Antiepileptic Drugs, 5th Edition

Phenobarbital and Other Barbiturates

53

Clinical Efficacy and Use in Epilepsy

Michel Baulac MD

Hôpital de la Salpetriere, Bat. P. Castaigne, Paris, France

The longevity of phenobarbital is extraordinary, in the way in which it continues to coexist with successive generations of antiepileptic drugs introduced to the market throughout the twentieth century. Although phenobarbital was previously used as a hypnotic and a tranquilizer, its antiepileptic properties were discovered in 1912, and it became a major first-line drug in the years between World War I and World War II. Then it lost ground progressively as newer drugs took its place, but it nevertheless remained among the most frequently used antiepileptic drugs in Europe. Phenobarbital is still a first-choice drug in developing countries for evident reasons of availability and cost. Even though this drug has been used as an antiepileptic agent for 90 years, evaluating its benefit:risk ratio remains relatively difficult, particularly because very few studies comply with the current standards, and comparisons with other antiepileptic drugs are not available in all clinical situations. Reports are sometimes conflicting, and most of the current knowledge relies on clinical experience. Phenobarbital presents broad-spectrum antiepileptic activity against all seizure types, except absences. Its efficacy appears, in the few comparative studies, either equivalent to or only slightly inferior to that of the other major established agents. However, its potential for inducing sedation and cognitive and behavioral changes limits its clinical use, particularly in children and in countries where many other therapeutic options are available. However, the advantages of phenobarbital remain: single daily dose, predictable pharmacokinetics, low systemic toxicity, and low cost. Furthermore, with its parenteral formulations, phenobarbital continues to occupy an important place in the treatment of status epilepticus. It can be anticipated, however, that the latest generation of antiepileptic drugs, introduced in the 1990s, will further reduce interest in phenobarbital, especially at a time when the emphasis is on improved safety and tolerability.

SPECTRUM OF EFFICACY

Phenobarbital is widely used in the treatment of localization-related epilepsies; it is effective against simple partial, complex partial, and secondarily generalized seizures (1, 2, 3). It is also efficacious against some seizure types of the generalized epilepsies, particularly generalized tonic-clonic, tonic, and clonic seizures. It is ineffective against, and may even aggravate, absence seizures, although it phenobarbital sometimes coprescribed with ethosuximide in patients with absence epilepsy to control concomitantly occurring generalized tonic-clonic seizures. Phenobarbital is also widely used in special situations such as neonatal seizures and generalized tonic-clonic status epilepticus.

CONTROLLED TRIALS IN ADULTS

The assessment of phenobarbital's efficacy is largely based on clinical practice, and relatively little information can be obtained from controlled trials. Among the rare publications, one of the most significant is by Mattson et al. (1). In a multicenter, double-blind trial, the efficacy and tolerability of carbamazepine, phenytoin, phenobarbital, and primidone were compared in 622 adults. These patients were randomly assigned to one of these drugs and were followed-up for 2 years or until the drug failed to control seizures or caused unacceptable adverse effects. Patients had been previously untreated (58%) or undertreated, and they had simple or complex partial seizures (265 patients) or secondarily generalized tonic-clonic seizures (357 patients) as their predominant seizure type. The overall treatment success rate, expressed in terms of retention on the allocated treatment, was highest with carbamazepine or phenytoin, it was intermediate with phenobarbital, and it was lowest with primidone. Differences in failure rates were mostly explained by the poorer tolerability of primidone and phenobarbital. Phenobarbital was as effective as the three other drugs in patients with tonic-clonic seizures, but carbamazepine was significantly more effective in the treatment of partial

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seizures. There was no statistical difference between phenobarbital and the other drugs with regard to the number of seizures in all patients at 12, 24, and 36 months, and there was also no difference between the time that therapeutic levels were achieved and the first recurrence of seizures. Total seizure control was obtained only in 30% of the patients during the first 12 months, a finding that underlines that the population enrolled in this study was different from the usual populations of patients with newly diagnosed epilepsy in whom the expectancy for seizure control is higher, 47% with a first drug (4). Complete control of tonic-clonic seizures was similar (carbamazepine, 48%; phenytoin, 43%; phenobarbital, 43%; and primidone, 45%). The complete control of partial seizures, however, was significantly better with carbamazepine than with phenobarbital (33%) or primidone (26%) at 18 months.

Another prospective randomized pragmatic trial assessed the comparative efficacy and toxicity of four major antiepileptic drugs, used as monotherapy in patients with newly diagnosed epilepsy (5). Between 1981 and 1987, 243 patients aged ≥16 years, with a minimum of two previously untreated tonic-clonic seizures or partial seizures with or without secondary generalization, were randomly allocated to treatment with phenobarbital, phenytoin, carbamazepine, or sodium valproate. The protocol was designed to conform with standard clinical practice. Efficacy was assessed by time to first seizure after the start of treatment and time to enter 1-year remission. The overall outcome with all of the four drugs was good, with 27% remaining seizure free and 76% entering 1-year remission by 3 years of follow-up. No significant differences among the four drugs were found for either measure of efficacy at 1, 2, or 3 years of follow-up, but this observation should be interpreted cautiously in view of the small sample size in each group. The overall incidence of unacceptable side effects, necessitating withdrawal of the randomized drug, was 10%. However, for the individual drugs, phenobarbital (22%) was more likely to be withdrawn than phenytoin (3%), carbamazepine (11%), and sodium valproate (5%). Some other studies have compared phenobarbital with carbamazepine, phenytoin, or primidone. Marjerrison et al. (6) compared phenobarbital and carbamazepine in 21 adult patients hospitalized on a long-term basis. One-half of the previous anticonvulsant and antipsychotic medication dose was replaced by a proportionate dose of double-blind capsule of either phenobarbital or carbamazepine. After 2 months, a crossover to the compound was effected and was maintained for 4 more months. No significant difference in the number of seizures per patient during the final months of each drug treatment phase was noted. White et al. (7), in a short double-blind study, found similar efficacy of phenobarbital, phenytoin, and primidone in 20 adult inpatients with partial seizures. All three drugs were more effective than placebo. Cereghino et al. (8) compared these three drugs in a prospective crossover double-blind study performed in 45 institutionalized drug-resistant adult patients with mainly focal and secondarily generalized tonic-clonic seizures. During each of the three 21-day treatment periods, one-third of the patients were assigned to receive phenobarbital (300 mg/day), one-third phenytoin (300 mg/day), and the other one-third carbamazepine (1,200 mg/day), as replacement for previous medication. In these patients, phenobarbital was equal in efficacy to carbamazepine or phenytoin. Benassi et al. (9) compared phenobarbital, phenytoin, and carbamazepine in a prospective double-blind crossover design in 18 patients with complex partial seizures and previous multiple-drug treatment. Phenobarbital and carbamazepine were more active than phenytoin and were associated with an improvement in 61%, 67%, and 32% of the cases, respectively.

CONTROLLED TRIALS IN CHILDREN

Mitchell and Chavez (2) administered phenobarbital or carbamazepine to 39 children with newly diagnosed partial seizures on a single-blind basis for 12 months. Dosage was adjusted to produce serum levels ranging from 15 to 24 µg/mL for phenobarbital and from 4 to 7 µg/mL for carbamazepine. Cognitive function and behavior were evaluated at the onset of the study and at 6- and 12-month follow-ups. There were no significant differences in outcome between the two groups; although carbamazepine caused more systemic problems (two rashes, one case of granulocytopenia), there was a nonstatistically significant trend toward better seizure control with carbamazepine. A long-term, randomized, open-label trial compared the efficacy and toxicity of four standard antiepileptic drugs used as monotherapy in children with newly diagnosed epilepsy (10a). Between 1981 and 1987, 167 children aged 3 to 16 years, who had had at least two previously untreated tonic-clonic or partial seizures, with or without secondary generalization, were randomly allocated to treatment with phenobarbital, phenytoin, carbamazepine, or sodium valproate. Six of the first 10 children randomized to phenobarbital had to be withdrawn from the study because of unacceptable, mostly behavioral, side effects, and it was considered unethical to assign further patients to phenobarbital treatment. More recently, phenobarbital was compared with phenytoin and with sodium valproate in a 2-year doubleblind trial in 151 children (aged 4 to 12 years) with newly diagnosed epilepsy in India (10b). All children had generalized tonic-clonic seizures. The three drugs were equally effective in controlling seizures, but phenobarbital caused hyperactivity problems more frequently and was considered as a possible first-choice treatment only in preschool children.

MODE OF USE

Indications

Although in the past phenobarbital was widely employed as a sedative and tranquilizer, in many countries it is now used

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almost exclusively for the treatment of epilepsy. The drug is employed in the following indications:

  1. Generalized epilepsies, but within this category mainly for tonic, clonic, and tonic-clonic seizures. Phenobarbital is ineffective against absence seizures and may even aggravate them (10c). Valproate and lamotrigine are usually considered to be the preferred agents for generalized epilepsies; phenobarbital and its derivatives are considered as second-line agents with reasonable efficacy, but, for most patients, less desirable toxicity profiles, particularly with regard to the effect of sedation and, in children, behavioral disturbances.
  2. Partial or localization-related epilepsies, whether or not the seizures become secondarily generalized. In this situation, phenobarbital has reasonable efficacy, but some trials suggest that it may be slightly less effective than carbamazepine, phenytoin, or valproate, and with a rather less acceptable toxicity profile.
  3. Convulsive status epilepticus. In these patients, intravenous benzodiazepines (e.g., diazepam, lorazepam, clonazepam) and phenytoin (or fosphenytoin) are usually the preferred agents. Phenobarbital, however, is a possible first-line alternative, and it can be effective when other therapies fail (11). It produces temporary sedation, but this is an acceptable price to pay for control of a life-threatening situation such as status epilepticus.
  4. Neonatal seizures, for which phenobarbital and phenytoin are the agents usually recommended. This is partly because both are marketed in preparations suitable for parenteral use, and in neonates it is often necessary to administer antiepileptic therapy by injection.

In terms of age range, phenobarbital may be used in all categories of patients. Besides the specific situations of neonatal seizures and status epilepticus, adults should remain the main target group for the long-term management of epilepsy with phenobarbital. The potential of phenobarbital for cognitive or behavioral adverse effects in children is of particular concern, because it may compromise learning capabilities, and therefore the use of this drug should be restricted whenever possible. Elderly patients also have substantial risks of insidious cognitive impairment or rheumatologic complications. Moreover, the potential for interactions with other treatments frequently prescribed in this age range, with a high rate of multiple disorders, often makes the use of phenobarbital suboptimal.

In terms of regulatory approval, the indications for phenobarbital rely on the proof of time and clinical experience. The drug may be used as monotherapy or polytherapy.

Dosing Recommendations

Starting Dosage and Titration

Except in urgent or relatively urgent situations in which temporary sedation may be acceptable for achieving seizure control, phenobarbital and other barbiturates are best introduced into therapy gradually. There are no specifically recommended procedures for this titration. It largely depends on the urgency of the need to control seizures, expectations about tolerability, and the size of the target dose for an individual patient. Patients should be made aware of potential early sedative effects and should be informed that these effects can be minimized with gradual titration of the drug.

In general, titration may be completed in 6 to 12 weeks. One-third of the expected maintenance daily dose may be prescribed for the first 2 or 3 weeks, after which the dose may be doubled if tolerability is acceptable. A further increment in dose is made 2 or 3 weeks after that, with perhaps a final increment another 2 or 3 weeks later. If this policy is followed, drug doses will be increased only when there has been time for steady-state conditions to apply at the previous dose. In patients whose seizures are frequent during the titration phase, no further dose increment will be necessary if seizures become fully controlled. Nor are doses increased if mild but tolerable adverse effects are present and too little time has passed since the last dose increment for the drug's effectiveness to be known. Some of the side effects, particularly sedation, may disappear when treatment is continued, owing to pharmacodynamic tolerance. The plasma concentrations of the drug may be measured after steady state has been achieved at the final target dose, so long as no adverse effects suggest that the dose needs to be reduced irrespective of the plasma concentration. The plasma phenobarbital concentration may serve as a provisional therapeutic concentration for the particular patient if the seizures appear fully controlled at that time or as a guide to the magnitude of further increases in dose likely to be tolerated if the seizures are not yet controlled. When rapid efficacy is needed, a loading dose of twice the usual daily maintenance dose, given for 4 days, brings the serum concentration to the steady-state value within 3 days.

Maintenance Dosage

The maintenance doses of phenobarbital that should be targeted initially range from 1 to 2.5 mg/kg/day in adults. Young adults 16 to 40 years old are generally treated with higher daily doses, 1.75 mg/kg on average, than adults >40 years old, in whom average daily doses of 1 mg/kg, or sometime less, may be sufficient. The drug may be given conveniently once daily at bedtime. At an early stage of therapy, if a standard dose as a function of age and body weight has been reached and is tolerated comfortably, or if plasma phenobarbital levels of ~15 µg/mL have been achieved, it is reasonable to make no further change in dose until the patient's clinical response becomes clear in time. In cases of seizure recurrence, delayed-onset adverse reactions, or modification of a concomitant medication susceptible of interactions, the phenobarbital dosage may need to be adjusted.

In children, because of changing pharmacokinetics, mainly shorter half-life values than in adults, maintenance dosages per body weight are generally higher. Specific indications for use

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of phenobarbital for the different seizure types in children are similar to those for adults, with a few exceptions. Rossi (16) studied the dosage of phenobarbital relative to age in children to achieve steady-state concentrations of 10 to 25 µg/mL. Infants from 2 months to 1 year of age require 2.31±0.74 mg/kg, children aged 1 to 3 years require 3.5±0.99 mg/kg, and children from 3 to 6.5 years of age require 4.79±1.31 mg/kg to achieve these plasma concentrations.

Optimal Range of Plasma Phenobarbital Concentrations

It is well known that the statistical concept of therapeutic drug concentrations has serious limitations and must be used cautiously. In the case of phenobarbital, the range of therapeutic concentrations is relatively broad. From a large sample of patients, Booker (12) concluded that the patients who respond to treatment with phenobarbital will do so with plasma levels between 10 and 40 µg/mL. In a study in untreated patients, Buchtal et al. (13) administered phenobarbital in small doses that were gradually increased and showed that the clinical response occurred at an average level of 10 µg/mL. Because of the long half-life of phenobarbital, its plasma concentrations show very little fluctuation during interdose intervals. Hence, predose measurement of the drug's plasma concentration rarely offers advantages over measurements carried out at any stage of the dosage interval, so long as steady-state conditions apply.

Many epileptic patients are completely seizure free with astonishingly low phenobarbital plasma levels. Prescribing higher doses in such patients is unnecessary. Conversely, a few patients may benefit from doses producing very high levels without significant toxicity. Like other drugs, phenobarbital must sometimes be increased to the maximum tolerated dose before being considered ineffective. In fact, in patients with uncontrolled epilepsy, higher plasma levels are found than in patients with controlled epilepsy (13, 14, 15). With staged progressive increments of phenobarbital doses, patients may remain free of adverse effects at plasma phenobarbital concentrations of ≥40 µg/mL, although by levels of 50 µg/mL, most patients experience some degree of mental dullness. The phenobarbital dose corresponding to these plasma drug concentrations may be 250 to 300 mg/day. However, one must be very attentive in the long term because adverse effects at these dose ranges, if not apparent at the beginning, may develop very insidiously later. The optimal phenobarbital dose and plasma concentration may vary with the type of syndrome or seizure. Schmidt et al. (3) found that higher concentrations were necessary for controlling partial seizures (37 µg/mL) than for controlling generalized tonic-clonic seizures alone (18 µg/mL).

Current Role in Epilepsy Management

In wealthy countries, a paradox exists in that phenobarbital is still widely used despite acknowledgment that it has no superiority in efficacy as compared with other antiepileptic drugs. Its broad spectrum of efficacy and indications make phenobarbital an easy product to prescribe, especially by nonexperts. Moreover, life-threatening adverse effects and blood or liver toxicity are very rare. All this ensures steady confidence with this compound in a disease context, epilepsy, in which many practitioners do not feel always very comfortable.

Even in specialists' practice, phenobarbital has a place among therapeutic options (17). It may be chosen as add-on drug when several attempts at polytherapy have failed, particularly in patients with refractory primarily or secondarily generalized tonic-clonic seizures. Phenobarbital may be used in combination with any of the marketed antiepileptic drugs, whether old or new. However, dose adjustments of concomitant antiepileptic drugs are often required.

The patient's choice also is important. Many patients initially treated with phenobarbital as monotherapy prefer continuing with it even when it is proposed that they switch to a more recent drug, with a better benefit:risk ratio, that is theoretically more appropriate to their epileptic syndrome. Reasons for the preference are multiple, including fear of change, which is not specific to phenobarbital, as well as the advantage of a single daily dose and the strong, yet erroneous, belief that taking the drug at night will not interfere with their daily activities.

Besides some specific situations such as neonatal seizures or status epilepticus, practitioners may choose phenobarbital for the long-term management of specific categories of patients. For example, because of its relatively long half-life, phenobarbital may offer better protection against seizures in patients who are prone to short periods of noncompliance with therapy, for example, patients with alcoholism. In patients temporarily unable to take oral treatment, phenobarbital can be given by daily intramuscular injection or intravenous infusion in the same dose as the clinically therapeutic oral dose until oral therapy can be resumed (18,19).

The foremost reasons for the important place still occupied by phenobarbital treatment are its low cost and its worldwide availability. Phenobarbital is recommended by the World Health Organization as the first-line drug for the treatment of epilepsies in developing countries (20). Its broad spectrum is well suited to treating patients in places with no neurologists or electroencephalographic facilities. However, concerns exist about the suitability of phenobarbital as an antiepileptic drug for children, owing to its adverse effects on cognition and behavior. A randomized comparison of phenobarbital and phenytoin, aiming at the detection of behavioral side effects, showed similar acceptability of the two drugs as monotherapy for childhood epilepsy in rural India (21), even though it has been argued that phenytoin is also a nonideal choice for pediatric epilepsies (22). Another study in India concluded that phenobarbital is not the ideal treatment for school-age children (10b), but cost and drug availability considerations may not

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allow alternative choices for many patients who live in the developing world.

Use in Special Populations

Neonatal Seizures

Seizures occur in 1% to 2% of neonates admitted to intensive care units. Treatment is usually with either phenobarbital or phenytoin, but phenobarbital is most frequently chosen (23,24, 25, 26, 27). This choice is not based on its proven superiority but is founded on many years of familiarity with this drug among pediatricians. Analysis of the literature is difficult because many neonatal motor events, clinically classified as seizures, are unaccompanied by electrical seizure activity and are the result of non-seizure-related abnormal neonatal movements (28,29). Conversely, not all true neonatal seizures are recorded with surface scalp electroencephalograms (24). Most studies describing the efficacy of phenobarbital in the treatment of neonatal seizures used purely clinical criteria for diagnosis and assessment of outcome, whereas it is clear that use of videoelectroencephalographic monitoring for proper diagnosis and assessment will certainly improve our current knowledge. Three series show very close agreement regarding the efficacy of phenobarbital as the initial agent in the treatment of neonatal seizures. Lockman et al. (24), in a study of 39 neonates with loading doses of approximately 20 mg/kg, noted seizure control in 32% of the infants. Van Orman and Darrvish (27), in a study of 81 neonates who had received loading doses of phenobarbital at 15 to 20 mg/kg, in combination with phenytoin, noted seizure control in 33% of this population. Painter et al. (26), in a study of 77 neonates, noted that 36% of the study population had their seizures controlled after loading doses of 15 to 20 mg/kg of phenobarbital. Gal et al. (23), however, reported efficacy of 85% in 71 neonates in whom phenobarbital was used as monotherapy, and doses ≤40 mg/kg were given to achieve or surpass plasma concentrations of 40 mg/mL. The lack of specific seizure definition, electrically or clinically, in all these series makes the interpretations of the differences difficult.

One publication reported a series of 59 neonates with seizures that were confirmed by electroencephalography (30). The neonates were randomly assigned to receive either phenobarbital or phenytoin intravenously, at doses sufficient to achieve a free plasma concentration of 25 µg/mL for phenobarbital and 3 µg/mL for phenytoin. Neonates whose seizures were not controlled by the assigned drug were then treated with both drugs. Seizure control was assessed by electroencephalographic criteria. Seizures were controlled in 13 of the 30 neonates assigned to receive phenobarbital (43%) and in 13 of the 29 neonates assigned to receive phenytoin (45%). When combined treatment was considered, seizure control was achieved in 17 (57%) of the neonates assigned to received phenobarbital first and 18 (62%) of those assigned to receive phenytoin first. The severity of the seizures was a stronger predictor of the success of treatment than was the assigned agent. Neonates with mild seizures or with seizures that were decreasing in severity before treatment were more likely to have their seizures end, regardless of the treatment assignment. The conclusion is that phenobarbital and phenytoin are equally but incompletely effective as anticonvulsants in neonates. With either drug given along, the seizures were controlled in fewer than half of the neonates.

Although all the potential toxicities of phenobarbital are important, its cardiovascular effects and effects on brain growth are of greater immediate concern in neonates (31). However, investigators have reported that high-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia may improve neurologic outcome (32). In a randomized, prospective study with a 3-year follow-up, phenobarbital, when administered in a dose of 40 mg/kg intravenously, appeared to be safe and was associated with a 27% reduction in the incidence of seizures and a significant improvement in neurologic outcomes at 3 years of age.

Febrile Seizures

Febrile seizures are the most common seizure disorder in childhood, occurring in 2% to 5% of children. Investigators agree (33,34) that although evidence indicates that continuous antiepileptic therapy with phenobarbital or valproic acid is effective in reducing the risk of seizure recurrence, the potential side effects associated with continuous antiepileptic therapy outweigh the relatively minor risks associated with simple febrile seizures. As such, long-term treatment is not recommended, although intermittent prophylactic use of rectal diazepam may be considered on a case-by-case basis.

Anticonvulsant prophylaxis, however, could be considered in patients with neurologic abnormalities, prolonged (>15 minutes) or focal seizures, high rate of recurrences, febrile seizures associated with transient or permanent neurologic deficits, or a family history of nonfebrile seizures. Even when two of these risk factors are present, only 13% of children develop epilepsy, and 87% of this high-risk group do not. If phenobarbital is chosen for prophylaxis in the treatment of seizures, it should not be used intermittently; it must be administered daily. Faero et al. (35) compared 59 patients <3 years old with 172 untreated children of the same age. Of 27 children who maintained plasma levels of 16 to 30 µg/mL, only one (4%) developed a new febrile seizure compared with seven (22%) of 33 children who maintained plasma levels between 8 and 15 µg/mL. The rate of febrile seizure development in the untreated population was 20%.

A retrospective meta-analytic review was conducted to assess the efficacy of various medications in the prevention

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of recurrent febrile seizures (36). Forty-five articles were taken into account, but only nine trials were randomized and were placebo controlled, four using phenobarbital, three using diazepam, one using pyridoxine, and one using phenytoin. In one of the phenobarbital trails, sodium valproate was also compared with placebo. The risk of recurrence was significantly lower in children receiving continuous phenobarbital therapy than in those receiving placebo (odds ratio, 0.54; 95% confidence interval [CI], 0.33 to 0.90). The odds ratio for recurrences in the sodium valproate group was 0.09 (95% CI, 0.01 to 0.78). No difference in the risk for recurrences was found between children receiving intermittent diazepam and those receiving placebo (odds ratio, 0.81; 95% CI, 0.54 to 1.22). The risk of recurrences in children receiving pyridoxine or phenytoin did not differ from the risk among children receiving placebo. In a number-needed-to-treat analysis, four children would have to be treated with sodium valproate (95% CI, 2 to 11) or eight children would have to be treated with phenobarbital (95% CI, 5 to 27), continuously, to prevent one febrile seizure. As discussed earlier, however, neither phenobarbital nor valproate is recommended because the risk of adverse effects outweighs the benefits in an unselected population of children with febrile seizures. Although a prospective population-based case-control study found that neither febrile seizures nor phenobarbital affected behavior, school performance, and neurocognitive attention outcomes adversely (37), another report suggested that early phenobarbital treatment for simple febrile seizures may lead to late cognitive effects (38). Possibly, long-term impairment of developmental skills (language, verbal) was triggered during the period of treatment.

Status Epilepticus

Although generalized convulsive status epilepticus is a life-threatening emergency, the best initial drug treatment is uncertain. Phenobarbital is known to have advantages and disadvantages in the treatment of status epilepticus. Its anticonvulsant action is long, thus allowing use in subsequent long-term therapy, but adverse effects are considerable and include respiratory depression, excessive sedation, and hypotension. Theoretically, phenobarbital achieves a maximum brain:plasma ratio much more slowly than does diazepam, and the response time in the treatment of status epilepticus therefore may be considerably slower. Although current trends favor the combination of diazepam or lorazepam with phenytoin (39), several studies have shown that the effectiveness of phenobarbital may be as good as, if not better than, the other options. In a randomized, nonblinded clinical trial evaluating 36 consecutive patients with generalized convulsive status epilepticus, Shaner et al. (40) compared phenobarbital with a combination of diazepam and phenytoin. There were 18 episodes of status epilepticus in each treatment group. Phenobarbital was initially administered intravenously at a rate of 100 mg/min until a dose of 10 mg/kg was achieved. If the patient continued to convulse 10 minutes after treatment was initiated, phenytoin was administered intravenously, and additional phenobarbital was delivered. In the other treatment group, diazepam was infused at 2 mg/min intravenously, and phenytoin was administered simultaneously at a rate of 40 mg/min until a loading dose of 18 mg/kg was achieved. If the patient continued to convulse after delivery of an initial 20-mg dose of diazepam, a continuous diazepam infusion was administered. Convulsions were controlled in all 36 patients within 7 hours. The median cumulative convulsion time, however, was shorter for those patients receiving phenobarbital (5 minutes) than for those receiving the combination of diazepam and phenytoin (9 minutes). Sixteen of the 18 patients (89%) treated with phenobarbital exhibited clinical convulsive activity for < 10 minutes, and no patient demonstrated activity for >25 minutes. Ten of 18 patients (56%) in the diazepam-phenytoin group convulsed for <10 minutes, and five experienced a cumulative convulsion time of >25 minutes. The frequency of complications (i.e., arrhythmias, hypotension, and need for intubation) was similar among the two regimens. Sixteen of 18 patients required phenobarbital doses <12 mg/kg. Eleven of 18 cases were controlled with phenobarbital alone at a mean serum concentration of 18.3 µg/mL. Statistical evaluation did not demonstrate a dramatic difference between the phenobarbital and diazepam-phenytoin groups, but 95% CIs demonstrated that the mean cumulative convulsion time for the phenobarbital regimen was between 0 and 14 minutes less than that of the diazepam-phenytoin regimen.

Orr et al. (41) also noted a higher incidence of intubation with attendant complications in children receiving diazepam compared with those receiving phenobarbital for acute seizures. The response time of seizure control was no different between phenobarbital and diazepam. Rather than the postulated 20-minute response latency noted by some investigators, Shaner et al. (40) noted a median response time to phenobarbital of 5.5 minutes. The finding is in keeping with experimental data demonstrating that although maximum brain:plasma ratios of phenobarbital may be achieved only after 60 minutes after administration, effective brain concentration of phenobarbital are achieved within 3 minutes (42,43). A comparison of four treatments for generalized convulsive status epilepticus was conducted by the Veterans Affairs Status Epilepticus Cooperative Study Group (44), in a 5-year randomized, double-blind, multicenter trial of four intravenous regimens: diazepam (0.15 mg/kg body weight) followed by phenytoin (18 mg/kg body weight), lorazepam (0.1 mg/kg), phenobarbital (15 mg/kg), and phenytoin (18 mg/kg). Five hundred eighteen patients were classified as having either overt generalized status epilepticus (defined as easily visible generalized convulsions) or subtle status epilepticus (indicating by coma and ictal discharges on the electroencephalogram,

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with or without subtle convulsive movements such as rhythmic muscle twitches or tonic eye deviation). Treatment was considered successful when all motor and electroencephalographic seizure activity ceased within 20 minutes after beginning the drug infusion and there was no return of seizure activity during the next 40 minutes. In the group of overt generalized convulsive status epilepticus, lorazepam was successful in 64.9% of those assigned to receive it, phenobarbital in 58.2%, diazepam plus phenytoin in 55.8%, and phenytoin in 43.6% (p = .02 for the overall comparison among the four groups). Lorazepam was significantly superior to phenytoin in a pairwise comparison (p = .002). Among the 134 patients with a verified diagnosis of subtle generalized convulsive status epilepticus, no significant differences among the treatments were detected (range of success rates, 7.7% to 24.2%). In an intention-to-treat analysis, the differences among treatment groups were not significant, either among the patients with overt status epilepticus (p = .12) or among those with subtle status epilepticus (p = .91). There were no differences among the treatments with respect to recurrence during the 12-hour study period, the incidence of adverse reactions, or the outcome at 30 days. Thus, phenobarbital is not less efficacious than lorazepam or diazepam plus phenytoin as initial intravenous treatment for overt generalized convulsive status epilepticus. Although benzodiazepines may be easier to use, and in spite of some theoretic limitations, phenobarbital may be as effective as any other treatment regimen in the therapy of status epilepticus.

Discontinuation of Therapy

Because phenobarbital has a relatively long half-life, even if intake of the drug is ceased abruptly, the antiepileptic effect should decline progressively during 1 or 2 weeks, and this should alleviate the risk of withdrawal seizures. Nevertheless, most clinicians prefer to withdraw barbiturates gradually during a period of some weeks or months, unless there is a good medical reason for ridding the body of the drug as quickly as possible, for example, because of a serious idiosyncratic adverse effect. Thus, the dose may be reduced by 25% of its initial value each month for 4 months or by 33% each month for 3 months. The effects on seizure recurrence of slow phenobarbital withdrawal have been assessed, in comparison with other antiepileptic drugs (45). Patients were randomized to either continued treatment or slow drug withdrawal. This study did not support the contention that barbiturates are more likely to be associated with withdrawal seizures, as compared with carbamazepine or phenytoin.

Contraindications and Precautions

Phenobarbital is contraindicated in persons with histories of previous hypersensitivity reactions to the agent and in patients with porphyria. Barbiturates should be used with cautions in persons with medically important disorders treated with therapeutic agents whose clearances are likely to be altered by the administration of an inducting agent such as phenobarbital. An example would be persons receiving oral anticoagulant therapy. Some of the alternative antiepileptic drugs (phenytoin, carbamazepine) possess similar disadvantages. Phenobarbital should also be used cautiously in persons with hepatic insufficiency and in elderly patients. In both these populations, lower-than-usual doses may be indicated (18).

REFERENCES

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