Advances in the Management of Hyperhidrosis

Morgan Parker, BS¹ and Mariana Phillips, MD^1,2

¹Virginia Tech Carilion School of Medicine, Roanoke, VA, USA
²Carilion Clinic Dermatology and Mohs Surgery, Roanoke, VA, USA

Conflicts of interest: The authors declare no conflicts of interest related to this manuscript and no funding was received.

Funding sources: None.

Abstract
Hyperhidrosis (HH), a condition characterized by excessive sweating beyond thermoregulation, significantly impairs quality of life. Conventional medications to treat HH include aluminum chloride hexahydrate, systemic anticholinergics, and botulinum toxin injections. New treatments have emerged including glycopyrronium bromide, sofpironium bromide, targeted alkali thermolysis, and microwave devices. This paper reviews the mechanism of action, efficacy, safety, and practical considerations associated with these treatments.

Keywords: hyperhidrosis, sweating, anticholinergics, botulinum toxin, sofpironium bromide, glycopyrronium, microwave thermolysis, targeted alkali thermolysis

Introduction

Hyperhidrosis (HH), characterized by excessive sweating beyond thermoregulatory needs, affects approximately 5% of the population. The condition impacts patients on social, emotional, and professional levels due to embarrassment and apprehension about their symptoms.¹ In addition, HH is associated with diminished quality of life with high rates of functional impairment, embarrassment, psychological distress, and social withdrawal.¹ The stigma surrounding sweating and lack of awareness regarding available treatments often lead to a delay in seeking professional help. Clinicians can quantify disease burden using the Hyperhidrosis Disease Severity Scale (HDSS), a patient reported 4-point scale that assesses the tolerability of the sweating and how it affects daily activities.¹

HH can be primary or occur secondarily to other medical disorders or medications. Eccrine sweat glands, innervated by the sympathetic nervous system, are primarily responsible for HH. The postganglionic neuron for sweat gland innervation releases acetylcholine which acts on muscarinic receptors located on the eccrine glands. Eccrine glands are activated in response to emotional stress or thermal regulation. The eccrine glands on the palms and soles, and to some degree the axilla, are most responsive to emotional stress, while those on the body predominately function in temperature regulation.¹ In HH, the eccrine sweat glands are histologically normal, but an exaggerated or abnormal response to emotional stress triggers excessive sweating.²

Treatment for HH depends on several factors including localized or generalized nature of the sweating, availability of treatment, anatomical location, comorbidities, adverse events (AEs), and tolerability.³ This paper reviews the current and emerging treatments for HH including topical therapies (sofpironium bromide, glycopyrronium bromide, targeted alkali thermolysis [TAT]), systemic therapies (oxybutynin, glycopyrrolate), neurotoxin injections, and device-based treatments (microwave thermolysis, iontophoresis), focusing on mechanisms of action, efficacy, safety, and practical applications. These agents are summarized in Table 1.

Table 1:

Discussion

Anticholinergic Treatments

Recent advancements have broadened the scope of treating HH, providing tailored approaches to address varying severities and forms. Sofpironium bromide (SB), a topical anticholinergic gel, marked a significant advancement in HH management. The gel is dispensed from a metered pump and one pump is typically applied to each axilla once daily, at bedtime. The gel is available at a 5% concentration and dose titration is not routinely required due to its localized mechanism of action and favorable tolerability profile. Phase 2 and 3 trials demonstrated efficacy, with substantial reductions in sweat production and improved patient-reported outcomes.^4-7 In a Phase 2 trial, 227 participants were randomized to 1 of 3 concentrations of SB or vehicle, with daily treatment to the axillae for 42 days.⁵ Application of 5%, 10%, and 15% SB gel resulted in 70%, 79%, and 76% of participants exhibiting ≥1-point improvement in HH Disease Severity Measure-Axillary (HDSMAx), respectively.⁵ Fifty-four percent of patients receiving the vehicle showed the same improvement. Two pivotal Phase 3 trials (CARDIGAN I and CARDIGAN II) included approximately 350 participants aged 9 years and older who applied 5% treatment gel once daily at bedtime to each axilla for 42 consecutive days.⁴ In these studies, gravimetric measures and HDSM-Ax scores revealed that over 60% of participants experienced a ≥50% reduction in sweating severity.⁴ The treatment was well tolerated, with the most common AEs (≥2%) being xerostomia, blurred vision, mydriasis, and urinary retention.⁴ The studies supporting SB efficacy and tolerability are summarized in Table 2.

Table 2:

Glycopyrronium tosylate (GT), another topical anticholinergic agent that is marketed as a wipe, gained attention through Phase 3 trials, ATMOS-1 and ATMOS-2. These were randomized, double-blind, vehicle-controlled trials conducted over a 4-week period, involving a total of 697 patients aged 9 years and older with primary axillary HH.⁸ Participants were randomized in 2:1 ratio to receive GT 3.75% or a vehicle solution applied via a pre-moistened cloth, once daily to each axilla. These trials reported significant reductions in sweat production and severity scores compared to placebo, achieving clinically meaningful results in over 50% of participants (Table 2). GT was generally well tolerated in patients with primary axillary HH; however, AEs such as xerostomia (24.2%), urinary retention (1.5%), headache (5%), and constipation (2%) were noted but were generally mild and self-limiting.⁸ GT is now US FDA-approved for primary axillary HH, offering a convenient and effective alternative topical treatment.

A novel non-anticholinergic treatment employs targeted alkali thermolysis (TAT) to reduce sweat production. This single-use patch is applied in the clinical setting to a dry axilla for approximately 3 minutes. The mechanism of action involves thermal destruction of the eccrine gland through an exothermic reaction related to the alkali in the patch.⁹ Clinical studies demonstrated significant sweat reduction lasting up to 3-4 months after a single application.¹⁰ One pivotal trial enrolled 120 participants to a bilateral axillary treatment with TAT patch or a control (“sham”) patch. Sixty-four percent of TAT-treated versus 44% of sham-treated participants improved on the HDSS from scores of 3 and 4 to scores of 1 and 2. The majority of study participants who received the medicated patch experienced a decrease in sweat to “not noticeable” or “tolerable” and ”never” or “sometimes” interferes with daily activities.¹⁰ The patch was well tolerated, with most AEs being mild and transient. In April 2023, the FDA approved the TAT patch as a single-use, non-invasive device for primary axillary HH in patients 18 years or older.¹¹

Systemic agents such as oxybutynin and glycopyrrolate have long been utilized off-label for HH. Randomized controlled trials (RCTs) have demonstrated their efficacy, with oxybutynin leading to significant reductions in sweat production and improved quality of life scores. In one RCT, patients were started on an oxybutynin dose of 2.5 mg per day and gradually increased the dose to 7.5 mg per day.¹² Sixty percent of patients treated with oxybutynin, compared to 27% of patients treated with placebo, improved at least one point on the HDSS.¹² In addition to this, the mean improvement in quality of life was better in the oxybutynin arm (6.9) compared to the placebo arm (2.3).¹² The extended-release formulation of oxybutynin may result in reduced peak plasma concentrations, potentially leading to decreased efficacy compared to the immediate-release formulation, although it may improve tolerability by minimizing fluctuations in drug levels.¹³ Similarly, the efficacy of glycopyrrolate has been established in smaller studies.¹⁴ A study reviewing case notes of 36 patients with primary HH determined that 1 mg glycopyrrolate administered twice per day is effective in treating primary HH, reduces anxiety, and improves the patient’s quality of life.¹⁴ These studies are outlined in Table 2. Dose escalation of systemic anticholinergic medications is based on clinical response; however, the systemic anticholinergic AEs often become intolerable at higher doses. Common AEs of systemic anticholinergics include xerostomia, constipation, and blurred vision. Additionally, patients may experience urinary retention, decreased gastrointestinal motility leading to abdominal discomfort, and in some cases, early memory impairment or cognitive dysfunction, particularly in elderly individuals.¹³

Contraindications to oral anticholinergic therapy include narrowangle glaucoma, urinary retention, gastric retention, myasthenia gravis, and severe ulcerative colitis due to their inhibitory effects on smooth muscle function.¹⁵ Topical anticholinergics, including GT wipes, should be avoided in patients with glaucoma and in those with significant autonomic dysfunction, as systemic absorption may exacerbate underlying conditions.¹⁵ Caution is also warranted when prescribing anticholinergics to patients taking other medications with anticholinergic properties such as tricyclic antidepressants, first-generation antihistamines, and certain antipsychotics due to additive effects.¹⁵ Careful screening and individualized risk-benefit assessment are essential before initiating therapy.

Injectable Botulinum Toxin

Botulinum toxin (BTX) including onabotulinumtoxin A, abobotulinumtoxin A, and incobotulinumtoxin A, represent a wellestablished treatment modality for localized HH. Two recent metaanalyses have confirmed the efficacy of BTX for the treatment of HH, reporting significant reductions in sweat production that can persist for 4-6 months post-treatment.^16,17 In addition to this, BTX injections exhibited fewer AEs compared to other treatments.¹⁷ The mechanism of action of BTX involves blocking acetylcholine release at the neuromuscular junction of eccrine sweat glands.¹⁸ By preventing acetylcholine-mediated stimulation of these glands, it effectively suppresses sympathetic cholinergic signaling, leading to reduction in sweat production at the injection site.¹⁸ While highly effective, BTX treatments are associated with injection site pain and require periodic re-administration, making them less ideal for needle-averse patients.^18,19 Neurotoxin injections are used in several anatomical sites including axillae, palms, soles, forehead, inframammary region, and groin. Peak response is typically observed 1-4 weeks post-injection, with an average duration of therapeutic effect ranging from 4-9 months, depending on dose, site, and individual response.²⁰

Microwave Thermolysis

Microwave thermolysis, a non-invasive, in-office procedure, induces destruction of eccrine and apocrine glands through precise thermal energy delivery. Since eccrine glands are destroyed, this therapeutic intervention can offer permanent results. The treatment is FDA-approved for primary axillary HH, and studies report significant and durable reductions in axillary sweating, with minimal downtime, low recurrence rate, and minimal systemic AEs. Unlike systemic or injectable treatments, microwave thermolysis is a single-use device administered by trained providers in a clinical setting. Pre-treatment skin preparation includes local anesthesia to minimize discomfort and to prevent thermal injury. A grid template is applied to guide precise energy delivery to the axillary region. Patients typically undergo 1-2 sessions spaced several months apart for optimal, permanent results. Patients can resume normal activities immediately, although swelling, discomfort, and numbness may persist for several days.²¹

Laser Therapy

Laser-based therapies, particularly subdermal 1064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) and 1320 nm Nd:YAG lasers, have shown promise in preliminary studies for axillary HH. These modalities involve selective photothermolysis of the eccrine glands, permanently reducing glandular activity.^22,23 Treatments aim to target the eccrine glands within the subcutaneous tissue. Goldman et al. described a technique in which a fiber optic laser tip was placed into an epidural needle.²² The needle was moved around in the subdermal plane following tumescent anesthesia. Seventeen patients were treated with subdermal 1064 nm laser (7,000 to 12,000 J/cm² were administered to each axilla). Ten patients (58.8%) had excellent reduction in HH as measured by comparison of before and after photos of the iodine starch test. One patient relapsed and required an additional treatment. AEs included one burn which was thought to be related to operator error, edema, seroma, scarring, sensory deficits related to concomitant nerve destruction, and temporary hair reduction. One case report described a 39-year-old African American woman with axillary HH symptoms resistant to traditional treatments.²³ She was treated with a subdermal 1320 nm Nd:YAG, a total of 8,810 J were delivered to each axilla.²³ This treatment demonstrated complete resolution of symptoms for 18 months after a single treatment, with no AEs and high patient satisfaction.^23,24 The 1320 nm wavelength may be particularly effective due to its high absorption in the dermis, where the eccrine glands are located.²³ While laser therapy offers minimally invasive alternatives for HH, further long-term studies are needed.

Conclusion

The past decade has seen significant advancements in the treatment of HH, with various therapeutic options now available. These include topical and oral treatments, BTX injections, device-based therapies like microwave thermolysis, and emerging laser-based therapies. Treatment selection is tailored to the patient’s goals while balancing the benefits and risks of each therapeutic option.

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