Palavras-chave
Cefaleia Histamínica - Enxaqueca Sem Aura - Consenso - Medicina Preventiva
Keywords
Cluster Headache - Migraine Without Aura - Consensus - Preventive Medicine
INTRODUCTION
The Brazilian Headache Society (SBCe, in the Portuguese acronym) appointed a committee
of authors with the objective of establishing a consensus with recommendations on
the prophylactic treatment of episodic migraine based on worldwide publications, as
well as on personal experience. The detailed research methodology and involvement
of the authors, along with an analysis of the therapeutic classes of beta-blockers,
anticonvulsants, tricyclic antidepressants, and monoclonal anti-CGRP antibodies are
described in the first part of the present document.
Methods
The SBCe, through the current board, appointed an ad hoc committee with the purpose
of creating the present Consensus on prophylactic treatment of episodic migraine (EM)
and developing recommendations for the management of these patients in order to disseminate
knowledge in the field of headache and assist medical professionals in their routine.
Twelve working groups were created, each dedicated to one or more classes of EM prophylactics.
The members were chosen by the Board of Directors of the SBCs according to the following
criteria:
The coordinator of each group was chosen for their expertise in headache, curriculum,
and practice in working with groups.
The participants in each group reviewed and discussed online the relevant topics,
on which they wrote the initial text. These texts were reviewed by another group and
returned to the original groups for corrections. The corrected texts were reviewed
and standardized by the coordinators of the groups. At the last virtual meeting, all
authors assessed and approved the final text of the Consensus.
The search for articles was carried out in the PubMed database, covering the period
from the earliest articles recorded until articles published in 2020. The included
studies ranged from case reports, case series, nonrandomized and/or non-controlled
clinical trials and randomized and controlled clinical trials to systematic reviews
and meta-analyses.
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS
ANGIOTENSIN-CONVERTING ENZYME INHIBITORS AND ANGIOTENSIN RECEPTOR BLOCKERS
General aspects
Actions mediated by the renin-angiotensin system (RAS) are recognized in extrarenal
sites such as the lungs, blood vessels, and central and peripheral nervous systems.
The presence of angiotensin 1 (AT1) and angiotensin 2 (AT2) receptors in regions like
the anterior and prefrontal cingulate cortex, the thalamus, the periaqueductal gray
matter, the tonsils, and the medulla emphasizes the idea that this system plays an
important role in regulating inflammation and oxidative stress, which may be related
to the pathophysiology of migraine.[1]
[2]
A possible genetic association between RAS and migraine has been considered. Studies
on angiotensin-converting enzyme (ACE) polymorphism in migraine patients have suggested
that there is a higher prevalence and frequency of attacks of migraine without aura
in people with the DD-ACE gene (homozygous for deletion).[3]
In addition, RAS interacts with neurotransmitters and endorphins acting on sympathetic
modulation and synthesis of prostacyclin, bradykinin, encephalin, and substance P,
both centrally and peripherally, thus suggesting that substances that modulate this
system may be relevant for the treatment of migraine.[4]
Lisinopril
Studies
A double-blind, randomized, crossover study comparing lisinopril with placebo in a
population of 47 patients showed that this drug was superior to placebo regarding
reducing the numbers of hours and days with headache, days with migraine, and the
pain severity index, which were all ∼ 20% lower after 12 weeks of follow-up.[5]
Enalapril
Studies
A single randomized double-blind study[6] compared the use of enalapril with placebo for 2 months in 40 patients with episodic
migraine. After a period of 1 month without prophylactic medication, the patients
were randomized to receive enalapril 5 mg or placebo for 2 months. The group that
used enalapril showed significant a reduction in duration, severity, and frequency
of headache attacks per month, as measured on a visual analogue scale (VAS; from 1
to 10) when compared with the placebo group.
Captopril
Studies
Captopril has been evaluated in a single double-blind, randomized Class III study
with 26 patients. Due to the small number of patients and to the high dropout rate
from the study (23%) due to side effects and inefficacy, it was concluded that the
data are insufficient to determine that captopril is not useful for the prophylaxis
of migraine.[7]
Candesartan
Studies
A study by Tronvik et al. evaluated the efficacy of candesartan 16 mg as a preventative
drug for migraine in 60 adult patients.[8] This was a double-blind, randomized, placebo-controlled study with patients who
had two to six migraine attacks per month. In the 1st month, the entire sample received only placebo, and then 30 patients were randomized
to receive 16 mg of candesartan for 12 weeks and, subsequently, placebo for another
12 weeks. The other 30 patients were randomized to do the opposite (receiving placebo
for 12 weeks and then receiving candesartan 16 mg for another 12 weeks).
Candesartan was superior to placebo when considering the mean number of days with
headache in the 12-week period of treatment as the main outcome. Analysis according
to intention to treat showed that during the 12 weeks of treatment, the patients had
an average of 13.6 ± 10.7 days with headache versus 18.5 ± 12.5 days during the 12
weeks of placebo (p = 0.001). There was no difference in adverse events between the two treatment groups.
In conclusion, candesartan 16 mg was superior to placebo in this 12-week crossover
study, both in the primary and in all secondary outcomes, except regarding lost working
days and the Health-Related Questionnaire SF-36, regarding quality of life.
In 2014, Stovner et al.[9] conducted a triple-blind study comparing candesartan cilexetil 16 mg, slow-release
propranolol 160 mg, and placebo. This was a placebo-controlled study, with a double
crossover between groups, evaluating 72 adult subjects with episodic or chronic migraine.
All patients received the 3 possible treatments for 12 weeks each. The primary outcome
was the number of days with migraine for 4 weeks. In a modified intention-to-treat
analysis, candesartan 16 mg was superior to placebo (2.95 versus 3.53 days) and was
not worse than slow-release propranolol 160 mg (2.91 days).
Telmisartan
Studies
A randomized, double-blind, placebo-controlled study in parallel groups to study the
effect of telmisartan 80 mg on migraine prevention showed that it was not superior
to placebo.[10] After 12 weeks, there was no statistically significant reduction in the number of
days with migraine (telmisartan group 80 mg = 1.65 ± 3.46 days and placebo group = 1.14 ± 3.78
days; p = 0.739). The side effects observed were similar in the two groups.
Conclusion
Among angiotensin-converting enzyme inhibitors (ACEIs) and Angiotensin Receptor Blockers
(ARBs), there is a consensus that candesartan is a good option for the preventive
treatment of EM (grade A recommendation). Despite weak evidence of efficacy, lisinopril
and enalapril can be used for the prophylaxis of EM, primarily as adjuvant therapy
in patients with associated arterial hypertension (grade C recommendation for both).
Captopril and telmisartan are not recommended for migraine prophylaxis (recommendation
grades U and B, respectively).
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
SELECTIVE SEROTONIN REUPTAKE INHIBITORS
General aspects
Selective serotonin reuptake inhibitors (SSRIs) are drugs that increase the intrasynaptic
serotonin levels through potent selective inhibition of serotonin reuptake,[11] with minimal effect on the reuptake of norepinephrine and dopamine.[12]
[13]
[14]
[15]
Citalopram/Escitalopram
Studies
For citalopram, two Class II studies with negative evidence have been conducted.[16]
Regarding escitalopram, there is only one Class III study, which compared it with
venlafaxine. In the escitalopram group, frequency, duration, and intensity decreased
significantly in the same proportions as with venlafaxine, but with a better safety
profile for escitalopram.
Fluoxetine
Studies
Four double-blind, parallel controlled clinical trials[17]
[18]
[19]
[20] and subsequent reviews suggested that fluoxetine was inefficacious for the prophylaxis
of migraine attacks.[21]
[22]
Sertraline
Studies
There is only one randomized prospective study (Class III), which revealed that sertraline
was ineffective for migraine prophylaxis.[23]
Fluvoxamine
Studies
In the study by Bánk,[24] with 70 participants, the individuals were randomly subdivided into 2 treatment
groups: amitriptyline (n = 32; 24 women; with a dose of 25 mg/day) and fluvoxamine (n = 32; 23 women; with a dose of 50 mg/day). At the end of the study, there was an
improvement in headache rates for both treatments.
Conclusion
There is insufficient evidence to indicate the use of citalopram, escitalopram, fluoxetine,
sertraline, fluvoxamine, paroxetine, or mirtazapine for migraine prevention.
SEROTONIN AND NORADRENALINE REUPTAKE INHIBITORS
SEROTONIN AND NORADRENALINE REUPTAKE INHIBITORS
Venlafaxine
General aspects
Venlafaxine is a potent inhibitor of presynaptic reuptake of serotonin and norepinephrine
and a weak dopamine reuptake inhibitor. Its metabolism is widely mediated by cytochrome
P450. The half-life times of venlafaxine and its active metabolite are 5 and 11 hours,
respectively, and their elimination occurs essentially through urine.[25]
Studies
A parallel, randomized, double-blind, placebo-controlled study evaluated 60 patients
in 3 groups for 10 weeks: venlafaxine 75 mg, 150 mg, or placebo. Significant reductions
in migraine frequency and consumption of analgesics were observed for the active groups.[26] Bulut et al.[27] conducted a double-blind, randomized, crossover clinical trial in which they analyzed
individuals with episodic migraine who used venlafaxine 150 mg/day and amitriptyline
75 mg/day. In both groups, there were significant reductions in the frequency, duration,
and intensity of migraine, with no statistical difference between them.
According to the meta-analysis by Wang et al.,[28] the clinical trials with venlafaxine are not very robust, since most of them were
considered to have a clear risk of bias. The mode of randomization was not reported
in all studies; two of them were blind while two were open; and most had no published
protocol. Despite these methodological limitations, venlafaxine promoted significant
reductions in the frequency, duration, and intensity of migraine.
Duloxetine
General aspects
Duloxetine acts as a double inhibitor of serotonin and norepinephrine reuptake, but
it weakly inhibits dopamine reuptake as well.[29]
Studies
Two studies were included: a Class II study and a Class III study. Young et al.[30] published a prospective study on duloxetine among patients without depression who
presented EM (on 4 to 10 days per month), and who were titrated for a final dose of
120 mg. In an intention-to-treat analysis, the subjects went from 9.2 ± 2.7 days to
4.5 ± 3.4 days of headache per month (p < 0.001). As a result, 52% of the patients had an improvement ≥ 50% in the number
of headache days. The authors concluded that duloxetine, at high doses, may be effective
in individuals with episodic migraine, even without depression.
In 2019, Kisler et al.[31] studied the preventive effect of duloxetine on EM through a prospective, placebo-controlled,
double-blind clinical trial with 27 patients (25 women) without depression. The patients
started at a dose of 30 mg/day of duloxetine in the 1st week and their dose was increased to 60 mg/day in the 2nd week, which was then continued until the end of 8 weeks of treatment. The authors
concluded that duloxetine was more effective than placebo in preventing migraine,
with improvements in the frequency of migraine attacks (2.0 versus 1.3), frequency
of migraine days per month (3.3 versus 1.7), and other parameters (intensity and self-esteem)
(3.3 versus 1.7).
Conclusion
There is a consensus that venlafaxine and duloxetine are probably effective for migraine
prophylaxis, especially in individuals who also have psychiatric comorbidities, such
as anxiety disorders and depression.
There is insufficient evidence to indicate the use of citalopram, escitalopram, fluoxetine,
sertraline, fluvoxamine, paroxetine, or mirtazapine for migraine prevention.
CALCIUM CHANNEL BLOCKERS
General aspects
Calcium channel blockers (CCBs) form a heterogeneous group of medications that began
to be studied for prophylactic migraine treatment in 1981.[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42] The mechanism of action of these drugs in migraine is debatable.[43]
[44] It has been postulated that blockade of calcium channels inhibits the entry of extracellular
calcium into the cells of the muscle layer of the brain vessels. However, direct blockade
of 5-HT receptors has been considered essential for calcium channel blockers to be
effective for migraine, especially regarding flunarizine[45]
[46] and verapamil.[47]
Flunarizine
General aspects
Flunarizine is the most widely used drug in this group. In addition to being a nonselective
calcium channel antagonist,[43] it blocks the voltage-dependent sodium channels[48]
[49] and can reduce the number of occurrences and the duration of cortical spreading
depression (CSD). It may decrease mitochondrial injury induced by CSD[50] and has antagonistic action for the dopaminergic receptor D2, which can also contribute
to the prophylactic migraine effect.[51]
Studies
Although there are 7 double-blind, randomized, placebo-controlled studies in which
flunarizine, in a single nocturnal dose of 10 mg, was shown to reduce the frequency,
the duration, and the intensity of migraine attacks, these studies do not present
the necessary requirements to categorize this finding as Level A evidence due to various
factors, especially the low number of subjects studied.[32]
[52]
[53]
[54]
[55]
[56]
[57]
Three meta-analysis studies corroborate the positive results from primary outcomes,[58]
[59]
[60] with the caveat in one of them[60] that the decrease in the frequency of headache attacks would take place at weeks
8, 12, 16, and 20, but not in week 4.
There are comparative studies, among which the ones of greatest relevance are precisely
those that demonstrated effects comparable with those from drugs of recognized efficacy
such as propranolol[60]
[61] and topiramate.[62]
[63]
The primary outcomes from other comparative analyses showed that the efficacy of flunarizine
was similar to that of metoprolol,[64] nifedipine,[65] valproate,[66] and topiramate.[62]
[63]
Nicardipine
Studies
In a single Class II study, nicardipine, at a dose of 20 mg twice daily, was evaluated
among 30 migraine patients. It was shown to have greater efficacy than placebo regarding
decreased frequency, intensity, and duration of attacks. However, a reanalysis of
this study[60] revealed, through the confidence interval (CI), that there was no statistical difference
in the frequency of migraine attacks. Therefore, there are no studies showing an indication
for use of nicardipine in prophylactic treatment of migraine. Nicardipine is no longer
commercialized in Brazil.
Nifedipine
Studies
There are two Class III studies on nifedipine for prophylactic treatment of migraine.
The first of these, with 24 patients, using 30 mg per day, revealed that there was
no difference in the primary outcome in relation to placebo.[67] The second, with 28 patients, using nifedipine at a dose of 5 mg, 3 times a day,
demonstrated its efficacy in reducing the frequency of attacks.[68] A meta-analysis on these two studies showed that nifedipine was not superior to
placebo.[60] In a comparative study with propranolol, the adverse events of nifedipine were the
main factor responsible for the high rate of abandonment among patients, and it was
concluded that this is not a drug of choice for prophylactic treatment of migraine.[69]
Nimodipine
Studies
There are three class II and three class III studies, all of them double-blind, randomized
and placebo-controlled, on the efficacy of nimodipine for migraine prophylaxis, with
discordant results. A meta-analysis using the results from these studies and others
concluded that there is no difference between nimodipine and placebo.[60]
Verapamil
Studies
The prophylactic effect of verapamil for treating migraine patients was evaluated
in two class III, double-blind, randomized, placebo-controlled studies, but with only
12 patients[70] and 14 patients.[39] The doses used were 240 mg per day[39] and 320 mg per day.[70] Although in both studies the results were considered positive, a subsequent reanalysis
of the results did not identify any difference in reducing the frequency of attacks.[60]
Conclusion
There is a consensus regarding the efficacy of flunarizine and its indication for
prophylactic treatment of migraine, taking into consideration the absolute and relative
contraindications. There is also a consensus that nicardipine, nifedipine, nimodipine,
and verapamil should not be used in migraine prophylaxis.
OTHER DRUGS
Antihistamine (Cyproheptadine)
General aspects
Cyproheptadine is a first-generation antagonist of H1 histaminergic receptors, 5-HT2
serotonergic receptors, and calcium channels. Cyproheptadine blocks the activity of
5-HT2 receptors in the vascular wall and platelets, thereby reducing platelet aggregation.[71]
Studies
A small number of clinical trials have shown that cyproheptadine is effective for
preventive treatment of migraine. In a double-blind, randomized crossover study involving
60 adult patients, cyproheptadine was shown to be safe and more effective than placebo
after 12 weeks, although the groups were not adequately matched, thus reducing the
study power (Class III).[72] A study by Rao et al.,[73] with a double-blind, randomized, placebo-controlled design, included 259 patients
aged between 16 and 53 years old divided into 4 groups: placebo, cyproheptadine, propranolol,
and cyproheptadine and propranolol for 12 months. It demonstrated that cyproheptadine
and propranolol were significantly more effective than placebo. The highest efficacy
was obtained when cyproheptadine and propranolol were used in combination (Class II).
Conclusion
Despite the small number of trials, cyproheptadine is a good choice for preventive
treatment of migraine, in association with other prophylactic drugs and in thinner
patients.
Serotoninergic antagonist (Pizotifen)
General aspects
Pizotifen is a serotonergic antagonist that acts primarily on 5-HT2A and 5-HT2C receptors. It has mild antihistamine and anticholinergic action.
Studies
The efficacy and safety of pizotifen were compared against placebo in adults,[74]
[75] showing good results for pizotifen. Randomized, double-blind comparative studies
comparing pizotifen with other drugs have sometimes included a placebo arm or more
than one arm with an active drug. In terms of efficacy, pizotifen was similar to the
comparison drug (iprazochrome,[75]
[76] flunarizine,[77]
[78]
[79]
[80] metoprolol,[81] prophylactic naproxen,[82] nimodipine,[83] propranolol, and amitriptyline),[84] while one study showed that pizotifen was less effective than cyclandelate.[85]
A double-blind, randomized, crossover dosing study was conducted to compare 2 schemes:[86] a single dose or 3 doses per day of pizotifen (equal total dose of 1.5 mg/day in
these two schemes). Their efficacy was similar, but there was better tolerability
of the single dose. Cleland et al.[87] conducted a partially open and partially double-blind study, both with crossover
design, to compare prophylaxis for migraine using pizotifen with treatment using sumatriptan
only in the attacks. Only when the patient had more than four migraine attacks per
month was it better to use pizotifen. Unfortunately, a German study[88] could not be evaluated here since it did not contain an abstract and the authors
of the present review were unable to obtain the original text. Level of evidence/recommendation:
3B.
Conclusion
Studies on pizotifen are typically old, sometimes designed before the criteria established
by the International Headache Society had been defined. Nonetheless, it is a safe
drug, even during pregnancy. Data are insufficient to determine the effectiveness
of Pizotifen.
Melatonin
General aspects
The mechanism of action of melatonin is thought to involve anti-inflammatory effects,
free radical elimination effects, inhibition of dopamine release, reduction of positive
regulation of proinflammatory cytokine, and protection of neurotoxicity through inhibiting
glutamate release.[89]
[90]
Studies
A randomized, double-blind, placebo-controlled study was conducted among 196 subjects
with episodic migraine with aura or without aura. Melatonin 3 mg was compared with
amitriptyline 25 mg and placebo for 3 months. Melatonin was better than amitriptyline
and placebo, with a reduction > 50% in the frequency of migraine.[91]
Conclusion
There is a consensus that melatonin is possibly effective for prophylactic treatment
of EM (Class II; Level C).
Alpha-Adrenergic blockers (Clonidine)
General aspects
Clonidine is an imidazole derivative that is an antagonist of the α2 presynaptic receptors
in the periphery and in the central nervous system (CNS). Peripherally, it inhibits
the release of norepinephrine from sympathetic nerves and decreases the sympathetic
tone by modulating vasodilation and constriction.[92]
[93] Centrally, it inhibits the electrical currents of calcium ions, thus mediating analgesia
in the spinal cord.[94]
Studies
Clonidine has been evaluated through double-blind and placebo-controlled studies[92]
[93]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102]
[103] and in comparisons with propranolol[104] and metroprolol[105] in different age groups. Some studies have not shown any evidence in favor of clonidine.
Other studies have presented conflicts, demonstrating some parameters of improvement
and others of equality to placebo. In the study comparing clonidine with propranolol,[104] the two agents had similar prophylactic effects. Because of the divergence of the
data, clonidine is not considered effective for prophylactic treatment of EM.
Conclusion
There is a consensus that clonidine is not effective for prophylactic treatment of
EM.
Neuroleptics (Quetiapine, Aripiprazole, and Ziprasidone)
General aspects
Neuroleptics antagonize serotonin (5-HT1a and 5-HT2), dopamine (D 1 and D2), histamine (H1), and adrenergic receptors (alpha-1 and alpha-2).[106]
Studies
Open case-control studies have evaluated quetiapine,[107]
[108] a case-control study has evaluated aripiprazole,[109] and there is a case report on ziprasidone.[110] All of these studies demonstrated that these agents were effective for controlling
EM attacks. However, the levels of evidence and recommendation were very low, which
means that there is no indication for their use as prophylactics.
Conclusion
The neuroleptics quetiapine and aripiprazole have been shown to be effective for treating
migraine in open case-control studies. Ziprasidone was not evaluated at all. For these
reasons, there is a consensus that although quetiapine and aripiprazole were effective
in open studies, they cannot be considered prophylactic due to lack of data from controlled
studies.
Vitamin K inhibitor (Warfarin)
General aspects
Warfarin is a vitamin K antagonist that acts by inhibiting platelet aggregation and
secretion of 5-hydroxytryptamine (5-HT),[111] acting in the coagulation cascade of intrinsic factors (factors II, VII, IX, X).[112]
Studies
Nine case reports[112]
[113]
[114]
[115]
[116]
[117]
[118]
[119]
[120] and two open studies have evaluated the use of warfarin.[111]
[121] The doses used were 5 to 10 mg in a single dose. However, most studies have reported
on the use of warfarin for maintaining INR between 2 and 3. The studies have suggested
that warfarin is effective for controlling EM attacks. In most studies, the improvement
of migraine was detected serendipically when using warfarin in associated clinical
situations such as pulmonary thromboembolism, peripheral venous thrombosis, and atrial
fibrillation. The clinical response seems to be more marked in cases of migraine with
aura.
Conclusion
Warfarin is possibly effective for prophylaxis of EM, especially in patients with
migraine with aura. There is a consensus that, due to the risk-benefit balance, warfarin
should not be used in migraine prophylaxis.
Leukotriene receptor antagonist (Montelukast)
General aspects
Leukotriene receptor agonists produce a reduction in proinflammatory mediators, specifically
in the production of leukotriene (LTB4) in leukocytes, thus altering platelet aggregability.[122]
[123]
[124]
[125]
Studies
Montelukast has been evaluated through a multicenter, double-blind placebo-controlled
study,[126] two case-control studies,[127]
[128] and four case reports.[129]
[130]
[131]
[132] The multicenter, double-blind, placebo-controlled study showed that this drug was
not more effective than placebo. The open case studies demonstrated drug effectiveness
and there was also a therapeutic response in the case reports. Montelukast is considered
a possibly ineffective drug for prophylactic treatment of migraine.
Conclusion
There is a consensus that montelukast should not be indicated for prophylactic treatment
of episodic migraine.
Statins (Simvastatin and Atorvastatin)
General aspects
Statins have anti-inflammatory properties,[133]
[134] vasomotor effects,[135] and effects on platelet coagulation,[136] in addition to central action on the trigeminal caudal nucleus.[137]
Studies
Atorvastatin 40 mg/day (n = 46) was compared in a double-blind study with sodium valproate 500 mg/day (n = 36) for prophylaxis of high-frequency migraine (6 to 15 days/month). After 3 months
of treatment, it was shown to be able to reduce the number of days with pain, the
duration and intensity of attacks, and the consumption of analgesics.[138]
In an open study, 20 mg simvastatin (n = 29 women with dyslipidemia) was compared with propranolol 60 mg (n = 25 women) for treatment of EM over a 90-day treatment period. Both groups reduced
the number of days with headache by > 50%.[139] In another study, use of simvastatin 20 mg + vitamin D 1,000 units twice daily was
compared with a placebo group for treatment of EM over a 24-week follow-up period.
In the simvastatin group, 25% of the patients reduced the number of migraine days
by > 50% with 12 weeks of treatment and 29% achieved this after 24 weeks of treatment.[140]
Conclusion
There is a consensus that atorvastatin and simvastatin are possibly effective for
prophylactic treatment of EM. However, they should be used primarily as adjuvant therapy
for patients with dyslipidemia ([Table 1]).
Table 1
Drugs, dosages, adverse effects, evidence level, recommendation level, and risks in
pregnancy and breastfeeding
|
Drug
|
Frequency of dosage and administration route
|
Adverse events
|
Evidence level
|
Recommendation level
|
Pregnancy/
breastfeeding
|
|
POSITIVE EVIDENCE
|
|
Angiotensin-converting enzyme inhibitors
|
|
Lisinopril
|
10–20 mg/day
2x/day; maximum 80 mg
orally
|
Dry cough, fatigue, dizziness, vertigo, lipothymia, hyperkalemia
|
1 class II study
|
Level C: possibly efficacious
|
C - D - D /
Use with care
Breastfeeding: Low risk
|
|
Enalapril
|
10–20 mg/day
1x or 2x/day; maximum 40 mg
orally
|
1 class II study
|
Level C: possibly efficacious
|
C - D - D /
use with care
Breastfeeding: Potential severe adverse events in the baby; stop medication or breastfeeding
|
|
Captopril
|
50 mg/day; up to 450 mg/day 3x/day
orally
|
1 class III study
|
Level U: conflicting data.
|
C - D - D /
use with care
Breastfeeding: Very low risk
|
|
Angiotensin receptor blockers
|
|
Candesartan
|
8–16 mg/day; maximum 32 mg
1–2x/day
orally
|
Dizziness, arterial hypotension, fatigue, paresthesia, hyperkalemia
|
2 class I studies
|
Level A: Established as efficacious
|
C - D - D /
Contraindicated
Breastfeeding: Low risk; moderately safe; monitor use
|
|
Calcium channel blockers
|
|
Flunarizine
|
5–10 mg/day
1x at night
orally
|
Somnolence, weight gain, depression, fatigue, vertigo, arterial hypotension, hypokinesis,
tremor, rigidity
|
Class II (≥ 2 studies)
|
Level B: Probably efficacious
|
Category C
Breastfeeding: High risk
|
|
Nicardipine
|
60–120 mg/day
3x/day
orally
|
Headache, dizziness, facial redness, dyspnea
|
1 class II study and 1 class IV study
|
Level U: conflicting data
|
Unknown fetal risk due to lack of studies
Breastfeeding: avoid it because of lack of information.
|
|
Nifedipine
|
10–60 mg/day -
1–3x/day
orally
|
Dizziness, leg edema, facial redness, headache
|
2 class III studies (1 positive and one negative)
|
Level U: conflicting data
|
Category C
Breastfeeding: very low risk
|
|
Drug
|
Frequency of dosage and administration route
|
Adverse events
|
Evidence level
|
Recommendation level
|
Pregnancy/
breastfeeding
|
|
Neuroleptics
|
|
Quetiapine
|
25–150 mg/ day
1 or 2x/day
Maximum 800 mg
orally
|
Excessive sedation, confusion, weight gain
|
2 class III studies
|
Level C: Possibly efficacious
|
Category C
Breastfeeding: Very low risk
|
|
Aripiprazole
|
5–20 mg/day
1x/day
Maximum 30 mg
orally
|
1 class III study
|
Level U: Conflicting data
|
Category C
Breastfeeding: Low risk
|
|
Ziprasidone
|
40–80 mg/day
2x/day
orally
|
1 class IV study
|
Level U: Conflicting data
|
Category C
Breastfeeding: High risk
|
|
Statins
|
|
Atorvastatin
|
10–80 mg/day- average 20 mg
1x/day
orally
|
Headache, dizziness, nausea, abdominal pain, insomnia
|
1 class II study
|
Level C: Possibly efficacious
|
Category X
Breastfeeding: High risk
|
|
Simvastatin
|
5-80 mg/day - average 20 mg
1x/day
orally
|
1 class II study and 1 class III study
|
Level C: Possibly efficacious
|
Category X
Breastfeeding: High risk
|
|
Vitamin K inhibitor
|
|
Warfarin
|
2.5–5 mg/day
Maximum 10 mg/day
(INR 2–3)
1x/day
orally
|
Digestive, urinary, oral, and nasal bleeding
|
2 class III studies
|
Level C: Possibly efficacious
|
Category X
Breastfeeding: Very low risk
|
|
Other drugs
|
|
Melatonin
|
3 mg/day
1x at night
orally
|
Fatigue, somnolence, difficulty in concentrating, depressive symptoms, headache, diarrhea,
abnormal dreams,
|
1 class II study
|
Level C: Possibly efficacious
|
C / C / C
Use with care
Breastfeeding: Very low risk
|
|
Cyproheptadine
|
1–6.5 mg/day
1x/day
orally
|
Somnolence,
increased appetite, weight gain, dry mouth, blurred vision, glaucoma
|
≥ 2 class III studies and 1 class II study
|
Level C: Possibly efficacious
|
Category B
Breastfeeding: Contraindicated
|
|
Pizotifen
|
1.5–3.0 mg/day
1–3x/day
orally
|
Weight gain
|
≥ 2 class II studies
|
Level B: Probably efficacious
|
Category B
Breastfeeding: Not recommended
|
|
Drug
|
Frequency of dosage and administration route
|
Adverse events
|
Evidence level
|
Recommendation level
|
Pregnancy/
breastfeeding
|
|
NEGATIVE EVIDENCE
|
|
Angiotensin receptor blockers
|
|
Telmisartan
|
40–80 mg/day
1x/day
orally
|
Dizziness, arterial hypotension, fatigue, paresthesia, hyperkalemia
|
1 class I study
|
Level B: Probably inefficacious
|
C - D - D /
use with care
Breastfeeding: High risk
|
|
Selective serotonin reuptake inhibitor
|
|
Sertraline
|
50–100 mg/day
1x/day
Maximum 200 mg
orally
|
See escitalopram
|
1 class II study
|
Level C: Possibly inefficacious
|
Category C
Breastfeeding: Very low risk
|
|
Fluoxetine
|
20–60 mg/day
1x/day
orally
|
≥ 2 class II studies
|
Level B: Probably inefficacious
|
Category C
Breastfeeding: Low risk
|
|
Citalopram
|
10–20 mg/day
1x/day
orally
|
2 class II studies
|
Level B: Probably inefficacious
|
Category B and C
Breastfeeding: Very low risk
|
|
Other drugs
|
|
Clonidine
|
25 to 75 µg/day
2x/day
Maximum 900 µg
orally
|
Anxiety, tiredness, dry mouth, dizziness, dyspnea, palpitations, nausea, vomiting,
stomachache, abdominal bloating, orthostatic hypotension, fainting, somnolence, rash,
headache, irritability, insomnia
|
≥ 2 class I studies
|
Level A: Established as not efficacious
|
Category C
Breastfeeding: High risk
|
|
Montelukast
|
5–20 mg/day
orally
|
Not reported
|
Class I, class II and class III studies
|
Level B: Probably inefficacious
|
Category C
Breastfeeding: Low risk
|
RATIONAL POLYTHERAPY
True polytherapy and false polytherapy
Polytherapy can be divided into two subtypes: 1) true polytherapy; and 2) false polytherapy.
The first consists of prescribing two or more drugs for treating migraine and the
second is a situation in which at least one drug is directed to treating comorbidity.[141]
Evidence and Justifications for rational polytherapy
Rational polytherapy in migraine is a topic that has been discussed for a long time.[142] Preventive treatment of episodic migraine always begins with monotherapy, but if
attacks become more frequent and refractory to monotherapy, the natural tendency is
to use associations of drugs in an add-on system.[143] Although this is a common practice in the offices of headache specialists, only
a small number of clinical trials have been conducted on polytherapy within migraine
prophylaxis.[143]
[144]
[145]
[Table 2] briefly describes the studies that have supported the use of polytherapy.
Table 2
Clinical trials that used polytherapy in episodic migraine
|
Study
|
Drug
|
Type
|
n
|
Doses
|
I
|
D
|
F
|
AC
|
AG
|
|
Bordini et al.
[146]
|
PPN
vs
FNZ
vs
PPN + FNZ
|
Double-blind and parallel randomized clinical trial
|
15
15
15
|
PPN 60 mg/day
FNZ 10 mg/day
|
S
|
NA
|
S
|
NA
|
A
|
|
Pascual et al.
[147]
|
BB
vs
VPA
vs
BB + VPA
|
Open clinical trial
|
52
|
BB 40–160 mg/day
VPA 300–1,000 mg/day
|
NA
|
NA
|
↓
|
NA
|
A
|
|
Rampello et al.
[16]
|
AMT
vs
CTP
vs
AMT + CTP
|
Open and parallel randomized clinical trial
|
44
44
29
|
AMT 50 mg/day
CTP 20 mg/day
|
NS
|
S
|
S
|
NA
|
A
|
|
Keskinboraet al.[148]
|
TPM
vs
AMT
vs
TPM + AMT
|
Double-blind and parallel randomized clinical trial
|
5
4
6
|
TPM 25–200 mg/day
AMT 10–150 mg/day
|
NS
|
NS
|
NS
|
NA
|
A
|
|
Domingues et al.
[149]
|
PPN
vs
NTP
vs
PPN + NTP
|
Double-blind and parallel randomized clinical trial
|
25
24
27
|
PPN 80 mg/day
NTP 40 mg/day
|
NA
|
NA
|
S
NS
S
|
NA
|
A
|
|
Krymchantowski et al.[150]
|
TPM
vs
NTP
vs
TPM + NTP
vs
TPM + PCB
vs
NTP + PCB
|
Parallel randomized, placebo-controlled trial
|
80
|
TPM 100 mg/day
NTP 30 mg/day
|
NA
|
NA
|
S
|
NA
|
A
|
|
Drug
|
Frequency of dosage and administration route
|
Adverse events
|
Evidence level
|
Recommendation level
|
Pregnancy/
breastfeeding
|
|
Nimodipine
|
90 mg/day –
3x/day;
Maximum 360 mg
orally
|
Vertigo, facial redness, muscle pain, abdominal pain, weight loss, pruritus
|
1 class I study (negative) 2 class II studies (negative) and 2 class III studies (positive)
|
Level U: Conflicting data.
|
Undetermined risk in pregnancy
Breastfeeding: Very low risk
|
|
Verapamil
|
120–480 mg/day
3–4x/day or R** 1–2x/day
orally
|
Constipation, skin erythema, headache
|
2 class IV studies
|
Level U: Conflicting data
|
Category C
Breastfeeding: Very low risk
|
|
Serotonin and noradrenaline reuptake inhibitors
|
|
Venlafaxine
|
37.5–150 mg/day
1x/day
orally
|
Insomnia, headache, dizziness, sedation, nausea, dry mouth, constipation, hyperhidrosis,
abnormal dreams, decreased libido
|
≥ 2 class II studies
|
Level B: Probably efficacious
|
Category C
Breastfeeding: Use with care
|
|
Duloxetine
|
30–120 mg/day
1x/day
orally
|
2 class II studies
|
Level B: Probably efficacious
|
Category C
Breastfeeding: Use with care
|
|
Serotonin reuptake inhibitors
|
|
Escitalopram
|
5–10 mg/day
1x/day
orally
|
Insomnia, nausea, headache, asthenia, diarrhea, anorexia, somnolence, anxiety, nervousness,
dry mouth, decreased libido, tremor, ejaculatory dysfunction, impotence, abnormal
dreams, constipation, vomiting
|
1 class III study
|
Level C: Possibly efficacious
|
Category B
Breastfeeding: Very low risk
|
|
Paroxetine
|
20 mg/day
2x/day
orally
|
1 class IV study
|
Level U: Conflicting data
|
Category D
Breastfeeding: Very low risk
|
|
Fluvoxamine
|
50 mg/day
1x at night
orally
|
Somnolence, constipation, dry mouth, nausea, weakness
|
1 class II study
|
Level C: Possibly efficacious
|
Category C
Breastfeeding: Very low risk
|
Abbreviations: A, adults; AC, consumption of analgesics; AMT, amitriptyline; BB, beta-blocker;
CTP, citalopram; D, duration; ES, age group; F, frequency; FNZ, flunarizine; I, intensity;
NA, not assessed; NS, not significant; NTP, nortriptyline; P, pediatrics; PCB, placebo;
PPN, propranolol; S, significance with p < 0.05; TPM, topiramate; VPA, valproic acid.
↓ reduction, but without statistical analysis
Conclusion
Monotherapy is the rule for the initial treatment of EM. In some situations, polytherapy
may be indicated. There is no consensus on when to indicate it. There is a consensus
that polytherapy should not be started until after at least 2 drugs with recommendation
level A and/or B have been tried, at appropriate doses and for a minimum of 6 weeks.
