Topical Pramoxine in Chronic Pruritus: Where do We Stand?

Sir,

Chronic pruritus is a debilitating symptom in terms of the burden, effect on the quality of life, and often recalcitrant nature to conventional treatment. Newer effective topical or systemic drugs are the need of the hour to enhance the dermatologist's armamentarium. Pramoxine represents one such promising topical formulation that has been in the market since the 1950s but its full potential has not been perhaps totally explored.

Pramoxine (4-[3-(p-butoxyphenoxymorpholine)) propyl] is a topically acting local anesthetic. Most local anesthetics have a lipophilic aromatic group and hydrophilic amine group, linked by an intermediate chain, usually an ester or amide. Pramoxine, however, has a morpholine moiety acting as the linkage ether making it structurally unique, with good potency and considerably fewer side effects (rare sensitizing potential and decreased cross-reactivity). Pharmacokinetically, it works well as a surface anesthetic, well tolerated on the skin and delicate mucous membranes with extremely low acute and subacute toxicity. Topical use near the eye and nose is avoided due to irritation potential. It has a faster onset of action providing itch relief within 3–5 min and is less expensive compared to eutectic mixture of local anesthetics (EMLA).[1] Safety in pregnancy is established with no maternal or fetal adverse effects noted in the use of hydrocortisone–pramoxine combination for hemorrhoids.[2] It is advisable, however, to wipe off pramoxine thoroughly before nursing if applied to the nipple-areola region. Accidental pramoxine ingestion is associated with nausea and vomiting without any serious adverse events.[3] No dose adjustment is required in patients with hepatic or renal dysfunction with safety established with use for chronic pruritus associated with the above conditions.

Pramoxine acts by decreasing the transmembrane permeability of sodium ions by reversibly binding and inhibiting voltage-gated sodium channels. This stabilizes and prevents membrane depolarization, resulting in conduction blockade due to failure to initiate an action potential. Since pain, itch, and thermal sensation share a common peripheral neural pathway (slow C fibers), pramoxine like other topical anesthetics exerts anesthetic as well as antipruritic effect. Pramoxine is an FDA-approved drug (since 1953), long in use in various subspecialties such as obstetrics (post-episiotomy pain relief), surgery (hemorrhoids), and dentistry. In dermatology, the use has been mostly off-label, for the treatment of various pruritic dermatoses with most studies in renal pruritus and atopic dermatitis. In a large study of 200 patients with various itchy dermatoses, pramoxine was effective in controlling pruritus in 57% of patients with cream formulation being more effective and preferred over gel formulation.[4] A randomized double-blind controlled trial involving 28 patients has shown significant improvement in itch intensity (61% reduction over 12% in controls) without adverse effects in patients with uremic pruritus (on hemodialysis) with twice-daily usage of pramoxine lotion.[5] Another study has also shown similar results confirming efficacy and safety.[6] Various formulations of pramoxine have been studied with encouraging results. A combination of lactic acid and pramoxine has shown significant improvement in skin hydration (P < 0.001) and dry itchy skin (P < 0.001) among 24 women subjects.[7] Ceramide containing formulations of pramoxine provides rapid and long-lasting relief in atopic dermatitis (24.6% reduction in mean itch severity 2 min post-application, and 58.0% reduction 8 h post-application) which is comparable with ceramide containing cream with hydrocortisone (18.5% reduction and 59.7% reduction, respectively) over an 8-h period. It is also well tolerated on continuous usage along with providing night-long itch relief (87.5% patients).[8] Another combination of hydrocortisone acetate and pramoxine cream has shown dramatic improvement in itch intensity after single-day use with early onset of action and significant mean percentage reduction in the visual analog scale of 31.74%.[9]

Although theoretically sensitization to pramoxine is rare, there have been a few reports of allergic contact dermatitis.[10] In a recent study of 232 patients, 3% of patients (n = 7) showed patch test positivity to pramoxine, which is in the range of well-known contact sensitizers such as neomycin and balsam of Peru.[11] A single case of anaphylaxis has also been described.[12]

Summing up, pramoxine is a potent, rapidly acting surface anesthetic and antipruritic agent having a good safety profile. The current level of evidence of pramoxine as an antipruritic agent is I with grade of recommendation being B. Combination formulations with ceramides or lactic acid can serve the dual purpose of moisturization and antipruritic effect, thus being useful in various chronic pruritic dermatoses. It can also be of value in pruritic dermatoses of pregnancy, wherein systemic options are limited. A concern that remains is contact sensitization to pramoxine becoming increasingly commoner. There is a dire need for large-scale investigator-initiated studies, to assess the effectiveness, safety, and tolerability of pramoxine.

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Conflicts of interest

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