PracticalDermatology

Primary focal hyperhidrosis is an idiopathic condition that can severely affect the social, emotional, and professional aspects of patients’ lives. The condition is characterized by focal, excessive sweating without a known cause. It most commonly affects the palms, soles, and axillae, as well as the face and scalp.¹ A variety of treatment options currently exist for primary focal hyperhidrosis, including topical therapies, botulinum toxin injections, iontophoresis, and microwave thermolysis. In more severe or resistant cases, systemic agents, suction curettage of eccrine sweat glands, and even sympathectomy may be considered. The first line treatment is usually topical therapies, which include antiperspirant salts and glycopyrronium tosylate wipes.²

Topical Antiperspirants

Topical antiperspirants are the first line treatment for primary focal hyperhidrosis. Antiperspirants contain aluminum salts, which are believed to exert their therapeutic effect by precipitating with mucopolysaccharides derived from the lining of the eccrine gland ducts. The precipitates cause membrane damage, which results in necrosis and sloughing of the epithelial cells within the ducts. The combination of precipitates and sloughed cells forms a plug that physically occludes the eccrine gland duct and prevents the release of sweat.³ Many of these antiperspirants utilize aluminum salts such as aluminum chloride or aluminum chloride hexahydrate as their active ingredients.⁴ Aluminum sesquichlorohydrate, another aluminum salt, has also recently begun to be studied and used as a treatment option.⁵

Aluminum Chloride. Aluminum chloride (AC) is commonly used in various strengths in over-the-counter (OTC) and prescription antiperspirants. AC is typically used to treat axillary hyperhidrosis and has been noted to be less effective for palmar and plantar hyperhidrosis.⁶ It’s recommended to apply the compound at night to completely dry skin to maximize its efficacy and decrease skin irritation.⁷

The reported efficacy and tolerability of aluminum chloride varies widely amongst studies. One study examined 691 patients with axillary hyperhidrosis treated with AC solutions and found that 82 percent achieved dryness or a tolerable amount of sweating. The same study found similar efficacy between AC 15% and 20% solutions, though less irritation with the 15% solution.³ Another study examined 25 subjects with focal axillary hyperhidrosis treated with either botulinum toxin type A injections or topical 20% aluminum chloride and found that AC was tolerated and effective, defined as an improvement of two points or greater on the Hyperhidrosis Disease Severity Scale (HDSS), in only 29 percent of subjects randomized to the AC cohort.⁸

The most common adverse effects of aluminum chloride include local itching and skin irritation. Clothing damage may also occur. The study of 691 patients above found that 70 percent of subjects experienced minor pruritus of short duration with AC application. However, severe pruritus was noted in nine percent of subjects. Additionally, moderate skin irritation was noted in 36 percent of subjects and severe irritation was noted in 14 percent of subjects.³ These side effects may preclude the use of AC as a treatment option, though many cases can be controlled with the application of topical corticosteroids the morning after AC application.⁹ Additional preventative measures include avoiding AC application to moist or wet skin, which allows for the formation of an irritating weak hydrochloric acid, and avoiding application shortly after shaving.⁷

Aluminum Chloride Hexahydrate. Aluminum chloride hexahydrate (ACH) is the hydrated formulation of AC salt. ACH has been noted to be an effective treatment option for both axillary and palmar hyperhidrosis. One of the very first antiperspirant formulations consisted of a 25% solution of ACH in distilled water. The solution was effective enough to reduce axillary sweating with application every other or third day, though proved to cause extreme local skin irritation and damage to clothing from its high acidity.¹⁰ In a case series of 65 patients with axillary hyperhidrosis treated with 20% ACH in absolute alcohol, 64 patients reported complete control of sweating with periodic application of the solution, most often every seven to 21 days. Of the 65 patients, 29 experienced local skin irritation, with 28 reporting that the irritation was relieved with application of 1% hydrocortisone cream the morning after ACH application.⁹

Regarding its use in palmar hyperhidrosis, a study of 12 patients treated with a 20% ACH in ethanol solution found that the solution significantly decreased skin water vapor loss on treated palms when compared to untreated palms. The patients also subjectively reported reduced sweating within 48 hours of application, though the effects lasted no longer than 48 hours after discontinuing treatment. Of note, four of 12 patients experienced skin irritation with ACH treatment, with one patient experiencing severe irritation requiring study withdrawal.¹¹

Aluminum Sesquichlorohydrate. Aluminum sesquichlorohydrate (AS) is another aluminum salt that appears to have first been tested in a topical foam formulation in 2008. The study examined the use of a 20% AS foam in the treatment of axillary and palmar primary hyperhidrosis. The study enrolled 20 subjects, with application of the foam nightly for two weeks and three times weekly for two weeks. At the conclusion of the treatment period, the foam was associated with a 61 percent reduction in eccrine sweating, as determined by a reduction in Minor test score. Of the 20 participants that enrolled and completed the study, one subject experienced a mild and transient itching sensation, but there were otherwise no adverse effects or local skin reactions reported over a four-week period.⁵

More recently, the Carpe company developed a 15% AS lotion for use in axillary and palmar hyperhidrosis. AS lotion was tested in a study of 20 healthy female subjects and was associated with a mean sweat reduction of 39.5 percent (median 60.4 percent) in an axilla treated with three applications of AS lotion when compared to the opposite untreated axilla of the same subject. This reduction was found to be statistically significant and was determined by before and after weights of cotton pads, which were held in the axillae during a sweat stimulation period in a heated room (D.M. Muratschew, MD, unpublished, 2017).

Of note, per FDA rules and regulations, an antiperspirant must achieve a sweat reduction of 20 percent or greater to be considered effective.¹² Regarding its efficacy in palmar hyperhidrosis, a similar study of 20 healthy subjects found that AS lotion was associated with a mean palmar sweat reduction of 24.5 percent (median 23.5 percent) in a hand treated with three applications of AS lotion when compared to the untreated hand of the same subject. The study used a similar objective measure to determine efficacy, namely cotton gloves weighed before and after a sweat stimulation period. The reduction was again found to be statistically significant (D.M. Muratschew, MD, unpublished, 2016).

Notably, across both above studies, there were no adverse events or skin reactions observed in any of the 40 subjects. Additionally, a designated irritation study was conducted using the patch testing methodology where 57 healthy subjects underwent an induction phase with patches containing AS lotion were applied to the mid thoracic back of each subject three times weekly for three weeks. The challenge phase consisted of a AS lotion patch applied to a virgin test site adjacent to the original induction site of each subject. No skin reactions or adverse reactions were observed in any of the 54 subjects who completed the study. The three subjects who did not complete the study discontinued their participation for other reasons, none of which were related to the test lotion (R.R. Eisenberg, MD, unpublished, 2016).

Glycopyrronium Tosylate. Glycopyrronium tosylate (GT) is a topical anticholinergic agent used to reduce axillary sweating. The drug acts as a competitive inhibitor of acetylcholine at sweat gland receptors, thus reducing stimulation of the glands and sweat production.¹³ The ATMOS-1 and ATMOS-2 trials were randomized controlled trials with 697 pooled subjects with primary axillary hyperhidrosis. The trials demonstrated that GT both reduced the severity of sweating as measured by ASDD-Item 2 and gravimetrically reduced sweat production. Specifically, 59.5 percent of patients treated with GT were noted to have at least a 4-point improvement from baseline in ASDD (Axillary Sweating Daily Diary) at four weeks, compared to 27.6 percent treated with vehicle. Additionally, 74.9 percent of patients treated with GT achieved a 50 percent or greater reduction from baseline in sweat production at four weeks, compared to 53.2 percent treated with vehicle.

Various treatment emergent adverse events (TEAEs) were noted throughout the trials, with most being mild to moderate in severity and less than four percent requiring treatment discontinuation. The most common TEAEs included dry mouth (24.2 percent of pooled GT subjects), application site pain (8.7 percent of pooled GT subjects), and mydriasis (5.7 percent of pooled GT subjects). Oropharyngeal pain and headache were also each noted in approximately five percent of the pooled GT subjects.¹⁴

Conclusion

In conclusion, a wide variety of topical therapies exist for the first-line treatment of primary focal hyperhidrosis. These include the time-tested aluminum chloride and aluminum chloride hexahydrate. Aluminum chloride has been demonstrated to be efficacious in the treatment of axillary hyperhidrosis but is also associated with the highest rate of skin irritation amongst the aluminum salts. Aluminum chloride hexahydrate has demonstrated efficacy in both axillary and palmar hyperhidrosis. While still associated with some local skin irritation, it appears to have lower rates overall when compared to AC. Additionally, this irritation is almost always relieved by a 1% hydrocortisone cream application the morning after treatment.

Aluminum sesquichlorohydrate has more recently become widely available and seems to be a better tolerated aluminum salt while still maintaining efficacy in treatment of both axillary and palmar hyperhidrosis.

Topical glycopyrronium wipes are also an effective treatment option, though their use may be limited by local skin irritation and/or anticholinergic side effects, including dry mouth and mydriasis, among others. Glycopyrronium wipes are currently only indicated for axillary hyperhidrosis. Beyond the above topical therapies, there exist other treatment modalities for cases refractory to topical treatment. These include botulinum toxin injections, iontophoresis, microwave thermolysis, laser treatments, systemic anticholinergics or alpha-2 adrenergic agonists, and surgical sympathectomies. These therapies, while efficacious, are associated with their own adverse effects and lack the convenience and ease of use of topical therapies.

Relevant funding sources for manuscript: None

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