Phenobarbital

Combinations

Barbexaclone is a combination of phenobarbital with levopropylhexedrine. Tetrabamate is a combination of phenobarbital, difebarbamate, and febarbamate.

Comparative studies

In a randomized trial in newly diagnosed patients, adverse reactions leading to withdrawal were more common with phenobarbital (22%, mostly drowsiness and lethargy) than with all other drugs combined (carbamazepine 11%, phenytoin 3%, valproate 5%) [ ].

In a 12-month, double-blind, randomized comparison of the behavioral adverse reactions to phenobarbital (n = 54) and carbamazepine (n = 54) in Bangladeshi children with epilepsy [ ]. Ten children developed excessive restlessness and hyperactivity. Four were taking phenobarbital and six carbamazepine. These were considered unacceptable in one patient taking phenobarbital and in three taking carbamazepine. There was no excess of behavioral adverse effects associated with phenobarbital.

Nervous system

Unusual manifestations of neurological toxicity of phenobarbital include regression of developmental milestones mimicking a neurodegenerative disorder in young children [ ] and unilateral choreiform hyperkinesia as a possible withdrawal symptom [ ].

In a 12-month trial in 109 epileptic children randomized to monotherapy with phenobarbital (maintenance dosage 3.0 mg/kg/day) or phenytoin (5.0 mg/kg/day) in rural India there were no significant differences in either efficacy or toxicity [ ]. In particular, behavioral adverse effects were not more common with phenobarbital. The findings suggest that phenobarbital is an acceptable first-line agent for childhood epilepsy in rural settings in developing countries.

In 114 patients, of whom 72% took phenobarbital, one had ataxia due to phenobarbital toxicity [ ].

Barbiturates occasionally cause nystagmus. A 37-year-old man with a history of seizures developed periodic alternating nystagmus along with other signs of primidone/phenobarbital toxicity [ ]. The nystagmus gradually diminished in cycle length and intensity, finally resolving with gradual drug withdrawal.

Psychiatric

Phenobarbital-induced behavioral disturbances, especially hyperkinesia, are especially common in children, with an incidence of 20–50%; drug withdrawal is required in 20–30% of cases. It is unclear whether and to what extent adults are affected in this way.

Endocrine

As well as enzyme induction, anticonvulsants can increase the binding of sex hormone-binding globulin. Since sex steroids bind with high affinity to sex hormone-binding globulin, and since phenobarbital increases sex hormone-binding globulin capacity, unbound active steroid concentrations will tend to fall during treatment with phenobarbital [ ]. In addition, in animals, phenobarbital increases steroid metabolism in both the gut wall and liver [ ].

Mineral balance

In 226 out-patients with epilepsy who were taking carbamazepine, phenytoin, phenobarbital, and sodium valproate, either monotherapy or in combination, hypocalcemia was more severe in those taking phenobarbital monotherapy than in those taking carbamazepine or phenytoin [ ]. None of those taking sodium valproate monotherapy had subnormal calcium concentrations. Concentrations of 25-hydroxycolcalciferol were similarly reduced and alkaline phosphatase increased in those taking phenobarbital, carbamazepine, and phenytoin, and were not altered in those taking sodium valproate.

Hematologic

A 22-year-old woman developed aplastic anemia after taking phenobarbital for 6 years [ ].

Liver

In two patients with a long history of epilepsy taking phenobarbital who suddenly died, the liver parenchyma showed rich portal inflammatory infiltrates and inflammatory reactions in the biliary ducts [ ]. The authors speculated that chronic liver damage in these patients had been caused by phenobarbital.

Skin

Rare effects of phenobarbital include erythroderma and an atypical lymphocytosis that mimics cutaneous T cell lymphoma [ ].

Drug rash with eosinophilia and systemic symptoms (DRESS) has been associated with the use of phenytoin, divalproex sodium, and phenobarbital [ ] and with phenobarbital alone [ , ].

Erythema multiforme [ , ], Stevens–Johnson syndrome [ , ], and toxic epidermal necrolysis [ ] have all been reported in patients taking phenobarbital. In some case the skin lesions have been associated with sites that had been exposed to radiation (the so-called EMPACT syndrome, more usually associated with phenytoin and cranial irradiation) [ ]; toxic epidermal necrolysis has also been reported in a patient with brain metastases treated with radiotherapy and taking phenobarbital [ ]. However, a review of the records of patients taking antiepileptic drugs, including phenobarbital, while undergoing radiotherapy for a high-grade glioma, in whom rashes occurred in 19%, and in whom phenytoin was most commonly implicated (93%) both before and during radiotherapy, most of the rashes (76%) occurred before starting radiotherapy. The authors reported that there did not appear to be an association between the use of cranial radiotherapy and the development of rashes associated with phenytoin or other antiepileptic drugs.

Musculoskeletal

The incidence of barbiturate-induced Dupuytren’s contracture, frozen shoulder, Ledderhose syndrome, Peyronie’s disease, fibromas, and joint pains may be up to 10% [ ]. Most affected patients develop connective tissue changes in the first year, although these become disabling at a later stage. These complications should be recognized early, since they are often reversible [ ].

Immunologic

Giant cell myocarditis has been reported in a patient taking phenytoin, phenobarbital, and mephobarbital and in one taking primidone [ ].

The antiepileptic hypersensitivity syndrome, a poorly defined entity, has occasionally been reported with phenobarbital [ ], with various manifestations. Cross-sensitivity among aromatic antiepileptic drugs occurs in about 50% of patients with a hypersensitivity reaction. In one case it occurred on first exposure to each of the offending drugs [ ].

Death

The efficacy of a single intramuscular dose of phenobarbital (20 mg/kg) in preventing seizures in childhood cerebral malaria has been the subject of a randomized, placebo-controlled study in 340 children in Kenya [ ]. Seizure frequency was significantly lower with phenobarbital than placebo: 18 versus 46 children had three or more seizures of any duration (OR = 0.32; 95% CI = 0.18, 0.58). However, mortality was doubled (30 versus 14 deaths; OR = 2.39; CI = 1.28, 4.64). The frequency of respiratory arrest was higher with phenobarbital than with placebo, and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam (OR = 32; CI = 1.2, 814). The authors felt that although phenobarbital was effective, the risks were too high to recommend using it.

Teratogenicity

In one series of 15 babies born to mothers who had taken phenobarbital during pregnancy there was significantly lower mean birth length, weight, and head circumference [ ].

In 88 women used phenobarbital 400–3000 mg in suicide attempts and later delivered live babies, 12 the exposed children and eight of 78 sibs were affected with congenital abnormalities (OR = 1.4; 95% CI = 0.6, 3.5) [ ]. Of the 88 exposed children, 34 were born to mothers who attempted suicide with phenobarbital between the 3rd and 12th postconceptional weeks; three had congenital abnormalities (diaphragmatic defect, multiple CA, undescended testis), but the authors thought that only diaphragmatic defects might be associated with phenobarbital used in suicide attempts.

The North American Pregnancy Registry has analysed data from 4899 women taking antiepileptic drug monotherapy and 442 women with epilepsy and no exposure to antiepileptic drugs [ ]. The antiepileptic drugs that were associated with higher risks of birth defects compared with unexposed patients were topiramate, valproate, and phenobarbital.

In a study of the use of phenobarbital in the mothers of 22 843 babies with congenital abnormalities and 38 151 matched controls without congenital abnormalities in the Hungarian Case-Control Surveillance System of Congenital Abnormalities, 149 (0.65%) of the former were born to mothers who reported having taken phenobarbital and 209 (0.55%) of the latter were born to mothers who reported having taken phenobarbital (OR = 1.3; 95% CI = 1.1, 1.7) [51]. Only hypospadias had an apparently higher risk after phenobarbital treatment in the critical period (OR = 2.4; 95% CI = 1.1, 5.4). However, if only medically recorded phenobarbital treatment was evaluated and multiple testing bias was considered, the association disappeared. This stresses the importance of excluding recall bias and multiple testing bias.

Use of methylphenobarbital during pregnancy has been associated with oral clefts and cardiac malformations [ ].

Fetotoxicity

After prenatal exposure to anticonvulsants, small head size has been observed in neonates and cognitive impairment in infancy. However, it is currently unknown whether these effects are permanent or disappear later in life. Head size and cognition have been studied in adults who had been exposed in utero to phenobarbital plus phenytoin and who as neonates had a significantly smaller occipitofrontal circumference than neonates who had been exposed to phenobarbital alone or controls (mean difference 0.7 cm) [ ]. There was no difference in cognitive functioning between the exposed and the control groups, and most of the exposed subjects had normal intellectual capacity. However, 12% of the exposed subjects versus 1% of the controls had persistent learning problems. In addition, more of the exposed subjects were mentally retarded. The authors concluded that the combination of phenobarbital plus phenytoin reduced neonatal head size, which was not associated with reduced cognitive functioning in adulthood, but was associated with learning problems and mental retardation.

Drug overdose

Phenobarbital overdose is reported from time to time [ , ] and can be fatal [ ]. Various treatments have been proposed [ ], including hemodialysis [ , ]. The administration of repeated doses of activated charcoal (“intestinal dialysis”) increases the rate of clearance of phenobarbital [ ], although in a prospective randomized study in 10 comatose patients it had no clear effects on the patients’ clinical course [ ]. In another study in 30 young patients multiple-dose activated charcoal alone was more effective in reducing plasma phenobarbital concentrations than either urinary alkalinization or the combined use of the two methods. In another study in 30 young patients multiple-dose activated charcoal alone was more effective in reducing plasma phenobarbital concentrations than either urinary alkalinization or the combined use of the two methods [ ].

Successful treatment of phenobarbital overdose can be followed by withdrawal symptoms [ ].