- Email: [email protected]
Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids
JBUR-4177; No. of Pages 6 burns xxx (2013) xxx–xxx
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids§ Rajeev B. Ahuja *, Pallab Chatterjee Department of Burns, Plastic, Maxillofacial and Microvascular Surgery, Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi 110 002, India
article info
abstract
Article history:
There is not much level 1 evidence based literature to guide management of hypertrophic
Accepted 9 September 2013
scars and keloids despite an array of therapeutic modalities at disposal. Intralesional (i/l)
Keywords:
Sporadic reports on use of i/l verapamil suggest its efficacy. Since verapamil has not found
Hypertrophic scars
sufficient mention as an effective alternative modality, it was decided to undertake a
Keloids
randomized study which could also address some additional clinical parameters.
triamcinolone injections have remained a gold standard in non surgical management.
Triamcinolone Verapamil Vancouver Scar Scale
A randomized, parallel group and observer blinded comparison with 40 patients (48 scars) was carried out to compare the effects of i/l triamcinolone (T) (22 scars) and verapamil injections (V) (26 scars). 1.5 ml was the maximum indicative volume decided in the study protocol for both the drugs (triamcinolone @40 mg/ml and verapamil @ 2.5 mg/ml). Patients included were aged between 15–60 years with scars ranging between 0.5–5 cm (but total area roughly <6 cm2), and scars under 2 years duration. Patients with keloidal diathesis were excluded. Injections were scheduled every three weeks until complete flattening of the scar or eight sessions, which ever came earlier. No concomitant therapies like massage, silicone gel or pressure garments were used. Scar evaluation at each stage was done by serial photographic records as well as by Vancouver Scar Scale (VSS). Comparative survival analysis between the two drugs was done using Kaplan Meier curves, and VSS scores were analyzed using Wilcoxon test and log rank test. Mean zero VSS scores were achieved with treatments in respect of scar height (T-12 weeks, V-21 weeks), vascularity (T-15 weeks, V-18 weeks) and pliability (T-15 weeks, V-21 weeks). The improvement in scar vascularity and pliability kept pace with decrease in scar height, in both the groups. There was not much difference in the rate of change of scar pigmentation with either drug but almost 60% patients in both the groups regained normal pigmentation. Our study adds to evidence of verapamil’s capability in flattening the raised scars. With an extremely low cost and fewer adverse effects it deserves better positioning in the wide armamentarium against hypertrophic scars. It also offers several therapeutic possibilities to alternate with triamcinolone or be used simultaneously in larger (or multiple) scars. # 2013 Elsevier Ltd and ISBI. All rights reserved.
§
This paper was presented at the 16th Congress of International Society for Burn Injuries at Edinburgh, UK, 9–13th September 2012. * Corresponding author. Tel.: +91 11 23231871; fax: +91 11 23222756. E-mail addresses: [email protected], [email protected] (R.B. Ahuja). 0305-4179/$36.00 # 2013 Elsevier Ltd and ISBI. All rights reserved. http://dx.doi.org/10.1016/j.burns.2013.09.029 Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
2
burns xxx (2013) xxx–xxx
1.
Introduction
Keloids and hypertrophic scars are dermal fibro-proliferative disorders unique to humans [1], which may lead to disfigurement, pain and pruritus [2]. Their management is still challenging as there is no universally accepted treatment regimen [3] and not much level 1 evidence based literature to guide management. This is despite an array of therapeutic modalities at disposal, because there are a multitude of etiological factors [4], less well understood pathophysiology [5], wide spectrum of disease [6] and limitations of targeted therapies. For less extensive hypertrophic scarring and keloids, intralesional (i/l) triamcinolone injections have remained a gold standard in non surgical management. It has been reported that scars treated with triamcinolone acetonide (T) showed decreased levels of the proteinase inhibitors alpha2-macroglobulin and alpha2-antitrypsin in the scar [5]. This leads to decreased collagenase (matrix metalloproteinase 1/MMP1) degradation which controls excessive and abnormal collagen seen in hypertrophic scars and keloids [5]. In 1990, Lee and Ping demonstrated that calcium channel blockers such as verapamil lead to decreased extracellular matrix production in scars [7]. It was further demonstrated that verapamil depolymerizes actin filaments to modify fibroblast morphology with a consequent increased secretion of procollagenase [8,9]. Subsequently, there have been sporadic reports of its use in hypertrophic scars and keloids suggesting its efficacy [10–12], but these studies were uncontrolled and with limited number of subjects. Moreover in two of these reports, i/l verapamil injections were used following excision of the lesion, and in combination with compression [10] or silastic sheets [11] for prophylaxis. The first randomized controlled trial to study verapamil was conducted by Margaret et al. [13] which suggested that i/l verapamil may be as effective as triamcinolone in the treatment of hypertrophic scars and keloids. Since this report was the only confirmatory evidence available in literature, and in spite of which verapamil has not found sufficient mention as an effective alternative modality in the treatment of hypertrophic scars and keloids, it was decided to undertake another randomized study which could also address some additional clinical parameters.
2.
Patients and methods
The study was conducted in the Department of Burns and Plastic Surgery, Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi. Approval of institutional ethics committee was obtained before commencing the study. Subjects were recruited between July 2011 and August 2012 from the outpatient clinic. It was a randomized, parallel group and observer blinded comparison between i/l triamcinolone (T) and verapamil injection (V). 1.5 ml was the maximum permissible injected volume of triamcinolone (concentration 40 mg/ml) and verapamil hydrochloride (concentration 2.5 mg/ml). Inclusion criteria included patients aged between 15–60 years old, scars of 0.5–5 cm in maximum dimension, regardless of the shape, but total area roughly <6 cm2 and scars under 2 years duration. Patients with evidence of any
infection or ulcer, in or near the scar, were excluded. Also excluded were pregnant females, and patients with a history of prior treatment with any intralesional injection. In patients with multiple hypertrophic scars two sites were recruited only if their total area appeared <6 cm2. No attempt was made to distinguish between hypertrophic scars and keloids but patients with keloidal diathesis were excluded on the basis of past personal or family history. Detailed history and demographic parameters were recorded, including etiology, duration of scarring and prior treatments. A minimum sample size of 44 scars (22 in each group) was calculated for a non inferiority trial design with triamcinolone as standard treatment and verapamil as the experimental drug based upon an alpha error of 5% and power of 80%, assuming a non-inferiority limit of 30%, and at least 80% cure rate for each group. The patients were randomly allocated to two groups A and B using a computer generated random sequence. Scars in group A received i/l triamcinolone acetonide and scars in group B received i/l verapamil hydrochloride, every three weeks for a maximum of eight sessions or till complete flattening of the scar, whichever came earlier. The injections were made at several points in the lesion with an insulin syringe and 24 gauge needle to achieve complete and evenly distributed blanching of the lesion at endpoint. No sedation/analgesia was used at the time of injection. Scar flattening was defined as <1 mm scar height over 90% of the lesion, by visual assessment. No concomitant therapies like massage, silicone gel or pressure garments were used. Scar evaluation at each stage was done by serial photographic records as well as by Vancouver Scar Scale (VSS) [14]. Scar height was accurately measured with calipers. Scar pliability was subjectively assessed by palpation. Scar vascularity was rated on visual inspection and the rate of refill after blanching. Blanching was achieved by a transparent plastic sheet with VSS score sheet pasted on it, as suggested by Baryza and Baryza [15]. Scar pigmentation was assessed after blanching and comparing the scar color with the surrounding skin. Assessments were done by two independent observers (trainee registrars working in another unit of the department) who were blinded to the treatment groups. The mean value of their scoring was recorded. The decreasing value of the score indicates clinical improvement of the scar. All patients were followed until 24 weeks even if scar flattening was achieved before it. The VSS scores, expressed as mean of all scars, were compared between Groups A and B using an unpaired 2 tailed t-test assuming a heteroscedastic sample variation at the various time point analyses. Comparative survival analysis between the two drugs was done using Kaplan Meier curves, and scores were statistically analyzed using Wilcoxon test and log rank test. Rate at which all the study parameters reduced to zero (zero is considered as the event), with the two drugs was compared for each of the four components of VSS. A p-value of <0.05 was considered to be statistically significant.
3.
Results
A total of 40 patients (20 in each group) were recruited and followed up for the study duration. Forty-eight scars were
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
3
burns xxx (2013) xxx–xxx
Table 1 – Scar etiology in both the groups.
Table 2 – Scar location in both the groups.
Scar etiology
Group A triamcinolone (n = 22)
Group B verapamil (n = 26)
Furuncle/ post-infective Surgery Burns Trauma
14
16
1 4 3
2 4 4
Scar location
Group A triamcinolone (n = 22)
Group B verapamil (n = 26)
16 1 1 4
18 2 1 5
Pre-sternal Extremities Face Torso/back
studied in these 40 patients (22 in Group A treated with triamcinolone; 26 in Group B treated with verapamil). Two scars were available in two (10%) and six (30%) patients in Groups A and B, respectively. The etiology of the scars in both the groups was comparable with post infective/furuncle being the most common (Table 1). Pre-sternal location was the most common site in both the groups (Table 2). Mean VSS scores for both treatment groups are presented in Table 3. Mean zero VSS scores were achieved with treatments in respect of scar height (T-12 weeks, V-21 weeks), vascularity (T-15 weeks, V-18 weeks) and pliability (T-15 weeks, V-21 weeks) (Table 3). The improvement in scar vascularity and pliability kept pace with decrease in scar height, in both the groups. There is not much difference in the rate of change of scar pigmentation with either drug (Table 3). However, the change in scar pigmentation during treatment is better reflected in Table 4. It can be observed that almost all the scars (21/22 in Group A and 25/26 in Group B) were hyperpigmented at the start of the treatment, and at the end of the 24 week observation period, 12/21 in Group A and 15/25 in
Group B had regained normal pigmentation, even if some scars became hypopigmented for a brief period (Table 4). The rate of improvement in scar characteristics is better reflected in Kaplan Meir survival curves (Fig. 1). On statistical analysis using log rank test and Wilcoxon test, the faster rate of improvement in scar height, vascularity and pliability seen with triamcinolone, is highly significant ( p < 0.0001). However, the difference in the rate of change in pigmentation with both the agents was not statistically significant. Although, change in scar width was not part of the assessment in VSS scores, it was noticed that in all presternal scars there was an appreciable increase in scar width with decrease in scar height, in both the groups. The increase in scar width was very apparent as 34/48 scars studied were pre-sternal in location (Figs. 2 and 3). This change was less noticeable in scars at other locations. Only minor adverse effects were noted with either drug (Table 5). Patients in both the groups experienced some pain during administration of the drug, which was well tolerated generally, but 2/64 injection episodes in Group A and 4/113
Table 3 – Mean VSS Scores during 24 weeks of follow-up. VSS parameters Drug
Height
V T
Vascularity
V T
Pliability
V T
Pigmentation
V T
Intralesional injection interval in weeks with mean VSS scores ( 95% CI) 0 wks
3 wks
6 wks
9 wks
12 wks
15 wks
18 wks
21 wks
24 wks
1.57 (1.38,1.77) 1.59 (1.38,1.80) 1.85 (1.62,2.08) 1.93 (1.72,2.15) 2.52 (2.31,2.73) 2.43 (2.17,2.69) 1.92 (1.77,2.07) 1.91 (1.73,2.09)
1.3 (1.13,1.49) 1.27 (1.08,1.46) 1.62 (1.37, 1.86) 1.39 (1.10,1.67) 2.12 (1.90,2.33) 1.61 (1.41,1.82) 1.85 (1.64,2.06) 1.86 (1.67,2.06)
1.07 (0.97,1.18) 0.95 (0.71,1.20) 1.23 (1.03,1.44) 0.84 (0.58,1.10) 1.71 (1.53,1.89) 0.93 (0.66,1.21) 1.69 (1.41,1.98) 1.64 (1.36,1.91)
0.76 (0.60,0.93) 0.09 ( 0.03,0.21) 0.77 (0.60,0.93) 0.34 (0.15,0.53) 1.29 (1.12,1.45) 0.23 (0.05,0.41) 1.62 (1.31,1.92) 1.59 (1.28,1.90)
0.38 (0.19,0.58) 0
0.15 (0.01,0.30) 0
0.03 ( 0.04,0.11) 0
0
0
0
0
0.62 (1.37,1.86) 0.09 (0.01,0.17) 0.79 (0.58,0.99) 0.05 ( 0.04,0.13) 1.46 (1.11,1.81) 1.27 (0.88,1.66)
0.12 ( 0.01,0.24) 0
0
0
0
0
0
0
0.35 (0.16,0.53) 0
0.08 ( 0.03,0.18) 0
0
0
0
0
1.23 (0.85,1.61) 1.18 (0.78,1.58)
1.15 (0.77,1.54) 1.09 (0.66,1.52)
0.92 (0.53,1.31) 0.91 (0.48,1.34)
0.85 (0.46,1.23) 0.82 (0.40,1.24)
Wks – weeks; V – verapamil; T – triamcinolone; CI – confidence intervals in parentheses.
Table 4 – Extent of improvement in hyperpigmented scars in both the groups. 0 week (Pre drug)
09 weeks
24 weeks
Pigmentation
Normal
Hypo-
Hyper-
Normal
Hypo-
Hyper-
Normal
Hypo-
Hyper-
Group A (n = 22) Group B (n = 26)
1 1
0 0
21 25
3 5
3 0
16 21
13 15
0 0
9 11
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
4
burns xxx (2013) xxx–xxx
Fig. 1 – Kaplan Meir survival curves for scar pliability, vascularity, height and pigmentation, in both the groups.
injection episodes in Group B required some analgesia to control pain.
4.
Discussion
The management of keloid and hypertrophic scar is ever evolving. With better understanding of pathophysiology of hypertrophic scars and keloids are emerging newer possibilities of treatment with verapamil [10–13], lasers [16],
Fig. 2 – (a) A 5 cm T 0.7 cm T 3 mm (height) longitudinal presternal scar, selected before first injection of triamcinolone. (b) Scar flattening at 12 weeks (4 injections). Note increase in scar width.
antimitotic drugs like 5FU [17] or bleomycin [18], interferon a 2b [19,20], and even botox [21,22]. However, in this milieu, the potential of verapamil seems underutilized as only one [23] out of three recent reviews on the subject [23–25] mentions it as a treatment option. Considering a better understanding of its mechanism of action [7–9], its reported efficacy [10–13], the less drastic adverse effects compared to the modalities mentioned above, and an extremely low cost, it deserves better positioning in the wide armamentarium against such scarring. Our study adds to evidence of verapamil’s capability in flattening the raised scars and the results seem to justify our belief. Majority of studies on intralesional injections for scarring can be criticized for lapses on one or several technical issues of trial; like not defining the scar age for recruitment and not specifying the drug dose per unit of the scar, the end point of each injection or the frequency of injections. None of these studies have also segregated scars in keloidal diathesis, which patho-physiologically behave quite differently [6]. These seem to us the obvious reasons for very varying results. We have attempted to bring more objectivity to our analysis by clearly defining the parameters for scar recruitment and injection. Relating 1.5 ml of drug volume to a scar area of around 6 cm2 was basically to ensure complete blanching of the lesion at the endpoint of injection. Therefore, 1.5 ml was the maximum indicative volume decided in the study protocol, although, all scars received between 0.7–0.9 ml of either drug in initial stages and between 1–1.5 ml as they softened. We also feel that the three weekly injection schedule selected by us on the basis of past studies should be reviewed to investigate a more frequent regimen as there is no strong evidence to support a three week interval between triamcinolone or verapamil injections. A Chinese study supports a combination of 5-FU (50 mg/ml) and triamcinolone (40 mg/ml) delivered intralesionally at weekly intervals in a prospective trial comparing it with weekly triamcinolone injections alone [26]. A closer analysis of the mean VSS scores in our study reveals that in the triamcinolone group 20/22 scars had in fact
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
5
burns xxx (2013) xxx–xxx
Table 5 – Adverse effects in the treatment groups. Adverse effect Pain-requiring analgesia Telangiectasia Skin atrophy
Group A (triamcinolone)
Group B (verapamil)
2/64 injection episodes 2/22 patients 4/22 patients
4/113 injection episodes 0/26 0/26
clinically investigated if the two drugs can be combined in a single injection to derive a synergistic and enhanced response. Such a trial is underway in our department but a similar trial has been conducted previously in an animal model [27]. The study concluded that combination therapy could reduce the dosage of both the drugs while achieving similar or better results than monotherapy [27].
5.
Fig. 3 – (a) A 3.5 cm T 1.5 cm T 3 mm (height) horizontal presternal scar before first injection of verapamil. (b) Scar flattening at 15 weeks (5 injections). Note the appreciable increase in scar dimension.
become flat in just 3 injections (0, 3 and 6 weeks) (Table 3) and the score of 0.09 in scar height observed at 9 weeks (Table 3) was just from slight residual hypertrophy in 2/22 scars. Similarly, in the verapamil group 22/26 scars became flat by 15 weeks (5 injections) (Table 3) and the score of 0.15 observed at 15 weeks was just from slight residual hypertrophy in 4/26 scars. The improvement in scar vascularity and pliability kept pace with the decrease in scar height but only 60% of the scars could regain normal pigmentation in 24 weeks of observation, in either group. Similar results were reported by Margaret et al. [13] using a fixed dose of 1 ml triamcinolone (40 mg/ml) and 1 ml of verapamil (2.5 mg/ml) for lesions up to 10 cm in length and scars up to 5 years in duration. However, we feel that for such large scars a fixed intralesional dose of 1 ml is less in achieving universal blanching of the lesion. Margaret et al. [13] also observed a decrease in scar width along with decrease in scar height whereas our results clearly show that at least in presternal areas, the hypertrophic scars and keloids definitely widen as the scar soften with therapy (Figs. 2 and 3). It is interesting to note that majority of scars in our study (34/48) were presternal in location, where surgical revision is not an option. As triamcinolone acts by decreasing proteinase (read collagenase) inhibitors [5] and verapamil acts by increasing procollagenase secretion [7–9], the end result with both the drugs is to increase collagenase levels to achieve collagen degradation within the scar. Besides, triamcinolone also improves the inflammatory milieu of the scar. It needs to be
Limitations of study
Quite like previous studies on this subject, we relied on measuring mean VSS scores to document our results. The VSS remains widely applicable to evaluate therapy and as a measure of outcome in burn studies even as these scar assessment scales are largely subjective clinical assessments and thus highly observer dependent [28]. Relying on scar evaluation by two blinded, but trained observers, in our study, was aimed at eliminating/diminishing the subjectivity of this assessment scale. Our study, limited to six months period of observation, cannot comment on the long term control of the scar tendency to hypertrophy. However, as all scars were followed for 24 weeks, regardless of the time when flattening was achieved, it was noticed that there was no tendency for the hypertrophy to recur, in either group. This period of observation, after scar flattening, was about 18 and 12 weeks respectively, for the triamcinolone and verapamil groups.
6.
Conclusions
Both triamcinolone and verapamil intralesional injections can achieve scar flattening in hypertrophic scars and keloids. Intralesional triamcinolone continues to be the gold standard for the first line treatment owing to its rapid and effective response. However, verapamil is almost equally effective and offers several therapeutic possibilities to alternate with triamcinolone or be used simultaneously in larger (or multiple) scars.
Conflict of interest There is no conflict of interest to report by any of the authors.
references
[1] Lorenz P, Bari AS. Scar prevention, treatment and revision. In: Gurtner GC, Neligan PC, editors. Plastic surgery. 3rd ed., Oxford: Elsevier Health Sciences; 2012. p. 302.
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
6
burns xxx (2013) xxx–xxx
[2] Urioste SS, Arndt KA, Dover JS. Keloids and hypertrophic scars: review and treatment strategies. Semin Cutan Med Surg 1999;18(2):159–71. [3] Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars. Arch Facial Plast Surg 2006;8(6): 362–8. [4] Brissett AE, Sherris DA. Scar contractures, hypertrophic scars and keloids. Facial Plast Surg 2001;17(4): 263–72. [5] Rockwell WB, Cohen IK, Ehrlich HP. Keloid and hypertrophic scars. A comprehensive review. Plast Recontr Surg 1989;84(5):827–37. [6] Burd A, Huang L. Hypertrophic response and keloid diathesis: two very different forms of scar. Plast Reconstr Surg 2005;116(7):150e–7e. [7] Lee RC, Ping JA. Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J Surg Res 1990;49(5):463–6. [8] Doong H, Dissanayake S, Gowrishankar TR, LaBarbera MC, Lee RC. The 1996 Lindberg award. Calcium antagonists alter cell shape and induce procollagenase synthesis in keloid and normal human dermal fibroblasts. J Burn Care Rehabil 1996;17:497–514. [9] Boggio RF, Freitas VM, Cassiola FM, Uryabashi Marcel Machado-Santelli GM. Effect of a calcium channel clocker (verapamil) on the morphology, cytoskeleton and collagenase activity of human skin fibroblasts. Burns 2011;37:616–25. [10] Lawrence WT. Treatment of ear lobe keloids with surgery plus adjuvant intralesional verapamil and pressure earrings. Ann Plast Surg 1996;37(2):167–9. [11] D’Andrea F, Brongo S, Ferraro G, Baroni A. Prevention and treatment of keloids with intralesional verapamil. Dermatology 2002;204(1):60–2. [12] Lee RC, Doong H, Jellema AF. The response of burn scars to intralesional verapamil: report of five cases. Arch Surg 1994;129(1):107–11. [13] Margaret Shanthi FX, Ernest K, Dhanraj P. Comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. Indian J Dermatol Venereol Leprol 2008;74(4):343–8. [14] Sullivan T, Smith J, Kermode J, McIver E, Courtemanche DJ. Rating the burn scar. J Burn Care Rehabil 1990;11: 256–60.
[15] Baryza MJ, Baryza GA. The Vancouver Scar Scale: an administration tool and its interrater reliability. J Burn Care Rehabil 1995;16(5):535–8. [16] Elsaie ML, Choudhary S. Lasers for scars: a review and evidence-based appraisal. J Drugs Dermatol 2010 Nov;9(11):1355–62. [17] Gupta S, Kalra A. Efficacy and safety of intralesional 5fluorouracil in the treatment of keloids. Dermatology 2002;204(2):130–2. [18] Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg 2006;32(8):1023–30. [19] Lee JH, Kim SE, Lee AY. Effects of interferon-alpha2b on keloid treatment with triamcinolone acetonide intralesional injection. Int J Dermatol 2008;47(2):183–6. [20] Ladak A, Tredget EE. Pathophysiology and management of the burn scar. Clin Plast Surg 2009;36(4):661–74. [21] Zhibo X, Miaobo Z. Intralesional botulinum toxin type A injection as a new treatment measure for keloids. Plast Reconstr Surg 2009;124(5):275–7. [22] Gauglitz GG, Bureik D, Dombrowski Y, Pavicic T, Ruzicka T, Schauber J. Botulinum toxin A for the treatment of keloids. Skin Pharmacol Physiol 2012;25(6):313–8. [23] Shockman S, Paghdal KV, Cohen G. Medical and surgical management of keloids: a review. J Drugs Dermatol 2010;9(10):1249–57. [24] Ogawa R. The most current algorithms for the treatment and prevention of hypertrophic scars and keloids. Plast Reconstr Surg 2010;125(2):557–68. [25] Gauglitz GG. Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol 2013;6:103–14. [26] Wu XL, Gao Z, Song N, Liu W. Clinical study of auricular keloid treatment with both surgical excision and intralesional injection of low-dose 5-fluorouracil and corticosteroids. Zhonghua Yi Xue Za Zhi 2009;28(89):1102–5. in Chinese. [27] Yang JY, Huang CY. The effect of combined steroid and calcium channel blocker injection on human hypertrophic scars in animal model: a new strategy for the treatment of hypertrophic scars. Dermatol Surg 2010;36(12):1942–9. [28] Fearmonti R, Bond J, Erdmann D, Levinson H. A review of scar scales and scar measuring devices. Eplasty 2010;10:e43.
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.elsevier.com/locate/burns
Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids§ Rajeev B. Ahuja *, Pallab Chatterjee Department of Burns, Plastic, Maxillofacial and Microvascular Surgery, Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi 110 002, India
article info
abstract
Article history:
There is not much level 1 evidence based literature to guide management of hypertrophic
Accepted 9 September 2013
scars and keloids despite an array of therapeutic modalities at disposal. Intralesional (i/l)
Keywords:
Sporadic reports on use of i/l verapamil suggest its efficacy. Since verapamil has not found
Hypertrophic scars
sufficient mention as an effective alternative modality, it was decided to undertake a
Keloids
randomized study which could also address some additional clinical parameters.
triamcinolone injections have remained a gold standard in non surgical management.
Triamcinolone Verapamil Vancouver Scar Scale
A randomized, parallel group and observer blinded comparison with 40 patients (48 scars) was carried out to compare the effects of i/l triamcinolone (T) (22 scars) and verapamil injections (V) (26 scars). 1.5 ml was the maximum indicative volume decided in the study protocol for both the drugs (triamcinolone @40 mg/ml and verapamil @ 2.5 mg/ml). Patients included were aged between 15–60 years with scars ranging between 0.5–5 cm (but total area roughly <6 cm2), and scars under 2 years duration. Patients with keloidal diathesis were excluded. Injections were scheduled every three weeks until complete flattening of the scar or eight sessions, which ever came earlier. No concomitant therapies like massage, silicone gel or pressure garments were used. Scar evaluation at each stage was done by serial photographic records as well as by Vancouver Scar Scale (VSS). Comparative survival analysis between the two drugs was done using Kaplan Meier curves, and VSS scores were analyzed using Wilcoxon test and log rank test. Mean zero VSS scores were achieved with treatments in respect of scar height (T-12 weeks, V-21 weeks), vascularity (T-15 weeks, V-18 weeks) and pliability (T-15 weeks, V-21 weeks). The improvement in scar vascularity and pliability kept pace with decrease in scar height, in both the groups. There was not much difference in the rate of change of scar pigmentation with either drug but almost 60% patients in both the groups regained normal pigmentation. Our study adds to evidence of verapamil’s capability in flattening the raised scars. With an extremely low cost and fewer adverse effects it deserves better positioning in the wide armamentarium against hypertrophic scars. It also offers several therapeutic possibilities to alternate with triamcinolone or be used simultaneously in larger (or multiple) scars. # 2013 Elsevier Ltd and ISBI. All rights reserved.
§
This paper was presented at the 16th Congress of International Society for Burn Injuries at Edinburgh, UK, 9–13th September 2012. * Corresponding author. Tel.: +91 11 23231871; fax: +91 11 23222756. E-mail addresses: [email protected], [email protected] (R.B. Ahuja). 0305-4179/$36.00 # 2013 Elsevier Ltd and ISBI. All rights reserved. http://dx.doi.org/10.1016/j.burns.2013.09.029 Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
2
burns xxx (2013) xxx–xxx
1.
Introduction
Keloids and hypertrophic scars are dermal fibro-proliferative disorders unique to humans [1], which may lead to disfigurement, pain and pruritus [2]. Their management is still challenging as there is no universally accepted treatment regimen [3] and not much level 1 evidence based literature to guide management. This is despite an array of therapeutic modalities at disposal, because there are a multitude of etiological factors [4], less well understood pathophysiology [5], wide spectrum of disease [6] and limitations of targeted therapies. For less extensive hypertrophic scarring and keloids, intralesional (i/l) triamcinolone injections have remained a gold standard in non surgical management. It has been reported that scars treated with triamcinolone acetonide (T) showed decreased levels of the proteinase inhibitors alpha2-macroglobulin and alpha2-antitrypsin in the scar [5]. This leads to decreased collagenase (matrix metalloproteinase 1/MMP1) degradation which controls excessive and abnormal collagen seen in hypertrophic scars and keloids [5]. In 1990, Lee and Ping demonstrated that calcium channel blockers such as verapamil lead to decreased extracellular matrix production in scars [7]. It was further demonstrated that verapamil depolymerizes actin filaments to modify fibroblast morphology with a consequent increased secretion of procollagenase [8,9]. Subsequently, there have been sporadic reports of its use in hypertrophic scars and keloids suggesting its efficacy [10–12], but these studies were uncontrolled and with limited number of subjects. Moreover in two of these reports, i/l verapamil injections were used following excision of the lesion, and in combination with compression [10] or silastic sheets [11] for prophylaxis. The first randomized controlled trial to study verapamil was conducted by Margaret et al. [13] which suggested that i/l verapamil may be as effective as triamcinolone in the treatment of hypertrophic scars and keloids. Since this report was the only confirmatory evidence available in literature, and in spite of which verapamil has not found sufficient mention as an effective alternative modality in the treatment of hypertrophic scars and keloids, it was decided to undertake another randomized study which could also address some additional clinical parameters.
2.
Patients and methods
The study was conducted in the Department of Burns and Plastic Surgery, Lok Nayak Hospital and Associated Maulana Azad Medical College, New Delhi. Approval of institutional ethics committee was obtained before commencing the study. Subjects were recruited between July 2011 and August 2012 from the outpatient clinic. It was a randomized, parallel group and observer blinded comparison between i/l triamcinolone (T) and verapamil injection (V). 1.5 ml was the maximum permissible injected volume of triamcinolone (concentration 40 mg/ml) and verapamil hydrochloride (concentration 2.5 mg/ml). Inclusion criteria included patients aged between 15–60 years old, scars of 0.5–5 cm in maximum dimension, regardless of the shape, but total area roughly <6 cm2 and scars under 2 years duration. Patients with evidence of any
infection or ulcer, in or near the scar, were excluded. Also excluded were pregnant females, and patients with a history of prior treatment with any intralesional injection. In patients with multiple hypertrophic scars two sites were recruited only if their total area appeared <6 cm2. No attempt was made to distinguish between hypertrophic scars and keloids but patients with keloidal diathesis were excluded on the basis of past personal or family history. Detailed history and demographic parameters were recorded, including etiology, duration of scarring and prior treatments. A minimum sample size of 44 scars (22 in each group) was calculated for a non inferiority trial design with triamcinolone as standard treatment and verapamil as the experimental drug based upon an alpha error of 5% and power of 80%, assuming a non-inferiority limit of 30%, and at least 80% cure rate for each group. The patients were randomly allocated to two groups A and B using a computer generated random sequence. Scars in group A received i/l triamcinolone acetonide and scars in group B received i/l verapamil hydrochloride, every three weeks for a maximum of eight sessions or till complete flattening of the scar, whichever came earlier. The injections were made at several points in the lesion with an insulin syringe and 24 gauge needle to achieve complete and evenly distributed blanching of the lesion at endpoint. No sedation/analgesia was used at the time of injection. Scar flattening was defined as <1 mm scar height over 90% of the lesion, by visual assessment. No concomitant therapies like massage, silicone gel or pressure garments were used. Scar evaluation at each stage was done by serial photographic records as well as by Vancouver Scar Scale (VSS) [14]. Scar height was accurately measured with calipers. Scar pliability was subjectively assessed by palpation. Scar vascularity was rated on visual inspection and the rate of refill after blanching. Blanching was achieved by a transparent plastic sheet with VSS score sheet pasted on it, as suggested by Baryza and Baryza [15]. Scar pigmentation was assessed after blanching and comparing the scar color with the surrounding skin. Assessments were done by two independent observers (trainee registrars working in another unit of the department) who were blinded to the treatment groups. The mean value of their scoring was recorded. The decreasing value of the score indicates clinical improvement of the scar. All patients were followed until 24 weeks even if scar flattening was achieved before it. The VSS scores, expressed as mean of all scars, were compared between Groups A and B using an unpaired 2 tailed t-test assuming a heteroscedastic sample variation at the various time point analyses. Comparative survival analysis between the two drugs was done using Kaplan Meier curves, and scores were statistically analyzed using Wilcoxon test and log rank test. Rate at which all the study parameters reduced to zero (zero is considered as the event), with the two drugs was compared for each of the four components of VSS. A p-value of <0.05 was considered to be statistically significant.
3.
Results
A total of 40 patients (20 in each group) were recruited and followed up for the study duration. Forty-eight scars were
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
3
burns xxx (2013) xxx–xxx
Table 1 – Scar etiology in both the groups.
Table 2 – Scar location in both the groups.
Scar etiology
Group A triamcinolone (n = 22)
Group B verapamil (n = 26)
Furuncle/ post-infective Surgery Burns Trauma
14
16
1 4 3
2 4 4
Scar location
Group A triamcinolone (n = 22)
Group B verapamil (n = 26)
16 1 1 4
18 2 1 5
Pre-sternal Extremities Face Torso/back
studied in these 40 patients (22 in Group A treated with triamcinolone; 26 in Group B treated with verapamil). Two scars were available in two (10%) and six (30%) patients in Groups A and B, respectively. The etiology of the scars in both the groups was comparable with post infective/furuncle being the most common (Table 1). Pre-sternal location was the most common site in both the groups (Table 2). Mean VSS scores for both treatment groups are presented in Table 3. Mean zero VSS scores were achieved with treatments in respect of scar height (T-12 weeks, V-21 weeks), vascularity (T-15 weeks, V-18 weeks) and pliability (T-15 weeks, V-21 weeks) (Table 3). The improvement in scar vascularity and pliability kept pace with decrease in scar height, in both the groups. There is not much difference in the rate of change of scar pigmentation with either drug (Table 3). However, the change in scar pigmentation during treatment is better reflected in Table 4. It can be observed that almost all the scars (21/22 in Group A and 25/26 in Group B) were hyperpigmented at the start of the treatment, and at the end of the 24 week observation period, 12/21 in Group A and 15/25 in
Group B had regained normal pigmentation, even if some scars became hypopigmented for a brief period (Table 4). The rate of improvement in scar characteristics is better reflected in Kaplan Meir survival curves (Fig. 1). On statistical analysis using log rank test and Wilcoxon test, the faster rate of improvement in scar height, vascularity and pliability seen with triamcinolone, is highly significant ( p < 0.0001). However, the difference in the rate of change in pigmentation with both the agents was not statistically significant. Although, change in scar width was not part of the assessment in VSS scores, it was noticed that in all presternal scars there was an appreciable increase in scar width with decrease in scar height, in both the groups. The increase in scar width was very apparent as 34/48 scars studied were pre-sternal in location (Figs. 2 and 3). This change was less noticeable in scars at other locations. Only minor adverse effects were noted with either drug (Table 5). Patients in both the groups experienced some pain during administration of the drug, which was well tolerated generally, but 2/64 injection episodes in Group A and 4/113
Table 3 – Mean VSS Scores during 24 weeks of follow-up. VSS parameters Drug
Height
V T
Vascularity
V T
Pliability
V T
Pigmentation
V T
Intralesional injection interval in weeks with mean VSS scores ( 95% CI) 0 wks
3 wks
6 wks
9 wks
12 wks
15 wks
18 wks
21 wks
24 wks
1.57 (1.38,1.77) 1.59 (1.38,1.80) 1.85 (1.62,2.08) 1.93 (1.72,2.15) 2.52 (2.31,2.73) 2.43 (2.17,2.69) 1.92 (1.77,2.07) 1.91 (1.73,2.09)
1.3 (1.13,1.49) 1.27 (1.08,1.46) 1.62 (1.37, 1.86) 1.39 (1.10,1.67) 2.12 (1.90,2.33) 1.61 (1.41,1.82) 1.85 (1.64,2.06) 1.86 (1.67,2.06)
1.07 (0.97,1.18) 0.95 (0.71,1.20) 1.23 (1.03,1.44) 0.84 (0.58,1.10) 1.71 (1.53,1.89) 0.93 (0.66,1.21) 1.69 (1.41,1.98) 1.64 (1.36,1.91)
0.76 (0.60,0.93) 0.09 ( 0.03,0.21) 0.77 (0.60,0.93) 0.34 (0.15,0.53) 1.29 (1.12,1.45) 0.23 (0.05,0.41) 1.62 (1.31,1.92) 1.59 (1.28,1.90)
0.38 (0.19,0.58) 0
0.15 (0.01,0.30) 0
0.03 ( 0.04,0.11) 0
0
0
0
0
0.62 (1.37,1.86) 0.09 (0.01,0.17) 0.79 (0.58,0.99) 0.05 ( 0.04,0.13) 1.46 (1.11,1.81) 1.27 (0.88,1.66)
0.12 ( 0.01,0.24) 0
0
0
0
0
0
0
0.35 (0.16,0.53) 0
0.08 ( 0.03,0.18) 0
0
0
0
0
1.23 (0.85,1.61) 1.18 (0.78,1.58)
1.15 (0.77,1.54) 1.09 (0.66,1.52)
0.92 (0.53,1.31) 0.91 (0.48,1.34)
0.85 (0.46,1.23) 0.82 (0.40,1.24)
Wks – weeks; V – verapamil; T – triamcinolone; CI – confidence intervals in parentheses.
Table 4 – Extent of improvement in hyperpigmented scars in both the groups. 0 week (Pre drug)
09 weeks
24 weeks
Pigmentation
Normal
Hypo-
Hyper-
Normal
Hypo-
Hyper-
Normal
Hypo-
Hyper-
Group A (n = 22) Group B (n = 26)
1 1
0 0
21 25
3 5
3 0
16 21
13 15
0 0
9 11
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
4
burns xxx (2013) xxx–xxx
Fig. 1 – Kaplan Meir survival curves for scar pliability, vascularity, height and pigmentation, in both the groups.
injection episodes in Group B required some analgesia to control pain.
4.
Discussion
The management of keloid and hypertrophic scar is ever evolving. With better understanding of pathophysiology of hypertrophic scars and keloids are emerging newer possibilities of treatment with verapamil [10–13], lasers [16],
Fig. 2 – (a) A 5 cm T 0.7 cm T 3 mm (height) longitudinal presternal scar, selected before first injection of triamcinolone. (b) Scar flattening at 12 weeks (4 injections). Note increase in scar width.
antimitotic drugs like 5FU [17] or bleomycin [18], interferon a 2b [19,20], and even botox [21,22]. However, in this milieu, the potential of verapamil seems underutilized as only one [23] out of three recent reviews on the subject [23–25] mentions it as a treatment option. Considering a better understanding of its mechanism of action [7–9], its reported efficacy [10–13], the less drastic adverse effects compared to the modalities mentioned above, and an extremely low cost, it deserves better positioning in the wide armamentarium against such scarring. Our study adds to evidence of verapamil’s capability in flattening the raised scars and the results seem to justify our belief. Majority of studies on intralesional injections for scarring can be criticized for lapses on one or several technical issues of trial; like not defining the scar age for recruitment and not specifying the drug dose per unit of the scar, the end point of each injection or the frequency of injections. None of these studies have also segregated scars in keloidal diathesis, which patho-physiologically behave quite differently [6]. These seem to us the obvious reasons for very varying results. We have attempted to bring more objectivity to our analysis by clearly defining the parameters for scar recruitment and injection. Relating 1.5 ml of drug volume to a scar area of around 6 cm2 was basically to ensure complete blanching of the lesion at the endpoint of injection. Therefore, 1.5 ml was the maximum indicative volume decided in the study protocol, although, all scars received between 0.7–0.9 ml of either drug in initial stages and between 1–1.5 ml as they softened. We also feel that the three weekly injection schedule selected by us on the basis of past studies should be reviewed to investigate a more frequent regimen as there is no strong evidence to support a three week interval between triamcinolone or verapamil injections. A Chinese study supports a combination of 5-FU (50 mg/ml) and triamcinolone (40 mg/ml) delivered intralesionally at weekly intervals in a prospective trial comparing it with weekly triamcinolone injections alone [26]. A closer analysis of the mean VSS scores in our study reveals that in the triamcinolone group 20/22 scars had in fact
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
5
burns xxx (2013) xxx–xxx
Table 5 – Adverse effects in the treatment groups. Adverse effect Pain-requiring analgesia Telangiectasia Skin atrophy
Group A (triamcinolone)
Group B (verapamil)
2/64 injection episodes 2/22 patients 4/22 patients
4/113 injection episodes 0/26 0/26
clinically investigated if the two drugs can be combined in a single injection to derive a synergistic and enhanced response. Such a trial is underway in our department but a similar trial has been conducted previously in an animal model [27]. The study concluded that combination therapy could reduce the dosage of both the drugs while achieving similar or better results than monotherapy [27].
5.
Fig. 3 – (a) A 3.5 cm T 1.5 cm T 3 mm (height) horizontal presternal scar before first injection of verapamil. (b) Scar flattening at 15 weeks (5 injections). Note the appreciable increase in scar dimension.
become flat in just 3 injections (0, 3 and 6 weeks) (Table 3) and the score of 0.09 in scar height observed at 9 weeks (Table 3) was just from slight residual hypertrophy in 2/22 scars. Similarly, in the verapamil group 22/26 scars became flat by 15 weeks (5 injections) (Table 3) and the score of 0.15 observed at 15 weeks was just from slight residual hypertrophy in 4/26 scars. The improvement in scar vascularity and pliability kept pace with the decrease in scar height but only 60% of the scars could regain normal pigmentation in 24 weeks of observation, in either group. Similar results were reported by Margaret et al. [13] using a fixed dose of 1 ml triamcinolone (40 mg/ml) and 1 ml of verapamil (2.5 mg/ml) for lesions up to 10 cm in length and scars up to 5 years in duration. However, we feel that for such large scars a fixed intralesional dose of 1 ml is less in achieving universal blanching of the lesion. Margaret et al. [13] also observed a decrease in scar width along with decrease in scar height whereas our results clearly show that at least in presternal areas, the hypertrophic scars and keloids definitely widen as the scar soften with therapy (Figs. 2 and 3). It is interesting to note that majority of scars in our study (34/48) were presternal in location, where surgical revision is not an option. As triamcinolone acts by decreasing proteinase (read collagenase) inhibitors [5] and verapamil acts by increasing procollagenase secretion [7–9], the end result with both the drugs is to increase collagenase levels to achieve collagen degradation within the scar. Besides, triamcinolone also improves the inflammatory milieu of the scar. It needs to be
Limitations of study
Quite like previous studies on this subject, we relied on measuring mean VSS scores to document our results. The VSS remains widely applicable to evaluate therapy and as a measure of outcome in burn studies even as these scar assessment scales are largely subjective clinical assessments and thus highly observer dependent [28]. Relying on scar evaluation by two blinded, but trained observers, in our study, was aimed at eliminating/diminishing the subjectivity of this assessment scale. Our study, limited to six months period of observation, cannot comment on the long term control of the scar tendency to hypertrophy. However, as all scars were followed for 24 weeks, regardless of the time when flattening was achieved, it was noticed that there was no tendency for the hypertrophy to recur, in either group. This period of observation, after scar flattening, was about 18 and 12 weeks respectively, for the triamcinolone and verapamil groups.
6.
Conclusions
Both triamcinolone and verapamil intralesional injections can achieve scar flattening in hypertrophic scars and keloids. Intralesional triamcinolone continues to be the gold standard for the first line treatment owing to its rapid and effective response. However, verapamil is almost equally effective and offers several therapeutic possibilities to alternate with triamcinolone or be used simultaneously in larger (or multiple) scars.
Conflict of interest There is no conflict of interest to report by any of the authors.
references
[1] Lorenz P, Bari AS. Scar prevention, treatment and revision. In: Gurtner GC, Neligan PC, editors. Plastic surgery. 3rd ed., Oxford: Elsevier Health Sciences; 2012. p. 302.
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029
JBUR-4177; No. of Pages 6
6
burns xxx (2013) xxx–xxx
[2] Urioste SS, Arndt KA, Dover JS. Keloids and hypertrophic scars: review and treatment strategies. Semin Cutan Med Surg 1999;18(2):159–71. [3] Leventhal D, Furr M, Reiter D. Treatment of keloids and hypertrophic scars. Arch Facial Plast Surg 2006;8(6): 362–8. [4] Brissett AE, Sherris DA. Scar contractures, hypertrophic scars and keloids. Facial Plast Surg 2001;17(4): 263–72. [5] Rockwell WB, Cohen IK, Ehrlich HP. Keloid and hypertrophic scars. A comprehensive review. Plast Recontr Surg 1989;84(5):827–37. [6] Burd A, Huang L. Hypertrophic response and keloid diathesis: two very different forms of scar. Plast Reconstr Surg 2005;116(7):150e–7e. [7] Lee RC, Ping JA. Calcium antagonists retard extracellular matrix production in connective tissue equivalent. J Surg Res 1990;49(5):463–6. [8] Doong H, Dissanayake S, Gowrishankar TR, LaBarbera MC, Lee RC. The 1996 Lindberg award. Calcium antagonists alter cell shape and induce procollagenase synthesis in keloid and normal human dermal fibroblasts. J Burn Care Rehabil 1996;17:497–514. [9] Boggio RF, Freitas VM, Cassiola FM, Uryabashi Marcel Machado-Santelli GM. Effect of a calcium channel clocker (verapamil) on the morphology, cytoskeleton and collagenase activity of human skin fibroblasts. Burns 2011;37:616–25. [10] Lawrence WT. Treatment of ear lobe keloids with surgery plus adjuvant intralesional verapamil and pressure earrings. Ann Plast Surg 1996;37(2):167–9. [11] D’Andrea F, Brongo S, Ferraro G, Baroni A. Prevention and treatment of keloids with intralesional verapamil. Dermatology 2002;204(1):60–2. [12] Lee RC, Doong H, Jellema AF. The response of burn scars to intralesional verapamil: report of five cases. Arch Surg 1994;129(1):107–11. [13] Margaret Shanthi FX, Ernest K, Dhanraj P. Comparison of intralesional verapamil with intralesional triamcinolone in the treatment of hypertrophic scars and keloids. Indian J Dermatol Venereol Leprol 2008;74(4):343–8. [14] Sullivan T, Smith J, Kermode J, McIver E, Courtemanche DJ. Rating the burn scar. J Burn Care Rehabil 1990;11: 256–60.
[15] Baryza MJ, Baryza GA. The Vancouver Scar Scale: an administration tool and its interrater reliability. J Burn Care Rehabil 1995;16(5):535–8. [16] Elsaie ML, Choudhary S. Lasers for scars: a review and evidence-based appraisal. J Drugs Dermatol 2010 Nov;9(11):1355–62. [17] Gupta S, Kalra A. Efficacy and safety of intralesional 5fluorouracil in the treatment of keloids. Dermatology 2002;204(2):130–2. [18] Naeini FF, Najafian J, Ahmadpour K. Bleomycin tattooing as a promising therapeutic modality in large keloids and hypertrophic scars. Dermatol Surg 2006;32(8):1023–30. [19] Lee JH, Kim SE, Lee AY. Effects of interferon-alpha2b on keloid treatment with triamcinolone acetonide intralesional injection. Int J Dermatol 2008;47(2):183–6. [20] Ladak A, Tredget EE. Pathophysiology and management of the burn scar. Clin Plast Surg 2009;36(4):661–74. [21] Zhibo X, Miaobo Z. Intralesional botulinum toxin type A injection as a new treatment measure for keloids. Plast Reconstr Surg 2009;124(5):275–7. [22] Gauglitz GG, Bureik D, Dombrowski Y, Pavicic T, Ruzicka T, Schauber J. Botulinum toxin A for the treatment of keloids. Skin Pharmacol Physiol 2012;25(6):313–8. [23] Shockman S, Paghdal KV, Cohen G. Medical and surgical management of keloids: a review. J Drugs Dermatol 2010;9(10):1249–57. [24] Ogawa R. The most current algorithms for the treatment and prevention of hypertrophic scars and keloids. Plast Reconstr Surg 2010;125(2):557–68. [25] Gauglitz GG. Management of keloids and hypertrophic scars: current and emerging options. Clin Cosmet Investig Dermatol 2013;6:103–14. [26] Wu XL, Gao Z, Song N, Liu W. Clinical study of auricular keloid treatment with both surgical excision and intralesional injection of low-dose 5-fluorouracil and corticosteroids. Zhonghua Yi Xue Za Zhi 2009;28(89):1102–5. in Chinese. [27] Yang JY, Huang CY. The effect of combined steroid and calcium channel blocker injection on human hypertrophic scars in animal model: a new strategy for the treatment of hypertrophic scars. Dermatol Surg 2010;36(12):1942–9. [28] Fearmonti R, Bond J, Erdmann D, Levinson H. A review of scar scales and scar measuring devices. Eplasty 2010;10:e43.
Please cite this article in press as: Ahuja RB, Chatterjee P. Comparative efficacy of intralesional verapamil hydrochloride and triamcinolone acetonide in hypertrophic scars and keloids. Burns (2013), http://dx.doi.org/10.1016/j.burns.2013.09.029