Antiepileptic Drugs, 5th Edition

Benzodiazepines

18

Clinical Efficacy and Use in Epilepsy

Dieter Schmidt MD

Head, Epilepsy Research Group Section, Berlin, Germany

Although the general use of benzodiazepines is increasingly out of favor, mainly because of the development of tolerance, dependence, and withdrawal in this class of drugs, their value for the treatment of epilepsy remains largely unchallenged. Benzodiazepines including diazepam, clonazepam, and lorazepam remain drugs of first choice for the treatment of early status epilepticus (1). In addition, the rectal administration of diazepam has become very useful for the acute treatment of ongoing seizures and serial seizures and for the prevention of febrile seizures (2). Benzodiazepines such as clobazam or clonazepam are very valuable for adjunctive therapy in some patients with refractory epilepsy. The mechanism of action, the chemistry, the biotransformation and pharmacokinetics, and the adverse effects of benzodiazepines are discussed in Chapters 16, 17, and 19, as well as in the literature (3, 4, 5). This chapter deals with the clinical efficacy and the use of clobazam, clonazepam, diazepam, lorazepam, midazolam, and nitrazepam in the short-term and long-term treatment of epilepsy.

CLOBAZAM

Clobazam has a 1,5 substitution instead of the usual 1,4-diazepine structure. The structure results in a reduction of the sedative effects when compared with diazepam in animal studies, without losing its anticonvulsant effect (5). Although it is not promoted commercially, clobazam continues to be widely used by many specialists for epilepsy, for at least two reasons. First, clobazam tablets and capsules are rapidly and highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy, and for controlling nonconvulsive status epilepticus. Second, clobazam is better tolerated than other benzodiazepines. These features have made clobazam an excellent second-line therapy in some patients with resistant epilepsy. The main disadvantage is the development of tolerance in as many as 50% of patients within weeks or months. Clobazam has been marketed in Europe since the 1970s and in Canada since 1988, but it is not available in the United States.

Clinical Efficacy

In nine placebo-controlled add-on trials in refractory epilepsy, clobazam was shown to be very effective as an adjunctive drug, leading to a mean reduction of seizures by 30% in patients with partial seizures unresponsive to other antiepileptic drugs (5). In several studies, a 50% reduction was seen in as many as half of the patients studied (6,7). This finding compares favorably with many of the currently available antiepileptic drugs. In addition, numerous open, single-arm studies were undertaken in patients with secondarily generalized seizures, Lennox-Gastaut syndrome, startle epilepsy, nonconvulsive status epilepticus, electrical status during slow-wave sleep, reflex epilepsies, alcohol withdrawal seizures, and benign childhood partial epilepsies (5). More recently, clobazam was tested in a large double-blind trial as first-line monotherapy in children with newly diagnosed partial epilepsy, and the drug was reported to be similar, in efficacy and tolerability, to monotherapy with phenytoin or carbamazepine (8,9).

Clobazam has a mild anxiolytic effect that is useful for many patients with chronic partial epilepsy. As discussed earlier, the development of tolerance is a clinical problem, and efforts to limit tolerance by drug holidays, treatment on alternate days starting with a low dose, or overcoming loss of efficacy with a higher dose have largely been unsuccessful. In view of the development of tolerance in many patients, it is not surprising that no clear relationship has been found between the serum concentration of clobazam or of the main metabolite and seizure control, and an optimum range of serum concentrations in chronic epilepsy has not been established.

Clinical Use

Clobazam should be considered as adjunctive therapy whenever treatment with a single first-line antiepileptic drug has not led to sufficient seizure control (Table 18.1).

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Although antiepileptic drug choice is to an extent arbitrary, given the lack of pragmatic large-scale trials to establish preference, clobazam is a valuable add-on drug because it is widely effective. In my practice, I use it primarily for patients with partial seizures, in whom it is rapidly effective; one knows, usually within 2 to 3 weeks of prescribing a 10-mg tablet or capsule at night, whether it will work. Clobazam is also a useful adjunctive drug for some patients with other seizures, such as patients with Lennox-Gastaut syndrome or reflex epilepsies. Clobazam can also be used for a short course of maintenance treatment after intravenous (i.v.) benzodiazepines in myoclonic status epilepticus, complex partial status epilepticus, and atypical absence status epilepticus. Furthermore, because of its high efficacy and modest side effects, clobazam is ideal for bridging a short period of increased seizure susceptibility (e.g., during examinations, overnight travel, attending a party, switching antiepileptic drugs). In the patient with catamenial epilepsy, it may be useful. In tonic status epilepticus, seizures may be worsened, and clobazam should be used with care.

TABLE 18.1. CLINICAL USE OF BENZODIAZEPINES IN EPILEPSY

Drug

Clinical Use

Main Advantages

Main Disadvantages

Clobazam

First-line adjunctive therapy for refractory partial and generalized seizures, intermittent therapy, nonconvulsive status epilepticus

Highly effective, better tolerated than other benzodiazepines, rapid onset of action

Tolerance in 50%, withdrawal problems

Clonazepam

Second-line adjunctive therapy in partial and generalized seizures (especially absence and myoclonic seizures), Lennox-Gastaut syndrome, and the premonitory stage of status epilepticus and early status epilepticus

Useful second-line adjunctive drug

Strong sedation, hypersalivation in some patients, tolerance

 

Second-line therapy for established status epilepticus

   

Diazepam

First-line treatment for the premonitory and early stages of status epilepticus (i.v., bolus, or rectal solution). Second-line for established status epilepticus (i.v. infusion)

Highly effective, rapid onset of action, several methods of administration

Sedation, tolerance, withdrawal problems

 

Nonconvulsive status epilepticus

   
 

Intermittent prophylaxis of febrile seizures, and home treatment of acute repetitive seizures (rectal solution or gel)

   

Lorazepam

First-line treatment for the early stage of status epilepticus (i.v. bolus) and for treatment of exit-of-hospital status epilepticus

Longer duration of action than diazepam, can be repeated often, rate of injection less critical

Sedation, frequent and rapid development of tolerance

Midazolam

Second-line treatment for the early stages of) status epilepticus (i.m, i.v. bolus, rectal solution

Effective, rapid onset of action, can be given i.m.

Respiratory depression, sedation

Nitrazepam

Second- to third-line adjunctive therapy in partial and generalized seizures (especially myoclonic seizures and infantile spasms)

Last resort for severe childhood epilepsies

Severe sedation and muscular hypotonia in some patients

i.v., intravenous; i.m., intramuscular.

Common practice use is given, individual preference may vary, and the list of clinical use is not exhaustive (see text).

Clobazam is usually administered orally at a dose of 10 to 20 mg/day, preferably taken at night or in a twice-daily regimen. The only available preparation is a 10-mg tablet or capsule. Higher doses should be generally avoided because the efficacy does not increase, and side effects become more common. If tolerance develops, the drug is slowly withdrawn at a rate of 10 mg per month. Although clobazam is a very well tolerated benzodiazepine at the recommended dosage, general precautions for the use of benzodiazepines apply.

CLONAZEPAM

Clonazepam is one of the oldest benzodiazepines available and is a potent anticonvulsant. Nevertheless, it has largely fallen out of favor for use in chronic epilepsy, mainly because of the development of tolerance, withdrawal symptoms, sedation, and bronchial hypersecretion (4). Clonazepam is still used as a second-line drug in the treatment of status epilepticus, both convulsive and nonconvulsive. In recent years, however, it has largely been superseded by the other benzodiazepines diazepam, midazolam, and lorazepam. Clonazepam was introduced in Europe in the 1970s and is marketed worldwide.

Clinical Efficacy

Clonazepam was introduced before controlled trials became mandatory for evaluation of efficacy and tolerability of

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antiepileptic drugs. It was studied in the 1970s and 1980s in a few, often small controlled clinical trials as adjunctive therapy in patients with partial and generalized seizures unresponsive to standard treatment (4). Clonazepam is a potent antiepileptic drug for adjunctive therapy of generalized absence and myoclonic seizures and also for partial seizures. However, because of sedation, problems during withdrawal, and hypersalivation, it is increasingly used as a second-line adjunctive drug only when better-tolerated adjunctive antiepileptic drugs have not been helpful. It has been evaluated in single-arm studies in partial and generalized epilepsy, and the effects have generally been modest. It has been used in benign rolandic epilepsy and also in epilepsia partialis continua. In the generalized epilepsies, the effectiveness of this drug is similar to that of ethosuximide for absence seizures (4,10), and it can be useful in myoclonic seizures, such as in juvenile myoclonic epilepsy and in Lennox-Gastaut syndrome. Clonazepam is also useful for bridge therapy while antiepileptic drugs are being changed or withdrawn (11). It is still used widely in the treatment of various forms of status epilepticus (Table 18.2). Its indications are the same as for diazepam, and its effectiveness is similar (1). Clonazepam can be given i.v. or as an oral and rectal solution. A few drops of the solution are swallowed as a last resort by some patients to control incipient seizures at home or when these patients are out of the house. Tolerance to the anticonvulsant effects (and the sedative and motor side effects) may occur within days in some patients, whereas in others tolerance to the anticonvulsant effect is seen after weeks and months. The mechanism underlying the development of tolerance remains elusive, and various maneuvers (as described earlier, in the section on clobazam) to overcome or to avoid tolerance are largely ineffective. Clonazepam may impair swallowing of saliva through muscle hypotonia and, as a consequence, may lead to pneumonia in some patients and also to drooling. Withdrawal of clonazepam may present also a problem, despite its long half-life, and it should be done cautiously. My experience is to do this in outpatients at a rate not faster than 0.25 mg per month. Withdrawal symptoms, which may be seen in as many as 50% of patients, include rebound seizures, anxiety, tremor, insomnia, and, in some patients, psychotic episodes. In view of the development of tolerance, it is not surprising that no clear relationship has been found between the serum concentration of clonazepam and seizure control, and an optimum range of serum concentrations in chronic epilepsy has not been established.

TABLE 18.2. COMPARATIVE EFFICACY OF DIAZEPAM AND CLONAZEPAM IN VARIOUS TYPES OF STATUS EPILEPTICUS

 

Diazepam

Clonazepam

Tonic-clonic status epilepticus

177/224 (79%)

21/24 (88%)

Absence status epilepticus

44/72 (61%)

56/67 (84%)

Partial status epilepticus

59/67 (88%)

35/40 (88%)

aSome patients had multiple injections or infusions, and most had additional therapy (1).

Clinical Use

Clonazepam is still used as an adjunctive drug in patients with a wide range of partial and generalized seizures who do not respond to standard treatment and better-tolerated adjunctive therapy (Table 18.1). It is used especially for the long-term treatment of myoclonic seizures and as a short course of maintenance therapy in myoclonic status epilepticus, as well as in atypical absence status epilepticus. Tonic status epilepticus can be worsened by clonazepam. Clonazepam is more widely used in children than in adults. Clonazepam is available as 0.5- and 2-mg tablets and as an oral solution. The initial oral dose is usually 0.25 mg, which is increased gradually to 0.5 mg and, if necessary, <4.0 mg/day, given at night or in twice-daily regimens. In children, the usual maintenance dose is between 1 and 3 mg/day (13).

Clonazepam is also a second-line drug for treatment of convulsive or nonconvulsive status epilepticus, but it has been superseded in many centers by diazepam, midazolam, and lorazepam. As an i.v. bolus, clonazepam is used in early status epilepticus, whereas for established status epilepticus, a short i.v. infusion may be used (1). Clonazepam has a similar onset of action but a longer duration of action and a lower rate of early relapse than diazepam. The drug accumulates during prolonged infusion, leading to hypotension, sedation, and, finally, respiratory arrest. Too rapid an infusion may lead to severe hypotension and syncope, and continuous infusion should be avoided if possible.

The usual preparation for emergency treatment is a 1-mL ampule containing 1 mg clonazepam. For treatment of early status epilepticus, clonazepam is usually given as a 1-mg bolus injection over 1 minute in adults, whereas 0.25 to 0.5 mg may be used in children. This dose can be repeated three times over a period of 3 hours, and clonazepam can also be given very slowly in dextrose (5%) or 0.9% sodium chloride solution (1 to 2 mg in 250 mL). Reduction of epileptiform electroencephalographic activity and a parallel decrease of seizures were seen in children after a single intramuscular (i.m.) injection of 0.02 mg/kg body weight/day (12), a finding suggesting that much lower doses may be useful, at least in some children.

DIAZEPAM

Diazepam is the most widely used benzodiazepine in epilepsy and is a drug of first choice for the treatment of the premonitory stages of status epilepticus, for early status epilepticus, for serial seizures, for prolonged seizures, and

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for the prophylaxis of febrile seizures. The usefulness of diazepam in treatment of status with its well-proven efficacy and rapid onset of action is, however, limited by frequent seizure relapse after initial control by bolus injection and by the unwelcome accumulation after repeated injection or continuous infusion with a risk of sudden respiratory depression, sedation, and hypotension (1,13). The rectal administration of diazepam solutions or gel is convenient, safe, and effective. Use of suppositories, i.m. administration, or long-term oral administration of diazepam is not recommended for treatment of epilepsy because of limited efficacy, poor tolerability, and general risks of this class of drugs. Diazepam was introduced in Europe in the 1970s and is marketed worldwide.

Clinical Efficacy

A single i.v. bolus of diazepam at a dose of 5 to 10 mg at a rate of 1 to 5 mg/min has been reported to stop initial seizure activity in 88% of patients with various seizure types in status epilepticus (2) (Table 18.2). In one study, i.v. diazepam, given as a bolus of 2 mg/min, stopped convulsions in 32% of patients after 3 minutes, in 68% of patients after 5 minutes, and in 80% of patients after 10 minutes (14). When bolus injections failed, a symptomatic cause was often found, such as acute infectious encephalopathies, several cerebral anoxia, and acute cerebral infarction. Seizures were controlled in 76% of the episodes treated with 10 mg diazepam i.v. and in 89% treated with 4 mg lorazepam i.v. in a double-blind study of status epilepticus (15). Both drugs were injected over a period of 2 minutes. Adverse effects occurred in 12.5%, including respiratory depression and sedation. A prospective comparison of i.v. diazepam plus phenytoin versus i.v. phenobarbital in the treatment of status epilepticus found both regimens similarly effective and comparable in safety (16). However, the combination of diazepam with phenobarbital is not recommended (see the later discussion on clinical use). In a large double-blind study of a total of 384 patients with convulsive status epilepticus, i.v. diazepam (0.15 mg/kg body weight) followed by i.v. phenytoin (18 mg/kg) was less effective and less easy to use than i.v. lorazepam and was as efficacious as phenobarbital (17).

The main disadvantages of diazepam (when given alone) are seizure relapse after i.v. injection and accumulation after prolonged infusion (Table 18.1). Seizure relapse is common and limits the usefulness of diazepam in status epilepticus. Only 50% of patients are seizure free 2 hours after a single injection (18): the relapse is caused by diazepam's rapid redistribution, resulting in an abrupt fall of its concentration in the brain, with a significant loss of anticonvulsant effect. Additional treatment is necessary, and numerous proposals have been made including the use of i.v. phenytoin, phenobarbital, lidocaine, and clonazepam (1), as well as a constant infusion of diazepam.

Continuous Infusion

The use of continuous diazepam infusion in patients with refractory status epilepticus was shown to be effective in 12 of 18 patients after failure of a bolus injection of 20 mg diazepam and an i.v. loading of 15 mg/kg phenytoin in the opposite arm (14). When seizures persisted, a continuous infusion of diazepam 4 to 8 mg/hr with 50 mg of diazepam in 500 mL dextrose/water was given for 3 hours. When diazepam is used as an infusion, a maximum of 20 mg should be dissolved and thoroughly mixed in a minimum of 250 mL of solvent. This solution will not precipitate in a 5% to 10% glucose solution or in a 0.9% saline solution. The infusion should be given immediately after mixing, and a large-caliber vein should be used. Significantly, compared with i.v. bolus injection, diazepam by continuous infusion may result in a lower incidence of respiratory depression and hypotension. Early clinical observations in adult patients with refractory status epilepticus reported control of seizures without side effects with continuous diazepam infusions ranging from 10 to 48 mg/day for 12 to 24 hours (18) to 75 to 100 mg/day and 140 to 200 mg /day for 2 to 7 days in adults and 3 to 4 mg /kg/day for 21 hours to 8 days in infants (2,19). Current recommendations for diazepam i.v. infusion for treatment of convulsive status epilepticus are 2 to 3 mg/kg/day in adults and 0.3 to 1.0 mg/kg/day in children (13). However, development of tolerance was noted with infusions lasting longer than 1 day (2). In view of the development of tolerance, it is not surprising that no clear relationship has been found between the serum concentration of diazepam or of its main metabolite and seizure control.

Although limited published data indicate that continuous i.v. infusions of diazepam are safe and effective, critics point out that diazepam accumulates on repeated injections or during continuous infusion, and this accumulation carries a high risk of causing sudden respiratory depression, sedation, and hypotension (1,13). Continuous electroencephalographic monitoring has been recommended to evaluate clinical effectiveness.

Rectal Solution or Gel

Although i.v. administration is the preferred immediate treatment, venous access is often difficult to achieve, and medical personnel may not be immediately available at the site of the emergency. In contrast, the rectal solution or gel of diazepam can immediately be given by parents at home or at any site, and it can be administered by paramedical personnel either for prehospital treatment or in the emergency room. In fact, visits to the emergency room may be reduced, and quality of life may improve.

The rectal solution of diazepam has been effectively used in children for the emergency treatment of ongoing seizures at home (20,21). An initial dose of 0.5 mg/kg was employed

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with a maximum of 20 mg per single dose. The convulsions were stopped within 15 minutes in 80% of the episodes. (20). Side effects occurred in four of 17 children and included temporary respiration difficulties in one patient aged 16 years who was receiving concomitant phenobarbital treatment and who had received 0.5 mg/kg of rectal diazepam. Urticaria and pruritus occurred in two children, and dizziness was noted in one 13-year-old patient.

Improvement in the quality of life was seen in 58% of patients after rectal administration of 0.3 to 0.5 mg/kg injectable solution in one study (21). Emergency room visits decreased, and cost savings were noted. The authors of this report concluded that rectal diazepam appears to be a practical method for the effective treatment of severe seizures at home (20,21). Home use of rectal diazepam solution (0.5 mg/kg) led to prompt cessation of seizures in 15 of 17 families, whereas in two, rectal diazepam was unsuccessful, and hospital treatment was needed (22). Rectal diazepam solution, in a dosage ranging from 0.4 to 1.2 mg/kg, has also been successful in the treatment of convulsions in the children's emergency room. In 71% of 55 children, convulsions ceased within 5 minutes, and in a further 7%, convulsions stopped within 5 to 10 minutes. In 16%, rectal diazepam was ineffective, but there was a rapid response to i.v. diazepam. Convulsions lasting more than 15 minutes could be controlled in only 46% in comparison with 81% for shorter convulsions. Four children had transient respiratory depression (23). In a prospective study, 44 children aged 6 months to 5 years were treated with a rectal solution of diazepam during 59 generalized seizures in a hospital. Diazepam i.v. solution was administered rectally with a disposable plastic syringe and a 6-cm-long plastic tube with a blunt tip. Children aged <3 years received 0.5 to 0.9 mg/kg per dose, whereas children >3 years old were given a dose of 0.6 to 0.8 mg/kg. Rectal diazepam was effective in 80% of the episodes. In 10%, rectal diazepam failed, although i.v. diazepam was effective, and in 10%, treatment with diazepam failed after rectal and i.v. administration. No significant respiration depression or other serious side effects were observed (24). The rapid and reliable anticonvulsant effect of diazepam given rectally makes this regimen a valuable alternative when i.v. administration is not feasible.

Rectal administration is also effective for the prevention of recurrent febrile convulsions. When diazepam solution (in a dose of 5 mg in children aged <3 years and 7.5 mg in those >3 years old) was administered rectally whenever the children's temperature was 38.5°C or more, recurrence rate was 12% compared with 39% for the randomized control group, who received diazepam rectally only for the acute treatment of an ongoing seizure. The risk of subsequent epilepsy was not lowered, however (25). No significant side effects were observed in this study. In another study conducted in Denmark, rectal diazepam (5 mg in children aged <3 years and 7.5 mg in those >3 years old) was given at home every 12 hours in children with previous febrile seizures whenever the children's temperature was 38.5°C or higher. Twenty-three of 89 children had a recurrence within 1 year, and 69 had side effects, none of which was serious. A control group receiving valproic acid suppositories showed a similar recurrence rate of 14 of 80 children. The recurrence rates with both treatments were low compared with figures for untreated controls in Denmark (32%), a finding suggesting that intermittent treatment was effective (26). Successful treatment of febrile seizures at home with rectal diazepam solution in a dose of 5 mg (children weighing <12 kg) or 10 mg (children weighing <12 kg) has been confirmed in a large study in Italy (27).

A single rectal administration of diazepam (20 to 30 mg) has also been used successfully to prevent serial seizures in adult patients with drug-resistant epilepsy who are prone to serial seizures. The onset of effect was noted approximately 10 minutes after drug administration, and the effective dose was 0.50 mg/kg (28,29). Preliminary data indicate that rapid achievement of diazepam serum concentrations of 500 to 700 ng/mL are needed for single-dose seizure control, and concentrations of >150 to 200 ng/mL are necessary for maintenance of seizure control (2).

A rectal diazepam gel became available in the United States in 1998. In several placebo-controlled trials, single and repeated rectal diazepam gel application in a dose of 0.2 to 0.5 mg/kg acutely reduced seizures in children, adolescents, and adults with episodes or clusters of repetitive seizures in a nonmedical or home setting (30, 31, 32, 33, 34). Somnolence was the only remarkable side effect, and respiratory depression was not seen (35). Local tolerability was good. Children received one dose at the onset of acute repetitive seizures and a second dose 4 hours later. Adults received three doses: one dose at seizure onset, and two more doses 4 and 12 hours after onset. Treatment was administered by a caregiver, such as a parent, who had received special training.

Oral Treatment

A single 20-mg oral dose of diazepam significantly reduced the incidence of serial seizures at plasma concentrations of 273±190 (SD) ng/mL (2). Oral intermittent diazepam given as prophylaxis of recurrent febrile seizures showed no difference to placebo (36, 37, 38). After excluding many protocol violators, however, and analyzing children actually receiving diazepam, investigators found a statistically significant reduction in the risk of febrile seizures (39). Oral diazepam is rarely used and is not recommended for the long-term treatment of epilepsy (2,13). Controlled trials showed that diazepam is less effective than phenytoin or phenobarbital for the treatment of generalized tonic-clonic seizures and is about as effective as pheneturide, a now obsolete agent, for the treatment of partial seizures (2). Sharing the fate of oral diazepam, clorazepate, a prodrug that is converted to the active antiepileptic drug N-desmethyldiazepam, is only rarely used for the treatment of epilepsy (40).

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Clinical Use

Diazepam is a drug of first choice to treat the premonitory stage of status epilepticus and early status epilepticus, serial seizures, and ongoing acute seizures (Table 18.2). Diazepam, i.v. at a dose of 10 to 20 mg, given at a rate of 1 to 5 mg/min, is an effective and safe first-line emergency treatment of the premonitory stage of status epilepticus and early status epilepticus in adults. In children, the dose is 0.25 to 0.5 mg/kg at a rate of 1 to 5 mg/min. Administration can be repeated once after 15 minutes if status epilepticus continues. When diazepam is injected slowly, side effects are rare in patients without risk factors. Resuscitation because of respiratory or cardiovascular depression is rarely necessary, but it should be available when risk factors are present. These factors include the following: rapid bolus injection; pretreatment with sedative drugs (e.g., phenobarbital); advanced heart, lung, or liver disease; and status epilepticus secondary to acute brain disease. If seizures continue after 30 minutes, infusion of diazepam is a second-line option in established status epilepticus. Alternative and preferred options include i.v. infusion of phenobarbital, phenytoin, or fosphenytoin (1,2,13). If diazepam infusion is used, preliminary experience suggests that an initial loading dose of 20 mg should be administered to control the seizures temporarily in an adult patient in an intensive care unit, followed by a continuous i.v. infusion of diazepam 2 mg/kg/day. The rate of infusion should be determined clinically; monitoring of plasma diazepam and N-desmethyldiazepam concentrations may be useful to detect accumulation, and close supervision of safety and tolerability (e.g., sudden respiratory depression and hypotension) and intensive videoelectroencephalographic monitory are strongly recommended. As pointed out earlier, accumulation may occur and may lead to sudden respiratory depression. If diazepam or alternative regimens including phenytoin or phenobarbital are not effective and status epilepticus continues for 1 hour, general anesthesia and muscle relaxants should be given (1).

When the i.v. route cannot be accessed without delay, the rectal administration of diazepam solution is the procedure of choice. Rectal diazepam is effective and safe for the immediate home treatment of prolonged seizures and serial seizures and for the initial treatment of status epilepticus. Furthermore, rectal diazepam is effective and safe for intermittent prophylaxis of febrile seizures and serial seizures.

Diazepam suppositories and i.m. and oral diazepam are not suited for emergency treatment. Oral diazepam may be clinically useful after i.v. use for a short course of maintenance therapy of myoclonic status epilepticus and complex partial status epilepticus. Diazepam can worsen tonic status epilepticus and should be used with caution. The possible teratogenic effect and the development of sedation and possibly a withdrawal syndrome in the neonate suggest a critical benefit: risk evaluation before diazepam is used during pregnancy. Although nursing is not generally discouraged, it may result in neonatal plasma concentrations in the range of 30% to 75% of the serum concentration of nursing mothers. Long-term diazepam exposure is fraught with the risk of overdose, dependence, and withdrawal, as well as poor efficacy because of the development of tolerance. Therefore, long-term use of this drug is neither safe nor effective for the treatment of chronic epilepsy, nor is it recommended for the prophylaxis of febrile seizures. The recommended rectal dose is 10 to 30 mg in adults, 0.5 to 0.75 mg/kg in children aged 2 to 5 years, 0.3 mg/kg in children aged 6 to 10 years, and 0.2 mg/kg in children aged <12 years. The administration can be repeated. If the rectal administration is not retained because of mucosal irritation, the dose should be repeated immediately. Training of relatives or nonmedical persons is recommended. One should keep the tube pressed together during extraction; resucking of the drug back into the tube is avoided.

The usual dosage of an i.v. bolus injection of undiluted drug is 10 to 20 mg in adults and 0.25 to 0.5 mg/kg in children at a rate of 1 to 5 mg/min. The bolus can be repeated at intervals of at least 15 minutes. If seizures persist in a patient with refractory status epilepticus in an intensive care unit, a continuous i.v. infusion of diazepam 2 mg/kg/day is one option. The rate of infusion should be clinical, and close supervision of safety and tolerability is strongly recommended.

LORAZEPAM

Lorazepam is considered by many physicians the preferred drug for the treatment of the early stage of status epilepticus. It has a longer duration of action and a smaller risk of respiratory depression and hypotension than diazepam (1). It has also been used for refractory status epilepticus.

Clinical Efficacy

Lorazepam was compared with diazepam for the treatment of status epilepticus, serial seizures, and ongoing acute seizures (3). Seizures were controlled in 76% of the episodes treated with 10 mg diazepam i.v. and in 89% of those treated with 4 mg lorazepam i.v. in a double-blind study of status epilepticus (15). The efficacy of lorazepam (4 to 10 mg i.v.) and of clonazepam (1 mg i.v.) was comparable in an early series of 64 patients with status epilepticus (41). Lorazepam was more effective than diazepam in patients with other epileptic seizures excluding generalized tonic-clonic seizures. Twelve percent of these seizure types were not controlled by lorazepam, and 32% of the episodes were not controlled by diazepam. In a large double-blind study of a total of 384 patients with convulsive status epilepticus, lorazepam (in an i.v. dose of 0.1 mg/kg and a maximal rate of administration of 2 mg/min) was more effective than

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phenytoin and was as efficacious as and easier to use than phenobarbital or a combination of diazepam and phenytoin (17). More clinical experience is needed to determine whether lorazepam can replace diazepam or phenytoin in the treatment of status epilepticus, but results from these studies (17,41) indicate that lorazepam is at least as effective as diazepam or the combination of diazepam and phenytoin in the initial treatment of status epilepticus. In a open, randomized study in children, lorazepam and diazepam were similarly effective in stopping acute seizures, but lorazepam caused respiratory depression less often, and no patient receiving lorazepam required admission to the intensive care unit for either respiratory depression or persisting status epilepticus (42), a finding confirming earlier observations that the rate of endotracheal intubation may be lower when lorazepam rather than diazepam is used for treatment of status epilepticus in children (43). Lorazepam, in high doses ranging up to 9 mg/hr, has also been used as an alternative to pentobarbital for treatment of refractory status epilepticus (44). There is large clinical experience with lorazepam in newborns, children, and adults. In a short-term placebo-controlled trial, 1 mg twice daily of oral lorazepam was effective as adjunctive therapy for partial seizures unresponsive to standard antiepileptic drugs (45).

In a recent comparison of 2 mg i.v. lorazepam, 5 mg i.v. diazepam and placebo for the treatment of out-of-hospital treatment of status epilepticus, both drugs were safe and more effective than placebo when administered by paramedics in adults with prolonged or repetitive generalize convulsive seizures (45a). An identical second injection was given if needed. Status epilepticus had been terminated in more patients treated with lorazepam (59.1%) or diazepam (42.6%) than patients given placebo (21.1%). The odds ratio for termination of status epilepticus at arrival was 1.9 (95% confidence interval, 0.8 to 4.4) in the lorazepam group as compared to the diazepam group. The rates of respiratory or circulatory complications after the study treatment had been administered were 10.6% for the lorazepam group, 10.3% for the diazepam group, and 22.5% for the placebo group. The authors concluded that lorazepam was likely to be a better therapy than diazepam for paramedic treatment of out-of-hospital status epilepticus in adults.

Clinical Use

An i.v. bolus of lorazepam is primarily used for the early treatment of status epilepticus as an alternative to diazepam (Table 18.1). During subsequent management, additional antiepileptic drugs are necessary because tolerance may develop within 24 hours The clearance of lorazepam is largely unaffected by mild to moderate renal and liver disease. Lorazepam is rarely used for oral treatment in epilepsy. The usual dosage of lorazepam in adults is an i.v. bolus of 0.07 mg/kg, usually 4 mg, repeated after 10 minutes if necessary; in children, a bolus of 0.1 mg/kg is recommended. The rate of injection should not exceed 1 mg/min.

MIDAZOLAM

Midazolam, as an i.v. bolus or as an i.m. or rectal solution, has been used as an alternative to diazepam or lorazepam for the treatment of the premonitory stage of status epilepticus and of early status epilepticus. It is more water soluble than diazepam and is rapidly absorbed after i.m., nasal, and buccal administration (46,47). Midazolam can be used when i.v. administration is inconvenient or is not possible.

Clinical Efficacy

Comparisons of buccal and i.m. midazolam with rectal diazepam have shown similar efficacy and onset of action (47). Midazolam i.m. is as effective as i.v. diazepam in stopping ongoing seizures, but it may have a faster onset of action (48). There is limited clinical experience with the use of midazolam in the treatment of status epilepticus in children and adults both for initial treatment and for infusion in refractory status. Cardiovascular depression, hypotension, and apnea have been reported requiring intubation for artificial respiration (49).

Clinical Use

Like diazepam, midazolam is short acting, and additional antiepileptic drugs are necessary in the management of status epilepticus to prevent relapse of seizures (Table 18.1). As with diazepam, the half-life of midazolam is prolonged in severe hepatic disease, and a 50% lower dose should be given. The usual dosage for i.m. injection is 5 to 10 mg in adults and 0.15 to 0.3 mg/kg in children; this can be repeated once. The i.v. bolus is 0.1 to 0.3 mg/kg, at a rate not exceeding 2 mg/min, which can also be repeated once. For buccal instillation, 10 mg can be given by catheter and syringe in children and adults.

NITRAZEPAM

Nitrazepam is largely confined to second-line or third-line treatment of severe childhood epilepsies, mainly West's syndrome (Table 18.1). Although quite effective, it is rarely used nowadays because of severe, and in some patients intolerable, drowsiness, ataxia, increase in bronchial secretions, hypersalivation (from nitrazepam-induced hypotonia of the muscles involved in the swallowing of saliva), and aspiration pneumonia in some patients (50). Nitrazepam has largely been superseded in the treatment of infantile spasms (West's syndrome) by vigabatrin, valproate, steroids, or adrenocorticotropic hormone.

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Clinical Efficacy and Use

Nitrazepam was introduced to the market at a time when controlled trials were not generally required for evaluation of efficacy. Nitrazepam seems to be effective for infantile spasms, in which it is associated with a response of 52% to 68% and fewer side effects compared with high-dose adrenocorticotropic hormone. The drug is also used as adjunctive therapy in the severe symptomatic generalized epilepsies such as Lennox-Gastaut syndrome and in severe myoclonic epilepsies. The unfavorable side effect profile precludes the wide use of nitrazepam, except for patients in whom standard therapy and better-tolerated second-line drugs have been ineffective. Apart from the dose-related side effects discussed earlier, leukopenia may occur, and sudden withdrawal may result in rebound seizures and delirium tremens. The usual dosage is <1 mg/kg/day in children and <0.5 mg/kg/day in adults. In most patients, the dose is between 1.25 and 10 mg/day.

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