Pharmacology and therapeutics

Long-term results of the use of oxybutynin for the treatment of plantar hyperhidrosis Nelson Wolosker1,2, MD, PhD, Marcelo P. Teivelis1, MD, Mariana Krutman1, MD, Rafael P. de Paula3, MD, Paulo Kauffman1, MD, PhD, Jose R. M. de Campos4,5, MD, PhD, and Pedro Puech-Le~ ao2, MD, PhD

1 Department of Vascular and Endovascular Surgery, Hospital Israelita Albert Einstein, ~o Paulo, SP, Brazil, 2Division of Vascular Sa Surgery, Hospital das Clınicas, University of ~o Paulo Medical School, Sa ~o Paulo, SP, Sa Brazil, 3Hospital das Clınicas da Faculdade ~o Paulo de Medicina da Universidade de Sa ~o Paulo, SP, Brazil, (HC-FMUSP), Sa 4 Thoracic Surgery Division, Hospital ~o Paulo, SP, Israelita Albert Einstein, Sa Brazil, and 5Thoracic Surgery Division, Hospital das Clınicas da Faculdade de ~o Paulo Medicina da Universidade de Sa ~o Paulo, SP, Brazil (HC-FMUSP), Sa

Correspondence Marcelo Teivelis, MD Department of Vascular and Endovascular Surgery Hospital Israelita Albert Einstein, Av. Albert Einstein, 627 - A1 Building Room 423, CEP: 05651-901 ~o Paulo, SP, Brazil Sa E-mail: dr.marcelo@consultoriovasculares. med.br

Abstract Background Plantar hyperhidrosis is a common illness with significant impact on quality of life. Oxybutynin presents good short-term results, but longer follow-up results are lacking. We evaluated oxybutynin effectiveness in patients who were not surgically treated and who had at least six months of follow-up. Methods From September 2007 to September 2013, 85 consecutive patients were enrolled in our institutional protocol for the “pharmacological-first” treatment of primary plantar hyperhidrosis with oxybutynin. Eight patients were lost to follow-up, 15 patients have not yet been under treatment for six months, and data were available for 39 patients (all female) treated for at least six months. Data at the start of the protocol, six weeks after beginning treatment, and at their final visit were analyzed. Results Twenty-three of the 77 patients (29.87%) did not improve after pharmacological therapy. From the 39 patients with more than six months of follow-up (median 16.9 months, range 9–71), 79.5% reported moderate/great improvement in excessive plantar sweating after six weeks of treatment, and this rate increased to 84.7% in the last follow-up visit; 82.85% showed improvement in other sites presenting hyperhidrosis. Dry mouth was the most common side effect; 51.6% of patients reported it to be moderate/ severe at the last visit. Conclusion In patients with good initial response to oxybutynin, more than 82% presented moderate or great improvement in plantar and other sites’ excessive sweating; dry mouth was the most common side effect but was tolerable and did not lead any patient to interrupt treatment.

Conflicts of interest: The authors declare no conflict of interest.

Introduction Excessive sweating in the feet – plantar hyperhidrosis (PLH) – is defined as a disease that predominantly affects patients’ feet. It is associated with a significant decrease in quality of life (QOL), compromising one’s professional, emotional, social, and leisure activities.1 This disease usually starts during childhood and is less common than the axillary and palmar presentations.2–4 Non-operative treatment possibilities (botulinum toxin, iontophoresis, and topical agents) demonstrate limited effectiveness.5 Lumbar sympathectomy (LS) – either chemical6,7 or surgically minimally invasive (endoscopic)8 – presents good results but with definite risks, such as

lymphatic leak, nerve misidentification, and sexual dysfunction.9 It has been demonstrated that patients with primary hyperhidrosis have a higher expression of acetylcholine and alpha-7 nicotinic receptors in sympathetic ganglia.10 Oxybutynin is an antimuscarinic drug, which was first associated with resolving hyperhidrosis in 1988.11 In the last 10 years, specific treatment with this drug began to be reported12,13 as a good initial alternative for treatment for excessive sweating. It has been used on treatment for axillary hyperhidrosis,14 and palmar15 and facial hyperhidrosis16 and underwent evaluation in a randomized placebo-controlled trial.17 Short-term results on pharmacological treatment of PLH have been published,18 605

ª 2015 The International Society of Dermatology

International Journal of Dermatology 2015, 54, 605–611

606

Pharmacology and therapeutics

Wolosker et al.

Long-term oxybutynin use in plantar hyperhidrosis

but long-term results in treatment with this particular drug are lacking. The aim of this study was to assess the long-term clinical efficacy in a series of consecutive patients (n = 85) with PLH treated with low doses of oxybutynin for at least six months (median = 16.9 months). Patients This was a non-randomized and uncontrolled study in accordance with the ethical standards from the associated 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, 85 consecutive patients with PLH as their main complaint were enrolled in our pharmacological-first protocol. Figure 1 graphically represents the series, treatment, and outcomes over time: 85 patients were enrolled; eight patients failed to attend their first follow-up visit. From the 77 initial patients, 23 did not improve with pharmacological treatment, and 15 have been under treatment for 40 kg followed the same protocol: during the first week, they received 2.5 mg of oxybutynin once a day at bedtime. From day 8–21, they received 2.5 mg twice a day, and from day 22, they received 5 mg twice a day. Pediatric patients weighing 83, QOL was considered very poor; (ii) 68–83, poor; (iii) 52–67, good; (iv) 36–51, very good; and (v) 20–35, it was considered excellent. Improvement in QOL after treatment was also classified into five different evolution levels: (i) when the total was >83, QOL was considered much worse; (ii) 68–83, slightly worse; (iii) 52–67, the same; (iv) 36–51, slightly better; and (v) 20–35, much better. The following parameters were studied: (i) negative impact of hyperhidrosis on QOL before treatment; (ii) improvement in QOL after treatment; (iii) the evolution of PLH (comparing results after six weeks of treatment and results at the last follow-up visit); and (iv) improvement at the last consult on the other sites of hyperhidrosis and complications. Consistency (see Tables 2 and 4) was calculated as the proportion of patients who remained in the same category (either 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 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 plantar sweating in the last follow-up visit, we divided the patients into two separate groups: the first group included patients who attributed grades of 0–4 (null/slight amelioration) to their symptoms at the last consult regarding amelioration of PLH, and the second group included the remaining patients (with moderate/great improvement), whose grades were from 5 to 10 at their final visit. For the above-mentioned analysis, data relating to the following patient characteristics were studied: body mass index (BMI), pretreatment QOL, and QOL after six weeks of treatment.

Pharmacology and therapeutics

and Pearson’s chi-squared test were used for analysis comparing groups. The significance level considered for all tests was P = 0.05. Results By inclusion criteria, all patients were followed for at least six months, ranging from 6 to 72 months (median = 16.9 months). QOL before treatment is presented in Table 1. More than 94% of patients reported poor or very poor QOL before treatment (Fig. 2). Improvement in QOL after six weeks of treatment is presented in Table 1. Approximately 5% of patients did not present improvement in QOL after six weeks of treatment (Fig. 3). Improvements in sweating after six weeks and in the last visit are presented in Table 2. After six weeks of pharmacological treatment, 79.5% of the patients reported moderate or great improvement in self-perceived sweating. In the last visit, 84.7% of the patients maintained moderate or great improvement in self-perceived sweating. Comparing the category of improvement on the analysis at six weeks and at last evaluation (Table 2) 46.2% of patients remained in the same category of improvement, 25.7% downgraded, and 28.1% improved in the long run. The change in subcategories was not statistically significant (McNemar’s test P = 0.227).

Statistical analysis Means and SDs were used in the descriptive analysis of parametrically distributed continuous variables, whereas frequencies were used for categorical variables. The McNemar test was used to compare self-reported improvement of hyperhidrosis and dry mouth over time, on the two consecutive analysis time points, and the kappa coefficient was used for analysis. Fisher’s exact test ª 2015 The International Society of Dermatology

Figure 2 Quality of life before treatment International Journal of Dermatology 2015, 54, 605–611

607

608

Pharmacology and therapeutics

Wolosker et al.

Long-term oxybutynin use in plantar hyperhidrosis

Table 3 Reports of improvement hyperhidrosis on the last visit

Palmar (n = 32) Axillar (n = 19) Thoraco-abdominal (n = 7) Facial (n = 4)

on

other

sites

of

Null/slight (%)

Moderate (%)

Great (%)

3 (9.38) 2 (10.53) 0

10 (31.25) 5 (26.31) 2 (28.57)

19 (59.37) 12 (63.16) 5 (71.43)

0

0

4 (100)

Table 4 Complaint of dry-mouth after 6 weeks of treatment and on the last visit Last visit

Six weeks Absent/light, n (%) Moderate/severe n (%) Total

Figure 3 Quality of life after 6 weeks of treatment

Improvement at last visit

Improvement after Null Count % of Total Slight Count % of Total Moderate Count % of Total Great Count % of Total Total Count % of Total

Slight

Moderate

Great

Total

6 weeks 0 0.0

2 5.1

2 5.1

0 0.0

4 10.2

0 0.0

1 2.6

0 0.0

3 7.7

4 10.3

1 2.6

1 2.6

6 15.4

4 10.3

12 30.8

1 2.6

0 0.0

7 17.9

11 28.2

19 48.7

2 5.1

4 10.3

15 38.5

18 46.2

39 100.0

McNemar test P = 0.227. Kappa: 0.160. Consistency: 46.2%. Worse: 25.7%. Better: 28.2%.

Improvements in other sites of hyperhidrosis – regarding only the last evaluation – are represented in Table 3: almost 90% of patients presented moderate or great improvement in other areas of excessive sweating. International Journal of Dermatology 2015, 54, 605–611

Moderate/ severe

Total

11 (28.2) 8 (20.5)

1 (2.6) 19 (48.7)

12 (30.8) 27 (69.2)

19 (48.7)

20 (51.3)

39 (100.0)

McNemar test P = 0.039. Kappa: 76.9%. Worse: 2.6%. Better: 20.5%.

Table 2 Comparison of self-assessment of improvement of hyperhidrosis of 6 weeks of treatment and last visit

Null

Absent/ light

McNemar P 0.039

0.534. Consistency:

Comparisons of dry mouth complaint after six weeks and on the last visit are shown on Table 4. No major side effects (e.g., intestinal obstruction) occurred in this population. Mild headache was reported by five patients (12.8%), urinary retention in three patients (7.7%), and somnolence and drowsiness were reported by two patients (5.12%). Comparisons of patients with null/slight improvement and patients with moderate/great self-perceived amelioration in sweating (on last visit) are presented on Table 5. None of the compared variables were predictors of outcomes after six months of treatment. Discussion It has been recognized that treatment with oxybutynin provides good short-term results in the amelioration of hyperhidrosis. The main contraindication is closed-angle glaucoma. Apart from this concern, it is a safe medication with limited tolerability due to antimuscarinic side effects for the administration of doses over 15 mg/day.20 The dose of 10 mg/day associated with the slow and progressive increase in doses used in our protocol lowers the incidence of side effects but maintains effectiveness and improves treatment adherence. An earlier series described by our group18 demonstrated that more than 70% of patients improved in selfª 2015 The International Society of Dermatology

Wolosker et al.

Long-term oxybutynin use in plantar hyperhidrosis

Table 5 Comparison between groups with null/slight improvement in sweating on last visit with moderate/great improvement Null/slight improvement n (%) Gender Female 6 (15.4) Male 0 Body mass index 2 (8.7) 25 kg/m2 4 (25.0) Age 40 years old 0 Pretreatment QOL Very poor 4 (15.4) Poor 1 (9.1) Good 1 (50.0) Very good 0 Excellent 0 QOL after 6 weeks of treatment Much worse 0 Worse 0 The same 0 Better 6 (33.3) Much better 0

Moderate/great improvement n (%)

P

33 (84.6) 0



21 (91.3) 12 (75.0)

0.205a

2 (100.0) 25 (80.6) 6 (100.0)

b

22 (84.6) 10 (90.9) 1 (50.0) 0 0

0.395a

0 0 2 (100.0) 12 (66.7) 19 (100.0)

b

a

Fisher’s exact test. Insufficient numbers for analysis.

b

perceived sweating after six weeks treatment, and more than 65% noted improved QOL. These initial findings encouraged us to research the long-term outcomes of oxybutynin use. Therefore, a larger cohort (n = 85) of patients who initiated pharmacological treatment with oxybutynin were analyzed; their progress was monitored, and we focused on those who had a good initial response (six weeks) and were treated for at least six months. We sought to know if the improvement was maintained long-term. Concerning overall patients’ characteristics, all patients that have been followed for six months or more were female (in opposition to the beginning of the series, in which 10 of 85 patients were male). Because of the retrospcetive nature of our study, we could not directly ask the male patients that started the protocol the reason why they never returned to the follow-up visit. We could hypothesize that these patients either were too anxious and unwilling to stay on medication that did not provide very short-term results or that they were not so severely affected by sweating in the feet (as most men wear shoes throughout the day, in opposition to women, who may want to wear sandals or other footwear that makes the ª 2015 The International Society of Dermatology

Pharmacology and therapeutics

excessive sweating in this region noticeable, thus leading more female patients to seek and maintain medical attention to this complaint). A previous study on PLH18 presented a 14.28% follow-up loss (five patients were lost on a cohort of 35). The current study presents a 9.4% loss to follow-up. We believe that our knowledge of good initial outcomes and our emphatic clarifications for patients about the expected risks and benefits of pharmacological treatment lead to our current smaller loss to follow-up. Patients were young adults (median: 29 years old) as usual for PLH, who seek medical attention around their thirties.9 Self-reporting (on a scale from 0 to 10) of his/her overall improvement impression was used, instead of an objective assessment of hyperhidrosis (which is technically feasible21,22 with sudorometers but unfortunately only at one specific point in time, not throughout the day). Hyperhidrosis is a bothersome – but not lethal – condition, and the goal of treatment is the patient’s subjective amelioration of symptoms, thus making self-reporting an adequate method for data collection. After six weeks, eight patients (20.6%) reported null/ slight amelioration in PLH but continued treatment. We can speculate this continuation is because, unlike surgical treatment, sudoresis in other parts of the body was considerably ameliorated, leading patients to prefer pharmacological treatment (in which improvement occurred in other sites of the body) instead of surgical treatment, which, in addition to surgical risks, may prompt patients to sweat in places where they previously did not, as occurs in compensatory hyperhidrosis (CH). At the last visit (median = 16.9 months), 25.7% of patients were found to have had a worsening of improvement category (e.g., a patient who reported great improvement after six weeks and moderate improvement at the last visit was considered to have worsened). One possible reason for that is non-adherence such as missed doses or drug holidays. Owing to 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. Nevertheless, 28.2% of patients presented improvement in category and more than 84% of patients reported moderate or great improvement in PLH over the course of the study. This apparent contradiction is explained because worsening between categories does not necessarily lower overall satisfaction with medical care (i.e., there may be some variation in the perceived amelioration of sweating, but this is not significant enough to cause patients to cease medication use). We can speculate that International Journal of Dermatology 2015, 54, 605–611

609

610

Pharmacology and therapeutics

Long-term oxybutynin use in plantar hyperhidrosis

because of these overall encouraging results, patients who deal initially well with the medication may maintain treatment indefinitely. The subanalysis (comparing patients with mild improvement and those with moderate/great improvement on PLH at last visit) comparing BMI and QOL (gender was not analyzed, as all patients were female) did not demonstrate any particular tendency or predictor of better outcomes. It is important to acknowledge that the small number in this series (n = 39) most likely contributed to an underpowered statistical analysis. When we take into account surgical and pharmacological treatment, it is important to educate patients on the fact that there is an interval of at least three 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 pharmacological approach is systemic, one can expect that several sites of hyperhidrosis will be treated, which is not a feature of surgical treatment. It is our group’s opinion that when a patient considers surgical treatment for hyperhidrosis, it is of utmost importance that he or she receives education clarifying the risks concerning the perioperative period and the risk of CH. Regrets following the procedure are, unfortunately, not rare (in one series,9 4% of patients who had been operated on would not have the procedure again if they could choose), and preoperative education and a pharmacological-first approach lowers the risk of treatment dissatisfaction for both patients and physicians. Patients with palmoplantar hyperhidrosis (i.e., excessive sweating with similar burden of both hands and feet) may be submitted to video-assisted thoracic sympathectomy for palmar hyperhidrosis, perhaps with very good results, may even have some amelioration in PLH, even when no LS is performed, but this improvement is usually not long-lasting,22 and CH can be due to thoracic sympathectomy. Some authors perform endoscopic LS after videoassisted thoracic sympathectomy23 for residual PLH. While this approach may provide good results, patients are submitted to two surgical procedures, with inherent perioperative risks, and are prone to CH. With pharmacological therapy, the patient may take one drug and treat two (or more) sites simultaneously. For those who cope well with dry mouth (the most frequent side effect of oxybutynin), this approach may prove fruitful. If the initial results are suboptimal, such as the presence of significant side effects or no improvement after six weeks of therapy, evaluation for LS or topical therapy should be considered, as this may be considered pharmacological treatment failure. However, if patients have had International Journal of Dermatology 2015, 54, 605–611

Wolosker et al.

good response after six weeks, and side effects have been tolerable, they tend to benefit from therapy as they maintain moderate/great improvement in plantar and other sites of significant sweating. Conclusion 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 six weeks, and after a median of 16.9 months, 84% of patients displayed moderate or great improvement in excessive sweating. References 1 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: 1642–1648. 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: 241–248. 3 Lear W, Kessler E, Solish N, et al. An epidemiological study of hyperhidrosis. Dermatol Surg 2007; 33: S69–S75. 4 Walling HW. Primary hyperhidrosis increases the risk of cutaneous infection: a case–control study of 387 patients. J Am Acad Dermatol 2009; 61: 242–246. 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: 821–840. 6 Kim WO, Yoon KB, Kil HK, et al. Chemical lumbar sympathetic block in the treatment of plantar hyperhidrosis: a study of 69 patients. Dermatol Surg 2008; 34: 1340–1345. 7 Yoshida WB, Cataneo DC, Bomfim GAZ, et al. Chemical lumbar sympathectomy in plantar hyperhidrosis. Clin Auton Res 2010; 20: 113–115. 8 Reisfeld R, Pasternack GA, Daniels PD, et al. Severe plantar hyperhidrosis: an effective surgical solution. Am Surg 2013; 79: 845–853. 9 Rieger R, Pedevilla S, P€ ochlauer S. Endoscopic lumbar sympathectomy for plantar hyperhidrosis. Br J Surg 2009; 96: 1422–1428. 10 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: 465–470. 11 LeWitt P. Hyperhidrosis and hypothermia responsive to oxybutynin. Neurology 1988; 38: 506–507. 12 Mijnhout GS, Kloosterman H, Simsek S, et al. Oxybutynin: dry days for patients with hyperhidrosis. Neth J Med 2006; 64: 326–328. ª 2015 The International Society of Dermatology

Wolosker et al.

Long-term oxybutynin use in plantar hyperhidrosis

13 Tupker RA, Harmsze AM, Deneer VHM. Oxybutynin therapy for generalized hyperhidrosis. Arch Dermatol 2006; 142: 1065–1066. 14 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: 520–526. 15 Wolosker N, Campos JR, Kauffman P, et al. An alternative to treat palmar hyperhidrosis: use of oxybutynin. Clin Auton Res 2011; 21: 389–393. 16 Wolosker N, de Campos JRM, Kauffman P, et al. The use of oxybutynin for treating facial hyperhidrosis. An Bras Dermatol 2011; 86: 451–456. 17 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: 1696–1700. 18 Wolosker N, de Campos JRM, Kauffman P, et al. Use of oxybutynin for treating plantar hyperhidrosis. Int J Dermatol 2013; 52: 620–623.

ª 2015 The International Society of Dermatology

Pharmacology and therapeutics

19 de Campos JR, Kauffman P, Werebe Ede C, et al. Quality of life, before and after thoracic sympathectomy: report on 378 operated patients. Ann Thorac Surg 2003; 76: 886–891. 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: 151–161. 21 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: 545–548. 22 Wolosker N, Ishy A, Yazbek G, et al. Objective evaluation of plantar hyperhidrosis after sympathectomy. Clinics (Sao Paulo) 2013; 68: 311–315. 23 Rieger R, Loureiro Mde P, Pedevilla S, et al. Endoscopic lumbar sympathectomy following thoracic sympathectomy in patients with palmoplantar hyperhidrosis. World J Surg 2011; 35: 49–53.

International Journal of Dermatology 2015, 54, 605–611

611

Long-term results of the use of oxybutynin for the treatment of plantar hyperhidrosis.

Plantar hyperhidrosis is a common illness with significant impact on quality of life. Oxybutynin presents good short-term results, but longer follow-u...
176KB Sizes 0 Downloads 6 Views