Aesth Plast Surg (2014) 38:968–975 DOI 10.1007/s00266-014-0400-9
ORIGINAL ARTICLE
NON-SURGICAL AESTHETIC
Topical Verapamil as a Scar Modulator Ricardo Frota Boggio • Leonardo Frota Boggio • Bruno Luiz Galva˜o • Glaucia Maria Machado-Santelli
Received: 19 February 2014 / Accepted: 13 August 2014 / Published online: 5 September 2014 Ó Springer Science+Business Media New York and International Society of Aesthetic Plastic Surgery 2014
Abstract Background Skin injuries and the consequent loss of tissue integrity triggers a sequence of cellular and biochemical events that lead to a healed wound. Any failure during this rather sophisticated process may result in pathological scarring. Methods To evaluate the efficacy of topical verapamil as a modulator of the healing process, a group of five observers (plastic surgeon, dermatologist, physiotherapist, biologist, and layman) analyzed pictures of 120 patients 3 months after abdominoplasty (60 patients) and mammoplasty (60 patients). Half of each group of patients used the topical verapamil scar modulator. Pictures were rated using the Stony Brook Scale. Results According to the classification established by us, the scars in patients who used topical verapamil scar modulator showed better results than those who did not (p \ 0.05). Patients treated with verapamil presented goodquality scarring (80 % of mammoplasty scars and 75.2 % abdominoplasty scars), while patients who did not use
healing modulators showed 48 and 51.2 % satisfaction for mammoplasty and abdominoplasty scars, respectively. No adverse reactions were observed or reported after the use of topical verapamil. Conclusions This is the first clinical trial that reports the use of topical verapamil as a modulator in the healing process in the postoperative period. Based on clinical results and on the high level of reliability and statistical significance, we concluded that verapamil at a concentration of 50 lM is an excellent choice as a scar modulator; its use avoids the development of keloids and hypertrophic scars after plastic surgery. Level of Evidence IV This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.
R. F. Boggio (&) G. M. Machado-Santelli Department of Cell and Development Biology, Institute of Biomedical Science, University of Sa˜o Paulo, Av. Prof. Lineu Prestes, 1524, ICB I rooms 306/307, Butantan, Sa˜o Paulo, SP 05508-900, Brazil e-mail:
[email protected]
Introduction
G. M. Machado-Santelli e-mail:
[email protected] L. F. Boggio B. L. Galva˜o Universidade Anhembi Morumbi, Rua Dr. Almeida Lima, 1.134 – Mooca, Sa˜o Paulo, SP 03164-000, Brazil e-mail:
[email protected] B. L. Galva˜o e-mail:
[email protected]
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Keywords Verapamil Keloids Calcium channel antagonist Fibroblasts Collagen
The occurrence of skin lesions and the consequent loss of tissue integrity initiate a sequence of cellular and biochemical events that culminate in a healed wound. Any failure in the healing process will result in pathological scarring such as keloids and hypertrophic scars [1–3]. A keloid is characterized by a high-profile fibrous lesion that extends beyond the margins of the original wound, is painful, itches, and appears red, and rarely regresses spontaneously. It usually appears around 3 months after the trauma, occurring predominantly in the earlobe, shoulder, and anterior chest. A keloid’s appearance is not related to
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the mobility of the injured area, and even minor traumas may cause large keloids. They are exclusive to humans, occur in both sexes, and are most commonly found in Africans, Caucasians, and Orientals, but not albino individuals. Histologically, keloids are characterized by large, thick collagen fibers, with few or even no myofibroblasts [4–7]. Hypertrophic scars are fibrous lesions that, unlike keloids, remain within the boundaries of the original wound and usually heal spontaneously, a few weeks after the trauma. They occur predominantly in the joints, and are closely related to movement of the affected area. The size of the hypertrophic scar usually has a direct relationship with the severity of the trauma. Histologically, hypertrophic scars are characterized by the presence of small blood vessels and collagen fibers randomly distributed in small groups of nodules. The presence of myofibroblasts is common [4–7]. Factors such as family history, prolonged inflammation, lesion site, age between 10 and 30 years, and pregnancy are risk factors for the development of dermal fibroproliferative disorders. Symptoms such as pain, itching, and burning may be present in keloid and hypertrophic scarring, especially the latter. The morbidity experienced by individuals with these fibroproliferative disorders ranges from cosmetic to serious limitations of movement [5–7]. There is a greater amount of collagen in hypertrophic scars and keloids compared with normal scars and skin, in a ratio of 3:1. Studies related this increased number of fibroblasts to increased levels of mRNA for ATP and collagen synthesis in these cells [8–10]. Despite improvements in the diagnosis and treatment of wounds, the treatment of keloids and hypertrophic scars is time consuming and involves few consistently successful approaches, making these disorders a real public health problem with a major impact on health-care costs [11, 12]. In recent decades, many researchers have been developing effective therapeutic methods to prevent and treat keloids and hypertrophic scars. Verapamil, a calcium channel blocker, has been recommended in the treatment of keloids and hypertrophic scars due to its ability to rebalance the biosynthesis of the extracellular matrix [13–17]. Intralesional verapamil injection has already been successfully used in the past for disorders in which there is overproduction of fibrous tissue. In 1994, Lee et al. [17] were the first to describe the use of injectable intralesional verapamil for the treatment of hypertrophic scars, with resolution of the scar in three of five cases treated. In 1996, Lawrence et al. [18] infiltrated the keloids of 31 patients with verapamil, with resolution of the lesions in 55 % of cases. In a study published in 2002, D’Andrea et al. [19] reported that perilesional keloid
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resection associated with the use of intralesional verapamil at a concentration of 2.5 mg/mL and a topical silicone plate led to healing of the lesions in 54 % of patients. In 2004, Copcu et al. [20] reported a satisfactory score of 6.4 (on a scale from 1 to 10) in 21 patients who were treated for keloids by a combination of surgery and intralesional verapamil. Based on these experiences and after testing local intralesional injection of verapamil for the treatment of stabilized keloids and hypertrophic scars, with good results, we began this study to determine the effectiveness of topical verapamil as a scar modulator. We used it in the early phases of healing for the prevention of keloids and hypertrophic scars in the immediate postoperative period after plastic surgery.
Patients and Methods Patients A review of the literature was performed, and the photographic records of patients who had undergone mammoplasty and abdominoplasty between January 2010 and December 2013 were examined. The patients were all females ranging in age from 31 to 65 years (mean = 43). Patients who smoked, had scar dehiscence, seroma, surgical wound infection, and did not use the verapamil when indicated (i.e., no use of verapamil for a single day during 3 months of treatment) were excluded. Of the patients who met the inclusion criteria, two study groups were formed. Patients in Group A (control) were Table 1 Stony Brook Scar Evaluation Scale Scar category
Score
Width [2 mm
0
\2 mm
1
Height Elevated or depressed compared to surrounding skin
0
Flat
1
Color Darker than surrounding skin (red, purple, brown, or black)
0
Same color or lighter than surrounding skin
1
Hatch marks or suture marks Present Absent
0 1
Overall appearance Poor
0
Good
1
Total score = sum of individual scores, 0 is worst and 5 is best
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Fig. 1 a Total and partial averages (issued by each evaluator) for secondary mammoplasty scars; 5 is the best scar quality and 0 the worst quality (p \ 0.05). b 1: verapamil used as a modulator in healing of mammoplasty scars (90 days); 2: no scar modulator used
operated on between January 2010 and November 2011 and did not use a scar modulator. They were divided into two subgroups: A1 with 30 abdominoplasty patients and A2 with 30 mammoplasty patients. Group B were operated on from December 2011 to December 2013 and also were divided into two subgroups: B1 with 30 abdominoplasty patients and B2 with 30 mammoplasty patients. These patients used a nonionic gel containing verapamil at a concentration of 50 lM beginning on the seventh
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postoperative day, 2 times a day for 90 days. Patients agreed to participate and signed a consent form. Verapamil gel was manipulated in a registered pharmacy under the seal of a medical control organization and supplied as free samples for the patients. The groups were formed regardless of skin type of the patients; 70 % of group A and 82 % of group B had skin types below 4. This study was subject to review by the Local Research Ethic Committee, and its duly authorized fulfillment.
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Results
Fig. 2 Appearance of mammoplasty scar after 3 months of regular use of verapamil (50 lM)
Procedures Two digital albums were created (Microsoft Power Point, Microsoft Corp., Redmond, WA, USA), containing anteroposterior, oblique, and profile views of the scars for all the subgroups. The photos were randomly distributed in each album, mingling patients from group A with those from group B; the observers were blinded to the group identity of all photos. The surgical scars were analyzed by five observers: a plastic surgeon, a dermatologist, a biologist, a physiotherapist, and a layman. The evaluation by the professionals with different occupations was used, based on healing as the main point of the different disciplines. A layman as an observer simulates the position of a potential patient considering plastic surgery. The scars were rated using the Stony Brook Scar Evaluation Scale [21] (Table 1). The following five criteria were rated according to their presence (0) or absence (1): longer than 2 mm, elevation or depression, depigmentation, suture marks or staples, and poor or satisfactory overall appearance. The total score was calculated by adding the individual scores of the five categories, with 0 indicating the worst aspect of the scar and 5 indicating the best appearance of the scar. Statistical Analysis Upon completion of the analysis by the observers, the scores were compiled and submitted for statistical analysis. According to the nature of the variables, the data were analyzed and appropriate tests applied: Cochran Q test for analysis of differences between evaluators, Cohen’s j test for analysis of agreement between pairs of raters, and Cronbach’s a test to analyze the correlation between concurrent evaluators for variables’ total. SPSS version 21.0 (SPSS, Inc., Chicago, IL, USA) was used to obtain the results.
According to the classification established by us, patients from the A1 group (mammoplasty and no scar modulator) had a mean score of 2.4 and those from the B1 group (mammoplasty and verapamil as a scar modulator) had an average score of 4.0. The standard deviations of the overall averages for the respective groups were 1.21 and 1.07 (Fig. 1a). Representative photographs of the results of three cases treated with verapamil and three untreated cases are seen in Fig. 1b, clearly showing the differences in the appearance of scars. Figure 2 shows the appearance of the scar 3 months after mammoplasty on a patient who regularly used topical verapamil (50 lM). The A2 group (abdominoplasty and no scar modulator) had a mean score of 2.56 and the B2 group (abdominoplasty and verapamil as a scar modulator) had a mean score of 3.76. The standard deviations of the overall averages for the respective groups were 0.56 and 0.48 (Fig. 3a). Representative photographs of the results of three cases treated with verapamil and three untreated ones are seen in Fig. 3b, clearly showing the differences in the appearance of scars. Figure 4 shows the appearance of the scar 3 months after abdominoplasty. The patient regularly used topical verapamil (50 lM). Differences in the quality of the scars of patients who used verapamil compared to scars of those who did not use any healing modulator were significant (p \ 0.05). Figures 1 and 3 illustrate two of the differences observed. Cochran’s Q test was used to verify possible differences between the five evaluators, and it showed a high correlation (p \ 0.05) among all compared to the overall averages (Table 2 The agreement between judges, when studied in pairs, was evaluated using Cohen’s j test, which demonstrated a high degree of agreement (j [ 0.750) (Table 3 Cronbach’s a test was used to assess the degree of agreement among the five raters, when assessed concurrently, for the variables’ total. The data are presented in Table 4. The values found with Cronbach’s a were statistically higher because all values were calculated at a significance below 5 % (0.050), implying that the data are internally consistent. There were no adverse reactions such as erythema, pruritus, or bullous lesions found in any of the cases in which verapamil was used as a healing modulator.
Discussion Regardless of the cause of tissue injury, it is very difficult to predict the course of the healing process, in which multiple factors influence the final appearance of the scar [23–25]. Despite improvements in diagnosis and therapy of
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Fig. 3 a Total and partial averages (issued by each evaluator) for secondary abdominoplasty scars; 5 is the best scar quality and 0 the worst quality (p \ 0.05). b 1: verapamil used as a modulator in healing of abdominoplasty scars (90 days); 2: no scar modulator used
wounds, there are still failures in the healing process. Complications such as lack of wound closure and the onset of contractures, keloids, and hypertrophic scars are still very frequent [26]. In recent years, the use of topical scar modulators after plastic surgery has been recommended by many surgeons to prevent the development of keloids and hypertrophic scars, yielding inconspicuous scars that are aesthetically acceptable to patients [27–33]. Topical healing modulators
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are very easy to apply, normally used at home, painless, well absorbed, and show proportional progressive results that are easy to accomplish and control, with very low indices of complications [34]. To our knowledge, this is the first clinical trial in which topical verapamil was used as a modulator to the healing process in the postoperative period. Calcium acts as a vital intracellular messenger and effector for most cells, including fibroblasts, which play a vital role in the
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Fig. 4 a, b Appearance of abdominoplasty scar after 3 months of regular use of verapamil (50 lM)
Table 2 Cochran’s Q test statistic (p \ 0.05) Sample
Entire sample
Without verapamil
With verapamil
Variable
Table 3 Analysis of agreement among raters
Significant (p) Mammoplasty
Abdominoplasty
Thickness
\0.001
\0.001
Height
\0.001
\0.001
Coloring
\0.001
\0.001
Brands suture or staple
\0.001
\0.001
General appearance
\0.001
\0.001
Thickness
\0.001
0.029
0.001
0.092
Coloring
\0.001
\0.001
Brands suture or staple
\0.001
\0.001
General appearance
\0.001
\0.001
Thickness
\0.001
\0.001
Height
\0.001
0.001
Coloring
\0.001
\0.001
Brands suture or staple General appearance
\0.001
\0.001
\0.001
\0.001
Height
Cohen’s j statistic
Level of agreement
j [ 0.750
High (or high)
0.400 B j B 0.750
Good (or moderate)
-1.000 B j \ 0.400
Marginal (or low)
Criteria defined by Landis and Koch (1977) for the interpretation of Cohen’s j statistic (in [22] ) Table 4 Cronbach’s a test statistics n
Cronbach’s a
Significance (p)
With verapamil
30
0.723
\0.001
Without verapamil
30
0.825
\0.001
Entire sample
60
0.876
\0.001
With verapamil
30
0.765
\0.001
Without verapamil
30
0.864
\0.001
Entire sample
60
0.877
\0.001
Group Mammoplasty
Abdominoplasty
Differences between the five evaluators
fundamental healing process [35]. Verapamil is a calcium channel blocker that acts specifically on the L-type calcium channels present in the cell plasma membrane, blocking the influx of calcium from the extracellular matrix to the cytoplasm. By blocking the entrance of calcium into the cells, verapamil helps reduce the cytosolic concentration of this ion, inducing a series of morphological alterations and its functions [35–38]. It is known that after tissue damage a number of substances are released within the wound, which amplifies the healing response. Platelet-derived growth factor (PDGF) and other factors such as transforming growth factor-b (TGF-b), vascular endothelial growth factor (VEGF), and interleukin-6 are fundamental in the modulation of
Values between 0.700 (inclusive) and 1.000 indicate high reliability
fibroblasts and in the production of the extracellular matrix. Verapamil present in the initial stage of the healing process reduces production of these substances and exercises potential control over cellular proliferation and angiogenesis [39]. In the first phase of healing, verapamil interferes with the synthesis of arachidonic acid, consequently liberating prostaglandins and leukotrienes [14]. The presence of these substances in high quantities in a healing wound can amplify inflammation, generating disordered cicatricial development. The second stage of wound healing is characterized by cell proliferation. Protein kinase C (PKC), which is indirectly activated by the calcium–calmodulin complex, is an important substance in the proliferation of fibroblasts. Reduction of the cytosolic concentration of the calcium–calmodulin complex induced by the blockade of the calcium influx into the cells inhibits
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the synthesis of PKC with a consequent reduction of fibroblast proliferation and control of the wound healing in this stage [14]. In 1989, Sank et al. [40] showed that high levels of calcium inhibited adhesion and the migration of keratinocytes in vitro and in vivo, and proposed the use of verapamil in the care of chronic wounds. It is important to point out that verapamil is capable of controlling cellular proliferation without negatively affecting viability [13–15, 17]. Keloids and hypertrophic scars are characterized by excessive production of collagen types I and III. The synthesis of collagen in keloids is three times higher than in hypertrophic scars and 20 times higher than in normal scars. Despite the fibroproliferative disturbance that occurs in these scars, there is still an increase in the concentration of hyaluronic acid that contributes to an increase in the volume of scar tissue [7]. The stage of maturation and remodeling is important for determining the final scar appearance. Some cases, as was observed by Giuliano et al. [39], suggested that verapamil is capable of inhibiting the production of cytokines, cellular proliferation, and the biosynthesis of the extracellular matrix. Boggio et al. [41, 42] reported the effects of verapamil on collagenase activity and the contraction of the matrix. The contraction of the extracellular matrix is stimulated in maturation and remodeling by various factors, including protein kinase C and the endothelin-I, which affect fibroblasts and myofibroblasts. Verapamil inhibits the synthesis of these substances, finally controlling scar contraction and allowing a good healing process [43]. Verapamil, when properly applied on scars in the first stage of healing, shows great potential for controlling the biosynthesis of its extracellular matrix. In the present study, the patients treated with verapamil showed good quality scars in 80 % of the mammoplasty cases and 75.2 % of the abdominoplasty cases, whereas only 48 and 51.2 % of the patients who did not use the healing modulator had of satisfactory healing after mammoplasty and abdominoplasty, respectively. Verapamil has been used in the treatment of a series of diseases, especially disorders of the cardiovascular system. Verapamil injected in keloids and hypertrophic scars has been effective without systemic alterations [17–20]. There were no adverse reactions to topical verapamil among the patients. Based on our clinical results and on the high level of reliability and statistical significance calculated from our observations on the effect of verapamil on scars from abdominoplasty and mammoplasty, it was concluded that topical verapamil, at a concentration of 50 lM, is an excellent scar modulator that prevents the development of keloids and hypertrophic scars in the postoperative period.
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Aesth Plast Surg (2014) 38:968–975 Acknowledgments This research project was developed according to the resolution 196/1996 of the Brazilian Health Council, after consideration and approval of Anhembi Morumbi University Research Ethics Committee (registration No. CAAE 07897312.9.0000.5492). Conflict of interest disclose.
The authors have no conflicts of interest to
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