Table 1.
Summary of included studies and quality of evidence.
| Author/Year | Intervention | Sample size; Mean age (years) (study/control) | Outcome assessment method | Finding summaryShort term (≤3 months) | Long term (>3 months) | Adverse Effect | Quality of Evidence (Grade) |
|---|---|---|---|---|---|---|---|
| (20) | Clonazepam (0.5 mg)Dosage: 0.5 mgDurations: 9 weeksRoute: Oral | 10/10; 67.5/65.4 | • Numerical pain ratings (0–10)• BDI• ZMS• Taste test• Smell test• Salivary flow rate | • NPS: Significant difference between clonazepam (MD: 2.9) and placebo (MD: −1.5), (p = 0.011)• Taste and saliva: Clonazepam group show significant increase in taste score (p = 0.023) and salivary flow (p = 0.033)• No significant difference between clonazepam and placebo in taste (p = 0.83) and salivary flow (p = 0.060)• Depression and mood. No significant difference | No side effect on psychology. | Moderate | |
| (19) | Clonazepam (0.5 mg)Dosage: 0.5–2.0 mg/dayDuration: 6 monthsRoute: Topical. Dissolved in mouth and spat out after 3 min | 33/33; 64.9 /64.9 | • VAS | • Significant decrease in VAS for Clonazepam (MD: −4.7)• 23 study group improved more than 50% (p < 0.05) and three were totally asymptomatic• Not significant decrease in control group (MD: −3.2)• Reduced in tasted alteration and dryness in clonazepam group | Test group: Five had sleepiness but did not require termination of treatment | Moderate | |
| (39) | Clonazepam (2 mg) Dosage: 2 mg/dayDuration: 4 months Route: Oral Pregabalin (150 mg)Dosage: 150 mg/dayDuration: 4 monthsRoute: Oral ALA (600 mg) Dosage: 600 mg/dayDuration: 4 monthsRoute: Oral | 25; 4325;4525;42 | • VAS | • Significant reduction in VAS score clonazepam (MD: −4.1, p < 0.001)• Significant reduction in pregabalin VAS score (MD: −4.7, p < 0.001)• No significant reduction in VAS score ALA (MD: −0.7) | • Four dizziness, two transient diarrhoea, two myalgia• Three increased appetite, one vertigo, one mild nausea, one diarrhoea• Two mild nausea, one myalgia | Very low | |
| (21) | Trazodone (100 mg) Dosage 1: 100 mgDuration 1: 4 daysDaily for 4 days Dosage: 200 mg Duration: 8 weeks Route: Oral | 11/17; 61.1/NA | • VAS• MPQ• BDI• Global assessment | • Eight in study group and 13 in placebo reported reduction in pain• Pain intensity was significant decreased in (p < 0.01) in both trazodone (MD: −1.4) and placebo group (MD: −1.3)• No significant difference between both groups in treatment effect and treatment by time interaction for pain intensity• No significant differences between the groups MPQ for influence of pain on eating, speaking, sleeping or for the suffering caused by the pain• No significant difference between both group in the patient’s global assessment of improvement or benefits of the treatment• Significant decreased in BDI for both groups in the depression score (p < 0.01) | Significant dizziness (p < 0.001) and drowsiness (p < 0.05) in trazodone group than placebo Test group:• 11 reported dizziness, nine drowsiness, five abdominal pain, three headache, two palpitation, two tremor, three dry mouth and one urinary incontinence | Moderate | |
| (30) | Crocin (15 mg)Dosage: 30 mg/dayDuration: 11 weeks Route: Oral Citalopram (10 mg)Dosage: 10 mg for first week followed by 20 mg dailyDuration: 11 weeks. Route: Oral | 26; 52.921; 49.0 | • VAS• HAD• DSM IV psychiatric diagnosis | • No significant difference in VAS mean score between crocin and citalopram (p = 0.98)• Significant reduced in crocin VAS (MD: −7.8, p < 0.001) Average recovery percentage of burning mouth score at the end of treatment for both crocin and citalopram was 87.45%• No significant difference in depression and anxiety between crocin and citalopram (p = 0.76) • Average recovery percentage of depression score at the end of treatment for crocin was 30.57% and citalopram was 30.79%• Average recovery percentage of anxiety score at the end of treatment for crocin was 15.44% and citalopram was 15.40% | Low | ||
| (22) | ALA (200 mg) Dosage: 600 mg/dayDuration: 2 monthsRoute: Oral Participant showing deterioration of symptoms within 4 months will be given another 1 month of supplement | 30/30; 45 /NA | • BMS symptomatology change scale (worsening; unchanged; slight improvement; decided improvement; resolution) | • Statistically significant symptom improvement with ALA (97%) compares with control (40%)• 87% ALA patients showed resolution or a decided improvement in symptom but none in control• None of ALA group has worsening of BMS symptoms but 20% in control | • 73% of ALA remains significantly stable (no changes) but 83% of control group shows significant deterioration | No adverse effect reported | Low |
| (24) | ALA Dosage: 800 mg/dayDuration: 8 weeksRoute: Oral | 23/16; 67/59.3 | • VAS | • No significant difference (p = 0.14) between ALA (MD: 2.2) or control (MD: 3.8) | Test group: One patient has gastrointestinal upset. | Low | |
| (26) | ALA (200 mg) Dosage: 600 mg/dayDuration: 2 monthsRoute: Oral | 29/25; 62.13/ 62.13 | • VAS • Symptoms response categories• (improvement; no change; worse) | • 64% in ALA and 27.6% in control group reported improvement of symptoms• No ALA patients and five control patients reported worsening of symptoms• Statistically significant differences between both groups (p = 0.009) | Low | ||
| (23) | • ALA (400 mg) and vitamin (C, PP, E, B6, 2, 1, 12, and folic acid)Dosage: 800 mg/dayDuration: 8 weeksRoute: Oral• ALA (400 mg)Dosage: 800 mg/day Duration: 8 weeks• Route: Oral | 18/20; 67.3/NA 14/20; 67.3/NA | • VAS• Weighted MPQ | • Significant reduction in pain intensity (VAS) for studies ALA and vitamin (MD: −0.95, p = 0.047) and ALA (MD: −1.79, p = 0.045)• ALA + vitamin: One of 18 improved and 17 of 18 no change or worse• ALA: Four of 14 improved and 10 of 14 no change or worse• No significant difference between both study groups and control group• Improvement in MPQ score with high placebo effect observed• No significant difference between all three groups in MPQ | • Significant reduction in pain intensity (VAS) for studies ALA and vitamin (MD −1.78, p = 0.047) and ALA (MD: −2.00, p = 0.045)• ALA + vitamin:• Six of 18 improved and 12 of 18 no change or worse• ALA:• Four of 18 improved and 14 of 18 no change or worse• No significant difference between both study groups and control group• No significant difference between three groups in MPQ | No adverse effect reported | Moderate |
| (25) | • ALA Dosage: 600 mg/dayDuration: 60 days Route: Oral • GABADosage: 300 mg/dayDuration: 60 daysRoute: Oral • ALA and GABADosage: 600 ALA and 300 GABA/dayDuration: 60 daysRoute: Oral | ALA:20GABA: 20ALA and GABA: 20Control: 60;57.5/NA | • Numerical category of burning scale:• Category 1: negative changes (deterioration)• Category 2: no changes• Category 3: with positive changes (improvements)• Category 4: with total recovery | • ALA: • Negative: 0%; No change: 45%; positive and total recovered: 55%• ALA 7× higher than control group• GABA:• Negative: 0%; no change: 50%; positive and total recovered: 50%• GABA 5.7× higher than control group• ALA + GABA: Negative: 0%; no change: 30%; positive and total recovered: 70%• ALA + GABA 13.2× higher than control group• Significant level of positive burning changes between group (p < 0.001) | Adverse effects appeared very mild. | Moderate | |
| (33) | • ALA (400 mg)Dosage: 800 mg/dayDuration: 8 weeksRoute: Oral• Capsaicin (250 mg chilli powder in 50 ml)Dosage: 750 mg/150 ml/dayDuration: 8 weeksRoute: Topical – oral rinse• Lysozyme lactoperoxidase (Biotene) Fiive times per day Duration: 8 weeksRoute: Topical – oral rinse | Size Short term:ALA: 14Capsaicin: 14Biotene: 14Control: 14Long term: ALA: 9 Capsaicin:9Biotene: 9Age ALA: 64Capsaicin: 62Control:62 | • VAS | • Significant improvement in VAS (p < 0.001) ALA: 57% improved (MD: −2.1). Capsaicin: 76% improved (MD: −3.2) Biotene: 57% remain unchanged (MD: −1.7)• No statistically difference in VAS between groups ALA, capsaicin and Biotene• No significant difference VAS improvement in control group• All study groups, ALA, capsaicin and biotene, were statistically superior to control groups | • Only capsaicin group shows significant reduction in VAS score (MD: −2.9) with 67% improved• ALA (MD: −1.8) and Biotene (MD: −1.8) failed to show statistically significant of VAS score improvement with 55% remain unchanged for Biotene and 55% improved with ALA• No difference in trend of VAS in control group | No adverse effects were reported for capsaicin | Low |
| (31) | Ultramicronised Palmitoylethanolamide (umPEA) (600 mg) Dosage: 1200 mgDuration: 60 daysRoute: Sublingual | 13/16NA | • NRS (scale 0 to 10) | • Significant decreased of spontaneous burning intensity between umPEA group (MD −3.8) and control group (MD: −1.3) (p = 0.001) | No statistically significant difference between umPEA (MD: −2.4) and control group (MD: −1.4). | No side effect observed | Low |
| (29) | Herbal catuama (310 mg) Dosage: 620 mg/dayDuration: 8 weeks Route: Oral | 30/30; 63.6/61.5 | • VNS (0–10)• Faces scale (FS) (Scale 0 to 5) – lesser is better | VNS: • At 8 weeks reduction in symptoms of test group was 52.4% and control group 24.2%• At 12 weeks after treatment onset, 51.3% reduction of symptom, and control reduction 18.8%• Significant difference between test group and control group at 8 weeks (p = 0.003) and 12 weeks (p = 0.001)FS• Significant difference between test group and control group at 8 weeks (p < 0.001) and 12 weeks (p = 0.001) | Test group: One patient with somnolence and weight gain, • one insomnia,• three exacerbation of symptoms in first week of treatment | Moderate | |
| (28) | Hypericum perforatum (300 mg) Dosage: 900 mg/dayDuration: 12 weeksRoute: Oral | 19/20; 65.9/63.9 | • VAS• Number of oral mucosa sites • Quality of health questionnaires (QOH). | • No significant difference between study (MD: −1.8) and control group (MD: −1.1) in VAS (p = 0.222)• Significant reduction in number of burning sites in study group• Both groups showed a better QOH and ability to cope with their symptoms at the end of trial | Test group: One had severe headache in the fifth week of therapy | Moderate | |
| (27) | Lycopene-enriched extra virgin oil (300 ppm) Dosage: 900 ppm/dayDuration: 12 weeks. Routes: Topical spray and swallowed | 26/24; 61.7/64.9 | • VAS* (grade 1 to 10)• SF-36 • OHIP-14• HAD • Patient Rated Benefit and Satisfaction | • Significant reduction in VAS score in both pain (MD: −3.0; p < 0.001) and burning (MD: −1.0; p = 0.003) symptoms• No significant differences between study and control group in VAS, SF-26, OHIP-14, HAD and Patient Rated Benefit and Satisfaction | No adverse effect reportedNo significant changes in participants’ lipid profile during the 12-week study period | Low | |
| (18) | N-acetyl-5-methoxytryptamine. Melatonin (MLT) (3 mg)Dosage: 12 mg /dayDuration: 8 weeksRoute: Oral | 16/16; 64.4/64.4 | • VAS • Number of sites• Patient global impression of pain changes• Symptom response categories (worse; no change; mild improvement; moderate improvement; strong improvement)• MOS • HRS | • No significant difference between MLT (MD: −0.6) and placebo (MD: −1.1) group in VAS score• Four MLT group and three control group reported improvement in pain changes• Overall, no change in the number of oral sites affected by pain was recorded• Decrease in the sleep scores for both groups but not statistically difference in sleep impairment between MLT and control group• Non-significant difference in Epworth• Sleepiness Scale (ESS) for diurnal sleepiness• Statistically significant decrease in anxiety for melatonin group (p < 0.05) | Test group: 40% of patients dropped out because of sideeffects: Four self-reported heavy tremor, sexual disturbances, blurred vision, and severe heavy-headiness; three lack of efficacy or pain improvement; one lost to follow-up. | Moderate | |
| (34) | Low level laser therapy: IR1W: 830 nm wavelength, 100 mW output power, continuous emissions, 3.57 W/cm2, 5 J energy per point, 176 J/cm2 radiant exposure, application time 50 sec per point. Duration: One session per week for 10 weeks. Total 10 sessions. IR3W: 830 nm wavelength, 100 mW output power, continuous emissions, 3.57 W/cm2, 5 J energy per point, 176 J/cm2 radiant exposure, application time 50 sec per point. Duration: Three sessions per week for 3 weeks. Total nine sessionsRed laser: 685 nm wavelength. 35 mW output power, continuous emissions, 1.25 W/cm2, 2 J energy per point, 72 J/cm2 radiant exposure, application time 58 sec per point. Duration: Three sessions per week for 3 weeks. Total 9 sessions | 20/19; 63.6/61.520/19;60.5/61.519/19;63.2 /61.5 | • VAS (0–100)• VNS (0–10)• OHIP 14 | VNS: • Significant difference between IR1W laser (MD: −4.45) and control (MD: −2.53) at 11 weeks, p = 0.005VAS: • Significant difference between IR1W laser (MD: −49.2) and control at 11 weeks; p = 0.004.VNS: • Significant difference between IR3W laser (MD: −5.1) and control (MD: −2.53) at 11 weeks; p < 0.0001VAS: • Significant difference between IR3W laser (MD: −53.0) and control at 11 weeks; p < 0.0001VNS:• No significant difference between red laser (MD: −3.74) and control (MD: −2.53) at 11 weeks; p = 0.12VAS:• No significant difference between red laser and control at 11 weeks, p = 0.13• No significant difference between IR1W, IR3W and red laser group | No adverse effect reported | Low | |
| (36) | Low level laser therapy (LLLT) Dosage: 810 nm wavelength, 12 J/cm2 per session in a continuous modeDuration: Twice a week session for 5 weeks consecutively Total 10 sessions | 10/10;60.3/67.6 | • VAS• SF-36• OHIP14• EES • SCL 90-R• MPQ | VAS:• 90% LLLT and 20% control reported improvement• Pain decreased significantly (p = 0.005) in the study group (MD: −2.9) versus control group (MD: 0.5)McGill:• No significant difference between LLLT and control group in PRI, NWC and PPIOHIP: • Non-significant reduction in LLLT (MD: 4.0, p = 0.31).• No significant difference between LLLT and control (p = 0.27)SF-36: • No significant difference between LLLT and control group in all categoriesEES:• No significant difference in LLLT (MD: −0.1, p = 0.83) and between control (p = 0.32)SCL-90-R:• Significant difference in interpersonal susceptibility (p = 0.02) and decrease in anxiety (p = 0.05) in LLLT group | N/A | Low | |
| (32) | Urea 10%3–4 times dailyDuration: 3 monthsRoute: Topical | 12/13; 66.3/58.4 | • EDOF-HC • Xerostomia questionnaire• QST | • Seven in study group and eight in control group have reduction in pain• No difference between study and control group pain intensity (p = 0.88); salivary flow (xerostomia) (p = 0.32); gustation (sweet p = 0.38, salty p = 0.69, sour p = 0.69, bitter p = 0.69); olfaction (p = 0.98); corneal reflex right (p = 0.20) and left (p > 0.99)• No significant differences in the somatosensory test between group (p > 0.05) | N/A | Low | |
| (35) | Transcranial magnetic stimulation (rTMS) Dosage: total of 30,000 pulses Duration: 10 sessionsRoute: Transcranial | 12/8; 63.4/64.4 | • VAS • BPI• SF- MPQ• PHQ-9• PGIC• CGI-I | VAS:• Significant reduction in pain with rTMS group (MD: −3.1, p = 0.002)• 75% reported > 50% decrease in BMS pain intensity• Significant difference between rTMS and sham group (MD: −2.8, p = 0.005)BPI:• Significant improvement for rTMS group (MD: −2.1, p = 0.003) and not in control groupSFMPQ:• Non-significant difference in affective score and present pain intensity in rTMS (MD: −1.2) and sham (MD: −0.8) groupPHQ-9:• No significant difference in rTMS (MD: −5.6) and sham group (MD: −1.0)PGIC:• Significant difference in rTMS (MD: 3.3, p < 0.01) but not in sham group (MD: 1.4)CGI-I:• Significant improvement in rTMS (MD: −2.3, p < 0.01) but not in sham group (MD: −0.62) | Seven in rTMS group and five in sham group had headache at the beginning treatment but very mild and tolerated and disappeared in one or two days | Low | |
| (38) | Tongue protectorDosage: 15 min 3 times/dailyDuration: 2 monthsRoute: Oral appliance | 25/25; 61.0/61.4 | • VAS• HAD• OHIP-49• SF-36 | • VAS: Significant difference (p < 0.001) between active (MD: −3.6) and control (MD: −1.4) group• HAD: Depression• Non- significant (p = 0.205) between active (MD: −1.0) and control groups (MD: −0.04)Anxiety• Non- significant (p = 0.69) between active (MD: −0.1) and control groups (MD: −0.2)• OHIP-49: Significant difference (p = 0.008) between active (MD: −18.4) and control (MD: −1.9)• SF-36: Significant difference (p < 0.05) between active and control group in physical role, bodily pain, general health, emotional role• Tongue protector group has better oral health (OHIP) and quality of life (SF-36) | No adverse effect observed | Very Low | |
| (37) | Cognitive therapy (CT) One hour once a week A total of 12–15 sessions | 15/15 | • VAS (1–7) | • Significant reduction in pain symptoms (VAS) in CT group (MD: −2.8, p < 0.001) than control group | • Significant reduction in CT group pain symptoms (VAS) (MD: −3.6, p < 0.001) than control group | N/A | Low |
VAS: Visual analogue scale; VNS: visual numerical scale; NRS: Numeric rating scale; MPQ: McGill Pain Questionnaire; BPI: Brief Pain Inventory; EDOF-HC: Orofacial Pain Clinic Questionnaire; SF-36: 36-Short Form Health Survey (SF-36); OHIP 14: Oral Health on Quality of Life; HAD: Hospital Anxiety and Depression Scale; BDI: Beck Depression Inventory; ZMS: Zerssen Mood Scale; PGIC: Patient Global Impression of Change; CGI-I: Clinical Global Impression for global Improvement Scale; EES: Epworth Sleepiness Scale; PHQ-9: Patient Health Questionnaires-9; HRS: Hamilton Rating Scale; SCL-90-R: Symptom Checklist-90-R; MOS: Medical Outcomes Survey of Sleep Scale; QST: Quantitative somatosensory testing; MD: mean difference from base line; ALA: Alpha lipoic acid; GABA: Gabapentin; N/A : Not available.