Chronic Pruritus in the Absence of Specific Skin Disease: An Update on Pathophysiology, Diagnosis, and Therapy

Nicoletta Cassano; Gianpaolo Tessari; Gino A. Vena; Giampiero Girolomoni

Am J Clin Dermatol. 2010;11(6):399-411.

Abstract and Introduction

Abstract

Chronic pruritus is a major and distressing symptom of many cutaneous and systemic diseases and can significantly impair the patient's quality of life. Pruritus perception is the final result of a complex network involving dedicated nerve pathways and brain areas, and an increasing number of peripheral and central mediators are thought to be involved. Itch is associated with most cutaneous disorders and, in these circumstances, its management overlaps with that of the skin disease. Itch can also occur without associated skin diseases or primary skin lesions, but only with nonspecific lesions secondary to rubbing or scratching. Chronic itch with no or minimal skin changes can be secondary to important diseases, such as neurologic disorders, chronic renal failure, cholestasis, systemic infections, malignancies, and endocrine disorders, and may also result from exposure to some drugs. The search for the cause of pruritus usually requires a meticulous step-by-step assessment involving careful history taking as well as clinical examination and laboratory investigations.
Few evidence-based treatments for pruritus are available. Topical therapy, oral histamine H₁ receptor antagonists, and phototherapy with UV radiation can target pruritus elicitation in the skin, whereas antiepileptic drugs, opioid receptor antagonists, and antidepressants can block signal processing in the CNS.

Introduction

Pruritus is defined as an unpleasant sensation inducing the desire to scratch.^[1] It is a major and distressing symptom of numerous and diverse cutaneous and systemic diseases. In some instances, pruritus is not associated with skin diseases or specific skin changes, but only with lesions secondary to rubbing or scratching and even with no or minimal skin changes. Chronic itch, defined on the basis of a duration of 6 weeks or more, may be difficult to diagnose and manage, and may have a strong impact on the quality of life of patients.^[1] This review focuses on recent advances in understanding the pathophysiology of itch, as well as on the diagnostic and therapeutic management of chronic itch not associated with skin diseases.

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Table I. Principal peripheral and central mediators involved in the generation or modulation of itch (modified from Paus et al., ³ with permission)
Mediators	Sources	Function
Acetylcholine	Autonomic cholinergic nerves, keratinocytes, lymphocytes, melanocytes, dermal fibroblasts, endothelial cells	Peripheral induction of itch, especially in atopic dermatitis
Calcitonin gene-related peptide	Sensory nerve fibers	Central modulation of itch and sensitization of nerve endings
Neurokinins, substance P	Sensory nerve fibers	Regulation of nerve growth factor expression and substance release from mast cells
Pituitary adenylate cyclase-activating polypeptide, vasoactive intestinal polypeptide	Nerve fibers, lymphocytes, endothelial cells, Merkel cells	Induces release of histamine
Gastrin-releasing peptide	Small and medium-size dorsal root ganglion	Itch sensation in the dorsal spinal cord
Corticotrophin-releasing hormone, pro-opiomelanocortin	Keratinocytes, mast cells	Release of histamine and of many cytokines
Nerve growth factor, brain-derived neurotrophic factor, neurotrophin-4	Keratinocytes, mast cells, fibroblasts, eosinophils	Induction of chemotaxis of eosinophils and inhibition of apoptosis in atopic dermatitis
TNFα, IL-1, IL-6, IL-31	Leukocytes, keratinocytes, endothelial cells, nerves	Upregulated in atopic dermatitis and prurigo nodularis
Endocannabinoids	Nerves, immune cells, keratinocytes, hair follicles	Peripheral antipruritic activity
Endovanilloids	Sensory neurons, mast cells, epidermal and hair follicle keratinocytes, Langerhans cells, smooth muscle cells, sebocytes	Induction and modulation of itch and pain
Opioids	Nerves, keratinocytes	Central induction of pruritus. Increased μ-receptor expression in atopic dermatitis
Kallikreins, proteases	Keratinocytes, endothelial cells, mast cells, platelets	Kallikreins may induce itch, while chymases degrade itch mediators
Histamine	Mast cells, keratinocytes, leukocytes	Stimulates specific itch fibers
Prostaglandins	Sensory nerve fibers, keratinocytes	Itch induction
Leukotriene B4	Sensory nerve fibers, keratinocytes	Itch induction

IL = interleukin; TNF = tumor necrosis factor.

Table II. Etiologic classification of itch according to the International Forum for the Study of Itch (data from Ständer et al. ¹)
Subtype	Relevant examples
Dermatologic: arising from skin; dry skin and any specific skin disease	Inflammatory: contact dermatitis, atopic dermatitis, asteatotic eczema, nummular eczema, stasis dermatitis, seborrheic dermatitis, urticaria, psoriasis, lichen planus, drug reactions, polymorphous light eruption, mastocytosis, pemphigoid, dermatitis herpetiformis, dermatomyositis
	Infections: pediculosis, scabies, parasitic disease, tinea corporis, impetigo, smallpox
	Neoplastic: cutaneous T-cell lymphomas
	Dermatoses of pregnancy: pruritic urticarial papules and plaques of pregnancy, prurigo of pregnancy, pemphigoid gestationis
Systemic: arising from diseases of organs other than the skin, metabolic or other multifactorial disturbances or from drugs	Endocrine and metabolic disorders: chronic renal failure (dialysis), liver diseases with or without cholestasis, thyroid diseases
	Infections: HIV, parasites, hepatitis C virus
	Hematologic diseases: polycythemia vera, lymphomas
	Tumors: solid organ tumors, carcinoid
	Drug-induced pruritus (with or without cholestasis)
Neurologic (neurogenic/neuropathic): arising from disorders of the central or peripheral nervous system and possibly also from liver disease	Multiple sclerosis; spinal or cerebral neoplasms, abscesses, or infarcts; phantom itch; postherpetic neuralgia; transverse myelitis; notalgia paresthetica; brachioradial pruritus; meralgia paresthetica; other conditions associated with nerve damage, compression or irritation, such as entrapment neuropathy, radiculopathy, or polyneuropathy (including diabetes mellitus, vitamin B12 deficiency, etc.)
Psychogenic/psychosomatic	Delusion of parasitosis, psychogenic excoriations, somatoform pruritus, associated with psychiatric disorders
Mixed	Coexistence of dermatologic and neurologic itch in HIV-infected patients or in patients with atopic dermatitis, association of uremic itch with skin xerosis, association of Hodgkin disease with potentially misleading paraneoplastic cutaneous manifestations, such as unexplained adult-onset eczema
Other (of unknown origin)	Senile 'idiopathic' pruritus, aquagenic 'idiopathic' pruritus, pruritus in anorexia nervosa

Table III. Relevant information to be collected from a patient's history
Item	Examples and/or comments
Personal and family history of cutaneous and extracutaneous disorders	Atopy, hypersensitivity reactions, and systemic diseases
Previous and concomitant drugs
Surgical procedures or recent hospitalizations	Use of volume expanders (hydroxyethyl starch)
Travel history	Infections or infestations that are endemic in particular geographic areas
Work and leisure activities	Exposure to irritating or sensitizing substances, fiberglass, mineral wool, biotic agents, etc.
Lifestyle and personal habits	Eating, smoking, alcohol consumption, drug abuse and addiction, sexual history, indoor environment, etc.
History of spinal injury	Arthritis, trauma, or chronic repetitive microtrauma (in presence of a suspected 'neuropathic' itch)
Mental state and personality characteristics
Recent development of other symptoms and/or signs, including but not limited to:	The following conditions should be suspected:
burning, pain, stinging, tingling, paresthesia, hypoesthesia or hyperesthesia, numbness, muscle weakness, cramps	sensory or sensorimotor neuropathy (neuroanatomic damage)
motor deficits	brain lesions
nocturnal sweating, fever, unexplained weight loss	Hodgkin lymphoma
weight loss	malignancies of various origin, HIV infection, malabsorption, hyperthyroidism
fatigue	malignancies, HIV infection, anemia
nausea, anorexia, malaise, fatigue	cholestasis
flushing and diarrhea	carcinoid syndrome

Table IV. Treatments for uremic pruritus
General measures^32,33
Regular use of emollients (even in patients who do not have pruritus)
Cool environment, loose clothes, avoid wool and artificial fibers
Improvement in the efficiency of the dialysis technique
Correction of the alterations of calcium-phosphorus metabolism
Parathyroidectomy can be considered in the case of secondary hyperparathyroidism
Topical treatments in localized mild pruritus ^32,33
Emollients
Capsaicin^a
Phototherapy with UVB ^32,33,40,41
Treatment of choice in moderate to severe uremic pruritus
Broad-band UVB more effective than narrow-band UVB
Systemic approaches in generalized pruritus ^36–39
Thalidomide^a
Gabapentin^a
Nalfurafine^a

a Efficacy proven in randomized placebo-controlled trials.

Table V. Treatments for pruritus associated with cholestasis ^44–47
Drug	Dosage	Possible adverse effects	Notes
First-line medical approach ^a
Naloxone	0.2 μg/kg/min IV infusion preceded by 0.4mg IV bolus	Opioid withdrawal-like syndrome	Transient adverse effects in a significant proportion of patients in RCTs
Naltrexone	Day 1, 25mg PO bid, then 50mg/day PO	Opioid withdrawal-like syndrome, potential hepatotoxicity	Transient adverse effects in a significant proportion of patients in RCTs
Rifampin (rifampicin)	300–600mg/day PO	Hepatotoxicity (controversial data about real risk)	Adverse effects similar to placebo in RCTs
Colestyramine (cholestyramine)	4–16 g/day PO	Constipation, bloating, malabsorption, interaction with many drugs	Adverse effects similar to placebo in RCTs
Phenobarbital (phenobarbitone)	2–5mg/kg/day PO	Sedation
Surgical management of biliary obstruction when indicated
Stenting or removal of gallstones
Other approaches ^b
Medical treatments
Anticholestatic agents: ademetionine (S-adenosylmethionine); ursodeoxycholic acid (not effective in primary biliary cirrhosis-associated pruritus; apparently effective and safe in cholestasis of pregnancy)
Cannabinoids (dronabinol)
Antidepressants: sertraline
UVB phototherapy
Others: anesthetics: propofol, lidocaine (lignocaine); bright-light therapy towards the eyes; antioxidants; androgens (danazol)
Invasive procedure in patients resistant to medical therapies (tried in a small number of cases)
Nasobiliary drainage or partial external diversion of bile; ileal diversion; hemodialysis; charcoal hemoperfusion; plasmapheresis and plasma perfusion; extracorporeal albumin dialysis, with molecular adsorbent recirculating system; plasma separation and anion adsorption

a Shown to be effective in RCTs.
b Only open-label trials or RCTs in small series of patients.
bid = twice a day; IV = intravenous; PO= orally; RCTs = randomized controlled trials.

Table VI. Principal drugs able to induce pruritus without skin changes ^43,74,75,77
Drug group	Examples
Antihypertensive drugs ACE inhibitors^a
	Angiotensin II antagonists (sartans)^a
	β-Adrenoceptor antagonists (β-blockers)^a
	Calcium channel blockers^a
	Methyldop^a
	Sildenafil^a
Antiarrhythmic drugs	Amiodarone^a
Anticoagulants	Ticlopidine^a
	Fractionated heparins
Antidiabetic drugs	Biguanides^a
	Sulfonylurea derivates
Hypolipemic drugs	HMG-CoA reductase inhibitors (statins)
Antibacterials and chemotherapeutics	Penicillins^a
	Cephalosporins
	Macrolides^a
	Carbapenems^a
	Monobactams
	Quinolones
	Tetracyclines^a
	Lincosamides^a
	Streptogramins
	Metronidazole
	Rifampin (rifampicin)
	Thiamphenicol
	Trimethoprim/sulfamethoxazole (cotrimoxazole)^a
	Antimalarials
Psychotropic drugs	Tricyclic antidepressants^a
	Selective serotonin reuptake inhibitors
	Antipsychotics^a
Antiepileptic drugs	Carbamazepine
	Fosphenytoin
	Oxcarbazepine
	Phenytoin
	Topiramate
Cytostatics	Chlorambucil
	Paclitaxel
	Tamoxifen
Cytokines, growth factors, and monoclonal antibodies	Granulocyte-macrophage colony-stimulating factor
	Interleukin-2
	Matuzumab
	Lapatinib
	Epidermal growth factor receptor inhibitors
Plasma volume expanders	Hydroxyethyl starch
Others	Antithyroid agents^a
	NSAIDs^a
	Corticosteroids^a
	Sex hormones^a
	Opioids
	Inhibitors of xanthine oxidase

a Can induce cholestatic liver injury.

Table VII. Principal systemic therapies for pruritus other than antihistamines
Medication	Dosage	Indication	Adverse effects
Fluvoxamine	25mg/day PO for 3 days then 50–100mg/day PO as needed	Various pruritic diseases⁹⁵	Drowsiness, vertigo, fatigue, headache, sexual dysfunction, nausea, vomiting
Gabapentin	300–1800mg/day PO; in dialysis patients, 100–300 mg PO after every dialysis session may be sufficient	Neuropathic,²⁵ uremic itch^a ^36,37,87	Drowsiness, constipation
Mirtazapine	15–45 mg/day PO	Generalized pruritus⁹³	Drowsiness, increased weight and appetite, dry mouth
Naloxone	0.2 μg/kg/min IV infusion daily preceded by 0.4mg IV bolus over 24 hours	Cholestatic itch^a ^44,45	Hepatotoxicity, nausea and vomiting, difficulty sleeping, reversal of analgesia
Naltrexone	Day 1, 25mg bid, then 50mg/day PO	Cholestatic itch^a ^44,45	Hepatotoxicity, nausea and vomiting, difficulty sleeping, reversal of analgesia
Paroxetine	20mg/day PO	Malignancy-related pruritus^a,⁹⁴ other pruritic diseases⁹⁵	Insomnia, sexual dysfunction
Phototherapy: UVA plus psoralen, UVB	Must be individually determined	Prurigo nodularis^a,^82,83 uremic pruritus^a40,41	Burns, photodamage, skin cancer
Thalidomide	100–200mg/day PO	Prurigo nodularis, uremic pruritus^a ³⁹	Teratogenic, peripheral neuropathy, drowsiness, constipation

a Randomized controlled trials available.
bid = twice a day; IV = intravenous; PO = orally.

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Chronic Pruritus in the Absence of Specific Skin Disease: An Update on Pathophysiology, Diagnosis, and Therapy

Abstract and Introduction

Abstract

Introduction

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