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THERAPEUTIC ROUND
Year : 2010  |  Volume : 55  |  Issue : 4  |  Page : 359-362
Mometasone-based triple combination therapy in melasma: Is it really safe?


Cutis Skin and Laser Clinic, Government Medical College, Srinagar, Kashmir, India

Date of Web Publication4-Jan-2011

Correspondence Address:
Imran Majid
Cutis Skin Clinic, Karanagar Chowk, Srinagar, Kashmir
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-5154.74545

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   Abstract 

Background: Kligman's triple combination formula has been one of the most popular treatment options in melasma over the last three decades. The original Kligman's formula has been modified in many ways over the years and the most recent modification that has been introduced is a triple combination of 2% hydroquinone, 0.025% tretinoin, and 1% mometasone. The use of this triple combination in patients with melasma has seen a sharp rise over the last few years and with this rampant use the side-effect profile of this triple combination has also come to the fore. Aim : The aim of the present study was to assess the overall safety of the mometasone-based triple combination treatment in the management of melasma. Materials and Methods: This retrospective study was performed on 60 patients of melasma who had used a mometasone-based triple combination treatment for at least 3 weeks anytime in the previous 1 year. The patients were given a preformed questionnaire wherein they assessed the overall effect of the triple combination treatment on their melasma during its use as well as after its withdrawal. The patients were specifically asked about the status of their disease as well as the sun sensitivity of their skin before and after the use of triple combination treatment. In addition, the patients were assessed by a single trained dermatologist for the presence of any adverse effects arising out of the triple combination treatment in the form of telangiectasia, hypertrichosis, acne, skin atrophy, etc. Results: Majority of patients (51.7%) had used the combination treatment well beyond the recommended duration. About one-third (36.7%) of the patients rated their melasma as worse at the time of filling the questionnaire as compared with their disease before the use of triple combination treatment. On clinical examination, the evidence of steroid side effects was seen in 26 patients (43.3%). Steroid-induced telangiectasia was the commonest finding, seen in all of these 26 patients. Steroid-induced skin atrophy, hypertrichosis, and acneiform eruption were seen in 19, 17, and 11 patients, respectively. Conclusions: The propensity of a mometasone-based triple combination treatment to cause steroid adverse effects on the facial skin should always be borne in mind when the same is prescribed as a treatment option in melasma.


Keywords: Melasma, triple combination treatment, mometasone


How to cite this article:
Majid I. Mometasone-based triple combination therapy in melasma: Is it really safe?. Indian J Dermatol 2010;55:359-62

How to cite this URL:
Majid I. Mometasone-based triple combination therapy in melasma: Is it really safe?. Indian J Dermatol [serial online] 2010 [cited 2019 Jan 15];55:359-62. Available from: http://www.e-ijd.org/text.asp?2010/55/4/359/74545



   Introduction Top


Melasma is a common acquired pigmentary skin disorder characterized by a macular pigmentation of the face involving the malar area, the cheeks, upper lips, and the forehead in varying combinations. The three major patterns of pigment distribution in melasma are centrofacial (cheeks, forehead, upper lip and nose), malar (cheeks and nose), and mandibular (mandibular area of cheeks). Melasma affects females much more commonly than males and majority of patients are in the third and fourth decades of their life. [1],[2] The severity of this disease is calculated on the basis of Melasma Area and Severity Index (MASI). [3] The treatment of melasma includes agents used topically or orally to decrease melanin production, sunscreens, antioxidants, etc. Hydroquinone is the prototype depigmenting agent used in melasma that exerts its effect by inhibiting tyrosinase, the rate limiting enzyme in melanin synthesis. [4],[5] This prototype drug is combined with many agents including retinoids and topical steroids to increase its efficacy in causing a pigment dilution in melasma. [6] Topical steroids have also been used in melasma either alone [7],[8] or in combination with hydroquinone and retinoids. [5] However, the rationale of using topical steroids especially the potent ones in melasma has always been a debatable issue. This is because the withdrawal of these steroids invariably leads to a relapse and their prolonged use is invariably associated with steroid adverse effects on the facial skin. [9],[10] Kligman's formula is one of the most popular combination therapies in the management of melasma that has been in use for more than two decades. [11] This original formula employed a mild steroid, dexamethasone 0.1% in combination with 0.1% tretinoin, and 5% hydroquinone in a cream base. [11] Kligman's formula has been modified in a number of ways over the years to suit different skin types. The most recent modification in this regard that has become quite popular in India is a triple combination of mometasone 0.1%, 2% hydroquinone, and 0.025% tretinoin in a cream base. A number of brands utilizing this combination are presently available in the Indian market and they are now being rampantly used by dermatologists and even by general practitioners for the treatment of melasma. In ideal circumstances the combination treatment is supposed to be used for a maximum of 4-8 weeks after which the treatment has to be stopped or withdrawn gradually and replaced with safer modalities of melasma management. This is because of the presence of mometasone in this combination which, being a mid-potent steroid has the propensity to cause steroid side effects on the face when used for more prolonged periods. However, what has been our observation with this treatment option is that in majority of cases the patient typically lands into a relapse the moment he or she stops the triple combination treatment and this invariably forces him or her to use the treatment once again even at times against medical advice. Any further attempts at stopping the treatment regimen in future are met with a similar fate. Many of these patients thus go on to use the regimen repeatedly or persistently for months together leading to a number of adverse effects on their facial skin. An additional problem with these patients who have already used a mometasone-based triple combination treatment in the past is that they become unresponsive or even intolerant to the usual safer modes of melasma treatment in future.


   Materials and Methods Top


This study was performed on 60 patients of melasma who had used a mometasone-based triple combination treatment for a minimum period of 3 weeks anytime in the past 1 year. Any history of application of topical steroids at anytime in the past was taken as an exclusion criterion and the patients were asked about the use of all steroid and steroid-combination brands in the past. Additionally, the patients were shown all these brands available commercially in the market to be absolutely sure about the nonapplication of topical steroids in the past. Patients who had shown intolerability to the triple combination treatment and thus used the treatment for 1 day to a few days only were also excluded from the study. All patients satisfying the above mentioned criteria were given a preformed questionnaire to fill wherein they were asked about their overall experience with the use of the mometasone-based triple combination therapy in the past. The patients were asked about the total duration of its use, its overall effect on their melasma during the application period, and also the sequalae after the treatment was stopped by these patients. Lastly, the patients were instructed to give their opinion about the overall effect the triple combination therapy has had on their facial skin as well as on their melasma especially after stopping the triple combination treatment. The patients were specifically asked to rate the severity of melasma they had before the initiation of triple combination treatment vis-ΰ-vis the severity of the disease at the time of filling the questionnaire. A subjective assessment was thus made and the patients were asked whether their disease had remained the same, deteriorated, or else become better as compared to their disease before starting the treatment with this combination. Patients who felt that their disease had aggravated after using the triple combination treatment were asked to give specific reasons for feeling so. They were specifically asked to comment upon the effect of triple combination treatment on the intensity of facial pigmentation as well as the area of involvement. Another question that was included in the questionnaire was the effect of triple combination treatment on the sensitivity of facial skin to sun exposure. The patients were asked to rate the sun-sensitivity of their facial skin at the time of filling the questionnaire. They were asked to comment upon the duration of sun exposure that they felt would lead to erythema or pruritus on their facial skin without a sunscreen use. The patients were thus asked to compare their present sun-sensitivity with the one before the use of triple combination treatment.

After filling the preformed questionnaire, the patients were also assessed clinically for the presence of any steroid side-effects on their facial skin including telangiectasia, atrophy, acneiform eruption, hirsutism/hypertrichosis, etc. The clinical assessment was performed by a single, nonblinded dermatologist.


   Results Top


The age of our patients ranged from 17 years to 39 years with a mean of 24.6 years. There were 14 males and 46 females in the study group [Table 1].
Table 1 :Age distribution of patients


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The duration of melasma ranged from 1 year to 9 years with a mean of 2.1 years.

In addition to the mometasone-based triple combination therapy, the patients had used hydroquinone and/or glycolic acid preparations in the past as treatment options for their melasma.

Majority of patients (31 out of 60) had used the triple combination treatment either recurrently or persistently for more than 3 months over the previous 1 year. The most common cause behind this was the rapid initiation of relapse after any attempt at discontinuation of the triple combination treatment. All of these patients claimed that their disease used to relapse within just a day or two whenever they tried to stop their triple combination treatment. Only 9 patients out of the total of 60 (15%) had used the treatment for a period of less than 4 weeks.

The average duration of triple combination treatment in our patients was about 11 weeks raging from 3 weeks to approximately 2 years [Table 2].
Table 2 :Duration of triple combination use and the incidence of adverse effects


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Subjective assessment of the triple combination treatment by the patients revealed that about one-third of the patients (22 out of 60) perceived their disease at the time of enrollment to be worse than what they had before the use of triple combination treatment. The rest (38 patients) claimed that their disease was the same as before and no patient rated his/her disease as better than what he/she had before the initiation of triple combination treatment. The most common worsening factor was an increase in the area of skin involvement that had occurred after stoppage of the triple combination treatment. Fifteen patients also rated the intensity of pigmentation as worse than before.

Another common observation recorded by more than 60% of the patients (38 out of 60) was an increase in the sun-sensitivity of their facial skin after triple combination treatment.

The clinical assessment of the facial skin in patients at the time of enrolment revealed the presence of steroid-induced telangiectasia in 26 patients, skin atrophy in 19 patients, hypertrichosis in 17 patients, and acneiform eruption in 11 patients [Figure 1]. The assessment was performed by a single, nonblinded observer in all these patients. The incidence of adverse effects was correlated with the duration of triple combination use and it was found that the chances of having adverse effects increase steeply when the duration of use increases beyond 2 months [Table 2]. None of the patients who had used the treatment option for less than 1 month showed any evidence of a steroid adverse effect on his/her facial skin. On the other side, the incidence of steroid adverse effects approached 100% as soon as the duration extended beyond 3 months of either continuous or recurrent use.
Figure 1 :Typical changes after the use of triple combination treatment

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   Discussion Top


The most important difficulty that comes in the way of treating melasma is the potential of the disease to relapse as soon as the treatment is stopped. While strict sun avoidance along with regular use of a broad-spectrum sunscreen does prevent this relapse in some of these patients the same does not hold universally true in this disease. So, in a general sense relapse is the rule rather than the exception in melasma. In such a scenario the ideal treatment option would thus be one that is able to offer a prolonged remission and at the same time, is safe even on repeated use. Treatment options like topical steroids fail miserably on both these counts when they are used in melasma. Topical steroids especially the more potent ones do give a relief in melasma but this relief is always short-lived and as soon as the topical steroid is discontinued the disease relapses again. Furthermore, continuous or repeated use of topical steroids has the potential to cause a lot of adverse effects on the facial skin. [7],[8]

The idea behind using a triple combination treatment as originally proposed by Kligman and Willis was that the topical steroid would minimize the irritation potential of the topical retinoid as well as that of hydroquinone in addition to having its own pigment inhibiting effect. The topical retinoid is used to increase the proliferation of keratinocytes as well as increase the penetration of hydroquinone. The original Kligman's formula has been modified in many ways over the last two decades to suit different skin types. One of these modified variants that has been tested extensively for its efficacy and safety employs a triple combination of 4% hydroquinone, 0.05% tretinoin, and 0.01% flucinolone acetonide. [12],[13] For the Indian skin which is mostly of Type 4 -6 Fitzpatrick skin type, the strength of hydroquinone was reduced to 2% and even the strength of topical tretinoin was reduced to 0.025%. However, what needs to be noted is that the topical steroid used in the original Kligman's formula as well as in most of these modifications has always been a mild one. What has happened over the last few years is that hydrocortisone that was employed in the original Indian combination treatments has been replaced by mometasone, a mid-potent topical steroid. These mometasone-based triple combinations have become really popular and their use has multiplied manifold over the last few years. The overall safety of these combinations has unfortunately never been studied in well designed clinical trials. What complicates the situation further is that these combinations are most often used for prolonged periods either by the patients themselves or from prescriptions by the treating physicians. The recommendation that the combination be stopped after about 4-8 weeks is followed rarely at all by the patients. Why this happens in most cases is that the patient lands into a relapse the moment he/she stops using the triple combination therapy and this invariably leads him/her to either continue the treatment of his/her either with or against medical advice. When these patients seek medical advice after months of continuous use of a mometasone-based triple combination treatment, their disease is almost invariably complicated by skin atrophy, telangiectasia, and other steroid adverse effects. The facial skin in these patients also shows an extreme sensitivity to sun exposure, probably because of the skin atrophy associated with the prolonged use of the steroid in the triple combination treatment. Typically these patients also complain that the area of involvement of melasma has also increased with prolonged or recurrent use of the triple combination treatment. This can also be explained on the basis of the variable degree of skin atrophy associated with the prolonged use of the triple combination treatment. This skin atrophy usually does not remain localized to the area of application of the steroid and extends to some extent beyond it as well leading to the involvement of this atrophied skin by the original disease. The facial skin in these patients also becomes intolerant to commonly used drugs for melasma. We have come across patients who had been using this triple combination treatment for more than a year continuously or repeatedly and the management of the disease in such patients becomes a real challenge.


   Conclusion Top


What this retrospective study has shown us is that a mometasone-based triple combination treatment should be prescribed after a thorough discussion with the patient regarding its potential to cause adverse effects on a prolonged use. The combination should be used with caution in those patients who are unlikely to come for regular follow-ups. And if the combination has already been used once and the patient presents with a relapse, the combination should be withheld and safer modes of melasma treatment should be employed.

 
   References Top

1.Sanchez NP, Pathak MA, Sato S, Fitzpatrick TB, Sanchez JL, Mihm MC Jr. Melasma: A clinical, light microscopic, ultrastructural and immunofluorescence study. J AM Acad Dermatol 1981;4:698-710.  Back to cited text no. 1
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2.Grimes PE. Melasma, Etiologic and therapeutic considerations. Arch Dermatol 1995;131:1453-7.  Back to cited text no. 2
[PUBMED]  [FULLTEXT]  
3.Kimbrough-Green CK, Griffiths CE, Finkel LJ, Hamilton TA, Bulengo-Ransby SM, Ellis CN, et al. Topical retinoic acid (tretinoin) for melasma in black patients. A vehicle-controlled clinical trial. Arch Dermatol 1994;130:727-33.  Back to cited text no. 3
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4.Amer M, Metwalli M. Topical hydroquinone in the treatment of some hyperpigmentary disorders. Int J Dermatol 1998;37:449-50.   Back to cited text no. 4
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5.Haddad AL, Matos LF, Brunstein F, Ferreira LM, Silva A, Costa D Jr. A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. Int J Dermatol 2003;42:153-6.   Back to cited text no. 5
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6.Taylor SC, Torok H, Jones T, Lowe N, Rich P, Tschen E, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis 2003;72:67-72.  Back to cited text no. 6
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7.Neering H. Treatment of melasma (chloasma) by local application of a steroid cream. Dermatologica 1975;151:349-53.  Back to cited text no. 7
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8.Kanwar AJ, Dhar S, Kaur S. Treatment of melasma with potent topical corticosteroids. Dermatology 1994;188:170.  Back to cited text no. 8
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9.Arndt KA, Bowers KE. Manual of dermatologic therapeutics. 6th ed. Philadelphia, Pa: Lippincott Williams & Wilkins; 2002.   Back to cited text no. 9
    
10.Goa KL. Clinical pharmacology and pharmacokinetic properties of topically applied corticosteroids. A review. Drugs 1988;36:51-61.   Back to cited text no. 10
    
11.Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 1975;111:40-8.  Back to cited text no. 11
    
12.Torok HM. A comprehensive review of the long-term and ­short-term treatment of melasma with a triple combination cream. Am J Clin Dermatol 2006;7:223-30.  Back to cited text no. 12
    
13.Torok H, Taylor S, Baumann L, Jones T, Wieder J, Lowe N, et al. A large 12-month extension study of an 8-week trial to evaluate the safety and efficacy of triple combination (TC) cream in melasma patients previously treated with TC cream or one of its dyads. J Drugs Dermatol 2005;4:592-7.  Back to cited text no. 13
    


    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2]

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