An evolving answer to excess sweating

Human bodies evolved to keep cool in the most blazing treeless landscapes, from Tanzania to Tucson, but even sweat glands need to cool down sometimes. This is the case for the rare but intrusive condition hyperhidrosis. For people with this condition, their hands, feet, underarms, head, groin, and scalp begin to sweat excessively. Hyperhidrosis appears spontaneously and early, according to Mark Ferguson, a thoracic surgeon and sweat specialist at the University of Chicago. “We'll see patients as early as middle school.”

Localized excessive sweating, or “focal" hyperhidrosis, can debilitate kids and adults (1). Skin infections turn up. Handling doorknobs and phones becomes a test. Socializing morphs from fun into a source of tremendous anxiety. “Sometimes they don't develop friendships, don't go out much, don't interact with groups,” he said. “It's very isolating.”

Sometimes they don't develop friendships, don't go out much, don't interact with groups. It's very isolating.
– Mark Ferguson, University of Chicago

Genetics likely play a role, but the exact cause remains unclear (1). What researchers know is that signals from the nervous system send sweat glands into overdrive. “It’s a sort of orphan condition,” Ferguson said. “One that isn't talked about much and isn't well understood.”

Pharmaceutical researchers hope to provide better solutions for the millions of people with sweat conditions. “We don't have the magic bullet yet,” said David Pariser, a dermatologist with the Eastern Virginia Medical School, but as researchers’ understanding of the science underlying hyperhidrosis evolves, the landscape for new and more effective treatments is larger than ever and continues to grow.

Targeting the source

One way to block excessive sweat is simply to stifle the body’s sweat-inducing communication with the sweat glands. Botox, the brand name for the botulinum toxin, is among the most common methods for doing so because it blocks neurons from releasing acetylcholine.

Acetylcholine stimulates nerves and signals to muscles to contract. In the same way that Botox cosmetic injections temporarily paralyze forehead muscles, Botox hand injections block the neuromuscular stimuli that drench people’s palms with sweat. The neurotoxin is a sledgehammer in theory, but in practice, targeted injections leave the sweat glands alone while halting the signals to them (2).

The doctor makes injections of botulinum toxin on the palms of a woman against hyperhidrosis.

Botox injections are one of the most effective treatments for excessive hand sweating.

Credit: iStock/dimid_86

“Botox injections, when done properly, give the best results of anything,” Pariser said. Clinicians already use Botox to stop sweating in underarms, hands, and feet. “Sweating in the underarm can be reduced to near zero almost all the time.” The treatment is 80 to 90 percent effective on hands (3).

The effect fades, however. Most people sweat more within a couple of months after treatment and go back to square one within the year, so patients must repeat injections indefinitely. That gets expensive, Pariser said, especially for feet and hands, which require at least twice as much of the neurotoxin as underarms.

Another strategy is to scorch the sweat gland directly. MiraDry, a handheld device approved by the FDA in 2011, delivers microwave radiation to the underarm (4). “It literally fries the sweat glands with microwaves,” Pariser said. It’s minimally invasive, available in more than 50 countries, and permanent. Some doctors opt for near infrared lasers developed for fat removal to destroy sweat glands (5).

Results from a recent clinical trial at Johns Hopkins University showed that MiraDry reduced sweating and reduced anxiety among 24 participants (6). The study volunteers received one or two sessions of microwave treatment and were examined for sweat severity, along with symptoms of anxiety, depression, and social avoidance. About half of the participants initially reported social anxiety. Although two microwave sessions were optimal for reduced sweating, the psychological improvements appeared after just one session.

Still, these approaches are less efficacious than Botox, and although permanent, MiraDry is only approved for use in underarms. For both a permanent and more powerful result, surgery is a potential option. During surgery, thoracic surgeons like Ferguson snip the sympathetic nerves near the ribs to halt their ability to signal to the sweat glands. The nerves don’t regrow, and Ferguson estimates an 80 percent success rate in underarms and up to a 99 percent success in hand sweating. “They're back at full speed very quickly. I tell the kids who are in school that if I operate on Thursday or Friday, they should be back in gym class on Monday,” he said.

Surgery, however, is not for everyone. The best candidates are those whose symptoms are focal, daily, spontaneous, and develop at a young age. Needless to say, it’s a major operation. “In my mind, everybody has to have failed a good try at conservative therapy before we discuss the possibility of surgery,” Ferguson added.

Pariser too urges caution for people considering surgery. “I would almost never do it for the underarms, no matter whether they failed one, two, five, or 20 treatments,” he said. Lasers, microwaves, and Botox perform about as well as surgery for underarms, and nerve surgery carries a serious risk called compensatory sweating, which causes more sweating elsewhere. The sweat glands are fine, but nerve function goes awry. “I tell people, there's nothing the matter with the light bulb. It's the switch that's stuck in the on position,” said Pariser.

The side effect is no joke. According to Pariser, patients call his society’s helpline almost weekly expressing thoughts of suicide because they sweat so much more than before. “I personally had a woman who had surgery for her hands,” he said. “She started sweating so much in her buttocks and groin, that she had to wear a diaper, or else she would sweat through her clothes and leave a puddle of sweat in the chair.” Statistics on compensatory sweating occurrence vary widely (7).

“There are stories over and over and over again about people who have this miserable complication, which you can't fix,” he added.

Off-label and on the rise

Besides clinical procedures like surgery, Botox, or MiraDry, there is a growing wave of research suggesting that off-label use of approved drugs could help treat hyperhidrosis too.

Oral anticholinergics, for example, prevent receptors in the nervous system from accepting acetylcholine. Different anticholinergics can treat bladder control, severe drooling, and peptic ulcers; patients with hyperhidrosis have reported off-label success with each (8).

“Those are good for some people,” Ferguson said, but oral anticholinergics dry out the whole system. That means reduced sweating but also dry mouth and eyes. Several long-term studies support use of the anticholinergic Ditropan in particular for hyperhidrosis, but about one third of patients who try oral anticholinergics off-label stop early because of side effects (9-12).

Topical anticholinergics can skirt systemic side effects, so some patients use bladder controlling gels off-label (13). Also, the FDA approved Qbrexza underarm wipes in 2018, which are individually sealed cloth sheets moistened with a solution of the anticholinergic molecule, glycopyrronium tosylate (14). Approximately 60 percent of clinical trial participants sweat significantly less after four weeks of treatment (15).

Researchers, including Pariser, are investigating topical anticholinergics further for treating hyperhidrosis. In 2021, he and his team reported a minimal risk of adverse events or systemic accumulation from topical anticholinergics (16).

Scientists also study how anticholinergics move through the skin to improve the drugs’ ability to treat excessive sweating in different parts of the body. In 2020, for example, researchers found that the skin from participants’ palms and soles absorbed the active ingredient in Qbrexza 40 times less effectively than underarm or abdomen skin (17). The researchers also discovered that “occluding” the treatment, by sealing it with a parafilm or saran wrap dressing for constant contact increased drug delivery up to 10-fold (17).

Topical anticholinergics may be especially handy for patients with amputated limbs, according to Stephanie Zone, a dermatologist at the University of Utah who has studied hyperhidrosis for more than 12 years. “One of the biggest problems that amputees have is that they sweat so much at the site of amputation that their prosthetics don't fit,” Zone said.

One of the biggest problems that amputees have is that they sweat so much at the site of amputation that their prosthetics don't fit.
- Stephanie Zone, University of Utah

Patients tell Zone that they can walk, run, and bike, thanks to wonderfully enabling prosthetics. After a few minutes of exercise, however, the sweat becomes a surprisingly disabling problem. “This is not a normal amount of sweating,” she said. “This is pooling sweat in the prosthetic.”

Some researchers have evaluated injecting Botox to amputation sites. That can be very effective, Zone explained, but it’s unsustainable for most people because amputation sites are so large (18). “You're going to need to put Botox essentially every two centimeters over that entire area,” she said. That could mean hundreds of shots every three months. “I really thought there was an opportunity for at-home, less interventional treatment.”

This expensive drawback led Zone to develop a trial of Qbrexza for the quality of life of patients with prosthetics (19). Each participant wiped either glycopyrronium tosylate cloths or placebo cloths on the skin and prosthetic. After four weeks, they switched to the other. Preliminary results suggest that the drug does improve prosthetic use. However, she noted, the results haven’t yet been published, and it’s possible that occluding the active ingredient like this brings minor side effects. The amputation site may absorb too much of the drug.

The hyperhidrosis horizon

With clinical procedures and off-label strategies, there is no shortage of treatment options for people with hyperhidrosis, but researchers are still eager to develop more effective treatments with the fewest side effects possible.

With topical aluminum and anticholinergics, “We hear from patients that there's burning and stinging to the point where they discontinue treatment,” said Howie McKibbon, chief executive officer of the pharmaceutical company Botanix Pharmaceuticals who has helped develop dermatological drug candidates for a handful of companies since 2010. He has worked to relieve conditions from atopic dermatitis to psoriasis, and now, at Botanix Pharmaceuticals, McKibbon develops a topical gel for underarm sweating, called Sofdra.

Sofdra is a 15 percent gel of sofpironium bromide, a novel anticholinergic designed specifically for hyperhidrosis. Botanix Pharmaceuticals researchers found that it reduced sweat meaningfully in 85 percent of clinical trial participants.

Botanix Pharmaceuticals expects US regulators to approve its anticholinergic gel by June 2024 (20). A five percent formulation of the gel already earned approval in Japan through Botanix Pharmaceuticals’s partner Kaken Pharmaceutical, which sold about 300,000 units in their second full year of sales, according to Botanix Pharmaceuticals.

“We believe that there's a place right up front to utilize this product,” McKibbon said, “before you get to Botox and certainly before you get to surgery.”

He is excited to give patients with hyperhidrosis a new option to help treat the condition. “It's the first new chemical entity that will ever be approved for hyperhidrosis,” McKibbon said. However, he noted, the chemical efficacy that researchers attain is important if patients want to use it, so Sofdra’s approval also includes its accompanying applicator device that keeps use safe and easy. “The focus has to be on the patient,” he said.

Other research groups are also developing minimally invasive options for excessive sweating. Atacama Therapeutics is evaluating whether its oral anticholinergic candidate can treat palm sweating. And California-based Candesant Biomedical recently revealed the first ever “sweat patch” to stem excess sweating called the Brella patch. This patch releases elemental sodium which reacts with water from sweat to produce heat that shuts down sweat glands. According to Candesant Biomedical, the “targeted alkali thermolysis” effect lasts up to four months and requires only one three-minute doctor visit (21). Regulators approved the patch for underarms in April 2023 (22).

Candesant Biomedical and Botanix Pharmaceuticals both plan to address palm and foot sweating as well. The sweat patch company is approaching feasibility testing for palm, facial, and foot hyperhidrosis (23). The challenge facing the gel, according to McKibbon, is that skin is harder to penetrate in the hands and feet. Botanix Pharmaceuticals may therefore use a patented technology called Permetrex to aid drug delivery. Permetrex formulations cause inactive ingredients to evaporate faster. This increases the concentration of the active ingredient on the skin and may drive better absorption.

Phase 3 results from a long-term trial in Germany revealed that another topical anticholinergic, glycopyrronium bromide cream, meaningfully reduces underarm sweating (24). As of last year, regulators from 12 European nations approved the topical cream developed by the German company Dr. Wolff Group. An American firm Therapeutics, Inc plans to test the cream against anticholinergic cloth wipes, according to the International Hyperhidrosis Society (25).

Improvements may even be on the horizon in surgery. Surgeons claim to have improved the thoracic surgical procedures by, for example, placing a clip on nerves instead of cutting them (26). The idea is that surgeons could preserve the nerves to reverse the clipping if patients pick up compensatory sweating after the fact. Other recent surgical studies have sought to predict compensatory sweating or reverse it with another surgery (27,28). However, neither Pariser nor Ferguson are yet convinced by any of the improvements.

Whatever the approach, hyperhidrosis researchers relish any uptick in awareness of the disease, especially because the demand for new drugs is so real. “They're looking for an answer,” McKibbon said of patients. “We have to put the information out there and remove any guilt that they might have that this isn't a real disease — show the empathy that's necessary — but then ultimately give them a product that works.”