The efficacy and safety of low‐dose diclofenac sodium 0.1% gel for the symptomatic relief of pain and erythema associated with superficial natural sunburn

ARTICLE

Auteur(s) : John MAGNETTE¹, Jean-Luc KIENZLER¹, Ioulia ALEKXANDROVA¹, Elly SAVALUNY¹, Abdallah KHEMIS², Saïd AMAL³, Mohamed TRABELSI³, Jean-Pierre CÉSARINI⁴

¹ Novartis Consumer Health SA, Nyon, Switzerland
² Hôpital L’Archet 2, Nice France
³ Hôpital Ell Razi, Marrakech, Morocco
⁴ INSERM Foundation A de Rothschild, 25 rue Manin, Paris, France

Article accepted on 17/04/2004

Sunburn is an inflammatory response to acute cutaneous solar damage, ranging in severity from mild painless erythema to painful erythematous skin associated with blistering and oedema. The pain associated with sunburn is a complex sensation and is felt as a burning and tightness of the skin. The initial response of the skin to ultra-violet (UV) irradiation is vasodilatation of the cutaneous blood vessels resulting in erythema. The time course for the development of erythema is biphasic with an initial immediate response often observed during exposure and delayed onset erythema, which begins 3-5 hours after exposure and increases in intensity between 12 and 24 hours [1, 2]. The histological changes during the delayed phase of UV-induced erythema are wavelength dependent, with longer wavelengths resulting in more pronounced dermal injury and shorter wavelengths resulting in both epidermal and dermal injury [3, 4]. The degree of erythema increases proportionally with total UV exposure (i.e. the dose) and is mediated, at least in part, by the release of prostaglandins, nitric oxide and vascular permeability factor [3]. Associated with vasodilatation is increased tissue permeability, which, in turn, promotes the influx of fluids and neutrophils into the dermis and the induction of pro-inflammatory cytokines [3, 5-7]. Peak infiltration of leucocytes occurs within 4-6 hours after irradiation, gradually increasing in number until 48 hours post-exposure [4]. Damage to the epidermal cells (keratinocytes) is evident as early as 2 hours after exposure and appears shortly before oedema [4]. Ultra-violet-induced apoptosis of damaged keratinocytes as well as epidermal Langerhans cells is maximal between 48-72 hours after exposure [4].
Prostaglandins and leukotrienes are potent mediators of the UV-B induced inflammation, generated by cyclo-oxygenase isozymes and 5-lipoxygenase, respectively from arachidonic acid. In addition, oxygen-derived free radicals are also liberated leading to the formation of isoprostanes by free radical catalysed peroxidation of arachidonic acid. Together these metabolites orchestrate the inflammatory response through a complex interaction with immune cells and other inflammatory mediators (e.g. cytokines such as tumour necrosis factor alpha and mast-cell-derived mediators such as histamine and substance P) in the surrounding microenvironment. In addition to the erythema response, prostaglandins (mainly PGE) mediate other UV-induced changes – suppressing contact sensitisation, increasing plasma exudation and regulating epidermal keratinocyte proliferation; while leukotrienes act as potent chemotactic agents, playing an important role in the influx of inflammatory cells.
The primary activity of non-steroidal anti-inflammatory drugs (NSAIDs) in first-degree sunburn can be explained by their localised effects within the epidermis as cyclo-oxygenase inhibitors, inhibiting the classical inflammatory cascade mediated by prostaglandins, which are implicated in sunburn within the first 24 hours [8-11]. A number of studies have reported the value of NSAIDs in the dose-dependent delay and reduction of erythema associated with sunburn, when applied topically or orally [9, 12-19]. In addition, a number of the newer generation coxibs (selective inhibitors of cyclooxygenase-2), and leukotriene modifiers have been recently evaluated in UVB-induced inflammatory models and shown to reduce erythema and oedema [20-22]. Moreover, a recent trial evaluating oral aspirin in combination with non-sedative histamine H1-receptor antagonist, mizolastine was also shown to be effective in suppressing the development of UVA/UVB-induced erythema in healthy volunteers [23].
Ibuprofen, which blocks COX-1 and COX-2, additionally shows an effect at a cellular level, reducing the number of apoptotic keratinocytes within the epidermis [19] and diminished heat and mechanical skin hypersensitivity induced by UVB [24, 25].
The antinociceptive effects of NSAIDs are well recognized because prostaglandins elicit a hyperalgesic response, or increased sensitivity, to touch by sensitizing the free end of pain neurons in peripheral inflammation. However, while these treatments have the theoretical potential to reduce the pain caused by the sunburn reaction, none have been shown to have an impact on pain in a clinical setting since almost all studies initiated therapy immediately before or after UVB exposure and focused only on erythema [12]. Hence, new more clinically meaningful evaluations are needed to assess the effectiveness of NSAIDs for the treatment (rather than prevention) of pain caused by sunburn at the onset of symptoms.
There is little evidence in the literature to support the use of systemic treatments (either antihistamines or corticosteriods) for the management of localised symptoms of mild sunburn [12]. The potential adverse effects with these agents, especially if given orally, are an important consideration for a self-limiting condition of mild first-degree sunburn and so provide a further rationale for evaluating the localised effects of topically applied NSAIDs. Currently, the management of mild sunburn (i.e. without blistering and involving less than 15-20% body surface of an adult) is generally self-treatment within the first 24 hours with oral fluids, the application of soothing topical emollient creams or evaporating lotions and, more actively, the use of oral NSAIDs (occasionally steroids) from the earliest onset of symptoms [26].
Diclofenac-Na 0.1% gel¹¹, a new low-dose formulation of diclofenac sodium is under investigation for short-term, intermittent non-prescription use for the management of superficial (first-degree) sunburn. Diclofenac is a potent anti-inflammatory compound, having dual inhibitory effect on both cyclo-oxygenase (with a preference to COX-2) and lipoxygenase pathways, which are involved in UVB-induced skin inflammation [27].Diclofenac-sodium 3% in 2.5% hyaluronic acid (HA) gel² has been found to be an effective topical treatment for actinic keratoses, a common and potentially pre-cancerous or intraepidermal form of squamous cell carcinoma, associated with chronic sun exposure [28]. Dose-finding studies were conducted to determine the minimal effective concentration of diclofenac gel and the optimal dose-regimen for the treatment of UV-induced pain/burning and erythema, using an indoor sunburn model in healthy Caucasians with skin phototypes II and III. The results of these preliminary studies give an indication that diclofenac-Na 0.1% gel is efficacious in symptom relief of superficial sunburn. Application of the product on large sunburned areas was associated with very low systemic absorption equivalent to less than 7% of the oral bioavailability of an equivalent oral dose given three times a day. First-degree sunburn did not increase the skin penetration of diclofenac [29].
This paper presents the results from a phase III, randomised, double-blind, parallel-group, vehicle-controlled clinical trial which was conducted to assess the efficacy, tolerability and acceptability of diclofenac-Na 0.1% gel in reducing the pain intensity and erythema associated with first-degree natural sunburn.

¹ Diclofenac sodium Emulgel^TM 1 mg/g (0.1%) (Novartis Consumer Health SA)
² Diclofenac sodium 3% w/w (Solaraze^TM; Bioglan)

Materials and methods

Subjects

During the months of June and July 2002, 172 subjects were enrolled from four centres in France and randomised in a ratio of 2:1 to receive either diclofenac-Na 0.1% gel or vehicle Emulgel^TM The subjects were drawn from a target population of healthy volunteers and well outdoor sunbathers between 18 and 55 years old with skin phototype II-IV (according to the Fitzpatrick classification) [30]. Subjects were required to have a normal tolerance to UV radiation and sun and previously untanned areas on the back, shoulders, and posterior area of the thighs. Subjects with known hypersensitivity to NSAIDs or who were receiving any medication in the week preceding the trial were excluded. Subjects prone to photodermatoses or who were immunosuppressed as well as those who had any evidence of a history of chronic illness or any condition, which might limit compliance were also excluded.

Study design

Subjects were screened in France and those who met all inclusion and none of the exclusion criteria were enrolled in the trial. The trial was conducted in Morocco. Subjects were exposed to the sun in order to induce first-degree sunburn on the back and posterior area of both thighs.
UV-induced erythema is one of the validated models to assess anti-inflammatory properties of a topical drug [31] with tests generally performed with minimal erythema doses (MED) [31]. In the present trial, the duration of sun exposure to induce first-degree sunburn was carefully monitored according to each subject’s skin sensitivity to sun (based on MED) so that subjects received 2.8 times their MED. The MED for each subject was established during a previous solar exposure to increasing doses of natural sunlight ranging from 0.7 to 2.8 standard MED (sMED) for skin phototype II; from 1.0 to 4.0 sMED for skin phototype III and from 1.4 to 5.6 sMED for skin phototype IV. The UV index during June in Morocco was expected to be between 8 and 12, which corresponds to 3 to 4.5 sMED per hour. A standard MED dose is equal to 2 Standard Erythemal Dose (SED) defined as 20 millijoules/cm² erythemally weighted at 297 nm, according to the human skin erythema action spectrum of the CIE/ISO norm.
Subjects were settled on comfortable beds, lying flat on their fronts, wearing hats and sunglasses, and non-exposed areas carefully protected by either a thick layer of sunscreen or by non- or poor UVB permeable clothes. Subjects were given refreshments and were kept cool with water on the lower legs, nape, and head.
MED values were then determined 24 hours (± 1 hour) after sun exposure using the 5-point visual erythema score. The MED was determined as the smallest dose of energy that produced a perceptible erythema reaching the borders of the exposure site at 24 hours, and the corresponding 2.8 MED was calculated. Pain intensity associated with a large area exposed to 2.8 MED was expected to be comparable to a 5 MED in small areas of skin, which was applied in previous indoor trials. This dose was chosen to induce pain of moderate intensity without significant skin oedema and to avoid significant systemic effects linked to sunburn.
The trial was conducted in Morocco because during June and July the peak UV Index is high (10-12) and the day-to-day variability in UV flow is low. To ensure comparable sunlight exposure, subjects were exposed to natural sun at the same time of day (between 10 am and 2 pm, solar time) using the same UV dosimeters as for the initial determination of MED and the exposure to 2.8 MED. The UV probe (PMA 2100 equipped with UVB outdoor detector PMA 2102; Solar Light Company Inc, Philadelphia, PA) and back-up dosimeter (Robertson-Berger model 5D, Solar light Company Inc, Philadelphia, PA) were positioned about 10 meters from the nearest subject exposed to the sun and as far away as possible from shadow and trees. The air temperature was also monitored in the field.
Previous studies of the evolution of symptoms after UV-irradiation and of the optimal dose-regimen, showed that at 6 hours after irradiation a majority of subjects exhibited a moderate pain and that two applications at 6 hours and 10 hours after irradiation is an optimal dose-regimen. Therefore, in the present study, the trial medication, either diclofenac-Na 0.1% Emulgel^TM gel or the corresponding vehicle Emulgel^TM gel was applied twice during the trial at 6 hours and 10 hours after the end of sun exposure. A 5 mg/cm² dose was applied by a trial nurse to the back and posterior area of both thighs, representing a surface of about 15% of the body surface, and then gently massaged into the skin to ensure appropriate product absorption. Hence for an average subject weighing 70 kg, the individual dose corresponded to 12.5 g Emulgel^TM (or 12.5 mg of diclofenac for active formulation), which was applied to 2400 cm² of the body surface.
No systemic or topical medication was allowed during the trial except in cases of excessive pain and the presence of severe systemic effects of sunburn when subjects were treated according to common medical practice and given paracetamol, ibuprofen or topical steroids and/or fluid infusions, as appropriate.
The study protocol was approved by the institutional review board and independent ethics committee of Saint-Louis Hospital, Paris. The study was conducted in compliance with the protocol, principles of Good Clinical Practice and Declaration of Helsinki.

Clinical evaluation

The primary endpoint was spontaneous pain intensity assessed by a Visual Analogue Scale (0-100 mm VAS, 0 as no pain and 100 as maximum pain) over 48 hours (from 7 hours to 54 hours after UV exposure). In addition, pain provoked by a standardised tactile stimulus (Monofilament West^TM hand, Connecticut Bioinstruments, Riverdale, NY, USA) producing horizontal friction movements was also assessed by VAS over the same time period. Overall pain relief was assessed using a 5-point oridinal scale and total pain relief calculated as the sum of the pain relief scores over 48 hours. Five-point scale visual score as well as colorimetric readings using the parameter a* (redness) and L* (luminance) performed with a Minolta Chromameter CR 300 (Minolta Corporation) were used to determine erythema intensity. The evolution in erythema from 7 to 54 hours after UV exposure was expressed as a change in visual scores and skin chromametry measures relative to baseline values (taken at 6 hours after UV exposure) and to untreated skin. The onset of pain relief and erythema reduction was also recorded at the first-time point when subjects reported some relief relative to baseline values. All topical and systemic adverse events were recorded throughout the trial as well as any changes in skin appearance (flaking, cracking, miliaria, blistering, peeling and bleeding) or skin tightness over 72 hours. Subjects assessed overall efficacy and safety of diclofenac-Na 0.1% gel and vehicle Emulgel^TM using a 5-point scale at the end of trial (72 hours after the initial dose). The acceptability of the trial medication on the sunburnt areas was assessed immediately after each application at 6 and 10 hours based on the cooling effects (as determined by subjects) and the ease of application (as determined by the nurse). Finally, the percentage of subjects who used rescue medication was also recorded.

Data analysis and statistical methods

Both a full analysis of all subjects who were randomised and administered medication and a per protocol analysis of the population were undertaken. Changes in safety and efficacy endpoints were defined relative to baseline measurements taken at 6 hours after UV exposure and before the first application of study medication. The area under the curves (AUCs) for spontaneous pain intensity (the primary efficacy variable), provoked pain and erythema parameters were calculated from 7 to 54 hours after UV exposure using the trapezoidal rule. The AUC was compared between the two treatment groups using an analysis of covariance (ANCOVA). The model included the terms: treatment, sex, and skin phototype (as factors), and age and baseline measurement as covariates. The AUC and baseline measurements were log-transformed. The odds ratio for pain relief and its 95% confidence interval were calculated one hour and 24 hours after the first treatment from a proportional odds model. The incidence of all treatment emergent adverse events was calculated and presented by treatment group and by body system using the Medical Dictionary for Regulatory Activities (MedDRA) preferred term. Adverse events were summarized by severity and relationship to trial medication. Safety data were analysed descriptively. In the following the full analysis set (intent-to-treat) results are shown.

Results

A total of 172 Caucasian subjects (71 males and 101 females, mean age 32.2 years) were randomised to receive either diclofenac-Na 0.1% gel (114 subjects) or vehicle Emulgel^TM (58 subjects). Treatment groups were comparable at baseline regarding demographic and baseline efficacy variables (Table I), and no differences between the treated and control sunburnt areas were recorded. Skin phototype distribution was representative of the native French population [33], with the majority of subjects (58%) with skin phototype III. A couple of randomized subjects had chromametry assessments in favour of skin phototype I, even if they were ranked as skin phototype II or III using the Fitzepatrick classification. The calculated 2.8 MED resulted in a similar level of pain and erythema in each group, resulting in moderate or strong erythema in the majority of subjects at baseline (Table I). Except for very sensitive subjects, no increase in body temperature was recorded. Hence, in the majority of subjects the 2.8 MED of sun exposure did not lead to systemic effects. The mean total dose of applied product was 10.87 ± 0.61 g (range: 8.7-12.1 g) for each application, applied at 6 and 10 hours after sun exposure.

Table I. Demographics at screening and at baseline (6 hours after sun exposure) in an intent-to-treat population

One hundred and one (88.6%) subjects in the diclofenac-Na 0.1% gel group and 52 (89.7%) subjects in the vehicle Emulgel^TM group completed the trial. There were no withdrawals or discontinuations due to adverse events or lack of efficacy. The main reason for the discontinuation in both treatment groups was administrative problems (conflicts in travel schedule) and had no impact on the primary criterion assessment. Two subjects on vehicle were discontinued as a result of major protocol violations (the application of sunscreen on tested areas).
Four (3.5%) subjects in the diclofenac-Na 0.1% gel group and two (3.4%) subjects in the vehicle Emulgel^TM group had major protocol violations. These were concomitant medication violations and use of sunscreen, which could interfere with the assessments. Four of these subjects were excluded from the per protocol analysis population entirely, while the data for two subjects were excluded at certain time points.

Efficacy

Spontaneous pain

As a result of sun exposure to 2.8 MED, a moderate to strong erythema was induced in all compliant subjects without local (oedema) or systemic complications. A significant level of spontaneous pain was recorded with a mean VAS at 6 hours of 25.0 ± 23.7 mm in the diclofenac-Na 0.1% gel group and 23.4 ± 23.8 mm in vehicle Emulgel^TM group. However, as expected, there was a high level of inter-subject variability in the level of spontaneous pain reported with 59 (34%) subjects reporting spontaneous pain of 30 mm or more and 28 (16%) of the trial population reporting no spontaneous pain at 6 hours; although some of these patients reported pain at a later time point. The time course for the change in mean spontaneous pain intensity (as measured by a visual analogue scale) is presented in Fig. 1. Spontaneous pain intensity in the diclofenac-Na 0.1% gel group decreased rapidly from the time of the first application at 6 hours up to 11 hours and stayed low until 30 hours, before increasing again at 42 hours post sun exposure. Spontaneous pain intensity also decreased in the vehicle Emulgel^TM group, but not to the extent observed in the diclofenac-Na 0.1% gel group. The maximum effect with active treatment was observed at 18 hours post sun exposure (or 8 hours after the second application), with a difference of 10 mm in VAS between the treatment groups. Comparing the AUC for spontaneous pain intensity between the two treatments from 7 to 54 hours confirmed a statistically significant lower spontaneous pain intensity of -312.6 mm.h in favour of diclofenac-Na 0.1% gel (p = 0.0003) (Table II).

Provoked pain

A similar time course for the resolution of provoked pain was observed, with a difference between subjects in each study group of 10.7 mm at 18 hours; and a maximum difference of 11.7 mm at 24 hours. Once again, comparing the AUC from 7 to 54 hours between the two groups confirmed a statistically significant lower provoked pain intensity in the group who received diclofenac-Na 0.1% gel (Table II).

Erythema

The time course of erythema (as measured by visual scores and colorimetry) showed a rapid reduction within the first 3 hours after the first application of diclofenac-Na 0.1% gel with a maximum effect within the first 18 hours after UV exposure, and then a plateau or a slight increase in erythema intensity (with the gradual wearing off of the treatment effect between 18 and 24 hours) (Fig. 2). However, 30 hours after sun exposure, comparison of the visual scores for erythema between the two treatment groups showed that there remained a statistically significant difference in favour of diclofenac-Na 0.1% gel. The adjusted odds ratio for treatment effect was 4.05 (95% CI: 2.08 to 7.90, p < 0.0001) from a proportional odds model.
The adjusted treatment effect of the AUC for visual scores for erythema from 7 to 54 hours was -21.09, (95% CI: 29.6 to 12.56, P < 0001) indicating a statistically significant difference in favour of diclofenac-Na 0.1% gel (Table II). The colorimetric results supported these findings with a greater reduction in both redness and brightness, as measured by adjusted a^* and L^* variables, respectively (Table II).

Onset of pain relief and erythema

The results from onset of pain relief (defined as the first time point when subjects reported some relief relative to baseline values) and total pain relief also indicated that diclofenac-Na 0.1% gel had superior pain relieving properties compared with vehicle. The pain relief commenced 1 hour after the first application of trial medication, with a higher proportion of subjects reporting no pain relief’ in the vehicle Emulgel^TM group (60%) than in the diclofenac-Na 0.1% gel group (45%) (Fig. 3). This difference approached statistical significance with an adjusted odds ratio of 0.55 (95% CI 0.30 to 1.02, p-value of 0.057 from the proportional odds model). Two hours later, and prior to the second application of study medication, the majority of the subjects (60.5%) on active treatment reported at least some pain relief and a clearly apparent difference in pain intensity of 7.5 mm between the subjects in each treatment arm was evident (Fig. 1). This result was confirmed when the majority of the subjects reported at least some pain relief’ (defined as onset of pain relief) at 9 hours in the diclofenac-Na 0.1% gel group, compared with 12 hours for the vehicle Emulgel^TM group. There was also a statistically significant difference in the distribution of pain relief between the two treatment groups 20 hours after the second Emulgel application (H30), with a higher proportion of subjects with “complete pain relief” in the Diclofenac-Na Emulgel^TM 1 mg/g (0.1%) gel group (40%) than in the vehicle Emulgel^TM group (23%). The adjusted odds ratio for treatment effect for H30 was 0.55, (95% CI: 0.31 to 0.98, p-value 0.0426 from a proportional odds model).
Evaluating the pain scores over 48 hours, total pain relief was shown to be statistically significantly better in the diclofenac-Na 0.1% gel group. The adjusted treatment effect was 22.43, (95% CI: 3.35 to 41.50; p = 0.0215 from an ANCOVA model).
A similar pattern was observed with the onset of erythema reduction, which was recorded within less than 3 hours (median 2.94 hours) in the active treatment group compared with 17.95 hours in the subjects on vehicle (p < 0.0001, log-rank test).

Treatment acceptability, safety and tolerability

Overall, more than half the subjects (55.3%) considered that the efficacy of diclofenac-Na 0.1% gel was ‘excellent’ or ‘good’ compared with only 32.8% in the Emulgel^TM vehicle group. Notably, nearly a quarter of subjects considered that the efficacy of the vehicle was poor’ compared with approximately 10% of subjects on active treatment; this difference was statically significant (p = 0.0014). The safety of the trial products was also perceived to be ‘excellent’, ‘very good’ or ‘good’ in 98% of subjects on diclofenac-Na 0.1% gel group and in 87.9% of subjects on the vehicle.
Before the first application of trial medication, 7 (6.1%) subjects in the diclofenac-Na 0.1% gel group and 5 (8.6%) subjects in the vehicle group used rescue medication compared with 2 (1.8%) subjects in the diclofenac-Na 0.1% gel group and 5 (8.6%) subjects in the vehicle group prior to the second application of trial medication.

Localised effects on the skin

In both groups, the cooling effect was considered to be ‘good’, ‘very good’ or ‘excellent’ by majority of subjects (85.1%) after the first and second application of diclofenac-Na 0.1% gel, and by 87.9% and 91.4% respectively after the first and second application of the vehicle. Skin tightness was reported by nearly half of subjects 6 hours after sun exposure (in 42.1% and 50.0% of subjects in the active and vehicle control groups, respectively) decreasing to 15.8% in the diclofenac-Na 0.1% gel group and 36.2% in the vehicle Emulgel^TM group at 10 hours. Flaking, cracking, blistering, peeling and bleeding was reported by one person in each group and miliaria was equally reported by 3.5% of subjects in each group. A burning sensation was reported in five (4.4%) subjects immediately after the first application of diclofenac-Na 0.1% gel and by one subject after vehicle.

Safety and tolerability

Reported treatment-emergent adverse effects were infrequent, generally mild and none were considered to be related to the trial medication. A similar reporting incidence was recorded in both groups (17.5% diclofenac-Na 0.1% gel and 19.0% with the vehicle Emulgel^TM) (Table III). Notably, headache was reported immediately after sun exposure in six out of the seven subjects. There was one incidence of a severe treatment emergent side effect in the diclofenac-Na 0.1% gel group (abdominal pain) and another in the vehicle Emulgel^TM group (burning sensation). No subjects were withdrawn from the trial due to adverse events.

Table III. Number (%) of subjects with treatment-emergent adverse events (TEAE)

Discussion

From the results of this study, it can be concluded that diclofenac-Na 0.1% gel is effective in reducing pain and redness after sunburn under natural outdoor conditions in a target population of healthy sunbathers with skin phototype II-IV who develop acute first-degree sunburn (i.e. a common sunburn, without blistering and a sunburned area not exceeding 15% of the body surface area). In this study, the first of two topical applications of diclofenac-Na 0.1% Emulgel^TM was applied 6 hours after the end of sun exposure rather than immediately after sun exposure, which would have been appropriate to demonstrate prevention of pain. This is consistent with the observations from our previous studies of the natural evolution of pain and erythema, which have shown that while erythema develops within 1-2 hours after sun bathing, the pain associated with sunburn does not develop until 5-8 hours later. Approximately 50% of maximum pain intensity associated with superficial sunburn is observed around 6 hours with a peak intensity of pain observed between 12 to 16 hours after exposure. As the principle aim of the trial was to measure the effectiveness of topical treatment for the management of pain and discomfort, active treatment was applied at 6 hours after irradiation when 50% of the maximum of pain was observed in order to maximise the treatment effect. Furthermore, application of the first dose 6 hours after sun exposure is much more in keeping with the real situation for most sunbathers who only appreciate the extent of the sunburn after the delayed erythema begins to develop a few hours after sun exposure and moderate pain presents. In order to avoid sun overexposure, sunbathers would be well advised to heed the initial warning signs of pain and it would be inappropriate to develop a treatment which prevents this initial warning signal.
Diclofenac-Na 0.1% gel showed consistent superiority compared with vehicle Emulgel^TM, up to 30 hours after application, with a difference approaching statistical significance in the reporting of pain relief just one hour after the first application. Two hours later, and prior to the second application of study medication, a clearly apparent difference in pain intensity of about 7.5 mm was evident between the subjects in the diclofenac-Na 0.1% gel and the vehicle group. Diclofenac-Na 0.1% gel was also efficacious in reducing erythema and other sunburn symptoms. The time course of erythema (as measured by visual score and colorimetry) after diclofenac-Na 0.1% gel was similar to the observed previous Phase II trials, with a rapid reduction within a few hours after the first application of trial medication, a maximum effect within 24 hours, and then a plateau or still an increase in erythema intensity. In a recent paper, Benrath, Gillardon and Zimmerman (2001) [34] observed the same two-peak profile based on skin blood flow. The first peak was observed 9 to 12 hours after UV exposure (linked to the release of prostaglandins, returning to baseline at 24-48 hours after UV exposure) and the second one at 36 hours, probably linked to the release of neuropeptides (where NSAIDs are not effective). Based on these findings, further applications of diclofenac would not be expected to significantly increase the pain relief and the erythema reduction. From a clinical point of view, the critical period for sunburn is the first 24 hours, where the pain is at its maximum (i.e. during the night following sun exposure). Any secondary increase of pain remained low with active treatment in this study at time points beyond 30 hours (12.1 ± 16.7 mm and 11.9 ± 18.6 mm at 42 and 54 hours after sun exposure, respectively). In addition, the results achieved with diclofenac-Na 0.1% gel in this study on the skin areas selected for treatment (back and thighs) would be expected to be achieved also on other skin areas, like the shoulders, as the efficacy of sunburn treatment is independent of specific location.
The results from this study demonstrate that the effectiveness of diclofenac-Na 0.1% gel is comparable, if not superior to other medicinal sunburn treatments such as topical corticosteroids [34], topical antihistamines [35], local anaesthetics [36] for the symptomatic relief of pain and redness. Diclofenac-Na 0.1% gel represents a rational treatment for sunburn compared with antihistamines/anaesthetics, which have proved to be largely ineffective for the management of superficial first-degree sunburn [12].
In addition to the anti-inflammatory effects of the active moiety, formulation-related properties (of the emulsion of lipids in hydro-alcoholic base) were also associated with a soothing, moisturizing and cooling effect, all which of add to the acceptability of this formulation for the topical treatment for common sunburn. The vehicle had a higher effect on pain reduction than was observed in previous indoor trials, where the spontaneous pain remained on a plateau after application of vehicle. In this trial, however, the effect on pain reduction particularly after the second application of the Emulgel^TM vehicle was clearly visible. This effect is partly due to the evaporating moiety leading to an equally effective cooling effect that was observed with both the active and vehicle Emulgel^TM formulations. Furthermore, the application of the Emulgel^TM also seemed to reduce the levels of skin tightness, although this effect was more frequently reported in the active treatment group.
A recognised limitation of the study was the relatively narrow evaluation of pain, which is a complex sensation with several manifestations [37], invariably described as prickling, burning, stinging and itching. However, of all the clinical and physical signs of sunburn, only pain and erythema have been evaluated using validated assessments. The assessment of pain in this study was limited to evaluation of spontaneous pain intensity and evoked pain (and the associated hyperalgesic response) as evaluated using Visual Analogue Scale [38] from 7 hours to 54 hours after UV exposure. Supporting this line of investigation are a number of recent publications [39-42] which describe the symptoms of localised inflammation after exposure to 2 or 3 MED as mainly characterised by hyperalgesia and allodynia, and which begin within a few hours of irradiation and peak about 24 hours later [43]. Indeed, our study confirmed that the maximum benefit with topical diclofenac in reducing time course for the resolution of provoked pain was between 18 and 24 hours after sun exposure. Comparing the AUC from 7 to 54 hours between the two groups confirmed the diclofenac-Na 0.1% gel was effective in lowering provoked pain intensity compared with the control. This type of hyperalgesia is observed in a variety of inflammatory conditions [44] and is thought to arise from the sensitization of the nociceptive sensory neurons innervating inflamed tissue and it may have a contribution from altered spinal processing of sensory information [45]. While the peripheral mediators of hyperalgesia are not well-characterised, it is thought that prostaglandins [46], leukotrienes, bradykinin, and nerve growth factor can produce some form of sensory neuron sensitisation [47]. A number of recently published papers have described the effectiveness of diclofenac [48], ibuprofen [49] COX-2 inhibitors [50] and bradykinin antagonists [51] in alleviating hyperalgesia through both central and peripheral mechanisms; although the side effects associated with the oral administration of these drugs tends to limit their application for this self-limiting condition.
Overall, the trial population who received diclofenac-Na 0.1% gel considered that the treatment was efficacious and safe. By contrast, nearly a quarter of subjects considered that the efficacy of the vehicle was poor’. From a practical point of view, both Emulgel^TM formulations were rated as easy to apply by the trial nurse. It is evident that sunbathers can easily comply with the recommended dose regimen, with a first application at onset of pain symptoms in the early evening (generally 6 hours after end of sun exposure) and, if needed, a further application 3 to 4 hours later, perhaps at bed-time for the management of natural superficial sunburn.

Conclusion

While there is no treatment that can reverse the acute inflammatory response caused by over-exposure to the sun, the topical application of diclofenac is nevertheless an appropriate and effective treatment for managing the discomfort and hyperalgesia associated with mild superficial sunburn. This pivotal efficacy study provides robust confirmation that diclofenac-Na 0.1% Emulgel^TM gel, administered as two applications over the same day, is effective and safe for the rapid relief of the symptoms of pain and redness associated with first-degree sunburn. n

Acknowledgements. The authors wish to thank Michel Jeanmougin, MD, for his constructive feedback and comments during the preparation of the protocol. The authors would also like to acknowledge the following investigators for their help and support on this trial: Catherine Queille-Roussel and Michèle Donteville from the Centre de Pharmacologie Clinique Appliquée à la Dermatologie Hôpital (CPCAD), Nice, France; Eric Royer from the Therapharm recherches, Caen, France; Brigitte Bisbal and François-Jean Michel from the Institut d’Expertise Clinique (IEC), Lyon, France. Finally, we would like to acknowledge especially the collaborative efforts between Philippe Césarini and Béatrice Jean, who were responsible for field UV-monitoring and colorimetric computerised data.

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