PRURITUS Catriona Mayland July 2002

Topics Definition Neuroanatomy Mediators Evaluation General treatment Systemic disorders Specific treatment

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