Keywords:
Migraine disorders - botulism - low level laser therapy
Palavras-chave:
Transtornos de enxaqueca - botulismo - laserterapia de baixa potência
Chronic migraine (CM) is a neurological disorder characterized by debilitating headaches,
affecting 2–3% of the general population[1], and is one of the main disorders found in neurological clinical practices. Chronic
migraine is a multifactorial condition involving altered modulation and control of
afferent pathways that are complex in nature. Overstimulation of the trigeminovascular
system is responsible for nociceptor activation, cortical spreading depression, mast
cell degranulation, release of inflammatory neurogenic mediators and change in ionic
channels[2]. Pain-producing structures of the cranium are regulated by sensory systems located
in the thalamus, hypothalamus and brainstem[1],[3],[4] and several mechanisms are putative targets for CM therapy.
Chronic migraine management includes acute medication optimization and a preventive
pharmacological and non-pharmacological approach[5],[6]. Current approved therapies are limited, with poor tolerability, refractory profiles
and unfavorable costs[7]. Thus, new CM preventive options are needed.
Botulinum toxin A (BT-A) has been approved for the use in CM prophylaxis. Botulinum
toxin A acts on C-unit, but not on Aδ, meningeal nociceptors, inhibiting mechanical
nociception to suprathreshold stimuli in peripheral trigeminal neurons, thus decreasing
pain. It blocks acetylcholine release at the presynaptic nerve terminal, decreasing
neuropeptides and releases other neurotransmitters from sensitized trigeminal endings[2],[6],[8].
Low level laser therapy (LLLT) has also been studied in several medical areas, as
it is effective for disorders requiring tissue regeneration, pain relief and reduction
of inflammation[9], treating nociceptive, neuropathic[10],[11] and musculoskeletal pain[12]. A meta-analysis has also provided evidence for treatment of neck pain[13],[14]. Possible mechanisms explaining the effects of LLLT are signaling molecules (ATP,
cyclic-AMP, NO) modifying the redox state of cells, free radical production and growth,
and transcription factor stimulation[15].
Although LLLT has been used and extensively studied in the treatment of neck pain,
limited information was available regarding migraine prevention. Thus, the development
of a protocol for CM was required. We designed this open label study to test the efficacy
of LLLT in CM compared with BT-A, as an additional option for treatment of CM.
METHODS
The protocol was approved by the Ethics Committee (CAAE: 31148614.0.0000.5505) and
all patients gave written consent to this study. The participants’ consent was obtained
according to the Declaration of Helsinki.
Patients were screened by neurologists from the Sector of Research and Treatment of
Headaches of the Neurology/Neurosurgery Department at the Universidade Federal de
São Paulo, Hospital São Paulo, and from other medical centers, over two years. Patients
were on stable doses of previously-prescribed prophylaxis medications for three months.
Fifty patients were interviewed but only 36 met the criteria for CM or accepted the
randomization process. The 14 excluded patients were unable to follow the LLLT protocol
or were unable to fill out the pain diary.
Patients were randomly distributed into two groups, to receive LLLT therapy or BT-A
as described in [Figure 1]. Each group comprised 18 patients. The patients had previously been diagnosed with
CM, according to the International Classification of Headache Disorders (International
Headache Society, 2014), having presented with headache more than 15 days/month. Although
these patients had frequent analgesic use, those overusing medication for headache
control were excluded, because they failed items C and/or D of the diagnostic criteria.
We also excluded patients with catamenial and tensional headache and patients with
fewer than 15 days/month of pain. The patients who agreed to participate in this study
remained consistent throughout all processes and no dropouts were registered in either
group.
Figure 1 Work Design and flow chart.
Before the onset of treatment, all patients filled out a headache diary for one month
and this period was designated as the baseline phase. When the patients started therapy
(BT-A or LLLT), all procedures were carried out by only one professional, to avoid
sources of bias.
The therapy protocol was as follows
BT-A: Botulinum toxin A (200 units) was injected (total of 155 units/31 points) in different
muscles such as the corrugator 10 units/ 2 points; procerus 5 units/1 point; frontalis
20 units/4 points; temporalis 40 units/8 points; occipital 30 units/6 points; cervical
paraspinalis 20 units/4 points; trapezium 30 units/6 points, according to the PREEMPT® study[16]. Before treatment (baseline), patients had completed a pain diary (30 days). During
the procedure, patients kept the headache diary for another 30 days and, after that,
another diary was completed during the post-treatment phase (30 days).
LLLT: Diode laser infrared (Diode Laser II from DMC Equipment Import & Export Ltd., Brazil)
with 100mW, wavelength 808 nm, dose 120J/cm2 during 33 sec/point, with light emitted in a continuous and timely manner, was applied
at the same anatomic points used to inject BT-A ([Table]). Each patient received a total of ten sessions of laser applications, twice a week,
for a month. During these procedures, the patients kept a headache diary for three
months, starting before treatment onset (baseline) (30 days), during the treatment
period (30 days), and another during the post-treatment phase (30 days).
Table
Areas of the LLLT and BT-A applications.
|
Head/Neck area
|
Dose (number of sitesa)
|
|
Frontalisb
|
20 units divided over 4 sites
|
|
Corrugadorb
|
10 units divided over 2 sites
|
|
Procerusb
|
5 units divided over 1 site
|
|
Occipittalisb
|
30 units divided over 6 sites
|
|
Temporalisb
|
40 units divided over 8 sites
|
|
Trapeziusb
|
30 units divided over 6 sites
|
|
Cervical paraspinal muscle groupb
|
20 units divided over 4 sites
|
|
Total Dose
|
155 units divided over 31 sites
|
aEach IM injection site = 0.1ml (5 units BTA);
bDose distributed bilaterally.
Patients from both groups returned for a follow-up visit and data from the three diaries
from each patient were extracted (base line, treatment phase and post-treatment).
The primary endpoint was the number of headache days, comparing the baseline with
the post-treatment phase. Medication use data was also collected, and anxiety levels
and sleep quality were ascertained by a qualitative score on a scale ranging from
0-10, as well. These parameters were evaluated using repeated measures ANOVA plus
the Bonferroni post-test, Student's t test, and factorial analysis and p ≤ 0.05 was
accepted as significant.
RESULTS
Comparing the age and sex of patients in the BT-A and LLLT groups displayed no statistical
differences, showing homogeneity between the two studied groups. The majority of patients
were women (two men and 16 women in the BT-A group; four men and 14 women in the LLLT
group). Both groups had similar ages (22 to 65 years, mean 42, in the BT-A group;
20 to 62 years, mean 42 in the LLLT group) (age: t test- t34 = 0.057; p = 0.9550) (sex: t test- t34 = 0.8790; p = 0.3855).
Patients from the BT-A group sometimes complained of worsening of the pain during
the first 72 hours after the BT-A application, which decreased on subsequent days.
Thirty days after the BT-A application, patients described relaxation of the cervical
and facial muscles.
Similarly, during the first four sessions (4 ± 1 sessions) of laser applications,
a few patients described a burning sensation on the trigger points, which disappeared
during treatment. This sensation was followed by analgesia and muscle relaxation of
the head and face, lasting from two to four hours after laser application. These trigger
points were active until the 6th session of LLLT, decreasing after this period as shown in [Figure 2].
Figure 2 Trigger points. Persistency of trigger points after LLLT application. Bars represent
mean ± standard error before and after 4±1 sessions during laser application. (p =
0.001).
Collateral effects of both procedures were described in the patient's diary during
treatment phase.
Patients from the BT-A group had a mean of 28 pain days/month during the baseline
phase, characterizing CM. Analyzing the pain days, the results showed a sharp decrease
during the treatment and post-treatment phases, when compared with the baseline phase
(p < 0.001). However, no difference was found in the post-treatment phase, when compared
with the treatment phase (p = 1.000) ([Figure 3, A])
Figure 3 Comparison between pain days (A) and medication use (B). Pain days and medication
use were compared during baseline, treatment and post-treatment in BT-A and LLLT groups.
No difference was found between BT-A and LLLT treatment.
In the LLLT group, the number of headache days sharply decreased, when the baseline
was compared with the treatment phase (p < 0.001) with further decrease in the post-treatment
phase (p < 0.001), showing a long-lasting effect of LLLT in CM. These patients initially
had a mean of 20 headache days/month decreasing to four, and then to two headache
days/month ([Figure 3 A]).
Thus, both treatments presented a similar performance concerning headache days F (1,499,
50,968) = 1.531 p = 0.227) showing that BT-A and LLLT were equally effective in CM
treatment ([Figure 3 A]).
During the baseline, patients in both groups referred to major medication intake.
This self-medication decreased when comparing the baseline versus the treatment phase,
and versus the post-treatment phase (p < 0.001) in the BT-A group, showing a decrease
in chronic medication intake. However, no difference was found when comparing the
treatment with the post-treatment phase (p = 0.597) ([Figure 3B]).
The number of days using acute medication was also modified in the LLLT group. An
important decrease in medication intake was observed in the treatment phase when compared
with the baseline (p < 0.001), and this decrease continued in the post-treatment phase
(p < 0.001). As well, the medication intake was similar between the BT-A and LLLT
groups (F (1,446, 49,179) = 2.341 p = 0.121) ([Figure 3B]).
Anxiety levels and sleep quality, analyzed using qualitative scores, showed no difference
between the groups. [Figure 4] shows no difference when anxiety and sleep disorders were compared between the BT-A
and LLT groups, but does show an improvement of both parameters during the treatment
phase in each group.
Figure 4 Anxiety and sleep. The presence of jitters (indicating anxiety) and sleep disorder
in BT-A and LLLT groups, during baseline, treatment and post-treatment. No difference
was found between BT-A and LLLT treatment.
DISCUSSION
This was a preliminary pilot study exploring the potential of LLLT and BT-A in the
treatment in CM. Our results showed that both approaches, BT-A as well as LLLT, reduced
headache days and medication intake. In addition, anxiety levels were reduced in the
BT-A group, while sleep quality improved in the LLLT group.
Although LLLT is a very promising therapy for pain disorders and a potential candidate
for an effective migraine prevention method, its study is very challenging: firstly,
because of uncertainty about the mechanisms of action of LLLT at the molecular, cellular
and tissue levels. Secondly, there is an extensive number of parameters that can be
chosen when designing different LLLT protocols, including: a) application sites in
the head and neck; b) the timing, frequency and repetition; c) the wavelength, dose,
irradiance; and d) pulsing and polarization. Furthermore, a biphasic dose response
should be carefully considered[17].
Our LLLT protocol, following BT-A PREEMPT injection sites, showed that this could
be a feasible strategy. However, a more specific, customized application according
to headache location, on a “follow the pain” basis, could also be utilized. In general,
there are four clinical targets for LLLT: a) lymph nodes to reduce edema and inflammation,
b) the injury or pain site to promote healing and reduce inflammation, c) nerves to
induce analgesia, d) trigger points to reduce tenderness and relax contracted muscle
fibers[13]. Our study showed that the 31 points that we employed could be utilized, with good
results.
Although both treatments seem effective in reducing CM pain, BT-A is efficient but
is expensive, while LLLT might be more cost-effective. Although LLLT requires longer
treatment, compliance may increase when the patient finds relief from pain. Thus,
BT-A is an invasive and expensive method, while the LLLT is a longer treatment (five
weeks), but is cheaper.
Our study has limitations and is presented as an initial approach on how to use LLLT
in migraine treatment. It was a head-to-head, open-label comparison, the patients
knew which treatment they were receiving, and we could not exclude the placebo effect.
Human interaction, a significant aspect affecting placebo response, was higher in
the LLLT arm. Double-blind, placebo-controlled trials are needed in future studies
to exclude the placebo effect. In addition, the trial period was limited and a longer
follow-up could be added in future trials, as repetitive BT-A injections/LLLT applications
and cycles could give information on the long-term benefit of LLLT and BT-A treatments.
Furthermore, the small sample size in our trial is a significant limitation.
According to our data, LLLT and BT-A may be used in a future approach for the treatment
of headache disorders but further studies are necessary to clarify this topic.
