Volum e 68 No. 3 1995
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`ISSN 0163-7258
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`hartl}acology
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`herapeutics
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`~ Pergamon
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`0163-7258(95)02014-K
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`Plwmwc Tha. Vol. 68. No. 3. pp . 425 - 434. 1995
`Copyright (~ 1995 EbL·vier Science Inc.
`Printed in G reat Brit a in . /\ 11 ri g ht s resc r veJ
`0 163-7258/95 $29 .00
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`Associate Editor : M. 1. BRODIE
`
`ADVERSE EFFECTS OF ESTABLISHED
`AND NEW ANTIEPILEPTIC DRUGS:
`AN ATTEMPTED COMPARISON
`
`BJARKE a ROGVI-HANSEN* and LENNART GRAM
`University Clinic of Neurology, Hvidovre Hospital,
`Kettegaards Aile 34, DK 2650 Hvidovre, Denmark
`
`Abstract-Seizures are but one aspect of the negative impact epilepsy has on patient s' li ves.
`Adverse effects of antiepil eptic treatment may affect the patient's quality of lite to an even greater
`extent than the occurrence of seizures. Adverse effects of antiepileptic drugs (AEDs) are common ,
`and because the differences in efficacy are often marginal, adverse etfects may be the most
`important hlctor in choos ing the best AED for the patient. The search tor more efli cient and
`less tox ic agents is constantly ongoing. Current evidence suggests that the new generation of
`AEDs is as effi cient as the established AEDs and exhibits fewe r adverse effects, but the scienti fi c
`evidence from randomi sed clinical trials comparing established and new AEDs with each ot her
`is still pending.
`
`Keywords - Ep il epsy, antiepileptic drugs, anticonvulsants, adverse effects, side etlects , rev iew.
`
`CONTENTS
`
`I . Introduction
`2. Methods and Definitions
`3. Common Adverse E ffects of Established Antiepileptic Drugs
`3. I . Phenobarbital
`3.2. Phenytoin
`3. 3. Primidone
`3 .4. Ethosuximide
`3.5 . Carbamazepine
`3.6 . Benzodiazepines
`3 . 7. Valproic ac id
`4. Common Adverse Effects of New Antiepileptic Drugs
`4.1. Vigabatrin
`4.2. Oxcarbazepine
`4 .3 . Gabapentin
`4.4. Lamotrigine
`5 . Discussion
`References
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`427
`428
`428
`429
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`43 1
`
`I . INTRODUCTION
`
`Depending upo n the type of e pile psy, 50- 90% of the patients can be "satisfactoril y controll ed ,"
`which m eans that the balance between seizures and adverse effects is tole rable to the pati ent. However,
`mo re than half of the patients treated with establi shed antie pile pti c drugs (AEDs) in mo no the ra py
`
`*Corresponding author.
`Abbreviations - AED, antiepi leptic drug ; CBZ , carbamazepine; ES M, ethosuximide: G P, gabapent in : H YCZ.
`10, 11-dihydro-10-hydroxy-carbazepine; LTG , lamotrigine; OXC, oxcarbazepine: PB. phenobarbital: PHT,
`phenytoin ; PRM , primidone; VGT, vigabatrin ; VPA, valproate.
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`w ill experience adverse effects (Mattson et al. , 1985) . As differences in effi cacy are often marg inal ,
`the ad verse effects may be the major factor in the cho ice of an AED.
`The search fo r new and bette r compounds is constantly ongo ing, but the ideal high-effi cacy/low(cid:173)
`frequ ency of adve rse-effect drugs still need to be identifi ed .
`This review focuses on the adverse effects of the best invest igated , newly licensed A EDs
`loxcarbazepi ne (OXC) , vigabatrin (YGT) , gabapenti n (G P) , lamotrigi ne (LTG)] compared with
`establ ished drugs [phenobarbital (PB) , phenytoi n (PHT), primidone (PRM) , ethosuximide (ES M) ,
`carbamazepine (C BZ) , benzod iazepi nes and va lproate (VPA)] .
`
`2 . METHODS AN D D EFINITIONS
`
`Adve rse effects are defined as unwanted insidious or delayed effects of drugs, which can be of
`tour di stinct types : (l) acute dose- related, (2) acute idiosyncratic, (3) chronic, and (4) teratogenicity.
`As establi shed , AEDs arbitra ril y are considered d rugs marketed in the period from 1912 (PB)
`to 1979 (VPA).
`
`3. COMMON A DVE RSE EFFECTS OF
`ESTA BLISH E D ANTIE PILEPT IC DRUGS
`
`3 . I . Phenobarbital
`
`PB was the fi rst ef-fective AED to be marketed more than 80 years ago and is still used worldwide.
`It exe rts its ant iconvul sive ettect by a GABA-agonistic, glutamate-antagonist mechanism (Mo rselli
`and Lloyd . 1985).
`PB is 40- 60% prote in-bound and has a half-life of about 100 hr. It is extensively metabolised
`by the cytochrome P450 system in the endoplasmic reticulum of the liver cells and exhibits considerable
`auto induction (Kutt and Pa ri s- Kutt , 1982) . This induction resul ts in an increase of the elimination
`rate of many endogenous and exogenous substances, including other AE Ds such as PHT and YPA
`(Pa rk and Breckenridge, 1981) .
`The know ledge of PB's effi cacy stems more from clinical practi ce than from clinical trials, but
`it seems to be as effecti ve as other, newer established agents (Cereghino et al. , 1975 ; Benassi et
`a!. , 1980; Mitchell and Chavez, 1987).
`The most predominant close-dependent acute adverse effect, experienced in almost 70% of patients,
`is sedati on, to wh ich pa rtial tolerance develops during chronic treatment (Prichard and Mattson ,
`1986). Coarse ning of fac ial features and Dupuyt rens' contracture frequently is associated w ith PB
`treatment, but it is potentially reversible (Schmidt, 1983) . Other toxic symptoms are lethargy, dysarthria,
`and lack of coord ination (Loiseau and Duche , 1991). Subnormal fo late levels are a relatively common
`feature d uring PB treatment (Reynolds , 1975) , as is a hemorrhag ic diathesis in neonates of mothe rs
`g iven PB (G ri ffi th s, 1981) , but other clinically relevant tox ic hemato logical symptoms are rare. The
`wide ly acknow ledged cogniti ve adverse effect of PB, in compari son w ith other established drugs,
`is most li kely due to a depression of ce rebral glucose metabolism (Theodore et al. , 1986) . Lo iseau
`and Duche (1991) fou nd th at the cog niti ve adve rse effects may be overemphasised .
`Teratogenic ity seems to be as low, or lower than, with other AEDs (Shapi ro et al. , 1976).
`
`3.2 . Phenyto in
`
`PHT was sy nthesized in 1908 as a result of a sea rch among nonsedative structural analogues of
`PB. The drug stab ilises neuronal membranes by adj usting the transmembrane resting flu xes of sodium ,
`as we ll as the fl ow of calcium and sod ium du ring depo lari zation (Woodbury, 1980) .
`PHT has a li mi ted aqueous solubility, and is metaboli sed by 0-order kinetics, which means that
`an increase in dose in a pat ient already saturated with PHT may increase the plasma level
`d isproportionately (Brow ne and Chang, 1989) . PHT is bound extensively to plasma proteins (about
`90 %) and metabo lised in the liver by glucuronidat ion to its inactive metabolite, which is excreted
`in th e urine . This biotransfo rmation is influ enced by a variety of drugs, resulting in accumulatio n
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`(e.g., CBZ, disulfiram , iso niazid , cimetidine) or increased exc retion (e.g., clonazepam , chron ic
`use of ethanol) (Kutt, 1991). PHT also inf-luences the elimination of other drugs (e.g., CBZ, d igoxin ,
`ant icoagulants) and, most importantly, steroids in fertile women taking oral contraceptives (Perucca,
`1982).
`Central and peripheral nervous toxicity is the most predominant effect of overdosage. Cerebellar(cid:173)
`vestibular sy mptoms, such as ataxia, diplopia , nystagmus, and ve rtigo, are common . Cerebellar atrophy
`has been associated with chronic PHT treatment , but whether this atrophy is caused by the treatment
`or seizures is disputed (Dam, 1977; Koller et a/. , 1981). Behavioral efiects include confusion , drowsiness,
`hyperactivity, and hallucinations. When PHT is administered intravenous ly, card iac arrhythmias,
`with or without hypotension , may occur.
`During chronic administration, cosmetic changes, such as hirsutism, ging ival hyperp las ia , and
`facial coarsening, make thi s agent especially troublesome in the treatment of young women.
`Gastrointestinal symptoms are often seen . Moderate elevat ion of hepatic enzy mes are common , but
`do not necessitate withdrawal of the drug.
`Idiosync ratic cuta neous reactions invo lving sk in , liver, and bone marrow are infrequent , but often
`necessitate drug withdrawal.
`The teratogenicity of PHT is well-described, and a "fetal hydantoin syndrome" has been described
`(Kutt, 1991) .
`
`3. 3 . Primidone
`
`The anticonvulsant et-lect of PRM is partly due to its active metabolites, especially PB, which
`accumulates during chronic medication. Protein binding is 20-30%, with a hal f- life of 4- 12 hr.
`When PRM is administered in combination with other enzy me- ind uc ing drugs , the PB/PRM ratio
`is increased from the normal 1- 2:1 to levels where mainly PB is responsible tor the clinical effects
`(Reynolds et a/. , 1972).
`The dose-dependent adverse effects show a complex picture because of the several active compounds
`and the gradual deve lopment of tolerance, but w ithout doubt , PRM ex hibits adverse attects of its
`own (Leppik et al. , 1984), leading to a feeling of intox ication, sedation, nausea, vert igo, and diplopia (cid:173)
`symptoms that can be attenuated by a slow build up of dosage. Mattson et a/. (1985) found that
`PRM was associated with signifi cantly more adverse effects than PB (gastroin testina l symptoms and
`loss of libido) , which makes the use of PRM instead of PB questionabl e (Brodie, 1990). On the
`other hand , in a comparative study, Herranz et a/. (1988) found that the overall rates of adverse
`et-lects leading to di scontinuation (8- 10%) resembled those of VPA and PHT. Idiosyncratic adverse
`effects, such as sk in rash, thrombocytopenia , lupu s, and lymphadenopathy, appear seldom.
`
`3.4. Ethosu ximide
`
`The succinimides were sy nthesised in the sea rch for less toxic agents to treat absence seizures
`in children.
`ESM is not protein-bound , has a half-li fe of 20- 60 hr, and its inactive metabolites are exc reted
`by the kidneys. The indication is absence seizures. Large interindividual diffe rences in drug d isposition
`have been noticed (Goulet er al., 1976).
`ESM seems to exert a sy nerg istic effect with YPA in otherwise refracto ry absence seizures (Rowan
`et al., 1983) . CBZ - and probably other enzyme-i nducing agents, such as PHT, PB, and PRM - tend
`to increase the metabolism of ESM (Warren eta!., 1980).
`Adverse etlects are reported in 0- 44% of th e patients in clitt'crent studies (Dreifuss, 1982) ,
`gastrointestinal symptoms being the most com mon besides drowsiness, lethargy, euphoria, and
`headache.
`Idiosyncratic adverse eftects seldom observed are skin reac tions, thrombocytopenia, and bone
`marrow depression.
`In animal models, ESM is less teratogenic than most other AEDs (Su llivan and McEihatton , 1977),
`but human expe ri ences a re too li mited to generalise (Kuhnz eta/., 1984).
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`3 . 5. Carbamazepine
`
`CBZ is chemicall y related to the tricyclic antidepressants and exerts its action by modifying the
`ionic conductance of excitable membranes (Ferrendelli , 1987) . It has a limited aqueous solubility
`and 75 % is plasma-protein- bound. As CBZ induces its own metabolism , the half-life may range
`from 5- 26 hr (Pitlick et a!. , 1976). This autoinduction means that as time goes by, higher doses
`are needed to maintain plasma concentrations.
`Pharmacokinetic interactions with other drugs are common (Baciewicz, 1986). CBZ accelerates
`the metabo lism of endogenous and exogenous hormones, including oral contraceptives and
`corticoste roids, and increases the elimination of ESM , VPA , and benzodiazepines. Commonly used
`medications, such as erythromycin and propoxyphene, markedly increase CBZ to toxic levels in
`a brief period of time (Dam et al., 1977; Wong eta!., 1983) . Given in combination with the other
`enzyme-inducing AEDs, CBZ may change the steady state in either direction by dual interaction
`(Zielinsky and Haidukewych, 1987).
`Toxic ity is generally low, with the most common symptoms being nystagmus and atax ia (Pellock ,
`1987). Acute intoxication induces coma, convu lsions, and respiratory depression . During chronic
`administ ration, patients may compla in of drowsiness, vertigo, nausea , and blurred vision. Rash may
`be seen in 2- 4% of the patients (Ramsay et a!., 1983). Water retention with a decreased plasma
`sodium is seen especiall y in elderly patients, but can be antagon ised by concomitant PHT treatment
`(Leppik , 1991) . The assoc iated cognitive adverse effects are less than with PHT (Andrewes et al.,
`1986; Aldenkamp et al. , 1994). Idiosyncratic effects, such as aplastic anemia , dermatitis , and
`eos inophilia , are seldom seen.
`The teratogenic effect of CBZ seems to be similar to other AEDs, but may be increased by polytherapy
`w ith PHT, VPA, and PB (Lindhout et al. , 1984). Spina bifida seems to occur in approximately 1%
`of th e offspring of pregnant women treated with CBZ (Kallen et al., 1989) .
`
`3.6. Benzodiazepines
`
`The large number of highly lipid-soluble benzodiazepines all exert their anticonvulsive effects
`as GABA-agonists. Most widely used in anticonvulsive therapy are the 1,4-benzodiazepines (clonazepam,
`lorazepam, diazepam, nitrazepam , and clorazepate dipotassium) and the 1,5-benzodiazepine, clobazam .
`Plasma protein binding varies from 85% (clonazepam) to 99% (d iazepam). The indications are
`myoclonic and generalised tonic-clonic seizures, status epilepticus, and as adjunctive therapy in refractory
`epilepsy.
`The drug interactions are relatively few, mainly being aggravation of the sedative effect in combination
`w ith hypnotics, antihistamines, opioids, and alcohol . The elimination may be decreased by cimetidine,
`di sulfiram, and oral contraceptives .
`The primary concerns in connection with benzodiazepine med ication are the cardiorespiratory
`depression during treatment of status epilepticus (Browne and Penry, 1973; Browne, 1983), the behavioral
`adverse effects, th e development of tolerance (Browne and Penry, 1973), and provocation of seizures
`during tapering (Robertson, 1986) .
`Cons idering their broad use as an xiolytics and hypnotics, the acute dose-related adverse effects
`of benzodiazepines as AEDs are predictable: sedation , drowsiness, dizziness, lethargy - being
`significantly less pronou nced with the 1,5-benzodiazepines (Remy, 1994) . In a retrospective investigation
`of 877 patients, The Canadian Clobazam Cooperative Group (1991) found that adverse effects were
`reported by 32% of the patients, which Jed to di scontinuation in 9%. Muscular incoord ination and
`hypoton ia together with increased salivary and bronchial sec retions frequently are encountered as
`toxic sy mptoms, especially in chi ldren. During chronic administration, tolerance to the CNS adverse
`effects usually develops, but they can result in di scontinuation of the drug. Attempts to reverse the
`tolerance by increasing the dosage seems futile, while addition of the benzodiazepine-receptor antagonist,
`flumazenil , seems promising, but needs further investigation (Schmidt, 1994) . In children, behavioral
`cha nges, including aggression, irritability, and hyperactivity, can cause difficulties.
`Although benzodiazepines ex hibit teratogenicity in animal studies, no teratogenic effect in humans
`has been reported , a fact that may simply reflect the limited use ofbenzodiazepines in pregnant epileptic
`women.
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`Adverse effects of AEDs
`
`3 . 7. Valproic Acid
`
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`
`VPA acid originall y was synthesized in 1882, being a vehicle of other possible AEDs, but its
`anticonvulsive effect was first di scove red in 1963. Its mechani sm of action is probably multifactorial ,
`influenc ing neurotransmitters such as GABA and aspartate, as well as stabilizing neuronal membranes.
`The plasma protein binding is 90%, and it is degraded into several active metabolites. However,
`there exists a curvilinear relationship of dose and serum levels due to a concentration-dependent
`bind ing (Gram eta!., 1979). VPA is the only established first-line AEDs that is not enzyme-inducing.
`CBZ, PHT, PB and ESM decrease VPA blood levels, sa licylates and PRM inc rease VPA blood levels
`(Levy and Koch, 1982) . A common adverse effect from the CNS is tremor (Karas et al., 1982).
`Stimulation of appetite and weight gain are seen in half of the treated patients (Dinesen eta/. , 1984).
`In a study of patients receiving long-term monotherapy, one-third of the patients developed at least
`one prominent hematologic abnormality, but none serious enough to discontinue therapy (May, 1993) .
`The most teared idiosyncratic complication is fulminant hepatitis, not consistently preceded by abnormal
`hepatic biochemistry, with an incidence of I in 20,000- 40,000 patients .
`VPA is associated with spina bifida, although the magnitude of the problem has been debated .
`The malformation seems to appear in 1-1.5% of the offspring of mothers undergoing VPA treatment
`(Lindhout and Schmidt, 1986).
`
`4. COMMON ADVERSE EFFECTS OF NEW ANTIEPILEPTIC DRUGS
`
`4.1. Vigabatrin
`
`VGT is a structural analogue of GABA that binds and inactivates GABA-transaminase irreversibly,
`increasing GABA and decreasing glutamate in the cerebral spinal fluid (Ben-Menachem et al. , 1988;
`Kalviainen et al. , 1993) and brain (Mattson et al., 1994). VGT is neither protein-bound nor metabolised .
`It does not induce hepatic enzymes, is eliminated by renal clearance, and has very tew interactions
`(Richens, 1991) . The elim ination half-life in healthy adu lts is approximately 7 hr -shorter in patients
`taking enzyme inducing AEDs- but as a consequence of its mechanism of action, there is no relation
`between plasma level s and the therapeutic effect.
`VGT is generally well-tolerated , with 5- 15% of patients withdrawing from treatment due to adverse
`etlects in 0.5 - to 5-year studies (Pedersen eta/. , 1985 ; Browne et al., 1987) . The most common
`adverse effects, occurring in 10- 12% of the patients, (Grant and Heel, 1991 ; Mumford and Cannon ,
`1994) are drowsiness, ataxia, and fatigue-especially during the initial phase of therapy. Psychotic
`episodes have been observed in a few percent of the patients. This may be due to forced normalisation
`or a decrease in binding of dopamine in the basal ganglia (Ring eta/., 1992) . However, no changes
`in mood have been noted in psychometric studies (McGuire eta/., 1992).
`The findings of microvacuolisation in CNS white matter in rodents and clogs have caused much
`controversy, but si milar findings have not been demonstrated in humans, neither by surgery/autopsy
`findings (Cannon et al., 1991 ; Mumford and Cannon, 1994), magnetic resonance imaging (Coc ito
`eta/. , 1992 ; Chiron and Dulac, 1992) , or neurophysiologic investigations (Hammond eta/. , 1991).
`VGT has shown a teratogenetic potential in animal studies, but the ex perience concerning human
`teratogenicity is still inconclusive.
`
`4 .2. Oxcarbazepine
`
`OXC is a keto-derivative of CBZ and a prodrug . Its anticonvulsive action probably is exc reted
`by interaction with sodium and potassium channels (Schmutz eta/., 1994). In humans, it is rapidly
`metabolised to the active compound, 10, 11-dihydro-10-hydroxy-carbazepine (HYCZ). The plasma
`binding of HYCZ is about 40%, with a half-life of 8- 14 hr. The enzyme- inducing potential of OXC
`is low, si nce it is not metabolised by the cytochrome P450-dependent enzymes normally invol ved
`in AED degradation (Larkin et al., 1991).
`OXC has fewer pharmacokinetic interactions than CBZ . Elimination of HYCZ is increased by
`CBZ, PHT, and PB by induction of hepatic enzymes (Tartara et al., 1993; McKee eta/., 1994),
`and OXC may decrease the bioavailability of some oral contraceptives (Kiosterskov-Jensen era/., 1992).
`
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`T he efficacy ofOXC in a 50% higher dose is the same as CBZ (Houtkooper et al. , 1987; Reinike ine n
`et al. , 1987; Dam et a/., 1989), but adverse effects are less frequent. The theoretical reason for
`the lower toxicity i , that OXC, unli ke CBZ , is not metaboli sed to any active epoxide metabolite
`(G ilham eta/., 1988). The most common adverse effects are drowsiness, dizziness, and fatigue occurring
`during initiation of treat ment , often resolving without interventio~. Less often reported are headache,
`dip lopia, atax ia, nystagmus, and nausea. Ra:.h is not seen as often as w1th CBZ . O n the contrary,
`patients developing rash during CBZ therapy can be contr?lled w1th OXC treatme~ t , smce only 27%
`of the patients c ross-react (Jensen eta!. , 1986). The cog111t1ve adverse effects are found to be s1mliar
`to PHT (A ikia eT a!., 1992) and placebo (McKee et al., 1994). The hyponatrem1c effect may be
`mo re pronounced for OXC compared with CBZ (Houtkooper et al. , 1987) . In a retrospective study
`of 947 OXC-treated patients, Friis et al. (1 993) found that adverse effects led to di scontinuation of
`treatment in 18% of the patients. Dam et al. (1989) reported that the number of dropouts was smaller
`for OXC than for CBZ.
`OXC teratogenic ity has not been shown in animal studies. However, the clinical experience with
`teratogeni city of OXC is minimal (Friis et al., 1993) . Facial dysmorphism in a child exposed to
`OXC in utero has been reported (Bulau et al., 1988).
`
`4.3. Gabapentin
`
`GP is a GABA-analogue synthes ized to mimic the steric conformation ofGABA, but its influence
`on the GABA-ergic system is still debated. Recently, a specific binding site in the brain has been
`identifi ed (Rock et a/. , 1993). The half-life of GP is 5- 7 hr, it is not protein-bound , and is excreted
`unchanged in urine.
`No pharmacokineti c interactions with other AEDs have been reported , but antac ids may reduce
`the bioava ilability (Busch eta/. , 1993) .
`Most frequ ently repo rted adverse etfccts (10- 20%) are somnolence, dizziness, ataxia , and fatigue.
`Less frequent ly (6- 9% ) , but more often than placebo, nystagmus, tremor, and diplopia have been
`reported (UK Gabapentin Study Group, 1990; Leiderman , 1994). There are no reports of seriou s
`idiosyncratic and/or skin reactions assoc iated with GP treatment, a fact that may be attributed to
`its lack of metabolic degradation .
`Animal studies have been unabl e to demonstrate a teratogenic eftect of GP, and there are no reports
`on the teratogen ic eltects in humans.
`
`4.4. Lamotrig ine
`
`LTG has a membrane-stabilising, antiglutamate effect. It is 60% protein-bound and has a half-li te
`of approximately 24 hr (Ramsay et al., 1991).
`Its interactions with other AEDs seem to be few, although enzyme-inducing AEDs (PB, PRM ,
`PHT, CBZ) inc rease LTG elimination and VPA decreases it (Richens, 1994).
`The most common adverse eflects reported are CNS related: dizziness, diplopia , ataxia , and blurred
`vi sion occurring in more than 10% of the patients and more often in combination with C BZ (Richens,
`1994) . The main reason tor w ithdrawal from LTG treatment in the trial s is rash (8- 10%) (Schacter
`eta!., 1992; Yuen, 1992), which may progress to a Stevens-Johnsons- like syndrome in an estimated
`I : 1000 pat ients (Richens, 1994). Co mpared with CBZ, the statistical ri sk of cutaneous adverse eftects
`are about the same (Pellock , 1987).
`LTG has been shown to be nonteratogenic in animal studies. An analysis of 42 pregnanc ies revealed
`no clear evidence (Richens, 1994), but so far, treatment during pregnancy is not recommended.
`
`5. DISCUSSION
`
`As shown by Kendrik and Trimble (1994), seizures are but one aspect of the negat ive impact
`epilepsy has on patients lives . In fact , adverse effects of the antiepileptic treatment may affect the
`patients' quality of I i te to a greater extent than the occurrence of seizures, and here I ies a trade-oft·
`for the treating physician , because highly effi cient AEDs are often associated with adverse effects,
`and an AED can have serious adverse effects in total absence of efficiency.
`
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`
`Adverse effects of AEDs
`
`431
`
`Most adverse effects of AEDs are dos~-dependent and revers ible . Among 767 outpatients, Buchanan
`(1992) found 134 patients (17%) with 155 adverse drug reactions. Most of the adverse drug reactions
`appeared to be pharmacodynamic in nature, and 85% of the patie nts experienced relief or improvement
`from w ithdrawal of the responsible drug.
`For AED s, there seem s to be a consensus, mainly built o n emp irical grounds, that certain drugs
`co rrespond to certa in seizure-types. Howeve r, with a few exceptions, the doc umentat ion for thi s
`strategy is not overwhelming (Chadwick and Turnbull , 1985; Chadwick, 1994) . In addition , there
`is still little ev idence from c linical trial s that one AE D possesses substantially greater efficacy than
`others (Mikati and Browne, 1988). This lack of evide nce a llows the c linic ian to pay a g reat deal
`of attention to the potential adverse effects of the AEDs.
`At thi s point , no direct comparative studies of estab lished ve rsu s new AEDs ex ist. The reason
`is that for regulatory purposes, new drugs are compared w ith placebo, and for ethical reasons, they
`arc introduced as add-on treatment. To compensate for thi s lack of randomised , controll ed comparative
`trial s, Bourgeois (1994) has suggested the use of a protective or therape utic index combining information
`about efficacy and toxicity for each AED. Brodie (1994) has launched a star rat ing system , taking
`into account six head ings : mechanism of action , pharmacokinetics, eft'i cacy, side effects, drug
`inte raction s, and a so-called comfort factor, which is the c linic ian's habit of prescribing what he
`o r she is used to presc ribing . In this star rating system , on a scale of 1- 4 stars, OXC, LGT, and
`YPA score highest with 4 stars, YGT, CBZ, and GP, 3 stars, PHT, 2 sta rs, and PB, I star.
`C urrent ev ide nce suggests that the new gene rat ion of AEDs is at least as eflicient as the established
`AEDs. In addition, several of the new drugs exhibit a number of favorable characteristics. They
`all have long half-lives, implying that they can be dosed once or tw ice daily, which g ives the best
`chances for opt imal com pi iance. Furthermore, seve ra l of the new compounds have low protein(cid:173)
`binding, suggesting less promine nt drug interaction s, compa red w ith the established AEDs . Some
`of the new drugs lack the enzyme-inducing properties, which is a well -known nuisance of the rnajority
`of the establ ished AEDs. C linical studies of some of the new AEDs indicate that due to the lesser
`toxi city, doses can be pushed in the hope of reaching se izure control without the severe adverse
`effects, which often is the limiting factor for establi shed AEDs. Fi na ll y, seve ral of the new AEDs
`have no te ratogenetic potential , at least in animal studies. Unfo rtunate ly, many years will pass betore
`we will know tor sure whether thi s rep resents a true benefit tor the pregnant epileptic woman.
`Even though the new AEDs look promising, in the future when efficacy has been established
`a lso in monothe rapy, comparative studies of efficacy and toxicity of old and new AEDs will have
`to be unde rtaken . Such co mparisons will be c ruc ial in finally determining whethe r we really have
`succeeded in developing more effective and/or less tox ic AEDs.
`
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