Keywords:
migraine disorders - amitriptyline - preventive medicine
Palavras-chave:
transtornos da enxaqueca - amitriptilina - medicina preventiva
Migraine is a highly-prevalent primary headache[1]. It affects nearly 16% of the world's adult population with a higher prevalence
in women[2]. Migraine is a neurological disorder leading to functional disability and drug therapy
is often indicated, widely used and scientifically substantiated for acute treatment[3],[4]. Prophylactic treatment is prescribed when attacks are frequent and disabling to
the extent of interfering with the quality of life[4]. It is also indicated when symptomatic treatment proves inefficient, poorly tolerated
or contraindicated[4]. Tricyclic antidepressants, such as amitriptyline, are widely employed to treat
various pain conditions as well as to prevent migraine[5],[6].
In the anatomical field innervated by the trigeminal nerve, the jaw-opening reflex
is equivalent to the nociceptive or flexor reflex and inhibits the activity of the
mandibular elevator muscles when orofacial mechanoreceptors, located in the mucosa
and periodontal ligament, are activated[7]. Based on this activation, as well as its potential relationship with headache mechanisms,
an inhibitory device for intraoral use was developed and proposed for migraine and
tension-type headache treatment[8],[9]. It is called the Nociceptive Trigeminal Inhibition Tension Suppression System (NTI-tss)
and has the structure of a prefabricated appliance that is fitted to the upper central
incisors, providing contact with the mandibular central incisors during mouth closure
and avoiding contact with all other teeth.
The use of intraoral appliances may exert a beneficial effect on headaches, including
migraine[10]. However, studies that investigated the efficacy of the NTI-tss in both headaches
and symptoms of temporomandibular disorders (TMD) have yielded mixed results[8],[9],[11],[12].
The objectives of this study were 1) to assess the efficacy of the NTI-tss in reducing
the frequency of migraine without aura attacks, 2) to compare its efficacy with the
use of a traditional preventive migraine drug (amitriptyline), and 3) to compare its
efficacy with a sham intraoral device that does not interfere with physical contact
between upper and lower teeth (non-occlusal splint).
METHODS
The study was conducted from March 2010 to December 2013 in an outpatient headache
clinic of a public university hospital in Rio de Janeiro, Brazil. Eligible participants
were consecutive adults, aged between 18 and 70 years, who sought treatment at the
premises. All patients were evaluated by an experienced neurologist and forwarded
to a dentist specializing in orofacial pain, who used the Research Diagnostic Criteria
for Temporomandibular Disorders guidelines[13]. In order to be eligible, the patients had to fulfill the criteria for migraine
without aura according to The International Classification of Headache Disorders,
2nd edition (ICH-2)[14]. In addition, other inclusion criteria were: 1) 1-2.5 attacks per week (4-10 per
month) during the previous two months; 2) the presence of natural maxillary and mandibular
anterior teeth or fixed dentures supported by natural teeth or osteo-integrated implants;
3) the presence of posterior natural teeth or teeth supported by osteo-integrated
implants in both dental arches in sufficient number to ensure mandibular occlusal
stability; 4) no upper and/or lower total dentures; and 5) a normal overbite and overjet
(no more than 2 mm). Exclusion criteria were: 1) undergoing orthodontic treatment;
2) the presence of periodontal disease; 3) acute signs and symptoms of TMD; 4) overuse
of symptomatic medication for headache[14]; 5) an inability to fill out the headache and pain diary; 6) being pregnant or lactating,
and 7) having a previous history of psychiatric disorder.
Among the 97 included patients, none reported acute pain in the region of the masseter
and/or temporal muscles during chewing or speech, and no pain during either maximum
mouth opening, or lateral mandibular movements and protrusion.
In the first group, patients were given 25 mg of amitriptyline, taken daily as a single
oral dose at night. The second group used the NTI-tss. The prefabricated appliance
was individually adapted directly to the maxillary central incisors using self-curing
acrylic resin. The appliance was installed and adjusted so that it attached to the
upper dental arch and established contact with the two lower central incisors. Attention
was given to make sure that the NTI-tss promoted disocclusion of the posterior teeth
and canines, both in closing the mouth and in performing the movements of right and
left laterality and protrusion, so that there would be no contact between the upper
and lower teeth in any mandibular position. The device had not only to be well retained,
but the patient should not have reported discomfort. In the third group, patients
were given an intraoral non-occlusal splint. The palatal coverage was made from self-curing
acrylic resin covering the entire hard palate. The appliance was adjusted so as not
to interfere with mouth closure in habitual occlusion or with tooth contacts during
mandibular movements. Both devices, the NTI-tss and non-occlusal splint, were supplied
free of charge to the patients, as was amitriptyline.
The devices had to be worn at nighttime and during the day whenever the patient experienced
symptoms of headache onset or even mild headache. Patients had to complete a headache
diary recording the frequency of the headaches and other mouth or mandibular pain.
Return visits of all patients were scheduled to occur after six and 12 weeks, and
they were reassessed by both the dentist and the neurologist. In addition, all patients
were emphatically instructed about the importance of wearing the appliances, or taking
the drug regularly.
Although the researchers knew in which group patients were being allocated, the studied
patients were blind to the device type and were all highly motivated regarding the
potential role of the intraoral devices for preventing migraine attacks. Additionally,
data analysis and statistical evaluation was made by a third party who did not know
the patient's group allocation. The study followed the recommendations of the Declaration
of Helsinki and all patients signed an informed consent form. The study was approved
by the local Ethics Committee (CAAE n° 0271.0.258.000-09).
Statistical analysis
Snedecor's F test analysis of variance (ANOVA) was used to analyze differences in
the frequency among the three groups at the time the patients entered the study. The
Kruskal-Wallis test was used to assess statistical differences among the three groups
at the six and 12 week reassessments. The Friedman test was employed to evaluate the
differences in each group individually at the different times. Finally, the one-way
ANOVA test followed by Tukey's pairwise comparisons were applied to assess differences
in the groups regarding the number of patients and age, and the chi-square test (X2) for gender and marital status. The significance level was set at P < 0.05.
RESULTS
Ninety-seven patients were included. Thirty-four patients in the amitriptyline group,
33 in the NTI-tss group and 30 in the non-occlusal splint group. Seventy-six patients
completed the study, 28 in the amitriptyline group, 25 in the NTI-tss group and 23
in the non-occlusal splint group ([Figure 1]). Reasons for not completing the study were: tolerability issues (five patients
in the amitriptyline group reported severe drowsiness); inability to complete the
diary (four patients in the NTI-tss group; four patients in the non-occlusal splint
group) and loss to follow up (one in the amitriptyline group; four in the NTI-tss
group and three in the sham device group).
Figure 1 Study flow sheet.
The demographic data are shown in [Table 1]. There were no differences in gender, age and marital status among the groups.
Table 1
Demographic data of 76 patients with migraine without aura before treatment with amitriptyline,
the NTI-tss or non-occlusal splint.
|
Variable
|
Amitriptyline
|
NTI-tss
|
Non-occlusal splint
|
|
Patients (number)
|
28
|
25
|
23
|
|
Gender - n (%)
|
|
Female
|
25 (89.3)
|
21 (84.0)
|
20 (86.9)
|
|
Male
|
3 (0.7)
|
4 (16.0)
|
3 (13.1)
|
|
Age (years) - mean ± SD
|
39.75 ± 12.5
|
40.12 ± 10.0
|
38.48 ± 11.0
|
|
Marital status (number)
|
|
Married
|
17
|
14
|
13
|
|
Single
|
8
|
9
|
8
|
|
Divorced
|
3
|
2
|
2
|
The mean weekly frequency of headache attacks is shown in [Table 2] and [Figure 2]. In the amitriptyline group, the frequency of attacks at baseline was 2.5 per week,
1.0 per week after six weeks and 0.9 after 12 weeks. The reduction was statistically
significant both between the baseline and six weeks, as well as between the baseline
and 12 weeks (p < 0.01).
Table 2
Headache frequency and reduction in the three groups at the moment of entering the
study and after 6 and 12 weeks of treatment (mean and standard deviation).
|
Variable
|
Initial
|
6 Weeks
|
12 Weeks
|
|
Amitriptyline
|
|
Frequency
|
2.5 (SD = 0.6)
|
1.0 (SD = 0.2)
|
0.9 (SD = 0.3)
|
|
Reduction (%)
|
–
|
60
|
64
|
|
NTI-tss
|
|
Frequency
|
2.3 (SD = 0.6)
|
1.4 (SD = 0.5)
|
1.2 (SD = 0.5)
|
|
Reduction (%)
|
–
|
39.1
|
47.8
|
|
Non-occlusal splint
|
|
Frequency
|
2.3 (SD = 0.6)
|
1.6 (SD = 0.5)
|
1.2 (SD = 0.4)
|
|
Reduction (%)
|
–
|
30.4
|
47.8
|
Figure 2 Frequency of headache attacks per week in groups A, B and C at baseline and after
6 and 12 weeks.
In the NTI-tss group, the frequency at baseline was 2.3 attacks weekly, 1.4 after
six weeks and 1.2 after 12 weeks. The reductions were statistically significant when
all times were compared (p < 0.01).
The non-occlusal splint group had a baseline frequency of 2.3 attacks per week, 1.6
after six weeks and 1.2 attacks per week after 12 weeks. Comparisons between reductions
at all times were significant (p < 0.01).
After six weeks, there was a reduction in the three groups, but the amitriptyline
group showed results statistically superior to both the NTI-tss group (p = 0.003)
and the non-occlusal splint group (p = 0.000). No difference was found between the
NTI-tss group and the non-occlusal splint group (p = 0.641). Assessment at 12 weeks
revealed that the amitriptyline group continued to show results statistically superior
to the NTI-tss group (p = 0.032) and the non-occlusal splint group (p = 0.010). No
differences were found between the NTI-tss and non-occlusal splint groups at 12 weeks
(p = 0.872).
The use of intraoral devices was well tolerated in both groups. No patient reported
changes in sensitivity or increased tooth mobility related to the use of the appliances,
and no patients withdrew because of tolerability issues in these two groups.
DISCUSSION
There is no consensus yet on the full pathogenesis of migraine and no single theory
can explain the constellation of symptoms during headache attacks[15]. However, certain factors play a potential role in preventing the worsening of the
headache and may therefore influence treatment outcome[16].
Migraine is a neurovascular syndrome involving abnormal neuronal excitability in the
cortex and central facilitation of pain associated with neurogenic inflammation, peripheral
activation and sensitization[17].
Peripheral factors may play a pathophysiological role in attack frequency[17],[18]. Nociceptive afferents arising from muscles of mastication can enhance central sensitization,
facilitating or contributing to headache escalation and chronicity. In addition, the
reduction of sensory stimuli originating in the craniomandibular muscles can reduce
central-sensitization[19].
Amitriptyline is a tricyclic antidepressant effectively used in the prophylaxis of
migraine independently of its antidepressant activity[6]. The present study corroborates previous findings about its efficacy[5].
The NTI-tss is a device approved by the United States Food and Drug Administration
for the prophylaxis of migraine[9]. However, its indication is controversial and not universally accepted[11],[12],[19]. This study showed that the effectiveness of the NTI-tss was lower than that of
amitriptyline (p < 0.05) and similar to the sham splint in the evaluations performed
after six weeks and 12 weeks. The non-occlusal device efficacy was also statistically
lower than that observed by the use of amitriptyline ([Table 2]).
The NTI-tss action is based on the assumption that an anterior stop point for the
bite decreases muscle activity in both clenching and grinding of the teeth due to
activation of the jaw-opening reflex[8],[9]. There are studies suggesting that oral appliances with only anterior tooth contact
may reduce the temporomandibular joint load[20] and lead to lower electromyographic activity both in the masseter and anterior,
as well as posterior, bundles of the temporalis muscle in awake individuals[21]. Although there is also evidence that the NTI-tss promotes an increased inhibitory
effect on electromyographic activity of the masseter muscle during sleep when compared
with a traditional stabilizing device, this reduction was not correlated with a decrease
of pain observed with both a visual analog scale and muscle palpation[22].
Temporomandibular disorders have been associated with various types of headache including
migraine without aura[23],[24],[25],[26]. The two disorders may share genetic and environmental factors and can result in
abnormal processing of nociceptive afferents and sensitization of the trigeminal system[25]. Additionally, it has been hypothesized that excessive isometric contraction of
the muscles of mastication, as may occur in some cases of bruxism, could increase
the amount of nociceptive inputs to the brain stem, which could, in turn, trigger
headache episodes during migraine[8],[9]. Although some studies have shown that oral appliances used to control symptoms
of TMD and reduce muscle activity can also reduce headaches[10], the intraoral appliances used in the present study did not reduce migraine frequency
significantly.
Potential adverse effects of the NTI-tss, such as changes in tooth position involving
overeruptions of non-included teeth or intrusion of teeth involved in the NTI-tss
contact and support[27], swallowing or aspirating the device[11], and joint pain[28] did not occur in the present study.
Non-occlusal splints do not have areas of contact with the teeth of the opposing arch
and, therefore, cannot mechanically alter the occlusion, or the position of the condyle
in the glenoid fossa, or the vertical occlusion dimension. Therefore, if their use
has any therapeutic effect at all, their mechanism of action probably stems from behavioral
changes or some other nonspecific effect such as the patient's positive expectations
regarding the treatment. Clearly, the therapeutic effect is not related to mechanical
changes in the maxillomandibular relationship[29]. Due to these characteristics, we used a non-occlusal splint in our study as a control
for the NTI-tss. Improvement by placebo effect is another important possibility[30].
Some limitations of this study can be outlined. The patients were diagnosed according
to ICH-2 criteria, but the mean frequency of attacks before entering the study was
subjectively reported by the patients and based on recall bias. No group was included
to investigate the effect of time on the natural history of symptoms. The eventual
possibility of a natural regression of migraine symptoms seems remote since the patients
exhibited no changes or improvement in clinical conditions for long periods up until
the moment that the interventions were introduced.
In conclusion, amitriptyline was significantly more effective in reducing the frequency
of headache attacks of migraine without aura than the NTI-tss and non-occlusal splint.
The NTI-tss showed similar results to that of the non-occlusal splint. The NTI-tss
should not be recommended as a first-choice treatment for migraine without aura as
it showed lower efficacy than amitriptyline and was similar to a non-occlusal splint.
