Dermatology

Pruritus

Pruritus

Are You Confident of the Diagnosis?

Pruritus can be best defined as a sensation that leads to the desire to scratch. It is important to make a distinction between chronic and acute pruritus. All humans experience the acute form for a limited amount of time during the course of life, such as the itch related to acute insect bite reaction or skin irritation. Chronic pruritus, which is defined by the International Society for the Study of Itch (IFSI) as itch that persists for 6 weeks and longer. It has a significant impact on the quality of life of millions of patients worldwide and is the focus of this chapter.

What you should be alert for in the history

It is imperative to determine whether the cause of chronic itch is related to a primary skin disease or secondary to a systemic disease. If a patient constantly scratches secondary skin lesions develop. These include:

  • Excoriations

  • Lichenification

  • Prurigo nodules

  • Hyperpigmentation or hypopigmentation

  • Bruising

  • Erosions

  • Butterfly sign - normal appearing skin in the middle of back outlined by a butterfly pattern of hyperpigmentation associated with repetitive scratching.

Generalized pruritus differs from localized pruritus. A patient with localized pruritus may have other sensory complaints such as burning sensation, the oss of sensation or hypersensitivity, as well as dermatomal distribution of pruritus. These should be evaluated carefully regarding possible neuropathic itch. In generalized pruritus one should obtain a careful history including drug intake, whether other family members are itching (scabies) and if there are other systemic complaints such as weight loss, night sweats.

Characteristic findings on physical examination

Search for primary skin versus secondary lesions. Examine the genitalia to rule out scabies. Skin signs may be clinically unapparent. Examine lymph nodes in cases of generalized pruritus.

The most important points you should elicit from a patient with pruritus are:

  • Duration - years, weeks, days

  • Localization - generalized, localized, site

  • Severity

  • Effect on sleep

  • History of itch in other personal contacts

  • Characterization - burning, pricking, formication

  • Periodicity - paroxysmal, continuous, occurring in short bouts, nocturnal

  • Factors that exacerbate itch - heat, water, dryness

  • Factors that alleviate itch - drugs or cooling agents

  • Drugs - opiates, aspirin, penicillin, antimalarials, targeted cancer therapies

  • History of atopy

  • Travel history

Diagnostic studies

Most patients with pruritus and a rash will not need further tests. A detailed history and examination often reveals the cause. Investigations for patients with pruritus with a rash may include a skin biopsy. Patients with itch on primarily normal, non-inflamed skin may need laboratory and radiological studies, adapted to the patient's history and pre-existing diseases. Suggested lab tests include: full (complete) blood count, liver function tests, and creatinine and thyroid function tests. Obtain a chest X ray and ultrasound in cases where lymphoproliferative diseases are suspected.

Secondary laboratory considerations may include stool examination for ova and parasites, screening for hepatitis B or C, HIV, serum protein electrophoresis, and immuno-electrophoresis. A computed tomography scan of the chest and abdomen may be justifiable to help rule out lymphoma. A skin biopsy is useful to exclude clinically unapparent cutaneous mastocytosis, bullous pemphigoid, or incipient mycosis fungoides.

Who is at Risk for Developing this Disease?

A list of skin diseases that commonly cause chronic pruritus includes:

  • Atopic eczema

  • Aging skin

  • Contact dermatitis

  • Chronic urticaria

  • Lichen planus

  • Lichen simplex chronicus

  • Psoriasis

  • Scabies

  • Seborrheic dermatitis

  • Scars

  • Superficial fungal diseases.

  • Xerosis

Systemic diseases that cause itch include:

  • Chronic renal disease

  • Cholestasis

  • Hyperthyroidism

  • Hematological disease and lymphoreticular malignancy

    • Hodgkin's disease

    • Polycythemia vera

    • Myeloid and lymphatic leukaemia

    • Myelodysplasia

    • Systemic mastocytosis

  • Solid malignant tumors (paraneoplastic manifestation)

HIV infection

Collagen disease

  • Dermatomyositis

  • Scleroderma

  • Sjogrens

Drugs (such as opioids, chloroquine, allopurinol)

  • Hydroxyethyl starch.

Psychogenic itch:

  • Somatoform disorders

  • Delusional parasitosis

  • Depression

  • Emotional factors such as stress and anxiety may exacerbate existing pruritus

Peripheral neuropathic itch:

  • Diabetes

  • Nerve entrapment including brachioradial pruritus

  • Notalgia parasthetica

  • Postherpetic neuropathy

Central neuropathic itch has been associated with:

  • Brain tumors

  • Cerebrovascular events.

  • Jacob Creutzfeld

  • Multiple sclerosis

What is the Cause of the Disease?

Pathophysiology

The common view is that the epidermis may act as receptor for itch, but a specific receptor has not been yet clearly identified. Keratinocytes and C nerve fibers express a variety of neural mediators and receptors, all of which appear to be involved in the sensation of itch. These include opioids, proteases, substance P, nerve growth factor (NGF) and neurotrophin 4, as well as their respective receptors, including μ- and κ-opioid receptors, proteinase-activated receptor-2 (PAR-2), vanilloid receptors, neurotrophic tyrosine kinase receptor type 1, and transient receptor potential (TRP) ion channels (particularly TRPV1 and TRPV3).

Recent studies provide evidence that indeed there are itch-specific receptors in the skin. A subset of C nerve fibers that contain MrgprA, a subfamily of a G-coupled protein receptors, were found to mediate itch sensation induced by chloroquine. Chloroquine is an antimalarial drug that is known to induce itch in humans, especially in those with dark skin color (Africans).

Another itch receptor in humans was found in lichen amyloidosis, a localized form of severe itch common in Asians and Hispanics. A mutation in the in the OSMR gene, which encodes oncostatin M receptor beta (OSMRbeta), an interleukin 31 cytokine receptor was found in these patients. IL-31 (a TH2 cell-derived cytokine) has a role in itch of atopic eczema ,prurigo nodularis and recent studies suggest it has a role in cutaneous T cell lymphoma itch (CTCL). An IL-31 antibody effectively reduced scratching behavior in an atopic dermatitis-like murine model.

An itch processing pathway activated by cowhage spicules (Mucuna pruriens) revealed an activation of peripheral nerve fibers in humans as well as its specific spinal projection neurons. The active ingredient in cowhage has been isolated as a cysteine protease (mucunanin) that activates proteinase activated receptor 2 (PAR2) and PAR4 in nerve fibers and keratinocytes. PAR2 receptors and their ligands, serine proteases, have previously been demonstrated to have a significant role in the itch associated with atopic eczema. Recently, cathepsin S, an endogenous cysteine protease secreted by keratinocytes, was found to induce itch. This finding suggests that cathepsin S may have a role as an itch mediator in inflammatory skin diseases.

Among the numerous lists of mediators, opioids have a major role in generalized pruritus. It has been known for decades that analgesia obtained with mu opioids induces itch, while mu antagonists, such as naltrexone, inhibit itch. It has been suggested that chronic itch is associated with an imbalance between mu and kappa opioid systems. This latter finding led to the development of a novel kappa opioid receptor agonist chronic pruritus shares many similarities with chronic pain including peripheral and central sensitization.

Therefore, many endogenous inflammatory mediators that are involved in chronic pain via sensitization of C nerve fibers such as prostanoids, serotonin, NGF and Transient Receptor Potential Vanilloid (TRPV)s also have a role in chronic pruritus. Moreover, robust activation in the brain in areas involved in central sensitization has been noted in chronic itch. This explains the rationale of using of gabergic drugs and anti-depressants in the treatment of chronic pruritus.

Systemic Implications and Complications

Patients with chronic pruritus often have the following complications:

  • Difficulty sleeping

  • Difficulty concentrating

  • Decreased sexual desire and sexual function

  • Agitation

  • Depression

Also, eczematous lesions resulting from scratching can become secondarily infected, particularly in patients with atopic eczema and in patients with widespread scabies.

Treatment Options

At present, there is no universally accepted therapy for itch. Instead, management of pruritus takes an individualistically tailored approach. Treating pruritus depends on identifying and removing the underlying cause, whether systemic or cutaneous. False hopes of highly effective treatment for those patients in whom no cause can be found should not be raised. Recent advancements in the pathophysiology of pruritus however has renewed interest in this distressing symptom and identified novel targets for therapy.

If it is not possible to treat the cause there are several preventive and therapeutic treatment options.

Preventive measures to reduce itch

Commonly used topical treatments include emollients and moisturizers, which restore and preserve the barrier function of skin. Emollients and barrier repair creams are not specific treatments for itch but often reduce pruritus through improved barrier function. Barrier creams help the stratum corneum to retain water. They are often effective treatments for itch associated with dry skin and atopic dermatitis as well as advanced aging skin itch. Acidifying the stratum corneum may also reduce itch. High pH solutions and soaps damage the skin barrier function and activate serine proteases that are known to induce itch. Acidic pH solutions are less damaging.

The sensation of itching is heightened if the skin is warm. Patients should therefore take measures to cool the skin, including taking tepid showers, wearing light clothes, and using air conditioning where appropriate. Cooling lotions, such as calamine lotion or menthol, up to 3%, may help.

Patients should be advised to use the following preventive measures to reduce itch:

  • Bathe in lukewarm water rather than hot water or cold water (hot and cold water can dry the skin)

  • Restrict time in the shower or bath

  • Apply a moisturizer immediately after bathing

  • Use a humidifier at home, especially in winter

  • Wear light and loose clothing that absorbs sweat

  • Avoid wearing wool or tight clothing

  • Avoid cleansers containing alcohol

  • Use coolants such calamine lotion or menthol 3%

  • Avoid rapid changes in environmental humidity

  • Avoid hot or spicy foods

  • Avoid alcohol

Topical Therapies

There is a lack of controlled studies for most topical antipruritic treatments. Many topical agents are claimed to be effective for pruritus; however, few claims are supported by more than anecdotal evidence. The list of topical therapies includes:

  • Emollients and moisturizers

  • Barrier creams

  • Topical corticosteroids

  • Immunomodulators (topical)

  • Antihistamines (topical)

  • Coolants and counterirritants

  • Capsaicin

  • Topical anesthetics (EMLA)

  • lauarmacrogols

  • Topical salicylates

  • Topical N-palmitoylethanolamine, a low potency cannabinoid agonist (Mimyx TM )

Emollients and barrier creams

Moisturizers, emollients and barrier repair creams are the mainstay of pruritus treatment in the elderly especially in cases associated with xerosis. They reduce pruritus through improved barrier function. More specifically, they help to prevent transepidermal water loss and possibly prevent entry of irritants and itch-causing agents. Topical therapies with a low pH may be especially useful in optimizing the skin barrier function through their maintenance of the normal acidic pH of the skin surface.

Topical corticosteroids

Topical corticosteroids should only be used to provide relief of itching associated with inflammatory skin diseases such as atopic dermatitis or psoriasis and contact dermatitis.

Topical immunomodulators

Topical immunomodulators that inhibit T lymphocyte activation, such as tacrolimus and pimecrolimus, are used primarily for atopic dermatitis of mild to moderate severity. Both of these medications have antipruritic effect possibly via their effect on TRPV1 receptor and may be useful in the following skin diseases:

Contact dermatitis:

  • Lichen planus

  • Facial seborrheic dermatitis

A good response has been achieved in diseases involving genitoanal pruritus, such as:

  • Lichen sclerosus et atrophicus

  • Genital psoriasis

  • Scrotal eczema

  • Genitoanal pruritus of undetermined origin

Common side effects of these agents are burning and stinging sensations.

Topical antihistamines

Doxepin, which is a tricyclic antidepressant with potent H1 and H2 antihistamine and atropine-like (anticholinergic) properties, is the most effective treatment. It has been shown to relieve pruritus in patients with:

  • Atopic dermatitis

  • Localized itch

It is available as a 5% cream. It is not suitable for children. Percutaneous absorption of doxepin causing drowsiness, occurs in about 25% of patients, and limits its usefulness. Allergic contact dermatitis and skin burning sensations are other relatively common side effects Other topical antihistamines are commonly used for insect bite reactions and localized itch, but are not effective for chronic itch.

Coolants and counterirritants

Menthol, camphor, and phenol stimulate the nerve fibers that transmit the sensation of cold, thereby masking the itching sensation. They have been used for centuries. These agents could be compounded with aqueous cream to make a 1% to 2% cream. Menthol 1% to 3% cream is popular with patients who have pruritic skin; higher concentrations can induce skin irritation. All of these compounds can cause skin irritation. There are particularly helpful for a subset of chronic pruritic patients who report that cooling their skin reduces their itch.

Capsaicin

Topical capsaicin acts through TRPV1 expressed on sensory skin nerves to release neuropeptides such as substance P. TRPV1 recently has been implicated in the pathogenesis of pruritus and thus may be the target through which capsaicin exerts its antipruritic effect. Beneficial effects of capsaicin have been reported in chronic, localized pruritic disorders, particularly those of neuropathic origin, such as notalgia paresthetica and brachioradial pruritus as well as other pruritic conditions (eg, prurigo nodularis, aquagenic pruritus and pruritus associated with chronic kidney disease). Unfortunately, concordance is poor because initial application causes an intense burning sensation. This side effect usually resolves after using the medication for a few days or with application of a topical anesthetic.

Topical anesthetics

Topical anaesthetics, including pramoxine 1% cream and a eutectic mixture of lidocaine and prilocaine 2.5% cream (EMLA), have a documented antipruritic effect, as does lidocaine 3% in an acid mantle cream and lotion. Topical anesthetics have been used effectively in neuropathic itch, such as postherpetic neuralgia, brachioradial pruritus, nostalgia parasthteica and facial and anogenital itch.

A transient burning sensation may occur at application sites. This usually resolves after a few days or by applying a topical anesthetic.

Polidocanol is a nonionic surfactant with both local anaesthetic properties and moisturizing effects. It was found to significantly reduce pruritus in patients with:

  • Atopic dermatitis

  • Contact dermatitis

  • Psoriasis

Topical salicylates

Topical acetylsalicylic acid significantly reduces itch in patients with lichen simplex chronicus. Topical salicylic acid solutions are keratolytic and may also increase hydration and soften the stratum corneum by decreasing its pH. Do not apply topical salicylates in acute inflammatory skin processes and in young children.

Topical low-potency cannabinoid agonist (N-palmitoylethanolamine)

Recent evidence of cannabinoid receptors on cutaneous nerve fibers supports the use of cannabinoid receptor agonists as topical antipruritics. Activation of these receptors by a topical cannabinoid agonist could significantly suppress pain as well as itch sensation and erythema. A cream with the cannabinoid agonist palmitoylethamolamine showed promising results in pilot trials of pruritus in:

  • Atopic dermatitis

  • Uraemic pruritus

  • Prurigo nodularis.

Systemic therapies

(Table I)

Table I.

An overview of systemic therapies for pruritus and recommended dosage : 
 Medication  Dose  Notes
Antihistamines Variable depending on medication  No direct effect on pruritus except in urticaria, sedating antihistamines may be useful through their soporific effects
Mirtazapine 7.5 - 15 mg orally at sleep      
Antidepressants
 Useful in nocturnal pruritus, may cause increased weight and appetite
             SNRIs Paroxetine 10 mg - 40 mg orally daily   Consider in psychiatric patients with pruritus
  Consider in psychiatric patients with pruritus
             SSRIs Fluvoxamine 25 -150 mg orally daily   Useful in cholestatic pruritus
Sertraline 75 -100 mg orally daily 
 µ-opioid receptor antagonists Naltrexone 25 – 50 mg orally daily  Useful in patients with cholestatic and CKD-associated pruritus, may cause nausea, vomiting and drowsiness
Butorphanol 1 – 4 mg intranasally daily  Useful in nocturnal and intractable pruritus, may cause nausea and vomiting as well as drowsiness
 ?-opioid receptor agonists
Nalfurafine 2.5 - 5 µg orally daily  Useful in CKD-associated pruritus, may cause insomnia, approved in Japan only
Gabapentin 100 – 3600 mg orally daily
 Neuroleptics  Useful in neuropathic pruritus, may cause drowsiness and weight gain
Pregablin 150 – 300 mg orally daily
 Substance P antagonist Aprepitan 80 mg orally daily  Benefical in pruritus associated with the Sézarysyndrome, expensive
Cyclosporin 2.5 – 5 mg/kg orally daily  Consider in atopic dermatitis patients with treatment refractory pruritus, monitor blood pressure and renal function, short term use
 Immunosuppressants
 Azathioprine 2.5 mg/kg orally daily  Consider in atopic dermatitis patients with treatment refractory pruritus, monitor for myelosuppression
     

Oral antihistamines

With the exception of urticaria, antihistamines have little effect on conditions associated pruritus. However, sedating (first-generation) antihistamines may have a role in patients where pruritus is exacerbated at night probably via their soporific effects

First-generation H1 antihistamines have marked sedative and anticholinergic actions. Second generation (low sedation) antihistamines have lower lipophilicity and consequently are associated with less drowsiness and other unwanted side effects. Sedative (first generation) antihistamines are useful in severe chronic urticaria with or without angioedema because they suppress pruritus and alleviate associated anxiety. Hydroxyzine 25-50 g is especially valuable in this context. These medications should be taken at bed time. Second generation antihistamines such as loratadine, desloratadine, and cetirizine are suitable in the daytime for relief of pruritus due to urticaria. H4 antagonists have recently been shown to have anti pruritic effect in animal studies.

Opiate antagonists and agonists

µ-opioid antagonists, such as naloxone and naltrexone, have been used for treating pruritus associated with:

  • Cholestasis

  • Chronic renal failure

  • Lymphoproliferative disease

  • Dermatological diseases such as atopic dermatitis.

Butorphanol is a commercially available opioid agonist-antagonist analgesic with both kappa-agonist activity and µ-antagonist activity. Previous studies have found that epidural butorphanol was effective in relieving pruritus associated with epidural morphine. It has been used to treat pruritus of chronic renal failure, cholestasis, lymphoma, and idiopathic generalized pruritus based on non-controlled case series and our personal experience. Intranasal butorphanol is an effective treatment for many patients with chronic, severe, and intractable pruritus due to systemic diseases and inflammatory skin diseases.

Nalfurafine hydrocholoride is a kappa opioid that has been launched in Japan for the treatment of pruritus of chronic renal failure and recently approved for cholestatic itch. Naltrexone is effective for treating some patients with severe, intractable pruritus. However, such µ-antagonists are associated with significant side effects including nausea and vomiting, hepatotoxicity, difficulty sleeping, and reversal of analgesia.

Selective serotonin reuptake inhibitors

The oral antidepressant mirtazapine has been shown to relieve itch in some patients. Mirtazapine is a central presynaptic alpha-2 noradrenergic inhibitor and specific serotonergic antidepressant. It has been shown to be effective in a low dose of 15mg at night when used to treat systemic pruritus:

  • Pruritus of skin inflammations

  • Nocturnal itch

In case reports the selective serotonin reuptake inhibitor paroxetine was demonstrated to influence severe pruritus due to:

  • Polycythemia vera

  • Paraneoplastic pruritus

  • Psychogenic itch

Other selective serotonin reuptake inhibitors have not shown as yet antipruritic effect but should be considered; eg, Venlafaxine, Duloxtine.

Gabapentin/ Pregabalin

Studies have shown that gabapentin is effective for treating itch, particularly:

  • Uremic itch

  • Brachioradial pruritus

  • Itch induced by multiple sclerosis

  • Other types of neuropathic itch

Pregabalin is a new neuropathic pain medication that has a structure and function similar to gabapentin with fewer side effects and can reduce neuropathic itch or alter the sensation of itch in systemic diseases.

Another drug that has effect on inhibition of itch via its effect on nerve fibers is thalidomide. It has been shown to be effective for prurigo nodularis and severe itch related to HIV, but due to high costs and side effects is rarely used. It is absolutely contraindicated in pregnancy.

Systemic immunomodulators such as azathioprine and cyclosporine and the new biologics such as anti-tumor necrosis factor have recently been shown to reduce itch in inflammatory skin disease such as atopic eczema and psoriasis. The biologics such as anti-tumor necrosis factor and the interleukin 17 antibodies as well as apremilast have recently been shown to reduce itch in inflammatory psoriasis.

Neurokinin 1 Inhibitors-a novel therapy

Aprepitant is a selective high-affinity NKR1-antagonist-the receptor for substance P an antiemetic given to cancer patients. A case series of 20 patients with chronic refractory pruritus treated with aprepitant 80mg for 1 week showed that 80% of the patients improved considerably. Those with dermatological diseases, such as atopic diathesis and prurigo nodularis improved the most. The side effects were mild, including nausea, vertigo, and drowsiness. It is, however, expensive and its efficacy as an antipruritic agent requires verification in randomized placebo-controlled studies. Newer anti neurokinin 1 inhibitors for itch are currently under phase 2 trials.

Phototherapy

Phototherapy has been used for more than a decade to treat different types of itch. Different wavelengths of phototherapy and techniques include UVB, UVA, combined UVA/UVB, long-narrow band UVB, and photochemotherapy with psoralens (PUVA) applied systemically or topically or as a bath.

Phototherapy is beneficial for itch associated with:

  • Atopic dermatitis

  • Psoriasis

  • Chronic renal failure

Remissions may last for as long as 18 months. Recent reports have suggested that narrow band UVB may be as effective for treating pruritus as broad band UVB or PUVA.

Behavioral therapy

In recent years, it has become increasingly clear that stress and other psychogenic factors are important in itch. Several studies have shown that behavioral modification therapy reduces the intensity and perception of itch. Other possible behavioral interventions include stress reduction and biofeedback. These treatments are especially effective for treating chronic pruritus associated with psychogenic cofactors such as stress and depression.

Complementary medicine

Chronic patients with itch seek complementary medicine in a similar way that chronic pain patients do. Recent studies suggest that acupuncture has a role in itch reduction in atopic eczema.

Table II outlines some more information on itch associated with specific cutaneous and systemic conditions and their treatment. The level of evidence in many treatments is based on case series and non-controlled studies and reflects expert opinion. Level of evidence in parenthesis is marked as:

Table II.

Treatment recommendations for itch associated with specific conditions
Diagnosis Treatment recommendation Comment
Pruritus in atopic eczema
Emollients and moisturisers (B)
Colloidal oatmeal (B)
Polidocanol and topical salicylates
Topical corticosteroids (A)
Topical immunomodulators (A)
Whether itch in patients with atopic eczema precedes skin lesions or vice versa is an unresolved issue. What is certain is that a vicious itch-scratch cycle exists in atopic patients, in which scratch damage enhances pruritus.
Pruritus in moderate to severe atopic eczema
Oral sedating antihistamines (C)
Sodium bicarbonate and tar baths (C)
Phototherapy (A)
Pruritus in severe atopic eczema
Double layer wet pyjama++ (B)
Oral immunomodulators +++ (A)
Selective serotonin reuptake inhibitors(B)
Opiate antagonists (B)
Pruritus in psoriasis
Topical corticosteroids
Topical tar (A)
Salicylic acid
Phototherapy for severe itch (A)
Selective serotonin reuptake inhibitors may be indicated (C)
Biologics ; anti TNF (A)
Itch in patients with psoriasis is a significant but under-recognised problem. Several studies have demonstrated that itch is a principal symptom of psoriasis. Among patients with psoriasis, 77% experience pruritus daily.
Pruritus due to end stage renal disease
Phototherapy (B)
Low dose gabapentin after dialysis (A)
Nalfurafine ( kappa agonist) ( A)x
Butorphanol
X -Currently only approved in Japan
One of the most distressing symptoms of chronic renal failure. It affects 20-60% of patients with chronic renal disease, especially those on dialysis. Scratching is common and patients may be heavily excoriated or the skin may appear lichenified or present with prurigo nodules. It has a significant impact on sleep and quality of life.
Pruritus of cholestasis
Opioid antagonists including naloxone and naltrexone (A)
Kappa agonist butorphanol (C)
Combination of bile salt lowering and opioid antagonist strategies (B)
Highly distressing and persistent. Often begins with an acral distribution, but later becomes more generalised. Patients with cholestatic pruritus have elevated plasma opioid levels in addition to elevated bile acids.
Pruritus in haematological disease and lymphoreticular malignancy
Selective serotonin reuptake inhibitors (B) Itch is common in haematological disorders. In widespread cutaneous T cell lymphoma (CTCL) and erythrodermic forms of CTCL, including Sézary syndrome (T cell leukaemia), itch is often severe and difficult to manage. In polycythemia vera, it occurs in about 50% of patients, is often precipitated by contact with water ("bath itch"), and is associated with raised blood histamine levels.
Butorphanol (C)
Phototherapy (B)
Aprepitant (C)
Drug induced pruritus
Oral antihistamines and oral corticosteroids, if stopping the drug is not possible (C)
Pruritus can be a side effect of a wide variety of medications. These include: OpiatesOral aspirinAntibiotics such as penicillinAntimalarial drugs such as quinidine and chloroquine.
The plasma cell expander hydroxyethyl starch accumulates in skin cells including nerve fibres and causes intense itch. Drugs that can cause cholestasis can cause itch secondary to this.
Pruritus of endocrine disease
Hyperthyroid related itch: treatment of the underlying disease including beta blockers (C) Generalised intractable itching is a recognised feature of thyrotoxicosis and may be a presenting symptom. Hypothyroidism is less frequently associated with itch.
For dry skin in hypothyroidism, use emollients (C)
Pruritus in infectious disease
Treat the underlying infection
Causes include: Scabies and mitesViral infections such as rubella and varicellaTropical and intestinal parasites such as trichinosis, onchocerciasis, and schistosomiasis.
Bacterial infections are rarely associated with itch except for cutaneous staphylococcal infections such as: FolliculitisImpetigo.
Fungal skin infections causing itch include dermatophytic infections and candidal skin infections.
Pruritus in HIV infection
Eosinophilic folliculitis: a combination of permethrin 5% and topical mid potency corticosteroids (C)
For severe cases of HIV prurigo: thalidomide (C)
Itch is an early symptom of HIV infection. It may be associated with skin disease (scabies, pediculosis, xerosis). It can be a result of systemic causes (hepatic disease, renal disease, lymphoma, adverse drug reaction, systemic and skin infection including Staphylococcus aureus and pityrosporum) or it occurs as a primary symptom of HIV. Eosinophilic folliculitis is an intensely pruritic eruption characteristically occurring in people with a CD4 count less than 300/µl.
Pruritus as a manifestation of solid malignant tumours
Selective serotonin reuptake inhibitors (B)
Opiate antagonists and agonists and gabapentin Neurokinin 1 antagonists(B)
Significantly less common in solid tumours than in lymphoproliferative disease. Although pruritus may occasionally be present years before the tumour becomes detectable, full investigation for a causative solid tumour is probably not worthwhile.
Pruritus associated with pregnancy
Topical corticosteroids
Oral non-sedating antihistamines (B)
Pruritus associated with pregnancy can be caused by primary skin rash such as polymorphic eruption of pregnancy or intrahepatic cholestasis.
Postherpetic neuralgia
Gabapentin and pregabalin
Topical capsaicin
Topical anaesthetics (C)
(All controlled studies assessed pain as an end point but not itch)
Data suggest that pruritus commonly accompanies acute zoster and postherpetic neuralgia, particularly lesions affecting the head, face, and neck.
Psychogenic itch
Psychogenic itch: antipsychotics and psychological therapies, if accepted
Patients with depression, fibromyalgia, and other somatoform disorders: selective serotonin reuptake inhibitors, gabapentin, or pregabalin (C)
Delusions of parasitosis is one of the more challenging types of itch. The patient often brings "evidence" in the form of collected fragments, although on examination the material proves to be non-specific debris. The patient holds a false belief that they are infested with parasites. The patients often refuse to see a psychiatrist.
Patients with depression, fibromyalgia, and other somatoform disorders can have severe itch.
Pruritus associated with burns and scars Intralesional injections of corticosteroids (B) Burn scars are associated with significant pruritus. Keloids are frequently associated with itch at the periphery of the lesion.
  • A for double blind studies

  • B for clinical trials containing 20 or more patients

  • C for clinical studies with fewer than 20 patients, case series, and expert opinion.

Optimal Therapeutic Approach for this Disease

Many of the above-mentioned antipruritics are used “off-label” and are not FDA-approved for this indication. Furthermore, the varying pathogenesis for pruritus in different disorders means that a universally accepted therapy is difficult to establish. In fact, many times a patient with chronic pruritus may have more than one origin for their pruritus. Therefore the management of chronic pruritus can be extremely challenging and an individualistic approach needs to be taken.

First-line therapies for generalized pruritus include

  • Mirtazapine15mg taken orally at bedtime (older patients start with low-dose 7.5mg at bedtime). Do not use in children younger than 10 years old

  • Sedating antihistamines: Hydroxyzine 25 mg up to 100mg a day in divided doses

  • Pregabalin 75mg twice daily (can increase up to 150mg twice daily) or Neurontin 400mg three times a day up to 3200mg per day in divided doses.

Patient Management

Experience is the key when it comes to antipruritic therapy. However, in our opinion, there are clinical scenarios where certain therapies may be especially valuable. Nocturnal pruritus can be a particular problem in some patients. We frequently use mirtazapine in such patients with good effect.

In patients with intractable nocturnal itch, it is our experience that butorphanol may be particular valuable. The beneficial effects of these agents on pruritus may in part be explained by their sedative properties. Recommended dose: 1mg/ per nostril, increase gradually every 2-3 days, maximum dose 4mg/day

For neuropathic pruritus:

  • Topical capsaicin 0.075% recommend using with EMLA 30 minutes prior to reduce burning sensations for 3 weeks

  • Oral gabapentin up to 3200mg/day or oral pregabalin up to 300mg/day are often employed as first-line agents.. Common side effects are drowsiness. leg edema, and increase in appetite

Unusual Clinical Scenarios to Consider in Patient Management

Of note, one may use a combination of low-dose mirtzapine and pregabalin or gabapentin in patients with recalcitrant chronic pruritus. This combination therapy targets the hypersensitization of nerve fibers that occurs in chronic itch sufferers.

Anogenital pruritus could be severe and intractable. In some cases it could be associated with a sacral nerve entrapment. We have also found that topical calcineurin inhibitors to be particularly effective for anogenital pruritus as well as promoxine with and without topical steroids. Oral gabapentin and pregabalin could be helpful.

In patients who report pruritus to be ameliorated with cooling, menthol is often of value. Patients with severe itch who report to respond to hot showers as a mean of reducing their itch for hours could continue this practice cautiously. Psychiatric patients with depression who experience pruritus may find treatment with SNRIs or SSRIs especially beneficial.

Fibromyalgia could cause intractable itch with pain and responds to combination of neuroleptics and SNRI`s.

Cholestatic itch: in our experience a combination of both bile salt–lowering and opioid antagonist strategies appear reasonable in the management of pruritus of cholestasis.

Holistic and psychologic therapies to reduce stress and itch intensity using methods of deep muscle relaxation, healing touch, acupuncture and biofeedback are highly recommended for patients with chronic intractable itch similar to the use of these methods in chronic pain.

What is the Evidence?

Yosipovitch, G, Bernhard, JD. "Clinical practice. Chronic pruritus". N Engl J Med. vol. 368. 2013 Apr 25. pp. 1625-34.

(A comprehensive review of pathophysiology, clinical presentation and management of chronic itch).

Stull, C, Lavery, MJ, Yosipovitch, G. "Advances in therapeutic strategies for the treatment of pruritus". Expert Opin Pharmacother. 2015 Dec 23. pp. 1-17.

(A comprehensive review of therapies for chronic itch.)

Metz, M, Ständer, S. "Chronic pruritus - pathogenesis, clinical aspects and treatment". J Eur Acad Dermatol Venereol 2010 Sep 15.

(A CME review on chronic itch with a treatment approach suggested by leading European experts in the field of itch.)

Ständer, S, Weisshaar, E, Mettang, T. " Clinical classification of itch, a position paper of the International Forum for the Study of Itch". Acta Derm Venereol. vol. 87. 2007. pp. 291-4.

(Practical definitions of chronic itch for the clinician.)

Tey, HL, Wallengren, J, Yosipovitch, G. "Psychosomatic factors in pruritus". Clin Dermatol. vol. 1. 2013. pp. 31-40.

(Comprehensive review of different forms of psychogenic itch and their management.)

Schut, C, Mollanazar, NK, Kupfer, J, Gieler, U, Yosipovitch, G. "Psychological interventions in the treatment of chronic itch". Acta Derm Venereol. vol. 96. 2016 1. pp. 157-61.

(Comprehensive review of psychological management of chronic itch)
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