Safety and efficacy of oxybutynin in patients with hyperhidrosis: systematic review and meta-analysis of randomized controlled trials

Background Sweating is a physiologic mechanism of human thermoregulation. Hyperhidrosis is defined as a somatic disorder where the sweating is exaggerated in an exact area because the sweat glands are hyperfunctioning. It negatively affects the quality of life of the patients. We aim to investigate patient satisfaction and the effectiveness of oxybutynin in treating hyperhidrosis. Methods We prospectively registered the protocol of this systematic review and meta-analysis on PROSPERO (CRD 42022342667). This systematic review and meta-analysis were reported according to the PRISMA statement guidelines. We searched three electronic databases (PubMed, Scopus, Web of Science) from inception until June 2, 2022, using MeSH terms. We include studies comparing patients with hyperhidrosis who received oxybutynin or a placebo. We assessed the risk of bias using the Cochrane risk of bias assessment tool (ROB2) for randomized controlled trials. The risk ratio was calculated for categorical variables, and the mean difference was calculated for continuous variables using the random effect model with 95% confidence intervals (CI). Results Six studies were included in the meta-analysis, with a total of 293 patients. In all studies, patients were assigned to receive either Oxybutynin or Placebo. Oxybutynin represented an HDSS improvement (RR = 1.68 95% CI [1.21, 2.33], p = 0.002). It also can improve the quality of life. There is no difference between oxybutynin and placebo regarding dry mouth (RR = 1.68 95% CI [1.21, 2.33], p = 0.002). Conclusion Our study suggests that using oxybutynin as a treatment for hyperhidrosis is significant and needs to be highlighted for clinicians. However, more clinical trials are needed to grasp the optimum benefit. Supplementary Information The online version contains supplementary material available at 10.1007/s00403-023-02587-5.


Introduction
Sweating is a physiologic mechanism of human thermoregulation [1]. Hyperhidrosis is defined as a somatic disorder where the sweating is exaggerated in an exact area because the sweat glands are hyperfunctioning [1,2]. The eccrine glands are concentrated in the regions such as the face, palms, axilla, and soles; therefore, these areas are mostly associated with hyperhidrosis [3]. The acetylcholine negative feedback loop is likely impaired in these patients, which can clarify how a physiologic response can change into pathological [4]. The prevalence is approximately 3% of this disorder in the United States [1]. Hyperhidrosis is classified into two types: primary and secondary, and the treatment and management can be different for each type. The primary disease (with no known cause) has more localized symptoms 1 3 and is present in life earlier. The secondary disease typically presents because of side effects of systemic disorders or medications, especially neurologic [4,5]. The diagnosis is based mainly on clinical bases, tests, and grading scales that are available to help in determining the localization and the severity [6]. The starch-iodine and gravimetry tests are usually used to determine the amount of sweat produced by specific area and localize the sites which need treatment [7]. For example, more than 50 mg of sweat per minute in the axillary area is considered hyperhidrosis [8]. The commonest grading scale used to assess the impact of sweating on the patient life and the response to treatment is the dermatology life quality index (DLQI) [9]. If a secondary cause is suspected, we may need laboratory work-up to rule out diabetes mellitus, neurologic disorder, infection, hyperthyroidism, or a medication adverse effect [3]. The treatment of secondary hyperhidrosis is treating the underlying cause or stoppage of the drug causing it [3].
Hyperhidrosis can lead to social, emotional, occupational, and psychological impairment [1]. Given the significant effect on the quality of life, identifying effective treatments is a research priority [10][11][12] No evidence has proved that either women or men are at increased risk [1]. The most commonly affected area is the palmar region [3]. Many therapy modalities are available: oral, topical, and injectable drugs, tap water iontophoresis, or more invasive medical treatments (e.g., suction curettage, laser therapy, endoscopic transthoracic sympathectomy, and microwave thermolysis) [13]. Over-the-counter aluminum chloride hexahydrate 20% is considered the first line of treatment for the disorder; it is given for 3 to 4 nights, then nightly as needed [14]. Patients often become intolerant of it in the long run. Furthermore, skin irritation can happen [15].
All topical agents can result in skin sensitization, and some, like potassium permanganate and tannic acid, can also lead to skin discoloration [14]. These agents can limit sweating by denaturing keratin and hence, occluding the sweat glands' pores. The duration of the effect is concise. Aluminum chloride gel can manage axillary sweating. While it does work, it is a potent irritant [14].
Botulinum toxin injection is the most studied hyperhidrosis therapy and demonstrates consistent improvement in sweat production as measured in the axillae and palms [8,16]. It can be considered first-or second-line therapy for hyperhidrosis affecting the face, palms, axilla, soles, or face [8,17]. Botulinum toxins bind synaptic proteins, which block the acetylcholine release from the cholinergic neurons, which innervate the eccrine sweat glands [18]. However, it is not often used because of localized numbness, weakness, and fears around its effectiveness; moreover, it causes pain [19].
Oxybutynin is an anticholinergic drug used to treat urinary frequency, incontinence, and overactive bladder [20].
Hyperhidrosis was originally linked to the antimuscarinic effects of oxybutynin in 1988. Elderly patients or individuals with primary severe hyperhidrosis where surgery isn't eligible for them are turning progressively to this treatment as an alternate or initial therapy [21].
A case reported in 1988 described a patient with hyperhidrosis who began taking oxybutynin for urinary urgency; his episodes of severe sweating vanished within a few hours [22]. In addition, four other cases have been documented. From here, a hypothesis was generated about oxybutynin's promising benefits on patients with hyperhidrosis [23][24][25].
To our knowledge, no studies have made a meta-analysis on the use of oxybutynin in the treatment of hyperhidrosis, and due to the side effects of other mentioned treatments being significant, oxybutynin represents a possible alternative. So, this study aims to investigate patient satisfaction and the effectiveness of oxybutynin in treating hyperhidrosis.

Methods
All the PRISMA statement guidelines were followed while reporting this systematic review and meta-analysis [26].
All steps have been done according to the Cochrane Handbook of Systematic Reviews and Meta-analysis of Interventions [27]. All steps of this study were prespecified, and the protocol was registered on PROSPERO (CRD42022342667).

Eligibility criteria
Included studies in our review fit our inclusion criteria as the following: Population: studies with patients who have hyperhidrosis or exercise-induced hyperhidrosis (physiologic sweating response to exercise).
Intervention: studies whose experimental group takes oral oxybutynin.
Comparator: studies where the control group received a placebo.
Outcome: studies that reported the transepidermal water loss, Hyperhidrosis disease severity scale, quality of life, dry mouth, and CNS adverse effects.
Study design: randomized studies that compare the oxybutynin group versus a placebo group.
We excluded studies reported as abstract only, review articles, observational studies, letters to the editor, comments, case reports, and studies that were not published in the English language.

Information sources and search strategy
We performed a comprehensive search of three electronic databases (PubMed, Scopus, Web of Science) from inception until 2 June 2022 using MeSH terms. Further, the references of the included studies were manually searched for any potentially eligible studies. The search strategy and results for each database are reported in (supplementary material 1).

Selection process
We removed duplicates by Endnote (Clarivate Analytics, PA, USA), and other records were screened independently by three authors in two steps: (1) title and abstract screening to determine the relevance to this meta-analysis, (2) full-text screening for the final eligibility to meta-analysis.

Data collection process and data items
Data were collected independently by four review authors and extracted into a uniform data extraction Excel sheet. The extracted data included (1) Characteristics of the included studies, (2) Characteristics of the population of included studies, (3) Risk of bias domains, and (4) Outcome measures. Any disagreement between the review authors was resolved by consensus or consultation.

Assessing the risk of bias in the individual studies
We used the Cochrane assessment tool 2 (ROB2) for randomized controlled trials. The risk of bias assessment included the following domains: bias arising from the randomization process, bias due to deviations from intended interventions, bias due to missing outcome data, bias in the measurement of the outcome, bias in the selection of the reported result, and other biases. The authors' judgments are categorized as "low risk," "high risk," or "some concerns" of bias [28].

Synthesis methods
The risk ratio was calculated for categorical variables such as adverse effects to estimate the effect size and compare oxybutynin and placebo groups.
For continuous variables such as transepidermal water loss, the mean difference was calculated to estimate the effect size to assess the difference in outcome measures between oxybutynin and placebo groups.

Choice of the meta-analysis model
We calculated the pooled effect size for all outcomes according to the DerSimonian Liard meta-analysis model. This random effect model assumes the included studies represent a random sample from the population and assigns a slightly higher weight to small studies on the expenses of larger studies. We chose this model because, unlike the fixed-effects model, it accommodates a larger standard error in the pooled estimate, which makes it suitable in case of inconsistent or controversial estimates. Thus, the calculated effects in our meta-analysis are conservative estimates that take into consideration the possible inconsistencies.

Assessment of heterogeneity
Heterogeneity among studies was assessed using the Chisquare test (Cochrane Q test) and the I-squared (I 2 ) and χ 2 tests. χ 2 p-value of < 0.1 indicates significant heterogeneity. I-square values ≥ 50% indicate high heterogeneity.

Reporting bias assessment
In the present study, we could not assess the existence of publication bias by Egger's test for funnel plot asymmetry, as according to Egger and colleagues [29], publication bias assessment is unreliable for < 10 pooled studies.

Sensitivity analysis
To test the robustness of the evidence, we conducted a certainty assessment through sensitivity analysis (also called leave-one-out meta-analysis). We ran sensitivity analysis in multiple scenarios for every outcome in the meta-analysis, excluding one study in each scenario to ensure the overall effect size was not dependent on any single study.

Literature search results
Our literature search process retrieved 815 records. Following title and abstract screening, 44 articles were eligible for full-text screening. Of them, six studies were included in the meta-analysis. The references of the included studies were manually searched, and no further articles were included. The PRISMA flow diagram of the study selection process is shown in Fig. 1.

Characteristics of the included studies
Six studies were included in the meta-analysis, with a total of 293 patients. In all studies, patients were assigned to receive either Oxybutynin or Placebo. A summary and baseline of the characteristics of the included studies are provided in Tables 1 and 2. Overall, the risk of bias in the included studies ranged from some concerns to low, according to the Cochrane risk of bias tool 2 (ROB2) (Fig. 2, and supplementary file sec "Methods").

Other sites
We found Costa et al. [30] representing this outcome at different sites in the body but unfortunately, we couldn't pool the results in a meta-analysis. It measures TEWL on the back, right foot, right hand, and abdomen. Results showed that oxybutynin significantly reduces the TEWL. The mean (SD) change of the back was − 27.4 (64.8), 0.8 (33.75), of the abdomen, was − 23.2 (49.8), 2.8 (36,2), of the right hand, was − 33.1 (48.4), − 7.9 (54.5), of the right foot was − 52.7 (80.9), − 10.4 (74.5) in the oxybutynin group and in the placebo group respectively.

Quality of life (QoL)
Two studies reported on the effect of oxybutynin on QoL; however, because they used different methods, they could not be pooled in a meta-analysis. However, we observed that in Wolosker et al. [2] there were 8 (34.8%) patients in the oxybutynin group in comparison to 0 (0%) in the placebo group showed much better improvement, and 9 (39.1%) in contrast to 3 (13.6%) in the placebo group showed a little better improvement.
In Costa Jr et al., this outcome was measured by the QoL questionnaire for hyperhidrosis, in which the lower value, the better QoL. Before the intervention, it was 52.3 ± 11.5 ''Good'' and 47.8 ± 13.0 ''Very Good'' for oxybutynin and placebo groups, respectively. After the intervention, the oxybutynin group showed much improvement, 34.0 ± 9.5 ''Excellent'' than the placebo group, which was still in the same category, 46.5 ± 12.2 ''Very Good''.

Central nervous system (CNS) adverse effects (headache, asthenia, dizziness, flush, blurring vision, drowsiness, urinary difficulty)
Three studies reported CNS adverse effects involving 230 patients. The overall analysis showed statistically significant differences between oxybutynin and placebo, favoring the placebo group according to CNS adverse effects (RR = 5.07,

Summary of findings
As far as we know, no previous systematic reviews have been published to investigate the outcomes of oxybutynin treatment for patients with localized or generalized/ primary or secondary hyperhidrosis. The analysis includes four comparisons with 293 patients divided into the oxybutynin and the placebo groups. Our pooled analysis showed a significant difference between the oxybutynin and the placebo groups in HDSS improvement, favoring the oxybutynin group, and a clear difference in CNS adverse effects favoring the placebo group. The analysis showed no statistical difference between the two groups according to TEWL either on the hand or the arm and no apparent difference according to dry mouth. We can't analyze the quality of life as it was reported by two different methods in two studies. In both studies, oxybutynin showed improvement in the quality of life.

Explanation of findings
Oxybutynin administration is associated with a low HDSS score, a decrease in the incidence of psychosocial functioning impairment, and an improvement in quality-oflife score. These effects contribute to the actual action of oxybutynin as it plays on the underlying mechanisms of HH. It contra verse acetylcholine receptors, especially muscarinic receptors M1, M2, and M3 [30]. By this antimuscarinic effect, it reduces sweating by limiting the role of acetylcholine on sweat glands. The non-statistical difference regarding TEWL does not necessarily deny the oxybutynin's effectiveness, as the patients in the studies that measured the TEWL were healthy and did an exercise to induce hyperhidrosis. A systematic review conducted by Cruddas et al. reported that anticholinergic therapy does not induce tachyphylaxis [31], which supports the effectiveness of oxybutynin in longterm usage [5]. It was reported that oxybutynin in the form of topical gel is the most commonly used anticholinergic as it provides a long duration of action extending to 84 h [32]. However, there is dreadful concern regarding oxybutynin since it is associated with CNS events that are favored by the ability to pass through the blood-brain barrier [13].
Adverse events from oral oxybutynin activity include dry eyes, mydriasis, headache, gastrointestinal symptoms, urinary retention, and orthostatic hypotension, but dry mouth is by far the most common side effect affecting 73.4%, 38.6%, and 68.8% of patients treated orally with oxybutynin [31]. However, our meta-analysis found no significant difference between the oxybutynin and placebo groups regarding the incidence of dry mouth. Despite the undesirable antimuscarinic effects of this medication, this drawback phenomenon can be prevented or even anticipated by using the stepwise up-titration approach that can achieve efficacy, tolerability, and therapeutic compliance, thus obtaining patient satisfaction [33]. If the patients can't tolerate the side effects, many therapy modalities are available: oral, topical, and injectable drugs, tap water iontophoresis, or more invasive medical treatments (e.g., suction curettage, laser therapy, endoscopic transthoracic sympathectomy, and microwave thermolysis [13].

Strength points
To date, this is the first meta-analysis to be published investigating the efficacy and safety of oxybutynin in patients with HH. Our research has several merits since it covers all Fig. 2 The risk of bias assessment Fig. 3 The comparison between oxybutynin and placebo according to transepidermal water loss the studies available in this vital area which gives our metaanalysis some strength. In addition, all included studies were randomized control trials that provide strong evidence.

Limitations
With the available data revised, we acknowledge that our meta-analysis has numerous limitations. For example, the number of eligible included studies in this meta-analysis is six, so we recommend more studies be conducted on the same vital topic. The difference in measuring each outcome makes it difficult to do the meta-analysis, and some studies were reported with us in systematic review only in some outcomes. No evaluation of patient satisfaction regards the drug's side effects and their impact on their quality of life. We can't make conclusions about the effectiveness of oxybutynin in patients with hyperhidrosis, as this study population was not exclusive to patients with hyperhidrosis and also included a healthy population.

Recommendations
We recommend further well-designed, high-quality, homogeneous RCTs with actually diseased patients with HH to investigate the efficacy and safety of oxybutynin. We recommend further evaluation of the impact of side effects of the drug on the patient's quality of life in future research, along with what should be done when the patients do not tolerate the drug. Also, future studies should compare the effect of the different treatment types.
Until the development of higher-quality evidence, we recommend the use of oxybutynin in patients with HH.

Conclusion
Our study suggests that using oxybutynin is significant and needs to be highlighted for clinicians. However, more clinical trials are needed to grasp the optimum benefit.