THERAPEUTIC CLASSES
Beta-blockers
General aspects
Beta-blockers are the most commonly used drugs in migraine prophylaxis worldwide.[11] The probable mechanism of action is through central regulation with reduction of
noradrenergic neuronal triggers, in addition to regulation of gamma-aminobutyric acid
(GABA) in the periaqueductal gray matter. Some beta-blockers act in the serotoninergic
system with reduced serotonin synthesis and with blockade of 5-hydroxytryptamine receptor
2B (5HT2B) and 2C (5HT2C).[12]
Propranolol
General aspects
Propranolol is a non-selective beta-blocker with hepatic metabolization, short half-life
(four to five hours), and high protein affinity (which should be considered when used
concomitantly with other high-protein molecules such as valproate, amitriptyline and
nortriptyline). Due to all these pharmacokinetic variables, propranolol should be
titrated slowly to reduce the likelihood of adverse effects.[13]
Although its liposolubility enbales it to cross the blood-brain barrier (BBB), it
does not act directly on the cerebral vessels; instead, it can centrally modulate
the sensitivity of the autonomic tone of the vessels to sensory stimuli during the
migraine attack.[14] Propranolol inhibits the production of nitric oxide by blocking nitric oxide synthase.
It also acts on glutamate receptors, with the inhibition of kainate-induced currents
and has a synergistic effect on N-methyl-D-aspartate (NMDA) blockers, which reduce
neuronal activity and have membrane-stabilizing properties.[12]
Studies
Propranolol is the beta-blocker with the highest number of studies of relevance for
EM prophylaxis. In a systematic review and meta-analysis,[15] among patients with an average of 4.9 days of pain/month, propranolol was superior
to placebo at the end of 8 weeks and 12 weeks in reducing the frequency of attacks.
In several double-blind, randomized, placebo-controlled studies,[16]
[17]
[18] propranolol has been shown to be safe and more effective than placebo after 8 and
12 weeks. A study[19] comparing propranolol with other medications that are considered first-line for
migraine prophylaxis indicated that propranolol has favorable results. Another study[20] comparing propranolol with valproate showed that propranolol was slightly superior
in reducing the number days of pain, with fewer side effects, but without statistical
significance. In yet another comparative study,[21] topiramate was superior to propranolol, but both drugs were used at low doses (50 mg
topiramate versus 80 mg propranolol/day respectively). However, at higher doses (160 mg/day
of propranolol), the result was the same as with topiramate at a dose of 1 mg/kg to
2 mg/kg, regarding the positive response rate, reduction of days of pain, frequency
of attacks, and use of abortive medications.[22]
Metoprolol
General aspects
Metoprolol is a selective beta-blocker (beta-1) with high liposolubility, thus having
good penetration in the BBB.[23] The beta-1 receptor blockade modulates inhibition of sodium ions (Na + ) and the
activity of tyrosine hydroxylase, reduces the neuronal activation threshold in response
to noradrenergic stimuli of the locus ceruleus, and regulates periaqueductal gray
matter activity.[24] Metoprolol has low affinity for 5-HT receptors and has a half-life from 3 to 7 hours,
with primarily hepatic metabolism. Due to pharmacokinetic variability, it requires
slow titration to avoid more serious side effects.[11]
Studies
There are four randomized, controlled, double-blind studies[25]
[26]
[27]
[28] comparing metoprolol at daily doses between 100 and 200 mg with placebo. They[25]
[26]
[27]
[28] have shown the superiority of this medication in reducing the frequency and intensity
of migraine attacks, and also the disability and days of analgesic use.
In comparison with other drugs, metoprolol is also shown to be effective in titratable
doses of up to 100 mg/day, compared with clomipramine 100 mg/day and placebo. Only
metoprolol showed significant reduction in the frequency and duration of attacks (p < 0.05).[29] A comparative study[30] between metoprolol 200 mg and propranolol 160 mg showed that both drugs were effective
in reducing the frequency of attacks, days of pain, pain intensity, and use of analgesic
medications, but there was no statistically significant difference between them.
A controlled study[27] evaluated the dose-response effect and showed that metoprolol was more effective
than placebo, and at a daily dose of 200 mg in comparison with 100 mg.
Timolol
General aspects
Like propranolol, timolol is a non-selective beta-blocker with no intrinsic sympathetic
activity. It is a lipophilic drug with central nervous system (CNS) penetration, has
good affinity for serotonergic receptors 5-HT2B and 5-HT2C, has hepatic clearance, low protein affinity, and short half-life, of 2 to 5 hours.
It can be titrated more quickly, unlike propranolol and metoprolol.[13]
Studies
In a randomized double-blinded study,[31] timolol (30 mg/day) was superior to placebo in reducing the frequency of attacks,
but there was no difference in pain intensity or duration. A multicenter crossover
randomized, controlled, double-blinded study[32] compared timolol to propranolol. Both drugs were superior to placebo regarding reduction
of the mean frequency and severity of attacks. There was no statistically significant
difference in the reduction of the frequency of attacks between the groups treated
with timolol and propranolol. The conclusion was that timolol had similar efficacy
to propranolol, compared with placebo, at a dose of 10 g, to 15 mg twice a day.[32]
Atenolol
General aspects
Atenolol is a selective beta-1 beta-blocker of low liposolubility, with a half-life
of six to seven hours, without intrinsic sympathetic activity.[23]
Studies
A randomized double-blinded study[33] with 24 patients showed that the atenolol 100 mg group was superior to placebo in
reducing the number of migraine days. However, only four patients were included in
the placebo group.
In a multicenter, randomized, controlled, double-blinded study,[34] atenolol 100 mg demonstrated a reduction in an outcome called integrated pain value,
which considered the frequency and intensity of attacks. This study[34] did not clearly explain the primary and secondary outcomes, or the reduction values,
nor did it explain what it considered the integrated pain value to be.
A crossover, randomized, double-blinded, placebo-controlled study[35] with 28 patients compared atenolol 100 mg with propranolol 160 mg and placebo. Atenolol
was shown to be more effective than placebo in reducing the number of days of pain.
Propranolol was superior to placebo, without statistical significance. In the comparison
between atenolol and propranolol, no statistically significant difference was observed.
The reduction in the number of days of pain in each group was not stated separately
in the study.[35]
Nadolol
General aspects
Nadolol is a non-selective beta-blocker, with low liposolubility and long half-life
(of 20 to 24 hours). It is metabolized in the liver, has moderate protein affinity
(28%), and is eliminated by the kidneys.[23]
Studies
In a randomized controlled study,[36] nadolol 80 mg and 160 mg once a day was compared with propranolol 160 mg (divided
into 2 intakes). It was found to be superior in efficacy and safety compared with
propranolol.[36] Currently, this medication is not available in Brazil.
Nebivolol
General aspects
Nebivolol is a third-generation cardio-selective agent that is highly selective for
the beta-1 receptor, with additional vasodilation effect mediated by a high release
of nitric oxide.[37] It has no intrinsic sympathetic mimetic activity and has little or no stabilizing
membrane activity. Its metabolism is hepatic, and its half-life is of 10 hours.[38]
Study
A double-blinded randomized study[39] was conducted among 30 migraine patients receiving 5 mg of nebivolol per day or
increasing doses of metoprolol (47.5 mg in the first week, 95 mg in the second week,
and 142.5 mg in the third to sixth weeks). The reduction in the mean frequency of
migraine attacks per month, after a 12-week period, was from 3.4 to 1.3 (metoprolol)
and from 3.3 to 1.6 (nebivolol), without statistical differences between the two groups.
Nebivolol showed efficacy similar to that of metoprolol and was a well-tolerated drug
at a dose of 5 mg, without the need for titration to achieve the therapeutic dose.[39]
Pindolol
General aspects
Pindolol is a non-selective beta-blocker with a high degree of intrinsic sympathetic
mimetic activity, low liposolubility, and a half-life of three to four hours.[23]
Studies
No statistically significant differences were observed in two studies comparing pindolol
(in doses of 2.5 mg/day and 5 mg/day,[40] and of 7.5 mg/day and 15 mg/day[41]) and placebo.
Conclusion
Among beta-blockers, propranolol and metoprolol are the drugs with the best evidence
regarding the reduction of migraine attacks in EM compared with placebo (Level A recommendation).
Anticonvulsants
Topiramate
General aspects
Topiramate acts on multiple molecular targets to increase inhibitory function, such
as voltage-dependent sodium channels, calcium channels, carbonic anhydrase, and glutamate
kainate receptors. It is well absorbed by the gastrointestinal tract, and its maximum
plasma concentration (Tmax) is reached in 2 to 3 hours. It binds little to plasma
proteins, and it is eliminated unchanged by the kidney and partially by oxidation
and hydrolysis. Its half-life of 20 to 30 hours becomes shortened by concomitant use
of liver metabolism-inducing drugs.[42]
Studies
Silberstein et al.[43] conducted a multicenter, double-blinded, randomized study on placebo-controlled
topiramate, and improvements occurred within the first month of treatment. Patients
in the topiramate group had a statistically significant improvement in the group that
used 100 mg/day, with a 54% reduction of migraine days/month (p = 0.001), compared
with patients treated with placebo (reduction of 22.6%). And Brandes et al.[44] conducted a multicenter, double-blinded, randomized study on topiramate controlled
by placebo and propranolol, in which the response rate was significantly higher with
topiramate at 50 mg/day (39%; p = 0.01), 100 mg/day (49%; p = 0.001) and 200 mg/day (47%; p = 0.001) than with placebo (23%). The use of rescue medication was reduced in the
groups that used topiramate 100 mg/day (p = 0.01) and 200 mg/day (p = 0.005). Diener et al. (2004)[22] compared topiramate, placebo and propranolol, and showed that topiramate and propranolol
had similar efficacy and were superior to placebo. With a 95% confidence interval,
both drugs diminished the frequency of days with migraine attacks and of use of acute
medication. Diamond et al. (2005),[45] based on these three studies, showed that topiramate, at a dose of 100 mg/day, led
to a significant increase in the quality of life of migraineurs for up to 6 months
since the beginning of treatment. These authors[45] evaluated quality of life using specific tests for migraineurs: the Mini-Sleep Questionnaire
(MSQ) and the Health-Related Quality of Life Assessment Questionnaire (HRQoL).
Sodium valproate/divalproate
General aspects
The anticonvulsant pharmacological properties of sodium valproate were first described
in 1975,[46] and its first evaluation regarding the treatment of migraine was published in 1988.[47] Its mechanism of action is related to increased GABA, blockage of voltage-dependent
sodium channels, and T-type calcium channels.[48] It reaches its plasma peak in up to 4 hours, and its half-life ranges from 8 to
12 hours in the conventional form, and is of up to 20 hours in the sustained-release
form. It is a weak inhibitor of the cytochrome P450 system, epoxidrase, and glucuronyltransferase,
and is almost entirely metabolized by the liver.[49]
Studies
There are consistent studies proving the efficacy of valproate/divalproate. Among
more than 2 thousand publications, there are 2 main prospective studies on the preventive
treatment of EM with valproate, and 4 on divalproate (a compound of valproic acid
and sodium valproate in the proportions of 1:1) at doses of 500 mg/day to 1,000 mg/day.[49] The two main studies on valproate (1000mg/dia), which were prospective, randomized
and double-blinded, included 63 patients. Hering and Kuritzky[50] (1992) conducted an 8-week study on 29 patients, comparing valproate at 800 mg/day
with placebo. Their study showed that the use of this medication resulted in a significant
reduction in the frequency of pain compared with placebo, with a mean total number
of attacks of 8.826 ± 6.066 with its use compared with an average of 15.586 ± 8.330
with placebo. Jensen et al.[20] (1994) analyzed 34 patients for 4 weeks, and observed a reduction about 50% or more
in the frequency of pain in the divalproate group, and of 18% in the placebo group.
The number of responders increased to 65% in the last 4 weeks of the open phase of
the study.[20] Mathew et al.[51] (1995) analyzed 107 patients in a multicenter, prospective, randomized, double-blinded
study lasting 16 weeks. There was a 48% reduction in the frequency of pain in patients
in the divalproate group, and of 14% in the placebo group, in relation to the initial
frequency. In addition, there was a significant reduction in the intensity and duration
of attacks in the treated patients.
Regarding valproate, valproic acid, and divalproate molecules, divalproate has been
shown to be most effective and best tolerated, especially in its sustained-release
form.[52]
Lamotrigine
General aspects
Lamotrigine is an anticonvulsant sodium-channel blocker that can suppress the release
of glutamate and aspartate. It blocks T-type calcium channels and inhibits native
voltage-dependent calcium channels (types N/P/Q/R) and 5HT3 receptors. This may reduce glutamate release from the ventral striatal limbic projections.
Chronic treatment with lamotrigine suppresses cortical spreading depression (CSD),
in accordance with its selective action on the migraine aura. Its half-life is of
29 hours, it is completely and rapidly absorbed after oral administration, it has
absolute bioavailability of 98%, and its plasma Cmax ranges from 1.4 to 4.8 hours.[53]
Studies
Two double-blinded placebo-controlled studies[54]
[55] on lamotrigine for the prophylaxis of migraine with and without aura have failed
to prove its efficacy. However, in one of these studies,[55] lamotrigine proved to be effective in reducing the monthly frequency of migraine
(one of its secondary outcomes). In three studies (open model)[56]
[57]
[58] that tested the efficacy of lamotrigine among individuals with migraine with aura,
with doses reaching 100 mg/day, there was a positive prophylactic effect on the frequency
and duration of the auras. In one of these studies,[56] after halting lamotrigine, there was recurrence of the aura episodes. In another
study,[57] the episodes of migraine with aura practically disappeared after three months of
treatment, but there was no impact of the treatment on episodes of migraine without
aura.
In another prospective, controlled, open study, in individuals with migraine with
aura and with/without headache, lamotrigine at doses of up to 300 mg/day was effective
in reducing the frequency and duration of the auras. In a prospective and retrospective
study[59] among subjects with complicated auras, which could be very frequent, long-lasting,
affecting the brainstem aura, hemiplegic, aphasic or without headache, there was satisfactory
control of 64% of these auras.
There is also a description of two cases in which lamotrigine was effective in controlling
(persistent auras) with durations ranging from three months to three years.[60]
Levetiracetam
General aspects
Levetiracetam is a drug that acts on type-N calcium channels and in the allosteric
inhibition of GABA and glycine-dependent currents and of synchronized and excessive
interneuronal activity.[61] It binds little (10%) to proteins and less than 40% is metabolized by acetamides,
without participation of the cytochrome P450 system. Most levetiracetam is excreted
unchanged by the kidneys, so dose adjustment is required in cases of renal failure.[62]
[63]
Studies
Two randomized double-blinded studies,[64]
[65] one placebo-controlled and one controlled with placebo and topiramate for migraine
prophylaxis, were conducted. In the first study, levetiracetam was superior in reducing
the frequency, intensity, disability and consumption of analgesics. The second study,
which was designed not to evaluate efficacy but to assess other parameters (post hoc),
showed that in most individuals the frequency of migraine was reduced in relation
to the baseline time, while the opposite was seen in the placebo group.
Three open studies[66]
[67] tested the efficacy of levetiracetam in the prevention of migraine. One was performed
in individuals with migraine with and without aura,[66] another, among elderly migraineurs,[67] and the third, only in individuals with migraine with aura.[68] In the first two,[66]
[67] there were significant reductions in the frequency of episodes in relation to baseline
and in the intake of symptomatic drugs, while in the third[68] there were reductions in the frequency, intensity and duration of headache episodes
and better aura control.
Gabapentin/pregabalin
General aspects
The modulation of the release of neurotransmitters exerted by gabapentin and pregabalin
is related to binding to the calcium channel α2δ1 subunit in neuronal membranes. Neither
of these agents undergoes hepatic metabolism. They do not bind to plasma proteins
and are excreted unchanged by the kidneys. The half-life of both gabapentin and pregabalin
ranges from five to nine hours.
Studies
Two double-blinded, placebo-controlled studies[69]
[70] were conducted. In one,[69] gabapentin enacarbil did not outperform placebo. In the other,[70] with gabapentin, the authors found a reduction of 50% or more in the occurrence
of migraine for 4 weeks compared with placebo — 50% or less — about 50% (46 × 16).
These results were not maintained when analyzed using the “intention to treat” criterion,
that is, when the population who received at least one dose of the medication under
study (active or placebo) was analyzed, not just the individuals who concluded the
whole study. In a randomized, open class-III study[71] controlled with topiramate, the use of gabapentin and topiramate led to a significant
reduction in the frequency, duration and severity of the episodes, and in the intensity
of pain. Although topiramate was more effective than gabapentin in all outcomes, it
also presented lower tolerability.[71] In a randomized, open, class-IV, uncontrolled study,[72] the authors observed a reduction in the frequency and intensity of migraine episodes,
and in the duration of pain, and they suggested that gabapentin doses of 1,200 mg/day
were as effective as 2,000 mg/day.
A randomized, double-blinded class-II study[73] compared pregabalin with sodium valproate in the prevention of migraine, and revealed
that both were effective after the first month, and that they were comparable in the
third month of treatment, in relation to the baseline, in terms of reduction in the
average monthly frequency, intensity and duration of migraine episodes. Although this
study[73] was conducted with an adequate number of subjects, both drugs were used at low doses
(valproate: 400 mg/day; pregabalin: 100 mg/day). In an uncontrolled open study[74] with a target dose of pregabalin of 300 mg/day, the authors found a statistically
significant reduction in the frequency of migraine episodes from the first to the
third month of treatment compared with the baseline. The greatest reduction in the
frequency of migraine episodes was observed in patients whose dose was increased in
the first month of therapy.
Carbamazepine
General aspects
Carbamazepine is a modulator of sodium channels of neuronal membranes. Its bioavailability
is high, reaching 90%, and its metabolism is hepatic.[75]
Studies
Regarding migraine, there is a single crossover placebo-controlled clinical trial[76] which only reports on the individuals who completed the entire study, and does not
provide information about exclusions and their reasons. The authors[76] reported an improvement in 38 out of 45 (84.4%) patients in the carbamazepine arm
and only in 13 out of 48 (27.1%) in the placebo arm (p < 0.001). The duration of the treatment was of 12 weeks. Mulleners et al.[77] (2015) calculated the confidence interval of this study and found it to be very
low (11.77; 3.92 - 35.32), which makes it difficult to assume that these results can
be properly interpreted.
Oxcarbazepine
General aspects
Oxcarbazepine is structurally related to carbamazepine; thus, it modulates sodium
channels of neuronal membranes, but also modulates the release of glutamate.[78]
Studies
Regarding migraine, only one randomized, double-blinded clinical trial[79] has tested oxcarbazepine (n = 85) versus placebo. There was no statistically significant
advantage of oxcarbazepine over placebo, except for the secondary variable of improvement
in functional capacity.
Vigabatrin
General aspects
Vigabatrin exerts its GABA-ergic effect through selective and non-competitive inhibition
of GABA-transaminase.[80]
Studies
There is a single double-blinded crossover trial,[81] in which 23 migraineurs were evaluated. However, due to the possible beta-type bias,
the duration of the study, and the possibility of potentially limiting and irreversible
adverse events, such as GABAergic retinopathy, a consensus was reached, which states
that vigabatrin should not be used for the preventive treatment of migraine.[81]
Clonazepam
General aspects
Clonazepam belongs to the benzodiazepine group and increases the effect of the GABA
neurotransmitter on GABA-A receptors in a highly potent and prolonged manner, besides
having a serotoninergic agonist effect.[82]
Studies
A double-blinded, placebo-controlled study[83] with clonazepam at doses of 1 mg/day to 2 mg/day revealed that its use led to a
reduction in the number of headache days compared with placebo.[83] However, due to the risk of addiction,[84] this is not a drug recommended for the prophylactic treatment of migraine.
Zonisamide (ZNZ)
General aspects
Zonisamide is an antiepileptic drug that has weak carbonic anhydrase-inhibiting action
and blocks voltage-dependent sodium channels, thus modulating GABA-ergic and glutamatergic
neurotransmission. In addition, it reduces the activity of the low-voltage T-type
calcium channels (they are found in the trigeminal ganglion and caudal nucleus) and
they play a role in mediating the release of calcitonin gene-related peptide (CGRP).[85]
Studies
Two randomized double-blinded studies[86]
[87] that compared ZNZ and another prophylactic drug for EM prophylaxis were evaluated.
In one,[86] ZNZ was superior to topiramate in reducing the intensity of migraine attacks; in
the other,[87] ZNZ had an efficacy similar to that of valproate, differing from the latter only
in terms of adverse events.
Three other studies[88]
[89]
[90] reported that ZNZ was effective in reducing the intensity and frequency of attacks:
a prospective open study[88] on patients who responded to topiramate but discontinued it due to adverse events;
another[89] on patients with refractory migraine; and a retrospective study[90] on patients who did not respond to topiramate. The doses used in these studies ranged
from 100 mg to 400 mg per day.
Conclusion
Among anticonvulsants, the most studied are topiramate and valproate/divalproate.
These have unambiguous efficacy, are well documented, and have A-level recommendation.
For levetiracetam, and ZNZ, the level of recommendation is B. For gabapentin/pregabalin,
the recommendation is C. There is no evidence to support the routine prescription
of lamotrigine, carbamazepine, oxcarbazepine, vigabatrin and clonazepam. However,
lamotrigine shows efficacy in the prophylaxis for migraine aura. When prescribing
an anticonvulsant, close attention needs to be paid not only to its efficacy but also
to its sedative, psychotropic, and systemic effects, which often compromise its tolerability.
Tricyclic antidepressants (TADs)
General aspects
The mechanism of action common to tricyclic antidepressants (TADs) at the presynaptic
level is the blocking of monoamine reuptake, mainly norepinephrine (NA) and serotonin
(5-HT), and, to a lesser extent, dopamine (DA). Tertiary amines (amitriptyline and
clomipramine) preferentially inhibit the reuptake of 5-HT, while secondary amines
(nortriptyline) inhibit that of NA. There are no significant differences in the selectivity
of presynaptic reuptake blockade. Postsynaptic activity varies depending on the neurotransmitter
system involved, and it is usually responsible for the side effects of these drugs.
Tricyclic antidepressants block the muscarinic (cholinergic), type-1 histaminergic,
α2- and β-adrenergic, and several rarer dopaminergic receptors. These actions do not
necessarily correlate with the antidepressant effect, but they may correlate with
the side effects. Blockade of the 5-HT1 receptor contributes to the therapeutic effect of TADs.[91]
The degree of blockade of monoamine reuptake varies according to the specific TAD,
and amitriptyline is the most potent, with the most complex pharmacological profile.
Its main metabolite is nortriptyline, which has a more pronounced effect as a transporter
of NA.[92]
Amitriptyline
Studies
Amitriptyline was evaluated in a randomized, double-blinded, controlled study[93] among migraineurs, with 94 patients receiving amitriptyline, and 92, placebo, for
20 weeks. Among the subjects with EM, amitriptyline was significantly more effective
than placebo in decreasing the frequency of headaches in the eighth week, but not
in the following weeks due to the large placebo effect.[93] In a randomized, double-blinded, non-inferiority study[94] comparing topiramate and amitriptyline in 331 migraine patients, 172 received topiramate,
and 159, amitriptyline, for 26 weeks. The efficacy was similar between the two medications.[94] In another comparative, randomized, double blinded, placebo-controlled study[95] comparing amitriptyline and melatonin among 196 migraineurs for 12 weeks, both medications
were significantly more effective than placebo in terms of decreasing the number of
days with headache.[95]
Clomipramine
Studies
Two studies have been conducted with clomipramine: one comparing it with placebo,[96] and the other, with metoprolol.[29] In both, clomipramine was not significantly better than placebo.
Nortriptyline
Study
In a Brazilian study comparing preventive treatments for migraine with low doses of
nortriptyline (25 mg/day) and propranolol (40 mg/day), alone or in combination, nortriptyline
alone was not effective in reducing the number of days with headache.[97]
Conclusions
Among TADs, amitriptyline is the best studied medicine, with evidence of significant
improvement through reduction of migraine attacks, compared with placebo (Level A
recommendation). Clomipramine has not been shown to be significantly more effective
than placebo. Although no randomized, double-blinded, adequate studies have been conducted
on nortriptyline, this drug is recognized by the participants of this consensus as
equally effective as amitriptyline and with fewer side effects, such as drowsiness
and weight gain.
Calcitonin gene-related peptide (CGRP) or CGRP-receptor monoclonal antibodies
General aspects
Calcitonin gene-related peptide is a 37-amino acid neuropeptide that is produced primarily
in the cellular body of ventral and dorsal root neurons. Two isoforms of CGRP (α and
β) have been described; they differ in three amino acids in humans, have different
tissue distributions, and are potent vasodilators.[98]
The α-CGRP isoform is expressed in the peripheral nervous system predominantly in
nociceptive fibers A∂ and C, which have wide distribution throughout the body, including
extensive perivascular distribution. The β-CGRP isoform is the predominant form expressed
in the enteric nervous system and pituitary system. The distribution of CGRP and CGRP
receptors in the CNS is complex and still little understood.[98]
[99]
Calcitonin gene-related peptide is located in the trigeminal nerve terminations and
trigeminal ganglion. Outside of the BBB, release of CGRP in trigeminal nerve terminations
results in vasodilation, inflammation, and (questionable) degranulation of dural mast
cells.[98]
With the development of monoclonal antibodies (MAbs), new methods of targeting CGRP
have emerged. With the target specificity inherent to MAbs, as well as typically prolonged
pharmacokinetic half-lives and the reduced potential for liver toxicity, CGRP-specific
MAbs are an excellent drugs for the migraine prevention.[99]
Currently, four MAbs (eptinezumab, erenumab, fremanezumab and galcanezumab) are indicated
in the treatments of EM. Erenumab specifically blocks the CGRP receptor, while the
others bind to the CGRP[100] molecule.
Erenumab
Studies
Two phase-3, controlled, randomized, multicenter clinical trials[101]
[102] were analyzed. In the first, the Study to Evaluate the Efficacy and Safety of Erenumab
(AMG 334) in Migraine Prevention (STRIVE),[101] 3 arms were compared: the erenumab 70 mg group, the erenumab 140 mg group, and the
placebo group, who were followed for 24 weeks. The erenumab groups showed a statistically
significant decrease in the number of migraine days in relation to the baseline frequency
(primary outcome), a decrease in the number of migraine days of more than 50% from
the third to the sixth months in relation to the baseline frequency, decreased use
of migraine-specific medication, and decreased impact of headache (secondary outcomes)
compared with the placebo group. There was no significant difference between those
who used 70 mg or 140 mg of erenumab.[101]
The second one, called Study to Evaluate the Efficacy and Safety of Erenumab (AMG
334) Compared to Placebo in Migraine Prevention (ARISE),[102] compared 2 groups: patients who received erenumab 70 mg and those who received placebo,
who were followed for 12 weeks. The erenumab group showed a statistically significant
decrease in the number of migraine days in relation to the baseline frequency (primary
outcome), a decrease in the number of migraine days greater than 50% in relation to
the baseline frequency, and decreased use of migraine-specific medication (secondary
outcomes) compared with the placebo group.[102]
Galcanezumab
Studies
Two randomized, controlled, multicenter, phase-3 clinical trials[103]
[104] on EM compared galcanezumab art doses of 240 mg in the first month, followed by
120 mg/month in the following months, galcanezumab at a dose of 240 mg/month, and
placebo. The patients were followed for six months. The results of the galcanezumab
groups were better than those of the placebo group, with statistical significance
in relation to the primary outcome [decrease in the Monthly frequency of headache
days (migraine characteristics in relation to the baseline frequency)] and secondary
outcomes: decrease greater than 50%, greater than 75%, and 100% in the number of headache
days, quality of life scales, and headache impact respectively. There was no difference
between the results of the two galcanezumab groups (120 or 240 mg). There was no difference
between the results of the two galcanezumab groups.[103]
[105]
Fremanezumab
Studies
Fremanezumab has been studied with regard to prevention of EM in 2 phase-3 clinical
studies.[105]
[106]
A monthly dose regimen of 225 mg or a higher single dose of 665 mg was compared with
placebo among 875 patients with a mean age of 41.8 years.[105] The number of migraine days during the 12-week period after the first dose was lower
in the study groups than in the placebo group. The average number of migraine days
per month decreased: from 8.9 days to 4.9 days in the monthly fremanezumab dosage
group; from 9.2 days to 5.3 days in the highest single-dose fremanezumab group; and
from 9.1 days to 6.5 days in the placebo group. This resulted in a difference between
the monthly and placebo dosages of -1.5 days, and between the highest single dose
and placebo of -1.3 days (p < 0.001).[105]
In the second study,[106] migraine patients who had previously had negative experiences with two to four classes
of preventive medications were assessed. Using the methodology to divide the groups,
329 patients with EM were included and the results were also positive, with a significant
difference between the fremanezumab groups and the placebo group.[106]
Eptinezumab
Studies
Eptinezumab differs from other MAbs in that it is administered intravenously rather
than subcutaneously. Two studies have been conducted in relation to EM. A phase-2
study[107] was carried out with administration of 1,000 mg of intravenous eptinezumab (81 patients),
compared with placebo (82 patients), and it showed that this drug present a good degree
of safety and tolerability and was superior to placebo with regard to improving the
number of migraine days per month.
The other study[108] evaluated 888 patients with EM who were randomized into 4 groups: eptinezumab 30 mg,
100 mg, or 300 mg, and placebo, with up to 4 intravenous infusions every 12 weeks.
Doses of 100 mg and 300 mg significantly reduced the number of migraine days per month,
with similar tolerability in comparison with the placebo group.[108] In a subsequent analysis,[109] the authors observed that the treatment was effective on the first day after the
initial dose.
