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Examining Hyperhidrosis: An Update on New Treatments
Carolyn I. Jacob, MD
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Examining Hyperhidrosis: An Update on New Treatments

Carolyn I. Jacob, MD
Primary hyperhidrosis is a debilitating condition that causes significant distress and financial burden for affected patients, triggering them to seek medical care for their excessive sweating. Once a diagnosis of primary hyperhidrosis has been established, treatment is initiated to help control sweat production and increase quality of life. While there are no current guidelines in the United States for the treatment of primary hyperhidrosis, there are International Hyperhidrosis Society guidelines that clinicians can use. Currently, a step-therapy approach with the least invasive treatments prioritized first is recommended; the patient’s reported disability should also be taken into consideration when selecting a first-line treatment. This update will discuss new treatment modalities, surgical procedures, associated comorbidities, and the impact on managed care of hyperhidrosis, so clinicians can tailor therapy, improve outcomes, and increase patient satisfaction.
Am J Manag Care. 2018;24:-S0
Hyperhidrosis is defined as excessive sweating beyond what is physiologically required for the body to thermoregulate.1 Excessive sweating can lead to significant impairment in the affected individual’s social life, mental health, and work/study life.1 Hyperhidrosis is classified as either primary or secondary, and determining the etiology is important for treatment. Primary hyperhidrosis is idiopathic and usually involves excessive sweating of axillae, palms, soles, face, scalp, or inguinal folds. Secondary hyperhidrosis results either from a medical condition or the use of medication and is focal or generalized. About 90% of hyperhidrosis cases are primary and affect the axillae.2,3

Recent studies indicate that the prevalence of Americans affected by hyperhidrosis is higher than originally determined. However, less than half of patients discuss the issue with their doctor.3 The exact mechanism causing primary hyperhidrosis is not well understood. It is thought that increased or uncontrollable sympathetic stimulation (via acetylcholine) of the eccrine sweat glands may be responsible for the excessive sweating.4 Furthermore, it is known that individuals with primary hyperhidrosis have a higher-than-normal basal level of sweat production and an increased response to normal stimuli such as stress.4 Once a diagnosis of primary hyperhidrosis has been determined, treatment is initiated to help control the sweating and increase the patient’s quality of life (QOL).

In the United States, there are no official guidelines for the treatment of hyperhidrosis. Therefore, most practitioners use the clinical guidelines of the International Hyperhidrosis Society (IHHS) with treatment algorithms for primary axillary, facial, gustatory, palmar, plantar, and generalized hyperhidrosis.5 The IHHS recommends a step-therapy approach in which patients would use conservative therapies first and step up to more invasive treatments depending on their responses.5

Nonsurgical Treatment Options

The IHHS guidelines recommend the use of topical antiperspirants as first-line treatment of primary focal hyperhidrosis.5 Patients with primary axillary hyperhidrosis often use nonprescription products (eg, zirconium salts), typically labeled as “clinical strength,” with good success. Patients who do not achieve relief will often seek care from their healthcare professional for something more effective, such as prescription topical or oral pharmacologic agents. The most common agents used orally for the treatment of hyperhidrosis are anticholinergic medications that competitively inhibit acetylcholine at muscarinic receptors.6 These agents work quickly, with most individuals seeing some improvement within a week of starting. Limitations of their use include large dose adjustments and subsequent adverse effects (AEs), such as xerostomia, blurred vision, sedation, and urinary retention.6,7

Topical and Systemic Agents

Aluminum chloride. Aluminum chloride (usually 20%) is a prescription antiperspirant that is a first-line treatment of axillary hyperhidrosis. The mechanism of action of aluminum chloride is 2-fold: obstruction of the eccrine sweat glands and destruction of the secretory cells.1 Proper education for application of this product is important to improve efficacy and decrease irritation. For example, topical aluminum chloride should be applied nightly for 1 week on dry, sweat-free skin (left in place for 6-8 hours) until desired sweat reduction occurs.5 Afterward, patients can extend the application interval to maintain their desired sweat control. The most common AE of aluminum chloride is skin irritation due to the formation of hydrochloric acid that results from the interaction between aluminum chloride and sweat present on the skin.5 If irritation occurs, the patient may apply topical hydrocortisone cream and should be advised to decrease frequency of application of aluminum chloride.

Glycopyrrolate. Glycopyrrolate is used off label for the treatment of primary hyperhidrosis. Its approved indication is for adjunctive treatment for peptic ulcer disease and chronic drooling but is known to decrease sweat production. Glycopyrrolate competes with

acetylcysteine at muscarinic receptors, causing anticholinergic effects.8 Furthermore, because glycopyrrolate has a quaternary ammonium group, it is highly polar and cannot pass the blood–brain barrier, limiting its central nervous system effects. Multiple studies have evaluated the efficacy of glycopyrrolate in the treatment of hyperhidrosis.8-13 For example, a 2012 study by Lee et al reported that glycopyrrolate (1 mg twice daily, then 2-8 mg/day) resulted in a 75% reduction in perspiration (P <.0001).8 In addition, the Milanez de Campos scale showed a significant change in mean scores (57.9 compared with 38.7).8 A 2017 systematic review by Cruddas et al was not able to collate outcome measures for glycopyrrolate due to too much variability.14 Treatment doses ranged from a start of 1 mg every other day or daily to doses that were increased gradually to 6 mg per day. Dry mouth was reported in 38.6% (range, 27.8%-63.2%) of individuals taking glycopyrrolate.14 For patients with craniofacial hyperhidrosis, pharmacy-compounded topical glycopyrrolate 2% can be used as a first-line treatment agent.15,16 This product can be applied every 2 to 3 days; it has a 96% success rate and nominal AEs.15,16

Glycopyrronium tosylate. Glycopyrronium tosylate (GT) is an anticholinergic treatment approved by the FDA for axillary hyperhidrosis in June 2018.17 It was the first therapy approved since miraDry and botulinum toxin (Botox) were approved for use.18 A topical therapy applied once daily to the axillae using a premoistened cloth, GT (Qbrexza) is approved for use in the United States for patients 9 years and older.19 In clinical trials, symptoms of sweating were improved as early as 1 week after starting treatment.20 Furthermore, pooled trial results showed that after 4 weeks, sweating severity improved by about 32% (vs 5% with placebo).20 AEs were mild to moderate and included dry mouth (16.9%-24.2%), erythema/area redness (17%), and burning/stinging (14.1%).20,21 The ATMOS-1 and ATMOS-2 trials were replicate, randomized, double-blind, vehicle-controlled, 4-week phase 3 trials. Coprimary end points were responder rate (≥4-point improvement from baseline) on item 2 (sweating severity) of the Axillary Sweating Daily Diary (ASDD) along with absolute change from baseline in axillary gravimetric sweat production at week 4.20 Pooled data from ATMOS-1 and ATMOS-2 showed that more GT-treated patients achieved ASDD item 2 response compared with vehicle (59.5% vs 27.6%) and had reduced sweat production from baseline (–107.6 mg/5 min vs –92.1 mg/5 min) at week 4 (P <.001 for both coprimary end points).20 Fewer than 4% of participants discontinued use of GT due to AEs.

Propantheline. Propantheline bromide and methantheline bromide are 2 other agents that are commonly used off label for the treatment of hyperhidrosis. Evidence for propantheline bromide is anecdotal, as no trials support its efficacy.14 However, it is still used as a secondary treatment for its anticholinergic properties. In addition, oral propantheline was studied by Danish researchers in the 1960s for the treatment of hyperhidrosis; it was found to be effective but had undesirable atropine-like AEs (eg, dry mouth and blurry vision).22 Topical propantheline bromide 5% solution (equal parts ethanol and glycerol) was also found to be effective, especially for axillae and plantar hyperhidrosis, without the AEs seen with oral therapy.22 More recently, a 2017 systematic review by Cruddas et al found reductions of 41% in axillary sweating and 16.4% in palmar sweating, and a 40.9% increase in the Dermatology Life Quality Index score with propantheline use.14

Oxybutynin. Oxybutynin is an FDA-approved muscarinic antagonist that is indicated for overactive bladder. Due to its anticholinergic properties, it is used off label for the treatment of primary hyperhidrosis and has been shown to be safe and effective.23 A systematic review by Cruddas et al showed that oxybutynin 2.5 mg daily (up to 10 mg daily) improved symptoms by an average of 76.2% (range, 60%-97%) and also improved QOL in 75.6% (range, 57.6%-100%) of patients.14 Dry mouth (the most common AE) occurred in 73.4% (range, 43.3%-100%) of patients who were taking 10 mg/day. In addition, patients may experience constipation, urinary retention, tachycardia, blurry vision, and drowsiness. As a result of these associated AEs, about 11% of patients stop taking oxybutynin despite good control of hyperhidrosis.14,24 In addition, there are many patients for whom oxybutynin would not be an appropriate treatment, such as geriatric patients and anyone with gastrointestinal disorders, urinary retention, or glaucoma.

Oxybutynin is now available in a different dosage form and/or combination that may be more tolerable. For example, transdermal oxybutynin was recently studied by Millán-Cayetano et al in oxybutynin-naïve patients and patients previously treated with oral oxybutynin.23 The study had a small sample size, but results indicated that transdermal oxybutynin may be more effective in patients who have not previously taken oral anticholinergic drugs.23 The authors concluded that larger studies are necessary to confirm their findings. Transdermal oxybutynin is available without a prescription. Patients should be counseled to rotate application sites and be informed that anticholinergic AEs usually are mitigated but are still possible with the transdermal patch.25 Another randomized study evaluated the safety, efficacy, QOL impact, and dry mouth AE of THVD-102, a fixed-dose combination of oxybutynin (7.5 mg) and pilocarpine (7.5 mg) in patients with primary focal hyperhidrosis.21 Results of the study showed no significant differences between THVD-102 and oxybutynin in primary focal hyperhidrosis. Furthermore, there was a statistically significant difference in reported dry mouth, with participants reporting less severe dry mouth with THVD-102 compared with oxybutynin.21

 
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