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doi: 10.1111/1346-8138.

12687 Journal of Dermatology 2015; 42: 64–69

ORIGINAL ARTICLE
Propranolol, doxycycline and combination therapy
for the treatment of rosacea
Jung-Min PARK,1 Je-Ho MUN,1 Margaret SONG,1 Hoon-Soo KIM,1 Byung-Soo KIM,1,2
Moon-Bum KIM,1,2 Hyun-Chang KO1,3
1
Department of Dermatology, School of Medicine, Pusan National University, 2Biomedical Research Institute, Pusan National University
Hospital, and 3Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital,
Busan, Korea

ABSTRACT
Doxycycline is the standard systemic treatment for rosacea. Recently, there have been a few reports on b-adren-
ergic blockers such as nadolol, carvedilol and propranolol for suppressing flushing reactions in rosacea. To our
knowledge, there are no comparative studies of propranolol and doxycycline, and combination therapy using
both. The aim of this study was to investigate and compare the efficacy and safety of monotherapy of proprano-
lol, doxycycline and combination therapy. A total of 78 patients who visited Pusan National University Hospital
and were diagnosed with rosacea were included in this study. Among them, 28 patients were in the propranolol
group, 22 the doxycycline group and 28 the combination group. We investigated the patient global assessment
(PGA), investigator global assessment (IGA), assessment of rosacea clinical score (ARCS) and adverse effects.
Improvement in PGA and IGA scores from baseline was noted in all groups, and the combination therapy was
found to be the most effective during the entire period, but this was statistically insignificant. The reduction rate
of ARCS during the treatment period was also highest in the combination group (57.4%), followed by the doxycy-
cline group (52.2%) and the propranolol group (51.0%). Three patients in the combination group had mild and
transient gastrointestinal disturbances but there was no significant difference from the other groups. We con-
clude that the combination therapy of doxycycline and propranolol is effective and safe treatment for rosacea and
successful for reducing both flushing and papulation in particular.

Key words: combination, doxycycline, propranolol, rosacea, treatment.

INTRODUCTION Beta-adrenergic blockers nadolol, carvedilol and propranolol


have been reported to suppress flushing reactions, particularly
Rosacea is a common chronic dermatological condition char- when associated with anxiety.7,8 Its therapeutic mechanism is
acterized by recurrent episodes of exacerbation and remission. to block the b2-adrenergic receptor on the smooth muscle of
It usually affects individuals between the ages of 30 and cutaneous arterial blood vessels resulting in vasoconstriction.
50 years and women are more affected than men.1,2 Classifi- To our knowledge, there is no comparative study between
cation of rosacea includes erythematotelangiectatic (ETR), pap- propranolol and doxycycline for rosacea and also no previous
ulopustular (PPR), phymatous and ocular subtypes.3–5 ETR is report on the efficacy of combination therapy of propranolol
characterized by flushing and persistent central facial erythema and doxycycline. Therefore, we investigated the efficacy and
and PPR presents with persistent facial erythema and transient safety of the monotherapies of propranolol and doxycycline,
papules or pustules, or both, in a central facial distribution.3 and the combination therapy of propranolol and doxycycline.
The etiology of rosacea is still unknown and this condition
has led to a therapeutic challenge. Although there is no cura-
METHODS
tive treatment for rosacea, tetracycline compounds have been
the mainstay therapy and among them, tetracycline and doxy- Patients
cycline are the standard systemic therapy of rosacea. Doxycy- Rosacea patients aged above 18 years who visited the outpa-
cline shows anti-inflammatory effects and antioxidant tient clinic of the Department Of Dermatology at Pusan
properties. It exhibits superior pharmacokinetic advantages National University Hospital from August 2008 to August 2012
and lesser toxicity than tetracycline, so it is widely used for were enrolled. The exclusion criteria were patients who had
rosacea.6 been treated with topical and systemic medications which can

Correspondence: Hyun-Chang Ko, M.D., Department of Dermatology, School of Medicine, Pusan National University, Geumoh-ro 20,
Mulgeum-eup, Yangsan-si, Busan, Gyeongsangnam-do 626-770, Korea. Email: hcko@pusan.ac.kr
Received 23 January 2014; accepted 29 September 2014.

64 © 2014 Japanese Dermatological Association


Propranolol and doxycycline for rosacea

affect the symptoms of rosacea (e.g. other antibiotics, isotretin- Methods


oin, corticosteroid, cyclosporin) or with laser that targeted the The study protocol was approved by the Pusan National Uni-
vasculature, such as flash pumped pulsed dye laser and versity Hospital institutional review board.
intense pulsed light, for the previous year. For the doxycycline At their first visit, the patients’ age, sex and disease duration
group, pregnant or lactating women and patients with accom- were recorded and the severity of the rosacea was assessed.
panying chronic renal failure, hepatic failure and myasthenia Subtypes of rosacea (ETR and PPR), distribution, aggravating
gravis were excluded. For the propranolol group, patients with factors and symptomatology were also checked.
bronchial asthma, hypotension, bradycardia, atrioventricular The global change assessment in the rosacea condition,
block, sinoatrial block and congestive heart failure were as assessed by the patient global assessment (PGA) and
excluded. investigator global assessment (IGA), was compared with

Table 1. Demographics and clinical manifestations of the patients

Propranolol Doxycycline Combination Total


group (n = 22) group (n = 15) group (n = 26) (n = 63)
Age, years (mean ! SD) 55.7 ! 12.7 47.4 ! 11.8 48.4 ! 12.6 50.6 ! 12.8
Sex (M : F) 2:9 4:11 4:9 16:47
Subtype (ETR : PPR) 19:3 4:11 9:17 32:31
Duration (months, mean ! SD) 33.3 ! 46.5 25.3 ! 30.1 29.2 ! 32.6 29.7 ! 37.0
Frequency in a day 3.0 ! 2.4 2.0 ! 1.7 2.0 ! 1.0 2.3 ! 1.8
Distribution, n (%)
Whole face 2 (9.1) 1 (6.7) 16 (61.5) 19 (30.2)
Cheek 20 (90.9) 14 (93.3) 21 (80.8) 55 (87.3)
Nose 2 (9.1) 7 (46.7) 15 (57.7) 24 (38.1)
Chin 3 (13.6) 5 (33.3) 16 (61.5) 24 (38.1)
Forehead 4 (18.2) 2 (13.3) 14 (53.8) 20 (31.7)
Periocular 3 (13.6) 2 (13.3) 3 (11.5) 8 (12.7)
Aggravation factor (n, compound factor) (%)
Heat 11 (50.0) 8 (53.3) 13 (50.0) 43 (68.3)
Emotional change 8 (36.4) 9 (60.0) 13 (50.0) 30 (47.6)
Exercise or bathing 6 (27.3) 6 (40.0) 6 (23.1) 18 (28.6)
Alcohol 5 (22.7) 3 (20.0) 6 (23.1) 14 (22.2)
Cold 4 (18.2) 3 (20.0) 3 (11.5) 10 (15.9)
Sun exposure 3 (13.6) 0 4 (15.4) 7 (11.1)
Other 1 (4.5) 0 0 1 (1.6)
Symptom (n, compound factor) (%)
Flushing 18 (81.8) 12 (80.0) 21 (80.8) 51 (81.0)
Itching 2 (9.1) 3 (20.0) 3 (11.5) 8 (12.7)
Tingling 5 (22.7) 1 (6.7) 4 (15.4) 10 (15.9)
Burning 1 (4.5) 0 0 1 (1.6)

ETR, erythematotelangiectatic; PPR, papulopustular; SD, standard deviation.

(a) (b)

Figure 1. (a) Mean physician global assessment and (b) inves-


tigator global assessment scores of rosacea patients through Figure 2. Mean assessment of rosacea clinical score (ARCS)
12 weeks. through 12 weeks.

© 2014 Japanese Dermatological Association 65


J.-M. Park et al.

Table 2. Mean scores of primary features in assessment of rosacea clinical score

Baseline 4 weeks 8 weeks 12 weeks P*


Propranolol group (mean ! SD)
Flushing 2.4 ! 0.5 1.7 ! 0.5 1.3 ! 0.6 0.7 ! 0.6 <0.05
Non-transient erythema 2.1 ! 0.4 1.8 ! 0.6 1.4 ! 0.6 1.1 ! 0.6 <0.05
Papules and pustules 1.7 ! 0.5 1.6 ! 0.5 1.6 ! 0.5 1.5 ! 0.5 0.23
Telangiectasia 1.9 ! 0.4 1.7 ! 0.5 1.4 ! 0.7 1.2 ! 0.7 <0.05
Doxycycline group
Flushing 2.1 ! 0.4 2.0 ! 0.4 1.7 ! 0.5 1.5 ! 0.5 <0.05
Non-transient erythema 2.4 ! 0.5 1.9 ! 0.5 1.7 ! 0.5 1.2 ! 0.4 <0.05
Papules and pustules 2.5 ! 0.5 1.6 ! 0.6 1.3 ! 0.8 0.8 ! 0.7 <0.05
Telangiectasia 2.4 ! 0.6 1.9 ! 0.5 1.8 ! 0.4 1.6 ! 0.5 <0.05
Combination group
Flushing 2.2 ! 0.5 1.5 ! 0.6 1.3 ! 0.7 0.7 ! 0.5 <0.05
Non-transient erythema 2.1 ! 0.3 1.7 ! 0.5 1.5 ! 0.5 1.0 ! 0.6 <0.05
Papules and pustules 2.3 ! 0.5 1.5 ! 0.6 1.1 ! 0.6 0.5 ! 0.5 <0.05
Telangiectasia 1.9 ! 0.4 1.7 ! 0.5 1.5 ! 0.6 1.2 ! 0.6 <0.05

*Baseline vs 12 weeks. SD, standard deviation.

baseline and scored on a 7-point scale, with +3 being mark- effect on flushing during the study period. In the combination
edly improved, +2 moderately improved, +1 mildly improved, group, 92.9% (26/28) of the patients completed the study. One
0 unchanged, "1 mildly worse, "2 moderately worse and patient changed doxycycline to roxithromycin and the other
"3 markedly worse.9 The assessment of rosacea clinical added laser therapy because of unsatisfactory effects.
score (ARCS) was also checked.4 PGA and IGA were Mean age was 50.6 years (range, 16–76), 47 patients were
checked at weeks 2, 4, 8 and 12 and ARCS at baseline and female and 16 were male. According to the subtypes, 32
at weeks 4, 8 and 12. Laboratory tests were done for com- patients were ETR patients and 31 PPR. Mean duration of dis-
plete blood cell count, liver and renal functions, and urinaly- ease was 29.7 months (range, 1–200) (Table 1).
sis before and during the treatment. Mean PGA scores in propranolol, doxycycline and the com-
The patients with rosacea were divided into three groups: bination group were 1.7, 1.9 and 2.0 after 12 weeks of treat-
28 patients treated with propranolol 10 mg three times a day ment, respectively. Mean IGA scores were the same as the
(propranolol group); 22 patients treated with doxycycline mean PGA scores at the end of the study. Propranolol and the
100 mg two times a day (doxycycline group); and 28 patients combination group tended to show rapid improvement within
treated with propranolol 10 mg three times a day and doxycy- 4 weeks but the doxycycline group caught up with the
cline 100 mg two times a day (combination group). improvement of these groups between 4 and 8 weeks (Fig. 1).
However, there were no statistically significant differences
Statistical analysis among the three groups.
The Kruskal–Wallis test was performed to evaluate differences Mean ARCS were 10.2, 11.3 and 11.6 in the propranolol,
between the three groups using the PASW for Windows (IBM, doxycycline and combination groups, respectively, at base-
Armonk, NY, USA). Student’s two-sample t-test was performed line and decreased to 5.0, 5.4 and 5.5 after the 12-week
to estimate the differences of the score for the primary features treatment. Reduction ratio of ARCS between baseline and
of ARCS between baseline and after 12 weeks of treatment. the end of the study was 51.0%, 52.2% and 57.3% in the
Statistical significance was defined as P < 0.05. propranolol, doxycycline, and combination groups, respec-
tively (Fig. 2). There also were no statistically significant dif-
ferences among the three groups at baseline and during the
RESULTS
treatment period.
Of the 78 subjects enrolled, 63 completed the study. In the
propranolol group, 78.6% (22/28) of patients completed the
study. Among the six patients who dropped out, other sys-
Table 3. Change of percentage in total assessment of rosacea
temic agents were added in the treatment of five patients
clinical score from baseline
(three with doxycycline, one with minocycline, one with isotre-
tinoin) and one patient decided to change to doxycycline Propranolol Doxycycline Combination
because of the unsatisfactory effects of the propranolol on the group (%) group (%) group (%) P
erythema and papules. In the doxycycline group, 68.2% (15/ 4 weeks 14.6 20.7 24.5 0.037
22) of the patients completed the study. Three patients added 8 weeks 29.2 29.6 36.4 0.436
propranolol, one patient added laser therapy, and three 12 weeks 42.4 43.1 60.0 0.003
patients changed to propranolol because of the unsatisfactory

66 © 2014 Japanese Dermatological Association


Propranolol and doxycycline for rosacea

(a)

(b)

(c)

Figure 3. Serial changes of rosacea patients after 12 weeks of treatment. (a) A 72-year-old woman (erythematotelangiectatic) in the
propranolol group. (b) A 41-year-old man (papulopustular) in the doxycycline group. (c) A 55-year-old woman (papulopustular) in the
combination group.

© 2014 Japanese Dermatological Association 67


J.-M. Park et al.

Table 4. Adverse effects during the study

Propranolol group (%) Doxycycline group (%) Combination group (%) Total (%)
Adverse effect 2 (9.0): dyspepsia (n = 1) 3 (20.0): gastrointestinal 3 (11.5): gastrointestinal 8 (12.7)
headache (n = 1) disturbance disturbance

The primary features in ARCS were analyzed separately to of propranolol in treating ETR is supposed to be by blocking
assess the specific effects of each treatment regimen. In the the b2-adrenergic receptor on the smooth muscle of cutaneous
propranolol group, the papules and pustules score showed a arterial blood vessels, resulting in vasoconstriction.5 Moreover,
partial reduction while the flushing score showed the biggest reactive oxygen species released by local inflammatory cells
decrease after the 12-week treatment, with statistical signifi- which contribute to the inflammation in rosacea can be
cance. In the doxycycline and combination groups, all primary controlled by the antioxidant properties of propranolol.18,19
feature scores showed a significant decline after the 12-week Although ETR is characterized by flushing and PPR is char-
treatment, and the papules and pustules scores revealed the acterized by papules and pustules, symptoms of both sub-
biggest drop at the end of the period (Table 2). In Table 3, types can be shared in mild form. As previously described, it is
changes of percentage in total ARCS from baseline were ana- known that doxycycline is more effective in PPR and proprano-
lyzed. At weeks 4 and 12, the combination group showed a lol seems to be more effective in ETR. Hence, we conducted
significantly higher percentage change than other groups. The this study to compare the efficacy between the monotherapies
propranolol group demonstrated a significantly lower percent- of doxycycline and propranolol and the combination of both.
age change than the doxycycline group at week 4, but they In the present study, the propranolol group showed a faster
showed similar percentage change after week 8 (Fig. 3). response than the doxycycline group regarding PGA and IGA
Adverse events were reported in 12.7% (8/63) of the within the first 4 weeks. Both groups demonstrated the same
patients. Dyspepsia and headache were experienced in 4.5% effectiveness at week 8 and, finally, the doxycycline group had
(1/22) of the patients in the propranolol group. Gastrointestinal higher PGA and IGA scores than the propranolol group by the
disturbances were found in 20.0% (3/15) and 11.5% (3/26) of end of the study. The doxycycline group showed drastic
the patients in the doxycycline and the combination group, improvement between weeks 4 and 8. The combination group
respectively. These side-effects were transient and self-limited showed the best effect among the three groups during the
and there were no serious events or discomfort that made the entire period and also rapid improvement within the first
patients stop the treatment (Table 4). 4 weeks.
Regarding ARCS, the combination group had the highest
reduction ratio among the three groups. In the analysis of pri-
DISCUSSION
mary features, after 12 weeks of therapy, with the exception of
Rosacea is a chronic inflammatory skin disease and yet the papules and pustules in the propranolol group, all of the
underlying pathophysiology is not entirely known.10 It is char- parameters showed statistically significant improvement com-
acterized by persistent erythema, telangiectasia, papules and pared with baseline. The propranolol group showed an espe-
even pustules on the face.11 Various causes have been found cially rapid response in flushing, and the doxycycline group
to act as aggravation factors of rosacea, such as emotional showed a notably faster effect in papules and pustules. The
change, heat, exercise, bathing, alcohol, cold and sun expo- combination treatment was effective in both flushing and pap-
sure, and it is difficult to avoid all provocative stimuli.12,13 Thus, ules and pustules. Regarding percentage change of total ARCS
the therapeutic approach of rosacea depends more on the from baseline, the combination group demonstrated signifi-
clinical subtype than a known etiology.14 cantly higher change at first visit and after 12 weeks. This
Treatment for rosacea includes topical anti-inflammatory result indicates that combination therapy of doxycycline and
agents, topical or systemic antibacterials, retinoids and laser propranolol can show fast and constant improvement of ARCS
therapy.14 Oral tetracycline, particularly tetracycline and doxy- in rosacea patients during 12-week treatment compared with
cycline, have been the mainstay of treatment of rosacea for a monotherapy.
long time. They are especially effective in treating PPR but also Our results show that the combination of doxycycline
ETR through inhibition of leukocyte-derived matrix-degrading 200 mg/day and propranolol 30 mg/day significantly reduced
metalloproteinases.15,16 Flushing usually does not respond to both flushing (70%) and papulation (82%) in rosacea over a
conventional rosacea treatment. Therefore, treatment of ETR period of 12 weeks. Wise20 reported that doxycycline 40 mg/
with severe flushing is challenging although some successes day improved 80–100% of inflammatory lesions and reduced
with beta-blockers such as nadolol, carvedilol and propranolol erythema by 50%. Ertl et al.21 demonstrated that isotretinoin
have been reported.7,17 Propranolol has not demonstrated 10 mg/day for 16 weeks showed 75% improvement of papular
objective evidence for direct effects on cutaneous blood ves- lesions and 38% reduction in erythema. Compared with previ-
sels in flushing, but a previous study reported that 88.9% (8/9) ous studies, combination therapy of doxycycline and propran-
of patients showed improvement of their symptoms and had olol is appropriate for patients with both flushing and
fewer flushing episodes while taking propranolol.7 The mechanism papulation.

68 © 2014 Japanese Dermatological Association


Propranolol and doxycycline for rosacea

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CONFLICT OF INTEREST: The authors have no conflict of
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interest to declare.
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© 2014 Japanese Dermatological Association 69