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Med Oral Patol Oral Cir Bucal. 2011 Aug 1;16 (5):e635-40. Dr ug therapy Bu rning Mouth Sy ndrome
e635
Journal section: Oral Medicine and Pathology
Publication Types: Research
Combination of alpha lipoic acid and gabapentin, its efcacy in
the treatment of Burning Mouth Syndrome: A randomized,
double-blind, placebo controlled trial
Edgardo López-D’alessandro 1, Livia Escovich 2
1 Master of Oral Medicine, Teacher researcher. Oral Medicine and Pharmacology Chairs. Faculty of Dentistry. National Univer-
sity of Rosario. Argentina
2 Professor of Oral Medicine. Director of the Master of Oral Medicine, Faculty of Dentist ry. National University of Rosario.
Argentina
Correspondence:
San Luis 4303- Rosario,
Santa Fe, Argentina,
Post-code: 2000
iaoodontología@hotmail.com
Received : 06/03/2010
Accepte d: 31/05/2010
Abstract
Burning Mouth Syndrome (BMS) is a disease that manifests as burning in the tongue or in any area of the oral
mucosa, in the absence of clinically veriable injuries.
Objectives: To verify the efcacy of alpha lipoic acid (ALA) and gabapentin (GABA), used individually and
jointly, to reduce the burning in patients with burning mouth and establish a drug therapy for the BMS.
Study Design: During April and May 2008, we conducted a randomized, double-blind, placebo-controlled trial
in the Department of Clinical Stomatology, Faculty of Dentistry, Rosario, Argentina. The gathering of patients
was between those ones with BMS who were treated in our service between March 2003 and March 2008 without
complying with the applied treatments. The 120 patients were randomly divided into 4 groups and were provided,
by lot and in a blinded fashion, with four different treatment cycles consisting of the following drugs: Group A
(n = 20) 600 mg / day of alpha lipoic acid for two months, Group B (n = 20) 300 mg / day of gabapentin for two
months, Group C (n = 20) a combination of both drugs for two months and Group D (n = 60) 100 mg / day of ce-
llulose starch for two months (control group).
Results and Conclusions: All 120 patients completed the treatment. The best response was obtained with the com-
bination of ALA + GABA, with a 70% of the cases with reduced burning in this group and a 13.2 times greater
chance of presenting positive changes for these patients than those taking placebo. The combined use of drugs that
act at different levels of the nociceptive system can be useful for the treatment of this syndrome.
Key words: Burning mouth syndrome, pharmacological treatment o� burning mouth, alpha lipoic acid, gabapen-urning mouth syndrome, pharmacological treatment o� burning mouth, alpha lipoic acid, gabapen-
tin, oral neuropathic pain.
López-D’alessand ro E, Escovich L. Combinat ion of alpha lipoic acid and
gabapentin, its efcacy in the t reatment of Burn ing Mout h Syndrome: A
randomized, double-blind, placebo controlled trial. Med Oral Patol Oral
Cir Bucal. 2011 Aug 1;16 (5):e635-40.
http://w ww.medicinaor al.com/medo ralfree01/v16i5/medor alv16i5p635.pdf
Article Number: 16942 http://www.medicinaoral.com/
© Medicina Oral S. L. C.I.F. B 96689336 - pISSN 1698-4447 - eISSN: 1698-6946
eMail: medicina@medicinaoral.com
Indexed in:
Science Citation Index Expanded
Journal Citation Reports
Index Medicus, MEDLINE, PubMed
Scopus, Embase and Emcare
Indice Médico Español
doi:10.4317/medoral.16942
http://dx.doi.org/doi:10.4317/medoral.16942
Med Oral Patol Oral Cir Bucal. 2011 Aug 1;16 (5):e635-40. Dr ug therapy Bu rning Mouth Sy ndrome
e636
Introduction
Burning mouth syndrome (BMS) is a disease charac-
terized by the presence of burning mouth, taste distur-
bances and dry mouth sensation in the absence of in-
juries that justify it (1-3). The sensation of “burning”
generally involves the tongue, at its tip and edges, and
can be extended to any area of the mouth. It often occurs
more frequently in women over 60 years in the peri-or
postmenopausal period; it is rarely found in men (1,2).
The etiology is unknown but it’s believed to be multifac-
torial; patients with BMS often have anxiety and clini-
cal depression (4,5). Among the important local factors
dental trauma, the presence of tartar, rough surfaces
prosthesis, allergic reactions to dental materials, chemi-
cal irritants of lipsticks, toothpastes and prolonged use
of mouthwashes may be included. Among the general
factors deciency states, deciencies of iron, folic acid
and vitamin B are important (6-9). Alpha Lipoic Acid is
a component produced in the body in very small quanti-
ties, being present in many foods such as spinach, broc-
coli and meats. This substance acts as a coenzyme in
various reactions, taking part in glycolysis - responsible
for the conversion of blood sugar into energy- and in
the regeneration of liver tissue damage. It also exerts
a neuro-regenerative action, because it crosses the he-
matoencephalic barrier and has a protective effect of
brain and nerve tissue (10,11). A systematic review of
the Cochrane Collaboration, noted that Alpha-Lipoic
Acid (ALA) may help in management of burning mouth
syndrome (12). Various studies have shown that the use
of ALA did not produce greater benets on the burning
mouth that the use of placebos (13,14). Gabapentin is an
anticonvulsant whose chemical structure consists of a
molecule of gamma-aminobutyric acid covalently linked
to a lipophilic cyclohexane ring. This drug was created
to act as an agonist of the inhibitory neurotransmitter
GABA of central activity since it is easily transferred to
the central nervous system (CNS) for having high lipid
solubility. The mechanism of action of this drug is still
unknown because it acts by increasing the discharge
promoted of GABA but without noting a steady reduce
in the potentials of action or affection of the calcium
channel current (15). The objective of this research was
to test the action of alpha lipoic acid and gabapentin
alone and jointly, on the symptoms of BMS.
Patients and Methods
We conducted a randomized clinical double-blind, pla-
cebo-controlled clinical trial among patients with BMS
seen at the Chair of Clinic Stomatology II of the Faculty
of Dentistry, Rosario, Argentina. The study was ap-
proved by the Bioethics Committee of the Institution.
Sample size was determined by considering a condence
level of 95% and an error rate of + / - 5%, determining the
need to include a number of 120 patients for our study.
The study was conducted during April and May 2008.
The 120 patients were selected among those patients
with BMS who have been treated at our service between
March 2003 and March 2008, without responding to the
applied treatments. A total of 120 patients with idiopathic
BMS of more than three months duration that wanted to
participate voluntarily were included. Polypharmacy pa-
tients using more than 3 systemically daily drugs, those
ones taking psychotropic and antihypertensives drugs as
well as patients with serious psychiatric conditions previ-
ously diagnosed were excluded. Patients with deciencies
of folic acid, vitamin B, carriers of anemias of any kind
and patients with Sjögren syndrome were also excluded.
Participants were warned of the possibility of access to
different drugs as well as the possibility of being treated
with placebo. An informed consent was signed where the
scope of the study and the freedom to leave treatment at
any time were specied, and also the provision of medi-
catio n following the com plet ion of the stud y was en sure d.
We performed an initial psychological diagnosis for all
patients through the application of the Hospital Anxiety
and Depression Scale (HAD) and the Hamilton Rating
Scale for Depression in order to meet the psychological
situation of our patients. Then we evaluated the presence
of burning through a numerical scale especially created
for this work, describing the burning from 0 to 4, where
the 0 value corresponded to the absence of burning, the
1 value to the presence of burning in a single area of the
tongue, the 2 value to two distinctive areas (tongue and
gums, tongue and lips or tongue and palate), the 3 value
to three areas and the 4 value corresponded to burning
spread throughout the mouth. This specic designed
scale, which considered the geographical distribution of
burning in dif fere nt are as of the mouth , allowed us to dis-
tinguish improvements or deteriorations of burning sen-
sation in the various assessments. The 120 patients were
randomly divided into 6 groups of 20 members each.
Once the groups were formed, our service attendants as-
signed a numerical order for each group being identied
as groups 1, 2, 3, 4, 5 and 6. On the other hand, six treat-
ment cycles were determined: cycles A, B, C, D, E and
F, so that cycle A (n = 20) corresponded to 600 mg / day
of ALA, the cycle B (n = 20) 300 mg / day of GABA, the
cycle C (n = 20) to the combination of both drugs and the
cycles D (n = 20), E (n = 20) and F (n = 20) were 100 mg
/ day of starch and cellulose (Placebo). The support staff
of our service made a draw with 6 balls to link the groups
with the cycles of treatment. After the draw, the three
groups were combined with cycles D, E and F to be treat-
ed with placebo, thus forming a single group for these
patients, Group D (n = 60) or control group proceeding to
medication delivery, allocation that was always masked
to both patients and researcher, through the use of cap-
sules of similar size and appearance so that just the sup-
port staff was the one who recorded the information until
Med Oral Patol Oral Cir Bucal. 2011 Aug 1;16 (5):e635-40. Dr ug therapy Bu rning Mouth Sy ndrome
e637
the end of the treatment (blind). The beginning of the ad-
ministration of the different drugs was concomitant for
all patients, as well as the evaluation of the effects, which
was made monthly and also blinded (double blind), al-
ways by the same researcher using the protocol described
above, which was completed for the rst time the day be-
fore the start of treatment and thirty and sixty days, re-
spectively. To evaluate the changes that occurred with the
taking of the different drugs, it was established that the
improvements (positive changes) involved the passage of
a certain level or numerical category of burning to a low-
er one, the deteriorations (negative changes) involved an
increase of a certain level of burning to a higher one and
the total resolution indicated the total absence of burning,
that is to say the transition from any higher value to zero
value. In this way four categories were obtained for the
analysis of the results: Category 1: with negative changes
(deterioration), Category 2: no changes; Category 3: with
positive changes (improvements) and Category 4: with
total recovery. The Chi- square test was used for the anal-
ysis to an independent variable with a predictive value (P
<0.05) and the Odds ratios were calculated to determine
the relationship between treatment and its effect on the
intensit y of the burni ng with ( P <0.01). All subjects were
evaluated through an Intention-to-Treat Analysis which
would take into account all patients although they could
discontinue the treatment.
Results
All patients included initially ended the study because
the duration of treatment lasted only 2 months and the
adverse effects that appeared were very mild. Of the
120 patients studied, 94 were females and 26 males with
a mean age of 14.1 ± 57.5 years, median: 57. The psy-
chological diagnosis showed 95 patients without pathol-
ogy (78%), 14 with anxiety (13%) and 11 with depres-
sion (9%). We assessed changes in levels of burning in
each group after one and two months of treatment. The
rst month of treatment, changes in levels of burning
were not dependent on the type of drug tested (p-value
= 0.293) (Fig. 1). After 2 months of treatment, we found
that the positive changes in the levels of burning, signif-
icantly depended on the type of drug assigned (p-value
<0.001) (Fig. 2). When relating the changes in patients
treated with ALA, GABA or the combination, and com-
paring them with changes in the group of patients who
received placebo, we observed the existence of a large
percentage of patients with negative changes within this
group (Fig. 3). When observing the patients who re-. 3). When observing the patients who re-3). When observing the patients who re-
ceived ALA, we found that 9/20 (45%) of these patients
did not presented changes, while the remaining 11/20
(55%) had positive changes or full recovery in the case.
Among the patients treated with GABA, 10/20 (50%)
remained unchanged while the rest manifested decrease
in the burning. Among those who were given the com-
bination of both drugs, only 6/20 (30%) remained un-
changed while 14/20 (70%) had positive changes. Final-
ly, and within the group of patients receiving placebo,
51/60 (85%) remained unchanged or worsened while
9/60 (15%) had positive changes. The calculation of odds
ratios determined that the possibility of presenting posi-
tive changes (or total resolution of the case) for patients
treated with ALA was 7 times higher than for those re-
ceiving placebo. For those patients who received GABA,
that possibility was 5.7 times higher than for the control
group and for the patients who received ALA and GABA
together, that possibility was 13.2 times higher than for
the control patients group (Table 1).
Fig. 1. Analysis of the changes after one month of treatment.
Med Oral Patol Oral Cir Bucal. 2011 Aug 1;16 (5):e635-40. Dr ug therapy Bu rning Mouth Sy ndrome
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Fig. 2. Analysis of the changes af ter two months of treatment.
Fig. 3. Comparison of the changes caused by the different dr ugs after two months.
Treatment Percentage of
Favorable Cases #
Possibility of
Favorable Results *
Alpha lipoic Acid
(ALA) 55% 7 times better
Gabapentin
(GABA) 50% 5.7 times better
Combination
(ALA+GABA) 70% 13.2 times better
Table 1. Favorable changes after two months of treat ment.
# Includes Pat ients wit h total case resolut ion.
* = ( p value< 0,001) compared with the placebo group.
Med Oral Patol Oral Cir Bucal. 2011 Aug 1;16 (5):e635-40. Dr ug therapy Bu rning Mouth Sy ndrome
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Re�erences with link s to Crossre� - DOI
Discussion
The communication of different therapeutic measures
to control the BMS is wide in the world literature (11-
20). The Gabapentin was used by White et al. (15) in
a case of a patient with BMS obtaining healing of the
case and it was subsequently used by Heckmann et al.
(16) who conducted a study with gabapentin in 15 pa-
tients, where the initial dose was 300 mg / day and then
grew at a rate of 300 mg every 48 hours to a maximum
of 2400 mg / day. Seven of the patients were treated
for two weeks, 6 patients for four weeks and another 2
patients for six weeks. Although 2 patients (13%) indi-
cated a decrease in pain of three points and another 2
patients (13%) showed a decrease of two points on the
VAS (visual analogue scale), the authors concluded that
gabapentin has little or no effect on the treatment of
BMS. In our study, we used GABA individually, with
xed doses of 300 mg daily for two months, getting no
major differences with the published studies, although
obtaining improvements when used it in combination
with ALA. Femiano et al. (17) used the ALA at a dose
of 600 mg / day and psychotherapy, in a parallel group
and placebo-controlled trial. This drug was chosen for
its neuroregenerative properties, demonstrated in the
treatment of diabetic neuropathy, another disease with
similar characteristics to the BMS that causes chronic
pain. In the group treated with a total of 48 patients, 5
patients (10%) experienced a slight improvement, 19 pa-
tients (40%) a clear improvement and 15 patients (31%)
recovered from the BMS. The 81% of patients treated
with the combination of ALA + Psychotherapy experi-
enced some improvement. In the placebo group only 6
patients (13%) experienced improvement, and this one
was classied as mild. At six months 19 patients (49%)
who had experienced improvement after two months
of treatment with ALA worsened. The same group has
published other studies with ALA under different con-
ditions but with similar results. Lopez Jornet et al. (20)
also used ALA in 30 patients but at a concentration of
800 mg daily for eight weeks with no statistically signif-
icant differences when comparing the treatment group
with the control group. Carbone et al. (12) conducted
a randomized, double-blind placebo-controlled study
among 54 women and 12 men who used 400 mg of ALA
daily together with vitamins, forming three groups ad-
ministered, for 16 weeks, with 400 mg / day of ALA,
400 mg / day of ALA + vitamins and Placebo, getting
similar effects in all three groups demonstrating a lack
of efcacy of ALA in BMS, as this did not produce bet-
ter effects than placebo. In a review of a series of 31
patients with BMS who took 600 mg / day in divided
doses of ALA, Steele et al. (13) determine that the drug
was benecial in only 11 patients of all patients sur-
veyed. Cavalcanti and da Silveira (14) performed a ran-
domized double-blind, placebo-controlled trial between
48 patients divided into two treatment cycles alternating
20-day 200 mg / day of ALA and 100 mg / day of cellu-
lose starch, but were not able to demonstrate the greater
efcacy of ALA over placebo. In our experience with
the administration of ALA in 20 patients, with a daily
dose of 600 mg for two months, we obtained similar
results to those of Femiano et al. (17), with a decrease of
the burning sensation in 55% of patients treated, being
the possibility of favorable changes 7 times higher for
patients who received ALA than for the control group.
Note that in our study we also indicated as a treatment
for one group the combination of ALA + GABA to try
to produce an action on both peripheral and central no-
ciceptive system, obtaining with this combination the
best results. Although effective treatments have been
exposed to particular cases, we are still looking for a
drug therapy that could be effective for most patients
with BMS.
Conclusions
Gabapentin and Alpha Lipoic Acid used both individu-
ally and jointly, were benecial for reducing the burn-
ing in patients with BMS. The most favorable results
were obtained with the administration of both drugs.
To establish specic therapies in the treatment of BMS,
further study of the pathophysiological mechanisms in-
volved in its pathogenesis would be required, as well
as determine the neurological changes involved in this
disease, focusing on this entity within the Central Sen-
sitization Syndromes. Given the limitations in time and
in the number of patients in our study, we recommend
conducting multicenter clinical trials in more prolonged
treatments, based on the combined use of drugs acting
at different levels of the nociceptive system, since that
could be the key to future advances in the treatment of
this disease.
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