- Email: [email protected]
Assessment of immediate pain relief with laser treatment in recurrent aphthous stomatitis
Vol. 116 No. 2 August 2013
Assessment of immediate pain relief with laser treatment in recurrent aphthous stomatitis Shesha Prasad R.,a and Anuradha Pai, MDSb The Oxford Dental College, Bangalore, Karnataka, India
Objectives. To compare immediate pain relief, healing time between minor recurrent aphthous ulcers treated with a single session of carbon dioxide (CO2) laser and a placebo. Study Design. A prospective clinical study was performed on 25 patients with minor recurrent aphthous stomatitis. Pretreatment pain levels were recorded using a numerical rating scale. Ulcers were randomized to either receive treatment or placebo. Pain levels were assessed immediately after treatment and after 24 h. Healing was assessed on days 3 and 4, and once every 2 days thereafter for 2 weeks. Results. Mean pain scores in the laser group were significantly reduced immediately after treatment (0.68 0.6) compared with pretreatment (8.48 0.71; P < .001). In contrast, the placebo group showed little difference in pain scores between pretreatment (8.08 0.70) and immediately after treatment (7.96 0.84). In the laser group, significant improvements in healing times were observed (4.08 0.81 vs. 7.84 0.90 days; P < .001). Conclusion. CO2 laser therapy in recurrent aphthous stomatitis (RAS) provides immediate pain relief sustained over 24 h, along with accelerated healing time. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:189-193)
Recurrent aphthous ulceration (RAU), commonly known as canker sores1 is a common oral mucosal disorder characterized by recurring ulcers in patients without the presence of any other systemic disease.2 It affects 5%-25% of the general population, predominantly in the age groups between 10 and 30 years.3 Despite detailed investigations by researchers, the etiology and pathogenesis of this condition have largely remained unknown.4 The challenges faced in determining RAU have been its non-specific histological features and a lack of reproducibility of identifiable endogenous and exogenous causes.3 The condition is routinely diagnosed based on recording a detailed patient history and comprehensive clinical examination.4 Several etiological factors such as local trauma, immunological factors, genetic background, allergic agents, nutrition deficiency, hormonal changes in women, physical or psychic stress, chemical irritants and infective agents have been suspected, but no definitive etiology has been established conclusively.1,2,5 Minor RAU (miRAU) is the most common subtype of this condition and it occurs on non-keratinized mucosa as recurrent, round, clearly defined, small painful ulcers with shallow necrotic centers, raised margins, and erythematous halo.4,6 The ulcers tend to be painful with the pain usually subsiding after 4-5 a
Post Graduate Student, Department of Oral Medicine and Radiology, The Oxford Dental College. b Professor, Department of Oral Medicine and Radiology, The Oxford Dental College. Received for publication Sep 29, 2012; returned for revision Feb 5, 2013; accepted for publication Feb 15, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.02.011
days. During their course, they can significantly interfere with eating and speaking affecting quality of life.6 Different treatment options for miRAU include systemic medications, topical applications, acupuncture, corticosteroids, psychotherapy, and combination therapy. In addition, accumulating evidence provides support of laser therapy in the treatment of oral mucosal lesions and aphthous ulcers.7 Recently, a study revealed that 75% of the patients experienced relief of pain immediately after low-level laser treatment and a total regression of the ulcer in 4 days when compared with a group treated with corticoid agent, where the regression was observed between 5 and 7 days.8 In particular, there have been reports of carbon dioxide (CO2) lasers being used to treat aphthous ulcers with considerable success with regard to pain relief. A study by Colvard and Kuo9 have reported the use of CO2 laser for ablation of aphthous ulcers while 3 other studies have also reported beneficial effects of CO2 lasers with regard to pain resolution in aphthous ulcers and host versus graft disease cases.6,8,10 With the presence of such preliminary evidences, lasers have emerged as one of the treatment modalities for this common, painful mucosal lesion. Unlike pharmacological interventions, it has no known side effects or deleterious interactions.6
Statement of Clinical Relevance A single session CO2 laser operated at 0.7w power with a de-focused hand piece 5-7 mm from the mucosal surface for 5-8 seconds in a non-ablative manner can be a promising treatment modality for RAS. 189
ORAL MEDICINE 190 Prasad R. and Pai
The present study was designed and undertaken to assess the efficacy of a single session CO2 laser treatment, at 10.6 nm wavelength, in a non-ablative manner to provide immediate pain relief in patients presenting with miRAU.
MATERIALS AND METHODS The study sample was composed of a total of 25 adults, with history of miRAU, selected from a pool of patients visiting the Department of Oral Medicine and Radiology at the Oxford Dental College in Bangalore, between July 2010 and May 2012. Local privately practicing physicians were requested to screen patients for history of recurrent oral ulcers and refer them to our institution out-patient clinic. The sample size was limited to 25 among the total of 42 patients who fulfilled the inclusion criteria as only those 25 were available for the complete duration of the study. The 25 subjects were selected based on the predetermined inclusion and exclusion criteria listed below. All subjects signed an informed consent to participate in the study. The clinical protocol was reviewed and approved by the ethics committee of the Oxford Dental College. Prior to enrollment into the study, all subjects underwent routine clinical examination from a qualified physician and necessary laboratory investigations were conducted. Those patients with authentic history of miRAU, with the presence of at least 2 discrete painful minor aphthous ulcers at the same time presenting to the hospital within 3 days of appearance of such ulcers were included in the study. Exclusion criteria were pregnancy, history of systemic disease or condition that could predispose the patient to develop oral ulcers, presence of any major herpetiform aphthae, traumatic ulcers, ulcers caused due to topical or systemic medications, and, ulcers currently under treatment. The enrolled patients agreed not to take analgesics before, during and 3 days after the procedure. STUDY DESIGN In each of these patients, 2 ulcers as measured by the investigator, of dimension approximately 1 cm or less were selected in different locations in the oral cavity. One of them was randomly allocated to be treated with CO2 laser (Union Medical Engineering Co., UM-L25 special edition, Korea), and the other served as a placebo. It was a single-blind study designed in a manner such that the patients were unaware as to which of the lesions was going to be treated with laser and which one would be selected as a placebo. Pain scores recorded prior to commencement of treatment were compared with those recorded immediately after the treatment and at 24 h following completion of treatment. Healing period of the laser treated ulcer was
OOOO August 2013
compared with the placebo ulcer on a follow-up visit conducted 3-4 days subsequent to treatment.
STUDY PROCEDURE Patients were requested to sip water before commencement of the treatment to keep the mucosa wet. Subsequently, a high water gel, devoid of any anesthetic properties, and composed of a combination of 90% water and 10% carboxymethyl cellulose (Shristi Pharmaceuticals, Bangalore) was applied on both the ulcers using a sterile cotton. The CO2 laser was operated at 0.7 W power, with a de-focused hand piece in a continuous mode for 5-8 s, at a distance of 5-7 mm away from the mucosal surface in spiral motion. The placebo lesion was irradiated with the same instrument, but with an inactive probe. The patients were requested to grade the pain of their ulcers on a numerical rating scale of 1-10, [score ‘0’ indicated no pain and score ‘10’ indicated maximum pain] before and immediately after the procedure. Scores were also recorded postoperatively after 24 h. In patients with more than 2 ulcers, Lignocaine gel (Lignox gel, Warren Pharmaceuticals, India) was prescribed to be applied 24 h postlaser treatment to manage pain in those ulcers that were neither part of laser group nor placebo. Healing time of the laser-irradiated ulcer was compared with the placebo in a recall clinical visit 3-4 days following completion of the treatment. The patients were evaluated every 2 days for the next 2 weeks. Total reduction of erythema and the absence of an ulcer clinically was considered as healed. Regular telephone calls were made once in an every 2 weeks for a period of 6 months to evaluate the recurrence rates of the ulcers. The findings of the recurrence rates of laserirradiated ulcers are not reported here. STATISTICAL ANALYSIS Data were analyzed using SPSS software version 13 (SPSS Inc., Chicago, IL, USA). ManneWhitney test was used to statistically analyze and compare mean pain scores between the 2 groups. Wilcoxon-signed ranks test was used to compare the change in mean pain scores from baseline to other time intervals within each group. A P value of <.05 was considered statistically significant. RESULTS Twenty-five subjects ranging in age from 18 to 40 years composed the study cohort. The overall mean age of the patients was 27.48 6.82 with no significant differences between the mean ages of men and women (28.20 6.11 and 26.40 7.99 respectively). The mean pretreatment pain scores in the laser and placebo groups were observed to be 8.48 0.71 and 8.08 0.70 respectively (Table I). Immediately after
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ORIGINAL ARTICLE Prasad R. and Pai 191
Table I. Comparison of pain scores between laser group and placebo before and after treatment Mean Laser Placebo
SD
SEM
Median
Mean difference
Z
P value
B
A
B
A
B
A
B
A
B
A
B
A
B
A
8.48 8.08
0.68 7.96
0.71 0.70
0.63 0.84
0.14 0.14
0.13 0.17
9.0 8.0
1.0 8.0
0.400
7.280
1.910
6.190
.056
<.001*
SD, standard deviation; SEM, standard error of the mean; B, before; A, after. *Denotes significant difference.
Fig. 1. Mean healing time (in days).
laser irradiation, the mean pain score in the laser group dramatically reduced to 0.68 0.63, whereas a significant reduction was not observed in the placebo group (7.96 0.84; P < .001; Table I). There were no clinically evident changes noted soon after treatment. Mean pain scores (with maximum score being 10) were compared 24 h subsequent to completion of treatment between laser treated and placebo ulcers. The mean pain score of the laser group at 24 h was 0.28 0.54 (P .001). Healing time (recorded in days) was also faster in the laser treated ulcers. Figure 1 shows that the mean healing score was 4.08 0.81 days for the laser treatment group compared to 7.84 0.90 days in the placebo group (P < .001). In the control group, the mean pain score before treatment was 8.08 0.70, and immediately after treatment it was 07.69 0.84, which was significantly higher when compared to laser group. A summary of results showing comparisons between the laser and placebo groups before treatment, immediately after treatment and 24 h after treatment are depicted in Figure 2.
DISCUSSION The results of this study showed that a single session of CO2 laser irradiation on miRAU enabled sustained reduction in pain immediately and significantly. Additionally, treatment also had a positive effect on healing duration of the lesions. The procedure was non-invasive, required no anesthetic agent and had no observable adverse effects on the mucosa. Numerous treatments have been proposed for RAS, and most of them are focused at decreasing the symptoms,
Fig. 2. Box plots showing comparison between laser and placebo groups before treatment, immediately after treatment and 24 h after treatment. Wilcoxon-signed ranked test was used to compare the boxes vs. baseline or immediately after laser treatment. Pain level was measured using a numerical analog scale (maximum score 10). * Denotes P < .001 and 5 denotes P ¼ .002.
reducing recurrences, and increase disease-free intervals. Since aphthous ulcers are mucosal lesions, where the pain experienced is disproportionate to the size of the lesion and have few proven and conclusive treatment modalities, this study was conducted to explore alternate treatments to effectively treat these lesions. Lasers were considered as the choice of alternate treatment due to some of their promising properties such as excellent water absorption property and their effective absorption by biological tissues.11 Additionally, lasers allow for the treatment to be delivered in high precision with minimal disturbance of surrounding structures.12 Lasers are also known to reduce edema9 and aid in wound sterilization13 and hemostasis.14 Some investigators who used the classical applications of CO2 lasers reported less post-therapeutic pain subsequent to laser irradiation. In a study by Zand et al.,6 the potential benefit of CO2 irradiation on aphthous ulcers was evaluated. Their study was composed of a sample of 15 patients with at least 2 discrete ulcers, where one among them was randomly allocated to receive laser irradiation at 1 W power and the other
ORAL MEDICINE 192 Prasad R. and Pai
received a placebo. Patients did not receive any anesthetic agent during treatment. The investigators reported an immediate and significant reduction in pain compared with the placebo group.6 In another study by Colvard and Kuo9 CO2 laser therapy was used to treat 25 miRAU lesions in 18 patients. Preoperative medication with ketoprofen and anesthesia with 1:200,000 2% isocaine with 1:20,000 neo-cobefrin was administered prior to laser irradiation. Each sore was irradiated with 4 W of CO2 generated photon energy through a 2 mm focal spot for photon pulse duration of 10 ms. Laser therapy either reduced or eliminated the preexisting pain and inflammation and displayed normal wound healing.9 The major drawback of this study was that they lacked controls to compare the beneficial effects rendered by the laser intervention. Our study included 25 placebo treated ulcers as controls that were evaluated for the same pretreatment and posttreatment parameters. Two interesting case reports by Elad et al.,11 have shown the beneficial merits of CO2 laser application in a non-ablative manner at 1 W for 2-3 s with reduction of pain in oral lesions of graft versus host disease (GVHD) and RAU. The procedure was not painful and did not require anesthesia. Following CO2 laser treatment, there were no visual effects of damage to the oral mucosa, such as coagulation, vaporization or erythema. The time of the procedure was lesser compared to the present study.11 A study conducted by Buller and Sela on a 50 year old female patient with stress related RAU showed a rapid and long-term pain relief following a CO2 laser application used in continuous mode at 1-1.5 W for 5 s.10 Whereas all the above studies used 1 W or more power for treatment of RAS, we obtained similar results at 0.7 W. We feel that this reduced wattage further reduces the exposure of laser radiation to the patient, thereby improving safety. To consider the differences in pain threshold for different individuals from our sample of 25 subjects, each patient served as his or her own control. The pain scores measured in VAS scale by Zand et al.6 demonstrated significant differences between pre-operative and post-operative readings (6.2 1.3 and 0.07 0.3). A similar scale of differences was observed in our study. The mean pain score reduced immediately from 8.48 0.71 to 0.68 0.63 subsequent to treatment in the laser group, whereas the placebo group demonstrated no such major differences between pre-operative and post-operative recordings. Both the Zand et al.6 report and our study, observed similar significant differences in mean pain values between the laser and placebo groups measured 24 h after the intervention was administered. The CO2 laser has a high precision with unique ability to be focused to a small focal spot size, with less
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damage to the surrounding tissues, producing consistent and predictable outcomes.12 An additional advantage is that the procedure is pain-free requiring no anesthesia to administer treatment. The analgesic effect of CO2 laser could be attributed to neural changes or suppression of inflammatory mediators caused by the laser, a finding that requires further validation.6 The laser application in the study was in a non-contact and non-ablative manner. But as a precaution to prevent thermal damage to the mucosa due to the heat produced by CO2 lasers,15 we applied high water content gel on the lesions prior to irradiation. Additionally, the wet mucosal surface augmented the effect of heat control. The moist mucosa and high water content gel controlled the temperature rise due to laser application on the ulcer surfaces, thereby providing enhanced comfort to the recipient. With these measures, we did not observe any visible effects of thermal damage on the mucosa. Another important parameter was healing of laser treated ulcers, which was hastened in this study. The mean healing time (in days) was found to be lower in laser group compared to placebo group (4.08 0.81 and 7.84 0.90 respectively). Previous studies have reported beneficial effects on wound healing due to low intensity laser application. A study by Hopkins et al.16 reported enhanced wound healing measured by the quantum of wound contraction. It was observed that laser treated wounds contracted 153% more than the placebo group when recorded 6 days subsequent to irradiation. The study suggested an indirect mechanism of action of lasers on the tissue surrounding the wound leading to enhanced contraction. A recently published article on the subject by Zand et al.17 reported a significant reduction in healing time for ulcers treated with CO2 lasers. The study also observed no visible damage to the mucosa and the complete procedure was painless requiring no anesthesia. The mechanisms by which laser can contribute to improved wound healing are not completely understood. Some of the explanations for this effect have been bio-stimulation for increased fibroblast numbers and migration,18 increased collagen organization in response to laser irradiation, anti-inflammatory effect evidenced through observing reduced neutrophil infiltrate,19 and promotion of growth factors and other substances in the blood stream.20 The present study provides evidence that CO2 laser therapy may help in the treatment of patients with miRAU. Future studies should be performed with a larger sample size that compare healing and recurrence rates between men and women, to warrant any gender based biases that may occur in the mechanism of action of this treatment. Major aphthous stomatitis and herpetiform ulcers can be included and evaluated for pain relief, healing and recurrences. Inclusion of these subtypes would provide an opportunity to study the
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modifications needed in laser parameters for treating these types of ulcers.
CONCLUSION A single session of CO2 laser treatment in non-contact, non-ablative, and non-invasive method without the use of any anesthesia offers a promising modality for pain relief (sustained until 24 h duration) and accelerated healing. However, further research is warranted to confirm the mechanisms involved in producing analgesic effect and accelerated healing. The authors thank Mr Thejasvi Venkateshmurthy, Stat Intelligence Network, Bangalore, for compiling the statistical data.
REFERENCES 1. Barrons RW. Treatment strategies for recurrent oral aphthous ulcers. Am J Health Syst Pharm. 2001;58:41-50. 2. Shashy RG, Ridley MB. Aphthous ulcers: a difficult clinical entity. Am J Otolaryngol. 2000;21:389-393. 3. Vincent SD, Lilly GE. Clinical, historic, and therapeutic features of aphthous stomatitis: literature review and open clinical trial employing steroids. Oral Surg Oral Med Oral Pathol. 1992;74: 79-86. 4. Ship JA. Recurrent aphthous stomatitis: an update. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1996;81:141-147. 5. Akintoye SO, Greenberg MS. Recurrent aphthous stomatitis. Dent Clin North Am. 2005;49:31-47. 6. Zand N, Ataie-Fashtami L, Djavid G, 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. 7. Genot MT, Klastersky J. Low-level laser for prevention and therapy of oral mucositis induced by chemotherapy or radiotherapy. Curr Opin Oncol. 2005;17:236-240. 8. De Souza TO, Martins MA, Bussadori SK, et al. Clinical evaluation of low-level laser treatment for recurring aphthous stomatitis. Photomed Laser Surg. 2010;28:85-88. 9. Colvard M, Kuo P. Managing aphthous ulcers: laser treatment applied. J Am Dent Assoc. 1991;122:51-53.
ORIGINAL ARTICLE Prasad R. and Pai 193 10. Sharon-Buller A, Sela M. CO2-laser treatment of ulcerative lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:332-334. 11. Elad S, Or R, Shapira MY, et al. CO2 laser in oral graft-versushost disease: a pilot study. Bone Marrow Transplant. 2003;32: 1031-1034. 12. Catone GA, Alling CC. Textbook on Laser Applications in Oral and Maxillofacial Surgery. WB Saunders; 1997:73e85. 13. Kesler G, Koren R, Kesler A, Hay N, Gal R. Histological changes induced by CO2 laser microprobe specially designed for root canal sterilization: in vivo study. J Clin Laser Med Surg. 1998;16: 263-267. 14. Darbar UR, Hopper C, Speight PM, Newman HN. Combined treatment approach to gingival overgrowth due to drug therapy. J Clin Periodontol. 1996;23:941-944. 15. Kutsch VK. Lasers in dentistry: comparing wavelengths. J Am Dent Assoc. 1993;124:49-54. 16. Hopkins JT, McLoda TA, Seegmiller JG, Baxter GD. Lowlevel laser therapy facilitates superficial wound healing in humans: a triple-blind, sham-controlled study. J Athl Train. 2004;39:223. 17. Zand N, Fateh M, Ataie-Fashtami L, Djavid GE, Fatemi S-M, 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. 18. Basso FG, Pansani TN, Turrioni APS, Bagnato VS, Hebling J, de Souza Costa CA. In vitro wound healing improvement by lowlevel laser therapy application in cultured gingival fibroblasts. Int J Dent. 2012;2012:1-6. 19. Lopes NNF, Plapler H, Lalla RV, et al. Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamsters. Lasers Surg Med. 2010;42:546-552. 20. Damante C, Micheli G, Miyagi S, Feist I, Marques M. Effect of laser phototherapy on the release of fibroblast growth factors by human gingival fibroblasts. Lasers Med Sci. 2009;24:885-891.
Reprint requests: Shesha Prasad R. Department of Oral Medicine and Radiology The Oxford Dental College Bommanahalli, Hosur Road, Bangalore 560068, Karnataka, India [email protected]; [email protected]
Assessment of immediate pain relief with laser treatment in recurrent aphthous stomatitis Shesha Prasad R.,a and Anuradha Pai, MDSb The Oxford Dental College, Bangalore, Karnataka, India
Objectives. To compare immediate pain relief, healing time between minor recurrent aphthous ulcers treated with a single session of carbon dioxide (CO2) laser and a placebo. Study Design. A prospective clinical study was performed on 25 patients with minor recurrent aphthous stomatitis. Pretreatment pain levels were recorded using a numerical rating scale. Ulcers were randomized to either receive treatment or placebo. Pain levels were assessed immediately after treatment and after 24 h. Healing was assessed on days 3 and 4, and once every 2 days thereafter for 2 weeks. Results. Mean pain scores in the laser group were significantly reduced immediately after treatment (0.68 0.6) compared with pretreatment (8.48 0.71; P < .001). In contrast, the placebo group showed little difference in pain scores between pretreatment (8.08 0.70) and immediately after treatment (7.96 0.84). In the laser group, significant improvements in healing times were observed (4.08 0.81 vs. 7.84 0.90 days; P < .001). Conclusion. CO2 laser therapy in recurrent aphthous stomatitis (RAS) provides immediate pain relief sustained over 24 h, along with accelerated healing time. (Oral Surg Oral Med Oral Pathol Oral Radiol 2013;116:189-193)
Recurrent aphthous ulceration (RAU), commonly known as canker sores1 is a common oral mucosal disorder characterized by recurring ulcers in patients without the presence of any other systemic disease.2 It affects 5%-25% of the general population, predominantly in the age groups between 10 and 30 years.3 Despite detailed investigations by researchers, the etiology and pathogenesis of this condition have largely remained unknown.4 The challenges faced in determining RAU have been its non-specific histological features and a lack of reproducibility of identifiable endogenous and exogenous causes.3 The condition is routinely diagnosed based on recording a detailed patient history and comprehensive clinical examination.4 Several etiological factors such as local trauma, immunological factors, genetic background, allergic agents, nutrition deficiency, hormonal changes in women, physical or psychic stress, chemical irritants and infective agents have been suspected, but no definitive etiology has been established conclusively.1,2,5 Minor RAU (miRAU) is the most common subtype of this condition and it occurs on non-keratinized mucosa as recurrent, round, clearly defined, small painful ulcers with shallow necrotic centers, raised margins, and erythematous halo.4,6 The ulcers tend to be painful with the pain usually subsiding after 4-5 a
Post Graduate Student, Department of Oral Medicine and Radiology, The Oxford Dental College. b Professor, Department of Oral Medicine and Radiology, The Oxford Dental College. Received for publication Sep 29, 2012; returned for revision Feb 5, 2013; accepted for publication Feb 15, 2013. Ó 2013 Elsevier Inc. All rights reserved. 2212-4403/$ - see front matter http://dx.doi.org/10.1016/j.oooo.2013.02.011
days. During their course, they can significantly interfere with eating and speaking affecting quality of life.6 Different treatment options for miRAU include systemic medications, topical applications, acupuncture, corticosteroids, psychotherapy, and combination therapy. In addition, accumulating evidence provides support of laser therapy in the treatment of oral mucosal lesions and aphthous ulcers.7 Recently, a study revealed that 75% of the patients experienced relief of pain immediately after low-level laser treatment and a total regression of the ulcer in 4 days when compared with a group treated with corticoid agent, where the regression was observed between 5 and 7 days.8 In particular, there have been reports of carbon dioxide (CO2) lasers being used to treat aphthous ulcers with considerable success with regard to pain relief. A study by Colvard and Kuo9 have reported the use of CO2 laser for ablation of aphthous ulcers while 3 other studies have also reported beneficial effects of CO2 lasers with regard to pain resolution in aphthous ulcers and host versus graft disease cases.6,8,10 With the presence of such preliminary evidences, lasers have emerged as one of the treatment modalities for this common, painful mucosal lesion. Unlike pharmacological interventions, it has no known side effects or deleterious interactions.6
Statement of Clinical Relevance A single session CO2 laser operated at 0.7w power with a de-focused hand piece 5-7 mm from the mucosal surface for 5-8 seconds in a non-ablative manner can be a promising treatment modality for RAS. 189
ORAL MEDICINE 190 Prasad R. and Pai
The present study was designed and undertaken to assess the efficacy of a single session CO2 laser treatment, at 10.6 nm wavelength, in a non-ablative manner to provide immediate pain relief in patients presenting with miRAU.
MATERIALS AND METHODS The study sample was composed of a total of 25 adults, with history of miRAU, selected from a pool of patients visiting the Department of Oral Medicine and Radiology at the Oxford Dental College in Bangalore, between July 2010 and May 2012. Local privately practicing physicians were requested to screen patients for history of recurrent oral ulcers and refer them to our institution out-patient clinic. The sample size was limited to 25 among the total of 42 patients who fulfilled the inclusion criteria as only those 25 were available for the complete duration of the study. The 25 subjects were selected based on the predetermined inclusion and exclusion criteria listed below. All subjects signed an informed consent to participate in the study. The clinical protocol was reviewed and approved by the ethics committee of the Oxford Dental College. Prior to enrollment into the study, all subjects underwent routine clinical examination from a qualified physician and necessary laboratory investigations were conducted. Those patients with authentic history of miRAU, with the presence of at least 2 discrete painful minor aphthous ulcers at the same time presenting to the hospital within 3 days of appearance of such ulcers were included in the study. Exclusion criteria were pregnancy, history of systemic disease or condition that could predispose the patient to develop oral ulcers, presence of any major herpetiform aphthae, traumatic ulcers, ulcers caused due to topical or systemic medications, and, ulcers currently under treatment. The enrolled patients agreed not to take analgesics before, during and 3 days after the procedure. STUDY DESIGN In each of these patients, 2 ulcers as measured by the investigator, of dimension approximately 1 cm or less were selected in different locations in the oral cavity. One of them was randomly allocated to be treated with CO2 laser (Union Medical Engineering Co., UM-L25 special edition, Korea), and the other served as a placebo. It was a single-blind study designed in a manner such that the patients were unaware as to which of the lesions was going to be treated with laser and which one would be selected as a placebo. Pain scores recorded prior to commencement of treatment were compared with those recorded immediately after the treatment and at 24 h following completion of treatment. Healing period of the laser treated ulcer was
OOOO August 2013
compared with the placebo ulcer on a follow-up visit conducted 3-4 days subsequent to treatment.
STUDY PROCEDURE Patients were requested to sip water before commencement of the treatment to keep the mucosa wet. Subsequently, a high water gel, devoid of any anesthetic properties, and composed of a combination of 90% water and 10% carboxymethyl cellulose (Shristi Pharmaceuticals, Bangalore) was applied on both the ulcers using a sterile cotton. The CO2 laser was operated at 0.7 W power, with a de-focused hand piece in a continuous mode for 5-8 s, at a distance of 5-7 mm away from the mucosal surface in spiral motion. The placebo lesion was irradiated with the same instrument, but with an inactive probe. The patients were requested to grade the pain of their ulcers on a numerical rating scale of 1-10, [score ‘0’ indicated no pain and score ‘10’ indicated maximum pain] before and immediately after the procedure. Scores were also recorded postoperatively after 24 h. In patients with more than 2 ulcers, Lignocaine gel (Lignox gel, Warren Pharmaceuticals, India) was prescribed to be applied 24 h postlaser treatment to manage pain in those ulcers that were neither part of laser group nor placebo. Healing time of the laser-irradiated ulcer was compared with the placebo in a recall clinical visit 3-4 days following completion of the treatment. The patients were evaluated every 2 days for the next 2 weeks. Total reduction of erythema and the absence of an ulcer clinically was considered as healed. Regular telephone calls were made once in an every 2 weeks for a period of 6 months to evaluate the recurrence rates of the ulcers. The findings of the recurrence rates of laserirradiated ulcers are not reported here. STATISTICAL ANALYSIS Data were analyzed using SPSS software version 13 (SPSS Inc., Chicago, IL, USA). ManneWhitney test was used to statistically analyze and compare mean pain scores between the 2 groups. Wilcoxon-signed ranks test was used to compare the change in mean pain scores from baseline to other time intervals within each group. A P value of <.05 was considered statistically significant. RESULTS Twenty-five subjects ranging in age from 18 to 40 years composed the study cohort. The overall mean age of the patients was 27.48 6.82 with no significant differences between the mean ages of men and women (28.20 6.11 and 26.40 7.99 respectively). The mean pretreatment pain scores in the laser and placebo groups were observed to be 8.48 0.71 and 8.08 0.70 respectively (Table I). Immediately after
OOOO Volume 116, Number 2
ORIGINAL ARTICLE Prasad R. and Pai 191
Table I. Comparison of pain scores between laser group and placebo before and after treatment Mean Laser Placebo
SD
SEM
Median
Mean difference
Z
P value
B
A
B
A
B
A
B
A
B
A
B
A
B
A
8.48 8.08
0.68 7.96
0.71 0.70
0.63 0.84
0.14 0.14
0.13 0.17
9.0 8.0
1.0 8.0
0.400
7.280
1.910
6.190
.056
<.001*
SD, standard deviation; SEM, standard error of the mean; B, before; A, after. *Denotes significant difference.
Fig. 1. Mean healing time (in days).
laser irradiation, the mean pain score in the laser group dramatically reduced to 0.68 0.63, whereas a significant reduction was not observed in the placebo group (7.96 0.84; P < .001; Table I). There were no clinically evident changes noted soon after treatment. Mean pain scores (with maximum score being 10) were compared 24 h subsequent to completion of treatment between laser treated and placebo ulcers. The mean pain score of the laser group at 24 h was 0.28 0.54 (P .001). Healing time (recorded in days) was also faster in the laser treated ulcers. Figure 1 shows that the mean healing score was 4.08 0.81 days for the laser treatment group compared to 7.84 0.90 days in the placebo group (P < .001). In the control group, the mean pain score before treatment was 8.08 0.70, and immediately after treatment it was 07.69 0.84, which was significantly higher when compared to laser group. A summary of results showing comparisons between the laser and placebo groups before treatment, immediately after treatment and 24 h after treatment are depicted in Figure 2.
DISCUSSION The results of this study showed that a single session of CO2 laser irradiation on miRAU enabled sustained reduction in pain immediately and significantly. Additionally, treatment also had a positive effect on healing duration of the lesions. The procedure was non-invasive, required no anesthetic agent and had no observable adverse effects on the mucosa. Numerous treatments have been proposed for RAS, and most of them are focused at decreasing the symptoms,
Fig. 2. Box plots showing comparison between laser and placebo groups before treatment, immediately after treatment and 24 h after treatment. Wilcoxon-signed ranked test was used to compare the boxes vs. baseline or immediately after laser treatment. Pain level was measured using a numerical analog scale (maximum score 10). * Denotes P < .001 and 5 denotes P ¼ .002.
reducing recurrences, and increase disease-free intervals. Since aphthous ulcers are mucosal lesions, where the pain experienced is disproportionate to the size of the lesion and have few proven and conclusive treatment modalities, this study was conducted to explore alternate treatments to effectively treat these lesions. Lasers were considered as the choice of alternate treatment due to some of their promising properties such as excellent water absorption property and their effective absorption by biological tissues.11 Additionally, lasers allow for the treatment to be delivered in high precision with minimal disturbance of surrounding structures.12 Lasers are also known to reduce edema9 and aid in wound sterilization13 and hemostasis.14 Some investigators who used the classical applications of CO2 lasers reported less post-therapeutic pain subsequent to laser irradiation. In a study by Zand et al.,6 the potential benefit of CO2 irradiation on aphthous ulcers was evaluated. Their study was composed of a sample of 15 patients with at least 2 discrete ulcers, where one among them was randomly allocated to receive laser irradiation at 1 W power and the other
ORAL MEDICINE 192 Prasad R. and Pai
received a placebo. Patients did not receive any anesthetic agent during treatment. The investigators reported an immediate and significant reduction in pain compared with the placebo group.6 In another study by Colvard and Kuo9 CO2 laser therapy was used to treat 25 miRAU lesions in 18 patients. Preoperative medication with ketoprofen and anesthesia with 1:200,000 2% isocaine with 1:20,000 neo-cobefrin was administered prior to laser irradiation. Each sore was irradiated with 4 W of CO2 generated photon energy through a 2 mm focal spot for photon pulse duration of 10 ms. Laser therapy either reduced or eliminated the preexisting pain and inflammation and displayed normal wound healing.9 The major drawback of this study was that they lacked controls to compare the beneficial effects rendered by the laser intervention. Our study included 25 placebo treated ulcers as controls that were evaluated for the same pretreatment and posttreatment parameters. Two interesting case reports by Elad et al.,11 have shown the beneficial merits of CO2 laser application in a non-ablative manner at 1 W for 2-3 s with reduction of pain in oral lesions of graft versus host disease (GVHD) and RAU. The procedure was not painful and did not require anesthesia. Following CO2 laser treatment, there were no visual effects of damage to the oral mucosa, such as coagulation, vaporization or erythema. The time of the procedure was lesser compared to the present study.11 A study conducted by Buller and Sela on a 50 year old female patient with stress related RAU showed a rapid and long-term pain relief following a CO2 laser application used in continuous mode at 1-1.5 W for 5 s.10 Whereas all the above studies used 1 W or more power for treatment of RAS, we obtained similar results at 0.7 W. We feel that this reduced wattage further reduces the exposure of laser radiation to the patient, thereby improving safety. To consider the differences in pain threshold for different individuals from our sample of 25 subjects, each patient served as his or her own control. The pain scores measured in VAS scale by Zand et al.6 demonstrated significant differences between pre-operative and post-operative readings (6.2 1.3 and 0.07 0.3). A similar scale of differences was observed in our study. The mean pain score reduced immediately from 8.48 0.71 to 0.68 0.63 subsequent to treatment in the laser group, whereas the placebo group demonstrated no such major differences between pre-operative and post-operative recordings. Both the Zand et al.6 report and our study, observed similar significant differences in mean pain values between the laser and placebo groups measured 24 h after the intervention was administered. The CO2 laser has a high precision with unique ability to be focused to a small focal spot size, with less
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damage to the surrounding tissues, producing consistent and predictable outcomes.12 An additional advantage is that the procedure is pain-free requiring no anesthesia to administer treatment. The analgesic effect of CO2 laser could be attributed to neural changes or suppression of inflammatory mediators caused by the laser, a finding that requires further validation.6 The laser application in the study was in a non-contact and non-ablative manner. But as a precaution to prevent thermal damage to the mucosa due to the heat produced by CO2 lasers,15 we applied high water content gel on the lesions prior to irradiation. Additionally, the wet mucosal surface augmented the effect of heat control. The moist mucosa and high water content gel controlled the temperature rise due to laser application on the ulcer surfaces, thereby providing enhanced comfort to the recipient. With these measures, we did not observe any visible effects of thermal damage on the mucosa. Another important parameter was healing of laser treated ulcers, which was hastened in this study. The mean healing time (in days) was found to be lower in laser group compared to placebo group (4.08 0.81 and 7.84 0.90 respectively). Previous studies have reported beneficial effects on wound healing due to low intensity laser application. A study by Hopkins et al.16 reported enhanced wound healing measured by the quantum of wound contraction. It was observed that laser treated wounds contracted 153% more than the placebo group when recorded 6 days subsequent to irradiation. The study suggested an indirect mechanism of action of lasers on the tissue surrounding the wound leading to enhanced contraction. A recently published article on the subject by Zand et al.17 reported a significant reduction in healing time for ulcers treated with CO2 lasers. The study also observed no visible damage to the mucosa and the complete procedure was painless requiring no anesthesia. The mechanisms by which laser can contribute to improved wound healing are not completely understood. Some of the explanations for this effect have been bio-stimulation for increased fibroblast numbers and migration,18 increased collagen organization in response to laser irradiation, anti-inflammatory effect evidenced through observing reduced neutrophil infiltrate,19 and promotion of growth factors and other substances in the blood stream.20 The present study provides evidence that CO2 laser therapy may help in the treatment of patients with miRAU. Future studies should be performed with a larger sample size that compare healing and recurrence rates between men and women, to warrant any gender based biases that may occur in the mechanism of action of this treatment. Major aphthous stomatitis and herpetiform ulcers can be included and evaluated for pain relief, healing and recurrences. Inclusion of these subtypes would provide an opportunity to study the
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modifications needed in laser parameters for treating these types of ulcers.
CONCLUSION A single session of CO2 laser treatment in non-contact, non-ablative, and non-invasive method without the use of any anesthesia offers a promising modality for pain relief (sustained until 24 h duration) and accelerated healing. However, further research is warranted to confirm the mechanisms involved in producing analgesic effect and accelerated healing. The authors thank Mr Thejasvi Venkateshmurthy, Stat Intelligence Network, Bangalore, for compiling the statistical data.
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ORIGINAL ARTICLE Prasad R. and Pai 193 10. Sharon-Buller A, Sela M. CO2-laser treatment of ulcerative lesions. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004;97:332-334. 11. Elad S, Or R, Shapira MY, et al. CO2 laser in oral graft-versushost disease: a pilot study. Bone Marrow Transplant. 2003;32: 1031-1034. 12. Catone GA, Alling CC. Textbook on Laser Applications in Oral and Maxillofacial Surgery. WB Saunders; 1997:73e85. 13. Kesler G, Koren R, Kesler A, Hay N, Gal R. Histological changes induced by CO2 laser microprobe specially designed for root canal sterilization: in vivo study. J Clin Laser Med Surg. 1998;16: 263-267. 14. Darbar UR, Hopper C, Speight PM, Newman HN. Combined treatment approach to gingival overgrowth due to drug therapy. J Clin Periodontol. 1996;23:941-944. 15. Kutsch VK. Lasers in dentistry: comparing wavelengths. J Am Dent Assoc. 1993;124:49-54. 16. Hopkins JT, McLoda TA, Seegmiller JG, Baxter GD. Lowlevel laser therapy facilitates superficial wound healing in humans: a triple-blind, sham-controlled study. J Athl Train. 2004;39:223. 17. Zand N, Fateh M, Ataie-Fashtami L, Djavid GE, Fatemi S-M, 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. 18. Basso FG, Pansani TN, Turrioni APS, Bagnato VS, Hebling J, de Souza Costa CA. In vitro wound healing improvement by lowlevel laser therapy application in cultured gingival fibroblasts. Int J Dent. 2012;2012:1-6. 19. Lopes NNF, Plapler H, Lalla RV, et al. Effects of low-level laser therapy on collagen expression and neutrophil infiltrate in 5-fluorouracil-induced oral mucositis in hamsters. Lasers Surg Med. 2010;42:546-552. 20. Damante C, Micheli G, Miyagi S, Feist I, Marques M. Effect of laser phototherapy on the release of fibroblast growth factors by human gingival fibroblasts. Lasers Med Sci. 2009;24:885-891.
Reprint requests: Shesha Prasad R. Department of Oral Medicine and Radiology The Oxford Dental College Bommanahalli, Hosur Road, Bangalore 560068, Karnataka, India [email protected]; [email protected]