Benzodiazepines bind to an allosteric site on the neuronal GABA_A receptor, a ligand-gated chloride channel, and enhance chloride conductance to hyperpolarize the neuronal membrane, thus augmenting inhibitory neurotransmission. Their high lipid solubility results in rapid central nervous system (CNS) penetration and they are particularly useful as first-line agents in the management of status epilepticus and seizures occurring repetitively in clusters. Their effectiveness in the chronic treatment of epilepsy is limited by their behavioral effects and their propensity for tolerance in patients with intractable epilepsy.

CHEMISTRY, PHARMACOLOGY, AND MECHANISM OF ACTION

The base compound is a 5-aryl-1,4-benzodiazepine structure composed of three ring systems. Modifications in the structure of the ring system have resulted in several compounds with antiepileptic activity but with different efficacy and side effect profiles. A 1-5-benzodiazepine, clobazam, was approved four decades ago in other countries, but has become available in the United States only recently (Figure 50.1). Benzodiazepines augment inhibitory neurotransmission by enhancing the activity of GABA at the GABA_A receptor (1). When GABA binds to the GABA_A receptor, it increases the frequency of openings of the chloride ion channel, which results in hyperpolarization of the membrane and a reduction in neuronal firing (2). Although benzodiazepines bind to an allosteric site on the GABA_A receptor, they do not activate it directly but rather modulate GABA binding and enhance the effect of GABA by increasing the frequency (not duration) of the chloride ion channel opening. This increases the inhibitory tone at GABA synapses, which limits neuronal firing and in turn reduces seizure activity (1). Benzodiazepines raise the seizure threshold, decrease the duration of epileptiform discharges, and limit their spread (3).

The action of benzodiazepines on the GABA receptor may be influenced both by the maturity of the brain and by disease. GABA synapses are present before glutamate synapses in early fetal development, and it has been suggested that GABA acts as the primary excitatory neurotransmitter in the immature brain (4). The potassium chloride transport that removes chloride ions is not expressed until later in development, enabling chloride ions to accumulate intracellularly, resulting in GABA synapses that are excitatory (4). The exact timing of the switch from GABA excitatory action to inhibitory action is not known but is believed to occur in utero (4). It has been hypothesized that the excitatory action of GABA in early development modulates neuronal migration and differentiation, and it has been suggested that benzodiazepine use in early pregnancy may have detrimental effects on fetal brain maturation (4).

ADVERSE EFFECTS

Toxicity

Respiratory and cardiovascular depression are the most common adverse effects of benzodiazepines used intravenously. Propylene glycol is a solvent used with intravenous diazepam and lorazepam, but not midazolam, and plays a major role in the respiratory depression associated with the first two drugs (5). Comedication with phenobarbital may exacerbate the cardiovascular and respiratory depression.

Chronic treatment with a benzodiazepine may be associated with sedation, fatigue, ataxia, cognitive dysfunction, drooling, and exacerbation of seizures. Abrupt discontinuation may lead to withdrawal symptoms. Headache and gastrointestinal symptoms can occur but are uncommon. Hematologic abnormalities, hepatic dysfunction, and allergic reactions are uncommon.

Tolerance

Although tolerance probably occurs with all antiepileptic drugs (6), it happens more often with benzodiazepines. The degree of tolerance in animal models is proportional to the agonist efficacy of the benzodiazepine (7). Tolerance to one benzodiazepine does not necessarily result in tolerance to the others (8). The mechanisms underlying tolerance are not clear but may involve downregulation of GABA_A receptors, altered postsynaptic sensitivity to GABA, or modification in the expression of genes that encode for the various GABA_A receptor subunits (9). Recent studies suggest that the interaction of benzodiazepines with the α1 subunit of the GABA receptor may play an important role (10,11).

FIGURE 50.1 Chemical structure of benzodiazepines.

The incidence of tolerance to the antiepileptic effect of benzodiazepines is influenced by the type and severity of the epilepsy. Thus, tolerance to clonazepam is observed much less often in patients with typical absence seizures than in patients with West syndrome or Lennox–Gastaut syndrome (LGS) (12). Similarly, tolerance to clobazam has been reported in 18% to 65% of patients in open studies (13–15), whereas in children who had been previously untreated or who had received only one drug (16), the incidence of tolerance to clobazam (8%) was similar to tolerance to carbamazepine (4%) and phenytoin (7%). This may also be related to the greater binding affinity of clobazam and its active metabolite N-desmethylclobazam to the α2 subunit of the GABA receptor over the α1 (17). Likewise, the intrinsic activity of binding to α1-containing receptors in vitro appears to be smaller than for those containing other α subunits (18).

INDIVIDUAL BENZODIAZEPINES

The use of benzodiazepines in status epilepticus and in the prevention of seizures is outlined in Tables 50.1 and 50.2, respectively.

Diazepam

Biotransformation, Pharmacokinetics, and Interactions

Rectal diazepam is absorbed via hemorrhoidal veins and then rapidly crosses the blood–brain barrier. Therapeutic blood levels are achieved within 5 minutes and peak levels within 20 minutes (19). Plasma concentrations of 500 ng/mL of diazepam, which are necessary for acute seizure control, were achieved in infants and children within 2 to 6 minutes following rectal administration of 0.5 to 1 mg/kg (20). Diazepam is absorbed more slowly following oral or intramuscular administration, and these routes are not recommended. Plasma levels decrease by as much as 50% within 20 to 30 minutes after a single bolus injection (19). This short duration of action following intravenous administration relates to its rapid distribution into fat tissue and to the high protein binding of diazepam.

Diazepam undergoes demethylation to N-desmethyldiazepam, a major metabolite that itself has significant antiepileptic and sedative properties (20). Diazepam and N-desmethyldiazepam are both highly protein bound to albumin (20). The elimination half-life of diazepam is 10 ± 2 hours in infants and 17 ± 3 hours in older children (20). The elimination half-life of N-desmethyldiazepam is longer than that of diazepam, and serum concentrations are two to five times higher in patients receiving long-term treatment (20). The metabolites of diazepam are conjugated with glucuronic acid in the liver and excreted by the kidney.

Diazepam does not significantly influence the pharmacokinetics of other drugs. Valproate comedication decreases protein binding and inhibits the metabolism of diazepam (21), which may result in increased sedation.

Clinical Efficacy

Diazepam is effective in the treatment of both convulsive and nonconvulsive status epilepticus and of acute repetitive seizures. Clinical effect is observed, usually within 10 minutes of intravenous administration, which is the optimal route for the treatment of status epilepticus (19,22). The rapid redistribution following a single dose results in an abrupt decline in brain concentration and reduction in the anticonvulsant effect. Consequently, a long-acting anticonvulsant, for example, phenytoin, should be administered concomitantly in children with status epilepticus. Rectal diazepam is absorbed rapidly, which may be useful in small children in whom intravenous access may be difficult. Limited data suggest continuous diazepam infusion may be effective in the treatment of refractory status epilepticus in children (23–25).

TABLE 50.1

TABLE 50.2

Rectal diazepam gel has been shown to be effective and safe in the management of children with prolonged or acute repetitive seizures (26). Sedation was the most common side effect, but no episodes of serious respiratory depression have been reported. Rectal administration can be performed by the parent, which permits treatment at home, decreases emergency room visits, and improves caregivers’ global evaluation (27). This is of particular value for children with a history of prolonged seizures (28).

Both oral (29) and rectal diazepam (30) administered intermittently at times of fever have been demonstrated in placebo-controlled studies to be effective in the prevention of recurrent febrile convulsions. Rectal diazepam was as effective as continuous phenobarbital in the prevention of recurrent febrile seizures (31). The potential toxicities associated with antiepileptic drug therapy have generally been considered to outweigh the relatively minor risks associated with simple febrile seizures (32). However, intermittent diazepam may be of value in children who have had a previous prolonged febrile seizure.

Childhood-onset encephalopathies associated with sleep-activated electroencephalographic (EEG) abnormalities may respond to oral diazepam at high doses (33–35). Oral diazepam (0.5 mg/kg) for 3 to 4 weeks following a rectal diazepam bolus of 1 mg/kg has been reported to be effective in electrical status epilepticus in sleep (ESES) (36). Oral diazepam at a dose of 0.5 mg/kg given 30 minutes before hemodialysis was effective in the prevention of hemodialysis-associated seizures in four children who had failed to respond to phenobarbital (37).

Adverse Effects

Sedation and ataxia occur commonly when diazepam is used in the treatment of status epilepticus or in the prevention of recurrent febrile convulsions. Respiratory depression and hypotension may occur following intravenous diazepam, particularly if administered rapidly or used in combination with phenobarbital (20), but are extremely rare following rectal diazepam (38). Mild thrombophlebitis may occur following intravenous administration, particularly if diazepam is mixed with a saline solution or is injected rapidly (20). Diazepam may induce tonic status epilepticus in children with epileptic encephalopathies (39). Intermittent oral diazepam prophylaxis has been associated with ataxia, sedation, lethargy, and irritability (40).

Clinical Use

In the treatment of children with status epilepticus, an initial intravenous dose of 0.2 to 0.3 mg/kg (maximum dose: 5 mg in infants and 10 mg in older children) of diazepam should be given slowly over 2 to 5 minutes (20). If needed, the dose may be repeated after 5 minutes. When intravenous access is not available, a rectal dose of 0.5 mg/kg has been used to a maximum of 20 mg (41,42). In refractory status epilepticus, continuous diazepam infusion has been used successfully (23). Treatment was initiated at 0.01 mg/kg/min and increased by 0.005 mg/kg/min every 15 minutes until seizures were controlled, or to a maximum dosage of 0.03 mg/kg/min. A subsequent report has described an infusion rate of up to 0.08 mg/kg/min (21). Diazepam may precipitate when the intravenous solution is administered in saline solution, and it may adsorb to polyvinyl tubing. Consequently, fresh solution should be prepared every 6 hours when continuous diazepam infusion is being used (43).

Rectal administration of diazepam should be considered when intravenous access cannot be obtained and when administration by a caregiver may be helpful, for example, when a child with a history of prolonged seizures lives far from medical services. The injectable solution can be administered rectally through a soft plastic intravenous catheter, and doses of 0.5 mg/kg have been reported to be effective in a prehospital setting with a maximum dose of 20 mg (19). Rectal diazepam gel (Diastat®) is available in unit doses of 5, 10, 15, and 20 mg and is easier to handle, faster to administer, and decreases the chance of dosing errors. Rectal doses of 0.5 mg/kg for children 2 to 5 years of age; 0.3 mg/kg between 6 and 11 years of age; and 0.2 mg/kg above 12 years to a maximum of 20 mg have been used successfully (44,45). A second dose may be repeated in 4 to 12 hours, if needed. If administered at home, caregivers should be given instructions as to when they should seek medical attention. The suggested dosage of oral or rectal diazepam used for febrile seizure prophylaxis is 5 mg every 8 hours when the rectal temperature is higher than 38.5°C, with a maximum of four consecutive doses to avoid drug accumulation (31).

Lorazepam

Biotransformation, Pharmacokinetics, and Interactions

Lorazepam is a 1,4-benzodiazpine that is metabolized rapidly through hepatic glucuronidation and is excreted by the kidneys (46). It is absorbed more rapidly when administered sublingually than orally or intramuscularly, and peak plasma levels are achieved within 60 minutes (47). The rectal absorption of lorazepam parenteral solution is slow and peak concentrations, which may not be reached for 1 to 2 hours, are much lower than those achieved following intravenous administration (48). First-pass hepatic transformation decreases the absolute systemic availability of oral lorazepam to 29% of that following intravenous administration (49). Lorazepam is 90% protein bound and rapidly crosses the blood–brain barrier. The maximal EEG effect of intravenous lorazepam is observed approximately 30 minutes after infusion, which is later than with intravenous diazepam, probably as a result of slower entry into the brain (50). Following intravenous administration, there is a rapid fall in blood levels because of the distribution phase. The elimination half-life is 10.5 ± 2.9 hours in children (51) but is longer in neonates (52). Less than 1% is excreted unchanged in the urine.

The clearance of lorazepam is not influenced by acute viral hepatitis (53) or renal disease (54). However, valproate reduces the clearance of lorazepam, possibly as a consequence of inhibition of glucuronidation (55). There are no other significant interactions with antiepileptic drugs (47), and, in contrast to other benzodiazepines, protein binding of lorazepam is not influenced by heparin (56).

Clinical Efficacy

Intravenous lorazepam has been shown to be more effective than intravenous diazepam in the treatment of status epilepticus; it has fewer side effects and has a longer duration of action (57,58). However, a more recent prospective randomized trial reported no significant difference between intravenous lorazepam and intravenous diazepam plus phenytoin in terms of median time to seizure termination (59). A Cochrane Review reported intravenous lorazepam to be at least as effective as intravenous diazepam and associated with fewer adverse events in the treatment of acute tonic–clonic convulsions (60). Children receiving long-term therapy with another benzodiazepine are less responsive to lorazepam in status epilepticus (61). Sublingual lorazepam has also been shown to be a convenient and effective treatment of serial seizures in children (62). A randomized controlled trial reported rectal diazepam to be more effective than sublingual lorazepam for cessation of prolonged seizures in children under 10 years of age (63). Intravenous or sublingual lorazepam was completely effective in preventing seizures in 29 children receiving high dose busulfan treatment (64). Lorazepam has also been reported to be useful in the treatment of postanoxic myoclonus (65).

Adverse Effects

Sedation is the most common side effect of lorazepam, and ataxia, psychomotor slowing, and agitation may also occur. Respiratory depression may occur but less often than with diazepam (57). The treatment of serial seizures with lorazepam has been associated with drowsiness, ataxia, nausea, and hyperactivity (62). Abrupt discontinuation of lorazepam has been associated with withdrawal seizures, which may occur up to 60 hours following its discontinuation (47). Lorazepam has been reported to cause tonic seizures in patients being treated for atypical absence status epilepticus (66–68). However, this effect is not common and the case reports have considered the reaction to be paradoxical.

Clinical Use

The recommended intravenous dose of lorazepam in children is 0.1 mg/kg (maximum dose: 4 mg) (22). The intravenous rate of administration should not exceed 2 mg/min. The dose can be repeated if necessary after 5 minutes. The risk of respiratory depression increases with greater than two doses of benzodiazepines. Sublingual doses of 0.05 to 0.15 mg/kg were effective in 8 of 10 children with serial seizures (62).

Midazolam

Biotransformation, Pharmacokinetics, and Interactions

Midazolam is a 1,4-benzodiazepine with a fused imidazole ring. Prior to administration, the benzodiazepine ring of midazolam is open and is water-soluble. However, following administration, the benzodiazepine ring closes at physiologic pH and midazolam becomes lipid-soluble (Figure 50.2). These characteristics permit absorption via the intramuscular route (with less pain at the injection site) and rapid transport across the blood–brain barrier. The absorption of intramuscular midazolam is rapid with 80% to 100% bioavailability, and peak blood levels are obtained after approximately 25 minutes (69). Pharmacologic effects are observed within 5 to 15 minutes but may not be maximal for 20 to 60 minutes (70). Intranasal absorption of midazolam also occurs rapidly, with mean time to seizure control of 3.5 minutes (range, 2.5–5.0 minutes) (71). Oral midazolam is absorbed relatively rapidly, with peak blood levels being achieved within 1 hour, but first-pass metabolism in the liver limits the availability to 40% to 50% of the oral dose. It is distributed rapidly and possesses a short elimination half-life (1.5–3 hours) in children. The relatively short half-life makes it less likely to accumulate and therefore more suitable for continuous infusion than diazepam or lorazepam. A longer half-life (6.5 hours) has been observed in critically ill neonates (72).

FIGURE 50.2 pH dependence and midazolam structure.

Midazolam is highly protein bound (96%–98%) and is metabolized extensively by the cytochrome P4503A4 enzyme system. Its metabolism is induced by phenytoin and carbamazepine (73). Medications that inhibit the activity of cytochrome P4503A4, for example, erythromycin and clarithromycin, may prolong the half-life of midazolam (74). Renal failure does not influence the pharmacokinetics of midazolam (75).

Clinical Efficacy

Intravenous midazolam was effective in the treatment of refractory status epilepticus in 43 of 44 children in two studies (76,77). The mean infusion rates in these two studies were 2.0 and 2.3 mcg/kg/min, with a maximum rate in one study of 18 mcg/kg/min. Midazolam appears to be as effective in stopping refractory status epilepticus as pentobarbital or thiopental and is associated with fewer adverse effects (78,79). Continuous intravenous midazolam infusion was as effective as continuous diazepam infusion in stopping refractory status epilepticus but was associated with a higher incidence of seizure recurrence (24). Continuous midazolam infusion was also effective in stopping refractory nonconvulsive status epilepticus in 82% of episodes but breakthrough seizures, which could only be detected by EEG in most patients, occurred in approximately one-half of the patients (80). Midazolam administered by continuous intravenous infusion (1.6–6.6 mcg/kg/min) was effective in controlling seizures refractory to phenobarbital in four of six neonates and was well tolerated (81).

The high water solubility of midazolam permits administration by a variety of routes. Intramuscular midazolam (15 mg) had a comparable effect to intravenous diazepam (20 mg) in the suppression of interictal spikes in adults within 5 minutes (82). Intramuscular midazolam was effective in stopping 64 of 69 prolonged seizures occurring in 48 children (83). A prospective study reported intramuscular midazolam to be more efficacious than intravenous diazepam in the treatment of acute seizures, with a faster cessation of seizures because of more rapid administration (84). In another randomized control trial, intramuscular midazolam was equally effective as rectal diazepam in controlling status epilepticus in children (85). That pediatric study followed publication of the original Rapid Anticonvulsant Medication Prior to Arrival Trial (RAMPARTS) that established the importance of the speed of administration by the intramuscular route compared to the intravenous route (86).

Buccal midazolam is increasingly being reported to be an effective and safe treatment for prolonged seizures in children (87–89). Three randomized trials have reported buccal midazolam to be as effective as rectal diazepam in terminating prolonged acute seizures in pediatric patients (90–92). Buccal midazolam was also associated with a similar or shorter response time to seizure control when compared to rectal diazepam. Buccal midazolam was reported to have a lower treatment failure rate when compared to rectal diazepam (91). In another multicenter, randomized controlled trial, buccal midazolam was reported to be more effective and faster than rectal diazepam in stopping seizures in children over 6 months of age presenting to the hospital without intravenous access (93). Buccal midazolam was not associated with an increased risk of respiratory depression. A randomized controlled trial comparing buccal midazolam to intravenous diazepam reported similar response rates in seizure control (94). In this study, the mean time for controlling seizures after administration of the drug was significantly less with intravenous diazepam but the mean time to administer the drug was faster in the buccal midazolam group. This resulted in the mean time for controlling seizures to be significantly less with buccal midazolam. A meta-analysis study reported nonintravenous (intranasal, buccal, intramuscular) midazolam to be as effective as intravenous diazepam in terminating status epilepticus in children and adults (95). Recent literature suggests that buccal midazolam is effective, safe, and easy to administer and should be considered for use in acute seizure treatment outside the emergency department by paramedics and caregivers where no intravenous access is available (87–89,96).

Intranasal administration of midazolam was less effective than intravenous diazepam in one study (97) but stopped prolonged febrile seizures more rapidly in another study (98). In addition, the time to seizure cessation was shorter with intranasal midazolam than with rectal diazepam, and parents felt that the intranasal route was a more favorable means of medication administration (99). Two further studies reported intranasal midazolam to be at least as effective as rectal diazepam in seizure cessation (100,101). There have not been any comparative trials of intranasal midazolam versus buccal midazolam for treatment of prolonged seizures in children. A preparation of intranasal midazolam is undergoing clinical trials in the United States.

Adverse Effects

Drowsiness and ataxia are the most common side effects. Apnea and hypotension may occur following rapid intravenous administration of a bolus of midazolam, but apnea has been reported in only one patient following intramuscular midazolam (84). Thrombophlebitis occurs less often than with diazepam (102). Paradoxical reactions including agitation, restlessness, and hyperactivity have been reported (103). Common adverse events in children receiving buccal midazolam include sedation, somnolence, depressed consciousness levels, nausea, and vomiting (88,91). Midazolam should be used with caution in patients with chronic renal failure, chronic respiratory insufficiency, and impaired hepatic or cardiac function (88).

Clinical Use

An initial intravenous bolus dose of 0.15 mg/kg (76,77) may be followed by continuous infusion at an initial rate of 1 mcg/kg/min, which may be increased subsequently by 1 mcg/kg/min every 15 minutes to achieve seizure control. Seizures are controlled at infusion rates less than 3 mcg/kg/min in most children, but rates up to 18 mcg/kg/min have been described (77). Intramuscular administration results in complete and rapid absorption and is particularly useful if intravenous access is not available or is difficult to obtain quickly. An intramuscular dose of 0.2 mg/kg has been used effectively in children (83). Intranasal and buccal midazolam are safe, effective, and easy to administer, making these routes particularly useful in the home setting. The usual dose is 0.2 to 0.3 mg/kg, maximum dose 10 mg.

Clobazam

Biotransformation, Pharmacokinetics, and Interactions

Clobazam differs from the 1, 4-benzodiazepines by the presence of a nitrogen atom in the 1 and 5 positions of the diazepine ring (Figure 50.1). It exerts its anticonvulsant effect by binding allosterically to the GABA_A receptor. Clobazam binds between the α₂ and γ₂ subunits on the GABA_A receptor, instead of the α₁ and γ₂ subunit like other benzodiazepines. The relative selectivity for the α₂ subunits decreases its likelihood of causing sedation and may also explain the decreased tendency for the development of efficacy tolerance with clobazam compared to other benzodiazepines (104) [Also cite: (17,18)].

Clobazam is relatively insoluble and cannot be administered intravenously or intramuscularly. Oral clobazam is absorbed rapidly, and peak concentrations are reached in 1 to 4 hours (105). It is highly lipophilic, distributed rapidly, and approximately 85% protein bound. Factors that influence protein binding, for example, liver disease, may affect the free and total levels of the drug (106). Clobazam is metabolized extensively in the liver via the cytochrome P450 pathway to several metabolites including N-desmethylclobazam, which also has antiepileptic activity. The elimination half-life of clobazam is 18 hours, and that of N-desmethylclobazam is 42 hours (106). Thus, blood levels of N-desmethylclobazam are approximately 10 times those of clobazam (107), and N-desmethylclobazam is considered to be responsible for most of the antiepileptic effect in patients receiving clobazam (106).

Comedication with phenytoin, phenobarbital, or carbamazepine increases the N-desmethylclobazam:clobazam ratio (108). However, clobazam has a wide therapeutic window; therefore, these metabolic changes are less likely to result in a clinically significant change (104). Clobazam increases phenytoin concentrations (109) and may result in phenytoin intoxication (110,111). Clobazam has also been reported to increase valproate levels, which may remain elevated for several weeks after the clobazam has been withdrawn (112) and may result in valproate toxicity (113). Mild increases in phenobarbital, carbamazepine, and carbamazepine epoxide have also been reported (109). Stiripentol is a CYP2C19 inhibitor that significantly increases N-desmethylclobazam levels (103,114,115). It has been recommended that the daily dose of clobazam be reduced to less than 0.5 mg/kg/day when used in combination with stiripentol (115,116).

Clinical Efficacy

Clobazam is effective against a wide range of seizure types and is relatively easy to use. The use of clobazam in the treatment of epilepsy was pioneered by Gastaut and Low, who reported its effectiveness in patients with partial seizures, idiopathic generalized epilepsy, reflex epilepsy, and LGS (117). The antiepileptic effect of clobazam in partial and tonic–clonic seizures has been demonstrated in several placebo-controlled studies (106).

The U.S. Food and Drug Association (FDA) has approved the use of clobazam as adjunctive treatment for LGS in people over 2 years of age. A multicenter, randomized, double-blind, phase II study examined the efficacy of clobazam at low dose (0.25 mg/kg/day) and high dose (1.0 mg/kg/day) as adjunctive therapy in patients with LGS (118). The frequency of seizures was reduced in both groups; however, the percentage of patients who experienced a reduction in weekly drop seizures was significantly higher in the high-dose group. There was no significant difference in adverse events reported. The most common adverse events were somnolence, lethargy, and sedation. A phase III, double-blind, placebo-controlled efficacy study also reported a similar dose response effect (119). Eligible patients from these two trials were enrolled in an open label extension trial. The majority of patients who initially responded well to the clobazam continued to do so after 3 years of treatment (120). Several other clinical studies have also reported clobazam to be effective in reducing drop seizures and total seizures in patients with LGS (104,121).

In addition, clobazam monotherapy has been demonstrated to be as effective as either carbamazepine or phenytoin in the treatment of children with partial seizures, tonic–clonic seizures, or both, who were previously untreated or who had received only one drug (16). Clobazam appears to have a broad spectrum of antiepileptic activity. In a large retrospective study comprising 1,300 refractory epileptic patients, including 440 children, more than 50% reduction in seizure frequency was observed for each seizure type (except tonic seizures) in 40% to 50% of patients, and complete seizure control was obtained in 10% to 30% (113). Clobazam has also been used for the treatment of benign focal epilepsies in children, including Panayiotopoulos syndrome and benign childhood epilepsy with centrotemporal spikes (122).

Clobazam has also been used as adjunctive therapy in the treatment of refractory epilepsy of various etiologies and seizure types (123,124). Dravet syndrome is a severe form of infantile onset epilepsy characterized by multiple seizure types that are treatment resistant. The combination of clobazam, valproate, and stiripentol has demonstrated efficacy in two randomized trials (116,125). The maximum dose of clobazam used in clinical trials was 0.5 mg/kg/day when used in combination with stiripentol (116). Clobazam has also been reported to reduce seizure frequency in patients with tuberous sclerosis complex (126). Its use has also been reported in the treatment of reflex epilepsies (127–129), startle epilepsy (130,131), epilepsy with continuous spike-waves during slow sleep (132), and eyelid myoclonia with absence (133). Complete seizure control was described in 20% of patients with temporal lobe seizures associated with hippocampal sclerosis, and 75% reduction in seizure frequency in a further 25% (134).

Clobazam taken intermittently for 10 days each month around the time of menstruation was effective in the treatment of catamenial epilepsy and was not associated with tolerance (135,136). Administration of intermittent clobazam has also been used successfully by the author in the treatment of seizures that occur periodically in clusters. Intermittent clobazam used for the first 48 hours of a febrile illness was reported to have similar efficacy as diazepam but less adverse effects in patients with a history of simple febrile seizures (137). Prophylactic clobazam has been used prior to bone marrow transplantation in the prevention of seizures induced by high-dose busulfan chemotherapy (138).

Adverse Effects

A major advantage of clobazam over the 1,4-benzodiazepines is the lower incidence of neurotoxicity. In a double-blind comparison of clobazam with phenytoin or carbamazepine in children, the incidence of side effects was similar (16). The side effects of clobazam are generally mild and resolve with dosage reduction. Drowsiness, short attention span, mood change, ataxia, and drooling may occur. These occur less commonly than in patients receiving 1,4-benzodiazepines (14). Marked worsening of behavior has been reported in some patients in open studies but does not appear to occur any more commonly than with carbamazepine or phenytoin (16). Excessive weight gain, which responds to withdrawal of the drug, has been reported (14). Hematologic and hepatic side effects have not been reported, and drug-induced skin rash is extremely rare.

Open studies in children have reported tolerance in 18% to 65% of patients (13–15,139,140), but most of these studies comprised patients who had been intractable to several antiepileptic drugs. In a controlled study in children who were previously untreated or who had received only one drug, the incidence of tolerance was similar in patients receiving clobazam (7.5%), carbamazepine (4.2%), and phenytoin (6.7%) (16).

Clinical Use

Clobazam should be started at a dosage of 2.5 mg/day in infants and young children and 5 mg/day in older children. The dose can be increased at 5- to 7-day intervals until the seizures are controlled or side effects occur. Although doses of up to 3.8 mg/kg/day can be administered to children without undue side effects, dosages greater than 1 mg/kg/day are rarely associated with improved seizure control (14). In teenagers and adults, the initial dose is 10 mg/day. The dose can be increased at 5- to 7-day intervals, but those who do not respond to 30 mg/day rarely respond to higher doses. Clobazam is usually administered at night or twice a day. To minimize the risk of withdrawal seizures, discontinuation should be done gradually over several weeks. Drug level monitoring is not clinically useful.

Clonazepam

Biotransformation, Pharmacokinetics, and Interactions

Clonazepam is a 1,4-benzodiazepine, and the bioavailability after oral administration is more than 80% with peak levels occurring between 1 and 4 hours (141). The high lipid solubility results in rapid distribution with easy passage across the blood–brain barrier. The protein binding is 86%. Clonazepam is metabolized initially by reduction to 7-amino-clonazepam and subsequently by acetylation (142). The metabolites, which are pharmacologically inactive, are conjugated to glucuronide and excreted by the kidney. Less than 1% is excreted unchanged in the urine. Clonazepam metabolism involves the hepatic cytochrome P-4503A4 (143) and comedication with carbamazepine or phenobarbital lowers blood clonazepam levels (141). Acetylation is also a major metabolic pathway; patients who are rapid acetylators are more likely to require higher doses to achieve a response (144). The serum half-life in children is 22 to 33 hours (145). The plasma half-life following intravenous administration in neonates is 20 to 43 hours (146).

Clinical Efficacy

Clonazepam is no longer a first-line antiepileptic medication, but its excellent antimyoclonic properties make it a useful adjunct in patients with juvenile myoclonic epilepsy who have achieved control of the generalized tonic–clonic seizures but continue to have disabling myoclonus (147,148). However, it may deprive patients of the warning jerks that precede the onset of a generalized tonic–clonic seizure (147). Clonazepam may also be effective in the treatment of other myoclonic epilepsies, including reflex myoclonic epilepsy, progressive myoclonic epilepsy, posthypoxic intention myoclonus, and epilepsia partialis continua (141). Partial epilepsy may also respond to clonazepam in combination with valproic acid (141). Oral clonazepam has been demonstrated in controlled studies to be effective in the treatment of absence (145,149,150), myoclonic (149), and atonic seizures (149). Open studies have suggested that clonazepam is also effective in the treatment of photosensitive epilepsy and of primary generalized tonic–clonic seizures, both as monotherapy (151) and in combination with valproic acid (152). Clonazepam monotherapy is associated with reduction in interictal rolandic discharges in children with benign rolandic epilepsy (153), and is more effective than valproic acid and carbamazepine in that regard (154). The addition of clonazepam was also effective in the treatment of children with partial seizures resistant to carbamazepine (155). Studies have demonstrated mixed results with respect to the efficacy of clonazepam in LGS (156). Intravenous clonazepam was effective in stopping tonic–clonic status epilepticus in all children in a small open study and was considered to have a longer duration of action than diazepam (157). The initial dose was 0.25 mg, which was repeated up to two times. Intravenous clonazepam was also effective in more than 80% of children and adults with absence status epilepticus (158).

Adverse Effects

The most common adverse effects of clonazepam include drowsiness, ataxia, incoordination, and behavioral changes (37,159). Comedication with phenobarbital usually exacerbates the drowsiness (160). Diplopia, nystagmus, dysarthria, excessive drooling, and hypotonia may also occur. Initiation of therapy at a low dose followed by a slow increase may reduce the neurotoxicity. Increased appetite and weight gain of more than 20% were reported in 9 of 81 children treated with clonazepam (159). Clonazepam may result in increased seizure frequency (161) and has been reported to induce tonic status epilepticus in LGS (162).

The development of tolerance to the antiepileptic effect of clonazepam is dependent on the type of epilepsy. Thus, tolerance did not develop in 23 children with partial epilepsy who were treated with clonazepam monotherapy or clonazepam in combination with carbamazepine (155). Similarly, tolerance to clonazepam was observed less often in patients with typical absence seizures than in patients with West syndrome or LGS (12). The use of alternate-day clonazepam has been reported to be associated with significantly less tolerance in an animal model (163), an effect also observed in children (164). Discontinuation of clonazepam may be complicated by transient worsening of seizure control, and status epilepticus may occur with abrupt withdrawal (12). Behavioral changes, including restlessness, dysphoria, sleep disturbance, and tachycardia, may also occur during clonazepam withdrawal, which should be done gradually (12).

Clinical Use

To minimize side effects, clonazepam should be started at a dose of 0.01 to 0.03 mg/kg/day in children under 30 kg and given in two or three daily dosages (165). The dose can be increased by 0.25 to 0.5 mg/day every 5 to 7 days to a total dose of 0.1 mg/kg/day, or 0.2 mg/kg/day in patients receiving drugs that induce microsomal metabolism. Maximum daily dose is 20 mg/day. Clonazepam was effective in seven of eight neonates with seizures when administered by slow intravenous infusion in doses of 0.1 mg/kg (146).

Nitrazepam

Biotransformation, Pharmacokinetics, and Interactions

Nitrazepam, a 1,4-benzodiazepine, is rapidly and totally absorbed in the gastrointestinal tract. It is highly protein bound (85%–90%) and has an elimination half-life of 24 to 31 hours (166). Nitrazepam is partially metabolized in the liver and then excreted in the urine. There are no clinically significant interactions with other antiepileptic drugs. Oral contraceptives, steroids, and cimetidine reduce nitrazepam clearance, and rifampin increases nitrazepam clearance (166).

Clinical Efficacy

Nitrazepam is generally considered a third-line adjunctive medication in the treatment of partial and generalized seizures, including the epileptic encephalopathies of childhood. Nitrazepam has been reported to be effective in the treatment of absence and primary generalized tonic–clonic seizures (167), myoclonic seizures (168), and partial seizures (168). Improvement in seizure control has also been reported in LGS and infantile spasms (166,169–171).

Adverse Effects

Drowsiness, ataxia, and incoordination, which are common side effects, may be diminished by initiation of treatment at a low dose followed by slow increase. Increased salivation is a well-recognized side effect of nitrazepam in children and is related to both hypersecretion of the tracheobronchial tree and abnormal swallowing, due to delay in cricopharyngeal relaxation (172). This may also result in feeding difficulties and aspiration pneumonia, particularly in children (168,173). Doses of nitrazepam greater than 0.8 mg/kg/day have been found to be associated with an increased risk of death in children (173), and the risk appears highest in children with intractable epilepsy younger than 3.4 years of age (174). Risk factors included feeding difficulties, recurrent respiratory tract infections, and aspiration pneumonia.

Clinical Use

To reduce the risk of side effects, nitrazepam should be started in children at a low dose (0.1–0.2 mg/kg/day) and the dosage increased every 5 to 7 days to a maximum of 0.8 mg/kg/day (173). Caution should be taken in patients younger than 4 years of age. Discontinuation of nitrazepam should be gradual to minimize the risk of withdrawal seizures.

Clorazepate

Biotransformation, Pharmacokinetics, and Interactions

Clorazepate is a prodrug that is decarboxylated in the stomach to the active medication N-desmethyldiazepam. Peak concentrations of N-desmethyldiazepam are normally achieved at 0.5 to 2 hours and, with the slow-release preparation, after 12 hours (175,176). Serum concentrations of N-desmethyldiazepam increase after meals, which may cause somnolence (175). N-desmethyldiazepam is 97% protein bound, largely to serum albumin (176). Although N-desmethyldiazepam has an elimination half-life of 55 to 100 hours, administration of clorazepate once daily is associated with unacceptable side effects because of the relatively high peak concentrations that follow its rapid absorption (176). N-desmethyldiazepam is metabolized extensively by the liver and its elimination half-life is prolonged in patients with liver disease. Drugs that induce hepatic microsomal metabolism enhance the clearance of N-desmethyldiazepam and patients taking these drugs require higher doses of clorazepate.

Clinical Efficacy

Clorazepate was introduced in the 1960s and there have been no controlled studies in children. Improvement in seizure control has been reported in children with partial (177) and generalized seizures (177–179), including children with LGS (177).

Adverse Effects

Sedation, ataxia, behavioral changes, and drooling, which are the most common side effects of clorazepate in children, often become less pronounced with time. Comedication with phenobarbital increases the probability of behavioral problems (178) and should be avoided. Idiosyncratic reactions are rare (176).

Tolerance limits the usefulness of clorazepate, but animal studies suggest that tolerance occurs less often with clorazepate than with diazepam or clonazepam (176). Withdrawal seizures and behavioral changes may complicate the discontinuation of therapy, which should occur slowly.

Clinical Use

The initial dose of clorazepate in children is 0.3 mg/kg/day, and the dose is increased gradually to achieve seizure control or until side effects appear, up to a maximum dose of 3 mg/kg/day (176,178).

REFERENCES

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