Agent
Indications
Major adverse effects
Coolants: menthol, camphor, phenol
Most pruritic conditions
Skin irritation
Capsaicin 0.025–0.1 %
• Neuropathic itch
• Prurigo nodularis
• Aquagenic pruritus
• Uremic pruritus
Initial burning sensation
Anaesthetics
Neuropathic itch
Numbness
Calcineurin inhibitors
Eczema (various types) and anogenital pruritus
Transient burning sensation
N-palmitoylethanolamine
Atopic dermatitis, dry skin
Skin irritation
Doxepin
• Atopic dermatitis
• Localised pruritus
• Drowsiness in 25 % of patients
• Allergic contact dermatitis
Aspirin and salicylates
Lichen simplex chronicus
Transient burning sensation
2.1 Emollients
Emollients, moisturisers and barrier repair creams are important antipruritics which soften the outermost layer of dry skin (stratum corneum) and improve skin barrier function. This is often impaired in inflammatory skin diseases and can be exacerbated by repetitive scratching, facilitating the entry of irritants, allergens and infectious pathogens that can precipitate itch (Elmariah and Lerner 2011). Transepidermal water loss (TEWL) can reflect impaired epidermal barrier function, leading to greater itch intensity, especially in patients with atopic dermatitis and at night, when TEWL is increased (Patel and Yosipovitch 2010). The choice of emollient should be based on the nature of the underlying condition, its severity and patient preference. Emollients are best applied after a bath or shower. They may contain preservative or other additives and can occasionally cause sensitisation.
Patients should avoid alkaline soaps, which increase the secretion of serine proteases, such as mast cell tryptase (an endogenous PAR2 agonist), that play an important role in mediating pruritus, via activation of protease-activating receptor 2. Such soaps should be avoided in favour of moisturisers and cleansers with a low pH, which are useful in improving skin barrier function by maintaining the natural acidic pH of the skin surface. If secondary infection is present, then it should be treated.
2.2 Oatmeal Moisturisers
Colloidal oatmeal has been used for centuries as a soothing agent to relieve itch and irritation associated with eczema and various dry skin dermatoses. Avenanthramides are phenolic compounds present in oats at approximately 300 parts per million (ppm). Avenanthramides showed a significant inhibition of tumour necrosis factor-alpha (TNF-alpha) and reduction of interleukin-8 (IL-8) release. Additionally, topical application of 1–3 ppm avenanthramides countered neurogenic inflammation and reduced pruritogen-induced scratching in a murine itch model (Sur et al. 2008).
2.3 Menthol
Menthol and aqueous cream combinations can be applied for short-term reduction of itch. Menthol (a naturally occurring terpene alcohol, C10H20O) has been used in dermatology for its cooling, antipruritic, analgesic and antiseptic properties. The cooling sensation appears to reduce itch and is effective in low concentrations (1–5 %) as higher concentrations can cause irritation (Yosipovitch and Bernhard 2013).
Itch is known to be aggravated by warmth and reduced by cooling the skin. Menthol induces a subjective feeling of cold lasting up to 70 min and thereby can reduce the sensation of itch. This may be via the transient receptor channels (TRP), which are a family of sensory receptors activated by both chemical and physical factors. TRPA1 and TRPM8, expressed in the subpopulation of C-fibres, with possible downstream release of substance P, appear to be highly sensitive menthol receptors and may play a part in the pathogenesis of itch. Of note, there is a subset of patients where menthol actually aggravates itch, and studies in primates suggest that A delta fibres that transmit cold may have some role in itch (Ringkamp et al. 2011).
Camphor activates the TRPV3 channel and has been used for centuries as an antipruritic. Although there is little literature on its effects and its antipruritic efficacy has not been evaluated in double-blind studies, it is used in conjunction with other topical and systemic therapies (Weisshaar et al. 2012).
2.4 Calamine
Calamine contains zinc oxide, ferric oxide and phenol. Its antipruritic effect is attributed to phenol with its cooling and mild local anaesthetic action. It is used to temporarily relieve itch in poison ivy and dermatitis.
2.5 Topical Anaesthetics
Topical local anaesthetic preparations include pramoxine 1 % and mixtures of lidocaine 2.5–5 % and prilocaine 2.5 % cream. They can treat itch due to neuropathic causes and facial or anogenital itch. Although the data is insufficient, there has been a report of pramoxine 1 % cream being useful in treating the itch of chronic kidney disease (Young et al. 2009). More data on the safety of long-term use over a large area of skin is required. Polidocanol has both local anaesthetic and moisturising properties. Polidocanol 3 % combined with urea 5 % reduced pruritus in patients in a number of skin diseases (Freitag and Hoppner 1997). Short-term application of topical local anaesthetics can be recommended with low risk of sensitisation in some situations (Weisshaar et al. 2012).
2.6 Capsaicin
Topical capsaicin is derived from chilli peppers and is an exogenous vanilloid used as a pain-relieving medication (Szolcsányi 2004). It exerts its antipruritic effect via TRPV1, which has been associated with the pathogenesis of itch (Imamachi et al. 2009). Unmyelinated peripheral C-nerve fibres at the site of itch can be desensitised by depletion of substance P (Jessell et al. 1978). Localised itch disorders, particularly those of neuropathic origin, such as notalgia paresthetica, brachioradial pruritus and postherpetic neuralgia, can be treated with capsaicin. It has also been used for psoriatic itch and uremic and aquagenic pruritus (Papoiu and Yosipovitch 2010; Tey and Yosipovitch 2011; Yosipovitch and Bernhard 2013). Concentrations of capsaicin ranging from 0.025 % up to 0.1 % are available as OTC and are commonly used.
The main adverse effect is an initial burning sensation which usually lasts several days. This may lessen compliance. Patients can be advised to apply a topical anaesthetic, such as lidocaine or eutectic mixture of local anaesthetic (EMLA), before application of capsaicin in the first 2 weeks of treatment in order to reduce the discomfort. The topical anaesthetic, in addition, serves as an antipruritic treatment in itself. Pretreatment with a topical anaesthetic gives effective reduction of burning sensation and attenuates heat hyperalgesia during capsaicin treatment.
A new, high-potency transdermal formulation containing capsaicin at 8 % has recently been approved in Europe and the USA. For the treatment of postherpetic neuralgia, a single 30- or 60-min application may provide up to 3 months of localised pain relief with minimal adverse effects. Although it is not indicated for neuropathic itch, this formulation has been reported to be effective in case series for neuropathic itch (Papoiu and Yosipovitch 2010; Metz et al. 2011).
2.7 Topical Glucocorticoids
Topical glucocorticoids are frequently used to treat patients with itch. They have an anti-inflammatory effect, rather than acting as a direct antipruritic, and range in potency. Inflammatory skin conditions have been effectively treated with both high- and moderate-potency preparations in randomised controlled trials. Hydrocortisone (2.5 %) has been shown to be significantly more effective than placebo in the reduction of itch that was induced experimentally (Zhai et al. 2000a). Clinical experience has shown that secondary manifestations of chronic itch (e.g. prurigo nodularis, lichen simplex chronicus) can be treated successfully with potent glucocorticoids (Weisshaar et al. 2012; Yosipovitch and Bernhard 2013).
The precise antipruritic mechanism of topical corticosteroids is not known. It is suggested that glucocorticoid receptors are activated, which in turn inhibit the action of cytokines and reduce the local inflammation; therefore, itch is controlled indirectly (Elmariah and Lerner 2011). Patients with noninflammatory itch usually do not benefit from topical corticosteroids.
The use of topical steroids in cases of generalised cutaneous disease, in the absence of a primary rash or in prolonged daily treatment should be limited to short periods and avoided long term (Weisshaar et al. 2012). Local adverse effects may include atrophy, striae, pigment alteration, acne, petechiae and telangiectasia, as well as potential systemic absorption, with hypothalamus-pituitary axis suppression. There may be a reduction in response after the administration of several doses of topical steroids (tachyphylaxis), which has been shown in experimental settings for itching disorders, including atopic dermatitis and psoriasis (Elmariah and Lerner 2011).
2.8 Topical Calcineurin Inhibitors
Tacrolimus and pimecrolimus are topical calcineurin inhibitors (TCIs) that have been shown to reduce itch in inflammatory skin conditions such as eczema (Kaufmann et al. 2006). Studies have also shown that TCIs can be successful in treating graft-versus-host disease, lichen planus, lichen sclerosis and prurigo nodularis (Ständer et al. 2006b). The mechanism of action of these agents in reducing itch is unclear and possibly multifactorial. TCIs regulate T-cell activation and inhibit the release of inflammatory cytokines. However, rather than acting solely through anti-inflammatory properties, these agents may also have an antipruritic effect that is mediated by the activation and subsequent desensitisation of TRPV1, located on unmyelinated peripheral C-nerve fibres. The efficacy of TCIs has been demonstrated in randomised trials, improving itch within 48 h of the first application and maintaining antipruritic effects throughout their continued use (Kaufmann et al. 2006).
Topical calcineurin inhibitors can cause an initial burning sensation, which may be due to activation of TRPV1. This may serve as a biomarker for antipruritic effect in those patients. The burning sensation generally reduces after repeated application over several days. TCIs do not cause skin atrophy with prolonged use and are therefore suitable for treating facial, genital and intertriginous areas of the skin. Patients with atopic dermatitis have been shown to have no significant risk of systemic immunosuppression or increase in the rate of serious infections (McCollum et al. 2010). In 2006, the FDA issued a black box warning of risk of lymphoma in paediatric or adult atopic populations using TCIs. This risk seems extremely rare (Siegfried et al. 2013). Long-term safety studies are required to investigate the risk of lymphomas (Elmariah and Lerner 2011).
2.9 Topical Antihistamines
Topical antihistamines are frequently used to treat itch; however, their value as a therapy for itching conditions is limited. Studies on topical antihistamines have been generally inconsistent and of inadequate design (Eschler and Klein 2010). Doxepin is an oral tricyclic antidepressant, which has also been manufactured as a topical 5 % cream and has been used successfully in patients with atopic dermatitis. It has anti-H1 and anti-H2 properties and is also thought to have some antimuscarinic effects (Drake et al. 1994). Doxepin is beneficial in patients with lichen simplex chronicus, nummular dermatitis and contact dermatitis (Patel and Yosipovitch 2010) but is ineffective in other conditions that cause itching (Yosipovitch and Bernhard 2013).
Adverse effects of topical doxepin, especially when applied to large areas, can include drowsiness caused by absorption through the skin, localised burning and allergic contact dermatitis. It is usually avoided in children and the elderly. Due to an increased risk of contact allergy, especially when the treatment exceeds 8 days, topical doxepin is not recommended by the latest chronic pruritus guidelines (Weisshaar et al. 2012).
2.10 Topical Cannabinoids
The efficacy of cannabinoids in pruritus has been demonstrated in a few studies. In a large industry-sponsored open-label trial in more than 3,000 patients, a cream containing N-palmitoylethanolamine (PEA) significantly reduced pruritus and improved disease severity in AD. PEA exhibits little affinity for cannabinoid receptors but may act by enhancing the effect of anandamide, an endocannabinoid, through inhibition of the enzyme fatty acid amide hydrolase (FAAH). Topical cannabinoids have been reported anecdotally to be effective for lichen chronicus, prurigo nodularis and uremic pruritus, with few to no side effects (Ständer et al. 2006a).
2.11 Topical Prostanoid Inhibitors
2.12 Miscellaneous Ion Channel Blockers
Topical strontium gel, a calcimimetic that blocks ion channels in nerves, has been shown in a double-blind study to inhibit itch induced by cowhage and histamine and has been used against different types of chronic itch (Zhai et al. 2000b; Papoiu et al. 2013).
3 Systemic Treatments
3.1 Systemic Antihistamines
Systemic antihistamines are the most frequently used drugs to relieve the symptoms of chronic itch due to dermatological and non-dermatological causes. First-generation antihistamines (chlorpheniramine, diphenhydramine, hydroxyzine and promethazine) are known to bind to H1 receptors as well as muscarinic, alpha-adrenergic, dopamine and serotonin receptors, which lead to a central sedative effect. They are therefore most useful at night for reducing itch and the itch-scratch cycle in a number of dermatoses, especially eczema and urticaria. Second-generation antihistamines (cetirizine, levocetirizine, desloratadine, ebastine, fexofenadine and loratadine) have little activity on non-histamine receptors—so are less sedative—and have longer durations of action (Weisshaar et al. 2012). Non-sedating H1-receptor antagonists are effective in the treatment of urticaria (Zuberbier et al. 2014; Maurer et al. 2013). However, histamine is not usually a major factor in conditions other than urticaria or mastocytosis, and so, while antihistamines such as loratadine, desloratadine, cetirizine and levocetirizine have commonly been used for daytime relief, the non-sedating H1-receptor and H2-receptor antagonists generally have limited use in treating itch (O’Donaghue and Tharp 2005). When choosing an antihistamine the disease, age and likelihood of other medical conditions or drug interactions should be considered. There is therefore not a single preferred antihistamine for the management of itch. Certain antihistamines (e.g. loratadine) are thought to be safer during pregnancy and lactation and in young children (Zuberbier et al. 2014; Lawlor 2014) (Table 2).
Table 2
Current systemic therapies for pruritus
Medication class | Medication and dosages | Main indication | Major side effect |
|---|---|---|---|
Antihistamine | 1st generation: usually only given at night due to their sedative effect Hydroxyzine Adults: 30–100 mg/day in 3 divided doses Children 30 months–15 years: 1 mg/kg/day in divided doses Diphenhydramine Adults: 25–50 mg bd Children > 2 years old: 1–2 mg/kg 6–8H Chlorpheniramine maleate Adults: 4 mg 6–8H Children: 0.1 mg/kg 6–8H | Nocturnal itch | Sedation |
2nd generation | |||
Loratadine Adults and children ≥12 years: 10 mg qd Children 2–12 years: >30 kg:10 mg qd; ≤30 kg:5 mg qd | Urticaria Mastocytosis Insect bite reactions | Infrequent Drowsiness Dry mouth | |
Cetirizine Adults and children ≥ 6 years: 10 mg qd or 5 mg bd Children 2–5 years: 2.5 mg bd or 5 mg qd Renal or hepatic insufficiency: reduce dosages by half | |||
Fexofenadine Adults and children ≥12 years: 60 mg bd or 180 mg qd Children 6–11 years: 30 mg bd Renal impairment: consider lower dose of 60 mg qd | |||
Anticonvulsants | Gabapentin 300–3,600 mg/day in 3 divided doses Reduced dose in renal impairment In dialysis patients, 100–300 mg after each dialysis | Neuropathic itch Uremic pruritus Prurigo nodularis Postburn pruritus | Drowsiness Leg swelling Blurred vision Constipation Ataxia |
Pregabalin 150–450 mg/day in 2–3 divided doses Dose reduction in renal impairment | |||
Mu-opioid receptor antagonists | Naltrexone 25–50 mg om | Pruritus associated with Cholestasis Atopic dermatitis Chronic urticaria | Nausea and vomiting Insomnia Reversal of opioid analgesia Hepatotoxicity rarely |
Kappa-opioid receptor agonists | Butorphanol 1–4 mg intranasally on | Butorphanol Drowsiness Nausea and vomiting | |
Nalfurafine 2.5–5 μg om | Uremic pruritus (nalfurafine) | Nalfurafine Insomnia | |
Antidepressants | Mirtazapine 7.5–15 mg on initially, up to 45 mg on | Malignancy-associated pruritus Nocturnal pruritus in atopic dermatitis | Mirtazapine Drowsiness Weight gain |
SSRIs Paroxetine 10–40 mg qd Sertraline 75–100 mg qd Fluvoxamine 25 mg for 3 days, then 50–150 mg qd | Consider in pruritus associated with depression and/or anxiety Pruritus associated with haematological malignancies and solid tumours (paroxetine) Cholestatic pruritus (sertraline) | SSRIs Drowsiness Insomnia Sexual dysfunction | |
Tricyclic antidepressants Doxepin 10–100 mg on Amitriptyline 25–75 mg on | Chronic idiopathic urticaria (doxepin) Neuropathic itch (amitriptyline) | Anticholinergic effects Drowsiness Dry eyes and mouth Blurred vision Urinary retention Cardiovascular effects Orthostatic hypotension Conduction disturbances | |
Thalidomide | 100–200 mg qd | Prurigo nodularis Uremic pruritus Actinic prurigo | Teratogenicity Peripheral neuropathy Drowsiness
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