Download role of phenobarbitone as an antiepileptic drug in 21st century

Role of Phenobarbitone as an
Antiepileptic Drug in 21st Century
16 : 5
P Satishchandra*, Madhu Nagappa*
*
Department of Neurology, National Institute of Mental Health & Neurosciences (NIMHANS),
Bangalore 560 029
Abstract
The pharmacotherapy of epilepsy has greatly expanded with the introduction of several anti-convulsants
in the last 2-3 decades. Yet phenobarbitone, the first effective anti-convulsant in neurological practice
continues to be the most commonly prescribed drug for epilepsy. In spite of a century long experience
with phenobarbitone, several controversies exist regarding its efficacy and tolerability. The latter
is particularly contributed by declining commercial interest and physician bias. In this chapter we
pay tribute to this oldest existing anti-convulsant and review the scientific literature on the existing
knowledge of the role of phenobarbitone as an anti-epileptic drug in the 21st century.
Introduction
Epilepsy is the most common, serious neurological disorder with an annual incidence of 50 per 100
000 population. Pharmacotherapy is the mainstay treatment for most epileptics. The history of antiepileptic drug development can be traced back to 1857 when potassium bromide was introduced by
Sir Charles Locock. The serendipitous discovery of the anticonvulsant properties of phenobarbitone
by Alfred Hauptmann in 1912, until then was known for its sedative and hypnotic properties, heralded
the modern, effective and relatively less-toxic anti-epileptic drug therapy. More than two decades
later, consequent to the screening of several potential therapeutic agents against ‘electrical seizures’
in cats by Merritt and Putnam, a second effective anti-convulsant, namely, phenytoin was introduced.
Since then a gamut of anti-epileptic drugs have been introduced following the systematic screening
of many thousands of compounds in animal models of epilepsy.1 Although the therapeutic options
in pharmacotherapy of epilepsy have significantly broadened, phenobarbitone continues to be the
most commonly prescribed anti-epileptic drug in clinical practice, especially in developing/ less
industrialized countries, notwithstanding the fact that its efficacy and tolerability are shrouded in
controversies. In this chapter, we review the evidence available from scientific literature on the role
of phenobarbitone in current neurological practice.
Mechanism of Action and Pharmacokinetics
Phenobarbitone or 5-ethyl-5-phenylbarbituric acid is a substituted barbituric acid, that exerts its antiepileptic action by facilitating GABA mediated inhibition. It increases the mean open duration of the
GABAA receptor, thereby increasing Cl- flux, hyperpolarizing the post-synaptic neuronal membrane
and interrupting the spread of epileptic activity. There are few studies that have looked into the
pharmacokinetic profile of phenobarbitone.2 Phenobarbitone can be administered by oral, intravenous,
and intramuscular routes. The oral bioavailability is approximately 95%, and the time taken to peak
plasma concentrations is 0.5-4 hours and 2-8 hours respectively when phenobarbitone is given by oral
and intramuscular routes. Hence, there is no statistically significant difference in pharmacokinetic
profile when phenobarbitone is administered orally or intramuscularly, except, in newborns and
premature babies where oral absorption of phenobarbitone is slow and incomplete.3
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Following intravenous administration, phenobarbitone is first
distributed to the highly perfused organs such as liver, kidney
and heart, but not the brain. Subsequently, in the second phase,
phenobarbitone is distributed uniformly into all body tissues
except fat. This relatively slow entry into the brain is related
to the low lipid solubility of phenobarbitone. The pKa of
phenobarbitone is similar to the plasma pH, hence the tissue
distribution of phenobarbitone is sensitive to variations in
plasma pH. Accordingly, in status epilepticus, due to focal
acidosis and increased blood flow to the brain, phenobarbitone
reaches the brain in a much faster manner.3
The CSF concentration of phenobarbitone ranges from 4360% of the plasma concentration and may be slightly higher
in infants. Phenobarbitone crosses the placenta and is excreted
in breast milk too. Elimination of phenobarbitone is slow and
follows first order kinetics, accounting for its very long half
life of 70-130 hours. The half life is the longest in newborns
ranging from 59-400 hours. It is metabolized in the liver by
cytochrome P450 mediated hydroxylation and excreted in
the urine.3 Alkalinisation of urine promotes phenobarbitone
excretion by reducing the passive re-absorption at the renal
distal tubules.4 The plasma concentrations of phenobarbitone
that produces a good seizure control ranges from 10-40mg/
L;4 partial seizures require a higher plasma concentration
of phenobarbitone as compared to generalized tonic
clonic seizures.5 Estimation of serum concentrations of
phenobarbitone is required only when toxicity is suspected
and is not recommended as a routine.6
Indications and Utility of Phenobarbitone
i.
Partial and Generalised seizures : Although phenobarbitone is the oldest existing anti-convulsant in clinical
practice, its efficacy has not been documented in many
rigorously conducted randomized control trials. Evidence for efficacy is mainly the outcome of uncontrolled
studies and case series. A landmark randomized double
blind controlled trial of anti-convulsant efficacy was the
Veterans Administration Cooperative Study, which recruited 622 adults with partial seizures and generalized
tonic-clonic seizures.7 Phenobarbitone was found to be
as effective as primidone, phenytoin and carbamazepine
in controlling generalized tonic-clonic seizures. Carbamazepine provided a better control of partial seizures.
This perceived difference was attributed to higher dropout rates in the phenobarbitone group due to adverse reactions. This has been replicated in other open labeled
studies also.5,8
and generalized tonic-clonic seizures. The seizure control rate of phenobarbitone was found to be the same as
that of other anti-convulsants. However, the paediatric
trial included only 10 children in the phenobarbitone
arm; the excessive occurrence of side effects precluded further allocation to this arm.9,10 Hence, more trials
comparing phenobarbitone with other anti-convulsants
in the paediatric age group are required. Trials in developing countries have confirmed the efficacy of phenobarbitone in children and adults.11-14
In summary, phenobarbitone is effective in partial seizures as well as generalized tonic-clonic seizures. There
is also evidence from clinical experience, but not from
randomized controlled trials, that phenobarbitone is
also effective in other generalized seizure types such as
myoclonic, clonic, atonic and tonic seizures. Phenobarbitone also has a role in the management of progressive
myoclonic epilepsies and tonic spasms in early infantile
epileptic encephalopathy.15,16 It is not effective in absence seizures.17,18 Phenobarbitone is recommended by
the World Health Organization as first-line anti-epileptic
drug for partial and generalized tonic–clonic seizures
for developing countries.19
ii.Neonatal Seizures : Phenobarbitone is routinely and
empirically used in the management of definite and
suspected neonatal seizures, even though this has never
been proven, as it is difficult to design an ethically acceptable randomized control trial.20 Several case series
have demonstrated the utility of phenobarbitone in neonatal seizures with a seizure control rate ranging from
36% to 85%.21-23 It is difficult to draw any definite conclusion because (i) neonatal seizures consist of heterogenous paroxysmal events quite different from other
seizures; there is a lack of specific seizure definition in
most studies; (ii) EEG confirmation is absent in most
studies; and (iii) dosages of phenobarbitone in the studies were varied, ranging from 20mg/kg to 40mg/kg.
A decade later, two randomized prospective trials form
UK, one in adults and one in children, compared the
efficacy of phenobarbitone, phenytoin, carbamazepine
and valproic acid in newly diagnosed partial seizures
750
One randomized trial compared the efficacy of phenobarbitone with phenytoin in neonatal seizures, using
EEG criteria for diagnosis.24 Seizure control rate was
similar irrespective of the drug assigned and the severity
of seizure was found to be a stronger predictor of outcome.24 A Cochrane review addressed the benefits and
side-effects of various anti-convulsants including phenobarbitone in neonatal seizures. Only two randomized
control trials were identified; it was not possible to support any particular anti-convulsant currently in use for
neonatal seizures.25 The role of phenobarbitone as drug
of choice in neonatal seizures is the outcome of clinical
experience. Its superiority over other anti-convulsants
remains to be established.
Role of Phenobarbitone as an Antiepileptic Drug in 21st Century
iii.Status Epilepticus : Phenobarbitone is recommended
in the management of refractory generalized status epilepticus that is unresponsive to benzodiazepines and
phenytoin.26 Baring phenobarbitone, the only other
drugs available in status are valproic acid, Levetiracetam and the anaesthetic agents. The current treatment
guidelines recommend the usage of benzodiazepineslorazepam/ diazepam- followed by phenytoin in the
initial management of status epilepticus. It has been
proven in atleast two studies that there is no statistically
significant difference in terms of efficacy or tolerability
when phenobarbitone initial monotherapy is compared
to benzodiazepine-phenytoin combination, benzodiazepine monotherapy and phenytoin monotherapy.27, 28
The major disadvantage of phenobarbitone usage is the
occurrence of respiratory depression necessitating ICU
admission and intubation following parenteral administration.
common side effect, especially at the start of treatment;
tolerance to sedation develops if phenobarbitone is initiated at a low dose and up-titrated slowly. In the Veterans
Affairs Cooperative Study acute sedation was not more
frequent with phenobarbitone when compared to primidone, carbamazepine or phenytoin. The development of
tolerance was evidenced by the fact that whereas 33%
of patients in the phenobarbitone arm initially reported
sedation, only 24% continued to report at 12 weeks.7
Contrary to the excessive sedation reported in adults,
children experience insomnia and behavioural disturbances as a result of phenobarbitone use, particularly
those with pre-existing brain disease.31, 32 When phenobarbitone was administered to children with febrile seizures, 42% developed hyperactivity, which improved on
withdrawing phenobarbitone.33 Compared to phenytoin,
carbamazepine and valproic acid, phenobarbitone was
associated with higher rates of discontinuation due to
behavioural side effects.10
Children with febrile seizures on phenobarbitone prophylaxis scored lower on the Stanford-Binet scales of intelligence compared to placebo. Even after discontinuing phenobarbitone, they had lower reading, spelling
and arithmetic scores compared to placebo controls.32
Adults with antenatal exposure to phenobarbitone have
also demonstrated a lower verbal intelligence score compared to controls.34 An adverse impact on cognition in
children using phenobarbitone as evidenced by reduced
verbal and performance intelligent quotient, memory
and concentration scores, visuomotor performance, spatial memory, short term memory, and vigilance tests has
been demonstrated as compared to normal subjects or
subjects receiving carbamazepine or valproic acid.31, 35
Heller et al demonstrated that phenobarbitone is more
likely to be discontinued because of adverse effects
when compared to phenytoin, carbamazepine and valproic acid.9 Other neurotoxic effects including depression, apathy, reduced libido and impotence have sometimes been reported in adults.7
On the other hand, when phenobarbitone was compared
to carbamazepine, no significant difference was noted in
cognition or behavior, while, there was a trend for better
seizure control and more systemic side effects with carbamazepine.36 Subsequent trials showed that patients receiving phenobarbitone, phenytoin, carbamazepine and
valproic acid have comparable performance on most
measures of neuropsychological assessment scales as
well as behavioral rating scales.12,37,38
In contrast to the high rates of cognitive side effects reported from developed countries, it has been observed
that there is no excess neurotoxicity reported from the
Drug interactions
Phenobarbitone induces the hepatic metabolism of
several drugs including (i) anti-convulsants: phenytoin,
carbamazepine, valproic acid, lamotrigine, ethosuximide,
felbamate, topiramate, zonisamide, tiagabine; (ii) other drugsoral contraceptive pills, warfarin, steroids and (iii) endogenous
hormones: vitamin D. The metabolism of phenobarbitone
itself is inhibited by valproic acid, chloramphenicol and
dextropropoxyphene.29
Drug overdose
The clinical features of overdose include excessive
drowsiness progressing to stupor and coma, ataxia, dysarthria,
and incoordination. Death occurs due to depression of
cardiorespiratory function. The severity of CNS depression is
higher in drug naïve patients, compared to chronically treated
patients for identical serum concentrations of phenobarbitone.4
Treatment consists of supportive care including mechanical
ventilation. There is limited evidence to support the use of
enhanced elimination in phenobarbitone overdose. Multiple
doses of activated charcoal is useful, while, the role of urine
alkalinisation is superfluous. Extracorporeal techniques such
as haemodialysis and haemoperfusion enhance elimination,
but the risk-benefit ratio is quite low; hence they may have a
role in life-threatening barbiturate toxicity.30
Adverse effects
i.Neurotoxicity: The adverse effects of phenobarbitone
on the central nervous system is the most important side
effect, responsible for maximum ambiguity, high rates
of discontinuation and declining popularity of phenobarbitone. The neurotoxic side effects include sedation, behavioural disturbances including hyperactivity, reduced
cognition, and depressed mood. Sedation is the most
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developing countries. In a large cohort of children and
adults with untreated epilepsy in rural Kenya, there was
no difference in seizure outcome or the incidence of
side effects when phenobarbitone was compared with
carbamazepine monotherapy. The rates of discontinuation were 3.3% and 5.3% in the phenobarbitone and
carbamazepine arms respectively.11 A systematic study
by Nimaga et al, in rural Mali demonstrated seizure
control in nearly 81% of epileptics treated with phenobarbitone, which translated to a better social functioning
in the form of employment and education. None of the
patients in this study had side effects severe enough to
warrant drug discontinuation.14
In a trial conducted in rural India, there was no significant difference in efficacy or behavior rating scores
among children randomized to phenytoin or phenobarbitone.12 A similar observation was reported from a large
paediatric cohort from Bangladesh.39 A large multi-centric study from rural China recruited 2455 patients with
generalized tonic-clonic seizures; the incidence of mild
side effects was 26.1% and phenobarbitone discontinuation-rate was only 1%.40 Phenobarbitone was associated
with a significant reduction in treatment related costs
while markedly improving seizure control.41
The Yelandur Study by Mani et al in rural South India
focused on the treatment of focal and generalized tonic
clonic seizures with phenobarbitone or phenytoin and
observed a 10-fold higher incidence of side effects in
the phenytoin group, with only 11% of patients being
lost to follow-up. This study however did not compare
the efficacy of treatment on seizure control between the
two groups.13
An open-labeled, multicentric, non-comparative study
to analyse the risk-benefits of treatment with phenobarbitone in adult patients with generalized tonic clonic
seizures and partial seizures with generalization was
undertaken by the author.42 Seventy-five subjects were
recruited of which 60 patients completed follow up at
one year and hence were included in the analysis. The
mean age at evaluation was 26.6 + 7.2 years; primary
generalized tonic-clonic seizures constituted 92%, while
the rest had simple/ complex partial seizures with generalization. Seizure freedom was achieved in 74.7% of
the patients at one year. The Global Efficacy was rated
excellent in 74.7% and 80% by the patient/ carer and investigator repectively. Likewise, Global Assessment of
Tolerability was rated excellent in 97.2% and 98.6% by
the patient/ carer and investigator respectively. Cognitive functions were assessed by a trained and qualified
neuropsychologist in all five centres using a validated
questionnaire. At initial evaluation, 7 had frontal executory dysfunction, and 4 had attention deficits. Evalua-
tion at the 6th month and 12th month of follow up demonstrated well-sustained neurocognition in the majority
with impairment in only 5 patients. Improvement was
noticed in frontal executory function, with control of
seizures.42
A Cochrane meta-analysis of four large trials compared
the effects of phenobarbitone vs phenytoin monotherapy
in children and adults with partial seizures and generalized tonic clonic seizures. There was a statistically
significant advantage for phenytoin, as phenobarbitone
was more likely to be withdrawn due to side effects
with seizure outcome being identical with either anticonvulsants.43 It is important to note here that there was
a significant heterogeneity among the individual trials.
Whereas the trials from UK had higher discontinuation
rates due to the cognitive side effects, a study from rural
India did not find any significant difference in behavioral rating scales.7,9,10,12
Yet another Cochrane meta-analysis compared phenobarbitone vs carbamazepine monotherpay for partial
seizures and generalized tonic clonic seizures. Phenobarbitone was more likely to be withdrawn than carbamazepine and there was no statistical heterogeneity.
There was no difference in the seizure outcome with
either anti-convulsant, although subgroup analysis surprisingly disclosed a favorable trend for phenobarbitone
in partial seizures and carbamazepine in generalized
seizures.44 These were open labeled trials and hence the
role of physician bias could not be ruled out.
A Chinese Cochrane meta-analysis of 20 trials concluded
that, whereas, phenobarbitone was not associated with a
higher incidence of adverse reactions when compared to
phenytoin, carbamazepine and valproic acid, the rate of
drug withdrawal was higher with phenobarbitone. This
is possibly a reflection of an exaggerated concern for
phenobarbitone related side effects.45
ii.Drug withdrawal : Abrupt withdrawal of phenobarbitone following long-term use is associated with a
withdrawal syndrome in the form of hyperexcitability,
tremor, irritability, generalized tonic-clonic seizures
or even convulsive/ non-convulsive status epilepticus.
Phenobarbitone should always be tapered gradually in
order to avoid these symptoms.4, 31
iii. Vitamin deficiencies:Mild-moderate folate deficiency
and macrocytosis occurs with phenobarbitone therapy,
but the clinical significance is not known. As mentioned
earlier, phenobarbitone induces the catabolism of vitamin D resulting in low calcium levels, occasionally secondary hyperparathyroidism, rickets, osteomalacia and
fractures.46 Periodic assessment of bone density, together with calcium and vitamin D supplementation may be
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Role of Phenobarbitone as an Antiepileptic Drug in 21st Century
Controversies and Declining Popularity
of Phenobarbitone
Table 1: Psychiatric and Cognitive Adverse effects of
anticonvulsants55,56
Carbamazepine
Irritability, reduced attention
Phenytoin
Depression, impaired attention, sedation, delirium, encephalopathy, agitated psychosis.
Valproate
Depression, fatigue, cognitive slowing
Benzodiazepines Paradoxical disinhibition syndrome – agitation, aggression, irritability, hyperactivity. Psychosis on abrupt
withdrawal.
Felbamate
Depression, anxiety, irritability, psychosis
Gabapentin
Aggression in children
Lamotrigine
Insomnia, agitation, emotional lability, psychosis
Levetiracetam
Depression, anxiety, irritability, emotional lability
Tiagabine
Depression, irritability, cognitive slowing, psychosis
Topiramate
Depression, psychomotor slowing, psychosis, impaired
cognition
Vigabatrin
Depression, aggression, psychosis
Zonisamide
Agitation, depression, psychosis
indicated in high-risk population. Neonatal coagulopathy secondary to ante-natal exposure to phenobarbitone
is also recognized which responds to prophylactic vitamin K administration.47
The available literature in the form of controlled/ uncontrolled
trials, case series as well as clinical experience has provided
an unequivocal evidence of efficacy of phenobarbitone in
the management of generalized epilepsy, neonatal seizures
and status epilepticus. The fact that phenobarbitone is the
oldest anti-epileptic drug, with nearly one hundred-year-rich
experience, and the most commonly prescribed anticonvulsant
underscores the fact that it has stood the test of time. The
declining popularity and physician bias against phenobarbitone
is mainly due to the perceived excessive neurotoxicity.
Notwithstanding the fact that significant adverse effect on
cognition leads to a high rate of discontinuation among
patients from developed countries, it has been observed
that there is no such excess neurotoxicity reported from the
resource-limited countries, where this drug continues to be
used very frequently. There may be several factors responsible
for this discrepant observation:
i.
iv.Connective tissue disorders: About 5-38% of patients
receiving phenobarbitone may develop connective tissue disorders in the form of Dupuytren’s contracture,
Peyronie’s disease, plantar fibromatosis, frozen shoulder, generalized joint pain and gum hyperplasia.4,48,49
v.Hypersensitivity reactions: Mild maculopapular or
morbilliform skin rashes occur in 1-3% of patients receiving phenobarbitone.4 Severe reactions in the form
of Stevens-Johnson syndrome and Toxic Epidermal
Necrolysis have only rarely been reported in patients
undergoing radiotherapy while receiving phenobarbitone.50, 51 Other rare adverse reactions include unmasking of systemic lupus erythematosus/ acute intermittent
porphyria, bone marrow aplasia and a barbiturate hypersensitivity syndrome characterized by rash, eosinophilia, fever and hepatic injury.31, 52
vi.Teratogenicity: There are mixed reports of teratogenic
potential of phenobarbitone compared to other anti-epileptic drugs. Earlier studies have shown that the teratogenic risk with phenobarbitone is similar to or even
lower than other anti-convulsants.53 The North American AED Pregnancy Registry on the other hand reported
major malformations in 6.5% of children with ante-natal
exposure to phenobarbitone including aortic coarctation, Tetralogy of Fallot, pulmonary atresia, and cleft
lip/ palate, as compared to other anti-convulsants except
valproic acid.54
Inherent methodological flaws in studies from developing countries - (a) semiology of seizures were not
accurately documented; (b) inconstant supply of phenobarbitone; (c) a significant number of patients were
lost to follow-up; (d) lack of systematic data for adverse
events; and (e) lack of formal testing for cognitive and
behavioral side effects. This is particularly the reason
why the initial studies in Africa did not lead to any definite conclusions regarding phenobarbitone efficacy.
ii. Lower doses used in resource-limited countries control
seizures effectively without adversely affecting cognition;
iii. Patients from low and middle income countries may
have a higher ‘tolerance threshold’ as treatment options
for uncontrolled seizures are few;
iv. Last but not the least, pharmacogenetics may contribute
to the differential cognitive side effects across different
ethnic groups.29
The reported efficacy and tolerability in poor nations is in
contradiction to high drop-out rate in developed countries.
Besides, psychopathology and cognitive deficits in epileptic
patients are known to be multifactorial, and anticonvulsants
are only one of the contributing factors. Sedating drugs such
as valproate, gabapentin, tiagabin and vigabatrin cause fatigue
and cognitive slowing. Activating drugs such as felbamate and
lamotrigine cause anxiety and aggression.55,56 The reported
efficacy and lower side effect profile makes newer antiepileptic drugs quite popular. But it has to be borne in mind
that the clinical experience is still limited. The occurrence
of neurotoxicity is one of the most important reasons why
phenobarbitone has been side-lined in the developed countries
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Medicine Update 2012  Vol. 22
where a whole gamut of newer anti-convulsants are available.
The excessive preoccupation with cognitive side effects of
phenobarbitone may not be completely justified as most of
the antiepileptic drugs have one form of cognitive/ behavioral
side effect or the other (Table 1).
Economic factors
The greatest advantage of phenobarbitone apart from the
broad-spectrum anti-epileptic action is the low cost. In fact,
the expenditure per year for a patient using phenobarbitone
is even lesser than the transport costs for physician visits.14
A recent study from an epilepsy clinic in North India
analysed the direct and indirect cost of epilepsy treatment,
including cost of travel and loss of productivity. The annual
cost of treatment with phenobarbitone amounted to US$ 11.
The cost of treatment with phenytoin, carbamezepine and
valproic acid were 2, 3 and 4 times respectively greater than
that of phenobarbitone.57 The newer anti-epileptic drugs are
obviously much more expensive. Phenobarbitone is a boon
for patients from resource-poor countries, where the choice
has to be made between phenobarbitone vs ‘no-treatment’
rather than between phenobarbitone and ‘newer anti-epileptic
drugs’.14
Low cost is not just phenobarbitone’s greatest asset but also
greatest liability having led the drug into commercial neglect.
Phenobarbitone may be allowed to fade from use at least in
affluent societies, not so much because of its limitations but
because its virtues are no longer promoted, as evidenced by
the fact that the last major study in the developed world on
phenobarbitone was conducted in 1987. Most of the recent
trials are from the resource-poor settings developing countries
where there is strong drive to establish phenobarbitone as an
effective anti-convulsant.
Conclusion
Epilepsy is a heterogenous disorder in terms of semiology,
aetiology and outcome. The most important consideration
in epilepsy management is the classification into focal or
generalized seizures because clinical experience dictates that
different anti-epileptic drugs have different efficacy against
different seizure types. In this context, phenobarbitone with
its broad spectrum of antiepileptic action, coupled with low
cost can be considered an ideal drug in a resource constrained
country such as India, particularly among the general masses.
Treatment with phenobarbitone will increase coverage while
reducing the treatment related costs simultaneously. Despite
the fact that it is the oldest anti-convulsant in clinical practice,
there is a relative paucity of objective and systematic analysis
of its efficacy, mainly due to lack of commercial interest;
besides, phenobarbitone is perceived to be a highly neurotoxic
drug in the developed countries.
With the data obtained from the recently conducted multi-
centric trial across five centres in India, one could confidently
conclude that phenobarbitone still has definite place in the
management of adult primary/ secondary generalized epilepsy
as monotherapy in the 21st century. Neurocognitive deficits
which have been feared, are far and few and outweigh its
efficacy.
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