Keywords:
Antibodies, Monoclonal - Costs and Cost Analysis - Efficacy - Health Services Needs
and Demand - Migraine Disorders - Headache - Pharmaceutical Preparations - Prescriptions
- Safety - Surveillance - Therapeutics
Palavras-chave:
Anticorpos Monoclonais - Custos e Análise de Custo - Eficácia - Cefaleia - Necessidades
e Demandas de Serviços de Saúde - Transtornos de Enxaqueca - Preparações Farmacêuticas
- Prescrições - Segurança - Vigilância - Terapêutica
INTRODUCTION
Migraine is a common neurologic disorder and the second cause of disability worldwide,
leading to more disability than all other neurologic diseases[1]. The prevalence of migraine is roughly 12% (18% in women and 6% in men) and approximately
2.5% of people with episodic migraine progress to chronic migraine, whose prevalence
is estimated at 1-2% of the general population[2]. Migraine ranked second in prevalence among non-communicable diseases, and as the
highest cause of disability among adults in Brazil[3], where care is provided by either public or private health sectors. The public health
sector is very under-resourced, leading to misdiagnosis and, consequently, to inappropriate
treatment[4], which should be improved by headache public policies.
ARE THERE UNFORESEEN PROBLEMS IN MIGRAINE PREVENTIVE TREATMENT?
ARE THERE UNFORESEEN PROBLEMS IN MIGRAINE PREVENTIVE TREATMENT?
Migraine manifests as a continuum, from episodic to chronic migraine[5]. Some modifiable risk factors such as frequency of attacks, obesity, medication
overuse, stressful life events, caffeine overuse and snoring, as well non-modifiable
risk factors such as age, gender, and socioeconomic status, are related to worsening
of migraine over time[6]. Therefore, migraine cannot be considered strictly as a monomorphic disease, but
as a spectrum of clinical manifestations influenced by genetic factors and lifestyle.
Because comorbid medical and psychological illnesses are prevalent in patients who
have migraine, comorbidities must be considered when choosing preventive drugs, particularly
in chronic migraine[7],[8]. However, until around 2015, there were unforeseen problems as to preventive treatment
of migraine with oral drugs, mainly due to lack of tolerance of side-effects and lack
of efficacy, leading to high discontinuation rates[9]. On the other hand, anti-CGRP monoclonal antibodies (mAbs) have shown better tolerance
profiles, based on the low dropout rates due to adverse events in clinical trials,
when compared to previous preventive medications. Furthermore, central nervous system
specific adverse events have not been described with mAbs to date, contrasting with
oral treatments[10]. In view of this new form of therapy, one question arises: “Can CGRP monoclonal
antibodies be first line therapy in migraine prophylaxis?”. Some caveats to this will
be explored below.
FIRST LINE THERAPY REFERRING TO MIGRAINE AND CURRENT TREATMENTS
FIRST LINE THERAPY REFERRING TO MIGRAINE AND CURRENT TREATMENTS
“First line therapy” is a current definition of the best treatment for a given disease
and clearly implies better outcomes and lower adverse event rates when compared to
other available treatments[11]. The term is most used in particular medical specialties (e.g., oncology), which
adopt standardized protocol treatments derived from evidence-based medicine. In fact,
alongside clinical examination, imaging, laboratory and other biological markers there
is a growing importance in medical decision-making[12]. Bearing this in mind, could it be applied to migraine? So far, after ruling out
secondary headaches, migraine diagnosis is fully dependent on medical skills and to
date there are no biological markers to ensure “the best” treatment option on an individual
basis[13]. Thus, for instance, mAbs can be the best option for a patient with a high adverse
events profile, whereas topiramate or propranolol, for example, could be useful for
patients who have not experienced side-effects and who possibly would not complain
of them during treatment. These patients could also benefit from treatment of other
medical conditions, such as systemic arterial hypertension, essential tremor, depression,
epilepsy, etc., which are not considered with mAbs[14]. In summary, oral drugs are helpful in treating migraine and its comorbidities,
while mAbs are targeted only at migraine treatment (despite subgroup analysis with
comorbid depression having responded to the blockade of CGRP pathway)[15].
CURRENT TREATMENTS AND MABS EFFICACY
CURRENT TREATMENTS AND MABS EFFICACY
Regarding efficacy, mAbs don’t seem to perform much better than the current prophylactic
oral drugs (at most, slightly better) in reduction of monthly migraine days compared
to placebo. [Table 1] shows this finding with mAbs, Level of evidence “A” oral preventive drugs and onabotulintoxin
A[16]-[18].
Table 1
Change in monthly migraine days.
|
Treatment
|
Mean difference (95% CI)
|
|
Eptinezumab vs. Placebo
|
-1.43 [-2.59, -0,36]
|
|
Erenumab vs. Placebo
|
-1.61 [-2.40, -0.84]
|
|
Fremanezumab vs. Placebo
|
-2.19 [-3.15, -1.25]
|
|
Galcanezumab vs. Placebo
|
-2.10 [-2.76, -1.45]
|
|
Topiramate vs. Placebo
|
-1.40 [-2.20, -0.50]
|
|
Divalproex sodium vs. Placebo
|
-1.50 [-2.20, -0.76]
|
|
Propranolol vs. Placebo
|
-1.00 [-2.10, -0.39]
|
|
Metoprolol vs. Placebo
|
-0.94 [-1.40, -0.46]
|
|
Onabotulintoxin A vs. Placebo*
|
-2.00 [-2.67, -1.27]
|
*Only chronic migraine; Crl: credible interval.
LONG-TERM SAFETY
Long-term safety is also relevant when selecting some first line therapy. One of the
greatest advantages of mAbs is the low adverse effect rates, (most of them of mild
intensity), leading to better adherence to treatment[19]. Nevertheless, monoclonal antibodies against CGRP pathway have been prescribed recently,
which raises some concern about their safety in the long term. Conversely, oral treatments
have been prescribed for decades and all their pros and cons are well known at this
point. In fact, they have withstood the test of time, despite some of them having
been discontinued by virtue, mainly, of lack of tolerance of side-effects (e.g.: pizotifen
and metisergide)[20]. Experience with earlier treatments causes confidence as to short and long-term
side effects, something not yet proven with mAbs.
CGRP IS INVOLVED IN OTHER SYSTEMS
CGRP IS INVOLVED IN OTHER SYSTEMS
The function of CGRP in both peripheral and enteric nervous systems is well established
- it is involved not only in migraine, but also other physiological processes and
in homeostatic responses during pathophysiological conditions. CGRP is present in
nerve fibers that innervate blood vessels and the heart, acts in the regulation of
blood pressure and may have a role in maintenance of cardiovascular homeostasis during
ischemic events and tissue remodeling in pulmonary hypertension. CGRP is also involved
in inflammatory processes and facilitation of wound healing. In addition, it is found
in the anterior pituitary, possibly influencing the regulation of hypothalamus-pituitary
tract functions. To date, there are no reports on safety issues related to these functions,
and only observation of side effects will confirm whether or not CGRP blockade causes
susceptibility to severe side-effects, at least to specific subpopulations[21].
CONCERNS WITH WOMEN IN CHILDBEARING AGE
CONCERNS WITH WOMEN IN CHILDBEARING AGE
Migraine mostly affects women during their fertile years. There are no controlled
studies of mAbs involving pregnant or lactating women. A limited number of safety
reports have indicated no specific maternal toxicities, major birth defects or increased
reporting of spontaneous abortions when mAbs is administered during pregnancy, exposure
shortly prior to pregnancy or breast-feeding[22]. CGRP may play a role in regulating uteroplacental blood flow and myometrial and
uterine relaxation, as well blood pressure control, raising the suspicion that its
blockade could cause gestational hypertension, preeclampsia or eclampsia[23]. Therefore, a woman of childbearing age should be advised as to the lack of safety
data of mAbs during pregnancy and lactation and, if she is currently on mAb and wishes
to get pregnant, be told that she should withdraw the treatment and wait a few months,
when one may assume that mAb has been entirely cleared.
MIGRAINE TREATMENT GUIDELINES
MIGRAINE TREATMENT GUIDELINES
Finally, recent guidelines retain the recommendation for starting the preventive treatment
of migraine with oral drugs. The American Headache Society Consensus Statement criteria
for initiating mAbs are[24]:
-
Prescribed by a licensed clinician;
-
Patient is at least 18 years of age;
-
Diagnosis of ICHD-3 migraine with or without aura (4-7 monthly migraine days) or
-
Diagnosis of ICHD-3 migraine with or without aura (8-14 monthly migraine days) or
-
Diagnosis of ICHD-3 chronic migraine (≥15 monthly headache days, at least 8 days with
migraine features).
And inability to tolerate (due to side effects) or inadequate response to an 8-week
trial of two or more of the following:
-
Topiramate
-
Divalproex sodium/valproate sodium
-
Beta-blocker: metoprolol, propranolol, timolol, atenolol, nadolol
-
Tricyclic antidepressant: amitriptyline, nortriptyline
-
Serotonin-norepinephrine reuptake inhibitor: venlafaxine, duloxetine
-
Other Level A or B treatments (established efficacy or probably effective) according
to AAN scheme for classification of evidence.
Inability to tolerate or inadequate response to a minimum of two quarterly injections
(6 months) of onabotulinumtoxinA (only for chronic migraine).
The recommendations of the European Headache Federation published in 2019 about the
use of mAbs in subjects with migraine are[25]:
In patients with episodic or chronic migraine who have failed at least two of the
available medical treatments or who cannot use other preventive treatments because
of comorbidities, side effects or poor compliance, we suggest the use of erenumab,
fremanezumab, or galcanezumab.
The Consensus of the Brazilian Headache Society on the treatment of chronic migraine
has not incorporated guidelines on CGRP mAbs, because they were not yet available
in Brazil in 2019[26].
Costs of CGRP mAbs are not entirely known but, presumably, these are higher than oral
treatments that are available. Further studies could provide information about the
economic impact of mAbs, taking into account direct and indirect costs related to
migraine[25].
In conclusion, undoubtedly CGRP monoclonal antibodies are a breakthrough in migraine
preventive treatment; their specific mode of action, rapid response and safety profile
to date show they are innovative and could soon be the first line therapy for episodic
and chronic headache. Nevertheless, the concept of “first line treatment” is not suitable
for migraine, since doctors should practice clinical examination skills to make a
proper diagnosis and “a tailor-made” treatment, taking into account age, comorbidities,
pregnancy risk, previous treatments, etc. Medical and psychiatric comorbid conditions
are addressed by current oral preventive drugs, but not by mAbs.
As with all new therapies, mAbs have not been subject to the test of time regarding
long-term side effects. Subpopulations could still be at risk while pregnant or breast-feeding
women, alcohol or drug abusers, people with cardio and cerebrovascular diseases as
well as severe mental disorders are the most relevant of these[25]. Finally, pharmacoeconomic factors play a decisive role in governmental decisions;
costs of mAbs are still a barrier to using them as first choice therapy for migraine
prophylaxis. Both the fact that they are new and costs are the reason why guidelines
only recommend the prescription of mAbs after failure of at least two oral drugs[10].
