Clinical Research Long-term Results of the Use of Oxybutynin for the Treatment of Axillary Hyperhidrosis Nelson Wolosker,1,2 Marcelo Passos Teivelis,1 Mariana Krutman,1 Rafael Pessanha de Paula,2 Paulo Kauffman,1 Jose Ribas M. de Campos,1,2 and Pedro Puech-Le~ao,2 S~ao Paulo, Brazil
Background: Axillary hyperhidrosis (AH) is a common disease, with a significant impact on quality of life (QOL). Good short-term results are reported with oxybutynin, but longer followup data are lacking. We evaluated its effectiveness in a large series of patients who were not surgically treated and who had at least 6 months of follow-up. Methods: From September 2007 to September 2013, 431 consecutive patients were enrolled in ‘‘pharmacological first’’ protocol for treatment of AH with oxybutynin. Thirty-four patients were lost to follow-up, and data are available for 397 patients treated for at least 6 weeks. Data at the start of the protocol, 6 weeks after beginning treatment, and at final visit were analyzed. Results: One hundred fourteen patients (28.7%) did not improve and were referred for surgery (sympathectomy). Eight patients (2.01%) presented significant side effects (e.g. dry mouth) and discontinued therapy. Twenty-six patients (9.4%) preferred surgery over pharmacologic treatment. Sixty-two patients have not yet been under treatment for 6 months. The 181 patients with more than 6 months of follow-up (median: 17 months, range: 6e72) were analyzed as follows: 82.9% of patients presented moderate or great improvement in AH and 89% of patients presented improvement in other sites of hyperhidrosis after a median of 17 months. Conclusions: In patients with good initial response to oxybutynin, >80% presented moderate or great improvement in axillary and in other sites of excessive sweating. Results were particularly better in women and those who presented better QOL after 6 weeks.
INTRODUCTION Axillary hyperhidrosis (AH) is characterized by excessive sweating primarily in the armpits. This condition usually affects patients’ quality of life (QOL), compromising emotional, social, professional, and leisure activities.1 This disease usually starts during the childhood or adolescence and is, by some authors, reported as the most common presentation of hyperhidrosis.2,3 1 Hospital Israelita Albert EinsteineHIAE, S~ao Paulo, S~ao Paulo, Brazil. 2 Hospital das Clı´nicas da Faculdade de Medicina da Universidade de S~ ao PauloeHCFMUSP, S~ao Paulo, S~ao Paulo, Brazil.
Correspondence to: Marcelo P. Teivelis, MD, Avenida Albert Einstein, 627/701, Office 423, A1 Building, S~ao Paulo, Brazil; E-mail: [email protected] Ann Vasc Surg 2014; -: 1–7 http://dx.doi.org/10.1016/j.avsg.2013.12.024 Ó 2014 Elsevier Inc. All rights reserved. Manuscript received: November 18, 2013; manuscript accepted: December 15, 2013; published online: ---.
Topical treatment includes iontophoresis and application of botulinum toxin. These procedures present good results but are time limited and demand frequent redo procedures.4,5 One possible surgical solution is excision/resection of the eccrine sweat glands, but this approach may present low efficacy, high recurrence rates,6 and unsightly scarring.7 Another surgical treatment optiondvideo-assisted thoracic sympathectomy (VATS)dhas a high success rate and low operative risk for the definite treatment of AH, but compensatory hyperhidrosis (CH) is usually a troublesome complaint, with up to 94% of patients referring to some degree of this distress.8 Regarding pathophysiological substrates for hyperhidrosis, it has been demonstrated that there is a higher expression of acetylcholine and alpha-7 nicotinic receptors in sympathetic ganglia.9 Oxybutynin is an antimuscarinic agent, initially described in the resolution of hyperhidrosis in 1988.10 In the last ten years, specific treatment with this drug began to be 1
2 Wolosker et al.
Annals of Vascular Surgery
reported for excessive sweating11,12: it has been used for palmar13, plantar14, and facial15 sweating, and has been studied in a randomized placebo-controlled trial.16 Short-term results on pharmacologic treatment of AH have been published,17,18 but longterm results in treatment with this particular drug are lacking. The aim of this study was to assess the long-term clinical efficacy of a large series of consecutive patients (n ¼ 181) with AH treated with low doses of oxybutynin for at least 6 months (median ¼ 17 months).
METHODS Patients This was a nonrandomized and uncontrolled study in accordance with ethical standards of the Committee of Ethics for Analysis of Research Projects on Human Experimentation from the institutions. Data were retrieved from our dedicated and prospective institutional protocol, which is standardized and has been in use at our facilities since 2001 for all patients with hyperhidrosis. From September 2007 to September 2013, a total of 431 consecutive patients with AH as their main complaint were enrolled in our ‘‘pharmacological first’’ protocol. Figure 1 graphically represents the series treatment and outcomes over time. Of the 431 patients enrolled, 34 (7.89%) patients failed to come to their first return. Of the 397 remaining, 114 (28.72%) patients did not improve after 6 weeks and were referred for VATS (and were operated if they were good surgical candidates). Eight additional patients improved in excessive sweating - but reported severe dry mouth and stopped oxybutynin; they were referred to surgical treatment and left the study. Two hundred seventy-five patients were treated with oxybutynin for 6 weeks. Twenty-six patients (9.45%) presented good results with the pharmacologic approach, but preferred surgical treatment (because of unwillingness to stay indefinitely on drug therapy) and were submitted to VATS. Six patients presented worsening of side effects, and stopped oxybutynin after 6 weeks but before 6 months. Sixty-two patients are currently under treatment but have been followed for 40 kg received the same protocol as adults. Patients with 83, the QOL was considered
very poor; from 68 to 83, poor; from 52 to 67, good; from 36 to 51, very good; and from 20 to 35, excellent. Improvement of QOL after treatment was also classified into five different evolution levels. When the total was greater than 83, QOL was considered much worse; from 68 to 83, slightly worse; from 52 to 67, the same; from 36 to 51, slightly better; and from 20 to 35, much better. The following parameters were studied: negative impact of hyperhidrosis on QOL before treatment, patients’ improvement in QOL after treatment, evolution of AH (comparing results after 6 weeks of treatment and results at the last follow-up visit), and improvements in the last consult on the other sites of hyperhidrosis and complications. Consistency (for Tables IV and VI) was calculated as the proportion of patients who remained in the same category (either of improvement in sweating or complaint of dry mouth) over time. Worsening was the proportion of patients who reported a less desirable category in the last visit compared with the sixth week result (e.g. if a patient reported initial great improvement and later considered it to be moderate, he was considered to have a worse result). Finally, enhancement was the proportion of patients who reached a more favorable category over time in a given variable. To assess predictors in the self-perceived amelioration of axillary sweating in the last follow-up visit, we divided the patients into 2 separate groups: the first group included patients who attributed grades of 0 to 4 (null/slight amelioration) to their symptoms at the last consult regarding amelioration of AH and the second group included the remaining patients (with moderate/great improvement), whose grades were from 5 to 10 at their final visit. Patients were compared regarding the following characteristics: gender, BMI, pretreatment QOL, and QOL after 6 weeks of treatment. Statistical Analysis Means and standard deviations (SDs) were used in the descriptive analysis of parametrically distributed continuous variables, whereas frequencies were used for categorical variables. McNemar test was used to compare self-reported improvement of hyperhidrosis and dry mouth over time, on the 2 consecutive analysis time points, and the kappa coefficient was used for analysis. Fisher’s exact test and Pearson chi-squared test were used on analysis comparing groups. The significance level considered for all tests was P ¼ 0.05.
4 Wolosker et al.
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Table IV. Comparison of self-assessment of improvement of hyperhidrosis of 6 weeks of treatment and last visit
Table VI. Complaint of dry mouth after 6 weeks of treatment and on the last visit Last visit
Improvement at last visit Comparison of selfassessment
Improvement after 6 weeks Slight Moderate Great Total
Slight Moderate Great Total [n (%)] [n (%)] [n (%)] [n (%)]
11 (6.0) 15 (8.3) 5 (2.8) 31 (17.1)
1 (0.6) 43 (23.7) 15 (8.3) 59 (32.6)
0 (0.0) 41 (22.7) 50 (27.6) 91 (50.3)
12 (6.6) 99 (54.7) 70 (38.7) 181 (100.0)
McNemar test P < 0.001; Kappa: 0.309; Consistency: 57.4%; Worse: 19.4%; Better: 23.3%.
Table V. Reports of improvement on other sites of hyperhidrosis on the last visit Sites of hyperhidrosis
Palmar (n ¼ 85) Plantar (n ¼ 76) Thoracoabdominal (n ¼ 48) Facial (n ¼ 32)
Null/Slight [n (%)]
Moderate [n (%)]
Great [n (%)]
5 (5.88) 7 (9.21) 5 (10.42)
17 (20) 22 (28.95) 10 (20.83)
63 (74.12) 47 (61.84) 33 (68.75)
3 (9.38)
11 (34.37)
18 (56.25)
RESULTS By inclusion criteria, all patients were followed for at least 6 months. Follow-up ranged from 6 to 72 months (median ¼ 17 months). QOL before treatment is presented in Table II. More than 97% of patients reported poor or very poor QOL before treatment. Improvement in QOL after 6 weeks of treatment is presented in Table III. More than 90% of patients presented (at least some degree of) improvement in QOL after 6 weeks of treatment. Improvements in sweating after 6 weeks and in the last visit are presented in Table IV. Definitions of consistency, worsening, and enhancement definitions are presented in the patients section. After 6 weeks of pharmacologic treatment, 93.4% of the patients reported moderate or great improvement in self-perceived sweating. At the last visit, 82.9% of the patients maintained moderate or great improvement in self-perceived sweating. Comparing the category of improvement on the analysis of 6 weeks and at last evaluation, 57.4% of patients remained
Six weeks
Absent/ Light Moderate/ Severe Total
Absent/ Moderate/ Total McNemar Light [n (%)] Severe [n (%)] [n (%)] P
63 (34.8) 36 (19.9) 99 (54.7)
30 (16.6) 52 (28.7) 82 (45.3)
93 0.539 (51.4) 88 (48.6) 181 (100.0)
McNemar test P ¼ 0.539; Kappa: 0.269; Consistency: 63.5%; Worse: 16.6%; Better: 19.9%.
in the same category of improvement, 23.3% improved, and 19.4% ‘‘downgraded’’ on the long run. The change in subcategories was statistically significant (McNemar test P < 0.001). Improvements in other sites of hyperhidrosisdregarding only the last evaluationdare represented on Table V. Most patients presented moderate or great improvement on the other places of excessive sweating. Comparisons of dry-mouth complaint after 6 weeks and on last visit are shown on Table VI. No major side effects (e.g. intestinal obstruction and acute glaucoma) occurred in this population. Nondisabling headache occurred in 14 patients (7.7%), constipation in 12 (6.6%), and urinary retention in 3 (1.6%), none of which lead patients to discontinue treatment. Analysis of the results regarding age, gender, BMI, pretreatment QOL, and QOL after 6 weeks of treatment are presented in Table VII. Female patients (P ¼ 0.002) and those with better QOL after 6 weeks (P ¼ 0.033) tended to have better outcomes after long-term treatment than their counterparts.
DISCUSSION Oxybutynin has provided good short-term results in the amelioration of hyperhidrosis. The main contraindication is closed-angle glaucoma. Excluding this concern, it is a safe medication but with limited tolerability due to antimuscarinic side effects, especially noted with the administration of doses >15 mg/day.20 The maximum dose of 10 mg/day, associated with the slow and progressive increase in dosage used in our protocol, lowers the incidence of side effects, maintains effectiveness, and improves treatment adherence. An earlier series described by our group demonstrated that 88.8% of patients improved in self-
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Long-term effects of oxybutynin on AH 5
Table VII. Comparison between the group with null/slight improvement in sweating at last visit with the group achieving moderate/great improvement Null/Slight improvement [n (%)]
Gender Women 15 (11.6) Men 16 (30.8) Body Mass Index Below 25 kg/m2 18 (14.6) Above 25 kg/m2 13 (22.4) Age 40 years 5 (20.0) Pretreatment QOL Very poor 19 (19.2) Poor 11 (14.1) Good 1 (25.0) Very good 0 (0.0) Excellent 0 (0.0) QOL after 6 weeks of treatment Much worse 0 (0.0) Worse 0 (0.0) The same 7 (41.2) Better 13 (15.5) Much better 11 (13.8) a
Moderate/Great improvement [n (%)]
P value
114 (88.4) 36 (69.2)
0.002b
105 (85.4) 45 (77.6)
0.195b
9 (100.0) 121 (82.3) 20 (80.0)
0.487a
80 67 3 0 0
(80.8) (85.9) (75.0) (0.0) (0.0)
0.456a
0 0 10 71 69
(0.0) (90.0) (58.8) (84.5) (86.2)
0.033a
Fisher’s exact test. Pearson chi-squared test.
b
perceived sweating after 6 weeks of treatment and 67.5% noted improved QOL.17 These initial data encouraged us to research the long-term outcomes of oxybutynin use. Therefore, a large cohort (n ¼ 431) of patients who initiated pharmacologic treatment was analyzed, and their progress was monitored. We focused on those who had a good initial response (6 weeks) and were treated for at least 6 months. We sought to know if the improvement was maintained in the long run. Concerning overall patients’ characteristics, they presented preponderance of female patientsdas is customary in hyperhidrosis patients2,4,21e24 and were young adults (median: 29 years). These findings were comparable to other studies in which most patients were around their 30s.2,3,5 Of the 431 initially studied subjects, 34 (7.89%) failed to return on the sixth week medical appointment. We imagine that at least some of these patients who were lost to follow-up may have been too anxious and unwilling to stay on medication that did not provide very short-term results. In a previous study on AH,17 there was a 19.6% follow-up loss (20 patients were lost on a cohort of 102). We believe that our knowledge of good initial outcomes, our emphatic clarifications for patients
about the expected risks, and the benefits of pharmacologic treatment lead to smaller loss to followup in our current study. Self-reporting (on a scale from 0 to 10) of the patient’s overall improvement impression was used, instead of an objective assessment of hyperhidrosis (which is technically feasible25 with sudorometers, but unfortunately only at 1 specific point in time, not throughout the day). Excessive sweating is a bothersomedbut not lethaldcondition, and the goal of treatment is the patient’s subjective amelioration of symptoms, thus making selfreporting an adequate method for data collection. Almost one-tenth of patients (9.45%, i.e. 26 patients), displayed good results with pharmacologic therapy, did not have significant side effects, but preferred VATS to pharmacologic treatment because of unwillingness to use medication indefinitely (either because they frequently forgot to take the medication or because they were worried of side effects that could arise from a very long-term usage of medication). When we analyze the 181 patients who were followed for more than 6 months, 12 of them (6.6%) reported null/slight amelioration in AH after 6 weeks, but continued treatment. We believe this
6 Wolosker et al.
continuation is because, unlike surgical treatment, sudoresis in other parts of the body was considerably ameliorated, leading patients to prefer pharmacologic treatment (in which improvement occurred in other sites of the body) instead of surgical treatment, which may prompt patients to sweat in places where they previously did not (CH). At the last visit (median ¼ 17 months), 19.4% of patients were found to have had a worsening of improvement category (a patient who reported great improvement after 6 weeks and moderate improvement at the last visit was considered to have worsened, for example). One possible reason for that is nonadherence, such as missed doses or ‘‘drug holidays’’. Because of the retrospective nature of this study, it is not possible to ascertain adherence by direct questioning or any other method. Another possible reason is tachyphylaxis, an occurrence that, to the best of our knowledge has not yet been reported for oxybutynin in hyperhidrosis. Nevertheless, 23.3% of patients presented improvement in category and >82% of patients reported moderate or great improvement in AH over the course of the study. We believe that because of these overall encouraging results, patients who dealt initially well with the medication may maintain treatment indefinitely. The subanalysis suggests that female patients tended to have better outcomes. This does not mean that male patients should not be pharmacologically treated, as male individuals achieved good responses (and have done so on other studies23), only not as outstanding as their female counterparts. Likewise, the fact that patients with better QOL after 6 weeks of treatment tended to achieve better outcomes by the final visit does not preclude patients who did not have such a significant initial response from continuing treatment. When we take surgical and pharmacological treatment into account, it is important to educate patients on the fact that there is an interval of at least 3 weeks between the initiation of drug use and the improvement in symptoms, as opposed to surgical treatment, in which the results are almost instant. This is important in maintaining adherence at the beginning of treatment. However, as the pharmacologic approach is systemic, one can expect that several sites of hyperhidrosis will be treated, which is not a feature of surgical treatment. We believe that when discussing with a patient about the possibilities of treatment for hyperhidrosis, it is very important that he or she is clarified about operative risks (which are, fortunately, rare26) and the risk of CH. Regrets after the
Annals of Vascular Surgery
procedure unfortunately are not so uncommon,27 and preoperative enlightenment and a ‘‘pharmacological first’’ approach lower the risk for patients and physicians regarding dissatisfaction with one’s treatment. If pharmacologic results are good, but the patient does not want nonsurgical treatment (for whichever reasons), referral to VATS should be considered, as long as the patient has had the chance to experience the reversible treatment for hyperhidrosis. If the initial results are suboptimal, such as the presence of significant side effects or no improvement after 6 weeks of therapy, evaluation for VATS or topical therapy should be considered, as this may be considered pharmacologic treatment failure. If patients have had good response after 6 weeks and are willing to stay on oxybutynin, they tend to benefit from therapy as they maintain moderate/ great improvement in axillary and other sites of significant sweating, and side effects tend to be tolerable.
CONCLUSIONS Our present data show that anticholinergic treatment with oxybutynin is feasible, with considerably positive results for those patients who were able to maintain therapy for 6 weeks, and after a median of 17 months, >80% of patients displayed moderate or great improvement in excessive sweating. The results for AH were better in female patients and in those who achieved better QOL after 6 weeks. REFERENCES 1. Weber A, Heger S, Sinkgraven R, et al. Psychosocial aspects of patients with focal hyperhidrosis. Marked reduction of social phobia, anxiety and depression and increased quality of life after treatment with botulinum toxin A. Br J Dermatol 2005;152:342e5. 2. Strutton DR, Kowalski JW, Glaser DA, et al. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol 2004;51:241e8. 3. Lear W, Kessler E, Solish N, et al. An epidemiological study of hyperhidrosis. Dermatol Surg 2007;33(1 Spec No.): S69e75. 4. Walling HW, Swick BL. Treatment options for hyperhidrosis. Am J Clin Dermatol 2011;12:285e95. Springer International Publishing. 5. Lakraj A-AD, Moghimi N, Jabbari B. Hyperhidrosis: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins. Toxins (Basel) 2013;5:821e40. 6. Hafner J, Beer GM. Axillary sweat gland excision. Curr Probl Dermatol 2002;30:57e63. 7. Connolly M, de Berker D. Management of primary hyperhidrosis: a summary of the different treatment modalities. Am J Clin Dermatol 2003;4:681e97.
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8. Chwajol M, Barrenechea IJ, Chakraborty S, et al. Impact of compensatory hyperhidrosis on patient satisfaction after endoscopic thoracic sympathectomy. Neurosurgery 2009;64:511e8. discussion518. 9. de Moura J unior NB, das-Neves-Pereira JC, de Oliveira FRG, et al. Expression of acetylcholine and its receptor in human sympathetic ganglia in primary hyperhidrosis. Ann Thorac Surg 2013;95:465e70. 10. LeWitt P. Hyperhidrosis and hypothermia responsive to oxybutynin. Neurology 1988;38:506e7. 11. Mijnhout GS, Kloosterman H, Simsek S, et al. Oxybutynin: dry days for patients with hyperhidrosis. Neth J Med 2006;64:326e8. 12. Tupker RA, Harmsze AM, Deneer VHM. Oxybutynin therapy for generalized hyperhidrosis. Arch Dermatol 2006;142:1065e6. 13. Wolosker N, Campos JR, Kauffman P, et al. An alternative to treat palmar hyperhidrosis: use of oxybutynin. Clin Auton Res 2011;21:389e93. 14. Wolosker N, de Campos JRM, Kauffman P, et al. Use of oxybutynin for treating plantar hyperhidrosis. Int J Dermatol 2013;52:620e3. 15. Wolosker N, JRM de Campos, Kauffman P, et al. The use of oxybutynin for treating facial hyperhidrosis. An Bras Dermatol 2011;86:451e6. 16. Wolosker N, de Campos JRM, Kauffman P, et al. A randomized placebo-controlled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg 2012;55:1696e700. 17. Wolosker N, de Campos JRM, Kauffman P, et al. The use of oxybutynin for treating axillary hyperhidrosis. Ann Vasc Surg 2011;25:1057e62.
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18. Try C, Messikh R, Elkhyat A, et al. Use of oral oxybutynin at 7.5 mg per day in primary hyperhidrosis. Rev Med Liege 2012;67:520e6. 19. de Campos JRM, Kauffman P, Werebe E de C, et al. Quality of life, before and after thoracic sympathectomy: report on 378 operated patients. Ann Thorac Surg 2003;76:886e91. 20. Arisco AM, Brantly EK, Kraus SR. Oxybutynin extended release for the management of overactive bladder: a clinical review. Drug Des Dev Ther 2009;3:151e61. 21. Cerfolio RJ, de Campos JRM, Bryant AS, et al. The Society of Thoracic Surgeons expert consensus for the surgical treatment of hyperhidrosis. Ann Thorac Surg 2011;91:1642e8. Elsevier Inc. 22. Wolosker N, Munia MAS, Kauffman P, et al. Is gender a predictive factor for satisfaction among patients undergoing sympathectomy to treat palmar hyperhidrosis? Clinics (Sao Paulo) 2010;65:583e6. 23. Wolosker N, Krutman M, Campdell TPDA, et al. Oxybutynin treatment for hyperhidrosis: a comparative analysis between genders. Einstein (Sao Paulo) 2012;10:405e8. 24. Vorkamp T, Foo FJ, Khan S, et al. Hyperhidrosis: evolving concepts and a comprehensive review. Surgeon 2010;8:287e92. 25. Ishy A, de Campos JRM, Wolosker N, et al. Objective evaluation of patients with palmar hyperhidrosis submitted to two levels of sympathectomy: T3 and T4. Interact Cardiovasc Thorac Surg 2011;12:545e8. 26. de Andrade Filho LO, Kuzniec S, Wolosker N, et al. Technical difficulties and complications of sympathectomy in the treatment of hyperhidrosis: an analysis of 1731 cases. Ann Vasc Surg 2013;27:447e53. 27. Smidfelt K, Drott C. Late results of endoscopic thoracic sympathectomy for hyperhidrosis and facial blushing. Br J Surg 2011;98:1719e24.
Background: Axillary hyperhidrosis (AH) is a common disease, with a significant impact on quality of life (QOL). Good short-term results are reported with oxybutynin, but longer followup data are lacking. We evaluated its effectiveness in a large series of patients who were not surgically treated and who had at least 6 months of follow-up. Methods: From September 2007 to September 2013, 431 consecutive patients were enrolled in ‘‘pharmacological first’’ protocol for treatment of AH with oxybutynin. Thirty-four patients were lost to follow-up, and data are available for 397 patients treated for at least 6 weeks. Data at the start of the protocol, 6 weeks after beginning treatment, and at final visit were analyzed. Results: One hundred fourteen patients (28.7%) did not improve and were referred for surgery (sympathectomy). Eight patients (2.01%) presented significant side effects (e.g. dry mouth) and discontinued therapy. Twenty-six patients (9.4%) preferred surgery over pharmacologic treatment. Sixty-two patients have not yet been under treatment for 6 months. The 181 patients with more than 6 months of follow-up (median: 17 months, range: 6e72) were analyzed as follows: 82.9% of patients presented moderate or great improvement in AH and 89% of patients presented improvement in other sites of hyperhidrosis after a median of 17 months. Conclusions: In patients with good initial response to oxybutynin, >80% presented moderate or great improvement in axillary and in other sites of excessive sweating. Results were particularly better in women and those who presented better QOL after 6 weeks.
INTRODUCTION Axillary hyperhidrosis (AH) is characterized by excessive sweating primarily in the armpits. This condition usually affects patients’ quality of life (QOL), compromising emotional, social, professional, and leisure activities.1 This disease usually starts during the childhood or adolescence and is, by some authors, reported as the most common presentation of hyperhidrosis.2,3 1 Hospital Israelita Albert EinsteineHIAE, S~ao Paulo, S~ao Paulo, Brazil. 2 Hospital das Clı´nicas da Faculdade de Medicina da Universidade de S~ ao PauloeHCFMUSP, S~ao Paulo, S~ao Paulo, Brazil.
Correspondence to: Marcelo P. Teivelis, MD, Avenida Albert Einstein, 627/701, Office 423, A1 Building, S~ao Paulo, Brazil; E-mail: [email protected] Ann Vasc Surg 2014; -: 1–7 http://dx.doi.org/10.1016/j.avsg.2013.12.024 Ó 2014 Elsevier Inc. All rights reserved. Manuscript received: November 18, 2013; manuscript accepted: December 15, 2013; published online: ---.
Topical treatment includes iontophoresis and application of botulinum toxin. These procedures present good results but are time limited and demand frequent redo procedures.4,5 One possible surgical solution is excision/resection of the eccrine sweat glands, but this approach may present low efficacy, high recurrence rates,6 and unsightly scarring.7 Another surgical treatment optiondvideo-assisted thoracic sympathectomy (VATS)dhas a high success rate and low operative risk for the definite treatment of AH, but compensatory hyperhidrosis (CH) is usually a troublesome complaint, with up to 94% of patients referring to some degree of this distress.8 Regarding pathophysiological substrates for hyperhidrosis, it has been demonstrated that there is a higher expression of acetylcholine and alpha-7 nicotinic receptors in sympathetic ganglia.9 Oxybutynin is an antimuscarinic agent, initially described in the resolution of hyperhidrosis in 1988.10 In the last ten years, specific treatment with this drug began to be 1
2 Wolosker et al.
Annals of Vascular Surgery
reported for excessive sweating11,12: it has been used for palmar13, plantar14, and facial15 sweating, and has been studied in a randomized placebo-controlled trial.16 Short-term results on pharmacologic treatment of AH have been published,17,18 but longterm results in treatment with this particular drug are lacking. The aim of this study was to assess the long-term clinical efficacy of a large series of consecutive patients (n ¼ 181) with AH treated with low doses of oxybutynin for at least 6 months (median ¼ 17 months).
METHODS Patients This was a nonrandomized and uncontrolled study in accordance with ethical standards of the Committee of Ethics for Analysis of Research Projects on Human Experimentation from the institutions. Data were retrieved from our dedicated and prospective institutional protocol, which is standardized and has been in use at our facilities since 2001 for all patients with hyperhidrosis. From September 2007 to September 2013, a total of 431 consecutive patients with AH as their main complaint were enrolled in our ‘‘pharmacological first’’ protocol. Figure 1 graphically represents the series treatment and outcomes over time. Of the 431 patients enrolled, 34 (7.89%) patients failed to come to their first return. Of the 397 remaining, 114 (28.72%) patients did not improve after 6 weeks and were referred for VATS (and were operated if they were good surgical candidates). Eight additional patients improved in excessive sweating - but reported severe dry mouth and stopped oxybutynin; they were referred to surgical treatment and left the study. Two hundred seventy-five patients were treated with oxybutynin for 6 weeks. Twenty-six patients (9.45%) presented good results with the pharmacologic approach, but preferred surgical treatment (because of unwillingness to stay indefinitely on drug therapy) and were submitted to VATS. Six patients presented worsening of side effects, and stopped oxybutynin after 6 weeks but before 6 months. Sixty-two patients are currently under treatment but have been followed for 40 kg received the same protocol as adults. Patients with 83, the QOL was considered
very poor; from 68 to 83, poor; from 52 to 67, good; from 36 to 51, very good; and from 20 to 35, excellent. Improvement of QOL after treatment was also classified into five different evolution levels. When the total was greater than 83, QOL was considered much worse; from 68 to 83, slightly worse; from 52 to 67, the same; from 36 to 51, slightly better; and from 20 to 35, much better. The following parameters were studied: negative impact of hyperhidrosis on QOL before treatment, patients’ improvement in QOL after treatment, evolution of AH (comparing results after 6 weeks of treatment and results at the last follow-up visit), and improvements in the last consult on the other sites of hyperhidrosis and complications. Consistency (for Tables IV and VI) was calculated as the proportion of patients who remained in the same category (either of improvement in sweating or complaint of dry mouth) over time. Worsening was the proportion of patients who reported a less desirable category in the last visit compared with the sixth week result (e.g. if a patient reported initial great improvement and later considered it to be moderate, he was considered to have a worse result). Finally, enhancement was the proportion of patients who reached a more favorable category over time in a given variable. To assess predictors in the self-perceived amelioration of axillary sweating in the last follow-up visit, we divided the patients into 2 separate groups: the first group included patients who attributed grades of 0 to 4 (null/slight amelioration) to their symptoms at the last consult regarding amelioration of AH and the second group included the remaining patients (with moderate/great improvement), whose grades were from 5 to 10 at their final visit. Patients were compared regarding the following characteristics: gender, BMI, pretreatment QOL, and QOL after 6 weeks of treatment. Statistical Analysis Means and standard deviations (SDs) were used in the descriptive analysis of parametrically distributed continuous variables, whereas frequencies were used for categorical variables. McNemar test was used to compare self-reported improvement of hyperhidrosis and dry mouth over time, on the 2 consecutive analysis time points, and the kappa coefficient was used for analysis. Fisher’s exact test and Pearson chi-squared test were used on analysis comparing groups. The significance level considered for all tests was P ¼ 0.05.
4 Wolosker et al.
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Table IV. Comparison of self-assessment of improvement of hyperhidrosis of 6 weeks of treatment and last visit
Table VI. Complaint of dry mouth after 6 weeks of treatment and on the last visit Last visit
Improvement at last visit Comparison of selfassessment
Improvement after 6 weeks Slight Moderate Great Total
Slight Moderate Great Total [n (%)] [n (%)] [n (%)] [n (%)]
11 (6.0) 15 (8.3) 5 (2.8) 31 (17.1)
1 (0.6) 43 (23.7) 15 (8.3) 59 (32.6)
0 (0.0) 41 (22.7) 50 (27.6) 91 (50.3)
12 (6.6) 99 (54.7) 70 (38.7) 181 (100.0)
McNemar test P < 0.001; Kappa: 0.309; Consistency: 57.4%; Worse: 19.4%; Better: 23.3%.
Table V. Reports of improvement on other sites of hyperhidrosis on the last visit Sites of hyperhidrosis
Palmar (n ¼ 85) Plantar (n ¼ 76) Thoracoabdominal (n ¼ 48) Facial (n ¼ 32)
Null/Slight [n (%)]
Moderate [n (%)]
Great [n (%)]
5 (5.88) 7 (9.21) 5 (10.42)
17 (20) 22 (28.95) 10 (20.83)
63 (74.12) 47 (61.84) 33 (68.75)
3 (9.38)
11 (34.37)
18 (56.25)
RESULTS By inclusion criteria, all patients were followed for at least 6 months. Follow-up ranged from 6 to 72 months (median ¼ 17 months). QOL before treatment is presented in Table II. More than 97% of patients reported poor or very poor QOL before treatment. Improvement in QOL after 6 weeks of treatment is presented in Table III. More than 90% of patients presented (at least some degree of) improvement in QOL after 6 weeks of treatment. Improvements in sweating after 6 weeks and in the last visit are presented in Table IV. Definitions of consistency, worsening, and enhancement definitions are presented in the patients section. After 6 weeks of pharmacologic treatment, 93.4% of the patients reported moderate or great improvement in self-perceived sweating. At the last visit, 82.9% of the patients maintained moderate or great improvement in self-perceived sweating. Comparing the category of improvement on the analysis of 6 weeks and at last evaluation, 57.4% of patients remained
Six weeks
Absent/ Light Moderate/ Severe Total
Absent/ Moderate/ Total McNemar Light [n (%)] Severe [n (%)] [n (%)] P
63 (34.8) 36 (19.9) 99 (54.7)
30 (16.6) 52 (28.7) 82 (45.3)
93 0.539 (51.4) 88 (48.6) 181 (100.0)
McNemar test P ¼ 0.539; Kappa: 0.269; Consistency: 63.5%; Worse: 16.6%; Better: 19.9%.
in the same category of improvement, 23.3% improved, and 19.4% ‘‘downgraded’’ on the long run. The change in subcategories was statistically significant (McNemar test P < 0.001). Improvements in other sites of hyperhidrosisdregarding only the last evaluationdare represented on Table V. Most patients presented moderate or great improvement on the other places of excessive sweating. Comparisons of dry-mouth complaint after 6 weeks and on last visit are shown on Table VI. No major side effects (e.g. intestinal obstruction and acute glaucoma) occurred in this population. Nondisabling headache occurred in 14 patients (7.7%), constipation in 12 (6.6%), and urinary retention in 3 (1.6%), none of which lead patients to discontinue treatment. Analysis of the results regarding age, gender, BMI, pretreatment QOL, and QOL after 6 weeks of treatment are presented in Table VII. Female patients (P ¼ 0.002) and those with better QOL after 6 weeks (P ¼ 0.033) tended to have better outcomes after long-term treatment than their counterparts.
DISCUSSION Oxybutynin has provided good short-term results in the amelioration of hyperhidrosis. The main contraindication is closed-angle glaucoma. Excluding this concern, it is a safe medication but with limited tolerability due to antimuscarinic side effects, especially noted with the administration of doses >15 mg/day.20 The maximum dose of 10 mg/day, associated with the slow and progressive increase in dosage used in our protocol, lowers the incidence of side effects, maintains effectiveness, and improves treatment adherence. An earlier series described by our group demonstrated that 88.8% of patients improved in self-
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Long-term effects of oxybutynin on AH 5
Table VII. Comparison between the group with null/slight improvement in sweating at last visit with the group achieving moderate/great improvement Null/Slight improvement [n (%)]
Gender Women 15 (11.6) Men 16 (30.8) Body Mass Index Below 25 kg/m2 18 (14.6) Above 25 kg/m2 13 (22.4) Age 40 years 5 (20.0) Pretreatment QOL Very poor 19 (19.2) Poor 11 (14.1) Good 1 (25.0) Very good 0 (0.0) Excellent 0 (0.0) QOL after 6 weeks of treatment Much worse 0 (0.0) Worse 0 (0.0) The same 7 (41.2) Better 13 (15.5) Much better 11 (13.8) a
Moderate/Great improvement [n (%)]
P value
114 (88.4) 36 (69.2)
0.002b
105 (85.4) 45 (77.6)
0.195b
9 (100.0) 121 (82.3) 20 (80.0)
0.487a
80 67 3 0 0
(80.8) (85.9) (75.0) (0.0) (0.0)
0.456a
0 0 10 71 69
(0.0) (90.0) (58.8) (84.5) (86.2)
0.033a
Fisher’s exact test. Pearson chi-squared test.
b
perceived sweating after 6 weeks of treatment and 67.5% noted improved QOL.17 These initial data encouraged us to research the long-term outcomes of oxybutynin use. Therefore, a large cohort (n ¼ 431) of patients who initiated pharmacologic treatment was analyzed, and their progress was monitored. We focused on those who had a good initial response (6 weeks) and were treated for at least 6 months. We sought to know if the improvement was maintained in the long run. Concerning overall patients’ characteristics, they presented preponderance of female patientsdas is customary in hyperhidrosis patients2,4,21e24 and were young adults (median: 29 years). These findings were comparable to other studies in which most patients were around their 30s.2,3,5 Of the 431 initially studied subjects, 34 (7.89%) failed to return on the sixth week medical appointment. We imagine that at least some of these patients who were lost to follow-up may have been too anxious and unwilling to stay on medication that did not provide very short-term results. In a previous study on AH,17 there was a 19.6% follow-up loss (20 patients were lost on a cohort of 102). We believe that our knowledge of good initial outcomes, our emphatic clarifications for patients
about the expected risks, and the benefits of pharmacologic treatment lead to smaller loss to followup in our current study. Self-reporting (on a scale from 0 to 10) of the patient’s overall improvement impression was used, instead of an objective assessment of hyperhidrosis (which is technically feasible25 with sudorometers, but unfortunately only at 1 specific point in time, not throughout the day). Excessive sweating is a bothersomedbut not lethaldcondition, and the goal of treatment is the patient’s subjective amelioration of symptoms, thus making selfreporting an adequate method for data collection. Almost one-tenth of patients (9.45%, i.e. 26 patients), displayed good results with pharmacologic therapy, did not have significant side effects, but preferred VATS to pharmacologic treatment because of unwillingness to use medication indefinitely (either because they frequently forgot to take the medication or because they were worried of side effects that could arise from a very long-term usage of medication). When we analyze the 181 patients who were followed for more than 6 months, 12 of them (6.6%) reported null/slight amelioration in AH after 6 weeks, but continued treatment. We believe this
6 Wolosker et al.
continuation is because, unlike surgical treatment, sudoresis in other parts of the body was considerably ameliorated, leading patients to prefer pharmacologic treatment (in which improvement occurred in other sites of the body) instead of surgical treatment, which may prompt patients to sweat in places where they previously did not (CH). At the last visit (median ¼ 17 months), 19.4% of patients were found to have had a worsening of improvement category (a patient who reported great improvement after 6 weeks and moderate improvement at the last visit was considered to have worsened, for example). One possible reason for that is nonadherence, such as missed doses or ‘‘drug holidays’’. Because of the retrospective nature of this study, it is not possible to ascertain adherence by direct questioning or any other method. Another possible reason is tachyphylaxis, an occurrence that, to the best of our knowledge has not yet been reported for oxybutynin in hyperhidrosis. Nevertheless, 23.3% of patients presented improvement in category and >82% of patients reported moderate or great improvement in AH over the course of the study. We believe that because of these overall encouraging results, patients who dealt initially well with the medication may maintain treatment indefinitely. The subanalysis suggests that female patients tended to have better outcomes. This does not mean that male patients should not be pharmacologically treated, as male individuals achieved good responses (and have done so on other studies23), only not as outstanding as their female counterparts. Likewise, the fact that patients with better QOL after 6 weeks of treatment tended to achieve better outcomes by the final visit does not preclude patients who did not have such a significant initial response from continuing treatment. When we take surgical and pharmacological treatment into account, it is important to educate patients on the fact that there is an interval of at least 3 weeks between the initiation of drug use and the improvement in symptoms, as opposed to surgical treatment, in which the results are almost instant. This is important in maintaining adherence at the beginning of treatment. However, as the pharmacologic approach is systemic, one can expect that several sites of hyperhidrosis will be treated, which is not a feature of surgical treatment. We believe that when discussing with a patient about the possibilities of treatment for hyperhidrosis, it is very important that he or she is clarified about operative risks (which are, fortunately, rare26) and the risk of CH. Regrets after the
Annals of Vascular Surgery
procedure unfortunately are not so uncommon,27 and preoperative enlightenment and a ‘‘pharmacological first’’ approach lower the risk for patients and physicians regarding dissatisfaction with one’s treatment. If pharmacologic results are good, but the patient does not want nonsurgical treatment (for whichever reasons), referral to VATS should be considered, as long as the patient has had the chance to experience the reversible treatment for hyperhidrosis. If the initial results are suboptimal, such as the presence of significant side effects or no improvement after 6 weeks of therapy, evaluation for VATS or topical therapy should be considered, as this may be considered pharmacologic treatment failure. If patients have had good response after 6 weeks and are willing to stay on oxybutynin, they tend to benefit from therapy as they maintain moderate/ great improvement in axillary and other sites of significant sweating, and side effects tend to be tolerable.
CONCLUSIONS Our present data show that anticholinergic treatment with oxybutynin is feasible, with considerably positive results for those patients who were able to maintain therapy for 6 weeks, and after a median of 17 months, >80% of patients displayed moderate or great improvement in excessive sweating. The results for AH were better in female patients and in those who achieved better QOL after 6 weeks. REFERENCES 1. Weber A, Heger S, Sinkgraven R, et al. Psychosocial aspects of patients with focal hyperhidrosis. Marked reduction of social phobia, anxiety and depression and increased quality of life after treatment with botulinum toxin A. Br J Dermatol 2005;152:342e5. 2. Strutton DR, Kowalski JW, Glaser DA, et al. US prevalence of hyperhidrosis and impact on individuals with axillary hyperhidrosis: results from a national survey. J Am Acad Dermatol 2004;51:241e8. 3. Lear W, Kessler E, Solish N, et al. An epidemiological study of hyperhidrosis. Dermatol Surg 2007;33(1 Spec No.): S69e75. 4. Walling HW, Swick BL. Treatment options for hyperhidrosis. Am J Clin Dermatol 2011;12:285e95. Springer International Publishing. 5. Lakraj A-AD, Moghimi N, Jabbari B. Hyperhidrosis: anatomy, pathophysiology and treatment with emphasis on the role of botulinum toxins. Toxins (Basel) 2013;5:821e40. 6. Hafner J, Beer GM. Axillary sweat gland excision. Curr Probl Dermatol 2002;30:57e63. 7. Connolly M, de Berker D. Management of primary hyperhidrosis: a summary of the different treatment modalities. Am J Clin Dermatol 2003;4:681e97.
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8. Chwajol M, Barrenechea IJ, Chakraborty S, et al. Impact of compensatory hyperhidrosis on patient satisfaction after endoscopic thoracic sympathectomy. Neurosurgery 2009;64:511e8. discussion518. 9. de Moura J unior NB, das-Neves-Pereira JC, de Oliveira FRG, et al. Expression of acetylcholine and its receptor in human sympathetic ganglia in primary hyperhidrosis. Ann Thorac Surg 2013;95:465e70. 10. LeWitt P. Hyperhidrosis and hypothermia responsive to oxybutynin. Neurology 1988;38:506e7. 11. Mijnhout GS, Kloosterman H, Simsek S, et al. Oxybutynin: dry days for patients with hyperhidrosis. Neth J Med 2006;64:326e8. 12. Tupker RA, Harmsze AM, Deneer VHM. Oxybutynin therapy for generalized hyperhidrosis. Arch Dermatol 2006;142:1065e6. 13. Wolosker N, Campos JR, Kauffman P, et al. An alternative to treat palmar hyperhidrosis: use of oxybutynin. Clin Auton Res 2011;21:389e93. 14. Wolosker N, de Campos JRM, Kauffman P, et al. Use of oxybutynin for treating plantar hyperhidrosis. Int J Dermatol 2013;52:620e3. 15. Wolosker N, JRM de Campos, Kauffman P, et al. The use of oxybutynin for treating facial hyperhidrosis. An Bras Dermatol 2011;86:451e6. 16. Wolosker N, de Campos JRM, Kauffman P, et al. A randomized placebo-controlled trial of oxybutynin for the initial treatment of palmar and axillary hyperhidrosis. J Vasc Surg 2012;55:1696e700. 17. Wolosker N, de Campos JRM, Kauffman P, et al. The use of oxybutynin for treating axillary hyperhidrosis. Ann Vasc Surg 2011;25:1057e62.
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18. Try C, Messikh R, Elkhyat A, et al. Use of oral oxybutynin at 7.5 mg per day in primary hyperhidrosis. Rev Med Liege 2012;67:520e6. 19. de Campos JRM, Kauffman P, Werebe E de C, et al. Quality of life, before and after thoracic sympathectomy: report on 378 operated patients. Ann Thorac Surg 2003;76:886e91. 20. Arisco AM, Brantly EK, Kraus SR. Oxybutynin extended release for the management of overactive bladder: a clinical review. Drug Des Dev Ther 2009;3:151e61. 21. Cerfolio RJ, de Campos JRM, Bryant AS, et al. The Society of Thoracic Surgeons expert consensus for the surgical treatment of hyperhidrosis. Ann Thorac Surg 2011;91:1642e8. Elsevier Inc. 22. Wolosker N, Munia MAS, Kauffman P, et al. Is gender a predictive factor for satisfaction among patients undergoing sympathectomy to treat palmar hyperhidrosis? Clinics (Sao Paulo) 2010;65:583e6. 23. Wolosker N, Krutman M, Campdell TPDA, et al. Oxybutynin treatment for hyperhidrosis: a comparative analysis between genders. Einstein (Sao Paulo) 2012;10:405e8. 24. Vorkamp T, Foo FJ, Khan S, et al. Hyperhidrosis: evolving concepts and a comprehensive review. Surgeon 2010;8:287e92. 25. Ishy A, de Campos JRM, Wolosker N, et al. Objective evaluation of patients with palmar hyperhidrosis submitted to two levels of sympathectomy: T3 and T4. Interact Cardiovasc Thorac Surg 2011;12:545e8. 26. de Andrade Filho LO, Kuzniec S, Wolosker N, et al. Technical difficulties and complications of sympathectomy in the treatment of hyperhidrosis: an analysis of 1731 cases. Ann Vasc Surg 2013;27:447e53. 27. Smidfelt K, Drott C. Late results of endoscopic thoracic sympathectomy for hyperhidrosis and facial blushing. Br J Surg 2011;98:1719e24.
