JEADV
DOI: 10.1111/jdv.12518
ORIGINAL ARTICLE
Efficacy and safety of topical glycopyrrolate in patients with facial hyperhidrosis: a randomized, multicentre, double-blinded, placebo-controlled, split-face study M.Y. Hyun, I.P. Son, Y. Lee, H.G. Choi, K.Y. Park, K. Li, B.J. Kim,* S.J. Seo, M.N. Kim, C.K. Hong Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea *Correspondence: B.J. Kim. E-mail: [email protected]
Abstract Background Although facial hyperhidrosis has been frequently associated with a diminished quality of life, various conservative modalities for its management are still far from satisfactory. Objective To evaluate the antiperspirant efficacy and safety of the topical glycopyrrolate on facial hyperhidrosis at specified posttreatment intervals. Methods Thirty-nine patients with facial hyperhidrosis were enrolled and treated with 2% topical glycopyrrolate on one-half of the forehead, whereas the other half of the forehead was treated with a placebo. All patients applied topical glycopyrrolate or placebo once a day for nine successive days. Each evaluation included weighing sweat and assessing the Hyperhidrosis Disease Severity Scale (HDSS) score and any adverse effects. Results Compared with the placebo-treated sides, topical glycopyrrolate-treated sides showed a reduction in the rate of sweat production at the forehead of 25.16 10.30% (mean SD) at 90 min after the first application (day 1), 29.63 7.74% at 24 h after the first application (day 2) and 36.68 11.41% at 24 h after eight additional successive daily applications (day 10) (all P < 0.025). There was a little more decrease in HDSS score with the topical glycopyrrolate-treated half of the forehead, but the difference was not statistically significant (P > 0.025). No serious adverse events were reported during the course of this study. Only one patient developed a transient headache after treatment. Conclusion Topical glycopyrrolate application appears to be significantly effective and safe in reducing excessive facial perspiration. Received: 10 October 2013; Accepted: 17 March 2014
Conflicts of interest None declared.
Funding sources None declared.
Introduction Hyperhidrosis is defined as excessive sweating beyond what is expected for thermoregulatory need and environmental conditions.1 Hyperhidrosis may be primary (likely resulting from overactivity of the sympathetic nervous system) or secondary to general medical conditions (including endocrine, neurologic, cardiovascular, infectious and neoplastic diseases) or pharmacologic effects.2 Criteria for the diagnosis of primary hyperhidrosis include focal, visible, excessive sweating of at least 6 months in duration without apparent cause, plus at least two of the following additional features: (i) bilateral and relatively symmetric distribution; (ii) at least one episode weekly; (iii) impaired daily activities; (iv) cessation of focal sweating during sleep; (v) onset before 25 years of age; and (vi) family history of primary focal hyperhidrosis.2 Although it is not usually a cause of major
JEADV 2015, 29, 278–282
morbidity, it is an occupationally disabling and socially embarrassing problem to those afflicted. Most commonly, primary hyperhidrosis appears on the axillas or palms but can also appear on the soles of the feet and the face. Features of facial hyperhidrosis include excessive and localized sweating on the scalp, forehead, nose and upper lip that can be triggered by heat and stressful stimuli.3 Although facial hyperhidrosis has been clinically overshadowed by palmar, plantar, and axillary hyperhidrosis, it can cause considerable psychological and social distress. Typical methods of treatment include the topical application of aluminium chloride or anticholinergic drugs, ionospheresis, oral medications, the hypodermic injection of botulinum toxin, sympathetic nerve block using alcohol, or sympathectomy. These methods each have advantages and disadvantages according to their mechanisms of action. The preferred treatment method for
© 2014 European Academy of Dermatology and Venereology
Topical glycopyrrolate in facial hyperhidrosis
primary hyperhidrosis should be one that is non-invasive and simple, with few complications and a low financial burden.4 In this regard, topical application can be a good initial treatment method, and topical anticholinergic agents have been reported to be an efficacious treatment for excessive facial sweating.4–6 This study investigated the efficacy and safety of topical glycopyrrolate on the symptoms of primary facial hyperhidrosis.
Materials and methods Inclusion criteria of subjects were as follows: (i) Healthy male or female aged 20–66 years; (ii) perspiration level of at least 100 mg of sweat for 20 min on each side of the forehead; (iii) criteria for the diagnosis of primary hyperhidrosis; (iv) a score of at least 3 on the Hyperhidrosis Disease Severity Scale (HDSS) during baseline evaluation (Table 1); and (v) not enrolled the similar clinical study during 6 months. Patients with facial hyperhidrosis for less than 6 months or with generalized or secondary hyperhidrosis were excluded. The study was performed in accordance with the Declaration of Helsinki (1975) and was approved by the institutional review board of Chung-Ang University Hospital and St. Paul Hospital. Before enrolment, patients were informed of the study procedures, risks, benefits and complications and provided written informed consent. We used 2% topical glycopyrrolate that was impregnated in cotton pads (SecureTM, Sung-Kwang Pharm. Co., LTD., Cheonan, Korea), which allowed the agent to be simply wiped onto the skin (Fig. 1). The placebo was identical in size and odour, etc.
Table 1 HDSS (Hyperhidrosis Disease Severity Scale). The scale is based on the question: ‘How would you rate the severity of your hyperhidrosis?’ Score
Patient response
1
My sweating is never noticeable and never interferes with my daily activities
2
My sweating is tolerable but sometimes interferes with my daily activities
3
My sweating is barely tolerable and frequently interferes with my daily activities
4
My sweating is intolerable and always interferes with my daily activities
(a)
279
The difference was whether or not it contained glycopyrrolate (Table 2). All patients were instructed to wash his or her face with soap and water before application to ensure optimal absorption; they were also given a complete demonstration of how to apply the test products, and the possible complications were explained. After each patient’s forehead was thoroughly cleansed and dried with gauze, topical glycopyrrolate was lightly rubbed on one-half of the forehead, whereas the other half served as a control and was treated with placebo. Patients were warned to avoid touching their eyes, noses and mouths before washing their hands after application of the test products. Sweat collections were performed by placing absorbent pads on both sides of the forehead. The study followed a double-blinded, split-face design with a pair of test products. Each patient applied the test products to the forehead once a day for 9 days. Topical glycopyrrolate was assigned according to randomization by a computer program to either the right or left forehead, and the opposite forehead received the placebo. A total of four evaluations were conducted at the following time points: at baseline (screening), 90 min after the first application (day 1), 24 h after the first application (day 2) and 24 h after eight additional successive daily applications (day 10). Each evaluation included weighing sweat and assessing the HDSS score and any adverse effects. On day 1, the evaluation was conducted 90 min after test product application to allow time for drying and absorption of the test products. Sweat stimulation was induced by having the patients sit in a room with controlled environmental conditions with regard to temperature (36.6–38.9°C) and relative humidity (30–40%) (DY-101TH, Temperature & Humidity Control Unit, DaeYang ETS Co., LTD., Hwaseong, Korea). During the first 40 min of the sweat stimulation period, each patient held unweighed absorbent pads on his or her forehead. This preliminary
Table 2 Compositions of SecureTM and placebo Product Secure
TM
Placebo
Composition 2% glycopyrrolate, ethanol, purified water, cotton pad Ethanol, purified water, cotton pad
(b)
Figure 1 (a) Cotton pad (53 mm diameter) for applying 2% topical glycopyrrolate or placebo and (b) the container used to prevent evaporation.
JEADV 2015, 29, 278–282
© 2014 European Academy of Dermatology and Venereology
280
warm-up period was followed by successive 20-min collection periods during which the patient held weighed absorbent pads on his or her forehead. The amount of sweat collected was quantified by gravimetric assessment. At each evaluation, two round absorbent pads (diameter of 5.3 cm) were prepared and weighed on a high-precision laboratory scale (accuracy 0.1 mg; MS204, NewClassic MF, Mettler Toledo, Switzerland). Prepared absorbent pads were simultaneously placed on each half of the forehead for 20 min and were then reweighed. To prevent error induced by evaporation, both pads were weighed at the same time. The difference in weight between the prepared absorbent pads and the reweighed absorbent pads after treatment was interpreted as sweat production.7 We interviewed each patient at screening, days 1, 2, and 10. Patients were asked to complete a questionnaire evaluating their degree of satisfaction and any complications experienced. The HDSS was used to measure disease severity; it is a disease-specific scale for hyperhidrosis that provides a qualitative measure of the severity of the patient’s condition based on how it affects their daily activities. Patients selected the statement that best represented their experiences with facial sweating (Table 1). Statistical analyses were performed using SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Results were expressed as the mean SD. A one-tailed value of P < 0.025 was considered statistically significant. A Wilcoxon signed rank test was used to compare the difference between the weight of the absorbent pads at baseline and after treatment with topical glycopyrrolate or placebo. Comparison between the sweat production at baseline and the sweat production at each visit was calculated using the following formula: (sweat production for the placebo at baseline sweat production for the placebo at each visit) 9 (sweat production for the topical glycopyrrolate at each visit sweat production for the topical glycopyrrolate at baseline) 9 100. A decreased ratio or reduction of sweat production was calculated using the following formula: (sweat production for the placebo sweat production for the topical glycopyrrolate) sweat production for the placebo 9 100. The Wilcoxon signed rank test was also used to compare the HDSS score at baseline with the HDSS score at each visit. Repeated measure ANOVA was used to check interaction between time and groups.
Hyun et al.
64.95 11.12% at the third follow-up (day 10) (P values were all 0.025). Because there was no interaction between time and groups, time which only could be the deviation factor did not affect the results. Only one patient experienced a transient headache after applying topical glycopyrrolate. No patients
Figure 2 Comparison between the sweat production at baseline and the sweat production at each visit
Results Thirty-nine patients who met the study criteria were enrolled. Thirty males and nine females had a mean age of 29.38 9.63 years. No patients were excluded from the analysis. Five patients had ever used deodorant on their axillae but it did not work well. There was no patient who had ever received any treatments for facial hyperhidrosis. There was no significant difference between the prepared pads before administration of topical glycopyrrolate or placebo. Sweat production (per cent of baseline) was 76.47 7.30% (mean SD) at the first follow-up (day 1), 72.17 7.24% at the second follow-up (day 2) and
JEADV 2015, 29, 278–282
Figure 3 Per cent reduction rate of sweat production on the forehead treated with topical glycopyrrolate compared with the placebo-treated half of the forehead at the following time points.
© 2014 European Academy of Dermatology and Venereology
Topical glycopyrrolate in facial hyperhidrosis
281
Table 3 Changes in HDSS score (Mean SD) Visit
HDSS score SecureTM
Placebo
Baseline
3.05 0.22
3.05 0.22
Second visit (Day 2)
2.21 0.80
2.33 0.87
Third visit (Day 10)
1.97 0.96
2.15 0.96
Baseline – Second visit
0.69 0.69
0.54 0.60
Baseline – Third visit
1.08 0.98
0.90 0.97
P value
Baseline - Second visit
0.398
Baseline - Third visit
0.502
experienced skin allergies or local reactions during the course of the study, and all were free of dermal side-effects. More serious complaints, such as blurred vision, dry mouth, dizziness and other complications, were not observed.
Discussion Eccrine sweat glands primarily assist the body in regulating its temperature in response to heat exposure or exercise. In about 1% of the population, the sympathetic nervous system is overactive, causing certain areas of the body to sweat at inappropriate times and in excess of what is necessary to maintain thermal regulation. This disorder is known as primary hyperhidrosis.8 Although primary hyperhidrosis is typically not a cause of major morbidity, it presents an occupationally disabling and socially embarrassing problem to those afflicted. Most commonly, hyperhidrosis appears on the palms but can also appear on the face, soles and the axilla. The causes of secondary hyperhidrosis include a number of neoplastic and neurologic disorders, metabolic diseases and drugs. The cause in each case should be identified and treated accordingly. The treatment of facial hyperhidrosis remains difficult, and treatment methods can be divided into those which affect the sweat glands directly and those which modify their innervations.9,10 Topical agents including aluminium chloride, formaldehyde, glutaraldehyde and potassium permanganate have been used but only have a short-term effect.11–14 In addition, oral anticholinergics have been tried, but adverse effects such as blurred vision and urinary retention limited their efficiency.15 Other treatments such as the surgical excision of affected areas, for example, the eccrine glands of the forehead, have been useful in appropriate cases.16 More recently, endoscopic sympathectomy has been used but can result in significant adverse effects such as compensatory hyperhidrosis, cardiac sympathetic denervation and Horner’s syndrome.17 Treatment of hyperhidrosis using botulinum toxin has been frequently used lately but also has limitations as it is effective only in specific areas such as the forehead.18,19 Moreover, it is not easily applicable to the entire face due to its high cost and the potential of creating an asymmetrical face or limiting facial expressions.
JEADV 2015, 29, 278–282
Anticholinergics are able to inactivate sweat glands via the action of acetylcholine and may be more attractive to patients than simply occluding sweat ducts with aluminium compounds, which can cause itching, stinging and skin irritation. Glycopyrrolate is a drug originally developed for peptic ulcer disease but is now used frequently in hyperhidrosis treatment since it also has a perspiration suppression effect. Glycopyrrolate competes with acetylcholine at the muscarinic receptor to create an anticholinergic effect. In addition, it is a drug in the highly polar quaternary ammonium group and cannot pass through lipid membranes, so it cannot penetrate the blood–brain barrier and has little effect on the central nervous system. In contrast, atropine sulphate and scopolamine hydrobromide are highly non-polar tertiary amines which can easily pass through lipid membranes.20 Therefore, when applied topically in lotion or cream form or by other methods such as an aqueous solution, glycopyrrolate has been associated with few adverse effects. Although topical application is often used to avoid systemic side-effects, it can result in contact sensitization, and the high concentration of drug needed for sufficient absorption through the skin can affect cholinergic nerve endings that may lead to systemic absorption and adverse effects.21 Despite these concerns, topical glycopyrrolate was well tolerated by most patients in this study. Lee et al.22 reported review study of 36 cases with primary hyperhidrosis treated by oral glycopyrrolate. While taking medication, 36.1% of patients experienced side-effects, such as oral dryness (27.8%), palpitations (11.1%), headache (2.8%) and other (8.3%). Amy et al.23 reported similar study of paediatric patients with hyperhidrosis treated by oral glycopyrrolate. In that study, 31 children took at least one dose of oral glycopyrrolate, and side-effects were noted by 29% of children, most commonly dry mouth (26%) and eyes (10%) and were dose related. One patient developed blurred vision, which resolved with dosing below 5 mg/d; one patient experienced palpitations and discontinued the medication. But in the study of Kim et al.24 which examined efficacy and safety of topical glycopyrrolate to 25 patients with focal hyperhidrosis, one patient with a mild headache that occurred in the evening after treatment and no other side-effects or complications were reported. And in our study only one patient experienced a transient headache after applying topical glycopyrrolate. Those were the evidence of fewer anticholinergic adverse effects with topical glycopyrrolate than with systemic glycopyrrolate. We found that use of the 2% topical glycopyrrolate pad resulted in a significant reduction in sweat production. The amount of sweat was decreased, as the number of daily applications increased during this study. This suggests that the action of topical glycopyrrolate may have some additive features; however, a treatment-free long-term follow-up is needed to verify this idea. The degrees of subjective feeling which patients answered with questionnaire were most satisfactory at not only topical gly-
© 2014 European Academy of Dermatology and Venereology
282
copyrrolate-treated half of the forehead but also placebo-treated half of the forehead. It seems to be difficult to make a clear differentiation between right and left forehead in sensing the amount of perspiration, although there was apparent difference in the volume of sweating. Serious side-effects were not observed in any of our patients. The use of 2% concentration on the forehead prevents possible systemic side-effects, whereas >2% concentration may be appropriate for the treatment of hyperhidrosis on other sites of the body such as the palms and soles. Although glycopyrrolate appears to be a satisfactory antiperspirant without critical adverse effects, further investigation is necessary for the objective evaluation of its safety and long-term results on the face. In conclusion, the short-term outcomes of our gravimetrically controlled study demonstrated that a topical formulation of 2% glycopyrrolate in aqueous solution is an effective treatment option for controlling focal facial hyperhidrosis. Our study suggests that topical glycopyrrolate can be applied on a daily basis or before certain occasions, such as prior to social activities, since it is convenient to use and effective in a single application.
References 1 Solish N, Bertucci V, Dansereau A et al. A comprehensive approach to the recognition, diagnosis, and severity-based treatment of focal hyperhidrosis: recommendations of the Canadian Hyperhidrosis Advisory Committee. Dermatol Surg 2007; 33: 908–923. 2 Hornberger J, Grimes K, Naumann M et al. Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol 2004; 51: 274–286. 3 Eisenach JH, Atkinson JL, Fealey RD. Hyperhidrosis: evolving therapies for a well-established phenomenon. Mayo Clin Proc 2005; 80: 657–666. 4 Kavanagh GM, Burns C, Aldridge RD. Topical glycopyrrolate should not be overlooked in treatment of focal hyperhidrosis. Br J Dermatol 2006; 155: 487. 5 Seukeran DC, Highet AS. The use of topical glycopyrrolate in the treatment of hyperhidrosis. Clin Exp Dermatol 1998; 23: 204–205. 6 Luh JY, Blackwell TA. Craniofacial hyperhidrosis successfully treated with topical glycopyrrolate. South Med J 2002; 95: 756–758.
JEADV 2015, 29, 278–282
Hyun et al.
7 Kinkelin I, Hund M, Naumann M, Hamm H. Effective treatment of frontal hyperhidrosis with botulinum toxin A. Br J Dermatol 2000; 143: 824– 827. 8 Stolman LP. Treatment of hyperhidrosis. Dermatol Clin 1998; 16: 863– 869. 9 Stolman LP. Treatment of excess sweating of the palms by iontophoresis. Arch Dermatol 1987; 123: 893–896. 10 White JW. Treatment of primary hyperhidrosis. Mayo Clin Proc 1986; 61: 951–956. 11 Shelley WB, Laskas JJ, Satanove A. Effect of topical agents on plantar sweating. Arch Dermatol 1954; 69: 713–716. 12 Juhlin L, Hansson H. Topical glutaraldehyde for plantar hyperhidrosis. Arch Dermatol 1968; 97: 327–330. 13 Gordon BI, Maibach HI. Eccrine anhidrosis due to glutaraldehyde, formaldehyde, and iontophoresis. J Invest Dermatol 1969; 53: 436–439. 14 Jensen O, Karlsmark T. Palmoplantar hyperhidrosis. Treatment with alcohol solution of aluminium chloride hexahydrate: a simple method of transpiration measurement. Dermatologica 1980; 161: 133–135. 15 Abell E, Morgan K. The treatment of idiopathic hyperhidrosis by glycopyrronium bromide and tap water iontophoresis. Br J Dermatol 1974; 91: 87–91. 16 Stenquist B. Axillary hyperhidrosis: a simple surgical procedure. J Dermatol Surg Oncol 1985; 11: 388–391. 17 Drott C. Gunnar Gothberg G, Claes G. Endoscopic transthoracic sympathectomy: an efficient and safe method for the treatment of hyperhidrosis. J Am Acad Dermatol 1995; 33: 78–81. 18 Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ 2001; 323: 596–599. 19 Wollina U, Karamfilov T, Konrad H. High-dose botulinum toxin type A therapy for axillary hyperhidrosis markedly prolongs the relapse-free interval. J Am Acad Dermatol 2002; 46: 536–540. 20 Ruchinskas R. Hyperhidrosis and anxiety: chicken or egg? Dermatology 2007; 214: 195–196. 21 H€ olzle E. Topical pharmacological treatment. Curr Probl Dermatol 2002; 30: 30–43. 22 Lee HH, Kim do W, Kim do W, Kim C. Efficacy of glycopyrrolate in primary hyperhidrosis patients. Korean J Pain 2012; 25: 28–32. 23 Paller AS, Shah PR, Silverio AM, Wagner A, Chamlin SL, Mancini AJ. Oral glycopyrrolate as second-line treatment for primary pediatric hyperhidrosis. J Am Acad Dermatol 2012; 67: 918–923. 24 Kim WO, Kil HK, Yoon KB, Yoon DM. Topical glycopyrrolate for patients with facial hyperhidrosis. Br J Dermatol 2008; 158: 1094–1097.
© 2014 European Academy of Dermatology and Venereology
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
DOI: 10.1111/jdv.12518
ORIGINAL ARTICLE
Efficacy and safety of topical glycopyrrolate in patients with facial hyperhidrosis: a randomized, multicentre, double-blinded, placebo-controlled, split-face study M.Y. Hyun, I.P. Son, Y. Lee, H.G. Choi, K.Y. Park, K. Li, B.J. Kim,* S.J. Seo, M.N. Kim, C.K. Hong Department of Dermatology, Chung-Ang University College of Medicine, Seoul, Korea *Correspondence: B.J. Kim. E-mail: [email protected]
Abstract Background Although facial hyperhidrosis has been frequently associated with a diminished quality of life, various conservative modalities for its management are still far from satisfactory. Objective To evaluate the antiperspirant efficacy and safety of the topical glycopyrrolate on facial hyperhidrosis at specified posttreatment intervals. Methods Thirty-nine patients with facial hyperhidrosis were enrolled and treated with 2% topical glycopyrrolate on one-half of the forehead, whereas the other half of the forehead was treated with a placebo. All patients applied topical glycopyrrolate or placebo once a day for nine successive days. Each evaluation included weighing sweat and assessing the Hyperhidrosis Disease Severity Scale (HDSS) score and any adverse effects. Results Compared with the placebo-treated sides, topical glycopyrrolate-treated sides showed a reduction in the rate of sweat production at the forehead of 25.16 10.30% (mean SD) at 90 min after the first application (day 1), 29.63 7.74% at 24 h after the first application (day 2) and 36.68 11.41% at 24 h after eight additional successive daily applications (day 10) (all P < 0.025). There was a little more decrease in HDSS score with the topical glycopyrrolate-treated half of the forehead, but the difference was not statistically significant (P > 0.025). No serious adverse events were reported during the course of this study. Only one patient developed a transient headache after treatment. Conclusion Topical glycopyrrolate application appears to be significantly effective and safe in reducing excessive facial perspiration. Received: 10 October 2013; Accepted: 17 March 2014
Conflicts of interest None declared.
Funding sources None declared.
Introduction Hyperhidrosis is defined as excessive sweating beyond what is expected for thermoregulatory need and environmental conditions.1 Hyperhidrosis may be primary (likely resulting from overactivity of the sympathetic nervous system) or secondary to general medical conditions (including endocrine, neurologic, cardiovascular, infectious and neoplastic diseases) or pharmacologic effects.2 Criteria for the diagnosis of primary hyperhidrosis include focal, visible, excessive sweating of at least 6 months in duration without apparent cause, plus at least two of the following additional features: (i) bilateral and relatively symmetric distribution; (ii) at least one episode weekly; (iii) impaired daily activities; (iv) cessation of focal sweating during sleep; (v) onset before 25 years of age; and (vi) family history of primary focal hyperhidrosis.2 Although it is not usually a cause of major
JEADV 2015, 29, 278–282
morbidity, it is an occupationally disabling and socially embarrassing problem to those afflicted. Most commonly, primary hyperhidrosis appears on the axillas or palms but can also appear on the soles of the feet and the face. Features of facial hyperhidrosis include excessive and localized sweating on the scalp, forehead, nose and upper lip that can be triggered by heat and stressful stimuli.3 Although facial hyperhidrosis has been clinically overshadowed by palmar, plantar, and axillary hyperhidrosis, it can cause considerable psychological and social distress. Typical methods of treatment include the topical application of aluminium chloride or anticholinergic drugs, ionospheresis, oral medications, the hypodermic injection of botulinum toxin, sympathetic nerve block using alcohol, or sympathectomy. These methods each have advantages and disadvantages according to their mechanisms of action. The preferred treatment method for
© 2014 European Academy of Dermatology and Venereology
Topical glycopyrrolate in facial hyperhidrosis
primary hyperhidrosis should be one that is non-invasive and simple, with few complications and a low financial burden.4 In this regard, topical application can be a good initial treatment method, and topical anticholinergic agents have been reported to be an efficacious treatment for excessive facial sweating.4–6 This study investigated the efficacy and safety of topical glycopyrrolate on the symptoms of primary facial hyperhidrosis.
Materials and methods Inclusion criteria of subjects were as follows: (i) Healthy male or female aged 20–66 years; (ii) perspiration level of at least 100 mg of sweat for 20 min on each side of the forehead; (iii) criteria for the diagnosis of primary hyperhidrosis; (iv) a score of at least 3 on the Hyperhidrosis Disease Severity Scale (HDSS) during baseline evaluation (Table 1); and (v) not enrolled the similar clinical study during 6 months. Patients with facial hyperhidrosis for less than 6 months or with generalized or secondary hyperhidrosis were excluded. The study was performed in accordance with the Declaration of Helsinki (1975) and was approved by the institutional review board of Chung-Ang University Hospital and St. Paul Hospital. Before enrolment, patients were informed of the study procedures, risks, benefits and complications and provided written informed consent. We used 2% topical glycopyrrolate that was impregnated in cotton pads (SecureTM, Sung-Kwang Pharm. Co., LTD., Cheonan, Korea), which allowed the agent to be simply wiped onto the skin (Fig. 1). The placebo was identical in size and odour, etc.
Table 1 HDSS (Hyperhidrosis Disease Severity Scale). The scale is based on the question: ‘How would you rate the severity of your hyperhidrosis?’ Score
Patient response
1
My sweating is never noticeable and never interferes with my daily activities
2
My sweating is tolerable but sometimes interferes with my daily activities
3
My sweating is barely tolerable and frequently interferes with my daily activities
4
My sweating is intolerable and always interferes with my daily activities
(a)
279
The difference was whether or not it contained glycopyrrolate (Table 2). All patients were instructed to wash his or her face with soap and water before application to ensure optimal absorption; they were also given a complete demonstration of how to apply the test products, and the possible complications were explained. After each patient’s forehead was thoroughly cleansed and dried with gauze, topical glycopyrrolate was lightly rubbed on one-half of the forehead, whereas the other half served as a control and was treated with placebo. Patients were warned to avoid touching their eyes, noses and mouths before washing their hands after application of the test products. Sweat collections were performed by placing absorbent pads on both sides of the forehead. The study followed a double-blinded, split-face design with a pair of test products. Each patient applied the test products to the forehead once a day for 9 days. Topical glycopyrrolate was assigned according to randomization by a computer program to either the right or left forehead, and the opposite forehead received the placebo. A total of four evaluations were conducted at the following time points: at baseline (screening), 90 min after the first application (day 1), 24 h after the first application (day 2) and 24 h after eight additional successive daily applications (day 10). Each evaluation included weighing sweat and assessing the HDSS score and any adverse effects. On day 1, the evaluation was conducted 90 min after test product application to allow time for drying and absorption of the test products. Sweat stimulation was induced by having the patients sit in a room with controlled environmental conditions with regard to temperature (36.6–38.9°C) and relative humidity (30–40%) (DY-101TH, Temperature & Humidity Control Unit, DaeYang ETS Co., LTD., Hwaseong, Korea). During the first 40 min of the sweat stimulation period, each patient held unweighed absorbent pads on his or her forehead. This preliminary
Table 2 Compositions of SecureTM and placebo Product Secure
TM
Placebo
Composition 2% glycopyrrolate, ethanol, purified water, cotton pad Ethanol, purified water, cotton pad
(b)
Figure 1 (a) Cotton pad (53 mm diameter) for applying 2% topical glycopyrrolate or placebo and (b) the container used to prevent evaporation.
JEADV 2015, 29, 278–282
© 2014 European Academy of Dermatology and Venereology
280
warm-up period was followed by successive 20-min collection periods during which the patient held weighed absorbent pads on his or her forehead. The amount of sweat collected was quantified by gravimetric assessment. At each evaluation, two round absorbent pads (diameter of 5.3 cm) were prepared and weighed on a high-precision laboratory scale (accuracy 0.1 mg; MS204, NewClassic MF, Mettler Toledo, Switzerland). Prepared absorbent pads were simultaneously placed on each half of the forehead for 20 min and were then reweighed. To prevent error induced by evaporation, both pads were weighed at the same time. The difference in weight between the prepared absorbent pads and the reweighed absorbent pads after treatment was interpreted as sweat production.7 We interviewed each patient at screening, days 1, 2, and 10. Patients were asked to complete a questionnaire evaluating their degree of satisfaction and any complications experienced. The HDSS was used to measure disease severity; it is a disease-specific scale for hyperhidrosis that provides a qualitative measure of the severity of the patient’s condition based on how it affects their daily activities. Patients selected the statement that best represented their experiences with facial sweating (Table 1). Statistical analyses were performed using SPSS version 18.0 for Windows (SPSS Inc., Chicago, IL, USA). Results were expressed as the mean SD. A one-tailed value of P < 0.025 was considered statistically significant. A Wilcoxon signed rank test was used to compare the difference between the weight of the absorbent pads at baseline and after treatment with topical glycopyrrolate or placebo. Comparison between the sweat production at baseline and the sweat production at each visit was calculated using the following formula: (sweat production for the placebo at baseline sweat production for the placebo at each visit) 9 (sweat production for the topical glycopyrrolate at each visit sweat production for the topical glycopyrrolate at baseline) 9 100. A decreased ratio or reduction of sweat production was calculated using the following formula: (sweat production for the placebo sweat production for the topical glycopyrrolate) sweat production for the placebo 9 100. The Wilcoxon signed rank test was also used to compare the HDSS score at baseline with the HDSS score at each visit. Repeated measure ANOVA was used to check interaction between time and groups.
Hyun et al.
64.95 11.12% at the third follow-up (day 10) (P values were all 0.025). Because there was no interaction between time and groups, time which only could be the deviation factor did not affect the results. Only one patient experienced a transient headache after applying topical glycopyrrolate. No patients
Figure 2 Comparison between the sweat production at baseline and the sweat production at each visit
Results Thirty-nine patients who met the study criteria were enrolled. Thirty males and nine females had a mean age of 29.38 9.63 years. No patients were excluded from the analysis. Five patients had ever used deodorant on their axillae but it did not work well. There was no patient who had ever received any treatments for facial hyperhidrosis. There was no significant difference between the prepared pads before administration of topical glycopyrrolate or placebo. Sweat production (per cent of baseline) was 76.47 7.30% (mean SD) at the first follow-up (day 1), 72.17 7.24% at the second follow-up (day 2) and
JEADV 2015, 29, 278–282
Figure 3 Per cent reduction rate of sweat production on the forehead treated with topical glycopyrrolate compared with the placebo-treated half of the forehead at the following time points.
© 2014 European Academy of Dermatology and Venereology
Topical glycopyrrolate in facial hyperhidrosis
281
Table 3 Changes in HDSS score (Mean SD) Visit
HDSS score SecureTM
Placebo
Baseline
3.05 0.22
3.05 0.22
Second visit (Day 2)
2.21 0.80
2.33 0.87
Third visit (Day 10)
1.97 0.96
2.15 0.96
Baseline – Second visit
0.69 0.69
0.54 0.60
Baseline – Third visit
1.08 0.98
0.90 0.97
P value
Baseline - Second visit
0.398
Baseline - Third visit
0.502
experienced skin allergies or local reactions during the course of the study, and all were free of dermal side-effects. More serious complaints, such as blurred vision, dry mouth, dizziness and other complications, were not observed.
Discussion Eccrine sweat glands primarily assist the body in regulating its temperature in response to heat exposure or exercise. In about 1% of the population, the sympathetic nervous system is overactive, causing certain areas of the body to sweat at inappropriate times and in excess of what is necessary to maintain thermal regulation. This disorder is known as primary hyperhidrosis.8 Although primary hyperhidrosis is typically not a cause of major morbidity, it presents an occupationally disabling and socially embarrassing problem to those afflicted. Most commonly, hyperhidrosis appears on the palms but can also appear on the face, soles and the axilla. The causes of secondary hyperhidrosis include a number of neoplastic and neurologic disorders, metabolic diseases and drugs. The cause in each case should be identified and treated accordingly. The treatment of facial hyperhidrosis remains difficult, and treatment methods can be divided into those which affect the sweat glands directly and those which modify their innervations.9,10 Topical agents including aluminium chloride, formaldehyde, glutaraldehyde and potassium permanganate have been used but only have a short-term effect.11–14 In addition, oral anticholinergics have been tried, but adverse effects such as blurred vision and urinary retention limited their efficiency.15 Other treatments such as the surgical excision of affected areas, for example, the eccrine glands of the forehead, have been useful in appropriate cases.16 More recently, endoscopic sympathectomy has been used but can result in significant adverse effects such as compensatory hyperhidrosis, cardiac sympathetic denervation and Horner’s syndrome.17 Treatment of hyperhidrosis using botulinum toxin has been frequently used lately but also has limitations as it is effective only in specific areas such as the forehead.18,19 Moreover, it is not easily applicable to the entire face due to its high cost and the potential of creating an asymmetrical face or limiting facial expressions.
JEADV 2015, 29, 278–282
Anticholinergics are able to inactivate sweat glands via the action of acetylcholine and may be more attractive to patients than simply occluding sweat ducts with aluminium compounds, which can cause itching, stinging and skin irritation. Glycopyrrolate is a drug originally developed for peptic ulcer disease but is now used frequently in hyperhidrosis treatment since it also has a perspiration suppression effect. Glycopyrrolate competes with acetylcholine at the muscarinic receptor to create an anticholinergic effect. In addition, it is a drug in the highly polar quaternary ammonium group and cannot pass through lipid membranes, so it cannot penetrate the blood–brain barrier and has little effect on the central nervous system. In contrast, atropine sulphate and scopolamine hydrobromide are highly non-polar tertiary amines which can easily pass through lipid membranes.20 Therefore, when applied topically in lotion or cream form or by other methods such as an aqueous solution, glycopyrrolate has been associated with few adverse effects. Although topical application is often used to avoid systemic side-effects, it can result in contact sensitization, and the high concentration of drug needed for sufficient absorption through the skin can affect cholinergic nerve endings that may lead to systemic absorption and adverse effects.21 Despite these concerns, topical glycopyrrolate was well tolerated by most patients in this study. Lee et al.22 reported review study of 36 cases with primary hyperhidrosis treated by oral glycopyrrolate. While taking medication, 36.1% of patients experienced side-effects, such as oral dryness (27.8%), palpitations (11.1%), headache (2.8%) and other (8.3%). Amy et al.23 reported similar study of paediatric patients with hyperhidrosis treated by oral glycopyrrolate. In that study, 31 children took at least one dose of oral glycopyrrolate, and side-effects were noted by 29% of children, most commonly dry mouth (26%) and eyes (10%) and were dose related. One patient developed blurred vision, which resolved with dosing below 5 mg/d; one patient experienced palpitations and discontinued the medication. But in the study of Kim et al.24 which examined efficacy and safety of topical glycopyrrolate to 25 patients with focal hyperhidrosis, one patient with a mild headache that occurred in the evening after treatment and no other side-effects or complications were reported. And in our study only one patient experienced a transient headache after applying topical glycopyrrolate. Those were the evidence of fewer anticholinergic adverse effects with topical glycopyrrolate than with systemic glycopyrrolate. We found that use of the 2% topical glycopyrrolate pad resulted in a significant reduction in sweat production. The amount of sweat was decreased, as the number of daily applications increased during this study. This suggests that the action of topical glycopyrrolate may have some additive features; however, a treatment-free long-term follow-up is needed to verify this idea. The degrees of subjective feeling which patients answered with questionnaire were most satisfactory at not only topical gly-
© 2014 European Academy of Dermatology and Venereology
282
copyrrolate-treated half of the forehead but also placebo-treated half of the forehead. It seems to be difficult to make a clear differentiation between right and left forehead in sensing the amount of perspiration, although there was apparent difference in the volume of sweating. Serious side-effects were not observed in any of our patients. The use of 2% concentration on the forehead prevents possible systemic side-effects, whereas >2% concentration may be appropriate for the treatment of hyperhidrosis on other sites of the body such as the palms and soles. Although glycopyrrolate appears to be a satisfactory antiperspirant without critical adverse effects, further investigation is necessary for the objective evaluation of its safety and long-term results on the face. In conclusion, the short-term outcomes of our gravimetrically controlled study demonstrated that a topical formulation of 2% glycopyrrolate in aqueous solution is an effective treatment option for controlling focal facial hyperhidrosis. Our study suggests that topical glycopyrrolate can be applied on a daily basis or before certain occasions, such as prior to social activities, since it is convenient to use and effective in a single application.
References 1 Solish N, Bertucci V, Dansereau A et al. A comprehensive approach to the recognition, diagnosis, and severity-based treatment of focal hyperhidrosis: recommendations of the Canadian Hyperhidrosis Advisory Committee. Dermatol Surg 2007; 33: 908–923. 2 Hornberger J, Grimes K, Naumann M et al. Recognition, diagnosis, and treatment of primary focal hyperhidrosis. J Am Acad Dermatol 2004; 51: 274–286. 3 Eisenach JH, Atkinson JL, Fealey RD. Hyperhidrosis: evolving therapies for a well-established phenomenon. Mayo Clin Proc 2005; 80: 657–666. 4 Kavanagh GM, Burns C, Aldridge RD. Topical glycopyrrolate should not be overlooked in treatment of focal hyperhidrosis. Br J Dermatol 2006; 155: 487. 5 Seukeran DC, Highet AS. The use of topical glycopyrrolate in the treatment of hyperhidrosis. Clin Exp Dermatol 1998; 23: 204–205. 6 Luh JY, Blackwell TA. Craniofacial hyperhidrosis successfully treated with topical glycopyrrolate. South Med J 2002; 95: 756–758.
JEADV 2015, 29, 278–282
Hyun et al.
7 Kinkelin I, Hund M, Naumann M, Hamm H. Effective treatment of frontal hyperhidrosis with botulinum toxin A. Br J Dermatol 2000; 143: 824– 827. 8 Stolman LP. Treatment of hyperhidrosis. Dermatol Clin 1998; 16: 863– 869. 9 Stolman LP. Treatment of excess sweating of the palms by iontophoresis. Arch Dermatol 1987; 123: 893–896. 10 White JW. Treatment of primary hyperhidrosis. Mayo Clin Proc 1986; 61: 951–956. 11 Shelley WB, Laskas JJ, Satanove A. Effect of topical agents on plantar sweating. Arch Dermatol 1954; 69: 713–716. 12 Juhlin L, Hansson H. Topical glutaraldehyde for plantar hyperhidrosis. Arch Dermatol 1968; 97: 327–330. 13 Gordon BI, Maibach HI. Eccrine anhidrosis due to glutaraldehyde, formaldehyde, and iontophoresis. J Invest Dermatol 1969; 53: 436–439. 14 Jensen O, Karlsmark T. Palmoplantar hyperhidrosis. Treatment with alcohol solution of aluminium chloride hexahydrate: a simple method of transpiration measurement. Dermatologica 1980; 161: 133–135. 15 Abell E, Morgan K. The treatment of idiopathic hyperhidrosis by glycopyrronium bromide and tap water iontophoresis. Br J Dermatol 1974; 91: 87–91. 16 Stenquist B. Axillary hyperhidrosis: a simple surgical procedure. J Dermatol Surg Oncol 1985; 11: 388–391. 17 Drott C. Gunnar Gothberg G, Claes G. Endoscopic transthoracic sympathectomy: an efficient and safe method for the treatment of hyperhidrosis. J Am Acad Dermatol 1995; 33: 78–81. 18 Naumann M, Lowe NJ. Botulinum toxin type A in treatment of bilateral primary axillary hyperhidrosis: randomised, parallel group, double blind, placebo controlled trial. BMJ 2001; 323: 596–599. 19 Wollina U, Karamfilov T, Konrad H. High-dose botulinum toxin type A therapy for axillary hyperhidrosis markedly prolongs the relapse-free interval. J Am Acad Dermatol 2002; 46: 536–540. 20 Ruchinskas R. Hyperhidrosis and anxiety: chicken or egg? Dermatology 2007; 214: 195–196. 21 H€ olzle E. Topical pharmacological treatment. Curr Probl Dermatol 2002; 30: 30–43. 22 Lee HH, Kim do W, Kim do W, Kim C. Efficacy of glycopyrrolate in primary hyperhidrosis patients. Korean J Pain 2012; 25: 28–32. 23 Paller AS, Shah PR, Silverio AM, Wagner A, Chamlin SL, Mancini AJ. Oral glycopyrrolate as second-line treatment for primary pediatric hyperhidrosis. J Am Acad Dermatol 2012; 67: 918–923. 24 Kim WO, Kil HK, Yoon KB, Yoon DM. Topical glycopyrrolate for patients with facial hyperhidrosis. Br J Dermatol 2008; 158: 1094–1097.
© 2014 European Academy of Dermatology and Venereology
This document is a scanned copy of a printed document. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material.
