Low-Level Laser Therapy and Topical Medications for Treating Aphthous Ulcers: A Systematic Review

Figures & data

Table 1 Search Terms and Strategies

Search Strategy	Search Terms and Boolean Operators	Number of Articles Retrieved
#1	Aphthous ulcer OR aphthous stomatitis OR recurrent Aphthous stomatitis
#2	Benzalkonium chloride
#3	Choline salicylate
#4	Lignocaine OR lidocaine
#5	Diclofenac
#6	Glucocorticoids
#7	Tetracyclines
#8	Laser*
#9	Low level laser therapy (LLLT) OR photobiomodulation
#7	#1 AND #8	83
#8	#1 AND #9	22
#9	#1 AND #2 AND #3 AND #4	1
#10	#1 AND #2	2
#11	#1 AND #3	3
#12	#1 AND #4	22
#13	#1 AND #5	0
#14	#1 AND #6	2
#15	#1 AND #7	1
	Total hits	136

Table 2 Description on Study Setting, Sample, Exposure, Outcome, and Conclusion of the Included Studies

Item	Author, Year	Study Setting	Sample Description	Laser Treatment	Topical Medication	Follow Up	Conclusion (Healing Time, Pain, Size of Ulcer, Reoccurrence)
1	Tezel et al, 200911	Turkey	Total sample: n=20 Male=7 Female=13 Laser group: n=10 Male=3 Female=7 Topical medication group: n=10 Male=4 Female=6	Anesthetic Gel (articaine 4%) + Nd:YAG laser 1.064 nm Dose: Under air-cooling with 2–3 minutes duration.	Triamcinolone Acetonide. Dose: Three times daily for 1 week.	Days 1, 4, and 7	Pain: Laser – immediate pain relief and faster healing Topical medication group - gradual reduction on day 5. Patient preference: Significant in Laser group Post-treatment complications (chewing, speaking lower in Laser group) Erythema – no difference in both groups.
2	De Souza et al, 201023	Brazil	Total sample: n=20 Male=8 Female=12 Laser group: n=15 Topical medication group: n=5 Age: up to 70 years	InGaA1P diode laser, 670 nm. Dose: 1 minute, laser pen touching the surface of lesion.	Triamcinolone acetonide administered four times daily, as long as lesion persisted.	Day 1 to day 7	Pain: 86.6% of the patients, having undergone laser treatment, reported a reduction in pain in the same session (P=0.0006). Regression time: No significant difference observed between the two groups.
3	Lalabonova and Daskalov., 201424	Bulgaria	Total sample: n=180 Male=31 Female=149 Mean age: 43.01 (1.05) years	SIX Laser TS diode laser – 658 nm. Dose: One session a day until symptoms abated.	Granofurin and Solcoseryl. Dose: Twice daily until symptoms disappeared.	Days 1, 2, 3, and 5	Pain: Laser group: Day 3=100% patients pain free Topical medication group: Day 5=44.4% pain free Erythema: Laser group: Day 3=100% patients with no erythema Topical medication group Day 5=22.3% patients with no erythema Epithelization: Laser group: Day 5=75.6% of patients with complete epithelization. Topical medication group: Day 5=37.8% patients with complete epithelization.
4	Jijin et al, 201625	India	Total sample: n=50 Male=29 Female=21 Laser group: n=25 Male=14 Female=11 Topical medication group: n=25 Male=15 Female=10 Age: 15–55 years	AMD laser 810 nm Dose: 30 seconds, and 3 times with 2 minute interval. Applied twice after day 1 day of treatment, followed by day 3 and day 7.	5% Amlexanox given four times daily for 7 days.	Days 1, 3,and 7	Pain: The mean pain score was significantly less in the laser group on day 3 than the Amlexanox group, but not by day 7.
5	Nasry et al, 201626	Egypt	Total sample: n=60 Male=23 Female=37 Age: 19–40 years	Group III: Diode laser, 970 nm Dose: 30–45 seconds with 15–20 seconds gap, 4 sessions. I, II, IV – applied 4 times, 5 days.	Group I: Herbal paste combination (Glycyrrhiza glabra + Acacia nilotica) Group II: Amlexanox Tabs (2 mg) Group IV: Placebo adhesive tablets.	Immediately, and on days 2 and 5	Pain and size: Group III – Laser group reported highest reduction in pain and ulcer size on day 5. Group I showed reduction in pain and size when compared to control group IV.

Table 3 Risk of Bias Assessment Using the Cochrane Guidelines (RoB-2)

Item	Signaling Question	Tezel et al, 200911	Lalabonova and Daskalov 201423	De Souza et al, 201024	Jijin et al, 201625	Nasry et al, 201626
Domain 1: Risk of bias arising from the randomization process (selection bias)
1.1	Was the allocation sequence random?	Yes	No	No	No	No
1.2	Was the allocation sequence concealed until participants were enrolled and assigned to interventions?	No	No	No	No	No
1.3	Did baseline differences between intervention groups suggest a problem with the randomization process?	No	No	No	No	No
Risk of bias judgment		Some concerns	Some concerns	Some concerns	Some concerns	Some concerns
Domain 2: Risk of bias due to deviations from the intended interventions (selection bias)
2.1	Were participants aware of their assigned intervention during the trial?	Yes	Yes	Yes	Yes	Yes
2.2	Were people delivering the interventions aware of participants’ assigned intervention during the trial?	Yes	Yes	Yes	Yes	Yes
2.3	Were there deviations from the intended intervention that arose because of the trial context?	No	No	No	No	No
2.4	Were these deviations likely to have affected the outcome?	N/A	N/A	N/A	N/A	N/A
Risk of bias judgment		Some concerns	Some concerns	Some concerns	Some concerns	Some concerns
Domain 3: Risk of bias due to missing outcome data (attrition bias)
3.1	Were data for this outcome available for all, or nearly all, participants randomized?	Yes	Yes	Yes	Yes	Yes
3.2	Is there evidence that the result was not biased by missing outcome data?	N/A	N/A	N/A	N/A	N/A
3.3	Could missingness in the outcome depend on its true value?	N/A	N/A	N/A	N/A	N/A
3.4	Is it likely that missingness in the outcome depended on its true value?	N/A	N/A	N/A	N/A	N/A
Risk of bias judgment		Low risk	Low risk	Low risk	Low risk	Low risk
Domain 4: Risk of bias in measurement of the outcome (detection bias)
4.1	Was the method of measuring the outcome inappropriate?	No	No	No	No	No
4.2	Could measurement or ascertainment of the outcome have differed between intervention groups?	No	No	No	No	No
4.3	Were outcome assessors aware of the intervention received by study participants?	Yes	Yes	Yes	Yes	No
4.4	Could assessment of the outcome have been influenced by knowledge of intervention received?	Yes	Yes	Yes	Yes	No
Risk of bias judgment		High risk	High risk	High risk	High risk	Low risk
Domain 5: Risk of bias in selection of the reported result (reporting bias)
5.1	Were the data that produced this result analyzed in accordance with a pre-specified analysis plan that was finalized before unblinded outcome data were available for analysis?	Yes	Yes	Yes	Yes	Yes
5.2	Multiple eligible outcome measurements (eg scales, definitions, time points) within the outcome domain?	Yes	Yes	Yes	Yes	Yes
5.3	Multiple eligible analyses of the data?	No	No	No	No	No
Risk of bias judgment		Low risk	Low risk	Low risk	Low risk	Low risk

Notes: Data from Sterne et al.19

Figure 1 PRISMA flow chart illustrating the study selection process.

Notes: PRISMA figure adapted from Liberati A, Altman D, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Journal of clinical epidemiology. 2009;62(10). Creative Commons.

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. 2009;27(1):101–106. doi:10.1089/pho.2008.2274

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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(Suppl 2):S85–S88. doi:10.1089/pho.2009.2661

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Hristina Lalabonova HD, Daskalov H. Clinical assessment of the therapeutic effect of low-level laser therapy on chronic recurrent aphthous stomatitis. Biotechnol Biotechnol Equip. 2014;28(5):929–933. doi:10.1080/13102818.2014.966526

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Jijin MJ, Rakaraddi M, Pai J, et al. Low-level laser therapy versus 5% amlexanox: a comparison of treatment effects in a cohort of patients with minor aphthous ulcers. Oral Surg Oral Med Oral Pathol Oral Radiol. 2016;121(3):269–273. doi:10.1016/j.oooo.2015.11.021

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Nasry SA, El Shenawy HM, Mostafa D, Ammar NM. Different modalities for treatment of recurrent aphthous stomatitis. A randomized clinical trial. J Clin Exp Dent. 2016;8(5):e517–e522.

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Sterne JAC, Savović J, Page MJ, et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898

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