockers – Beta blockers Disease Specific Interventions • Cholestatic disease – – – – Rifampicin Androgens Urso Stenting • Uraemia – – – – Erythropoitin UVB phototherapy Parathyroidectomy Transplantation Disease Specific Interventions • PCV – alpha interferon • Fe deficiency – iron • Thyroid disorder Miscellaneous • • • • • Phototherapy TENS Acupuncture Psychotherapy Relaxation Problems in Palliative Medicine • Most terminal phase • Changing organ function • Systemic treatment may be toxic, impractical Conclusions • Pathophysiology not fully understood • Peripheral and central mechanisms • Often associated with systemic diseases 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! 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 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 Capsaicin • Anti-inflammatory • Reduces substance P from nerve endings • Inhibits itch transmission • Use : localised pruritus e.g. uraemia Thalidomide • • • • Reduce TNF synthesis Anti-inflammatory ? Interfere with cytokine production Use : uraemia Cimetidine • Role not established • Enhance effect anti-histamines • Use : uraemia haematological malignancies 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 Role • CRF • Haematological malignancies • Depressive disorders • Neuroleptics / benzodiazepine use 5-HT3 Antagonists • • • • • Ondansetron Serotonin mediator of itch Use : cholestasis, uraemia, spinal opiods Expensive Often IV use Opiod Antagonists • Counteract endogenous opiods • Can be impractical • Naltrexone (oral preparation) • Use : CRF, hepatogenic & haematological pruritus • ‘opiod abstinence syndrome’ • Buprenorphine • Partial agonist • • • • Nalbuphine Mixed agonist-antagonist Needs further evaluation Opiod rotation Anaesthetic Agents • • • • • Lignocaine Abnormal pattern cutaneous innervation Associated peripheral neuropathy Use : uraemia Toxic adverse effects • Propofol • Subhypnotic doses in hepatogenic pruritus • Opiod induced – ? Inhibit dorsal root transmission – ? Blocks Sequestrants • • • • • • Cholestyramine Reduce bile acids Remove other pruritogens Use : cholestasis Unpalatable Diarrhoea • Charcoal • Use : uraemia • ?chelates metabolites • Heparin Disease Specific Drugs • • • • • Uraemia Erythropoietin UVB phototherapy Parathyroidectomy Transplantation Disease Specific Drugs • Cholestatic disease • Androgens – Stanazol, methytestosterone • Rifampicin • Biliary stenting definitive treatment Ultraviolet Light • UVB • Reduce content vitamin A • Inhibit release histamine & proliferation mast cells • Use : renal and liver disease, AIDS • • • • • • PUVA Ultrastructural changes in nerves Increase sensory thresholds Reduce end-organ responsiveness ? Stabilise mast cells Use : pruritic dermatoses Others • TENS – Induction on ‘lateral inhibition’ in spinal cord • • • • Acupuncture Plasma exchange Psychotherapy Relaxation