- Email: [email protected]
Recurrent aphthous stomatitis and pain management with low-level laser therapy: a randomized controlled trial
Vol. 117 No. 5 May 2014
Recurrent aphthous stomatitis and pain management with low-level laser therapy: a randomized controlled trial Margit Albrektson,a Lennart Hedström, DDS, MDS,a and Håkan Bergh, MD, PhDb Public Dental Services Varberg, Varberg, Sweden; Research & Development Unit, County of Halland, Halmstad, Sweden
Objective. The aim of the study was to determine whether low-level laser therapy (LLLT) has an analgesic effect in patients with recurrent aphthous stomatitis (RAS). Study Design. A randomized single-blinded placebo-controlled trial was conducted with LLLT (wavelength, 809 nm; power, 60 mW; pulse frequency, 1800 Hz; duration, 80 seconds per treatment; dose, 6.3 J/cm2) in 40 patients with RAS. The intervention group was treated with LLLT on 3 occasions, with a 1-day interval. The control group was treated similarly, without any laser power. Pain perception (visual analog scale [VAS] rating) and patients’ experience of eating, drinking, and brushing teeth was registered. Results. VAS rating decreased (day 0 until day 2) from 84.7 to 31.5 (LLLT) and from 81.7 to 76.1 (placebo) (P < .0001). LLLT also relieved the difficulty of drinking, eating, and brushing teeth. Conclusions. LLLT reduced the pain and the inconvenience of eating, drinking, and brushing teeth for patients with RAS, compared with placebo. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:590-594)
Recurrent aphthous stomatitis (RAS) is an inflammatory ulcer that affects the oral mucous membrane. Recent studies on the etiology and pathogenesis include different inflammatory reactions such as cell-mediated immune response caused by T cells, inflammatory cytokine tumor necrosis factor a, and heat shock proteins.1 The condition is characterized by a painful yellowish ulcer with an erythematous halo that heals spontaneously. In the literature, aphthae are divided into 3 types: minor aphthous (2-10 mm in diameter), which is the most common; major aphthous (also called periadenitis mucosa necrotica, >10 mm in diameter); and herpetiform ulceration (multiple small ulcers).2 The disease causes many problems for the patient owing to pain, leading to difficulties in eating, drinking, and maintaining oral hygiene. Over the years, several therapies to relieve pain, reduce the frequency of recurrence, prevent new aphthae, or a combination of those have been tested, but no cure has been found. Management of aphthous stomatitis is either topical or systemic. Topical therapy includes avoiding certain foods, treatment with local anesthetics (lidocaine gel, benzydamine), protective bioadhesives (cyanoacrylate), antiseptic or anti-inflammatory therapies (chlorhexidine gluconate, triclosan, amlexanox), local antibiotics (tetracycline, chlortetracycline), and topical steroids
Clinical trial registration number EPN 2009/552. The study was supported by the Research & Development Unit, County of Halland. a Public Dental Services Varberg. b Research & Development Unit, County of Halland. Received for publication Sep 26, 2013; returned for revision Jan 17, 2014; accepted for publication Jan 25, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.01.228
590
(triamcinolone acetonide).1-3 Systemic therapy (colchicine, pentoxifylline, corticosteroids, dapsone, thalidomide, cyclosporine, and infliximab) is mostly used in severe cases of aphthous stomatitis.1 Laser (light amplification by stimulated emission of radiation) is a concentrated form of energy with different wavelengths. Depending on the wavelength used, a different mode of action is performed. Colvard and Kuo4 treated 18 patients with minor RAS using a CO2 laser (wavelength, 10 600 nm), of whom 89% were pain free immediately after treatment. In 2009, Zand et al.5 conducted a single-blinded, placebocontrolled study in which CO2 laser was used to treat 30 minor aphthous lesions, which resulted in lower pain scores for the laser group. Zand et al.6 also found that CO2 laser promoted healing in minor recurrent aphthous stomatitis. In a recent study from 2013 by Prasad and Pai,7 a single session of CO2 laser was a promising treatment modality for RAS. Nd:YAG (neodymium:yttrium-aluminum-garnet) laser (wavelength, 1064 nm) is also used in the treatment of RAS. Tezel et al.8 compared a single session of Nd:YAG laser and triamcinolone acetonide medication used 3 times daily for 1 week in 20 patients and found a significant reduction in pain after treatment in the laser group.
Statement of Clinical Relevance This randomized clinical trial found that low-level laser therapy reduces pain in recurrent aphthous stomatitis and reduces symptoms caused by eating food, drinking beverages, and brushing teeth.
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The aforementioned types of laser have a wavelength of 1000 to 10 000 nm, whereas low-level lasers have a wavelength of 600 to 900 nm. CO2 and Nd:YAG lasers have different penetration depths and affect the oral mucosa photothermally, causing vaporization/carbonization. Low-level lasers function in a biostimulation mode that causes photochemical reactions in the cells, resulting in tissue repair and pain relief due to a variety of effects on the inflammation, such as the release of cytokines, reduction of edema, effect on mitochondria and immune cells, and promotion of wound healing.9 Low-level laser therapy (LLLT) has been used in the treatment of inflammatory and painful conditions such as herpes labialis, RAS, other stomatitis, oral mucositis, hypersensitive teeth, alveolitis, temporomandibular joint pain, and trigeminal neuralgia.10-14 However, very few studies have been performed on the treatment of RAS with LLLT, and none have found a significant reduction of pain or symptoms,15,16 although it has been documented that HeNe and diode lasers have an in vitro effect on tissue repair processes, depending on wavelength and output dose.17 Thus, the aim of this study was to determine whether LLLT has an analgesic effect in acute minor RAS, and if it reduces symptoms caused by the consumption of food and beverages and the brushing of teeth.
MATERIAL AND METHODS Study design The study was designed as a randomized, single-blinded, placebo-controlled clinical study, conducted between September 2009 and April 2012. The trial was approved by the Ethical Committee of Lund University (2009/552) and was conducted in accordance with the Declaration of Helsinki. Patient selection All patients aged over 10 years attending Public Dental Services in Varberg, Sweden, owing to pain from ulcers in the mouth, were invited to participate in the study. Patients younger than 18 years required written consent from their parents. They were first examined by one of the authors (L.H.) to establish the diagnosis of RAS. Patients with other oral mucosal ulcers other than RAS were excluded. Only patients with a history of minor RAS, duration of 3 days or less, and the presence of one or more painful ulcers, regardless of size, in the buccal or labial nonkeratinized oral mucosa were included for study. In cases of multiple ulcers, the most painful ulcer was chosen for treatment. Patients with a known systemic disease that predisposed them to RAS (e.g., Behçet disease) or undergoing systemic treatment for RAS were excluded. None of the participating patients had any earlier experiences of laser therapy.
ORIGINAL ARTICLE Albrektson, Hedström and Bergh 591
Information about the study was provided by one of the authors (M.A.), and the participant had to sign a consent form. Study procedure Patients who agreed to take part in the study were randomly allocated by tossing a coin, done by another person than the operator, to either the treatment or placebo group. All treatment was carried out by one of the authors (M.A.), who was not blinded to the procedure. On day 0, before treatment with laser/placebo, the patient had to fill out a questionnaire containing items about sex, age, and duration of the ulcer. The patients were told not to take any topical or systemic medications or products from day 0 to day 3, although they could have been taking such medicines before entering the study. The laser equipment used was a GaAlAs (galliumaluminum-arsenic) semiconductor therapy laser with a glass rod T4 (Elexxion AG, Radolfzell, Germany) with the following parameters: wavelength, 809 nm; power, 60 mW; pulse frequency, 1800 Hz; duration, 80 seconds per treatment; and dose, 6.3 J/cm2. In the treatment group, the laser glass rod was held in direct contact to the ulcer for 80 seconds, whereas in the placebo group, the same procedure took place but without any power, about which the patient was not aware. This procedure was repeated on days 1 and 2. On day 1, the patients were asked to rate the pain on a visual analog scale (VAS) before laser/placebo treatment and also completed information about their subjective experience of eating, drinking, and brushing their teeth. On day 3, the author responsible for the treatment (M.A.) called each participant and asked the following questions (not validated): What is your subjective experience of eating today? None, slight, moderate, or severe difficulties? What is your subjective experience of drinking today? None, slight, moderate, or severe difficulties? What is your subjective experience of tooth brushing today? None, some, or severe difficulties? These questions were the same as in the survey questionnaire stated below. Instrument A survey questionnaire with ordinal scales was filled in by the patients at each visit concerning their subjective experience of eating, drinking, and brushing teeth. For eating and drinking, there were 4 response alternatives (no, slight, moderate, and severe difficulties), and for brushing teeth there were 3 (none, some, and severe difficulties). The patients had to fill out this questionnaire just before starting the treatment with placebo/ laser. They were also requested to grade the pain of their ulcer on a horizontal 100-mm visual analog scale (VAS) (0 mm ¼ no pain; 100 ¼ severe pain)
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Table I. Description and comparison of study groups according to age, sex, number of days with current ulcer, frequency and dissemination of recurrent aphthous stomatitis, and present medical treatment before start of the study Laser group Placebo group (n ¼ 20) (n ¼ 20) Age (y), median (IQR) Sex, male/female, n Debut of current ulcer within: 1 day 2 days 3 days Recurrent aphthous stomatitis 1 time per month Multiple ulcers Present medical treatment None Analgesics Nonsteroidal antiinflammatory drug Topical corticosteroids Combination
22.5 (16.7) 5/15
27.5 (25.0) 11/9
20% 45% 35% 55%
30% 50% 20% 45%
85%
60%
55% 20% 5%
60% 35% 5%
10% 5%
0% 0%
P .218 .056 .280*
.274 .080 .438*
Fig. 1. The laser group’s and placebo group’s mean value and error bars of visual analog scale (VAS) rating of aphthous stomatitis pain before treatment with low-level laser therapy (day 0), 1 day after the first treatment (day 1), and 1 day after the second treatment (day 2). The P value refers to the change in VAS rating between the laser and the placebo group from day 0 to day 1.
Statistical method for comparison between groups: nonparametric Mann-Whitney U test. IQR, interquartile range. *One-point comparison of mean range.
(not validated) before treatment. The pain score was registered on days 0, 1, and 2 just before starting the treatment. Statistical analysis Based on clinically empirical experiences, we expected an improvement of 50% in self-rated pain scores among patients compared with the placebo group. The calculation was based on a significance level of 5% and a b error of 20% (power ¼ 80%). By this assumption, we needed approximately 17 cases in each group. Median value and interquartile range are presented. Statistical analysis was conducted by means of the nonparametric Mann-Whitney U test, in which the study groups were compared in terms of age, sex, and number of days with the ulcer in question. The same test was used to compare the parameters (ulcer pain and subjective experience of eating, drinking, and brushing teeth) in their change over time from day 0, day 1, and day 2. The level of statistical significance was set at P < .05. Data were analyzed using IBM SPSS Statistics, version 20 (IBM Inc).
RESULTS Twenty patients in each group completed the study, with no reported adverse events. None of the patients were smokers. A description and a comparison of the study groups are presented in Table I. The placebo group in terms of age (median), sex distribution, and
Fig. 2. Number of patients in the laser group (n ¼ 20) and in the placebo group (n ¼ 20) with moderate or severe difficulty with eating and drinking before treatment (day 0) and the following 3 days after treatment.
duration of the ulcer treated were not significantly different from the treatment group. The pain score decreased in the laser group on day 1 (VAS rating changed from 84.7 to 56.2) and more on day 2 (VAS rating changed from 56.2 to 31.5) (P < .0001). In the placebo group, the pain score changed from 81.7 to 80.7 (day 0 to day 1) and to 76.1 on day 2 (Figure 1). Difficulty in eating was moderate or severe for all participants at the start of the trial (Figure 2). In the laser group, 15 of 20 (75%) participants had moderate or severe difficulty on day 1, 4 of 20 (20%) on day 2, and none on day 3. In the placebo group, all participants had moderate or severe difficulty on days 1 and 2, whereas on day 3, 17 (85%) still had moderate or severe eating difficulty (P < .0001). The same pattern was found when comparing moderate or severe difficulty with drinking between the laser and the placebo group (see Figure 2). Ninety percent (18 of 20) patients in the laser group and 80%
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Fig. 3. Number of patients in the laser group (n ¼ 20) and in the placebo group (n ¼ 20) with severe difficulty in performing tooth brushing before treatment (day 0) and the following 3 days after treatment.
(16 of 20) patients in the placebo group reported moderate or severe difficulties in drinking on day zero. On day 1, 10 of 20 (50%) of the participants in the laser group had moderate/severe difficulties in drinking, and on day 2 only 1 of 20 (5%), whereas in the placebo group the same number, 16 of 20 (80%), were found on both day 1 and day 2. The P value was P < .001 for day 0 to day 1. For day 0 to day 2 and for day 0 to day 3, the P value was P < .0001. The difference was not so pronounced for participants who reported severe difficulty with brushing teeth (Figure 3). On day 1, 10 of 20 (50%) patients in the laser group reported severe difficulty in brushing teeth comparing with 15 of 20 (75%) in the placebo group (P < .006), and on day 2 only 1 of 20 (5%) in the laser group vs 13 of 20 (65%) in the placebo group had severe difficulty in brushing teeth (P < .0001).
DISCUSSION This randomized controlled study found that LLLT has an analgesic effect in acute minor RAS compared with placebo. LLLT also significantly reduced pain when eating, drinking, and brushing teeth. This contrasts with the findings of Howell et al.,15 who used an HeNe laser (633 nm, 0.34 J/cm2) in 12 patients with a history of aphthous lesions. They found no significant difference between 66 untreated ulcers and 46 laser-treated ulcers in a study in which each patient served as her/his own control. In contrast, de Souza et al.16 conducted a randomized clinical evaluation of LLLT (InGaAlP diode laser, 670 nm, 3 J/cm2) in the treatment of RAS in 15 patients and found that LLLT with a topical steroid reduced pain levels after the first LLLT session. However, the level of reduction was not statistically significant. In our study, we used LLLT equipment with a higher wavelength (809 nm) and output (6.3 J/cm2) compared with the 2 aforementioned trials. These different parameters can explain our positive results on pain relief of recurrent aphthous ulcers and reduced difficulties
ORIGINAL ARTICLE Albrektson, Hedström and Bergh 593
when eating, drinking, and brushing teeth. In their meta-analysis, Enwemeka et al.18 studied the effect of low-power lasers (<500 mW) on conditions such as sores and ulcer wounds and concluded that laser therapy is effective in tissue repair and pain control but may be influenced by wavelength. Similar results were also found in another meta-analysis by Woodruff et al.,19 who stated that LLLT is effective but influenced by several parameters, most especially energy density. The present results indicate the efficacy of LLLT for relieving pain in RAS with respect to VAS rating of pain and difficulties in eating, drinking, and brushing teeth after the first treatment with laser, with persistent effects up to day 3. However, the findings are dependent on several parameters and require a well-defined protocol to compare them with other studies. Nevertheless, this treatment method is very simple and safe and can be provided by dental personnel in many countries, as LLLT does not require any special certification for using this type of equipment, in contrast to the use of lasers with higher wavelengths. However, there are some methodologic limitations. A doubleblinded study would have been preferable, but the present study was performed single-blinded, because it was difficult to blind the operator as well as the participants. Although the VAS is a validated scale, the other measured items were not previously validated. This is probably of minor importance, because the questionnaire was completed by each patient, who reported her/his own experience of eating, drinking, and brushing teeth from day 0 to day 3. Finally, it is important to note that the laser group had more patients who had RAS for a slightly longer time compared with the placebo group at entry; however, there was a nonsignificant statistical difference between the 2 study groups with respect to the debut of the ulcer.
CONCLUSIONS This randomized single-blinded placebo-controlled study found that LLLT has a pain-relieving effect on minor RAS compared with placebo. LLLT also reduces the pain caused by eating, drinking, and brushing teeth. We express our thanks to Professor Bertil Marklund for helpful comments, to Dr Amir Baigi for helpful statistical advice, and to the manager Britt Lindau and the staff at the Public Dental Clinic, Varberg. REFERENCES 1. Scully C, Porter S. Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg. 2008;46:198-206. 2. Brocklehurst P, Tickle M, Glenny AM, et al. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database Syst Rev. 2012:CD005411. http://doi:10.1002/14651858. CD005411.pub2.
ORAL MEDICINE 594 Albrektson, Hedström and Bergh 3. Scully C. Clinical practice: aphthous ulceration. N Engl J Med. 2006;355:165-172. 4. Colvard M, Kuo P. Managing aphthous ulcers: laser treatment applied. JADA. 1991;122:51-53. 5. Zand N, Ataie-Fashtami L, Djavid GE, et al. Relieving pain in minor aphthous stomatitis by a single session of non-thermal carbon dioxide laser irradiation. Lasers Med Sci. 2009;24: 515-520. 6. Zand N, Fateh M, Ataie-Fashtami L, Djavid GE, Fatemi SM, Shirkavand A. Promoting wound healing in minor recurrent aphthous stomatitis by non-thermal, non-ablative CO2 laser therapy: a pilot study. Photomed Laser Surg. 2012;30:719-723. 7. Prasad RS, Pai A. Assessment of immediate pain relief with laser treatment in recurrent aphthous stomatitis. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116:189-193. 8. Tezel A, Kara C, Balkaya V, Orbak R. An evaluation of different treatments for recurrent aphthous stomatitis and patient perceptions: Nd:YAG laser versus medication. Photomed Laser Surg. 2008;26:1-6. 9. Chung H, Dai T, Sharma SK, Huang YY, Carroll JD, Hamblin MR. The nuts and bolts of low-level laser (light) therapy. Ann Biomed Eng. 2012;40:516-533. 10. Wilder-Smith P. The soft laser: therapeutic tool or popular placebo? Oral Surg Oral Med Oral Pathol. 1988;66:654-658. 11. Pinheiro A, Cavalcanti ET, Pinheiro T, et al. A. low level laser therapy is an important tool to treat disorders of the maxillofacial region. J Clin Laser Med Surg. 1998;16:223-226. 12. Toida M, Watanabe F, Goto K, Shibata T. Usefulness of low level laser for control of painful stomatitis in patients with hand-footmouth disease. J Clin Laser Med Surg. 2003;21:363-367.
OOOO May 2014 13. Hode L. Healing laser [in Swedish]. Swedish Laser Medical Society. Available at: http://www.slms.org/pdf/laser-som-laeker.pdf. 14. Migliorati C, Hewson I, Lalla RV, et al. Systematic review of laser and other light therapy for the management of oral mucositis in cancer patients. Support Care Cancer. 2013;21:333-341. 15. Howell RM, Cohen DM, Lynn Powell G, Green JG. The use of low energy laser therapy to treat aphthous ulcers. Ann Dent. 1988;47:16-18. 16. de Souza TOF, Martins MAT, Bussadori SK, et al. Clinical evaluation of low level laser treatment for recurring aphthous stomatitis. Photomed Laser Surg. 2010;28:85-88. 17. da Silva JP, da Silva MA, Almeida APF, Lomdardi I, Matos APM. Laser therapy in the tissue repair process: a literature review. Photomed Laser Surg. 2010;28:17-21. 18. Enwemeka CS, Parker JC, Dowdy D, Harkness EE, Sanford L, Woodruff LD. The efficacy of low-power lasers in tissue repair and pain control: a meta-analysis study. Photomed Laser Surg. 2004;22:323-329. 19. Woodruff LD, Bounkeo JM, Brannon WM, et al. The efficacy of laser therapy in wound repair: a meta-analysis of the literature. Photomed Laser Surg. 2004;22:241-247. Reprint requests: Lennart Hedström, DDS, MDS Public Dental Services Box 1254, S-43236 Varberg Sweden [email protected]
Recurrent aphthous stomatitis and pain management with low-level laser therapy: a randomized controlled trial Margit Albrektson,a Lennart Hedström, DDS, MDS,a and Håkan Bergh, MD, PhDb Public Dental Services Varberg, Varberg, Sweden; Research & Development Unit, County of Halland, Halmstad, Sweden
Objective. The aim of the study was to determine whether low-level laser therapy (LLLT) has an analgesic effect in patients with recurrent aphthous stomatitis (RAS). Study Design. A randomized single-blinded placebo-controlled trial was conducted with LLLT (wavelength, 809 nm; power, 60 mW; pulse frequency, 1800 Hz; duration, 80 seconds per treatment; dose, 6.3 J/cm2) in 40 patients with RAS. The intervention group was treated with LLLT on 3 occasions, with a 1-day interval. The control group was treated similarly, without any laser power. Pain perception (visual analog scale [VAS] rating) and patients’ experience of eating, drinking, and brushing teeth was registered. Results. VAS rating decreased (day 0 until day 2) from 84.7 to 31.5 (LLLT) and from 81.7 to 76.1 (placebo) (P < .0001). LLLT also relieved the difficulty of drinking, eating, and brushing teeth. Conclusions. LLLT reduced the pain and the inconvenience of eating, drinking, and brushing teeth for patients with RAS, compared with placebo. (Oral Surg Oral Med Oral Pathol Oral Radiol 2014;117:590-594)
Recurrent aphthous stomatitis (RAS) is an inflammatory ulcer that affects the oral mucous membrane. Recent studies on the etiology and pathogenesis include different inflammatory reactions such as cell-mediated immune response caused by T cells, inflammatory cytokine tumor necrosis factor a, and heat shock proteins.1 The condition is characterized by a painful yellowish ulcer with an erythematous halo that heals spontaneously. In the literature, aphthae are divided into 3 types: minor aphthous (2-10 mm in diameter), which is the most common; major aphthous (also called periadenitis mucosa necrotica, >10 mm in diameter); and herpetiform ulceration (multiple small ulcers).2 The disease causes many problems for the patient owing to pain, leading to difficulties in eating, drinking, and maintaining oral hygiene. Over the years, several therapies to relieve pain, reduce the frequency of recurrence, prevent new aphthae, or a combination of those have been tested, but no cure has been found. Management of aphthous stomatitis is either topical or systemic. Topical therapy includes avoiding certain foods, treatment with local anesthetics (lidocaine gel, benzydamine), protective bioadhesives (cyanoacrylate), antiseptic or anti-inflammatory therapies (chlorhexidine gluconate, triclosan, amlexanox), local antibiotics (tetracycline, chlortetracycline), and topical steroids
Clinical trial registration number EPN 2009/552. The study was supported by the Research & Development Unit, County of Halland. a Public Dental Services Varberg. b Research & Development Unit, County of Halland. Received for publication Sep 26, 2013; returned for revision Jan 17, 2014; accepted for publication Jan 25, 2014. Ó 2014 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2014.01.228
590
(triamcinolone acetonide).1-3 Systemic therapy (colchicine, pentoxifylline, corticosteroids, dapsone, thalidomide, cyclosporine, and infliximab) is mostly used in severe cases of aphthous stomatitis.1 Laser (light amplification by stimulated emission of radiation) is a concentrated form of energy with different wavelengths. Depending on the wavelength used, a different mode of action is performed. Colvard and Kuo4 treated 18 patients with minor RAS using a CO2 laser (wavelength, 10 600 nm), of whom 89% were pain free immediately after treatment. In 2009, Zand et al.5 conducted a single-blinded, placebocontrolled study in which CO2 laser was used to treat 30 minor aphthous lesions, which resulted in lower pain scores for the laser group. Zand et al.6 also found that CO2 laser promoted healing in minor recurrent aphthous stomatitis. In a recent study from 2013 by Prasad and Pai,7 a single session of CO2 laser was a promising treatment modality for RAS. Nd:YAG (neodymium:yttrium-aluminum-garnet) laser (wavelength, 1064 nm) is also used in the treatment of RAS. Tezel et al.8 compared a single session of Nd:YAG laser and triamcinolone acetonide medication used 3 times daily for 1 week in 20 patients and found a significant reduction in pain after treatment in the laser group.
Statement of Clinical Relevance This randomized clinical trial found that low-level laser therapy reduces pain in recurrent aphthous stomatitis and reduces symptoms caused by eating food, drinking beverages, and brushing teeth.
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The aforementioned types of laser have a wavelength of 1000 to 10 000 nm, whereas low-level lasers have a wavelength of 600 to 900 nm. CO2 and Nd:YAG lasers have different penetration depths and affect the oral mucosa photothermally, causing vaporization/carbonization. Low-level lasers function in a biostimulation mode that causes photochemical reactions in the cells, resulting in tissue repair and pain relief due to a variety of effects on the inflammation, such as the release of cytokines, reduction of edema, effect on mitochondria and immune cells, and promotion of wound healing.9 Low-level laser therapy (LLLT) has been used in the treatment of inflammatory and painful conditions such as herpes labialis, RAS, other stomatitis, oral mucositis, hypersensitive teeth, alveolitis, temporomandibular joint pain, and trigeminal neuralgia.10-14 However, very few studies have been performed on the treatment of RAS with LLLT, and none have found a significant reduction of pain or symptoms,15,16 although it has been documented that HeNe and diode lasers have an in vitro effect on tissue repair processes, depending on wavelength and output dose.17 Thus, the aim of this study was to determine whether LLLT has an analgesic effect in acute minor RAS, and if it reduces symptoms caused by the consumption of food and beverages and the brushing of teeth.
MATERIAL AND METHODS Study design The study was designed as a randomized, single-blinded, placebo-controlled clinical study, conducted between September 2009 and April 2012. The trial was approved by the Ethical Committee of Lund University (2009/552) and was conducted in accordance with the Declaration of Helsinki. Patient selection All patients aged over 10 years attending Public Dental Services in Varberg, Sweden, owing to pain from ulcers in the mouth, were invited to participate in the study. Patients younger than 18 years required written consent from their parents. They were first examined by one of the authors (L.H.) to establish the diagnosis of RAS. Patients with other oral mucosal ulcers other than RAS were excluded. Only patients with a history of minor RAS, duration of 3 days or less, and the presence of one or more painful ulcers, regardless of size, in the buccal or labial nonkeratinized oral mucosa were included for study. In cases of multiple ulcers, the most painful ulcer was chosen for treatment. Patients with a known systemic disease that predisposed them to RAS (e.g., Behçet disease) or undergoing systemic treatment for RAS were excluded. None of the participating patients had any earlier experiences of laser therapy.
ORIGINAL ARTICLE Albrektson, Hedström and Bergh 591
Information about the study was provided by one of the authors (M.A.), and the participant had to sign a consent form. Study procedure Patients who agreed to take part in the study were randomly allocated by tossing a coin, done by another person than the operator, to either the treatment or placebo group. All treatment was carried out by one of the authors (M.A.), who was not blinded to the procedure. On day 0, before treatment with laser/placebo, the patient had to fill out a questionnaire containing items about sex, age, and duration of the ulcer. The patients were told not to take any topical or systemic medications or products from day 0 to day 3, although they could have been taking such medicines before entering the study. The laser equipment used was a GaAlAs (galliumaluminum-arsenic) semiconductor therapy laser with a glass rod T4 (Elexxion AG, Radolfzell, Germany) with the following parameters: wavelength, 809 nm; power, 60 mW; pulse frequency, 1800 Hz; duration, 80 seconds per treatment; and dose, 6.3 J/cm2. In the treatment group, the laser glass rod was held in direct contact to the ulcer for 80 seconds, whereas in the placebo group, the same procedure took place but without any power, about which the patient was not aware. This procedure was repeated on days 1 and 2. On day 1, the patients were asked to rate the pain on a visual analog scale (VAS) before laser/placebo treatment and also completed information about their subjective experience of eating, drinking, and brushing their teeth. On day 3, the author responsible for the treatment (M.A.) called each participant and asked the following questions (not validated): What is your subjective experience of eating today? None, slight, moderate, or severe difficulties? What is your subjective experience of drinking today? None, slight, moderate, or severe difficulties? What is your subjective experience of tooth brushing today? None, some, or severe difficulties? These questions were the same as in the survey questionnaire stated below. Instrument A survey questionnaire with ordinal scales was filled in by the patients at each visit concerning their subjective experience of eating, drinking, and brushing teeth. For eating and drinking, there were 4 response alternatives (no, slight, moderate, and severe difficulties), and for brushing teeth there were 3 (none, some, and severe difficulties). The patients had to fill out this questionnaire just before starting the treatment with placebo/ laser. They were also requested to grade the pain of their ulcer on a horizontal 100-mm visual analog scale (VAS) (0 mm ¼ no pain; 100 ¼ severe pain)
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Table I. Description and comparison of study groups according to age, sex, number of days with current ulcer, frequency and dissemination of recurrent aphthous stomatitis, and present medical treatment before start of the study Laser group Placebo group (n ¼ 20) (n ¼ 20) Age (y), median (IQR) Sex, male/female, n Debut of current ulcer within: 1 day 2 days 3 days Recurrent aphthous stomatitis 1 time per month Multiple ulcers Present medical treatment None Analgesics Nonsteroidal antiinflammatory drug Topical corticosteroids Combination
22.5 (16.7) 5/15
27.5 (25.0) 11/9
20% 45% 35% 55%
30% 50% 20% 45%
85%
60%
55% 20% 5%
60% 35% 5%
10% 5%
0% 0%
P .218 .056 .280*
.274 .080 .438*
Fig. 1. The laser group’s and placebo group’s mean value and error bars of visual analog scale (VAS) rating of aphthous stomatitis pain before treatment with low-level laser therapy (day 0), 1 day after the first treatment (day 1), and 1 day after the second treatment (day 2). The P value refers to the change in VAS rating between the laser and the placebo group from day 0 to day 1.
Statistical method for comparison between groups: nonparametric Mann-Whitney U test. IQR, interquartile range. *One-point comparison of mean range.
(not validated) before treatment. The pain score was registered on days 0, 1, and 2 just before starting the treatment. Statistical analysis Based on clinically empirical experiences, we expected an improvement of 50% in self-rated pain scores among patients compared with the placebo group. The calculation was based on a significance level of 5% and a b error of 20% (power ¼ 80%). By this assumption, we needed approximately 17 cases in each group. Median value and interquartile range are presented. Statistical analysis was conducted by means of the nonparametric Mann-Whitney U test, in which the study groups were compared in terms of age, sex, and number of days with the ulcer in question. The same test was used to compare the parameters (ulcer pain and subjective experience of eating, drinking, and brushing teeth) in their change over time from day 0, day 1, and day 2. The level of statistical significance was set at P < .05. Data were analyzed using IBM SPSS Statistics, version 20 (IBM Inc).
RESULTS Twenty patients in each group completed the study, with no reported adverse events. None of the patients were smokers. A description and a comparison of the study groups are presented in Table I. The placebo group in terms of age (median), sex distribution, and
Fig. 2. Number of patients in the laser group (n ¼ 20) and in the placebo group (n ¼ 20) with moderate or severe difficulty with eating and drinking before treatment (day 0) and the following 3 days after treatment.
duration of the ulcer treated were not significantly different from the treatment group. The pain score decreased in the laser group on day 1 (VAS rating changed from 84.7 to 56.2) and more on day 2 (VAS rating changed from 56.2 to 31.5) (P < .0001). In the placebo group, the pain score changed from 81.7 to 80.7 (day 0 to day 1) and to 76.1 on day 2 (Figure 1). Difficulty in eating was moderate or severe for all participants at the start of the trial (Figure 2). In the laser group, 15 of 20 (75%) participants had moderate or severe difficulty on day 1, 4 of 20 (20%) on day 2, and none on day 3. In the placebo group, all participants had moderate or severe difficulty on days 1 and 2, whereas on day 3, 17 (85%) still had moderate or severe eating difficulty (P < .0001). The same pattern was found when comparing moderate or severe difficulty with drinking between the laser and the placebo group (see Figure 2). Ninety percent (18 of 20) patients in the laser group and 80%
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Fig. 3. Number of patients in the laser group (n ¼ 20) and in the placebo group (n ¼ 20) with severe difficulty in performing tooth brushing before treatment (day 0) and the following 3 days after treatment.
(16 of 20) patients in the placebo group reported moderate or severe difficulties in drinking on day zero. On day 1, 10 of 20 (50%) of the participants in the laser group had moderate/severe difficulties in drinking, and on day 2 only 1 of 20 (5%), whereas in the placebo group the same number, 16 of 20 (80%), were found on both day 1 and day 2. The P value was P < .001 for day 0 to day 1. For day 0 to day 2 and for day 0 to day 3, the P value was P < .0001. The difference was not so pronounced for participants who reported severe difficulty with brushing teeth (Figure 3). On day 1, 10 of 20 (50%) patients in the laser group reported severe difficulty in brushing teeth comparing with 15 of 20 (75%) in the placebo group (P < .006), and on day 2 only 1 of 20 (5%) in the laser group vs 13 of 20 (65%) in the placebo group had severe difficulty in brushing teeth (P < .0001).
DISCUSSION This randomized controlled study found that LLLT has an analgesic effect in acute minor RAS compared with placebo. LLLT also significantly reduced pain when eating, drinking, and brushing teeth. This contrasts with the findings of Howell et al.,15 who used an HeNe laser (633 nm, 0.34 J/cm2) in 12 patients with a history of aphthous lesions. They found no significant difference between 66 untreated ulcers and 46 laser-treated ulcers in a study in which each patient served as her/his own control. In contrast, de Souza et al.16 conducted a randomized clinical evaluation of LLLT (InGaAlP diode laser, 670 nm, 3 J/cm2) in the treatment of RAS in 15 patients and found that LLLT with a topical steroid reduced pain levels after the first LLLT session. However, the level of reduction was not statistically significant. In our study, we used LLLT equipment with a higher wavelength (809 nm) and output (6.3 J/cm2) compared with the 2 aforementioned trials. These different parameters can explain our positive results on pain relief of recurrent aphthous ulcers and reduced difficulties
ORIGINAL ARTICLE Albrektson, Hedström and Bergh 593
when eating, drinking, and brushing teeth. In their meta-analysis, Enwemeka et al.18 studied the effect of low-power lasers (<500 mW) on conditions such as sores and ulcer wounds and concluded that laser therapy is effective in tissue repair and pain control but may be influenced by wavelength. Similar results were also found in another meta-analysis by Woodruff et al.,19 who stated that LLLT is effective but influenced by several parameters, most especially energy density. The present results indicate the efficacy of LLLT for relieving pain in RAS with respect to VAS rating of pain and difficulties in eating, drinking, and brushing teeth after the first treatment with laser, with persistent effects up to day 3. However, the findings are dependent on several parameters and require a well-defined protocol to compare them with other studies. Nevertheless, this treatment method is very simple and safe and can be provided by dental personnel in many countries, as LLLT does not require any special certification for using this type of equipment, in contrast to the use of lasers with higher wavelengths. However, there are some methodologic limitations. A doubleblinded study would have been preferable, but the present study was performed single-blinded, because it was difficult to blind the operator as well as the participants. Although the VAS is a validated scale, the other measured items were not previously validated. This is probably of minor importance, because the questionnaire was completed by each patient, who reported her/his own experience of eating, drinking, and brushing teeth from day 0 to day 3. Finally, it is important to note that the laser group had more patients who had RAS for a slightly longer time compared with the placebo group at entry; however, there was a nonsignificant statistical difference between the 2 study groups with respect to the debut of the ulcer.
CONCLUSIONS This randomized single-blinded placebo-controlled study found that LLLT has a pain-relieving effect on minor RAS compared with placebo. LLLT also reduces the pain caused by eating, drinking, and brushing teeth. We express our thanks to Professor Bertil Marklund for helpful comments, to Dr Amir Baigi for helpful statistical advice, and to the manager Britt Lindau and the staff at the Public Dental Clinic, Varberg. REFERENCES 1. Scully C, Porter S. Oral mucosal disease: recurrent aphthous stomatitis. Br J Oral Maxillofac Surg. 2008;46:198-206. 2. Brocklehurst P, Tickle M, Glenny AM, et al. Systemic interventions for recurrent aphthous stomatitis (mouth ulcers). Cochrane Database Syst Rev. 2012:CD005411. http://doi:10.1002/14651858. CD005411.pub2.
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