Benzodiazepines in epilepsy: pharmacology and pharmacokinetics

Review Article

Benzodiazepines in epilepsy: pharmacologyand pharmacokinetics

Introduction

Much attention has been focused on the introduc-tion of new antiepileptic drugs (AEDs) into the USmarket during the past 15 years. Nonetheless,benzodiazepines (BZDs), which have been usedsince the 1960s, remain important in epilepsymanagement and are the drugs of first choice forstatus epilepticus and seizures associated with post-anoxic insult. Benzodiazepines also continue toplay major roles in treating other conditions suchas febrile seizures, acute repetitive seizures andalcohol withdrawal seizures. The major clinicaladvantages of BZDs are high efficacy rates, rapidonset of action and minimal toxicity. Few otherdrugs possess comparable attributes.

All BZDs share similar neuropharmacologicproperties including anxiety reduction, sedation,sleep induction, anticonvulsant effects and musclerelaxation (1). There are, however, differencesamong BZDs in affinity for receptor subtypes,which may produce different pharmacologiceffects. Thus, some BZDs are more effective thanothers as anticonvulsants; few of the approxi-mately 35 BZDs available worldwide (2) are usedfor managing epilepsy. Diazepam and lorazepamare primarily used for management of seizureemergencies, whereas clobazam, clonazepam andclorazepate are commonly used in chronic epilepsymanagement. Midazolam often is used as analternative to diazepam and lorazepam in seizureemergencies and for treating refractory status

Acta Neurol Scand 2008: 118: 69–86 DOI: 10.1111/j.1600-0404.2008.01004.x Copyright � 2008 The AuthorsJournal compilation � 2008 Blackwell Munksgaard

ACTA NEUROLOGICASCANDINAVICA

Riss J, Cloyd J, Gates J, Collins S. Benzodiazepines in epilepsy:pharmacology and pharmacokinetics.Acta Neurol Scand 2008: 118: 69–86.� 2008 The Authors Journal compilation � 2008 Blackwell Munksgaard.

Benzodiazepines (BZDs) remain important agents in the managementof epilepsy. They are drugs of first choice for status epilepticus andseizures associated with post-anoxic insult and are also frequently usedin the treatment of febrile, acute repetitive and alcohol withdrawalseizures. Clinical advantages of these drugs include rapid onset ofaction, high efficacy rates and minimal toxicity. Benzodiazepines areused in a variety of clinical situations because they have a broadspectrum of clinical activity and can be administered via several routes.Potential shortcomings of BZDs include tolerance, withdrawalsymptoms, adverse events, such as cognitive impairment and sedation,and drug interactions. Benzodiazepines differ in their pharmacologiceffects and pharmacokinetic profiles, which dictate how the drugs areused. Among the approximately 35 BZDs available, a select few areused for the management of seizures and epilepsy: clobazam,clonazepam, clorazepate, diazepam, lorazepam and midazolam.Among these BZDs, clorazepate has a unique profile that includes along half-life of its active metabolite and slow onset of tolerance.Additionally, the pharmacokinetic characteristics of clorazepate(particularly the sustained-release formulation) could theoreticallyhelp minimize adverse events. However, larger, controlled studies ofclorazepate are needed to further examine its role in the treatment ofpatients with epilepsy.

J. Riss1, J. Cloyd1, J. Gates2,S. Collins3

1Center for Orphan Drug Research, Department ofExperimental and Clinical Pharmacology, College ofPharmacy, University of Minnesota, Minneapolis, MN,USA; 2Minnesota Epilepsy Group�, St Paul, MN, USA;3Ovation Pharmaceuticals, Inc., Deerfield, IL, USA

Key words: benzodiazepines; epilepsy;pharmacokinetics; pharmacology; clorazepate

James Cloyd, PharmD, McGuire Translational ResearchFacility, 2001 6th Street SE, Minneapolis, MN 55455,USATel.: +1 612 624 4609Fax: +1 612 626 9985e-mail: [email protected]

Accepted for publication January 28, 2008

69

epilepticus. The BZDs also have widely varyingpharmacokinetic profiles, with differences inabsorption, onset and duration of action andformation of active metabolites. Thus, pharmaco-kinetic differences often dictate the use of specificBZDs, route(s) of administration and formula-tion(s). Additionally, the nature and importance ofside effects and drug interactions have been iden-tified and clarified in recent years.The purpose of this review was to provide

clinicians with information for selecting BZDsand for managing BZD therapy in their patients.The article considers BZD pharmacology, phar-macokinetics, use in epilepsy management, toler-ance and withdrawal. Also included in this reviewis an analysis and discussion of the effects of misseddaily doses of immediate- and extended-releaseclorazepate formulations on plasma N-des-methyldiazepam (DMD) concentrations.

Benzodiazepine pharmacology

There are three principal c-aminobutyric acid(GABA) receptor subtypes. Ligand-activated ionchannels that are selectively blocked by bicucullineand modulated by steroids, BZDs, and barbitu-rates are known as GABAA receptors (3). Thesecond receptor subtype, GABAB, consists ofG-protein-coupled, seven-transmembrane recep-tors, which are selectively activated by (R)-())-baclofen and 3-aminopropylphosphinic acid andare blocked by phaclofen (3). Transmitter-gatedchloride channels, GABAC receptors, are selec-tively activated by certain conformationallyrestricted GABA analogs and are not modulatedby steroids, BZDs or barbiturates (3).Benzodiazepines bind to GABAA receptors,

ionotropic transmembrane proteins located in theneuronal membranes of the central nervoussystem (CNS) (3). The GABAA receptor consistsof a pentameric structure with multiple subunitsthat are necessary for normal physiologic func-tion. The receptor subunits are assembled fromcombinations of 19 polypeptides (i.e. a1–6, b1–3,c1–3, d, e, p, h and q1–3) (4); different subunitcombinations determine the pharmacologic prop-erties of the receptor (5, 6). The number andtypes of subunits vary depending on the locationof the receptor in the CNS (7). The inhibitoryneurotransmitter GABA binds to the receptor toopen the chloride ion gates and produce aninhibitory current (6, 8). Binding of BZDs to thec subunit of the receptor is important in thepotentiation of GABAergic inhibition (9). Differ-entiation between BZDs and GABA is impor-tant. Benzodiazepines do not substitute for

GABA, but instead enhance the inhibitory effectsof GABA. Benzodiazepines allosterically bind tothe receptor at a different location than GABAdoes and enhance the chloride channel�s conduc-tance by increasing the frequency of gated chan-nel opening (6, 7, 10–12).In the search for BZD site ligands with higher

therapeutic selectivity and a more favorable safetyprofile, GABAA receptor subtypes have long beenconsidered promising targets (13). The pharmaco-logic relevance of GABAA receptor subtypes hasbeen identified using a gene knock-in strategy inrodents. Based on in vivo point mutations,a-1-GABAA receptors have been found to mediatesedation and anterograde amnesia and to par-tially mediate anticonvulsant activity, whereasa-2-GABAA receptors mediate anxiolysis (14, 15).The basic chemical structure of BZDs is formed

from the fusion of a benzene ring and a seven-membered diazepine ring (16) (Fig. 1). Clobazam isan exception with its 1-5-BZD structure (17). Thecommon chemical structure of the BZDs accountsfor their similar mechanisms of action.In pharmacologic terms, BZD potency refers to

the in vivo affinity of the drug (or its activemetabolites) for its receptor (18). Benzodiazepinesare classified as low, medium (e.g. clorazepate anddiazepam) or high (e.g. clonazepam and loraze-pam) potency (18, 19).

Benzodiazepine pharmacokinetics

Benzodiazepines have differences in their physio-chemical properties, most notably lipid solubility,which influence their rate of absorption anddiffusion into tissue compartments and their phar-macokinetics. Each BZD has a unique pharmaco-kinetic profile that must be considered when theoptimal agent is selected for a particular patientand condition. Key factors to consider include

N

N

R1

R3

R7

ortho

R2

O

Figure 1. General chemical structure of 1,4- benzodiazepines.

Riss et al.

70

route of administration, rate and extent of absorp-tion, metabolism, formation of active metabolites,elimination and drug interactions (20).

Absorption and distribution

When orally administered, most BZDs are exten-sively and rapidly absorbed, with bioavailabilitiesvarying from 80% to 100% and times to peakconcentration ranging fromminutes to several hours(Table 1). Midazolam is an exception, with low oralbioavailability due to metabolism by cytochromeP-450 (CYP) enzyme 3A5 in intestinal epithelialtissue, which can reduce by up to 50% the fraction ofthe dose reaching the bloodstream (24). Benzodiaze-pines cross the blood–brain barrier rapidly,although the diffusion rate into the brain varies bydrug and is largely determined by lipophilicity (21).The faster thediffusion rate, the earlier is theonset ofpharmacodynamic effects. Rapid entry of BZDsinto the CNS and highly perfused tissues is consis-tent with their short distribution half-lives (21, 25).Following rapid uptake, BZDs redistribute into lesswell-perfused tissues; the rate of redistribution is thefastest for themost lipid-soluble drugs (25). After anintravenous (i.v.) BZD administration, BZD phar-macokinetics can be characterized by a multicom-partmentalmathematical model, with the first phasebeing distribution, followed by a longer eliminationphase. Benzodiazepines also have large volumes ofdistribution, are highly bound to plasma proteins(Table 1) and readily cross into the placenta andbreast milk (25).

Metabolism and elimination

Benzodiazepines differ in their rates of eliminationand the formation of pharmacologically activemetabolites (Table 2). The elimination half-life(t1 ⁄ 2) of a BZD or of its active metabolite is usedto categorize BZD duration of effect: short acting(�<10 h; lorazepam, midazolam), intermediateacting (10–24 h; clonazepam) or long acting(>24 h; clobazam, clorazepate and diazepam) (43).Benzodiazepine metabolism is primarily cata-

lyzed by CYP-dependent hydroxylation, demeth-ylation and nitroreduction (26, 44, 45). The CYPisoenzymes catalyzing these reactions include 3A4,3A5, 2B6, 2C9 and 2C19 (Tables 2 and 3). Uridinediphosphate glucuronosyltransferase is alsoinvolved in the conjugationof someBZDs (Table 3).Several BZDs have active metabolites. Diazepam

and clorazepate are metabolized into the long-actingmetabolite DMD (56). With multiple doses, thepharmacologic and toxic effects of diazepam areattributable to the parent drug, DMD, and otherminor active metabolites (i.e. temazepam and oxaz-epam) (24). By contrast, clorazepate undergoes rapidand complete chemical conversion to DMD in thegastrointestinal tract; its pharmacologic effects arelargely due toDMD (24, 56).N-Desmethyldiazepamundergoes glucuronidation to form a glucuronideconjugate (25%) and is hydroxylated (50%) by CYP2C19 and CYP 3A4 to form oxazepam (24, 37).Approximately 5–9% of DMD is excretedunchanged in the urine (24). The t1 ⁄ 2 of DMDranges widely from 20 to 179 h (24, 33, 34, 38).Other BZDs also have pharmacologically active

metabolites. Clobazam is demethylated into anactive metabolite (N-desmethylclobazam) (27).Midazolam is rapidly converted by CYP 3A4 andCYP 3A5 to 1-hydroxymidazolam, which contrib-utes approximately 10% to the biologic activity ofits parent drug (24, 41). Clonazepam and loraze-pam undergo extensive metabolism, but no activemetabolites are formed (18, 24).

Effects of pharmacokinetics and pharmacodynamicson BZD use – The differences in BZD pharmacoki-netics and pharmacodynamics must be consideredin order to use these drugs safely and effectively.Equivalent doses of BZDs differ as much as 20-foldbecause of differences in potency (57). The intensityof single-dose effects may vary, even if equipotentdoses are used, because of varying oral absorptionrates (58). Duration of action should be consideredwhen choosing a BZD. When maintenance therapyis required (e.g. epilepsy and anxiety), long-actingBZDs are preferred because of their prolonged t1 ⁄ 2,as effective drug concentrations can be maintained

Table 1 Summary of absorption and distribution pharmacokinetics of selectedBZDs

Drug F (%) Tmax

Proteinbinding

(% bound)

Distributionhalf-lifea

(min) Vd (l ⁄ kg)

Clobazam 87 1.3–1.7 h 82–90 NA 0.87–1.83Clonazepam >80 1–4 h 86 30 min (21) 1.5–4.4Clorazepateb PO: 100

IM: 91PO: 0.5–2 h

IM: 2.7–11 h96–98 6–29 min (22) 0.7–2.2

Diazepam PO: 100R: 90 (23)

PO: 30–90 minIM: 30–60 minR: 10–45 min

96–99 2–13 min (21) 0.95–2.0

Lorazepam PO: 99IM: 96SL: 94

PO: 2.4 hIM: 1.2 hSL: 2.3 h

93.2 <11 min (21) 0.85–1.5

Midazolam PO: 40IM: 100

PO: 0.5–0.97 hIM: 0.24–0.51 h

96 4–19 min (21) 0.7–1.7

Values refer to adults receiving monotherapy and are from Anderson and Miller(24) unless otherwise specified. BZD, benzodiazepine; F, bioavailability; Tmax, timeto maximum concentration; Vd, volume of distribution; NA, not applicable; PO, oral;IM, intramuscular; R, rectal; SL, sublingual.aAfter intravenous administration.bPharmacokinetics for N-desmethyldiazepam after administration of clorazepate.

Benzodiazepines in the treatment of epilepsy

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without the need for frequent dosing (56). Short-acting BZDs are preferred for intermittent hyp-notic therapy, when the duration of action of thedrug should be restricted to night-time, allowingpatients to awaken feeling refreshed, withouthangover effects (56).

Drug–drug interactions

Benzodiazepines interact with other drugs such ascertain antidepressants, AEDs (e.g. phenobarbital,

phenytoin and carbamazepine), sedative antihista-mines, opiates, antipsychotics and alcohol (44, 57,59), which may result in additive sedative effects.As discussed earlier, BZD metabolism is com-

plex and largely catalyzed by CYP isoenzymes.Consequently, there is potential for interactionsbetween BZDs and drugs that induce or inhibitCYP isoenzymes. The clinical importance of theseinteractions depends on the net effect of inhibitionor induction on the metabolic pathway of aparticular BZD. For example, inhibition of aminor pathway may have little impact on drugconcentration, whereas inhibition of a majorpathway may result in enhanced clinical effect ortoxicity. By contrast, addition of an enzyme-inducing drug that affects even a relatively minorpathway may lead to a clinically important reduc-tion in plasma BZD concentration. For BZDs withactive metabolites, the addition of an inhibitor orinducer may affect only the parent drug, only themetabolite, or both. Clinicians should exerciseparticular caution when using BZDs with selectiveserotonin reuptake inhibitors, cimetidine, macro-lide antibiotics and antimycotics; these drugs mayinhibit reactions catalyzed by certain CYP isoen-zymes and, therefore, inhibit the metabolism ofmany BZDs, which results in increased plasmaBZD concentrations (44). Conversely, potentenzyme inducers (e.g. phenytoin, phenobarbitaland carbamazepine) substantially increase clear-ance and reduce the t1 ⁄ 2 of certain BZDs (44). Fora detailed review of pharmacokinetic drug interac-tions involving BZDs, see Tanaka (44).Oral contraceptive steroids may inhibit the

metabolism of some BZDs that undergo oxidativemetabolism or nitroreduction and acceleratethe metabolism of some BZDs that are conjugated.Interactions between BZDs and oral contraceptivesare described in detail by Back and Orme (60).

Table 2 Summary of metabolism and elimination pharmacokinetics of selected BZDs

Drug Primary metabolic pathway Active metabolitesElimination half-life of

parent druga (h)Elimination half-life ofactive metabolites (h)

Clobazam Demethylation (26) N-desmethylclobazam (27) 10–30 (28) 36–46 (28)Clonazepam Nitroreduction (CYP 3A4),

acetylation (NAT), hydroxylation (29–31)NA 19–60 (32) NA

Clorazepate Decarboxylation, glucuronidation,hydroxylation (CYP 2C19 and 3A4) (24)

DMD (major), oxazepam (minor) (24) NA 20–160 (24, 33, 34)Oxazepam: 6–24 (18)

Diazepam Demethylation (CYP 2C9, 2C19, 2B6, 3A4,and 3A5), hydroxylation (CYP 3A4 and 2C19),

glucuronidation (24, 35, 36)

DMD (major), oxazepam (minor),temazepam (minor) (24, 35, 37)

21–70 (23, 38) DMD: 49–179 (33, 38)Oxazepam: 6–24 (18)

Temazepam: 8–24 (18)Lorazepam Glucuronidation (24) NA 7–26 (39, 40) NAMidazolam Hydroxylation (CYP 3A4 and 3A5) (25, 41, 42) 1-hydroxymidazolam (minor) (24) 1–4 (24) 1 (24)

BZD, benzodiazepine; CYP, cytochrome P-450; NAT, N-acetyltransferase; NA, not applicable; DMD, N- desmethyldiazepam.aHealthy subjects.

Table 3 Enzyme-mediated BZD metabolism and drug interactions

Enzymeassociatedwithmetabolism

BZDsubstrates Inhibitors Inducers

CYP 2C19 Diazepam (46) Fluvoxamine (46) Dexamethasone (48)MHD (weak) (47) Phenobarbital (48)Omeprazole (46) Phenytoin (49)

Oxcarbazepine (46) Rifampin (46)Ticlopidine (46) St John�s wort (50)Topiramate (46)

CYP 3A4 Clonazepam (29) Azole antifungals(e.g. ketoconazole) (46)

Carbamazepine (46)

Diazepam (46) Cimetidine (46) Phenobarbital (48)Midazolam (46) Clarithromycin (46) Phenytoin (46)

Diltiazem (46) Rifabutin (46)Erythromycin (46) Rifampin (52)

Fluoxetine (51) Rifapentine (51)Grapefruit juice (46) St John�s wort (50)

HIV proteaseinhibitor (46)

Nefazodone (46)Sertraline (51)

UGT Lorazepam (53) Valproate (55) Carbamazepine (55)Oxazepam (54) Lamotrigine (weak) (55)

Phenobarbital (55)Phenytoin (55)Rifampin (52)

BZD, benzodiazepine; CYP, cytochrome P-450; MHD, monohydroxy derivative; HIV,human immunodeficiency virus; UGT, uridine diphosphate glucuronosyltransferase.

Riss et al.

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Special populations

Elderly patients – Pharmacokinetics in older indi-viduals differ from those in younger individualsbecause of age-related changes in physiology and thelikelihood of concurrent diseases. Elderly individu-als often have variable drug absorption, decreasedplasma protein–drug binding due to lower albuminconcentrations, and reduced hepatic and renalclearance (61). Additionally, many elderly individ-uals take multiple medications, which increase theirrisk of drug–drug interactions. Therefore, treatmentof the elderly can be challenging.Increased sensitivity of older patients to BZDs is

partly due to reduced drug metabolism (whencompared with younger adults), which can result indrug accumulation (62). Furthermore, BZD phar-macologic effects appear to be greater in elderlypatients than in younger patients even at similarplasma BZD concentrations (63, 64), possiblybecause of age-related changes in drug–receptorinteractions, post-receptor mechanisms and organfunction. When a BZD is prescribed for an elderlypatient, the initial maintenance dose should be halfthat recommended for younger adults (57), andBZD use should be only short term (limited to2 weeks) (65). A short-acting BZD may be prefer-able for treating an elderly patient because such adrug is better tolerated than is a BZD or BZDactive metabolite with a long t1 ⁄ 2 (64).

Pediatric patients – Limited information is availableregarding BZD absorption in children. Often,before children are administered medications, thetablet is crushed or the capsule is opened, and thecontents are mixed with food or drink. Food andbeverages may affect BZD bioavailability, butstudies investigating this issue in children arelacking.Drug metabolism is variable in children and

depends on the biotransformation pathway. Cyto-chrome P-450-catalyzed metabolism tends to below at birth, but exceeds adult values by age2–3 years; thereafter, CYP-catalyzed metabolismdecreases, reaching adult levels around puberty(66). Metabolism via glucuronidation tends to below in neonates, reaching adult levels by age3–4 years (66). In neonates, the t1 ⁄ 2 of clorazepateis prolonged and clearance is decreased (67).Infants have reduced hydroxylation metabolism,which results in a decreased clearance of diazepam(68). The t1 ⁄ 2 of midazolam is shorter in childrenthan in adults: 0.79–2.83 h in children (69) vs 1.36–4 h in adults (24). Clinicians should consider howpatient age may affect BZD clearance, becauseclearance will affect BZD dosing.

Special formulations of BZDs

Extended-release drug formulations can helppatients with epilepsy achieve their primary treat-ment goals of controlling seizures while reducingside effects by minimizing fluctuations in drugconcentration and by improving compliance.Extended-release formulations may also improvequality of life and patient satisfaction withtreatment, in part by simplifying dosage regimens(70). Currently, clorazepate is the only BZDavailable in both a sustained-release, single-dose(Tranxene�-SD, Ovation Pharmaceuticals, Deer-field, IL, USA) formulation (11.25- and 22.5-mgtablets) and an immediate-release formulation thatrequires multiple doses per day (Tranxene� T-Tab;3.75-, 7.5- and 15-mg tablets) that is approved inthe USA for the treatment of seizures. Some BZDsare also available as oral liquids [diazepam (Diaz-epam Intensol; 5 mg ⁄ml), lorazepam (LorazepamIntensol; 2 mg ⁄ml) and midazolam (generic only;2 mg ⁄ml)], disintegrating tablets [clonazepam(Klonopin� Wafer; Roche Pharmaceuticals,Nutley, NJ, USA; 0.125-, 0.25-, 0.5-, 1- and 2-mgtablets)] or a rectal gel [diazepam (Diastat�

AcuDial; Valeant Pharmaceuticals International,Costa Mesa, CA, USA; 2.5-, 10- and 20-mgdelivery systems)].

Effect of extended-release formulations on plasmaBZD concentrations: pharmacokinetic simulationswith clorazepate – Our group has performed simu-lation studies of plasma DMD concentrations overtime to investigate differences between clorazepateformulations and to characterize the effect ofmissed doses with or without replacement dosesunder steady-state conditions when using thesustained-release and immediate-release formula-tions (71). These simulations were briefly describedby Kaplan and DuPont (72), but detailed resultsare reported herein. The following simulationswere performed for both formulations usingWinNonlin� (Pharsight Corporation, version 4.1:Mountain View, CA, USA) software and a two-compartment, first-order, oral-absorption pharma-cokinetic model: (1) steady-state conditions, (2)missed dose(s) without replacement and (3) misseddose(s) with replacement at the next scheduleddose. The following dosing schedules for thesustained-release and immediate-release formula-tions were entered to attain steady-state conditions(>7 days): clorazepate sustained-release 22.5 mg –one tablet orally every 24 h for 20 days; andclorazepate immediate-release 7.5 mg – one tabletorally three times daily (given 6 h apart) for20 days. The resulting simulated plasma DMD


73

concentrations over time are depicted in Figs 2–4.The mean steady-state plasma DMD concentrationwas approximately 0.71 lg ⁄ml for the immediate-release formulation and 0.73 lg ⁄ml for the sus-tained-release formulation. The time to maximumconcentration was 2.43 and 9.20 h for the imme-diate-release and sustained-release formulationsrespectively. Table 4 shows the effects of misseddoses on plasma DMD concentrations. When amissed day�s dose of the immediate-release formu-lation was simulated, peak-to-trough differences(compared with steady state) increased by0.05 lg ⁄ml (38.5%) with no dose replacementand increased by 0.29 lg ⁄ml (223.1%) withreplacement of the missed doses (Table 4). How-ever, when a missed day�s dose of the sustained-release formulation was simulated, peak-to-troughdifferences increased by 0.01 lg ⁄ml (5.9%) with nodose replacement and increased by 0.24 lg ⁄ml(141.2%) with replacement of the missed dose(Table 4).Despite the long half-life of DMD, a missed

day�s dosing can result in altered peak-to-troughconcentration ratios. Overall, the differencesbetween peak and trough plasma DMD concen-trations after a missed daily dose of clorazepateincreased more with the immediate-release formu-lation than with the sustained-release formulation(Table 4). There was little difference between thetwo formulations in peak and trough concentra-tions following a missed day�s dose. Although theeffect was modest, the sustained-release tabletmaintained higher trough concentrations after amissed daily dose and replacement of the misseddose. This effect may prevent breakthrough sei-zures in some patients. Additionally, when amissed daily dose was replaced, the sustained-release formulation resulted in a smaller change inpeak concentrations, which may reduce the risk ofdrug toxicity.

Use of benzodiazepines in epilepsy

Efficacy

Benzodiazepines are among the most useful AEDsavailable for treating status epilepticus and acuterepetitive seizures and for febrile seizure prophy-laxis. Benzodiazepines were used in epilepsy man-agement as early as 1965, when Gastaut et al. (73,74) administered i.v. diazepam to treat statusepilepticus. Since then, several other BZDs havebeen used for a variety of seizure disorders(Table 5).Several randomized controlled trials support the

use of BZDs (particularly diazepam and loraze-

Missed dose

Missed doses

0 100 200

1.0

0.8

0.6

0.4

0.2

0.0300

Time (h)

Pre

dict

ed D

MD

con

cent

ratio

n (µ

g/m

l)

400 50050 150 250 350 450

Figure 3. Simulated plasma N-desmethyldiazepam (DMD)concentration over time for immediate-release clorazepate(solid line, 7.5 mg given every 6 h for three daily doses) andsustained-release clorazepate (dashed line, 22.5 mg once daily),missed daily dose(s) without replacement.

0 100 200

1.0

0.8

0.6

0.4

0.2

0.0300

Time (h)

Pre

dict

ed D

MD

con

cent

ratio

n (µ

g/m

l)

400 50050 150 250 350 450

Figure 2. Simulated plasma N-desmethyldiazepam (DMD)concentration over time for immediate-release clorazepate(solid line, 7.5 mg given every 6 h for three daily doses) andsustained-release clorazepate (dashed line, 22.5 mg once daily)with no missed doses.

Missed dose

Replaced dose

Misseddoses

Replaced doses

0 100 200

1.0

0.8

0.6

0.4

0.2

0.0300

Time (h)

Pre

dict

ed D

MD

con

cent

ratio

n (µ

g/m

l)

400 50050 150 250 350 450

Figure 4. Simulated plasma N-desmethyldiazepam (DMD)concentration over time for immediate-release clorazepate(solid line, 7.5 mg given every 6 h for three daily doses) andsustained-release clorazepate (dashed line, 22.5 mg once daily),missed daily dose(s) replaced at next day�s dose.

Riss et al.

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pam) as initial drug therapy in patients with statusepilepticus (77–80). Intermittent use of BZDs isespecially suitable for patients with clusters ofrepetitive seizures (81). Fewer studies have evalu-ated the clinical efficacy of BZDs in chronicepilepsy. Nevertheless, BZDs are useful as adjunc-tive agents in treating certain patients with bothpartial and primary generalized seizures (81).Benzodiazepines are versatile drugs that can beemployed in a variety of clinical settings because oftheir broad spectrum of activity and multipleformulations and because they can be administeredby several routes (81).

Diazepam – Diazepam is a drug of first choice fortreatment of early status epilepticus and acuterepetitive seizures and for febrile seizure prophy-laxis. It can be administered as an i.v. bolus, as acontinuous infusion, or rectally, which enhances its

utility in managing seizure emergencies. Fourrandomized controlled trials support diazepam asa drug of first choice for managing status epilep-ticus (77–80). Success rates of i.v. diazepam fortreating status epilepticus vary. In a randomizeddouble-blind study comparing diazepam andlorazepam, Leppik et al. (80) found that 76% ofstatus epilepticus episodes (25 of 33) were termi-nated by one or two diazepam doses (5 mg ⁄min).In a randomized, non-blinded trial of patients>15 years of age with status epilepticus, Shaneret al. (78) reported that seizures were aborted in<10 min in 55.6% of patients (10 of 18) treatedwith diazepam (2 mg ⁄min) and phenytoin(40 mg ⁄min). A randomized, double-blind, multi-center Veterans Affairs cooperative study wasdesigned to compare the effectiveness of fourtreatments for overt or subtle status epilepticus(79). Three hundred eighty-four patients with overt

Table 4 Effects of missed doses on simulated plasma DMD concentrations (71)

Simulation schemea

Formulation

Clorazepate sustained-release Clorazepate immediate-release

1 2 3 1 2 3

Peak ⁄ trough differenceb at steady state (lg ⁄ ml) 0.17 NA NA 0.13 NA NAPeak ⁄ trough differenceb after missed dose(s) (lg ⁄ ml) NA 0.18 0.41 NA 0.18 0.42Change in peak plasma DMD concentrations (%) NA )29.6 6.0 NA )27.1 9.6Change in trough plasma DMD concentrations (%) NA )44.1 )41.9 NA )48.8 )48.8

DMD, N-desmethyldiazepam; NA, not applicable.aSimulation scheme: 1 = no missed doses; 2 = missed daily dose(s) without replacement; 3 = missed daily dose(s) with replacement.bDifference between maximum plasma DMD concentration and minimum plasma DMD concentration.

Table 5 Recommended clinical uses of benzodiazepines

Drug Trade Name Generic availability Product-labeled uses (75) Common uses in epilepsy (76)

Clobazam Frisium NA Not FDA approved First-line adjunctive treatment for treatment-resistantpartial and generalized seizures, intermittenttherapy and non-convulsive status epilepticus

Clonazepam Klonopin Yes Panic disorder, epilepticseizures (alone or adjunct)

Second-line adjunctive treatment for partial andgeneralized (particularly absence and myoclonic)

seizures, early status epilepticus andLennox–Gastaut syndrome; second-line

treatment of status epilepticusClorazepate Tranxene T-Tab

Tranxene-SDYes Anxiety, alcohol withdrawal,

adjunctive treatment of partial seizuresAdjunctive treatment of partial seizures (75)

Diazepam Valium Yes Anxiety, alcohol withdrawal,muscle relaxant, epileptic seizures

First-line treatment for early status epilepticus;second-line therapy for established

status epilepticus; treatment ofnon-convulsive status epilepticus;

intermittent prophylactic therapy forfebrile seizures; and at-home treatment of ARS

Lorazepam Ativan Yes Anxiety, pre-anesthetic to induce amnesia,antiemetic adjunct, status epilepticus

First-line treatment for early status epilepticusand out-of-hospital status epilepticus

Midazolam Versed Yes Anesthesia, preoperative and proceduralsedation

Second-line therapy for early status epilepticus

NA, not applicable; FDA, US Food and Drug Administration; ARS, acute repetitive seizures.


75

status epilepticus and 134 patients with subtlestatus epilepticus were randomly assigned toreceive either diazepam (0.15 mg ⁄kg) followedby phenytoin (18 mg ⁄kg), lorazepam (0.1 mg ⁄kg)alone, phenobarbital (15 mg ⁄kg) alone orphenytoin (18 mg ⁄kg) alone. Treatment with diaz-epam plus phenytoin was successful in 55.8% ofpatients (53 of 95) with overt status epilepticus and8.3% of patients (three of 36) with subtle statusepilepticus (79). Alldredge et al. (77) conducted arandomized double-blind trial to determine theeffectiveness of i.v. diazepam, lorazepam andplacebo on status epilepticus when the drugs wereadministered by paramedics before patients arrivedat the hospital. They found that status epilepticuswas terminated by the time of arrival in theemergency department in 42.6% of the 68 patientstreated with one or two 5-mg doses of i.v.diazepam (infused over 1–2 min). Limited pub-lished data indicate that continuous i.v. infusionsof diazepam are safe and effective (82–84).Use of i.v. diazepam can result in seizure relapse

within 2 h of a single injection in approximately50% of patients (76). Therefore, multiple injectionsor continuous infusion may be required, which canlead to drug accumulation and possibly to acuterespiratory depression, sedation and hypotension(76). The development of tolerance has also beenreported for infusions lasting >24 h (85). Recom-mended dosing guidelines for i.v. diazepam forconvulsive status epilepticus are 0.15–0.25 mg ⁄kg inadults and 0.1–1.0 mg ⁄kg in children (86). Inplacebo-controlled trials, rectal diazepam gel(doses of 0.2–0.5 mg ⁄kg) reduced seizure recurrencein children, adolescents and adults who had clustersof repetitive seizures in a non-medical or homesetting (87–90). Rectally administered diazepammay also be effective for short-term prophylaxis(at doses of 5–10 mg or 0.3–0.6 mg ⁄kg in patientsweighing <10 kg) in children prone to febrileseizures (91–93), andhigher doses of rectal diazepam(20–30 mg) have been used in adult patients withdrug-resistant epilepsy who are prone to serialseizures (94, 95). Use of oral diazepam is notrecommended for long-term epilepsy treatment (76).

Lorazepam – Lorazepam is generally given as an i.v.bolus at doses of 0.05–0.1 mg ⁄kg over 2 min, andthe dose may be repeated in 10 min. The i.v.formulation is approved by the US Food andDrug Administration (FDA) for the treatment ofstatus epilepticus. Results from four comparativestudies (three of blinded design) have suggested thatlorazepam is superior to phenytoin and as effectiveas clonazepam, diazepam or the combination ofdiazepam and phenytoin in the initial treatment of

status epilepticus (77, 79, 80, 96). In the previouslymentioned study by Alldredge et al. (77), i.v.lorazepam (2 mg, one to two doses) administeredto 66 adults with repetitive or ongoing generalizedseizures lasting >5 min terminated convulsions bythe time of arrival at the emergency department in59.1% of patients. Similarly, Leppik et al. (80)found that one or two lorazepam doses (4 mg each)terminated seizures in 89% of status epilepticusepisodes. In the Veterans Affairs cooperative studyof status epilepticus, lorazepam terminated seizuresin 64.9% of patients and was significantly moreeffective than phenytoin (P = 0.002) (79). A non-blinded trial by Sorel et al. (96) compared i.v.lorazepam (4–10 mg, one to two doses) and clo-nazepam (1 mg, one to two doses) in 61 patients. Inlorazepam-treated patients, 53.0% had ‡75%improvement, as did 39.6% of clonazepam-treatedpatients, as measured by electroencephalograms.Clinical results were comparable between groups,with 67.9% of lorazepam-treated patients and69.0% of clonazepam-treated patients having‡75% improvement. Large lorazepam doses (0.3–9 mg ⁄h) have been used as an alternative to pento-barbital for treating refractory status epilepticus; forall nine cases in an open-label study, lorazepamterminated status epilepticus (97).Clinical studies in children have been mostly

unblinded and have included retrospective andprospective designs. In a prospective open-labelstudy, Appleton et al. (98) compared i.v. or rectallorazepam and diazepam treatments in 86 children.A single dose terminated seizures in 76% ofpatients treated with lorazepam and in 51% ofpatients treated with diazepam; the differencebetween treatments was not statistically significant.Qureshi et al. (99) performed a comparative auditof i.v. lorazepam and diazepam. The authorssuggested that lorazepam is probably as effectiveas diazepam is for stopping acute seizures inchildren. Seizures were controlled within 15 minin 65% of diazepam-treated patients (11 of 17)(median time, 3 min) and in 65% of lorazepam-treated patients (20 of 31) (median time, 5 min).The effectiveness of lorazepam in the treatment

of patients with chronic epilepsy has been evalu-ated in relatively few studies (100). In a short-term,placebo-controlled trial, adjunctive oral lorazepamtherapy was effective (i.e. reduced seizure fre-quency significantly more than placebo did,P < 0.01) for treating partial seizures that wereunresponsive to standard AEDs (101).

Clonazepam – As reviewed by Browne (102), clo-nazepam has been shown to be efficacious intreating patients with both partial and generalized

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seizures. Clonazepam is used primarily as anadjunctive therapy to treat patients with a widerange of treatment-resistant primary and second-arily generalized seizures (103). During the 1970sand 1980s, the use of adjunctive clonazepam wasevaluated in a few, mostly small, controlled clinicaltrials in patients with partial and generalizedseizures that were refractory to standard treat-ments (76, 104). Uncontrolled studies of clonaze-pam in patients with partial and generalizedepilepsy have generally shown modest effects (76).In generalized epilepsies, clonazepam is effectivefor treating patients with absence seizures (105,106). In one study, 70% of children with absenceseizures treated with clonazepam (seven of 10) hada ‡ 75% reduction in seizure frequency after8 weeks of treatment, and an additional 10% ofchildren (one of 10) had a 30% reduction in seizurefrequency (105). Clonazepam also can be useful intreating patients with myoclonic seizures (107). It isconsidered the drug of choice in certain rarechildhood epilepsy syndromes (108). It is alsoeffective in controlling status epilepticus; a reviewof several studies (109–120) of i.v. clonazepam usein status epilepticus found the drug to be effectivein approximately 80–90% of patients (107). Clo-nazepam has been shown to be effective asadjunctive therapy for complex partial seizures,absence seizures, tonic–clonic seizures and myo-clonic seizures (121, 122).

Midazolam – Midazolam is the only availablewater-soluble BZD; solubility is achieved whenthe injectable solution is buffered to a pH of 2.9–3.7 (123). In the treatment of status epilepticus,midazolam can be administered by i.v. bolus,continuous i.v. infusion or i.m. injection. It canalso be administered buccally or nasally (124, 125).Rectal administration is not recommended becauseof poor bioavailability (126). Although it is usedfor many seizure types, midazolam does not havean FDA-approved indication for seizures.Clinical experience with midazolam for treating

status epilepticus (as initial treatment or forrefractory status epilepticus) is limited (76). Inthree controlled clinical trials, the efficacy ofintranasal midazolam was similar to or betterthan that of i.v. or rectal diazepam (124, 127, 128).Midazolam has also been found to be safe andeffective when administered as a continuous infu-sion to treat refractory generalized convulsivestatus epilepticus (129–133). In a randomized trialcomparing buccal midazolam with rectal diazepamin children, the drugs showed similar efficacy andonset of action (125). In that study, seizurecessation was achieved in 75% of cases (30 of 40)

with midazolam and in 59% of cases (23 of 39)with diazepam treatment (P = 0.16). Results fromanother randomized controlled trial that comparedbuccal midazolam with rectal diazepam for emer-gency treatment of seizures in children suggestedthat midazolam was more effective than diazepam(134). Therapeutic success (defined as cessation ofvisible signs of seizure activity within 10 min ofdrug administration, lack of respiratory depressionand no further seizures within 1 h) was noted in56% of midazolam-treated patients (61 of 109) and27% of diazepam-treated patients (30 of 110), a29% difference between groups; (95% confidenceinterval, 16–41%). Open-label studies have sug-gested that intranasal midazolam is safe andeffective for acute seizure management in children(124, 127, 128, 135, 136). In a prospective,randomized, open-label study, intranasal midazo-lam was as safe and effective as i.v. diazepam wasfor managing febrile seizures, with 88% of seizures(23 of 26) responding to initial treatment withmidazolam and 92% (24 of 26) responding todiazepam (124). Intranasal midazolam takes lesstime to administer than i.v. diazepam does but hasdisadvantages. Often, the parenteral formulationhas been used for intranasal administration. Alarge volume is required to deliver a therapeuticdose, making administration difficult becausemuch of the solution may leak out of the nose orbe swallowed (137). Additionally, pain is commonwith intranasal midazolam administration, whichmay indicate irritation of the nasal mucosa due tothe low pH (3–4.3) of the formulation (137–139).Finally, the short t1 ⁄ 2 of midazolam (24) may putpatients at risk of seizure recurrence as plasmaconcentrations rapidly decline.

Clobazam – Although not currently approved inthe USA, clobazam is commonly used elsewhere asadjunctive therapy for patients with refractoryepilepsy (103). It is highly effective as adjunctivetherapy for partial and generalized seizures, forintermittent therapy and for controlling non-convulsive status epilepticus, and it produces lesssedation than other BZDs do (140). Its use islimited by the potential for the development oftolerance. However, a portion of patients (up to25%) may remain seizure free while taking adjunc-tive clobazam for long periods (141–144). TheCanadian Clobazam Cooperative Group reportedthat, on the basis of results from a retrospectivestudy, 40–50% of patients could be maintained onclobazam for 4 years or longer (141).In several double-blind, placebo-controlled,

add-on trials in patients with refractory epilepsy,adjunctive clobazam was shown to be effective


77

(17, 145–152). In a crossover study of 21 patients,a >50% reduction in seizure frequency wasseen in 52% of patients receiving clobazam (145).In another crossover study, Schmidt et al. (146)reported a seizure frequency reduction of ‡75% in40% of patients receiving adjunctive clobazam.These findings compare favorably with adjunctivetherapy results for many AEDs currently availablein the USA. Clobazam was studied in a largedouble-blind trial as first-line monotherapy inchildren with partial, partial with secondary gen-eralization or primary generalized tonic–clonicseizures and was reported to have efficacy andtolerability similar to that of monotherapy withphenytoin or carbamazepine (153, 154). Seizurefreedom was maintained for the entire 12 monthsof the study for 23%, 25% and 11% of patientsrandomly assigned to receive clobazam, carbamaz-epine and phenytoin respectively.

Clorazepate – The effectiveness of adjunctive clor-azepate for various treatment-resistant seizures hasbeen demonstrated; however, the clinical experi-ence and data available are less extensive forclorazepate than for other BZDs (103). An open-label clinical study of clorazepate therapy sug-gested that the drug might be useful as an add-ontreatment for generalized major and minor seizures(e.g. absence, akinetic and myoclonic) (155). Inthat study, an excellent response (defined ascomplete seizure control or seizure control thatproduced a notable improvement in social, educa-tional or vocational assessment) was observed for19% of patients with major generalized seizures(three of 16), 39% of patients with absence seizures(seven of 18), 33% of patients with akineticseizures (three of nine) and 57% of patients withmyoclonic seizures (four of seven). Other double-blind (156) and open-label (157–159) studies havedemonstrated the efficacy of adjunctive clorazepatefor both partial (simple and complex) and gener-alized seizures.Clorazepate also appears to be useful in child-

hood epilepsy. In an open-label, add-on study,22% of patients with Lennox–Gastaut syndrome(two of nine) had a partial response (<75%reduction in seizure frequency) to clorazepate(158). In an uncontrolled, open-label study of 18children with Lennox–Gastaut syndrome or otherconditions with atypical absence seizures, theauthors stated that five patients (28%) had anexcellent response and eight patients (44%) had agood response to adjunctive clorazepate therapy,although the terms �excellent� and �good� were notclearly defined (160). Other studies have foundgood results with clorazepate in the treatment of

refractory childhood epilepsies. In an open-labelstudy by Naidu et al. (161), 11 children withgeneralized seizures (absence and atonic) whoreceived clorazepate as monotherapy (n = 4) oras adjunctive therapy with valproate (n = 7) had areduction in the number of clinically observedseizures. In another open-label study, clorazepatewas added to standard AEDs in 29 children withvarious seizure disorders; 72% of patients experi-enced improved seizure control (162).

Adverse effects

Although BZDs as a class are well tolerated,clinicians should be aware of potential safety issuesassociated with BZD use. Drowsiness and confu-sion may be indicative of over-sedation, a dose-related extension of the sedative ⁄hypnotic effectsof BZDs (62, 163, 164). Over-sedation is moreproblematic in the elderly than in younger patients,and it may occur at lower doses in the elderly (165,166). Elderly patients treated with BZDs canexperience confusion, amnesia, ataxia and hang-over effects (62). Benzodiazepine use is also asso-ciated with falls, a possible result of over-sedationin elderly patients (167).Benzodiazepines may cause amnesia, particu-

larly anterograde amnesia (168). This effect issometimes deliberately utilized in presurgical med-ication (169). However, memory impairment mayalso be associated with clinical doses of orallyadministered BZDs (168).For individuals who use BZDs long term, the

possible degree of recovery and the extent ofresidual impairment that may remain after thedrugs are withdrawn are unclear (170). In a meta-analysis, Barker et al. (170) concluded that long-term BZD users show recovery of function invisuospatial skills, attention ⁄ concentration, gen-eral intelligence, psychomotor speed and non-verbal memory assessments after withdrawal. Theauthors found, however, that significant cognitiveimpairment was more persistent in long-term usersthan in control groups or in normative data. Theauthors reported that the study data did notdemonstrate complete restoration of functionwithin the first 6 months following discontinuationof BZD use; they suggested that longer than6 months may be needed for recovery from somedeficits.Paradoxical excitement is sometimes associated

with BZD use and may include exacerbation ofseizures in patients with epilepsy (171). Childrenand elderly patients, patients with a history ofalcohol abuse and individuals with a history ofaggressive behavior ⁄anger may be more likely to

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experience paradoxical excitement effects than areother patients (172). Additionally, BZDs can causeor aggravate depression (57).Dependence refers to the compulsion to take a

drug to produce a desired effect or to preventunpleasant effects that occur when the drug iswithheld. Dependence develops in almost one-third of patients who are treated with BZDs for‡4 weeks (173). A withdrawal syndrome upon BZDdiscontinuation (see Tolerance and withdrawalsection) is a common manifestation of BZD depen-dence (173). High BZD dosage and potency, shortduration of BZD action, long duration of therapyand premorbid dependent personality traits are riskfactors for the development of BZD dependence(173). Potent BZDs with relatively short t1 ⁄ 2 (e.g.triazolam, alprazolam and lorazepam) appear tocarry the highest risk of dependence (173).Substantial differences in adverse event occur-

rences associated with the BZDs profiled here havenot been reported in large randomized, controlledtrials comparing BZDs. Some study results havesuggested that diazepammay have greater effects onrespiratory depression than are observed with otherBZDs such as lorazepam andmidazolam (174, 175).Additionally, although BZDs are generally knownto affect memory, some studies have shown thateffects differ depending on the BZD used. Loraze-pam appears to impair both explicit memory andimplicit memory, and although diazepam impairsexplicit memory, results regarding impairment ofimplicit memory by diazepam are mixed (176–179).The adverse event profiles of BZDs should be

considered when decisions are made regardingtherapy. Clinicians should weigh the possiblebenefits of therapy with BZDs against the potentialadverse effects.

Tolerance and withdrawal

Tolerance

Tolerance to AEDs is associated with a progressiveincrease in the number and severity of seizures andan increased risk of withdrawal seizures in thepresence of a constant maintenance dose. Toler-ance to several BZDs has been demonstrated inexperimental epilepsy models (180–185). Becauseof the development of anticonvulsant tolerance,BZDs are generally considered unsuitable for long-term control of epilepsy (57, 186). Increasing theBZD dose may overcome anticonvulsant tolerance.However, tolerance may recur at the higher dose,and adverse effects may persist or worsen.Cross-tolerance between BZDs occurs and

appears to be drug specific. Ramsey-Williams

et al. (187) demonstrated that after 3 weeks ofdiazepam treatment, rats developed cross-toleranceto the anticonvulsant effects of clobazam, clonaze-pam and midazolam. Rats treated with midazolamfor 3 weeks developed cross-tolerance to diazepambut not to clobazam or clonazepam. The authorssuggested that differences in tolerance and cross-tolerance could result from differential regulationof receptor subunit expression by each drug andfrom differences between the drugs in their inter-actions with receptors at the time of testing.When BZDs are used as anticonvulsants, the

time to onset of tolerance varies, and thepotential of a BZD to induce anticonvulsanttolerance does not appear to have any relation-ship with its chemical or pharmacokinetic prop-erties (188). Differences in the development ofanticonvulsant tolerance have been reported forvarious BZDs in an amygdala-kindling ratmodel. Young et al. (185) found that toleranceto clobazam developed within 3 days of initialdrug exposure, whereas tolerance to clonazepamdeveloped gradually over the course of a 19-daystudy. Rosenberg et al. (189) compared theanticonvulsant activity of clonazepam, clobazamand diazepam in rats and found that tolerancedeveloped most rapidly to clobazam and mostslowly to clonazepam.In studies investigating anticonvulsant tolerance,

animals treated with clorazepate exhibited a lateronset or a lesser degree of tolerance than did thosetreated with either diazepam (190–192) or clonaze-pam (184, 192). Nonetheless, clinicians must beaware of the possibility of tolerance with long-termclorazepate administration. In a study comparingclorazepate and clobazam, tolerance was defined asinitial seizure freedom, marked efficacy (‡80%seizure frequency reduction) or efficacy (‡50%seizure frequency reduction) followed by anincrease in seizure frequency to a level greaterthan that seen with initial treatment. Toleranceoccurred in 48% of patients treated with cloraze-pate for ‡4 weeks, but in only 24% of patientstreated with clobazam for ‡3 months (193). How-ever, when the dosage was maintained orincreased, clorazepate once again became effectivein 50% of patients who had previously developedtolerance. Likewise, in 70% of patients who haddeveloped tolerance to clobazam, the drug onceagain became effective with an increased dosage orat the same dosage. The mechanism responsible forsuch reversal of tolerance is unclear.Tolerance to some side effects of BZDs can also

develop. The onset of tolerance to the sedativeeffects of BZDs usually occurs within 1–2 weeks(194, 195). Memory and cognition, however, often


79

remain impaired in patients on long-term BZDtherapy without full recovery (57, 196).The differences in time to onset of tolerance to

the various pharmacologic effects of BZDs suggestthat different mechanisms may be involved (197).One putative mechanism for the development oftolerance is simple down-regulation of GABAreceptors in response to prolonged BZD exposure;however, studies testing this hypothesis havereported mixed results (197). Li et al. (198) sug-gested that down-regulation of BZD receptorbinding sites could not fully explain the develop-ment of tolerance because tolerance to some BZDshas been observed even when no changes in BZD-receptor binding were noted (187).Several other mechanisms for BZD tolerance

have been proposed on the basis of animal and cellculture models. These processes include uncouplingof allosteric linkage between GABA and BZDsites, changes in the turnover of receptor subunitsand changes in receptor gene expression (197).Considering the evidence that tolerance to thevarious behavioral effects of BZDs develops atdifferent rates and that behavioral effects of BZDsare mediated by different GABAA receptor sub-types, Bateson (197) proposed that multiple mech-anisms mediate tolerance and dependence. Hedescribed a unified model of molecular mecha-nisms underlying tolerance that incorporates themolecular processes discussed above. This modelassumes that initial potentiation of the GABAresponse leads to desensitization and that pro-longed desensitization could result in uncoupling(as either a signal for or a consequence of receptorinternalization, i.e. endocytosis). Subsequent toreceptor internalization, degradation of certainreceptor subunits could provide a signal forchanges in GABAA receptor gene transcription.Depending on the receptor subtypes involved, aswell as the brain region and neuronal cell types,this model could account for the temporal differ-ences in the development of tolerance to thedifferent effects of BZDs.The reason for differences in time to tolerance

between the various BZDs is not entirely clear. Theslow onset of tolerance to the anticonvulsant effectof clorazepate could be due to a low degree ofintrinsic activity of DMD at the BZD receptor.Gobbi et al. (199) demonstrated that diazepam andDMD have the same affinity for the central type ofBZD receptors, but when the intrinsic activity ofDMD was calculated, it proved to be a partialagonist, with intrinsic activity approximately 43%that of diazepam.Clinicians should consider the possibility of

tolerance when evaluating response to BZD ther-

apy. Although tolerance may develop more rapidlyto some BZDs than to others, it is important tonote that tolerance generally renders BZDs unsuit-able for long-term control of epilepsy.

Withdrawal

When BZD therapy is discontinued, patients mayexperience recurrence of their original symptoms,rebound (appearance of original symptoms, but ata more intense level) or withdrawal (appearance ofnew symptoms that were not present before treat-ment). Withdrawal symptoms from BZDs rangefrom mild (e.g. insomnia and anxiety) to severe(e.g. seizures and psychosis). Distinguishingbetween symptoms of withdrawal and return ofthe patient�s original symptoms may be difficult.Numerous reports have identified certain predic-

tors of the occurrence or increased severity ofwithdrawal symptoms: higher BZD dose (200–204), longer duration of BZD use (202, 203, 205,206), immediate cessation or rapid tapering of theBZD dose (200, 203, 204, 207–209), history of drugabuse (202, 203), dependence on other drugs (209),personality pathology (e.g. neuroticism and depen-dency) (203) and a diagnosis of panic disorder (203).A number of studies have investigated withdrawalsymptoms associated with the BZDs reviewedherein. Some reports have suggested that BZD t1 ⁄ 2does not influence withdrawal symptoms (208, 210).However, results from other studies have suggestedthat, compared with long-t1 ⁄ 2 BZDs, BZDs withshort t1 ⁄ 2 are associated with faster onset of with-drawal symptoms or more severe withdrawal symp-toms when BZD therapy is stopped abruptly (211,212). In a meta-analysis of seven studies, Hallforsand Saxe (213) found that patients treated withshort-t1 ⁄ 2 BZDs were more likely to experiencerebound anxiety than were patients treated withlong-t1 ⁄ 2 BZDs. Additionally, rebound anxiety wasnoted to develop more rapidly in patients treatedwith short-t1 ⁄ 2 BZDs than in patients treated withlong-t1 ⁄ 2 BZDs. Finally, results from sleep labora-tory studies suggest that rebound insomnia andwithdrawal symptoms are more likely to be associ-ated with BZDs that have a short or intermediatet1 ⁄ 2 than with BZDs that have a longer t1 ⁄ 2, such asdiazepam (214).

Conclusions

Benzodiazepines are indicated for the treatment ofseizure emergencies and epilepsy. They are amongthe most useful AEDs available for treating patientswith status epilepticus or acute repetitive seizures.They have the clinical advantages of being highly

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effective, with a rapid onset of action and relativelylow toxicity. Benzodiazepines can be used in avariety of clinical situations because they can beadministered by several routes and in differentformulations. However, BZDs have shortcomings.Tolerance may develop over time, making BZDsunsuitable for use in long-term epilepsy manage-ment. Additionally, withdrawal symptoms, somesevere, may develop after cessation of BZD therapy.Other shortcomings include adverse events, such ascognitive impairment and sedation, and drug inter-actions. Clorazepate is unique among BZDs in thatit is associatedwith slow onset of tolerance, its activemetabolite has a long t1 ⁄ 2, and it is available as asustained-release formulation, all of which may,theoretically, help minimize adverse effects andwithdrawal symptoms. However, it is important tonote that the clinical experience and available dataare less extensive for clorazepate than for otherBZDs. Studies of clorazepate in patients withepilepsy have mainly been small, open-label inves-tigations. Larger controlled studies are needed tofurther examine the role of clorazepate in thetreatment of patients with epilepsy.

Acknowledgements

We dedicate this review to the memory of John R. Gates, MD,a coauthor, colleague and eminent epileptologist who passedaway during the preparation of the paper. This review wassupported by Ovation Pharmaceuticals, Inc.

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Benzodiazepines in epilepsy: pharmacology and pharmacokinetics