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Current and Emerging Medical Therapies for Primary Hyperhidrosis

Hyperhidrosis is defined as the production of sweat beyond what is physiologically necessary to maintain thermal homeostasis. This disease state may (and typically does) have a significant impact on the patient’s quality of life. Medications including antiperspirants, anticholinergics, and botulinum toxin have been shown to be effective in the management of hyperhidrosis. Several medical device technologies have also proven to be effective. This review article will explore the current and emerging pharmacological and medical device treatments for hyperhidrosis and provide a framework for treating patients who suffer with primary forms of hyperhidrosis.


INTRODUCTION
Hyperhidrosis is defined as the production of sweat beyond what is physiologically necessary to maintain thermal homeostasis. This condition can be categorized as primary (idiopathic) or secondary (related to a known cause). Several studies have estimated that 1.6-2.9% of the United States population have been affected by primary hyperhidrosis [1][2][3][4][5][6][7]. One study conducted outside the United States has reported a prevalence as high as 16.3% of the population [3]. The pathophysiology of this disorder is poorly understood but primary hyperhidrosis has been postulated to have a genetic component.
The diagnosis of primary focal hyperhidrosis is made via the history and physical examination with a focus on the consensus conference diagnostic criteria. The criteria require at least a 6-month history of focal and visible sweating without secondary causes [12]. In addition, at least two of the following criteria must be met: bilateral and symmetric hyperhidrosis, impairment of activities of daily living, onset at age less than 25 years old, at least one episode per week, family history of the disease, or an absence of symptoms during sleep [12]. Exclusion of medications that can cause hyperhidrosis including anticholinesterases, selective serotonin reuptake inhibitors, tricyclic antidepressants, glaucoma agents, bladder stimulants, opioids, and sialagogues remains essential to ensure proper diagnosis [13]. The marked impact of primary hyperhidrosis on a patient's quality of life has been measured in clinical trials using the validated Hyperhidrosis Disease Severity Scale [14][15][16]. Treatment of hyperhidrosis has focused on improving symptoms, reduction of the sweat and its inherent socially stigmatizing impact, and subsequently improving the quality of life of the patients [1]. The objective of this article is to explore the current and emerging pharmacological and medical device treatments for hyperhidrosis and to provide a framework for treating patients. Surgical options including curettage, skin excision, and sympathetic block for hyperhidrosis will be covered in a separate paper.

METHODS
A search regarding current treatments was conducted through 5 July 2016 using PubMed,

CURRENT THERAPIES FOR HYPERHIDROSIS
Current therapies for hyperhidrosis are divided into several categories including topical, oral, and injectable medications and medical devices.

Topical Therapies
Antiperspirants which usually contain aluminum salts are the first-line treatment for hyperhidrosis because of their safety profile, cost-effectiveness, and efficacy [17][18][19]. Preparations in the United States can vary in the amount of metal salts up to 25% depending on the aluminum compound used [20].
Antiperspirants are believed to work by obstructing the distal eccrine sweat gland ducts [19,21]. Patients with hyperhidrosis who use these products may develop miliaria due to the ongoing production of sweat inferior to the blocked sweat duct, but long-term blockage may lead to functional and structural degeneration of the eccrine acini which does not cause harm to the patient in the process of reducing sweat production [21].
A case series published by Scholes [23]. Skin irritation is a common limiting adverse event with aluminum chloride hexahydrate.
The irritation occurs when the compound is applied to moist skin allowing the formation of weak hydrochloric acid [25]. In one study, 36% of all patients reported moderate irritation and 14% reported severe irritation [23]. Other adverse effects include itching and stinging on application which improved with continual usage [23]. Some studies have shown that application of a low-potency steroid, such as topical hydrocortisone, in the morning can decrease irritation [22,26]. Applying aluminum chloride hexahydrate to completely dry skin greatly reduces the risk of focal skin irritation [25]. To ensure the skin is dry, some clinicians have recommended avoiding washing the axillae prior to the application of aluminum chloride hexahydrate, drying the axillae with a blow dryer on a cool setting, or applying the medication at nighttime and removing it in the morning [25].
Topical glycopyrrolate 2% is a medication believed to improve hyperhidrosis through its anticholinergic properties by competitively binding the muscarinic acetylcholine receptors [27]. Several case reports and a few randomized trials have been conducted to evaluate its efficacy in facial hyperhidrosis. One study of 25 patients with facial hyperhidrosis showed that 96% were partially or fully satisfied with the results of the medication [28]. Another study of 39 patients with facial hyperhidrosis showed a reduction of sweat production on the forehead of 25% 90 min after application with no significant improvement in the Hyperhidrosis Disease Severity Scale [29]. However, the results in axillary hyperhidrosis have been less clinically meaningful. An uncontrolled study of 35 patients with axillary hyperhidrosis who had failed aluminum chloride hexahydrate therapy was unable to show a consistent and meaningful benefit from glycopyrrolate compounded in Cetomacrogol Cream BP [30]. Glycopyrrolate may be used topically twice daily although some authors recommend applying it nightly [31].
Patients should be advised to avoid the nose, mouth, and eyes as the anticholinergic properties can prevent ocular accommodation [31].
Formaldehyde and glutaraldehyde are not commonly used in the treatment of primary focal hyperhidrosis, as these agents can cause localized skin irritation, allergic sensitization, and central nervous system toxicity [25,32].

Oral Therapies
Oral anticholinergics are a potential treatment for hyperhidrosis but are occasionally limited by the side effect profile. A retrospective chart review of 45 patients with hyperhidrosis who were prescribed glycopyrrolate showed a 67% response rate with 6 patients not responding to treatment and 9 patients discontinuing therapy secondary to developing adverse events including dry mouth and gastrointestinal disturbances [33]. A retrospective chart review in children has shown improvement in 90% of all patients, with the most common side effects being dry mouth (26%) and dry eyes (10%) [34].
Oxybutinin, a competitive antagonist at the postganglionic muscarinic receptors, is another potential treatment for hyperhidrosis. A prospective, randomized, placebo-controlled trial for the initial treatment of hyperhidrosis showed improvement in greater than 70% of patients with palmar and axillary hyperhidrosis and greater than 90% of patients with plantar hyperhidrosis [35]. A subsequent study showed a 60% improvement in the Hyperhidrosis Disease Severity Scale and a significant improvement in the Dermatology Life Quality Index [36]. Dosing in the literature varies greatly from 2.5 to 5 mg twice daily with dry mouth being the main dose-limiting adverse event [35,37]. Bornaprine is an oral anticholinergic with limited commercial availability which has been studied in hyperhidrosis; however, the central nervous system adverse events limit the usage of this medication [38].
Other oral medications have been suggested to be effective in hyperhidrosis but have limited data and are of limited value given the availability of alternative therapies. These include beta-blockers,

Medical Device Therapies
Iontophoresis, the passing of an ionized substance through intact skin, is a treatment method that delivers 15-20 milliamps of current through tap-water to treat hyperhidrosis [70,71].
The exact mechanism of action is unclear, but several hypotheses exist including the inhibition of sympathetic nerve transmission, ion deposition obstructing the sweat gland, and local alterations of pH inhibiting the sweat gland [72][73][74][75]. Initial treatment of 8 sessions in a 28-day period showed a 81% reduction in sweat with maintenance therapy required to maintain the effect [76]. Common adverse events include discomfort, vesiculation, and erythema [77]. Microwave thermolysis has also been shown to be an effective treatment for hyperhidrosis.
Microwaves heat by physical rotations of molecules with high dipole moment such as the ionic water in eccrine glands while avoiding low dipole moment molecules such as fat [16]. A study of a device using this technique in axillary hyperhidrosis showed a 89% response rate after treatment with 69% maintaining the effect at 12 months [16]. Adverse events include temporary tenderness, swelling, and numbness [82].

Adjunctive Therapies
In addition to pharmaceutical and medical device therapies, several adjunctive therapies 83% of all patients experienced a greater than or equal to 50% reduction in sweat production as measured using a gravimetric assessment [94]. In this study, patients followed for 12 months showed long-lasting effects [94].
Another study utilizing the VASER showed that 11 out of 13 patients had a significant reduction in sweat production and odor without recurrence in 6 months [95]. In addition, ultrasound has been reported to have been used to induce a therapeutic stellate ganglion block in a patient with efficacy for at least a few weeks [96].

DISCUSSION
Hyperhidrosis is a disorder of excess sweat production which can have a dramatic impact on a patient's quality of life. The disease state appears to have a genetic component, given the presence of a family history. Hyperhidrosis likely represents a dysregulation of the sympathetic and parasympathetic systems.
More research is needed to better understand the true pathophysiology of the disease process. Advisory Committee has developed treatment algorithms for clinicians to follow [97]. Many more therapies are currently in development.
Utilizing the best treatment along with education and empathy will increase a patient's compliance and lead to a meaningful clinical outcome. 86. Goldfischer ER, Sand PK, Thomas H, Peters-Gee J.

ACKNOWLEDGMENTS
Efficacy and safety of oxybutynin topical gel 3% in