Keywords Epilepsy - Therapeutics - Anticonvulsants
Palavras-chave Epilepsia - Terapêutica - Anticonvulsivantes
INTRODUCTION
The comprehensive treatment of people with epilepsy (PWE) should strive to offer a
life free from the constraints associated with epilepsy. As recently mentioned by
the World Health Organization (WHO) in establishing the Intersectoral Global Plan
on Epilepsy and other neurological diseases (IGAP), managing seizures is just one
aspect of treating this long-term illness. One of the strategic objectives of this
global plan is to ensure that individuals have access to appropriate anti-seizure
medications (ASM) based on their specific requirements (such as children, adolescents,
and women of childbearing age). Unfortunately, PWE living in low- and middle-income
countries face greater concerns due to difficult access to services for epilepsy and
anti-seizure medications (ASM). These factors, combined with misconceptions, stigma,
and lack of knowledge, result in treatment gaps and a disproportionate burden for
patients, families, and society. Part of the treatment gap results from a lack of
information and misconceptions related to ASMs.
The development of new antiseizure medications (ASMs) in the last thirty years created
new possibilities in treating epilepsy, considering the different profiles of pharmacodynamics
and pharmacokinetics. While only some of the newer ASMs have been approved in Brazil,
they are not being utilized to their full potential. Different studies have broadly
discussed the positive impact of these new ASMs, resulting in significant changes
in treatment rationale and clinical practice worldwide. Most benefits are associated
with improved quality of life, less drug interaction, reduced impact on cognition
(and comorbidities), and fewer adverse effects.[1 ]
[2 ]
[3 ]
[4 ]
[5 ]
[6 ]
[7 ]
[8 ]
Unfortunately, little discussion has been raised in Brazil about the worldwide changes
in ASM usage. Expanding the knowledge about the new ASMs from a practical point of
view may help physicians change their old perspectives to offer newer ASM alternatives
for PWE. [Table 1 ] shows the older and newer ASMs considered in this discussion.
Table 1
Older and new antiseizure medications
Older
Newer
Phenobarbital
Phenytoin
Primidone
Carbamazepine
Valproate
Oxcarbazepine
Lamotrigine
Topiramate
Gabapentin and Pregabalin
Vigabatrin
Levetiracetam
Lacosamide
Perampanel
Cannabidiol
Note: *Although cannabidiol is not a new medication, its use for some epilepsy syndromes
(i.e., Lennox-Gastaut and Dravet Syndrome) has been established more recently.
PHARMACOLOGICAL ASPECTS
Are the new ASMs better than the older ones?
How can we compare the ASMs? One specific ASM can be considered superior due to a
combination of different aspects, including higher efficacy, tolerability, safety,
and retention rates. As efficacy is the main result in clinical trials, it should
be the focus to start the evaluation of a specific ASM.
Previous studies comparing newer with older ASMs showed no differences in terms of
efficacy.[5 ]
[9 ] Despite the development of new ASMs and different mechanisms of action ([Figure 1 ]), seizure control is similar to the older ASMs.[7 ]
[10 ] There are few studies evaluating the head-to-head efficacy of ASMs. Recent evidence
comes from the SANAD (Standard and New Antiepileptic Drugs) studies conducted in the
United Kingdom for focal and generalized epilepsies. Data from these studies are presented
in [Figure 2 ]. There is no evidence of improved efficacy of the newer ASMs for focal epilepsy.[11 ]
[12 ]
[13 ]
Figure 1 Mechanisms of action of antiseizure medications available in Brazil (Adapted from[48 ]
[49 ]
[50 ]).
Note: *Lamotrigine, Topiramate and Oxcarbazepine did not differ from Carbamazepine,
while *Gabapentin was less effective than carbamazepine for focal epilepsies. ** Lamotrigine
was less effective than valproate for generalized epilepsies, while there was no significant
difference between valproate and topiramate. Adapted from.[15 ]
[16 ]
Figure 2 Comparison of efficacy of antiseizure medications for focal (the newer ASMs were
compared to carbamazepine) and generalized epilepsy (the newer ASMs were compared
to valproate).
In terms of efficacy, it is essential to consider seizure type. It has been recognized
that some ASMs are not appropriate for generalized seizures. The most striking example
is juvenile myoclonic epilepsy (JME), as myoclonic and absence seizures may worsen
with carbamazepine, oxcarbazepine, and phenytoin. Valproate has proven to be the best
choice for generalized epilepsies, surpassing lamotrigine, levetiracetam, and topiramate.[13 ] However, extreme caution is necessary when treating women of childbearing age due
to increased risks of teratogenesis associated with valproate.[14 ]
So, what are the advantages of the new ASM?
One of the main advantages of newer ASMs is their improved tolerability and safety
profiles. While the older ASMs (such as phenobarbital, phenytoin, and carbamazepine)
are associated with a significant risk of long-term clinical side effects, the newer
ASMs are generally better tolerated and have fewer interactions with other drugs.
This improved profile can be particularly beneficial for patients with comorbidities
or those requiring polytherapy.[15 ]
[16 ]
Enzyme induction effects
Studies suggest that enzyme induction should be a concern in epilepsy treatment.[17 ] Older ASMs are more frequently associated with the enzyme induction phenomenon (usually
linked to the cytochrome P450 enzyme induction) than the newer ones ([Figure 3A ]). Enzyme induction is an essential factor to be considered in ASM selection for
PWE due to the problems associated with drug interaction and metabolic effects.[8 ]
[12 ]
[13 ]
Figure 3 Relationship between antiseizure medications and Enzyme induction (A ) (Adapted from[24 ]
[51 ]). (B ) Negative effects of enzyme induction due to drug interactions and metabolic effects
(Adapted from[8 ]
[18 ]
[24 ]
[35 ]
[36 ]).
Enzyme induction is associated with increased cholesterol levels and decreased effects
of statins and other cardiovascular medications. These changes, added to factors such
as reduced physical activity and other unhealthy lifestyle habits, may increase the
cardiovascular risk of PWE.[18 ]
[19 ]
[20 ] One recent study showed a 21% increase in risk for individuals who used enzyme inducers
ASMs after ten years of exposure.[21 ] Problems related to enzyme induction are not limited to cardiovascular effects.
There is a reduction of vitamin D and bone mass density, which results in the early
occurrence of osteopenia and osteoporosis and an increased risk of fractures. Besides,
the enzyme inducers may decrease the sex hormones, which negatively impact the bone
mass and cause sexual dysfunction.[22 ] Another investigation demonstrated normalization of the levels of testosterone,
progesterone, cholesterol, and low-density lipoprotein after switching from carbamazepine
to lacosamide as adjunctive therapy to levetiracetam (based on a cross titration over
four weeks, followed by an 8-week maintenance period).[23 ]
There is also a reduction in the effect of other medications, including anticoagulants,
chemotherapy, immunosuppressors, anti-infective agents (including HIV treatment),
and contraceptives. Reduced levels of various medications can cause serious issues,
ranging from undesired pregnancies to ineffective chemotherapy and the progression
of cancer. [Figure 3B ] shows some of these negative aspects of the enzyme-inducing ASMs.[4 ]
[24 ]
[25 ]
Teratogenesis
Another major issue with the ASMs is related to the treatment of women of reproductive
age. Some ASMs should be avoided due to the increased risks of teratogenicity, cognitive
impairment, learning deficits, increased risk of autism spectrum disorder, and attention
deficit hyperactivity disorder in children exposed to some ASM intrauterus.[26 ]
[27 ]
Some newer agents, particularly levetiracetam and lamotrigine, are considered safe
for women of childbearing age. Some older ASMs, such as oxcarbazepine and carbamazepine,
also showed reassuring safety data.[27 ] Conversely, valproate, and topiramate have been repeatedly associated with an increased
risk of teratogenicity, followed by phenobarbital and phenytoin. Unfortunately, there
is insufficient data related to teratogenicity for many of the newer ASMs, including
lacosamide, perampanel, clobazam, and cannabidiol ([Figure 4 ]).[26 ]
[27 ]
Figure 4 Illustration of the teratogenic risk profile of antiseizure medications (Adapted
from[26 ]
[27 ]).
Tolerability
Although the efficacy of new and old ASMs are similar when the medication is adequate
for the seizure type, the tolerability may vary according to individual characteristics
and comorbidities. Personal lifestyle and comorbidities need to be accounted for when
choosing an ASM. For example, levetiracetam should be avoided for individuals with
a history of anxiety, depression, and other psychiatric disorders; likewise, valproate
should be avoided for patients with obesity. On the contrary, some individuals may
benefit from topiramate's effect for weight loss (as long as they do not present glaucoma
or nephrolithiasis). Some ASMs present a neutral profile regarding the impact on cognition
(such as levetiracetam and lamotrigine), while others may cause significant cognitive
dysfunction (phenobarbital and topiramate). Some of these potential effects of ASMs
are presented in [Table 2 ].
Table 2
Characteristics of Potential adverse effects and comorbidities associated with ASMs
(Adapted).[1 ]
[2 ]
[6 ]
[28 ]
[44 ]
[45 ]
[46 ]
[47 ]
Abbreviations: PB, phenobarbital; PHT, phenytoin, TPM, topiramate; BZD, benzodiazepines,
such as clobazam, clonazepam; LTG, lamotrigine; LEV, levetiracetam; LCM, lacosamide;
CBZ, carbamazepine; OXC, oxcarbazepine; PER, perampanel; GBP, gabapentin; PGB, pregabalin.
As illustrated in [Table 2 ], there is no ideal ASM (i.e., without the potential to cause adverse effects). Although
there are various profiles of mechanisms of action ([Figure 1 ]) and side effects, in general, there are no major differences in tolerability among
the new ASM.[28 ] Out of the newer ASMs, topiramate and oxcarbazepine have the highest likelihood
of causing intolerable side effects, which result in the earlier discontinuation of
these medications.[28 ]
PRESCRIPTION PATTERNS AND CHALLENGES
PRESCRIPTION PATTERNS AND CHALLENGES
What is happening in Brazil?
Unfortunately, the ASḾs approval in Brazil usually happens several years after the
initial consent in the USA (FDA) and Europe (EMA) ([Figure 5 ]). One striking example is Levetiracetam, whose approval was delayed 19 years, preventing
several patients from benefiting from this ASM. While both the US and Europe already
have access to other newer ASMs, we remained mainly restricted to relatively older
drugs in Brazil. These delays have hindered access to newer ASMs for decades, leading
to less desirable prescription patterns with the frequent use of enzyme-inducing ASMs.[29 ] As physicians tend to use medications they are more acquainted with, faster approval
is desirable to generate an earlier comprehension of the characteristics of the newer
drugs and, consequently, faster construction of more appropriate protocols. All these
difficulties impair an adequate treatment for PWE.
Figure 5 The chronological evolution of ASMs approval by the Food and Drug Administration
(FDA) (red squares) and the Brazilian Health Regulatory Agency (ANVISA, blue dots)
in the last 30 years. Only two ASMs (oxcarbazepine and vigabatrin) were approved by
ANVISA before the FDA in this period.[52 ]
[53 ]
Although many of the new-generation ASMs are currently available in Brazil (i.e.,
lamotrigine, levetiracetam, lacosamide, perampanel, pregabalin, gabapentin, vigabatrin,
oxcarbazepine, topiramate, rufinamide, and cannabidiol), most are not distributed
by the Brazilian unified health system (Sistema Único de Saúde [SUS]). The SUS provides
(free of charge to the population) the first-generation ASMs clonazepam, valproate,
as well as the enzyme-inducer ASMs [EI-ASMs] phenobarbital, phenytoin, and carbamazepine
at the primary care health units. In addition, some of the newer ASMs (lamotrigine,
levetiracetam, topiramate, vigabatrin, and gabapentin), and clobazam may also be obtained
through SUS; however, requiring much paperwork and bureaucracy from physicians and
associates, with several barriers for patients and caregivers to reach the specialized
pharmacy dispensaries.
PWE often face challenges in obtaining the correct prescription (along with the necessary
paperwork) and accessing specialized dispensaries. Additionally, they frequently experience
frustration due to the inadequate availability of proper anti-seizure medication at
these specialized centers.[30 ] Adding to the challenges of accessing newer ASMs, there are only a limited number
of specialized epilepsy centers in the country, mostly in large cities. PWE from smaller
towns are seldom prescribed and face several obstacles in obtaining newer medications.
What is happening in the world?
Different studies have demonstrated a clear trend toward using newer ASMs in many
countries in the last years, as illustrated in [Figure 6 ]. Some countries have reduced the use of carbamazepine and phenytoin in favor of
increasing levetiracetam and lamotrigine.[31 ] These changes have been driven mainly by better safety and tolerability profiles,
with less enzyme induction activity.
Figure 6 Changes in prescribing patterns over time for antiseizure medications in different
countries followed by the time period evaluated: United Kingdom (UK: 2003-2016), Japan
(2015-2018), China (2013-2018), United States (US: 2012-2019) and Germany (2008-2020).
(Figure adapted from[31 ]
[54 ]
[55 ]
[56 ]
[57 ]
[58 ]:).
Interestingly, using changes of ASM prescription practices in the UK as an example
did not lead to an increase in cost. The median standardized monthly direct health
care cost was £229 for the EI-ASMs and £188 for the non-EI-ASM cohorts. The median
cost was higher for the EI-ASMs cohort in every year of follow-up, and the median
time to treatment failure was also shorter in the EI-ASM cohort (468 vs. 1194 days).
Based on their findings, the authors suggested that changing treatment practices could
potentially improve patient outcomes and reduce overall costs.[32 ] This is likely because there are more complications associated with the use of outdated
drugs, requiring more frequent laboratory tests, as well as the need for vitamin and
hormonal supplementation. Additionally, there is a requirement for increased dosages
of concomitant medications, as their serum levels are reduced by EI-ASM.
Another study from Germany also showed a decrease in the prices of new ASMs, while
the overall expenses remained stable, despite an increase in the prescription of newer
and non-enzyme-inducing medications for PWE.[33 ]
Should Brazil start changing its prescription pattern?
Choosing an ASM for a PWE is the next step after a proper diagnosis. This choice is
crucial because the chances of being seizure-free after the failure of the first two
ASM regimens is only around 10%.[34 ]
Most people who started on treatment will continue to use ASMs for many years, eventually,
for the rest of their lives. Therefore, a personalized choice requires balancing efficacy,
long-term effects, tolerability, and safety. These ideas align with the objective
of offering an integral treatment for PWE: controlling seizures and avoiding adverse
effects and long-term problems.
Considering all the available evidence, we believe there is a need for a change in
the prescription pattern in Brazil. While the delay in approving the newer ASMs has
hindered and postponed these changes for decades in Brazil (with the extreme example
of levetiracetam, which could have benefited many patients with focal and generalized
epilepsies), the current presence of newer ASMs in the Brazilian market has been insufficient
to motivate neurologists and non-neurologists to change their pattern of prescriptions.
Several factors may contribute to the persistent trend of prescribing outdated ASMs,
particularly the enzyme inducers. Examples of such ASMs include the 58-year-old carbamazepine,
the 85-year-old phenytoin, and the 111-year-old phenobarbital. Firstly, many physicians
are familiar with and accustomed to these ancient drugs. Secondly, these medications
are relatively inexpensive and more easily accessible at primary care facilities.
There are other reasons why physicians may be hesitant to modify their prescriptions.
These include misconceptions and a lack of understanding regarding the advantages
of newer ASMs. Additionally, obtaining the newer ASMs can be quite challenging due
to excessive paperwork and limited dispensary centers, as discussed below.
Moreover, the newer ASMs often come with higher price tags and may not be covered
by the public healthcare system.
ACCESS TO ASMs IN BRAZILIAN PUBLIC HEALTH SYSTEM: PAPERWORK, BUREAUCRACY, AND LACK
OF AVAILABILITY
ACCESS TO ASMs IN BRAZILIAN PUBLIC HEALTH SYSTEM: PAPERWORK, BUREAUCRACY, AND LACK
OF AVAILABILITY
The vast majority of PWE in Brazil depend upon ASMs provided by the public system,
and the oldest medications are usually the only ones available. Not only that, but
the law dictates that the cheapest formulation should be purchased and distributed
by the public system, regardless of the “quality” of the product. It is important
to acknowledge that seizure control may be lost when generic and other brand formulations
are provided by the public health system and there is a need to review the process
and ensure that bioequivalence and other pharmaceutical aspects of the medications
purchased by the government reach the desired standard.
Therefore, in many instances, the main problem is not that neurologists ignore the
advantages of newer ASMs, but rather that they have no choice other than to prescribe
the old drugs. The Clinical Protocol and Therapeutic Guidelines for Epilepsy (PCDT
– Protocolo Clínico e Diretrizes Terapêuticas para Epilepsia) implemented by the Brazilian
government has many issues. The old drugs are considered first-line medications, and
the newer ones are available only for switch after failure.
Many factors need immediate attention. First, from a medical standpoint, it is necessary
to provide nationwide ongoing education to spread scientific knowledge and motivate
both young and experienced doctors to tailor their prescriptions based on individual
patient characteristics and requirements. Secondly, there is an urgent need to streamline
administrative processes and facilitate access to the latest ASMs within the public
healthcare system. There is a need to diminish the paperwork needed to provide newer
medications for PWE. There is no point in requiring new forms when patients have been
obtaining ASMs month after month. The diagnosis is clear and requires continuous treatment
for seizure control. The bureaucracy is a step with no obvious reason that just limits
access for PWE.
Newer ASMs should be available as first-line therapy in the public health system for
the reasons discussed previously. Furthermore, under current rules, the use of two
new ASMs as polytherapy is not permitted. There is no scientific basis for this, and
it ends up being another barrier to better treatments for PWE in the Brazilian public
system.
The current system is not user-friendly for PWE, especially considering that some
may have cognitive impairments, memory issues, and other additional medical conditions,
while many are unemployed, unable to drive, and face difficulties with public transportation.
Unfortunately, the centers are not evenly distributed throughout the country, and
ASMs are often unavailable.
There is a lack of continuous availability of ASMs in the public health dispensary,
and the official bureaucracy installed by the health system are reasons that contribute
to the non-prescription of these new-generation ASMs. Therefore, our medical societies
must educate and pressure government authorities on this topic, with the support of
society, especially PWE, families, and patient associations.
We hope this short review raises the attention to the importance of different aspects
related to the care of PWE. Among the different problems PWE encounter, some can be
avoided with an appropriate choice of ASM and better access to treatments.
PRACTICAL RECOMMENDATIONS FOR CHOOSING ASMs
PRACTICAL RECOMMENDATIONS FOR CHOOSING ASMs
In a country as big as this, there are areas where numerous patients face difficulty
in receiving proper medical care and struggle due to a lack of diagnosis. On the other
hand, there are other regions where individuals with accurately diagnosed epilepsies
could have access to newer ASMs, but most physicians choose to stick with outdated
prescription practices. Here, we provide a few suggestions for physicians who are
not specialists but are responsible for treating patients with epilepsy in an outpatient
setting:
Personalize the ASM selection based on epilepsy type, age, gender, drug interaction,
side effects, and comorbidities profile; rationale: the most suitable medication should
be selected for each patient, as some patients may experience greater benefits or
harm based on clinical profile. For instance, patients with arrhythmia may experience
harm from sodium channel blockers. Those with psychiatric symptoms may deteriorate
if given levetiracetam ([Table 1 ]), and carbamazepine and phenytoin may increase seizure frequency in patients with
primary generalized epilepsies such as JME.[12 ]
[13 ] Therefore, levetiracetam for PWE with arrhythmia, lamotrigine for PWE with epilepsy
and psychiatric issues and valproate for men with JME would be better choices.
Prefer non-EI-ASM for newly-diagnosed patients. Rationale: as previously described,
non-EI-ASMs are related to better adherence, tolerability, and quality of life and
fewer long-term side effects and drug interactions ([Figure 3 ]).[8 ]
[18 ]
[24 ]
[35 ]
[36 ]
After choosing an appropriate ASM according to the seizure type, consider exploring
it to the maximum tolerable doses instead of using many ASMs in low doses. Avoid the
association of multiple ASMs. Rarely use three ASMs, almost never four, and never
more than that; rationale: monotherapy is commonly a better choice as it reduces drug
interactions and side effects and maximizes adherence.[37 ]
[38 ]
In PWE and comorbidities, consider choosing a unique ASM for treating epilepsy and
the comorbidities (e.g., lamotrigine or valproate to treat psychiatric symptoms);
rationale: as in item 3, the fewer medications, the better.
Be aware of common potential drug interactions, especially for EI-ASM (phenytoin,
carbamazepine, phenobarbital, topiramate, oxcarbazepine, and primidone) and inhibitors
(valproate and cannabidiol); rationale: pharmacodynamic and pharmacokinetic drug interactions
can potentially cause loss of efficacy and intoxication (both for ASM-ASM and ASM-other
drugs interactions – as contraceptives, anticoagulants, and others) ([Figure 3 ]).[8 ]
[18 ]
[35 ]
[36 ]
Avoid valproate, topiramate, phenobarbital, and phenytoin for women of childbearing
age; rationale: they are highly teratogenic and should not be prescribed for childbearing-age
women ([Figure 4 ]).[26 ]
[27 ]
In the absence of newer ASMs, prefer carbamazepine (for focal epilepsies), valproate
(for generalized or unknown onset), and benzodiazepines (as adjunctive ASM). Avoid
prescribing phenobarbital, primidone, and phenytoin; rationale: phenobarbital, primidone,
and phenytoin have a considerable number of chronic irreversible side effects, such
as cerebellar atrophy, gingival hyperplasia, osteoporosis, and connective tissue disorders.[6 ]
[20 ]
[39 ]
Avoid combining ASMs with similar mechanisms of action (e.g., lamotrigine and carbamazepine,
lacosamide, oxcarbazepine, and phenytoin); rationale: it usually does not yield better
seizure control and may potentiate the side effects. The combination of ASMs with
different mechanisms (such as lamotrigine + levetiracetam or clobazam) may improve
the chances of seizure control and reduce adverse reactions.[40 ]
Especially in the presence of chronic comorbidities (osteoporosis, high cardiovascular
risk, infections, transplants, autoimmune diseases, cancer), consider referencing
EI-ASM users for an epilepsy specialist; rationale: as far as we know, no studies
in the literature evaluate the impacts of changing EI-ASM to non-EI-ASM over time.
However, patients at high risk of side effects or drug interactions may benefit from
change. Considering the side effects and the seizure risks related to scheme modifications,
it is reasonable to refer the patient to an epilepsy specialist.
Frequently and actively access side effects (especially those not usually reported,
like sexual dysfunction); rationale: PWE frequently suffer side effects from ASMs
(especially older ASMs).[41 ] An adequate treatment of side effects (which may include changing the ASM) may improve
the quality of life and adherence ([Table 2 ]).
In conclusion, this review focused on PWE that will start a medication. Changing ongoing
epilepsy treatments is often complex and risky and should be performed in specific
situations after assessing the risk-benefit ratio. ASM choices for PWE starting treatment
should be personalized, considering seizure type (different efficacy profile), age,
gender, and comorbidities. Choices should not be based on immediate cost alone but
on overall cost-benefit. Recent data show that newer ASMs are generally better choices
due to the lack of enzyme induction, drug interaction, and safety in women of childbearing
age.[10 ]
[11 ]
Worldwide evidence and prescription patterns have changed and point to lamotrigine
and levetiracetam as the best options for treating epilepsy. Lacosamide is an attractive
option but presents a higher cost and is currently unavailable in the public health
system. Valproate is the most effective ASM for generalized epilepsies[42 ]; however, its teratogenic potential poses a risk for women of childbearing age,
limiting, but not excluding, its use.[43 ] We hope that the prescription pattern in Brazil will change, reflecting better care
for people with epilepsy, based on the availability of new ASMs in recent years and
the possibility of obtaining them in public health system dispensaries.
Bibliographical Record
