Itch and pain are key symptoms of atopic dermatitis (AD) that significantly affect quality of life; various classes of treatment aim to reduce these symptoms.
Nonpharmacologic and topical therapies are effective for mild or moderate itch or pain symptoms and for maintenance therapy of AD.
Systemic therapies that target the immune system are effective as antipruritics, but many have side effects that limit their use.
Newer biologic and small-molecule therapies have been developed to target itch-mediated signaling pathways and have shown exciting results in AD patients.
Several experimental therapies are on the horizon that target nonhistaminergic itch pathways and show promise in clinical trials.
Pruritus, or itch, is the predominant feature of atopic dermatitis (AD) and it is an essential diagnostic feature of the disease ( ). The underlying mechanism of AD and the itch that it causes is multifactorial due to a complex interplay of genetic, environmental, and immunologic factors. A key aspect of AD pathogenesis and target of many first-line interventions is dysfunction of the physical epidermal barrier that contributes to transepidermal water loss (TEWL). TEWL has been shown to be associated with itch intensity in AD patients ( ). Barrier disruption allows for entry of irritants, allergens, and pruritogens from the external environment, leading to immune activation and inflammation, and pruritus. Defects in the barrier also lead to alkalization of the skin pH, promoting protease activation and upregulation of pruritogenic receptors and proinflammatory neuropeptides. The type 2 immunologic response, also key to pathogenesis of this disease, is mediated by cytokines such as interleulin-4 (IL4) and IL13, which are targets of newer AD medications. Other key immune mediators in AD are IL2, IL31, and IL33. Itch in AD is known to be nonhistaminergic in nature and not responsive to antihistamine medications. Emerging evidence shows that hypersensitivity of the neural pathways that conduct nonhistaminergic itch sensation in the peripheral and central nervous system may play a role in pathogenesis of this and other chronic pruritic diseases ( ).
Itch experienced in AD may vary from patient to patient, but surveys have shown that people with AD tend to experience itch more frequently at night, have high pleasurability with scratching, and have itch accompanied by a sensation of heat ( ). Aggravating factors commonly reported by AD patients include stress, perspiration, and skin dryness ( ). Skin pain is often reported in patients with AD, and while this is at least partially explained by scratching or excoriated lesions, a subset of AD patients experience painlike itch independent of scratching that is similar to neuropathic pain ( ). Pain is most often described by patients as burning, stinging, soreness, or tightness of the skin and is most likely to accompany lesions on the hands, feet, and around the mouth. AD-related pain has similar triggers to those associated with itch (i.e., sweat, stress, and warm temperatures) ( ). Skin pain is not often directly measured as part of standardized AD disease scores but has been shown to strongly correlate with measures of AD severity and symptoms (e.g., Patient Oriented Eczema Measure [POEM] and Eczema Area and Severity Index [EASI]) as well as poorer sleep and increased itch on numeric rating scales ( ). Quality of life is reported by patients to be greatly affected by their symptoms, as is seen in chronic itch of various etiologies ( ). The neurosensory mechanisms underlying pruritus in general and involving AD in particular are discussed in greater detail in Chapter 16 .
The goal of therapy in AD is to significantly reduce or eliminate the patient’s symptoms, namely pruritus and pain, while also reducing the burden of skin lesions and preventing infection. Itch is not only a bothersome symptom but also leads to scratching, which promotes further inflammation of the skin, excoriations, and the potential for infection and chronic skin changes. This itch-scratch cycle must be interrupted to prevent these complications. Numerous treatment methods have been proposed for reducing symptoms of itch and pain in AD, ranging from at-home skin care techniques to systemic medications to integrative medicine approaches. This chapter aims to review those techniques that have demonstrated efficacy in reducing the burden of these symptoms.
Nonpharmacologic therapies: Moisturization and bathing practices reducing itch
The goal of moisturization is to improve the epidermal barrier, so to limit TEWL and prevent exposure to irritants and allergens causing itch. Moisturizing agents are readily available over the counter (OTC) and are integral to the daily therapy of AD and can be used as an adjuvant to topical or systemic treatments. While moisturization has been shown to effectively reduce xerotic and pruritic symptoms of AD, systematic review has not shown a specific topical moisturizer to be most effective in AD ( ). Considering there are minimal adverse effects to moisturizer application, patients are recommended to reapply frequently and in liberal amounts. Additional moisturization and skin barrier repair recommendations are discussed in Chapter 22 .
There is limited evidence informing the recommended frequency or duration of bathing for individuals with AD, but many practitioners recommend warm water bathing up to once daily for no longer than 10 minutes. Bar soaps used while bathing are often alkaline in pH (~pH 10), which can lead to increased activity of proteases in the epidermis and subsequent degradation of the barrier function and activation of itch receptors ( ; ). To reduce the potential for exacerbation of pruritus, nonsoap cleansers (synthetic detergents or syndets) with a neutral or low pH (~pH 5–7) are recommended. Additional bathing recommendations are discussed in Chapter 26 .
Oatmeal-based products derived from the plant Avena sativa have been used for many years as an additive to bathing products and moisturizers. Colloid oatmeal agents have been shown to help with restoring normal skin pH, improve barrier integrity, reduce itch, and act as an antioxidant and antiinflammatory ( ). Formulations used as moisturizers or bathing products have been shown to improve AD-related symptoms, including pruritus, with regular use and are generally well tolerated ( ). Additional complementary and alternative modalities are discussed in Chapter 26 .
Topical pharmacologic treatments
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).
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 ( ).
Cyclosporine A, an immunosuppressant targeting T cells and IL2, has the strongest body of evidence among the systemic immunosuppressants as a first-line systemic agent for short-term use in moderate to severe AD ( ). In RCTs, cyclosporine has demonstrated significant reduction in pruritus and improvement of quality of life measures among those with AD ( ). The use of cyclosporine in AD is limited by its numerous potential adverse effects, including opportunistic infection secondary to immunosuppression, nephrotoxicity, hypertension, and increased risk of certain malignancies ( ). In addition to these effects, rapid discontinuation of cyclosporine may cause a rebound flare of AD symptoms. This effect can be mitigated by tapering and coadministration of other systemic agents ( ).
Azathioprine is a purine analog that interferes with DNA production and therefore B- and T-cell proliferation that has been shown to be efficacious in AD and is used off-label for treatment of refractory disease ( ). In RCTs, azathioprine has demonstrated significant antipruritic effects and quality of life improvements in AD patients in comparison to placebo ( ). In a comparison trial with methotrexate, comparable reductions in pruritus measures and quality of life improvement were achieved with each treatment ( ). Azathioprine has apparent antipruritic effects aside from its use in AD, as it has been shown to be effective in patients with itch of unknown etiology ( ). Its adverse effect profile includes the potential for lymphocytopenia, for which laboratory monitoring may be considered, as well as a hypersensitivity reaction that occurs in a subset of patients within the first few weeks of treatment ( ). Of particular concern is the apparent increased risk of nonmelanoma skin cancer, associated with increased dosage, duration of use, and sun exposure ( ). Reduced activity of the thiopurine methyltransferase (TPMT) due to genetic polymorphisms is common in the general population and affects the toxicity of azathioprine. Thus baseline TPMT levels should be obtained prior to initiating therapy, with dosage adjustments accordingly.
Methotrexate is an oral medication that inhibits dihydrofolate reductase, inhibiting the synthesis of purines and limiting T-cell proliferation. The off-label use of methotrexate in AD is typically limited to refractory AD, and it has been shown to be effective in improving AD symptoms, including itch ( ). In a comparison trial with azathioprine, similar efficacy in reducing pruritus was noted between the two agents ( ). Low-dose methotrexate (up to 15 mg weekly) can be effective for itch caused by inflammatory skin diseases ( ). Adverse effects of methotrexate are well described as nausea and gastrointestinal upset. Although they are uncommonly seen at low doses, hepatoxicity and bone marrow suppression are concerns with use of this medication, and laboratory monitoring may be considered. Because of its antifolate mechanism of action, concurrent folate supplementation (skipping folate on the day of methotrexate intake) is recommended to reduce the potential for hematologic effects.
Mycophenolate mofetil is an immunosuppressant that inhibits B- and T-cell proliferation by blocking de novo purine synthesis. Multiple studies have demonstrated its efficacy in reducing AD symptoms, including pruritus, and it is considered an alternative systemic therapy for refractory AD ( ). A single-blinded RCT showed mycophenolate mofetil may be as effective as cyclosporine for AD maintenance therapy and showed comparable antipruritic effect, but it requires a longer treatment time to show benefit ( ). Gastrointestinal complaints are common with use of this medication, which can be mitigated by use of the enteric-coated formulation. Also hematologic adverse effects are a concern, warranting laboratory monitoring for cytopenia ( ).
Dupilumab is a monoclonal antibody targeting the receptor for IL4 that blocks Th2-mediated inflammatory signaling, and has demonstrated in large RCTs to be an effective treatment for moderate to severe AD ( ). Significant improvement in pruritus scores was seen within 2 weeks of initiating therapy in these trials along with improvements in quality of life and sleep ( ). A longer term study showed significant improvements in pruritus scores maintained through 52 weeks with a significant reduction in peak pruritus rating of up to 56.2% versus 28.6% for placebo ( ). Adverse effects known to be associated with dupilumab include conjunctivitis and injection site reactions. Considering its dramatic effects on AD symptoms and favorable safety profile, dupilumab may be considered for first-line treatment of severe AD or AD-related pruritus.
Additional biologic therapies that target the AD inflammatory signaling pathways show promise with respect to their antipruritic effects in early phase RCTs. Nemolizumab is an IL31 inhibitor that has demonstrated antiitch efficacy in phase 2 trials for patients with moderate to severe AD ( ). IL13 is a cytokine produced by Th2 lymphocytes, which can induce IgE production. Similar to IL4, IL13 is an important player in AD pathogenesis, and IL13 mRNA expression is elevated in patients with AD and increases with disease severity ( ). Lebrikizumab is a monoclonal antibody against IL13 that was tested in a phase 2 trial in AD patients and was used in combination with topical corticosteroid therapy. It showed significant improvement in EASI scores, along with a reduction in pruritus scores, and improvements in sleep loss ( ). IL17, an inflammatory cytokine produced by Th17 cells, is elevated in AD patients (particularly in Asian patients) ( ). Secukinumab, a monoclonal antibody directed against IL17A, is currently approved for plaque psoriasis, and a place 2 trial for adults with moderate to severe AD is currently in its recruitment phase ( ).
The Janus kinase (JAK) inhibitors are small-molecule agents that target the JAK-STAT pathway activated by cytokine signaling. Tofacitinib has FDA approval for use in rheumatologic conditions and has demonstrated antipruritic effects in case series of patients with AD ( ). Other agents—baricitinib, abroctinib, and upadacitinib—show promise for rapid antipruritic effects in AD in phase 2 and 3 trials ( ). Emerging immunomodulators and targeted treatments are further discussed in Chapter 23 .
Phototherapy (ultraviolet A [UVA] and UVB) has long been used for treating inflammatory skin conditions such as AD and psoriasis. It has a local immunosuppressive effect by targeting activated T cells ( ). Low reactive level laser therapy was also shown to reduce itch sensation in AD patients ( ). However, compliance and feasibility of obtaining regular phototherapy is a challenge for patients and physicians.
Interventions to reduce stress and anxiety can be beneficial in patients with chronic itch, who suffer from significant emotional and psychological distress. Habit reversal training, relaxation training, and cognitive behavioral therapy can be offered to patients in addition to medical therapy if they are open-minded to alternative therapies ( ). In patients with AD, psychological interventions can reduce disease severity, itch intensity, and scratching behavior ( ). Acupuncture, as well as progressive muscle relaxation techniques, can significantly reduce pruritus in patients with AD ( ). Complementary and alternative modalities are further discussed in Chapter 26, Chapter 27 .
Drugs targeting neural sensitization
Neural hypersensitization plays an important role in chronic pruritus and in AD-related itch, and it may be reduced by certain treatments ( ). Gabapentinoid anticonvulsant medications such as gabapentin and pregabalin can be used to manage pruritus as well as chronic pain. Although not yet tested in studies for AD, this class of medications has been shown to be effective in treating different types of itch and to reduce neural sensitization ( ). Weight gain, drowsiness, and lower extremity edema are side effects ( ).
Kappa agonists and mu antagonists
Butorphanol is a mixed κ-opioid receptor agonist and μ-opioid receptor antagonist that reduces itch sensation transmission in the central nervous system ( ). It is administered intranasally and has been shown to be effective in patients with intractable pruritus of different types, including inflammatory skin conditions such as atopic eczema ( ). μ-Antagonists such as naltrexone have also been reported to reduce the itch of AD ( ).
Mirtazapine, a serotonergic antidepressant, can be used in low dosages to decrease nocturnal pruritus, which is a common problem in patients suffering from AD ( ). It also has been shown to increase the nociceptive threshold in healthy subjects ( ). Furthermore, it may indirectly reduce itch through its anxiolytic properties. The most common side effects of mirtazapine are somnolence, appetite stimulation, and weight gain ( ). Therefore mirtazapine is a good option in AD patients who are anxious, thin, itchy, and need to sleep better.
Chronic pruritus is mediated mainly through the nonhistaminergic pathway ( ). Transient receptor potential ankyrin (TRPA) and transient receptor potential vanilloid (TRPV) channels are cation channels involved in generating action potentials in response to certain pruritogens via unmyelinated C fibers ( ). Therefore TRP channel inhibitors are potential targets for itch management. The long-term antipruritic effect of botulinum neurotoxin A in mice is thought to be associated with the downregulation of TRPA1 and TRPV1 ( ). Furthermore, RNA sequencing has shown that overexpression of TRPV1 in itchy skin correlates with itch intensity in AD patients, and TRPA1 gene expression was increased in itchy atopic skin ( ).
Nav 1.7 inhibitors
Voltage-gated sodium (Nav) channels are activated by TRPV1 and TRPA, and control action potentials involved in itch propagation ( ). In animal models, a Nav 1.7 monoclonal antibody provided pain relief and neuropathic and inflammatory itch reduction ( ). Furthermore, a Nav 1.7 antagonist reduced pain and itch in rodent models, suggesting Nav 1.7 to be a promising therapeutic target for both itch and pain in AD ( ). Neu-P12, an investigational drug that is a combination of a TRPV1 antagonist with a Nav 1.7 inhibitor, has been recently developed for the treatment of itch ( ).
Topical nonsteroidal antiinflammatory agents
Tapinarof is a new topical nonsteroidal agent that has shown efficacy in patients with AD and psoriasis. Its antiinflammatory properties are mediated through the activation of the aryl hydrocarbon receptor (AhR), which is expressed in various cell types, including human skin. Tapinarof induces barrier gene expression in keratinocytes and reduces Th17 cytokine responses, which are beneficial in treating AD symptoms ( ). A phase 2 trial was conducted for tapinarof in AD patients, which showed treatment efficacy with minimal adverse events ( ).
Substance P activates the neurokinin-1 (NK-1) receptor, which is involved in nonhistaminergic itch signaling; gene transcripts of substance P and NK-1 are elevated in atopic patients ( ). An oral NK-1 receptor antagonist, serlopitant, improved pruritus scores in patients suffering from chronic pruritus in a phase 2 clinical trial with no significant safety concerns ( ). Serlopitant also reduced pruritus scores in AD patients in a phase 2 clinical trial; however, the differences were not statistically significant. Overall, with serlopitant meeting the primary endpoint in three of four studies assessing its efficacy in chronic pruritus, NK-1 antagonism is a promising mechanism for itch reduction across a range of patient populations ( ). Tradipitant is another NK-1 inhibitor undergoing a phase 2 trial, which has shown preliminary improvements in itch of AD patients ( ).
Patients with AD suffer from itch and pain, which can severely affect their quality of life. There are many different treatment options available aimed at combatting these symptoms, summarized in Tables 25.1 and 25.2 . For mild AD and maintenance therapy, nonpharmacologic therapies, such as moisturization and bathing practices, can improve itch and pain. For mild to moderate AD, topical therapies, including corticosteroids, calcineurin inhibitors, PDE4 inhibitors, and various analgesics and anesthetics, are helpful. For moderate to severe AD, systemic therapies that suppress the immune system can be effective; however, these have a multitude of side effects that limit their use as a long-term therapy. For moderate to severe AD, biologic agents that specifically target itch-mediated signaling pathways have been very effective with few known side effects. There are also a variety of drugs that decrease neural sensitization, which can be helpful in reducing chronic itch and pain. These drugs targeting neural sensitization have been shown to decrease pain. The analgesic effects of the other antipruritic agents have not been specifically studied but could be a potential avenue for future investigation. Complementary therapies intended to reduce stress and anxiety can be beneficial when used in conjunction with other therapies. Furthermore, several experimental therapies that specifically target nonhistaminergic itch pathways are currently being tested in clinical trials and have shown promising results.
|Name||Mechanism of action||Recommended dosing||Side effects||Other notable points|
|Topical corticosteroids||Antiinflammatory, reduces itch-related cytokines||Available in very low potency (i.e., hydrocortisone 0.25%) to very high potency (i.e., clobetasol 0.05%)||Atrophic skin changes, telangiectasias, striae, easy bruising potential for systemic effects (i.e., HPA suppression) with high potency or large surface area use||Not recommended for areas of thin skin (face, neck, intertriginous areas)Used for WWT with dilution|
|Topical calcineurin inhibitors (tacrolimus, pimecrolimus)||Immunomodulation of T cells and inhibition of cytokine release, activation of TRPV1 ion channels||Tacrolimus 0.03%, 0.1% ointment Pimecrolimus 1% cream||Application site burning upon application||Suitable for areas of thin skin and face FDA black box warning for lymphoma and skin cancer risks|
|Crisaborole||PDE4 inhibition, inhibition of inflammatory cytokines||2% ointment||Well tolerated, reports of mild application site burning|
|Capsaicin||TRPV1 receptor activation||0.025%–0.1% formulations||Burning, erythema at application site in first 2 weeks of use (reduced by application of topical anesthetic such as lidocaine)||Avoid mucosal areas and eyes|
|Pramoxine||Inhibition of voltage-gated sodium channels||1% formulations||Well tolerated, reports of contact dermatitis and application site irritation|
|Menthol||Activates TRPM8 ion channels, cooling effect||1%–5% formulations||May cause cold-induced pain or irritation at higher concentrations||Recommended for patients that report relief of symptoms with cooling of the skin|
|Polidocanol||Anesthetic with antipruritic properties||3% formulations||Well tolerated, reports of mild application site irritation|
|Ketamine-amitriptyline-lidocaine||NMDA receptor and sodium channel blockade||10% ketamine, 5%, amitriptyline, 5% lidocaine cream||Mild application site burning, erythema; potential for psychoactive effects if ingested; case report of systemic effects from topical overuse||Contains controlled substance (ketamine)Limit use to <20% body surface area|
|Topical cannabinoids (i.e., PEA)||Increases activity of endogenous cannabinoids and agonism of cannabinoid receptors||PEA 0.3%||Well tolerated, reports of mild application site irritation|