Clinical Evaluation of High and Low-Level Laser Treatment (CO2vsInGaAlP Diode Laser) for Recurrent Aphthous Stomatitis.

STATEMENT OF THE PROBLEM: Recurrent aphthous stomatitis (RAS) is one of the most common lesions in the oral cavity. Due to its multifactorial nature, there is no definitive treatment for RAS. Laser therapy is one of the suggested treatments to reduce patient's discomfort.
PURPOSE: The purpose of the present clinical trial is to assess the effect of low and high level laser therapy on pain control and wound healing of RAS. MATERIALS AND
METHOD: Thirty six patients with minor RAS were divided into three groups. Group 1 (n=14) received CO2 laser, group 2 (n=12) were treated with InGaAlP Diode laser and group 3 (n=10) received sham laser as placebo. All patients were evaluated daily up to 15 days after receiving one session of laser therapy. Pain severity before and after treatment, wound healing, patient's satisfaction, and functional disturbance before and after treatment were recorded for each patient.
RESULTS: According to statistical analysis, pain reduction after treatment in group 1 was 7.00±2.41, in group 2 was 2.08±2.31, and in group 3 was 1.40±1.77. In addition, a significant difference was observed in the reduction of functional complications in CO2 laser treated patients compared to the other two groups.
CONCLUSION: High-level laser treatment showed analgesic effects on RAS, but no healing was observed. Low-level laser therapy demonstrated no positive effect on recurrent aphthous ulcers.

RCT Entities:   Population Interventions Outcomes

Introduction

Recurrent aphthous stomatitis (RAS) is a common disorder of the oral cavity which affects 5-66% of adult patients and 20% of the general population. [1-2] The prevalence is higher among children and female patients.[3] The starting age seems to be between 10 to 19 years[4] and decreases in severity and frequency with aging.[5] Clinically, RAS is characterized by one or several recurrent painful ulcerations of the oral mucosa.[6] The lesion is a round or oval shallow ulcer with circumscribed erythematous margin and a yellow or gray base.[7] RAS has three different types: minor, major and herpetiform.[8] Even though a definitive etiologic factor(s) is not well understood for RAS, predisposing factors, such as age, gender, local conditions, systemic disorders, immunologic factors, psychological stress, medications, genetic, and microbial conditions are suggested to be involved.[9-12] Since the etiology is unknown, an approved curative therapy for RAS is lacking. Treatments are mostly nonspecific and often of limited efficacy. According to the literatures, available managements include topical agents like analgesics, antiseptics, corticosteroids, systemic therapy (such as pharmacologic therapy) and physical therapy, such as surgical removal, debridement and laser application.[13-14] Laser is a unique form of energy which is widely used in medicine and dentistry due to its reparative, analgesic, and anti-inflammatory benefits. Different types of laser such as CO2, Nd:YAG and InGaAlP Diode are used for treatment of complications on soft and hard tissues. High level lasers, such as CO2 laser, have the possibility of using at high powers (ranging from fractions of a watt to 25 W or more), while low level lasers, such as InGaAlP Diode, operate in the milliwatt range(1-500 mW). Recently, several studies have revealed that low level laser therapy can be advantageous in the treatment of oral aphthous lesions by improving the process of wound healing and pain reduction and does not cause any serious adverse effect(s).[15-19] However, there appear to be few publications on the therapeutic effects of high level laser treatment on RAS. In view of the fact that RAS causes discomfort in patients and considering the potential therapeutic effects of laser on oral lesions, this study aimed to investigate and compare the efficacy of low and high level laser treatments on RAS in a randomized clinical trial.

Materials and Method

This study was designed as a randomized double-blind placebo-controlled clinical trial to evaluate the effect of low and high level laser therapy on RAS and comparing their efficacy. The study protocol was approved by the Ethics Committee of Shiraz University of Medical Sciences with the code number IRCT 2012120911702N1. The patients signed a consent form and were informed about the nature of the procedure before starting. Forty patients with aphthous lesions presented to the Oral and Maxillofacial Medicine Department of Shiraz Dental School between October 2012 and February 2013 voluntarily participated in the study. Patients were examined by a clinician and the diagnosis was confirmed through patient history and clinical examination. The inclusion criterion was patients with one minor RAS of less than 72 h duration or two nearby minor aphthous lesions of less than 72 h at the same side of oral cavity (the size of the two lesions plus the distance between them was not more than 9 mm). The exclusion criteria were patients who were not fulfilling the inclusion criteria, had serious and dangerous systemic diseases (including severe kidney, liver , and heart problems), pregnant and lactating women, patients treated with topical or systemic medication for RAS, such as corticosteroid therapy, antibiotics or analgesics during the previous month. Forty patients were divided into three groups with the method of simple randomization. The lesions of patients in group 1 were treated with CO2 laser, those in group 2 were treated with InGaAlP Diode laser and the group 3 received sham laser (placebo group). Four of the patients (one from group1 and three from group 3) did not complete the procedure and were excluded from the study. The patients and the clinician who recorded the data were blind to the types of treatment applied.

The ulcers in group 1(n=14) were ablated with CO2 laser (DEKA, 10600 nm) for about 5-10 seconds depending on the size of the lesion (scanning over the lesion until ablating the whole surface). The laser was irradiated with power output of 2W in continuous mode and the distance between the tissue and laser source was 12.5mm. In group 2 (n=12), InGaAlP Diode laser (AZOR-2K, 660nm) was emitted in pulse mode, frequency 80Hz, power output 25mW, power density 3J/cm², focal spot size 9.04mm for 4 minutes. The laser pen was in contact with the surface of the lesion. Group 3 (n=10) were treated with the low level laser (AZOR laser) inactive probe in contact with the lesion for 4 minutes. In all groups, no topical or injectable anesthesia was applied before the procedure and all patients received a single session treatment. The patients who had two ulcers at the same side were treated as same as the patients with single ulcer (the whole area of two ulcers were covered with the laser pen through only one application). Pain severity (both the idiopathic/ noncontact and contact pain) was evaluated with visual analogue scale (VAS) before and after treatment. Idiopathic or noncontact pain means the spontaneous pain which is felt by the patient without any stimulation of the ulcer. The patients’ condition was followed up daily for 15 days after the treatment and their pain intensity was recorded using the VAS and the day in which the pain disappeared was noted. As the criteria for healing of the ulcer, we recorded the day in which the lesion was re-epithelialized while a remnant of lesion was still visible in clinical examination. We asked the patients about their satisfaction of the treatment and functional complications (interruption of the aphthous lesions with normal daily activities like speaking, chewing and brushing) before and after treatment. They were requested to grade these subjective data on a VAS. The collected data was analyzed statistically with Kruskal-Wallis, Mann-Whitney, Repeated measurement-one way ANOVA and Post Hoc Tests. The significant level (a) in this study was 0.05.

Results

In the present study, 38.8% (n=14) of the patients were in CO2 laser group (group 1), 33.3% (n=12) received InGaAlP Diode laser therapy (group 2) and 27.7% (n=10) were in placebo group (group 3). The mean age of the patients in group 1, 2 and 3 was 34.6, 32.6 and 30.2, respectively. Group 1 consisted of 8 male and 6 female patients, group 2 involved 7 male and 5 female patients and group 3 comprised of 4 male and 6 female patients. There was no significant difference in the efficacy of therapies between genders.

The effect of the low and high level laser treatment on pain intensity was assessed using VAS and the results were compared to evaluate the efficiency of the investigated treatments. The difference between the three groups was not significant for idiopathic pain before and after treatment (p> 0.05).The contact pain reduction immediately after treatment in group1 was 7.00±2.41, in group2 was 2.08±2.31 and in group3 was 1.40±1.77.These results were significantly different between groups 1 and 2 (p= 0.000) and also groups 1 and 3 (p= 0.000).The difference in the reduction of post treatment contact pain; however, was not significant between groups 2 and 3 (p> 0.05).

Group1 experienced no pain 5.07±4.14 days after treatment, whereas group2 had no pain 3.00±2.08 days after laser therapy and group3 was pain free on the day 1.10±1.85. Statistically, group 1 patients experienced pain for a longer duration in comparison to the placebo group (p= 0.009). No significant difference was obtained between groups 1 and 2, as well as groups 2 and 3 (p> 0.05). Table 1 shows the percentage of pain free patients on different days after treatment in three groups.

Table 1

The percentage of pain free patients on different days in all groups

Pain cut (VAS=0)	Group 1	Group 2	Group 3
Day 1	21.40%	0	0
Day 3	42.80%	33.30%	33.30%
Day 7	71.40%	91.60%	91.60%
Day 10	85.70%	100%	100%
Day 12	100%

VAS=visual analogue scale, Pain cut=the condition in which patients have no pain (VAS=0)

All the patients reported functional complications during chewing, brushing and even speaking. The functional disturbances before and after treatment were decreased by 8.57±1.50, 7.50±2.19 and 6.00±2.44 in group 1, 2 and 3, respectively. The difference was significant between groups 1 and 3 (p= 0.012), but statistically no reduction of functional disturbance was observed between groups 1 and 2, and also groups 2 and 3.

The comparison of the efficacy of the utilized lasers on the duration of ulcer repair showed no significant differences in the repair time of the lesions (p> 0.05) between the three groups. The percentages of healed ulcers of all groups on the follow-up days are demonstrated in Table 2. Statistically, the three groups revealed no satisfaction of laser treatment (p> 0.05).

Table 2

The percentage of healed ulcers on different days in all groups

Wound Healing	Group 1	Group 2	Group 3
Day 1	0	0	0
Day 3	14.20%	8.30%	10%
Day 7	57.10%	41.60%	80%
Day 9	71.40%	83.30%	100%
Day 14	85.70%	100%
Day 15	100%

The comparison of the clinical data and statistical analysis of the three groups are listed in Table 3.

Table 3

Comparison of pain reduction, pain cut, wound healing, patient´s satisfaction ,and decrease in functional complications

Variables	Group 1	Group 2	Group 3	P value
Idiopathic Pain Reduction	1.71±3.02	0.58±0.90	1.00±2.30	Not significant
Contact Pain Reduction	7.00±2.41	2.08±2.31	1.40±1.77	0.000
Pain Cut(Day)	5.07±4.14	3.00±2.08	1.10±1.85	0.012
Wound Healing(Day)	7.21±4.20	7.92±3.52	6.40±1.83	Not significant
Patient´s Satisfaction(VAS)	6.79±3.06	7.58±1.73	6.70±2.05	Not significant
Decrease in Functional Complications(VAS)	8.57±1.50	7.50±2.19	6.00±2.44	0.016

VAS=visual analogue scale, Pain cut (Day)=the day in which patients have no pain (VAS=0)

Discussion

Laser therapy is currently widely used in medical field due to its beneficial therapeutic effects, such as analgesia, anti-inflammation and wound healing. Although not completely known, laser therapy acts through different suggested mechanisms including modulation of natural substances (histamine, acetylcholine, opioid peptides, kinins, prostaglandin, interleukin, interferon and tumor necrosis factor), changes in impulse conduction of nociceptors and effects on lymphocyte metabolism. Laser therapy can also improve microcirculation and oxygenation of the tissue and stimulate epithelial, endothelial, and mesenchymal cell growth.[20-36]

In our study, we used CO2 laser with 10600 nm, and 2 W parameters in continuous mode until ablating the whole ulcer and InGaAlP Diode laser, 660 nm, 25 mW and 3 J/cm2 in pulse mode for 4 minutes. Laser was emitted for just one session in both groups. Results revealed that CO2 laser was more effective in pain reduction in comparison to InGaAlP Diode laser and also the placebo group. The difference in pain reduction was not statistically significant between InGaAlP Diode laser and placebo group. Patients who were treated with CO2 laser experienced more pain reduction immediately after treatment compared to the other two groups; however, they suffered from pain for a longer period of time. Statistically, the applied treatments in our study did not reduce the healing time of the lesions. CO2 laser therapy resulted in decreasing the functional disturbances (speaking, chewing, and brushing), whereas InGaAlP Diode laser was not effective in pain and functional complication reduction. No visible side effect was observed during and after the laser therapy.

There are limited numbers of studies in which the effect of low and high level laser treatment on RAS were compared. De Souza et al.[37 has employed InGaAlP Diode laser (670 nm, 50 mW and 3 J/cm² in continuous mode) on minor RAS once per day until the ulcer disappeared and compared the laser therapy results with topical triamcinolone 4 times a day. InGaAlP Diode laser therapy had analgesic and healing effects in comparison to topical corticosteroid which is in contrast with the results of our present study. This discrepancy may be due to the difference laser power output, mode of laser irradiation and the number of treatment sessions between the studies. Khademi et al.[38] compared single-session InGaAlP Diode laser therapy (660 nm, 25 mW and 3 J/cm² in continuous mode) with placebo group. Their study showed reduction of pain and healing time after laser therapy, which may be due to the continuous mode of laser irradiation, which was the only difference between this study and our work.[38]

Zand et al.[39] suggested single-session CO2 laser therapy for minor RAS. They applied the laser in non-thermal way with the power of 1 W.[39] Similar to our study, CO2 laser treatment reduced pain immediately after irradiation in comparison to placebo. The results which were reported by Sharon-Bulle et al.[40] and Colvard et al.[41] using CO2 laser in ablative manner are in agreement with our study. More recently, Zand et al.[42] evaluated non-thermal non-ablative 1 W CO2 laser on wound healing of minor RAS for one session. Their study revealed that laser treatment can improve healing of the ulcers which is in contrast to our results.[42] The use of the non-ablative method in this study may explain the different results obtained compared to ours.

Tezel et al.[43] and Arabaci et al.[44] compared the effects of Nd:YAG laser (1.064 nm, power output 2W) with topical corticosteroid (triamcinolone acetonide 0.1%). Both of them reported more pain reduction after Nd:YAG laser treatment and fewer functional complications in consistent with our study, but faster healing and better patient acceptance with laser which was not appeared significant in ours. The study by Parkins[45] demonstrated immediate pain reduction and faster healing after Nd:YAG laser application on aphthous lesions. Employing a different type of laser in these studies may explain the inconsistency which was observed between the aforementioned results and the present study.

Concerning a few limitations in our study, it would be ideal to conduct this type of study with patients having multiple simultaneous lesions in their oral cavity and to compare the effect of different laser types on the same person; however, it was not possible to find enough patients having this condition and also fulfilling our inclusion criteria. It is noteworthy to mention that RAS has a recurrent nature; therefore, further studies are required to evaluate the effect of laser therapy on the recurrence of aphthous lesions.

Generally, our study showed that high level laser treatment of RAS could significantly reduce the pain and decrease the functional disturbances in patients with a single treatment session and more importantly, these benefits occurred immediately after the treatment. Since RAS causes discomfort in patients and has a recurrent nature, this type of therapy can be extremely invaluable to patients. Certainly, more controlled clinical trials are required to establish an ideal protocol for the use of lasers in the treatment of oral lesions.

Conclusion

CO2 laser reduced pain intensity of RAS immediately after treatment, although the pain remained longer after this type of laser treatment in comparison to InGaAlP Diode laser. CO2 laser treatment also resulted in fewer functional complications in comparison to placebo group. The investigated laser therapies could not significantly reduce the wound healing time.