Address correspondence to Meir Bialer, Faculty of Medicine, School of Pharmacy, Institute for Drug Research, The Hebrew University of Jerusalem, POB 12065, Jerusalem 91120, Israel. E-mail:

Phenobarbital, 5-ethyl-5-phenyl barbituric acid, was introduced to treat epilepsy in 1912. Phenobarbital was the second barbiturate in clinical use, following barbital’s (Veronal, or 5,5-diethyl barbituric) introduction in 1903 (Cozanitis, 2004). The history of barbiturates as antiepileptic drugs (AEDs) began in 1912 with Hauptmann’s report that a patient with epilepsy had fewer seizures when given phenobarbital for sedation (Hauptmann, 1912). In 1919, Horlein, while working for Bayer, introduced phenobarbital (Luminal); the patent rights were granted to Bayer in 1916. Phenobarbital was rapidly recognized as a better and safer AED than bromides; consequently it replaced bromides, which had been the only AEDs used since 1857 (Dundee & Mellroy, 1982). Phenobarbital has a more prolonged pharmacologic action that its predecessor and soon became the “king of the barbiturates,” both in the hospital and in outpatient care (Shorter, 1997). The initial clinical success of phenobarbital and other barbiturates affected the design of subsequent AEDs (e.g., phenytoin, primidone, and ethosuximide) developed between 1938 and 1962, in that their chemical structures resemble that of phenobarbital. However, the empirical discovery of carbamazepine (1962) and the serendipitous discovery of valproic acid (1967) led to subsequent AEDs having chemical structures that are diverse and completely different from that of phenobarbital (Bialer & White, 2010; Bialer, 2012a).

One hundred years after the discovery of phenobarbital’s antiepileptic activity, the mechanism of its antiepileptic activity is still not completely understood. At least in part this is due to the lack of specific barbiturate antagonists and the fact that barbiturates exert diverse effects on synaptic function apart from their potentiating action on γ-aminobutyric acid (GABA)ergic transmission. However, at clinically relevant concentrations, phenobarbital acts primarily as a GABA potentiator, although it is weaker than hypnotic/anesthetic barbiturates such as pentobarbital. Furthermore, hypnotic/anesthetic barbiturates such as pentobarbital act also on calcium channels and, at anesthetic levels, directly open GABAA receptor–associated chloride channels. In addition, effects on extrasynaptic GABA receptors may be involved in the sedative/hypnotic effects of barbiturates. Overall, potentiation of synaptic GABAergic transmission is the most likely mechanism of the antiepileptic action of phenobarbital, but contributions of additional mechanisms such as blockade of non–N-methyl-d-aspartate (NMDA) [2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid) (AMPA/kainate] receptors and voltage-activated calcium channels cannot be ruled out (Löscher & Rogawski, 2012).

Several observational studies undertaken in developing countries over the last decade have confirmed phenobarbital’s efficacy and safety for the common epilepsies. This was particularly so in the substantial demonstration project undertaken in rural China. Phenobarbital is still widely used for neonatal and childhood seizures and for drug-resistant convulsive and nonconvulsive status epilepticus. Recent data have confirmed, in a prospective cohort of women taking phenobarbital as monotherapy, that the drug can be associated with a range of congenital defects in exposed infants. Data over the last 10 years, including a systematic review, showed no important differences between the tolerability of phenobarbital compared to that with other AEDs. Finally, cognitive test scores and mood ratings in 136 people with epilepsy receiving phenobarbital for a year were similar to those in 137 age-, sex-, and education-matched controls in a number of Chinese villages. Indeed, there were some cognitive gains in the patients possibly due to improved seizure control.

The following AEDs were introduced between 1990 and 2012: eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, pregabalin, retigabine, rufinamide, stiripentol, tiagabine, topiramate, vigabatrin, and zonisamide. All of these AEDs (except vigabatrin and tiagabine) were developed empirically using mechanism-unbiased anticonvulsant animal models. The empirical nature of the discovery of these AEDs, coupled with their multiple mechanisms of action, explains their diverse chemical structures. With 16 AEDs introduced in the last 22 years and the older AEDs still in use, the antiepileptic market is crowded. Consequently, epilepsy alone is not attractive in 2012 to the pharmaceutical industry, even though the clinical need to treat refractory epilepsy remains unmet. Therefore, future design of new AEDs must also have the potential to treat nonepileptic central nervous system (CNS) disorders, such as bipolar disorder, neuropathic pain, migraine, and restless legs syndrome.

The barbiturates were once used as sedative-hypnotic drugs but have been largely replaced in this role by the much safer benzodiazepines (Mihic & Haris, 2011). In contrast, phenobarbital is still used worldwide in epilepsy and is still the most cost-effective pharmacologic treatment for epilepsy. Phenobarbital thus has a healthy future, particularly in helping to close the treatment gap in low- and middle-income countries during its second century of clinical use. Recently, phenobarbital celebrated its first 100 years with a special Centenary Symposium during the 10th European Congress on Epileptology (ECE) in London (September 30–October 4, 2012.). The symposium comprised the following four lectures, and their manuscripts (proceedings) make up this special Phenobarbital Epilepsia supplement: (1) How phenobarbital chemical structure affected the development of subsequent new AEDs (Bialer, 2012b); (2) How theories evolved concerning the mechanism of action of barbiturates (Löscher & Rogawski, 2012); (3) How phenobarbital revolutionized the drug treatment of epilepsy (Yasiry & Shorvon, 2012); and (4) The current position of phenobarbital in epilepsy and its future (Brodie & Kwan, 2012).

Remarkably, and with the exception of aspirin (1899) and paracetamol or acetaminophen (first used in medicine in 1893 but gained popularity only after 1949) (Grosser et al., 2011), Phenobarbital is the only synthetic drug and the only barbiturate that is still widely used worldwide 100 years after its introduction to clinical practice.


MB has received in the last 3 years speakers or consultancy fees from BioAvenir, CTS Chemicals, Desitin, Janssen-Cilag, Rekah, Sepracor, Tombotech, UCB Pharma, and Upsher Smith. MB has been involved in the design and development of new antiepileptic and CNS drugs as well as new formulations of existing drugs. PS has no conflicts of interest relevant to this manuscript. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.