Journal of Dermatology 2014; 41: 1–6
doi: 10.1111/1346-8138.12687
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-adrenergic 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 propranolol, 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 doxycycline 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 conclude 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 Rosacea is a common chronic dermatological condition characterized by recurrent episodes of exacerbation and remission. It usually affects individuals between the ages of 30 and 50 years and women are more affected than men.1,2 Classification of rosacea includes erythematotelangiectatic (ETR), papulopustular (PPR), phymatous and ocular subtypes.3–5 ETR is characterized by flushing and persistent central facial erythema and PPR presents with persistent facial erythema and transient papules or pustules, or both, in a central facial distribution.3 The etiology of rosacea is still unknown and this condition has led to a therapeutic challenge. Although there is no curative treatment for rosacea, tetracycline compounds have been the mainstay therapy and among them, tetracycline and doxycycline are the standard systemic therapy of rosacea. Doxycycline shows anti-inflammatory effects and antioxidant properties. It exhibits superior pharmacokinetic advantages and lesser toxicity than tetracycline, so it is widely used for rosacea.6
Beta-adrenergic blockers nadolol, carvedilol and propranolol have been reported to suppress flushing reactions, particularly when associated with anxiety.7,8 Its therapeutic mechanism is to block the b2-adrenergic receptor on the smooth muscle of cutaneous arterial blood vessels resulting in vasoconstriction. To our knowledge, there is no comparative study between propranolol and doxycycline for rosacea and also no previous report on the efficacy of combination therapy of propranolol and doxycycline. Therefore, we investigated the efficacy and safety of the monotherapies of propranolol and doxycycline, and the combination therapy of propranolol and doxycycline.
METHODS Patients Rosacea patients aged above 18 years who visited the outpatient clinic of the Department Of Dermatology at Pusan National University Hospital from August 2008 to August 2012 were enrolled. The exclusion criteria were patients who had 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: [email protected] Received 23 January 2014; accepted 29 September 2014.
© 2014 Japanese Dermatological Association
1
J.-M. Park et al.
affect the symptoms of rosacea (e.g. other antibiotics, isotretinoin, corticosteroid, cyclosporin) or with laser that targeted the vasculature, such as flash pumped pulsed dye laser and intense pulsed light, for the previous year. For the doxycycline group, pregnant or lactating women and patients with accompanying chronic renal failure, hepatic failure and myasthenia gravis were excluded. For the propranolol group, patients with bronchial asthma, hypotension, bradycardia, atrioventricular block, sinoatrial block and congestive heart failure were excluded.
Methods The study protocol was approved by the Pusan National University Hospital institutional review board. At their first visit, the patients’ age, sex and disease duration were recorded and the severity of the rosacea was assessed. Subtypes of rosacea (ETR and PPR), distribution, aggravating factors and symptomatology were also checked. The global change assessment in the rosacea condition, as assessed by the patient global assessment (PGA) and investigator global assessment (IGA), was compared with
Table 1. Demographics and clinical manifestations of the patients Propranolol group (n = 22) Age, years (mean SD) 55.7 12.7 Sex (M : F) 2:9 Subtype (ETR : PPR) 19:3 Duration (months, mean SD) 33.3 46.5 Frequency in a day 3.0 2.4 Distribution, n (%) Whole face 2 (9.1) Cheek 20 (90.9) Nose 2 (9.1) Chin 3 (13.6) Forehead 4 (18.2) Periocular 3 (13.6) Aggravation factor (n, compound factor) (%) Heat 11 (50.0) Emotional change 8 (36.4) Exercise or bathing 6 (27.3) Alcohol 5 (22.7) Cold 4 (18.2) Sun exposure 3 (13.6) Other 1 (4.5) Symptom (n, compound factor) (%) Flushing 18 (81.8) Itching 2 (9.1) Tingling 5 (22.7) Burning 1 (4.5)
Doxycycline group (n = 15)
Combination group (n = 26)
Total (n = 63)
47.4 11.8 4:11 4:11 25.3 30.1 2.0 1.7
48.4 12.6 4:9 9:17 29.2 32.6 2.0 1.0
50.6 12.8 16:47 32:31 29.7 37.0 2.3 1.8
1 14 7 5 2 2
(6.7) (93.3) (46.7) (33.3) (13.3) (13.3)
16 21 15 16 14 3
(61.5) (80.8) (57.7) (61.5) (53.8) (11.5)
19 55 24 24 20 8
(30.2) (87.3) (38.1) (38.1) (31.7) (12.7)
8 9 6 3 3 0 0
(53.3) (60.0) (40.0) (20.0) (20.0)
13 13 6 6 3 4 0
(50.0) (50.0) (23.1) (23.1) (11.5) (15.4)
43 30 18 14 10 7 1
(68.3) (47.6) (28.6) (22.2) (15.9) (11.1) (1.6)
21 (80.8) 3 (11.5) 4 (15.4) 0
51 8 10 1
(81.0) (12.7) (15.9) (1.6)
12 (80.0) 3 (20.0) 1 (6.7) 0
ETR, erythematotelangiectatic; PPR, papulopustular; SD, standard deviation.
(a)
(b)
Figure 1. (a) Mean physician global assessment and (b) investigator global assessment scores of rosacea patients through 12 weeks.
2
Figure 2. Mean assessment of rosacea clinical score (ARCS) through 12 weeks.
© 2014 Japanese Dermatological Association
Propranolol and doxycycline for rosacea
Table 2. Mean scores of primary features in assessment of rosacea clinical score Baseline Propranolol group (mean SD) Flushing Non-transient erythema Papules and pustules Telangiectasia Doxycycline group Flushing Non-transient erythema Papules and pustules Telangiectasia Combination group Flushing Non-transient erythema Papules and pustules Telangiectasia
4 weeks
8 weeks
12 weeks
P*
2.4 2.1 1.7 1.9
0.5 0.4 0.5 0.4
1.7 1.8 1.6 1.7
0.5 0.6 0.5 0.5
1.3 1.4 1.6 1.4
0.6 0.6 0.5 0.7
0.7 1.1 1.5 1.2
0.6 0.6 0.5 0.7
doi: 10.1111/1346-8138.12687
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-adrenergic 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 propranolol, 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 doxycycline 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 conclude 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 Rosacea is a common chronic dermatological condition characterized by recurrent episodes of exacerbation and remission. It usually affects individuals between the ages of 30 and 50 years and women are more affected than men.1,2 Classification of rosacea includes erythematotelangiectatic (ETR), papulopustular (PPR), phymatous and ocular subtypes.3–5 ETR is characterized by flushing and persistent central facial erythema and PPR presents with persistent facial erythema and transient papules or pustules, or both, in a central facial distribution.3 The etiology of rosacea is still unknown and this condition has led to a therapeutic challenge. Although there is no curative treatment for rosacea, tetracycline compounds have been the mainstay therapy and among them, tetracycline and doxycycline are the standard systemic therapy of rosacea. Doxycycline shows anti-inflammatory effects and antioxidant properties. It exhibits superior pharmacokinetic advantages and lesser toxicity than tetracycline, so it is widely used for rosacea.6
Beta-adrenergic blockers nadolol, carvedilol and propranolol have been reported to suppress flushing reactions, particularly when associated with anxiety.7,8 Its therapeutic mechanism is to block the b2-adrenergic receptor on the smooth muscle of cutaneous arterial blood vessels resulting in vasoconstriction. To our knowledge, there is no comparative study between propranolol and doxycycline for rosacea and also no previous report on the efficacy of combination therapy of propranolol and doxycycline. Therefore, we investigated the efficacy and safety of the monotherapies of propranolol and doxycycline, and the combination therapy of propranolol and doxycycline.
METHODS Patients Rosacea patients aged above 18 years who visited the outpatient clinic of the Department Of Dermatology at Pusan National University Hospital from August 2008 to August 2012 were enrolled. The exclusion criteria were patients who had 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: [email protected] Received 23 January 2014; accepted 29 September 2014.
© 2014 Japanese Dermatological Association
1
J.-M. Park et al.
affect the symptoms of rosacea (e.g. other antibiotics, isotretinoin, corticosteroid, cyclosporin) or with laser that targeted the vasculature, such as flash pumped pulsed dye laser and intense pulsed light, for the previous year. For the doxycycline group, pregnant or lactating women and patients with accompanying chronic renal failure, hepatic failure and myasthenia gravis were excluded. For the propranolol group, patients with bronchial asthma, hypotension, bradycardia, atrioventricular block, sinoatrial block and congestive heart failure were excluded.
Methods The study protocol was approved by the Pusan National University Hospital institutional review board. At their first visit, the patients’ age, sex and disease duration were recorded and the severity of the rosacea was assessed. Subtypes of rosacea (ETR and PPR), distribution, aggravating factors and symptomatology were also checked. The global change assessment in the rosacea condition, as assessed by the patient global assessment (PGA) and investigator global assessment (IGA), was compared with
Table 1. Demographics and clinical manifestations of the patients Propranolol group (n = 22) Age, years (mean SD) 55.7 12.7 Sex (M : F) 2:9 Subtype (ETR : PPR) 19:3 Duration (months, mean SD) 33.3 46.5 Frequency in a day 3.0 2.4 Distribution, n (%) Whole face 2 (9.1) Cheek 20 (90.9) Nose 2 (9.1) Chin 3 (13.6) Forehead 4 (18.2) Periocular 3 (13.6) Aggravation factor (n, compound factor) (%) Heat 11 (50.0) Emotional change 8 (36.4) Exercise or bathing 6 (27.3) Alcohol 5 (22.7) Cold 4 (18.2) Sun exposure 3 (13.6) Other 1 (4.5) Symptom (n, compound factor) (%) Flushing 18 (81.8) Itching 2 (9.1) Tingling 5 (22.7) Burning 1 (4.5)
Doxycycline group (n = 15)
Combination group (n = 26)
Total (n = 63)
47.4 11.8 4:11 4:11 25.3 30.1 2.0 1.7
48.4 12.6 4:9 9:17 29.2 32.6 2.0 1.0
50.6 12.8 16:47 32:31 29.7 37.0 2.3 1.8
1 14 7 5 2 2
(6.7) (93.3) (46.7) (33.3) (13.3) (13.3)
16 21 15 16 14 3
(61.5) (80.8) (57.7) (61.5) (53.8) (11.5)
19 55 24 24 20 8
(30.2) (87.3) (38.1) (38.1) (31.7) (12.7)
8 9 6 3 3 0 0
(53.3) (60.0) (40.0) (20.0) (20.0)
13 13 6 6 3 4 0
(50.0) (50.0) (23.1) (23.1) (11.5) (15.4)
43 30 18 14 10 7 1
(68.3) (47.6) (28.6) (22.2) (15.9) (11.1) (1.6)
21 (80.8) 3 (11.5) 4 (15.4) 0
51 8 10 1
(81.0) (12.7) (15.9) (1.6)
12 (80.0) 3 (20.0) 1 (6.7) 0
ETR, erythematotelangiectatic; PPR, papulopustular; SD, standard deviation.
(a)
(b)
Figure 1. (a) Mean physician global assessment and (b) investigator global assessment scores of rosacea patients through 12 weeks.
2
Figure 2. Mean assessment of rosacea clinical score (ARCS) through 12 weeks.
© 2014 Japanese Dermatological Association
Propranolol and doxycycline for rosacea
Table 2. Mean scores of primary features in assessment of rosacea clinical score Baseline Propranolol group (mean SD) Flushing Non-transient erythema Papules and pustules Telangiectasia Doxycycline group Flushing Non-transient erythema Papules and pustules Telangiectasia Combination group Flushing Non-transient erythema Papules and pustules Telangiectasia
4 weeks
8 weeks
12 weeks
P*
2.4 2.1 1.7 1.9
0.5 0.4 0.5 0.4
1.7 1.8 1.6 1.7
0.5 0.6 0.5 0.5
1.3 1.4 1.6 1.4
0.6 0.6 0.5 0.7
0.7 1.1 1.5 1.2
0.6 0.6 0.5 0.7
