Itch and Pain Treatments

Topical corticosteroids

Topical corticosteroids (TCS) are the first-line pharmacologic treatment for AD, often introduced for maintenance therapy and use in the treatment of acute flares ( ). While TCS do not have a direct antipruritic effect, multiple studies have shown that routine use reduces AD symptoms, including itch and pain due to their antiinflammatory properties and reduction in itch-related cytokines such as IL31 ( ). TCS are available in various potencies that range from very low (class VII; e.g., hydrocortisone 0.25%) to very high (class I; e.g., clobetasol 0.05%). In general, the lowest potency to achieve control of disease for that patient should be used so to minimize adverse effects. Some evidence shows that moderate-to-high potency TCS offer a greater antipruritic effect than low potency ( ). Side effects of TCS on the skin are dependent on the potency, frequency, and location of application of the agent and include atrophic changes of the skin, telangiectasias, striae, and easy bruising ( ). Skin atrophy is more likely to occur in older patients and with use of higher potency TCS in areas of the body where the skin is thin (e.g., face, neck, intertriginous areas) or with occlusive therapies. Systemic side effects such as suppression of the hypothalamic pituitary axis are possible when using high-potency dosages or with extensive body surface usage.

Topical calcineurin inhibitors

Topical calcineurin inhibitors (TCIs) are a more recently introduced class of nonsteroid antiinflammatory treatments for AD. The antipruritic effectiveness of TCIs may be due in part to their stimulatory effect of the transient receptor potential ion channel member 1 (TRPV1) in cutaneous nerves ( ). These topicals (e.g., tacrolimus 0.03% or 0.1%, pimecrolimus 1%) have been shown to reduce pruritus scores in AD and may be as effective as midpotency TCs ( ). In a randomized trial, pruritus scores with pimecrolimus 1% were significantly improved by 56% versus only 34% with vehicle alone, and benefit was noted within 48 hours of treatment ( ). Similar reduction of pruritus scores and maintenance of the antipruritic effect was also demonstrated in a 26-week study ( ). Because these agents are nonsteroidal they are preferred for areas prone to steroid-induced atrophy (i.e., face). TCIs have the notable adverse effect of burning of the skin upon application, but this effect typically diminishes after several days of use ( ). The US Food and Drug Administration (FDA) placed a black box warning on TCIs, based on animal studies and case reports showing an increased incidence of malignancy, particularly lymphoma and skin cancers, in patients with AD using this medication ( ) but recent meta-analyses have not confirmed this association ( ).

Topical phosphodiesterase-4 inhibitors

Crisaborole is a phosphodiesterase-4 (PDE4) inhibitor that reduces the release of proinflammatory cytokines ( ). This nonsteroidal topical is used for the treatment of mild to moderate AD and has shown effectiveness in phase 3 studies in reducing itch in AD ( ). In a post hoc analysis of randomized controlled trials (RCTs), crisaborole has been demonstrated to have a rapid effect on pruritus score reduction, evident within 2 to 6 days of use ( ). Reduction of pruritus while using this topical medication has been shown to lead to significant improvements in quality of life scores among patients ( ). Crisaborole is generally well tolerated with use in thin or sensitive skin areas for which TCS are not appropriate ( ). The drug has a favorable safety profile and is generally well tolerated with adverse effects such as application site burning reported infrequently.

Topical anesthetics, analgesics, and cooling agents

Topical anesthetics, analgesics, and cooling agents work by activating the nociceptors, thermoreceptors, or otherwise modulating cutaneous neural pathways. Capsaicin’s antipruritic properties are due to activation of the transient receptor potential 1 (TRPV1) receptors in keratinocytes and nociceptive C-nerve fibers. Application of topical capsaicin (0.025%–0.1% or 8% patch) has been shown to be effective in pain and itch relief of various etiologies ( ). Of note, topical capsaicin has an initial burning effect that can be avoided with pretreatment with topical anesthetics (i.e., lidocaine or EMLA). The topical anesthetic pramoxine 1% is available in formulations with ceramide moisturizers and has been shown to have antipruritic properties and provide relief in patients with AD-related itch ( ). Menthol activates thermosensitive TRPM8 ion channels present on sensory nerves to induce a cooling effect on the skin. As an antipruritic in 1% concentration, menthol is particularly useful for patients with AD who report that cooling of the skin (e.g., cold showers) improves their pruritic symptoms ( ). Menthol also has analgesic properties at low concentrations (e.g., ≤1%) but may cause irritation and cold-induced pain at higher concentrations. Polidocanol 3% concentration is another topical anesthetic with antipruritic efficacy demonstrated in a large observational study with few adverse effects noted ( ).

Topical ketamine blocks N -methyl- d -aspartate receptors (NMDA) and sodium channels to reduce the sensitivity of peripheral nerves. A combination cream of ketamine 5% to 10%, amitriptyline 5%, and lidocaine 5% (KAL) has been used in the treatment of chronic pruritus, and in one study, including patients with AD, pruritus scores were significantly improved with relief achieved within a few minutes on average ( ). KAL has been reported to be well tolerated in limited clinical studies, with burning sensation and redness reported in a minority of patients ( ). Ketamine is a controlled substance with potential for psychoactive effects if ingested, and therefore patients should be advised to not ingest the product and to limit use to prescribed areas only (<20% body surface area).

Topical cannabinoids

Endocannabinoids such as N-palmitoylethanolamine (PEA), an agonist of the cannabinoid 2 receptor, have been demonstrated to have antiinflammatory and antipruritic properties ( ). An open-label, noncontrolled, prospective cohort study in a group of nearly 2500 subjects with AD demonstrated that a cream containing PEA decreased pruritic symptoms by 47% within 6 days and by 60% after 4 to 6 weeks, improved sleep quality reported by patients, and was well tolerated ( ).

Wet wrap treatment

Wet wrap treatment (WWT) consists of a topical agent (i.e., TCS) applied to the skin and then covering the area with a wetted layer of bandages or nonirritant fabric (i.e., cotton) followed by an overlying layer of dry fabric. WWT may be left on for several hours and is typically continued for several days up to 2 weeks. WWT is often recommended for severe flares or recalcitrant disease to attain a relatively rapid reduction in symptoms, including itch. This method reduces itch through various mechanisms, including cooling of the skin, improving penetration of topical medications, and providing a physical barrier to prevent excoriation. The presence of a physical barrier may also prevent stimulation of cutaneous nerve fibers that are in close proximity to the damaged skin barrier ( ). WWT has been shown to be efficacious in reducing objective and subjective AD symptoms, including pruritus, as well as improvement in quality of life measures ( ). Because of the enhanced effect of the topical agents being applied it is recommended that low to medium potency corticosteroids be used or they be diluted to 5% to 10% of their original strength ( ).