Hyperhidrosis is characterized by excessive sweating, and is often due to autonomic dysfunction inducing the hypersecretion of eccrine sweat glands.1 It affects nearly 5% of the population,2 and usually starts between the ages of 14 and 25.1,2 Hyperhidrosis can be categorized as primary (in over 90% of the cases), or secondary. Primary hyperhidrosis (PH) is associated with excessive neurogenic activity on normal eccrine glands. Its pathophysiology is complex and can be due to a dysfunctional autonomic nervous system, and/or abnormal emotional control.3 Secondary hyperhidrosis is induced by various disorders such as infections, neoplasms, neuroendocrine disorders, or drugs (Table 1).1

Focal hyperhidrosis (FH) is the most common form of PH and typically affects the armpits, palms, soles, groin, inframammary fold, and/or craniofacial area.1 It can trigger skin maceration, fungal or bacterial infections, and irritative dermatitis. FH can have a significant impact on the patients’ quality of life, affecting social activities, exercise, work, and studies.4–6 A recent systematic review found rates of anxiety in up to 49% of these patients, and rates of depression in up to 60% of them.5 In Spain, a cross-sectional study (n = 100) described a 20% rate of depression and a proportional relationship between the severity of hyperhidrosis and depressive symptoms.4 Hyperhidrosis runs underdiagnosed and undertreated in children, and can impact the quality of life significantly, even in children younger than 12 years.7

The management of FH is complex. There are multiple topical, systemic, minimally invasive, and surgical alternatives currently available. Topical antiperspirants are generally recommended as a first-line therapy, especially to treat cases of mild FH.8 In cases of moderate-to-severe FH that remain unresponsive to topical antiperspirants, topical anticholinergics,8 or oral anticholinergics,9,10 botulinum toxin injections,11,12 and various devices such as iontophoresis, radiofrequency,13 ultrasound, and microwave thermolysis14 are often used. In refractory cases, various surgical techniques such as sympathectomy can be useful.15 In this article, wéll be reviewing the role of topical anticholinergics in the management of HF in both children and adults.

In prepubertal individuals, FH primarily affects the palms and soles in 90% of the cases followed by the armpits and the face (15% and 6%, respectively).1,16 In adults, the most common location is the armpits (50%), followed by the soles of the feet (30%), palms (24%), and face (10%).1 Simultaneous involvement of multiple regions of interest is a common finding.1 FH may have a lower prevalence in the elderly, suggesting regression of the condition in advanced age.1

In most cases, the diagnosis is clinical. However, in patients in whom hyperhidrosis appears past the age of 25 with generalized, asymmetrical, or unilateral hyperhidrosis, or during sleep, or with systemic symptoms (Table 1) secondary hyperhidrosis should be ruled out, and the corresponding additional tests should be performed based on clinical suspicion. The most common secondary causes are endocrine disorders such as diabetes mellitus, hyperthyroidism, and hyperpituitarism, followed by neurological disorders.17

Among the assessment scales used in the management of hyperhidrosis, the most widely used ones, according to a recent systematic review, are the Hyperhidrosis Disease Severity Scale (HDSS) (Table 2), and the Dermatology Life Quality Index (DLQI). A different scale used is the Hyperhidrosis Quality of Life Index (HidroQoL).6 An objective method of assessment is to measure sweat production by gravimetry.

The goals of hyperhidrosis treatment are to reduce sweating and improve the patients’ quality of life. This can be achieved by reducing sweat production by the sweat glands, and/or the number of these.11 Some basic recommendations18 are summarized in Table 3.

Overall, topical antiperspirants are recommended as the first-line therapy to treat axillary and palmoplantar FH.11,18 However, they tend to be more effective in milder forms.11 Antiperspirants are over-the-counter topical products that contain mineral salts, such as aluminum salts, in various concentrations (6%,19 15%,20 20%,21,22 or 30%,23 among others). Their adverse events (AEs) include local irritation.18 Table 4 explains the mechanism of action and recommendations for their use. Despite being widely used in the routine clinical practice,24 we have not found any studies conducted in children to date on the use and tolerability of antiperspirant products (aluminum salts).

Anticholinergics reduce sweating by competitively blocking the muscarinic receptors of acetylcholine in the eccrine sweat glands.

The management of hyperhidrosis can be complex, with multiple therapeutic alternatives available, including pharmacological treatments, medical devices, or surgical procedures. Table 6 shows the advantages and disadvantages of these therapies. Currently, the FDA-approved pharmacological therapies to treat AH include topical glycopyrronium and botulinum toxin A (BTX-A).15,18 No other drugs have ever been approved by the FDA for the management of FH in different parts of the body. Systemic anticholinergics such as oral oxybutynin are widely used off-label in the routine clinical practice, both in children and adults, with multiple studies showing good results to treat FH in general (axillary, palmoplantar, and craniofacial) with acceptable tolerability.10,15,46–51 Multiple RCTs, prospective studies, and systematic reviews support the effectiveness and tolerance of topical anticholinergics to treat FH, including AH, PH, PPH, and CFH.11,24,42,52. Topical glycopyrronium, which has been evaluated in, at least, 8 RCTs (including nearly 2000 patients)25–28,31,36,37is the topical drug on which more evidence has been accumulated to this date. Its use may limit the development of anticholinergic symptoms such as xerostomia seen in nearly 12% of the patients on long-term topical glycopyrronium therap.25 However, it is present in around 75% of the patients treated with systemic anticholinergics such as oxybutynin.10 It can also reduce serious AEs, and the risk of therapy discontinuation, reported in 2.7% of the cases on long-term topical glycopyrronium, and 17% of the patients on oral oxybutynin.49 We should mention that in recent years, several studies have suggested that there is an association between the use of systemic anticholinergics and the development of dementia, and caution is advised when prescribing them to middle-aged or elderly patients.53,54 Topical glycopyrronium has a level of evidence 1+, and a grade A recommendation for the management of AH, according to the Scottish Intercollegiate Guidelines Network (SIGN) classification.

Until recently, topical glycopyrronium had to be compounded in Spain, at a high cost, which limited its use. However, in April 2023 it became available in Spain as a pharmaceutical product (Axhidrox, Cantabria Labs), with an annual cost of nearly €200 for the 1st year (and then €160/year). It was already available in, at least, 11 European countries. It has been approved by the European Medicines Agency (EMA) and the Spanish Agency of Medicines and Medical Devices (AEMPS) to treat AH in adults. It is the only topical anticholinergic approved by the AEMPS for the management of AH. Regarding its topical administration, 2 pulses of the product (cream) should be applied to each armpit every night within the first 4 weeks, and then, starting on week 5, 2 pulses per armpit 2 nights/week. Other glycopyrronium formulations can also be commercially found in North America. Thanks to its efficacy and safety profile, we believe it could be considered as a first-line pharmacological treatment for moderate/severe AH in adults (after failed topical antiperspirant therapy). Regarding its use in other parts of the body (palms/soles and craniofacial area), we should mention that most clinical trials and evidence currently available come from patients with AH, and it is not currently approved for use in such locations. However, we believe that the safety profile of topical glycopyrronium, along with logistical issues (cost and availability), would allow its off-label consideration for the management of PH, PPH, and FH with a poor response to other treatments, or in the absence of other therapeutic alternatives. Patients should be advised to avoid touching their eyes with the product, especially when applied to the face or hands, to avoid mydriasis and transient blurred vision. Other therapeutic alternatives that should be considered for different types of FH include oral anticholinergics such as oxybutynin (level of evidence 1- and grade B recommendation), iontophoresis, especially useful in cases of palmar and/or plantar FH, which could be limited by its cost (although not particularly expensive in the mid-term) and availability,24 and BTX-A injections (level of evidence 1+ and grade A recommendation to treat AH), which are highly effective but may also be limited by availability, cost, and (especially in children) the pain associated with the procedure. In refractory cases, various medical devices, and surgical procedures such as sympathectomy can be considered.18

Pediatric FH has been misrepresented in clinical trials despite the impact it can have on this population.24 In this subgroup, the assessment of the risk-benefit ratio plays a predominant role and should be carefully considered.24 (Table 6) Despite the lack of studies in children, antiperspirants with aluminum salts are widely advised as the initial treatment for AH, PH, and PPH in children.24 Topical glycopyrronium has shown good efficacy and an excellent safety profile in 2 RCTs including children,2,34 making it a potential first-line pharmacological treatment for refractory moderate/severe AH in children on topical antiperspirants. Its use has been approved to treat AH, but it can also be a valid alternative to treat PH and PPH. Oral oxybutynin has also been successfully used with good tolerance in children.16 It is advisable to titrate the dose, starting from 2.5mg and up-titrate gradually, while anticipating expected AEs such as xerostomia. Iontophoresis and BTX-A are other alternatives that should be considered. We have not found any trials in children on minimally invasive therapies to be able to make recommendations in this regard. Sympathectomy remains the last resort for non-responders.

This review is limited by its narrative nature and is not a systematic literature review. Additionally, many of the studies analyzed are retrospective in nature, or have heterogeneous methodologies, with various evaluation methods and follow-up periods. Additionally, no well-designed comparative studies have ever been conducted assessing the superiority of one agent over the other. However, we should mention that there is a pretty large number of RCTs available.

FH is a prevalent condition with the potential to impact the patients’ quality of life significantly. Based on safety, efficacy, and cost, we consider that topical glycopyrronium could be the first pharmacological option to treat moderate/severe AH refractory to topical antiperspirants in both children and adults. In other parts of the body, such as palms, soles, or the facial area, topical glycopyrronium could also be considered as an alternative in refractory cases to other treatments, although its use would be off-label. It would be interesting to develop new RCTs to assess its utility in these cases.

None declared.

Daniel Morgado Carrasco, and Raúl de Lucas declared to have received fees from Cantabria Labs.