FormalPara Key Summary Points

Beta-blockers are safe and cost-effective agents in treating multiple dermatological conditions.

They are considered as good alternative therapeutic agents by dermatologists, they can be used as a mono-therapy, or as an adjuvant therapy combined with other current disease-specific therapeutic modalities.

Their role has been reviewed for several dermatological disorders in 2017 and 2018, furthermore, new dermatological conditions have been reviewed in this article such as acne vulgaris, atopic dermatitis, telangiectasia, ulcers, and keloids.

Although studies showed promising outcomes, further research is needed to provide more information in order to provide sufficient evidence.

Introduction

The use of beta-blockers in treating cutaneous diseases has been expanding among dermatologists worldwide over the past decade. Since the first coincidental discovery of the therapeutic effect of propranolol on infantile hemangioma by Leaute-Labreze et al. [1], research has been carried out in order to investigate their efficacy and safety in treating other skin diseases. In general, beta-blockers are proven to be safe and cost-effective agents, which is why they are considered a good alternative by dermatologists.

Beta-blockers, also known as beta-adrenergic receptors (ß-AR) antagonists, are a class of medications that are primarily used to treat cardiovascular diseases. There are three types of ß-ARs: ß1-AR, ß2-AR, and ß3-AR, which are located primarily in the heart and different tissue organs. ß2-AR is found to be highly expressed in major skin cell types; keratenocytes[2], fibroblasts [3], melanocytes [4] and secretory coil of apocrine glands [5]. Therefore, ß2-ARs antagonists are the most commonly used in dermatology. They are available for administration orally, intravenously, and topically.

To our knowledge, there has been no comprehensive systematic review to date summarizing the role of both systemic and topical beta-blockers in dermatology. Systematic reviews are robust evidence that consolidate extensive overview and deliver more reliable and clear answers to inform physicians. They are essential for clinical practice in order to guide clinicians and ensure the optimal care for patients. Moreover, it will help in identifying research gaps in this topic for further research. Thus, we are aiming to review recent and relevant published literature in order to provide a holistic evidence-based summary about the role of beta-blockers in dermatology.

Methods/Literature Search

For this systematic review, an electronic-based literature search was carried out during October to December 2021 in the databases PubMed (MEDLINE), SCOPUS (EMBASE), and Cochrane Library. Furthermore, bibliographic sources were also reviewed for the selected articles. The Preferred Reporting Items for Systematic Reviews and Meta-analyses 2020 (PRISMA) guidelines were followed [6]. All published literature about the role of beta-blockers in dermatology for the period between January 2016 and December 2021 were searched. MeSH terms/keywords were used to build for our search, such as beta-blockers, adrenergic beta-antagonists, dermatological diseases, or skin disorders. We were primarily seeking literature about the use of beta-blockers in dermatology. For the search techniques and medical subject headings, different combinations of keywords were used. A detailed search strategy can be found in the supplements. This review included all research articles that were published between the years 2016 and 2021 on the role of beta-blockers in treating various dermatoses. Non-human subject research and non-English studies were omitted.

During the preliminary literature search, screening and eligibility assessment were carried out independently by two authors. The publications were first screened based on their titles, then the abstracts, all irrelevant articles were excluded in the secondary screening, and relevant articles were chosen for full-text screening. The full-text screened publications were also eliminated when there was a lack of information relevant to our research goal. From the selected articles, author names, year of publication, sample size, research design, level of evidence, dermatoses, interventions and outcomes were retrieved.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

Eligible Studies

A total of 126 publications were retrieved from different databases, of which 59 articles were included in our review after excluding non-eligible papers, in accordance with our inclusion and exclusion criteria (Fig. 1). The included articles comprised 16 meta-analyses and systematic reviews, 18 clinical trials, 20 observational cohort studies and case–control studies, five case series and case reports. The relevant findings of the included studies are summarized in Tables 1, 2, 3, 4, 5, and 6.

Fig. 1
figure 1

PRISMA 2020 flow diagram for new systematic reviews

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Table 1 Systemic beta-blockers in dermatological therapy (systematic reviews and meta-analysis)
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Table 2 Systemic beta-blockers in dermatological therapy (interventional studies)
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Table 3 Systemic beta-blockers in dermatological therapy (observational studies, case series/report)
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Table 4 Topical beta-blockers in dermatological therapy (systematic reviews and meta-analysis)
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Table 5 Topical beta-blockers in dermatological therapy (interventional studies)
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Table 6 Topical beta-blockers in dermatological therapy (observational studies, case series/report)
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Mechanism of Action

The exact mechanism of action of beta-blockers in dermatological conditions is likely multifactorial and unclear. Researchers have proposed several theories to interpret their therapeutic effects in various dermatoses [7]. In general, they may inhibit angiogenesis in dermatoses of vascular origin, such as rosacea [8], inhibit β-adrenergic receptors in melanocytes, and slow tumor growth in dermatoses of non-vascular origin, such as melanoma [9], and may also promote wound healing [10].

Mode of Administration

In dermatology, beta-blockers are either orally or topically administered, depending on the medication type, severity of the condition, and disease presentation. Propranolol, atenolol, bisoprolol, nadolol, and carvedilol are the most common systemically administered beta-blockers in dermatology (Tables 1, 2, 3). Similarly, timolol, propranolol, betaxolol, and carteolol are the most common agents topically applied as creams, solutions, gels, and ointments (Tables 4, 5, 6).

Dermatoses and the role of beta-blockers

Previously reviewed dermatoses:

Infantile hemangioma/PHACE/LUMBAR syndrome

Systemic beta-blockers

Multiple studies have demonstrated the efficacy and safety of oral propranolol for infantile hemangioma (IH) in term and preterm infants, including superficial, deep, and even syndromic cases, including PHACE [11]. A study by Bayrart et al. [12] concluded that atenolol is at least as effective as propranolol and exhibits a lower risk of bronchospasm. In addition, a study by Gumina et al. [13] used atenolol as a substitute for propranolol for the management of sleep disturbances in the treatment of IH, which resulted in improvement or resolution of sleep issues in most patients. However, propranolol did not substantially impair the sleep quality and pattern [14]. No increased risk of adverse effects was observed in preterm versus term patients treated with oral propranolol [15].

Topical beta-blockers

Beta-blockers can be used as monotherapy or in combination with other systemic therapies for mixed IH [16]. Topical timolol 0.5% gel was favored over topical timolol maleate 0.1% and topical propranolol [17]. No differences were observed in the reduction of SIH size from either oral propranolol or topical timolol maleate, with the advantage of topical administration being minimal absorption and systemic adverse effects [18]. However, topical administration appears to have a slower onset of action (12–16 weeks) [19]. These results may replace oral propranolol as a first-line therapy for SIH, and they are of additive value in treating MIH when combined with other interventions [16]. However, a study by [17] Randall A. et al. warned about their use in lesions located on mucosal surfaces and in the periocular region due to unpredictable systemic absorption.

Pyogenic granuloma

Topical beta-blockers

Propranolol gel (4%, twice daily) was evaluated; most patients had complete or almost complete resolution, and only a minority experienced local irritation [20]. In RCTs comparing topical timolol, propranolol, and placebo, topical beta-blockers twice daily achieved complete resolution in most of the patients [21]. No substantial difference was observed in the clinical responses of the beta-blockers groups [21]. Topical timolol (0.5% gel, twice daily) was evaluated for EGFR-induced pyogenic granuloma-like lesions and paronychia. Complete and partial response was observed in 52% of the lesions; partial response was achieved in 36% [22].

Rosacea and acne

Topical beta-blockers

Al Mokadem et al. [23] conducted a multicentric interventional study that included an equal number of acne and rosacea patients (58 patients for each disease). Application of 0.5% topical timolol maleate each night for 8 weeks markedly reduced the number of comedones, papules, total lesion count, pustules, and acne severity. However, the improvement in rosacea was not statistically significant.

In addition to carvedilol and nadolol, propranolol has also been studied for rosacea and acne. Jade Logger et al. [24] reviewed their role in nine articles (one RCT, one cohort study, one case–control study, three case reports, and three case series). Propranolol and carvedilol were the most effective in reducing erythema and flushing with a rapid onset of symptom control; however, nadolol did not show similar results.

Melanoma

Systemic beta-blockers

De Giorgi et al. [25] studied the effect of beta-blockers exposure on reducing the risk of progression of thick malignant melanoma in a prospective study during 2011–2013. A total of 53 patients, with histologically confirmed stage IB to IIIA cutaneous melanoma and no evidence of metastasis, participated in the study and were divided into 19 cases and 34 controls. The cohort patients were instructed to take oral propranolol (80 mg daily) as an off-label adjuvant treatment. After a median follow-up of 3 years, they concluded that propranolol protected patients from disease recurrence and death.

After a median follow-up time of 8 years and a median duration of beta-blockers use of 7.6 years, De Giorgi et al. [26] carried out another prospective study in 2020 on previously included patients with malignant melanoma stage II–IIIA (T2, N0 or N1, M0). They found that 45% of the patients in the untreated group and 30% of the patients in the treated group had disease progression. Thirty-two patients (35%) in the untreated group and five patients (17%) in the treated group died from melanoma. The initial result of the difference in mortality was confirmed after a longer follow-up period.

Dimitrios Katsarelias et al. [27] conducted a nationwide Swedish population-based retrospective register study on 12,738 patients, of which 3702 were exposed to beta-blockers and 9036 were non-exposed patients. In their study, they could not confirm the finding that the use of beta-blockers had a positive impact on survival in patients with melanoma.

Currently reviewed dermatoses:

Post-acne erythema

Topical beta-blockers

A study by Afra T.P. et al. [28] demonstrated the therapeutic effect of topical timolol maleate 0.5% ophthalmic solution in a case of remarkable post-inflammatory erythema and atrophic scars. They observed a significant improvement in post-inflammatory erythema; only shallow rolling scars were left with no pigmentation. No local or systemic adverse effects were noted.

Acne scars

Topical beta-blockers

A double-blind clinical trial of 25 participants with atrophic acne scars, who underwent ablative fractional carbon dioxide laser therapy, demonstrated the effect of the application of topical 0.5% timolol after laser therapy, where it restored the skin barrier compared with placebo [29]. No local or systemic adverse effects were reported [29].

Keloids

Systemic beta-blockers

In a single-institution case–control study, the effect of the administration of beta-blockers (carvedilol, bisoprolol, and atenolol) was observed in treating scars and keloids after pacemaker implantation in 45, 12, and 33 patients, respectively [30]. They found that patients with keloids or hypertrophic scars, after cardiac device implantation, tended to be less likely to take beta-blockers than control patients with normal scars.

Ulcers and wounds

Topical beta-blockers

In a clinical trial, Abdelmaksoud et al. [31] studied three patients with chronic leprosy ulcers after completing the WHO-recommended regimen (1% topical propranolol in liposomal gel for 3 months). Two of the three patients showed complete healing of the ulcers at the 6-month follow-up. In the third patient, the ulcer showed only modest signs of healing. Sensory function, particularly in terms of pain, was restored in all patients.

Ganary Dabiri et al. [32] found that the application of topical timolol on wounds and scars resulted in cosmetically favorable effects compared to controls.

Vestita et al. [33] studied one patient with a deep chronic ulcerating lesion of the right sole who was treated with topical propranolol for 3 weeks. At the end of the treatment period, the ulcer had dramatically improved, and after another week, the lesion had completely healed; then, at the follow-up 1 year later, no recurrence was seen.

They also reported a retrospective study [34] that included 82 patients affected by non-healing loss of substance associated with diverse etiologies (venous, diabetic, post-surgery, post-radiation, pressure, mistreated burns). All patients were administered topical timolol for 6 weeks and received an appropriate standard of care. A statistically significant improvement in the percentage of area reduction (up to 98.75%) and mean size was noted in all groups except for diabetic and pressure ulcers.

Systemic beta-blockers

Rai et al. conducted the first randomized control trial to study the effect of topical timolol on wound healing in 20 patients with chronic leg venous ulcers [35]. They demonstrated a substantial reduction in the size of the ulcer in patients in the timolol group (86.80%) compared to that in patients in the saline group (43.82%) after 4 weeks of treatment. No side effects were observed, and the treatment was well tolerated [35].

Eczema

Topical beta-blockers

Pawar et al. [36, 37] conducted two clinical trials that included one patient with eczema in each to study the effect of topical timolol on erosions and fissures on palms of hands and heels of feet. Healing of erosions and fissures was observed in both studies.

Topical glucocorticoid-induced skin telangiectasia

Topical beta-blockers

Li et al. investigated the potential effect of topical timolol maleate (0.5%) eye drops (TMEDs) on topical glucocorticoid-induced skin telangiectasia [38]. A total of 30 female patients with facial skin telangiectasia were included, wherein one cheek of each patient was assigned to the treatment group and the other to the control group. For the treatment group, topical twice-daily application of TMEDs was combined with 0.1% tacrolimus ointment once or twice daily for 8 weeks. Cheeks in the control group were administered 0.1% tacrolimus ointment alone. After 4 weeks, marked improvements in erythema and telangiectasia were observed in the treatment group. In addition, marked subsidence of expanded capillaries was observed after 8 weeks of treatment, in contrast to the control group, wherein telangiectasia remained clearly visible. No adverse effects were observed.

Kaposi sarcoma

Topical beta-blockers

A study by Abdelmaksoud et al. [39] reported the efficacy of topical timolol gel in a case series of four patients with Kaposi sarcoma (KS) on antiretroviral therapy, three with the classical type and one with HIV; all patients showed significant improvement.

Discussion

This review emphasizes that beta-blockers have been proven to be safe and well tolerated in treating several dermatological disorders, they are cost-effective, and easily available alternative/adjuvant therapies in dermatology.

To date, propranolol is the only FDA-approved beta-blocker for therapeutic use in IH [19, 40], other beta-blockers are being used off-label to treat various skin conditions. They were used as a monotherapy or in combination with other treatment modalities such as lasers, radiation, chemotherapy, corticosteroids, or others.

Among all, IH was mostly investigated. They studied the therapeutic effect of beta-blockers in different types of IH, also, favorable drug options, settings, and regimens. Essentially, beta-blockers were safe and well tolerated in the treatment of IH in both systemic and topical formulations at all levels of evidence. However, a case of severe transient hypertriglyceridemia was recently reported to be associated with administering systemic propranolol for treating ulcerated IH in a 1-month-old infant. Further research is needed to explore this association [41]. Topical beta-blockers were particularly beneficial for treating superficial IH. The role of beta-blockers was investigated as a monotherapy, and adjuvant therapy where combination of beta-blockers with other modalities induced a synergistic effect that improved the outcome and reduced the duration of treatment and adverse effects. Although propranolol is the treatment of choice for both proliferating and ulcerated IH, pulsed dye lasers still play a major role in residual IH [42]. Moreover, treating IH with propranolol was more cost-effective when delivered in outpatient settings [43]. Monitoring of vital signs is not necessary in normal conditions [44], and routine cardiac screening using electrocardiogram and echocardiogram prior to outpatient visits is not definitely indicated [45]. There was no definite conclusion for the duration of using propranolol, as well as when to stop and how. However, an appropriate time to retain efficacy and avoid adverse effects is suggested. Ultrasound is helpful in assessing treatment efficacy upon termination by measuring IH thickness and vascularity [46]. Patients with IH who received oral propranolol should be followed up to at least 6 months [47].

Topical beta-blockers have been proven to be efficacious and safe in treating PG as well, mostly for small, superficial infantile PG and PG-like lesions induced by EGFR-I [22]. They can postpone or obviate surgical treatment, especially in children, for whom they are the first-line treatment, also, in large lesions by reducing its size. The only limitation of beta-blockers here is their inability to perform histological examinations [48]. Although the adverse effects and systemic absorption appeared to be negligible in all included studies, further research is needed to identify the maximal dosage and duration.

Their role in rosacea was limited to reducing the non-inflammatory lesions of acne and the symptoms of erythematotelangiectatic rosacea. It showed a modest therapeutic effect in papulopustular rosacea [23]. Similarly, topical timolol was only beneficial in alleviating the symptoms of telangiectasia in facial corticosteroid addiction dermatitis symptoms; other symptoms were not investigated [38]. They can also be considered as a great adjuvant therapy in melanoma, as they improved morbidity and mortality.

In addition to previously reviewed dermatoses in 2017 and 2018 [49, 50], our systematic review included recent studies about the role of beta-blockers in different dermatological diseases. Topical timolol resulted in favorable outcomes in post acne erythema and scars [23, 28, 29]. It resulted in decreased acne severity, less erythema, and pigmentation. It also showed an improvement in erythema and telangiectasia in topical glucocorticoid-induced skin telangiectasia [38]. In keloids [30], they yielded good results in treating and preventing as well. Most recently, topical timolol showed an interesting and promising effect in eczema; its effect was reported in treating non-healing erosions and fissures of palms of the hand as well as heels of feet [36, 37]. Although there are new studies on the role of beta-blockers in dermatology, however, the evidence is not sufficient yet to be conclusive. Further studies are needed to provide vital information including the optimal dosing, type, and duration of treatments, efficacy, as well as adverse events.

In this systematic review, the heterogeneity of the evidence created a challenge in shaping a concise and comprehensive summary. Each type of evidence posed distinct sources of bias and limitations. Common limitations of clinical trials include small sample size that affected the robustness of their findings, and specific population characteristics such as skin phototype, which restricted generalizability. A short treatment period was also a drawback in some trials because some biophysical parameters had not returned to baseline by the end of the study. Although no abnormal symptoms were reported, vital signs were not monitored, which would have helped to precisely detect possible side effects such as bradycardia or hypotension. Stronger evidence than case series/studies was required to determine the best therapeutic types, vehicles, and regimens for beta-blockers. Also, this study was restricted to a certain time scope, in which some dermatological diseases such as angiofibromas, angiolymphoid hyperplasia with eosinophilia, and angiosarcoma could not be addressed. However, they were explicitly reviewed by Chen et al. [50], in which they concluded the effectiveness of beta-blockers in treating dermatoses of vascular origin and promoting wound healing.

Conclusions

Beta-blockers are proven to be safe and cost-effective agents in treating multiple dermatological conditions. Thus, dermatologists should consider them as good alternative/adjuvant therapies in treating several skin conditions.