Benzodiazepines are among the most useful AEDs available for treating status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis. Benzodiazepines were used in epilepsy management as early as 1965, when Gastaut et al. (73, 74) administered i.v. diazepam to treat status epilepticus. Since then, several other BZDs have been used for a variety of seizure disorders (Table 5).
Table 5. Recommended clinical uses of benzodiazepines
|Clobazam||Frisium||NA||Not FDA approved||First-line adjunctive treatment for treatment-resistant partial and generalized seizures, intermittent therapy and non-convulsive status epilepticus|
|Clonazepam||Klonopin||Yes||Panic disorder, epileptic seizures (alone or adjunct)||Second-line adjunctive treatment for partial and generalized (particularly absence and myoclonic) seizures, early status epilepticus and Lennox–Gastaut syndrome; second-line treatment of status epilepticus|
|Yes||Anxiety, alcohol withdrawal, adjunctive treatment of partial seizures||Adjunctive 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 of non-convulsive status epilepticus; intermittent prophylactic therapy for febrile 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 epilepticus and out-of-hospital status epilepticus|
|Midazolam||Versed||Yes||Anesthesia, preoperative and procedural sedation||Second-line therapy for early status epilepticus|
Several randomized controlled trials support the use of BZDs (particularly diazepam and lorazepam) as initial drug therapy in patients with status epilepticus (77–80). Intermittent use of BZDs is especially suitable for patients with clusters of repetitive seizures (81). Fewer studies have evaluated the clinical efficacy of BZDs in chronic epilepsy. Nevertheless, BZDs are useful as adjunctive agents in treating certain patients with both partial and primary generalized seizures (81). Benzodiazepines are versatile drugs that can be employed in a variety of clinical settings because of their broad spectrum of activity and multiple formulations and because they can be administered by several routes (81).
Diazepam is a drug of first choice for treatment of early status epilepticus and acute repetitive seizures and for febrile seizure prophylaxis. It can be administered as an i.v. bolus, as a continuous infusion, or rectally, which enhances its utility in managing seizure emergencies. Four randomized controlled trials support diazepam as a drug of first choice for managing status epilepticus (77–80). Success rates of i.v. diazepam for treating status epilepticus vary. In a randomized double-blind study comparing diazepam and lorazepam, Leppik et al. (80) found that 76% of status epilepticus episodes (25 of 33) were terminated by one or two diazepam doses (5 mg/min). In a randomized, non-blinded trial of patients >15 years of age with status epilepticus, Shaner et al. (78) reported that seizures were aborted in <10 min in 55.6% of patients (10 of 18) treated with diazepam (2 mg/min) and phenytoin (40 mg/min). A randomized, double-blind, multicenter Veterans Affairs cooperative study was designed to compare the effectiveness of four treatments for overt or subtle status epilepticus (79). Three hundred eighty-four patients with overt status epilepticus and 134 patients with subtle status epilepticus were randomly assigned to receive either diazepam (0.15 mg/kg) followed by phenytoin (18 mg/kg), lorazepam (0.1 mg/kg) alone, phenobarbital (15 mg/kg) alone or phenytoin (18 mg/kg) alone. Treatment with diazepam plus phenytoin was successful in 55.8% of patients (53 of 95) with overt status epilepticus and 8.3% of patients (three of 36) with subtle status epilepticus (79). Alldredge et al. (77) conducted a randomized double-blind trial to determine the effectiveness of i.v. diazepam, lorazepam and placebo on status epilepticus when the drugs were administered by paramedics before patients arrived at the hospital. They found that status epilepticus was terminated by the time of arrival in the emergency department in 42.6% of the 68 patients treated with one or two 5-mg doses of i.v. diazepam (infused over 1–2 min). Limited published data indicate that continuous i.v. infusions of 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 approximately 50% of patients (76). Therefore, multiple injections or continuous infusion may be required, which can lead to drug accumulation and possibly to acute respiratory depression, sedation and hypotension (76). The development of tolerance has also been reported for infusions lasting >24 h (85). Recommended dosing guidelines for i.v. diazepam for convulsive status epilepticus are 0.15–0.25 mg/kg in adults and 0.1–1.0 mg/kg in children (86). In placebo-controlled trials, rectal diazepam gel (doses of 0.2–0.5 mg/kg) reduced seizure recurrence in children, adolescents and adults who had clusters of repetitive seizures in a non-medical or home setting (87–90). Rectally administered diazepam may also be effective for short-term prophylaxis (at doses of 5–10 mg or 0.3–0.6 mg/kg in patients weighing <10 kg) in children prone to febrile seizures (91–93), and higher doses of rectal diazepam (20–30 mg) have been used in adult patients with drug-resistant epilepsy who are prone to serial seizures (94, 95). Use of oral diazepam is not recommended for long-term epilepsy treatment (76).
Lorazepam is generally given as an i.v. bolus at doses of 0.05–0.1 mg/kg over 2 min, and the dose may be repeated in 10 min. The i.v. formulation is approved by the US Food and Drug Administration (FDA) for the treatment of status epilepticus. Results from four comparative studies (three of blinded design) have suggested that lorazepam is superior to phenytoin and as effective as clonazepam, diazepam or the combination of diazepam and phenytoin in the initial treatment of status epilepticus (77, 79, 80, 96). In the previously mentioned study by Alldredge et al. (77), i.v. lorazepam (2 mg, one to two doses) administered to 66 adults with repetitive or ongoing generalized seizures lasting >5 min terminated convulsions by the time of arrival at the emergency department in 59.1% of patients. Similarly, Leppik et al. (80) found that one or two lorazepam doses (4 mg each) terminated seizures in 89% of status epilepticus episodes. In the Veterans Affairs cooperative study of status epilepticus, lorazepam terminated seizures in 64.9% of patients and was significantly more effective 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 clonazepam (1 mg, one to two doses) in 61 patients. In lorazepam-treated patients, 53.0% had ≥75% improvement, as did 39.6% of clonazepam-treated patients, as measured by electroencephalograms. Clinical results were comparable between groups, with 67.9% of lorazepam-treated patients and 69.0% of clonazepam-treated patients having ≥75% improvement. Large lorazepam doses (0.3–9 mg/h) have been used as an alternative to pentobarbital for treating refractory status epilepticus; for all nine cases in an open-label study, lorazepam terminated status epilepticus (97).
Clinical studies in children have been mostly unblinded and have included retrospective and prospective designs. In a prospective open-label study, Appleton et al. (98) compared i.v. or rectal lorazepam and diazepam treatments in 86 children. A single dose terminated seizures in 76% of patients treated with lorazepam and in 51% of patients treated with diazepam; the difference between treatments was not statistically significant. Qureshi et al. (99) performed a comparative audit of i.v. lorazepam and diazepam. The authors suggested that lorazepam is probably as effective as diazepam is for stopping acute seizures in children. Seizures were controlled within 15 min in 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 evaluated in relatively few studies (100). In a short-term, placebo-controlled trial, adjunctive oral lorazepam therapy was effective (i.e. reduced seizure frequency significantly more than placebo did, P < 0.01) for treating partial seizures that were unresponsive to standard AEDs (101).
As reviewed by Browne (102), clonazepam has been shown to be efficacious in treating patients with both partial and generalized seizures. Clonazepam is used primarily as an adjunctive therapy to treat patients with a wide range of treatment-resistant primary and secondarily generalized seizures (103). During the 1970s and 1980s, the use of adjunctive clonazepam was evaluated in a few, mostly small, controlled clinical trials in patients with partial and generalized seizures that were refractory to standard treatments (76, 104). Uncontrolled studies of clonazepam in patients with partial and generalized epilepsy have generally shown modest effects (76). In generalized epilepsies, clonazepam is effective for treating patients with absence seizures (105, 106). In one study, 70% of children with absence seizures treated with clonazepam (seven of 10) had a ≥ 75% reduction in seizure frequency after 8 weeks of treatment, and an additional 10% of children (one of 10) had a 30% reduction in seizure frequency (105). Clonazepam also can be useful in treating patients with myoclonic seizures (107). It is considered the drug of choice in certain rare childhood epilepsy syndromes (108). It is also effective in controlling status epilepticus; a review of several studies (109–120) of i.v. clonazepam use in status epilepticus found the drug to be effective in approximately 80–90% of patients (107). Clonazepam has been shown to be effective as adjunctive therapy for complex partial seizures, absence seizures, tonic–clonic seizures and myoclonic seizures (121, 122).
Midazolam is the only available water-soluble BZD; solubility is achieved when the 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 can also be administered buccally or nasally (124, 125). Rectal administration is not recommended because of poor bioavailability (126). Although it is used for many seizure types, midazolam does not have an FDA-approved indication for seizures.
Clinical experience with midazolam for treating status epilepticus (as initial treatment or for refractory status epilepticus) is limited (76). In three controlled clinical trials, the efficacy of intranasal midazolam was similar to or better than that of i.v. or rectal diazepam (124, 127, 128). Midazolam has also been found to be safe and effective when administered as a continuous infusion to treat refractory generalized convulsive status epilepticus (129–133). In a randomized trial comparing buccal midazolam with rectal diazepam in children, the drugs showed similar efficacy and onset of action (125). In that study, seizure cessation 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 from another randomized controlled trial that compared buccal midazolam with rectal diazepam for emergency treatment of seizures in children suggested that midazolam was more effective than diazepam (134). Therapeutic success (defined as cessation of visible signs of seizure activity within 10 min of drug administration, lack of respiratory depression and no further seizures within 1 h) was noted in 56% of midazolam-treated patients (61 of 109) and 27% of diazepam-treated patients (30 of 110), a 29% difference between groups; (95% confidence interval, 16–41%). Open-label studies have suggested that intranasal midazolam is safe and effective for acute seizure management in children (124, 127, 128, 135, 136). In a prospective, randomized, open-label study, intranasal midazolam was as safe and effective as i.v. diazepam was for managing febrile seizures, with 88% of seizures (23 of 26) responding to initial treatment with midazolam and 92% (24 of 26) responding to diazepam (124). Intranasal midazolam takes less time to administer than i.v. diazepam does but has disadvantages. Often, the parenteral formulation has been used for intranasal administration. A large volume is required to deliver a therapeutic dose, making administration difficult because much of the solution may leak out of the nose or be swallowed (137). Additionally, pain is common with intranasal midazolam administration, which may indicate irritation of the nasal mucosa due to the low pH (3–4.3) of the formulation (137–139). Finally, the short t1/2 of midazolam (24) may put patients at risk of seizure recurrence as plasma concentrations rapidly decline.
Although not currently approved in the USA, clobazam is commonly used elsewhere as adjunctive therapy for patients with refractory epilepsy (103). It is highly effective as adjunctive therapy for partial and generalized seizures, for intermittent therapy and for controlling non-convulsive status epilepticus, and it produces less sedation than other BZDs do (140). Its use is limited by the potential for the development of tolerance. However, a portion of patients (up to 25%) may remain seizure free while taking adjunctive clobazam for long periods (141–144). The Canadian Clobazam Cooperative Group reported that, on the basis of results from a retrospective study, 40–50% of patients could be maintained on clobazam 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 (17, 145–152). In a crossover study of 21 patients, a >50% reduction in seizure frequency was seen in 52% of patients receiving clobazam (145). In another crossover study, Schmidt et al. (146) reported a seizure frequency reduction of ≥75% in 40% of patients receiving adjunctive clobazam. These findings compare favorably with adjunctive therapy results for many AEDs currently available in the USA. Clobazam was studied in a large double-blind trial as first-line monotherapy in children with partial, partial with secondary generalization or primary generalized tonic–clonic seizures and was reported to have efficacy and tolerability similar to that of monotherapy with phenytoin or carbamazepine (153, 154). Seizure freedom was maintained for the entire 12 months of the study for 23%, 25% and 11% of patients randomly assigned to receive clobazam, carbamazepine and phenytoin respectively.
The effectiveness of adjunctive clorazepate for various treatment-resistant seizures has been demonstrated; however, the clinical experience and data available are less extensive for clorazepate than for other BZDs (103). An open-label clinical study of clorazepate therapy suggested that the drug might be useful as an add-on treatment for generalized major and minor seizures (e.g. absence, akinetic and myoclonic) (155). In that study, an excellent response (defined as complete seizure control or seizure control that produced a notable improvement in social, educational or vocational assessment) was observed for 19% of patients with major generalized seizures (three of 16), 39% of patients with absence seizures (seven of 18), 33% of patients with akinetic seizures (three of nine) and 57% of patients with myoclonic seizures (four of seven). Other double-blind (156) and open-label (157–159) studies have demonstrated the efficacy of adjunctive clorazepate for both partial (simple and complex) and generalized seizures.
Clorazepate also appears to be useful in childhood 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 18 children with Lennox–Gastaut syndrome or other conditions with atypical absence seizures, the authors stated that five patients (28%) had an excellent response and eight patients (44%) had a good response to adjunctive clorazepate therapy, although the terms ‘excellent’ and ‘good’ were not clearly defined (160). Other studies have found good results with clorazepate in the treatment of refractory childhood epilepsies. In an open-label study by Naidu et al. (161), 11 children with generalized seizures (absence and atonic) who received clorazepate as monotherapy (n = 4) or as adjunctive therapy with valproate (n = 7) had a reduction in the number of clinically observed seizures. In another open-label study, clorazepate was added to standard AEDs in 29 children with various seizure disorders; 72% of patients experienced improved seizure control (162).
Although BZDs as a class are well tolerated, clinicians should be aware of potential safety issues associated with BZD use. Drowsiness and confusion may be indicative of over-sedation, a dose-related extension of the sedative/hypnotic effects of BZDs (62, 163, 164). Over-sedation is more problematic in the elderly than in younger patients, and it may occur at lower doses in the elderly (165, 166). Elderly patients treated with BZDs can experience confusion, amnesia, ataxia and hangover effects (62). Benzodiazepine use is also associated with falls, a possible result of over-sedation in elderly patients (167).
Benzodiazepines may cause amnesia, particularly anterograde amnesia (168). This effect is sometimes deliberately utilized in presurgical medication (169). However, memory impairment may also be associated with clinical doses of orally administered BZDs (168).
For individuals who use BZDs long term, the possible degree of recovery and the extent of residual impairment that may remain after the drugs are withdrawn are unclear (170). In a meta-analysis, Barker et al. (170) concluded that long-term BZD users show recovery of function in visuospatial skills, attention/concentration, general intelligence, psychomotor speed and non-verbal memory assessments after withdrawal. The authors found, however, that significant cognitive impairment was more persistent in long-term users than in control groups or in normative data. The authors reported that the study data did not demonstrate complete restoration of function within the first 6 months following discontinuation of BZD use; they suggested that longer than 6 months may be needed for recovery from some deficits.
Paradoxical excitement is sometimes associated with BZD use and may include exacerbation of seizures in patients with epilepsy (171). Children and elderly patients, patients with a history of alcohol abuse and individuals with a history of aggressive behavior/anger may be more likely to experience paradoxical excitement effects than are other patients (172). Additionally, BZDs can cause or aggravate depression (57).
Dependence refers to the compulsion to take a drug to produce a desired effect or to prevent unpleasant effects that occur when the drug is withheld. Dependence develops in almost one-third of patients who are treated with BZDs for ≥4 weeks (173). A withdrawal syndrome upon BZD discontinuation (see Tolerance and withdrawal section) is a common manifestation of BZD dependence (173). High BZD dosage and potency, short duration of BZD action, long duration of therapy and premorbid dependent personality traits are risk factors for the development of BZD dependence (173). Potent BZDs with relatively short t1/2 (e.g. triazolam, alprazolam and lorazepam) appear to carry the highest risk of dependence (173).
Substantial differences in adverse event occurrences associated with the BZDs profiled here have not been reported in large randomized, controlled trials comparing BZDs. Some study results have suggested that diazepam may have greater effects on respiratory depression than are observed with other BZDs such as lorazepam and midazolam (174, 175). Additionally, although BZDs are generally known to affect memory, some studies have shown that effects differ depending on the BZD used. Lorazepam appears to impair both explicit memory and implicit memory, and although diazepam impairs explicit memory, results regarding impairment of implicit memory by diazepam are mixed (176–179).
The adverse event profiles of BZDs should be considered when decisions are made regarding therapy. Clinicians should weigh the possible benefits of therapy with BZDs against the potential adverse effects.