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Keywords:

  • History;
  • Antiepileptic drugs;
  • Epilepsy;
  • Treatment gap;
  • International League Against Epilepsy

Summary

  1. Top of page
  2. Summary
  3. The Drug Treatment of Epilepsy 1959–1988
  4. The Drug Treatment of Epilepsy 1989–2009
  5. Therapy of Epilepsy in 2009
  6. Acknowledgments
  7. References

The drug therapy of epilepsy evolved enormously in this 50 year period. Advances in therapeutics included the incorporation of pharmacokinetics into clinical practice, enormous advances in neurochemistry, a trend to antiepileptic drug monotherapy, better drug assessment, better understanding of therapeutic outcomes, and the recognition of the large epilepsy treatment gap in many countries. An unprecedented range of new drugs was introduced in this period. Before 1989, these included carbamazepine, valproate, ethosuximide, and the benzodiazepines. Since 1989, 13 more new drugs have been licensed and marketed and there are others in the pipeline. The International League Against Epilepsy and its leading figures have played an important role in these developments. In this period, too, there has been a rapid expansion in research and development within the pharmaceutical industry and a rise in the value of the antiepileptic drug market. In parallel, governmental regulation of pharmaceuticals has greatly increased. To what extent the overall prognosis of epilepsy has improved as a result of these activities is an interesting and perplexing question.

Drug therapy evolved enormously in the 50-year period, and continues to evolve. It is convenient to divide this half century into two—a first period of 30 years (1959–1988) and a second period of 20 years (1989–2009). There are good reviews of the scientific and clinical aspects of the drug therapies considered herein, and this article does not reiterate these aspects in any detail; rather the main purpose here is to attempt to document the evolution of therapy and the major milestones during this 50 years with a special emphasis on the role of the ILAE and Epilepsia, and to provide a context and overview of these milestones from the point of view of clinical practice. Such an attempt can be obviously only selective and highly subjective. Furthermore, the events are really much too recent to provide a historical perspective, especially on the past 20 years.

The Drug Treatment of Epilepsy 1959–1988

  1. Top of page
  2. Summary
  3. The Drug Treatment of Epilepsy 1959–1988
  4. The Drug Treatment of Epilepsy 1989–2009
  5. Therapy of Epilepsy in 2009
  6. Acknowledgments
  7. References

This was a period with a number of remarkable developments: carbamazepine, valproate, and the benzodiazepine drugs were discovered and introduced; extraordinary advances occurred in the basic sciences of pharmacology and neurophysiology; therapeutic drug monitoring (TDM) was introduced and had a major impact on epilepsy; a series of highly influential physicians became important players in the field of epilepsy therapeutics; the pharmaceutical industry rapidly expanded with concomitant rapid commercialization of the therapeutic arena; and regulation and restriction arose in parallel.

The International League Against Epilepsy (ILAE), too, grew in this period in terms of size and importance, and began—as an organization—to influence epilepsy practice, not least through the establishment of “commissions,” of which the most important was the Commission on Antiepileptic Drugs, and the active involvement of its leaders with drug therapy. ILAE conferences were the showplace for information about these new drugs, and Epilepsia was increasingly the journal of first choice for publishing in this area. These aspects are described in detail in the ILAE centenary history (Shorvon et al., 2009b) and are not considered further here. This omission, however, should not be taken to detract from the vital facilitatory role of the ILAE in epilepsy therapy. These were also the postwar period years of plenty, characterized for most of the time by sustained economic growth and optimism; in these years major advances were made in epilepsy therapy, and the basic approach to therapy that evolved during this period remains virtually unchanged today.

Therapy in 1960

A good place to start this historical consideration of these years is Lennox’s two-volume textbook (Lennox, 1960). Lennox was the first president of the ILAE after its reawakening in 1937 and also largely responsible for nursing the ILAE and its journal through the second world war (Shorvon et al., 2009b). This book, written in Lennox’s typical flowery style, was the definitive American text. Like most others before him (including Turner, Muskens, and Wilson), Lennox discusses treatment under a series of headings of which drug therapy is only one: hygienic and metabolic; drug therapy; surgical therapy; and psychotherapy. The most novel departure in the structure of the book compared to previous texts was the section on psychotherapy, which reflected the impact of Freudian thought and the rise of psychoanalytic psychotherapy.

Perhaps surprisingly from the perspective of today, hygiene had first place in Lennox’s book. This heading included various lifestyle issues and diet, and the recommendations were similar to those of earlier authors (for instance Kinnear Wilson, Muskens, and Turner). Lennox wrote, “The close relationship of measures that make for good health is exemplified by the fact that Hygeia, the goddess of health, was no other than the daughter of Aesculapius, the god of medicine.” In regard to diet, Lennox had no particular recommendation except for an endorsement of the ketogenic diet, but he commented: “In spite of the proven value of the ketogenic diet, it is little used today except in certain long-established centers, such as the Mayo and Johns Hopkins Clinics and the colonies of Denmark and Holland. The reasons are obvious: effective medicines are now available, the diet is limited and distasteful to the patient, and time-consuming and expensive for the parent.” Lennox considered dehydration to be ineffective, starvation to be temporarily helpful, activity to be encouraged and convulsive therapy to have some place: “To hold a drowning man under the water seems no more illogical than to give an epileptic a convulsant drug. Yet fire can be fought with fire, and cowpox prevents smallpox”(Fig. 1).

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Figure 1.   The colorful covers of the textbook of Lennox.

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The focus of this chapter is on drug therapy, and to this Lennox devoted 100 pages of his book. He offered “fifteen suggestions that as possible guide lines lead towards successful drug therapy,” all of them homespun of the type “Treat the patient,” not just his symptoms, “Prescribe adequate dosage” and “[Watch] the waves” [i.e., the electroencephalography (EEG)]. His philosophy no doubt partly reflected the complacency and smugness of his class, but the principles of therapy he outlined have been very influential and indeed are essentially similar to those that determine treatment today—and this despite 50 years of subsequent clinical research and a massive literature.

Lennox detailed his “therapeutic arsenal,” 16 drugs “in use in the United States” (see Table 2). He prefaced his list with a section on the question of drug-induced fatalities. Lennox wrote strangely that “agranulocytosis may be an ‘act of God’ coming or going without any explanation that man can offer.” Clearly drug risks concerned physicians less then than now. Nevertheless, this was the first major epilepsy book in which drug-induced fatalities were a prominent consideration. Severe skin and blood reactions were discussed, principally in connection with mesantoin, Phenurone, the diones, and Diamox (Table 1).

Table 2.   Annual cost of anticonvulsant drugs available in the United States in 1960 [at 2007 values (derived from Lennox, 1960)]
Drug Daily dose (mg/day)Cost for a year’s supply Manufacturer
  1. 2007 values calculated on the basis of the change in consumer price index (CPI) between 1960 and 2007 (an approximately 70-fold rise in CPI over this period).

Bromide4,000140
Celontin (methsuximide)900476Parke, Davis
Dexedrine (dextro-amphetamine sulphate)10308Smith, Kline and French
Diamox (acetozolamide)1,0001,225Lederle
Dilantin (phenytoin)400203Parke, Davis
Gemonil (metharbital)400203Abbott
Mebaral (mephobarbital500343Winthrop-Stearns
Mesantoin (mesantoin)600147Sandoz
Milontin (phensuximide)2,000644Parke, Davis
Mysoline (primidone)1,500992Ayerst, McKenna and Harrison
Paradione (paramethadione)900462Abbott
Peganone (ethotoin)1,500441Abbott
Phenobarbital20077
Phenurone (phenacemide)1,500399Abbott
Tridione (trimethadione)900399Abbott
Table 1.   Lennox’s “therapeutic arsenal”
Noncommercial official namePatented trade namePossible danger to
  1. Phenurone and Diamox were noted to be often effective against petit mal as well, and phensuximide to be often effective against grand mal (From Lennox, 1960, 2:845).

  2. aDrugs of initial choice.

  3. bDrugs of second choice.

Grand mal and psychomotor seizures
 Bromides Bromides 
 PhenobarbitalaLuminal 
 MethobarbitalMebaral 
 DiphenylhydantoinaDilantin 
 MesantoinMesantoinBlood
 EthotoinPeganone 
 PrimidoneaMysoline 
 PhenacemidePhenuroneBlood, liver
 MethsuximideaCelontin 
 AcetazolamideDiamox? Blood
 TrimethadionebTridioneBlood, kidney
 ParamethadioneaParadione?Blood, ?kidney
 PhensuximideaMilontin 
 Ethylmethylsuccinimide Zarontin 
 Quinacrine hydrochlorideAtabrine 
 MetharbitalGemonil 

At the top of Lennox’s list were bromides, which owing to their side effects and relative ineffectiveness were “little used today.” Barbiturates were greeted more enthusiastically. Lennox mentioned that 2,500 compounds had been synthesized, and of these 50 compounds were marketed of which phenobarbital was the most frequently used for epilepsy. Mephobarbital (Mebaral) he pronounced “the only barbiturate besides phenobarbital effective against epilepsy” and a drug that seemed to have more effect on “petits” (Lennox’s familiar name for petit mal). He was enthusiastic about phenytoin, especially for patients “with long-standing convulsions previously unrelieved by phenobarbital,” although Mesantoin outranked it on several points, and indeed he favored their combined use: “Mesantoin and Dilantin are Damon and Pythias in respect to their suitability for joint action. Similarity of action gives a doubled therapeutic effect; the dissimilarity of their side reactions keeps these within bounds.” Ethotoin was said to be one of the 1,500 compounds screened by Abbott Laboratories in the previous 8 years (presumably using the Merritt Putnam method) and although effective, was associated with a high rate of blood dyscrasia. Primidone was “especially welcomed as a contribution from abroad” (manufactured by ICI in England). Phenacemide was “what in athletics might be called a triple threat because, more than any other drug, it acts against each of the three main types of seizures, and especially against the most feared psychomotor seizures. However, it is also a triple threat to the patient himself because of possible effect on the marrow, the liver or the psyche.” Given one chance in 250 of not surviving this treatment, he asked, “Is the risk too great?” Methsuximide (Celontin), useful in the treatment of petit mal was like a “pusher” locomotive. Acetazolamide (Diamox) was noted to “lack … staying power”—in other words, tolerance. Trimethadione (Tridione) “heads the list of drugs that are peculiarly beneficial to persons subject to petits, and less distinctly for the other members of the petit mal triad …. World-wide acceptance of Tridione was attained more quickly than acceptance of Dilantin, [but] Tridione had no competitor.” Paramethadione (Paradione) he thought to be somewhat better than trimethadione for the treatment of petit mal but worse for grand mal. Phensuximide (Milontin), ethlymethlysuccinimide (Zarontin), quinacrine hydrochloride (Atabrine), and metharbital (Gemonil) were also mentioned briefly, as well as two combination compounds and three “accessory preparations” and some tranquilizing drugs. Cost was an important issue for Lennox. Table 2 shows his list of the costs of drugs (to the patient in the United States) converted to current values. Note how inexpensive the drugs were at this time (Table 2).

Advances in epilepsy therapeutics 1959–1989

This period was one of rapid growth in clinical therapeutics, in many areas of medicine. In the field of epilepsy, four particular topics are worth specific mention here, in view of their great general importance to epilepsy therapeutics. These were all again areas in which the ILAE and ILAE leaders played important roles (see Shorvon et al., 2009b).

TDM and the rise of pharmacokinetic study of antiepileptic drugs

The application of pharmacokinetic principles to epilepsy therapy was a most important clinical advance in the 1960s and 1970s. It is covered elsewhere in this issue, but here I provide a brief overview of the early development and subsequent clinical milestones. This was a topic in which ILAE officers took an active lead, and the involvement of the League was undoubtedly a factor in recognizing the importance of these principles in clinical epilepsy practice. Indeed, this was an area in which epilepsy initially at least was in the vanguard of the medical specialisms.

The measurement of antiepileptic drug serum levels began to be studied systematically in the late 1950s, although the technologies had been available for some years before. This early development was methodology driven (as is almost always the case when new technologies are introduced, for instance in EEG and neuroimaging). It was also stimulated by the regulatory requirement for pharmacologic information by the pharmaceutical industry. Extensive studies of bromide, ethosuximide, phenytoin, and phenobarbital were conducted initially, and within a decade or so the clinical pharmacokinetic properties of all the antiepileptic drugs—their absorption, distribution, metabolism, and excretion—were fully documented. In the 1960s, too, the measurement of serum levels of drugs entered clinical practice, and soon, in advanced units in several countries, laboratories were routinely measuring levels. Initial studies were conducted in the late 1950s and early 1960s by Fritz Buchthal (the husband of Margaret Lennox-Buchthal, the future editor of Epilepsia) and colleagues, who found a relationship between the blood levels of phenytoin and phenobarbital and antiepileptic their efficacy and central nervous system (CNS) side effects (Buchthal & Svensmark, 1960; Buchthal et al., 1960; Svensmark & Buchthal, 1963, 1964; Buchthal et al., 1968; Buchthal & Svensmark, 1971). The classic paper by Kutt and Penry (1974) was particularly influential. These were landmark studies and spawned an enormous explosion of interest in TDM, and in pharmacokinetic studies of antiepileptic drugs. Phenytoin was of course a lucky choice, as the strong level–effect relationships and the saturation kinetics render clinical serum level measurements extremely useful. This does not apply to many other drugs, and had phenytoin not been a dominant therapy, it is possible that the whole field of TDM in epilepsy might not have flourished.

In the late 1960s, a fairly comprehensive definition of the pharmacokinetic parameters of all the available antiepilepsy drugs had been achieved. These data were now required for registering drugs, and studies were stimulated in part by the pharmaceutical industry. During the 1970s, it also became clear that studies were needed in special populations such as children, the elderly, those with renal and hepatic disease, and pregnant women. By the early 1980s, the characterization of the hepatic enzyme systems was largely complete, and the relevant factors, both environmental and genetic, were intensively studied.

A veritable industry has arisen related to drug interactions. This started with the study of phenytoin in the mid-1960s, and by 1972 large-scale interactions with warfarin, disulfiram, sulthiame, phenobarbital, digoxin, chloramphenicol, isoniazid, methylphenidate, and chlordiazepoxide had been defined. The finding of the massive interaction between sulthiame and phenytoin also largely terminated the use of the former drug. Interaction studies have continued ever since, and although the database is progressively enlarged as new drugs are introduced, the basic principles have not changed. In the 1980s, the subgroups of the P450 hepatic enzyme system (and to a lesser extent the UDP-glucuronosyltransferase [UGT] and other systems) were characterized, and their genetic and epidemiologic features explored. The regulatory agencies in the 1980s responded by requiring the pharmaceutical industry to provide more and more interaction data prior to licensing and to register data about dosage adjustments (sometimes very complex, as was the case for instance with lamotrigine). This not only increased the duration and cost of drug development but also stimulated interest in producing drugs that avoided metabolic processes at the hepatic enzyme level. Interactions were also a major factor in the move to monotherapy in epilepsy.

In the last decade, in vivo testing models for determining the relevance of individual enzymes has provided a mechanism for the preclinical prediction of drug interactions. Another area of interest is that of pharmacogenomics. This has focused on drug targets, cerebral drug transporters, hepatic enzyme activity, and susceptibility to idiosyncratic reactions. The work on hepatic enzymes and idiosyncrasy has been useful, but, to date, pharmacogenetic work on drug targets and transporters has not made discoveries of any clinical utility (Fig. 2).

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Figure 2.   An early attempt to encourage the use of serial blood-level estimations.

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Epilepsy developments in the United States: the Epilepsy Section and Epilepsy Branch at the NIH 1959–1988

By 1970, there was considerable disquiet in the American epilepsy community about the lack of new drugs. No drug had been licensed in the United States for 10 years, and yet there was a sizeable population of intractable patients and all 13 contemporary drugs had side effects that were of increasing concern. European colleagues were able to use various compounds that were not available in America, including carbamazepine, valproate, sulthiame, and clonazepam. This was partly attributed to the restrictions imposed by the Kefauver–Harris amendments but also due to the prevalent view within the pharmaceutical industry that epilepsy “did not need new drugs.”

In 1959, Richard Masland was appointed director of the National Institute of Neurological Diseases and Blindness (a post he held until 1968). Masland had previously been professor of neurology and psychiatry at the Bowman Gray School of Medicine at Wake Forest College in Winston-Salem and had a prior interest in epilepsy. Soon after his appointment, he decided to set up an epilepsy section, and in 1966 he recruited the young J. Kiffin Penry, who has worked with him at Bowman Gray, to head up the section. This was a momentous decision, for over the next two decades while at the National Institutes of Health (NIH), Penry (later also ILAE president) led an enormous revival of epilepsy research in the United States. The epilepsy “section” was later transmuted into a “branch,” and Penry was appointed its head and also director of the Neurological Disorders Program. In these positions Penry spearheaded a range of activities that was without parallel. An effort due largely to Penry’s focused vision, his energy, and his extraordinary enthusiasm. He first set about reviewing current research. He realized that no company was developing antiepileptic drugs and no large-scale facility for assessing drugs existed, apart from work carried out by Goodman and Swinyard in Utah. A report was commissioned from James Coatsworth (1971) that showed that current therapy was old-fashioned and inadequate. On the basis of this assessment, Penry set up the Antiepileptic Drug Development Program in 1969, which had a number of arms. Six “comprehensive centres” for epilepsy across the country were established to act as a focus for research and training. An ad hoc committee was created to design clinical trial protocols that would be acceptable to the U.S. Food and Drug Administration (FDA). Six drugs licensed in Europe were then evaluated in a series of controlled clinical trials, via NIH contracts, conducted at medical universities and a state hospital. On the basis of these trials, three drugs received FDA approval and were marketed (carbamazepine, 1974; clonazepam, 1975; and valproic acid, 1978) and three were rejected (sulthiame, albutoin, and mexiletine) on the basis that they failed to provide sufficient evidence of clinical efficacy. When Roger Porter (future ILAE secretary-general) was appointed to the Epilepsy Branch, he with Penry formed two new sections: a section on preclinical pharmacology headed by Harvey Kupferberg and a section on technical information headed by Billy White. Both were to prove highly influential. In a third important development, to fill the void in preclinical anticonvulsant research and to stimulate new drug development, Penry then launched, with Kupferberg and Ewart Swinyard, a preclinical anticonvulsant screening project (ASP) in 1975 and a toxicity testing project in 1979 (Fig. 3).

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Figure 3.   J. Kiffin Penry, one of the most important figures in 20th century epileptology.

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The ASP was based at the University of Utah, where it remains an enduring legacy of the Penry period at NIH (Krall et al., 1978; Kupferberg, 1989). The program provides facilities for screening new compounds for antiepileptic drug action, at no cost, for academic medicinal chemists and the pharmaceutical industry. Within 2 years of its establishment, 1,780 compounds had been tested, which originated from academic sources and the pharmaceutical industry. In these initial 2 years, 27% of compounds were shown to have antiepileptic efficacy, of which 21% were potent and 13 were thought to have potential in the treatment of human epilepsy and entered clinical trial. This program was also set up partly in response to the belief then that the commercial value of new antiepileptics was not sufficient for the pharmaceutical industry to take on the full cost. Criticisms have been leveled at the preclinical screening program, of which the most fundamental is that the screening methods—initially only the maximal electroshock (MES) and pentylenetetrazol (PTZ) tests—will identify me-too compounds and miss compounds with novel action. (Levetiracetam, for instance, an extremely important antiepileptic drug with a novel mechanism of action, would have been discarded in the ASP screening protocol.) However, the program continues, and 800 new compounds are tested each year, currently with an initial screening program of MES, subcutaneous pentylenetetrazol (scPTZ), and 6-Hz psychomotor seizure tests. A total of more than 22,000 compounds have been investigated since the program’s inception. Three compounds that were initially identified in the program have been licensed (felbamate, topiramate, and lacosamide). The program was also involved in pharmacologic work and model profiling of other compounds initially screened by the pharmaceutical company (for instance drugs such as gabapentin, lamotrigine, levetiracetam, and retigabine). Random screening is still one preferred method of drug discovery, and the relatively small number of drugs licensed from the huge number of screened compounds is an illustration of the mountain that has to be climbed.

Another very important project orchestrated by Penry and the Epilepsy Branch was the production of the book Antiepileptic Drugs, which was immediately and has remained the standard work on the topic and is now in its fifth edition. Penry had a remarkably prodigious written output, and among the large bibliographical projects he launched was a compilation of all published epilepsy articles extracted from the Index Medicus, another indispensible stimulus to epilepsy research (Penry & Rapport, 1973). On July 29, 1975, the U.S. government established a Commission for the Control of Epilepsy and Its Consequences, which in 1978 published an enormous four-volume report (Commission for the Control of Epilepsy and Its Consequences, 1978). Penry, being an employee of NIH, was not a member of this commission, but he influenced it from outside. Numerous recommendations were made for developing epilepsy services, and this report stimulated funding and activities in the field of epilepsy for a generation. Prior to these NIH activities, epilepsy in the United States, as elsewhere, had been a rather backward subject of little general interest. By the time Penry left the NIH in 1988, there were excellent academic centers of epilepsy throughout the country.

Antiepileptic drug monotherapy

One of the most influential changes in treatment strategy—the emphasis on single-drug therapy (monotherapy)—dates from the late 1970s. This became possible with the introduction of a wider range of new effective drugs (carbamazepine and valproate) and the widespread adoption of TDM. Prior to this, combination therapy was in effect the norm, even for newly diagnosed patients. A survey in 1975 of 11,720 patients from 15 centers in four European countries showed that the mean number of drugs taken per patient was 3.2, of which 84% were antiepileptic drugs (Guelaen et al., 1975). Furthermore, many pharmaceuticals were available in combination preparations. Reynolds, future ILAE president, and his colleagues pioneered a series of studies demonstrating that, with appropriate use of serum level monitoring, both new patients and chronic patients were often better off with single-drug therapy (Reynolds et al., 1976; Shorvon & Reynolds, 1977; Shorvon et al., 1978; Shorvon & Reynolds, 1979; Reynolds & Shorvon, 1981). Another factor in the previous trend to polytherapy was the poor quality of antiepileptic drug trials. Of 155 studies of carbamazepine and phenytoin reviewed in 1980, for instance, only 17% studied the drug in monotherapy, and of these none were controlled, all were of <100 patients, all were of <6 months duration, and none were of new patients (Shorvon et al., 1981).

All this was to change over the next two decades. Monotherapy became a theme in many national and international ILAE conferences and workshops and a byword in advanced therapy. Most combination preparations of antiepileptic drugs were removed from the market. There was a marked swing to monotherapy protocols in patients with epilepsy, and the nearly universal recommendation that antiepileptic monotherapy be initiated in new patients with the disorder. By the late 1980s the regulatory authorities had began to request monotherapy trials. Without them, a license for a drug would be granted only for use in combination therapy. The latter requirement can be viewed rather cynically as a mechanism for restricting spending on novel drugs, for no drug of which I am aware is effective in polytherapy but not monotherapy. The requirement certainly had the effect of greatly delaying licensing of new drugs for use in monotherapy in new patients.

Monotherapy as a concept had become central to drug prescribing, and remains so (by mid-2007, the PubMed database contained more than 2,300 references to anticonvulsant monotherapy). Recently, and perhaps as a counterreaction, the concept of rational polytherapy—that is, combinations of drugs with different modes of action that might have a synergistic as opposed simply to an effect—has been mooted, but there is little robust clinical evidence that this is advantageous.

The treatment of epilepsy in developing countries and the concept of the epilepsy treatment gap

From its beginnings, the ILAE has shown an interest in global aspects of epilepsy therapy, but a focus on the specific problems of epilepsy in developing countries really dates only from the mid-1980s, when thereafter successive ILAE presidents showed a particular commitment to developing countries. In 1985, a landmark was the setting up of an ILAE Commission (1985) for Developing Countries. This interest reflected the more general engagement of the public in Western countries in the plight of Asia and Africa, which dates from the early 1970s and is now at the center of political debate. Epidemiologic studies of epilepsy were first carried out in the 1970s and showed that epilepsy was, as everyone always knew anyway, a universal phenomenon that respected no national or racial boundaries. Incidence and prevalence rates showed then, and have continued to show, approximately similar findings in most parts of the world, albeit with a tendency to generally higher rates in developing countries and some clusters of very high rates. The higher proportion of children in populations of developing compared to developed countries meant also that the total number of people with epilepsy is highest in developing countries. Furthermore, before 1980, most of what is accepted dogma about the clinical aspects of epilepsy derived from studies done in the developed world and simply extrapolated to the situation in the developing world. This of course is highly inappropriate, and particularly in relation to sociocultural aspects.

Various large-scale research projects were launched to investigate therapeutic endeavors, and some were affiliated with the ILAE. Among these were the studies of ICBERG (International Community Based Epilepsy Research Group), which carried out a series of studies that were the topic of an entire session at the League’s International Congress in New Delhi in 1989.

Table 3.   The first reported treatment gap figures
CountryEstimated numbers of people with active epilepsya Estimate number of people receiving treatmentb Treatment gapc
  1. aBased on a prevalence of active epilepsy of 0.5%.

  2. bBased on drug supply figures, minimum standard doses, monotherapy.

  3. cThe percentage of people not receiving therapy at any one time.

Pakistan450,00022,00094%
Philippines270,00014,00094%
Ecuador55,00011,00080%

The “epilepsy treatment gap” was a term coined by Shorvon and colleagues (Shorvon & Farmer, 1988; Ellison et al., 1989) as part of the ICBERG activities. It refers to the percentage of patients in a defined population on any one day, with active epilepsy, who are not receiving anticonvulsant medication. The treatment gap was first calculated theoretically by dividing the figures for antiepileptic drug supply to a country by the estimated number of patients in the country with epilepsy (using an assumed prevalence of nonfebrile seizures of 0.5%, monotherapy, standard anticonvulsant drug dosages, and drug consumption figures based on commercial data). The method produced shocking results—an estimated treatment gap of 94% in Pakistan and the Philippines and 60% in Ecuador, for instance (Shorvon & Farmer, 1988). The one common factor in developing countries is a general lack of medical treatment available for people with epilepsy and the lack of programs to help sufferers. This is partly because epilepsy is not a fashionable disease whose control would bring political kudos. But other important factors include the challenge of treating a chronic condition, lack of reliable drug supplies, cultural views of patients, and the often very inadequate levels of medical manpower.

In 1997, in partnership with the International Bureau for Epilepsy (IBE) and the World Health Organization (WHO), the ILAE launched the Global Campaign against Epilepsy (GCAE). This campaign was conceived by then ILAE president Ted Reynolds and is the culmination of ILAE interest in global epilepsy issues. A primary goal of the GCAE is to reduce the epilepsy treatment gap through community-based interventions, and to address the other problems listed previously. How successful this will be is as yet not known, but a recent review of treatment gap figures suggests indeed that it may be lessening (Mbuba et al., 2008). Another important output of the GCAE was an atlas of epilepsy care that was published in 2005 (World Health Organization, 2005) and which provides information about resources for epilepsy cases from 160 countries. The data show that there are high levels of inadequate care and large inequalities of care—with low-income countries generally faring very poorly.

As a reaction to the hegemony of modern Western pharmaceuticals, one intriguing aspect of epilepsy treatment that has been explored in the last 40 years is the value of traditional therapies still employed in all cultures. A detailed description of these is outside the scope of this article, and some are outlandish and even ridiculous to Western eyes. However, they are widely practiced and adhered to. Nor is the use of alternative medicine confined to developing countries. A recent survey of all members of the Epilepsy Federation of Arizona found that 44% had used a nonconventional treatment for their seizures at some time (Sirven et al., 2003).

Antiepileptic drugs introduced into clinical practice between 1958 and 1988

During this period, a series of highly effective new drug therapies became available, some of which have endured and remain at the center of therapeutics today Table 4.

Table 4.   Drugs licensed in European countries 1958–1988
  1. Licensing varied from country to country and so given here is the date of first licensing or the first mention of its clinical use, in a country in Europe.

1958Ethosuximide
1962Sulthiame
1960Chlordiazepoxide
1963Chlormethiazole
1963Diazepam
1965Carbamazepine
1967Valproate
1968Clonazepam
1975Clobazam
1985Progabide
Ethosuximide (Zarontin)

One of the first groups of compounds to emerge in the euphoria that followed phenytoin was the oxazolidine-diones. Trimethadione (Tridione) was one of the first, but its use was limited by unpleasant side effects, especially hemeralopia, and occasionally exfoliative dermatitis and agranulocytosis. Miller and coworkers within the Parke-Davis Company, the manufacturer of phenytoin and indubitably then the “epilepsy” company, systematically explored other succinimides (Miller et al., 1951; Miller & Long, 1953). Based on this work, three derivatives were identified, licensed, and marketed: phensuximide (Milontin, 1953), methsuximide (Celontin, 1957), and then the ethyl derivative, ethosuximide (1958). The latter drug, α-ethyl-α-methylsuccinimide, initially studied as its laboratory name PM 671, was then given the approved name ethosuximide and the trade name Zarontin in 1958. The structural chemistry of all three succinimides is similar. Ethosuximide differs from Milontin by the substitution of an ethyl in place of a phenyl group at position 3 of the basic ring structure, and from Celontin by addition of a methyl group with the phenyl group.

In the 1950s it was recognized that these minor chemical changes result in a markedly different anticonvulsant spectrum and efficacy. And so it was. Celontin shows clear effectiveness in both petit mal and psychomotor seizures, but Milontin and Zarontin only in petit mal, with Zarontin far more powerful at clinically acceptable doses.

Ethosuximide acts by blocking the low-voltage T-type calcium channel, a mechanism that was identified only in 1984, some 16 years after the drug’s licensing. It was investigated in animal studies first, by protecting rats against the effects of Metrazol-induced seizures at a dose of 125 mg/kg. Toxicology was reported in monkeys, showing normal biochemical and hematologic findings and a reasonable side-effect profile. Zimmerman and Burgemeister (1958) were the first to report its effect in 109 cases of petit mal epilepsy, mixed petit mal (what we would probably now call atypical absence epilepsy in Lennox-Gastaut syndrome), and petit mal combined with other seizures. The drug was trialed at the high dose of 1,750 mg/day. An 85% reduction against baseline seizure rates during a follow-up of 10–96 weeks was reported. Forty-two percent obtained complete control, and 24% obtained 80–99% control. The drug proved much more effective in “pure petit mal” than in mixed petit mal or in petit mal combined with other seizures (grand mal and psychomotor), an effect independent of baseline seizure frequency, and no tolerance was observed. Toxic side effects comprised drowsiness, dizziness, nausea, and gastric distress, and were reported in only nine patients. Other reports followed, which were essentially confirmatory (Vossen, 1958; Heathfield & Jewesbury, 1961; Livingston et al., 1962, 1965). Heathfield and Jewesbury (1961) used doses that would be accepted as conventional today (most patients on 500–750 mg/day) and reported a more conventionally recognizable side-effect profile (34% of patients reporting apathy, depression, drowsiness, nausea, vomiting, and leukopenia). All of these early authors recognized that Zarontin was superior in effect, and caused less toxicity, than the other succinimides.

Psychosis as a side effect was first reported among the 60 patients studied by Lorentz de Hass and Stoel (1960). A case of Stevens-Johnson reaction was first reported in 1963 (Muller, 1963), and of drug-induced of systemic lupus erythematosus in 1968 (Livingston et al., 1968). The first case of fatal pancytopenia was reported in 1962 (Mann & Hebenicht, 1962), and it has since become clear that the drug has a significant propensity to cause acute and severe allergic reactions of many types.

A significant advance in the use of ethosuximide was the introduction of serum level monitoring. A rather nonspecific assay was published in 1963 (Hansen, 1963). A gas–liquid chromatography method was published in 1965, and by 1969, a modification of this method was in routine clinical use. The relation of efficacy to serum levels was first reported in 1970 (Haerer et al., 1970) in 21 patients and then by Penry et al. (1972) who found maximum clinical control at levels of 40–80 μg/ml. Sherwin et al. (1973) carried out a similar study and found that 93% of those controlled on ethosuximide had plasma levels above 40 μg/ml and confirmed the excellent correlation between effectiveness and plasma level. The conclusion from these studies has been repeatedly confirmed, and even today ethosuximide plasma levels remain an indispensible guide.

From about 1960, there was little disagreement among physicians that ethosuximide was the drug of choice for typical absence seizures, but it had limited effect on tonic–clonic seizures or atypical absence. Valproate was licensed in France in 1967 and was soon shown to be as effective as ethosuximide in controlling absence (but no more effective), and also to have a broader spectrum and to be safer. Rather surprisingly, it was not for many years that ethosuximide was replaced by valproate as the drug of first choice in absence epilepsy. Perhaps this was because valproate licensing was so delayed in the United States, or perhaps because of Parke-Davis’s reputation in epilepsy. Even into the late 1980s, ethosuximide was still widely prescribed as first-line therapy, and it has only been in the last 5 or so years that the drug was finally relegated to the far margins of conventional therapy.

Methsuximide (Celontin)

Methsuximide, with phensuximide and ethosuximide, was discovered in the systematic exploration of the oxazolidine-diones (Miller et al., 1951; Miller & Long, 1953). The first human studies were reported by Zimmerman (1951, 1953, 1954), Zimmerman & Burgemeister (1958), and it was licensed in 1957. It was soon recognized to have effects in psychomotor as well as petit mal seizures. The drug is highly metabolized, and the active metabolite is largely N-desmethyl-methsuximide. The first studies of correlation between serum levels and seizure control and toxicity were published in 1972. Although the drug shows the same general toxicity profile as other succinimides, it has a much smaller risk of serious hematologic or dermatologic allergy, and it has continued to have a minor place in therapy, right up to the present day.

Ethotoin (Peganone)

Ethotoin is a hydantoin drug, similar to phenytoin, and was found as the result of the large screening of hydantoin drugs. Ethotoin has fewer side effects than phenytoin, particularly in relation to the cosmetic effects of gingival hyperplasia and hirsutism, but it is less effective and because of its short half life requires frequent dosing. It also in some patients requires high doses (up to 3,000 mg/day). Although it was moderately popular when launched, it never achieved the position of phenytoin and is now only occasionally prescribed. It was manufacturered by Abbott and then sold on, and is now available from Ovation Pharmaceuticals.

Sulthiame (Ospolot)

This drug was produced in the laboratories of Bayer by Helferich and Kleb (1960) and launched in Europe in the early 1960s. It is a sulphanilamide drug, somewhat related to acetazolamide, and is a carbonic anhydrase inhibitor and this is probably its main mode of action. It became widely used for the treatment of partial seizures. However, a randomized clinical trial in the United States, carried out as part of the NIH initiative, was negative and for this reason this agent was never licensed in America (Green et al., 1974). Soon after its launch, a major interaction with phenytoin was recognized with sometimes very large increases in phenytoin levels when used in co-medication (Hensen et al., 1968). Because of this, doubts arose as to whether sulthiame has intrinsic antiepileptic action. It remained fairly commonly prescribed until the fashion for monotherapy prevailed and the view that its efficacy was mediated largely via the interaction with phenytoin gained general acceptance, and then in 1986 sulthiame was withdrawn from the market in the United Kingdom and then other countries. Although licensed originally for use in partial seizures, a specific action in benign rolandic epilepsy has been suggested, and the drug was also used in West syndrome, for myoclonic seizures, and for behavioral disorders. The ownership of sulthiame was transferred to Desitin in 1993 and it is sold in a few European countries only nowadays.

Carbamazepine (Tegretol)

By the end of the World War II, research into antiepileptic drug therapy (indeed, all drugs) was largely conducted, not as before by the universities and medical schools, but by pharmaceutical companies (valproate was a major exception). The rise of the pharmaceutical industry and its power and domination of the epilepsy agenda is a story as yet untold. Carbamazepine was developed in this way by the Swiss pharmaceutical firm Geigy, and was perhaps the first drug to produce large profits in the field.

Carbamazepine, initially known as G32883, was a compound first produced by Walter Schindler at Geigy in 1953 (Schindler & Häfliger, 1954). It has a tricyclic structure, similar to that of Tofranil, and was first investigated as a drug for depression and psychosis. Its effects on neuralgic pain were discovered by animal screening, and clinical trials confirmed its usefulness (Blom, 1962). It was in fact licensed and marketed in 1962, first for trigeminal neuralgia (although even then the blurb described it as a “new anticonvulsant drug”). Its antiepileptic effects had been investigated clinically in 1959, and first reported in 1963 by Bonduelle et al. (1964) and Lorgé (1964). In 1964, Jongmans (1964) published in Epilepsia a series of 70 patients treated with carbamazepine who were refractory to conventional drugs. Seventeen of 43 patients with grand mal seizures were rendered seizure-free, and 7 improved by >75%. Seven of 24 patients with psychomotor seizures were rendered seizure-free, and 3 improved by >75%. Doses of 600–2,400 mg were used, and no patient was withdrawn because of side effects. Its positive psychotropic effect was also noted. The drug rapidly gained a reputation in Europe as a very promising new antiepileptic. The first controlled trial was undertaken at a hospital for the mentally subnormal in 1966 (Bird et al., 1966). Tegretol was substituted for existing therapy with phenobarbitone in 50% of the subjects and compared to the continuation of phenobarbital in the other 50%. Identical white tablets were produced containing phenobarbital, phenytoin, primidone, and carbamazepine, and the staff and patients were blinded to which drug was being taken. The study was conducted over 18 months in 45 patients, and carbamazepine was found to have an antiepileptic action equivalent to that of phenobarbital, phenytoin, and primidone given either separately or in combination. It was hoped that there would also be a psychotropic effect, but no difference between groups was noted. Four patients on carbamazepine died during the study, but this was felt by the investigators (one of whom worked for Geigy) to be no more than would be expected. Seven more controlled (or semicontrolled) trials were reported over the next 10 years (Rajotte et al., 1967; Marjerrison et al., 1968; Pryse-Phillips & Jeavons, 1970; Cereghino et al., 1974; Rodin et al., 1974; Simonsen et al., 1975; Troupin et al., 1977). In 1965, the drug was approved for use as an anticonvulsant in the United Kingdom, but approval in the United States was delayed until 1974. Its principal mechanism of action—the blockade of sodium channels—was not recognized until 1983, although earlier studies in peripheral nerves (Schauf et al., 1974) had demonstrated that carbamazepine reduced sodium current in Myxicola giant axons but only at supramaximal concentrations. The effects on repetitive firing were first demonstrated in peripheral nerves and then in cell culture of spinal cord neurons (McLean & Macdonald, 1986)(Fig. 4).

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Figure 4.   an early advertisement for carbamazepine.

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There are several important subsequent landmarks in the history of carbamazepine. With the advent of serum level monitoring in around 1972, a tentative therapeutic range was set with an upper limit of 10 mg/100 ml (Meinardi, 1971). A series of clinical trials in the 1980s established its value in monotherapy (Reynolds & Shorvon, 1981), but it was not until the mid-1990s that formal randomized trials in newly diagnosed patients were carried out (Heller et al., 1995; de Silva et al., 1996). Within 10 years of its first licensing, carbamazepine became very widely used and had with phenytoin become the drug of first choice in psychomotor and grand mal epilepsy. By 1965, the first reports of idiosyncratic rash, hematologic toxicity, and hepatic dysfunction were made, and the drug began to acquire a reputation for inducing hypersensitivity. The rate of reactions seemed to fall after these years, and some early cases may have been due to the incipient rather than the active molecule. The rate of agranulocytosis is now known to be about 0.5 cases per 100,000 treated persons, and the rate of hepatic failure 16 per 100,000. It was not until 2004 that the strong association of Steven-Johnson syndrome with HLA-B*1502 was noted in the Han Chinese, resulting in 2007 in an NIH advisory letter recommending human leukocyte antigen testing prior to starting carbamazepine (Chung et al., 2004). The teratogenic potential of carbamazepine was recognized first in the early 1970s. The risk of malformations is now considered to be about 2–4%, which is lower than that of any of the other well-characterized antiepileptic drugs. In 1984, the first of several slow-release formulations was produced, but it took another decade or so for the slow-release formulations to become the preferred routine method of administration.

Most of the major characteristics of carbamazepine were identified early on, and by the late 1960s, data were available on the pharmacokinetics, its potential for complex drug interactions, and its common neurologic and gastrointestinal side effects (dose-related). Its major routes of biotransformation were also known, but it was not until 1972 that the epoxide was recognized as a metabolite. Its central role in toxicity and the effects of drug interactions were not established until the late 1970s. Its excellent efficacy in partial and secondarily generalized epilepsy was recognized from the very first trials, as was the risk of exacerbation of absence and myoclonic seizures, and its relatively limited value in the generalized epilepsies and syndromes. Another important landmark was the introduction of slow-release formulations (which curiously differ completely in the United States and in Europe) and the recognition that many of the transient peak-dose side effects of carbamazepine are alleviated by this formulation in a twice-daily regimen.

By the mid-1980s, carbamazepine was the most prescribed antiepileptic drug in Europe and it remains so. Some 40 years after its introduction, it is still the gold standard for comparative studies of antiepileptics and the drug to beat for any new compound. By 1989, 2,700 citations for carbamazepine had already appeared in the medical literature (and by 2008, there were 11,052), and the drug is probably the most-cited and most-studied compound in the history of epilepsy.

Valproate sodium and its derivatives (Epilim, Depakene, Convulex, Depakine, Epival)

Dipropylacetic acid (as valproate was then better known) was synthesized in 1881 and had been used for about 80 years as an organic solvent, when in Grenoble in 1962, a small pharmaceutical company, La Laboratoire Berthier, directed by two brothers (les frères Meunier) decided to test a series of compounds in the rat for tranquillizing action. This was carried out in collaboration with George Carraz from the University of Grenoble. Dipropylacetic acid was chosen as the solvent, and when all compounds were found to be apparently antiepileptic in this model, the Meunier brothers decided to test the solvent alone. Immediately it was obvious that the organic solvent had marked antiepileptic action. The laboratory then started to develop valproate in-house and carried out the first experimental study of the compound in 1963 in 16 rabbits given the convulsant Cardiazol and protected by intraperitoneal, rectal, and intravenous routes (Meunier et al., 1963). In those days, clinical testing could be started early (the thalidomide tragedy was soon going to put pay to this) and so it was with valproate. In 1964, Carraz and colleagues published the first clinical report of the effect of the sodium salt of dipropylacetic acid (sodium valproate, Carraz et al., 1964). The drug had been initiated in November 1963 in 16 patients with largely previously intractable petit mal and grand mal epilepsy. Thirteen of the 16 cases showed marked improvement in the study, which was carried on for up to 7 months. Some patients were rendered seizure-free, and the authors noted that petit mal as well as grand mal and psychomotor seizures were improved. It was soon apparent that more resources than were possible in this small laboratory were needed, and the drug was sold on and licensed in the mid-1960s by Sanofi-Labaz. The new company rapidly promoted the drug, and in 1967 it was approved in France and then in other European countries (Spain 1970; Belgium and Holland 1971; and Britain, Switzerland, and Italy since 1972). By 1970, valproate was being widely used in Europe. The drug was not launched in the United States largely because of the lack of enthusiasm from Abbott, which held the U.S. license. Kiffin Penry, the current ILAE president, then led a campaign to the U.S. Senate seeking access to the drug. The FDA then took the unprecedented step of requiring Abbott Laboratories to supply information on valproate so it could be considered for expedited approval (Thomas, 1998). The battle for the approval of valproate was dramatized in a 1987 ABC television movie, “Fight for Life,” starring Jerry Lewis, in which Penry was portrayed as Dr. Monroe Keith. Partly as a result of Penry’s campaign, the drug was eventually licensed in 1976 in the United States, albeit initially only for the treatment of absence seizures.

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[   An early advertisement for valproate. ]

The effects of valproate against absence epilepsy, myoclonic epilepsy, and tonic–clonic seizures (especially when part of the syndrome of idiopathic generalized epilepsy) were well recognized by the early 1970s. Simon and Penry (1975) published a major review of the drug that formed the basis of the subsequent FDA approval. They found reports of 13 clinical trials, including two double-blind crossover studies (Suzuki et al., 1972; Rowan et al., 1983), and carried out what was essentially an early meta-analysis of the 10 trials that had sufficient data, in 1,020 patients, and found that more than 50% had a reduction in tonic–clonic, myoclonic, and absence seizures and about one-third of patients with partial seizures. By the early 1970s the effect of valproate on EEG—the abolition of photosensitivity and of spike-wave paroxysms—and the effects in atypical absence were also recognized and the pharmacokinetics fully established. The drug was rapidly gaining prominence and increasingly being recommended as first-line therapy.

The problems that dogged the prescription of valproate throughout this period were anxieties over its safety, and the slowness in acknowledging all aspects of valproate toxicity is rather shocking. The rather common cognitive side effects and effects on hair were also early identified, as was the encephalopathy (two patients in the initial trials were rendered comatose). The common effects on weight were surprisingly not recognized for many years, and even as late as 1983, Dreifuss wrote that increased appetite resulting in obesity was an “occasional” problem. The first report of teratogenicity was by Dalens et al. (1980), of a dysmorphic child, and by Gomez (1981), of a neural tube defect. In 1982, the increased incidence of myelomeningocele in children exposed to valproate in utero was described, which (15 years after licensing) established the risks of the drug in pregnancy (Robert & Guibaud, 1982). The possibility that valproate also results in an increased incidence of childhood learning disability was not reported until 2001 (Adab et al., 2001). Hyperammonemia was first reported in 1981 (Coulter & Allen, 1980), and the risks of the drug in ornithine transcarbamylase (OTC) deficiency also in 1981. The first hepatic deaths were reported in 1978, and in 1987 these were definitively reviewed by Dreifuss, who found a risk of fatal hepatic dysfunction ranging from 1:500 in children 0–2 years old receiving valproate as polytherapy to 1:37,000 in patients receiving valproate as monotherapy, with no hepatic fatalities reported in patients older than the age of 10 years who were receiving valproate as monotherapy (Dreifuss et al., 1987). The reports of pancreatitis were first made in 1979 and resulted in another review by Dreifuss and colleagues in 1993 (Asconapé et al., 1993). The possibility that the drug caused polycystic ovarian syndrome and other hormonal problems was first reported in the 1990s, in findings promulgated largely by a single research group and often unconfirmed by others. These risks have still not been clearly defined.

These various problems have limited the use of the drug, which is a pity given its clear efficacy. But even today, valproate remains one of the two most prescribed antiepileptic drugs (sharing the honor with carbamazepine) and a clear favorite in the idiopathic generalized epilepsies. The value of valproate was emphasized in the recent SANAD study (Marson et al. 2007a). In the generalized epilepsy arm, valproate proved superior in efficacy to both lamotrigine and topiramate, confirming its place as the drug of choice in generalized epilepsy. The old lady it seems can still hold her own.

1,4-Benzodiazepine drugs (chlordiazepoxide, diazepam, clonazepam)

A most significant pharmacologic development of the postwar period in general psychiatry was the development of a new class of drugs, the benzodiazepines. These compounds have had a major impact on popular Western society and culture and have entered the folklore of the age (for instance, the “little yellow pills” and “mother’s little helpers” of the famous Beatles song). They helped fuel a revolution in biological psychiatry and its social reaction, the antipsychiatry movement of the 1960s. Of course, the main impact of this class was its antianxiolytic and hypnotic action, but the benzodiazepines were also early recognized to have antiepileptic effects. The “benzodiazepine story” as related by the protagonists at the time is an intriguing insight into contemporary pharmaceutical development. In 1952, the first reports of the clinical effects of chlorpromazine were published, and its obvious commercial importance and rapid success led the pharmaceutical industry into a race to discover other psychoactive drugs that might have improved properties. The Swiss pharmaceutical giant Roche was a leader in the field, and had developed a range of animal-testing models for assessing sedative properties. Leo Sternbach was a medicinal chemist in charge of a research laboratory in New Jersey, who as a Jew had fled the Nazis in 1941 and who decided in the mid-1950s to investigate the pharmaceutical actions of a group of compounds he had created, which came to be known as the benzodiazepines (Sternbach, 1980). They were attractive candidates, as they were readily produced, capable of chemical manipulation to produce a whole family of compounds, largely unstudied in pharmacology, and had the “look” as he later put it, of being biologically active. He chose first to study benzheptoxdiazines and synthesized a range of these with different side-chain products. Initially no biologic action was found, and his laboratory was then asked to focus on other research areas. In cleaning up, his technician found a few hundred milligrams of some crystallized compounds that were thought to be quinazoline 3-oxides prepared in 1955. They decided to submit these for animal screening. The results were unexpectedly exciting—the drugs had powerful sedative and antiepileptic effects. Sternbach pressed on. He found first that the compounds were not in fact quinazoline oxides but had a seven-membered diazepine ring. In May 1958, a broad patent was filed for the 2-amino-1,4-benzodiazepine 4-oxides and various substituents in the benzo- and phenyl rings. It was granted in July 1959. An intensive pharmacologic program of work ensued, and one of the original compounds, given the generic name chlordiazepoxide, proved superior to its derivatives and was submitted for licensing to the FDA. In short order, in 1960, the compound was approved and licensed under the name of Librium. Sternbach then carried out further chemical exploration and discovered that the N-oxide function was not necessary for the pharmacologic action (contrary to the then hypothesis on mechanisms of action) but that biologic activity depended on the presence of a chlorine in the 7-position. With additional manipulation, another compound, given the name diazepam, was discovered and found to have a broader spectrum of activity than Librium, stronger antiepileptic and muscle relaxant properties, and very low toxicity. Following clinical studies, the drug was licensed in 1963 under the name Valium. In the next 15 years, more than 4,000 related compounds were synthesized and screened, and by 1978, 23 compounds had been licensed worldwide (including eight in the United States). It is instructive to note that the compounds were not produced rationally in the sense that they were designed with a specific epilepsy or anticonvulsant mechanism in mind, but initially rather randomly discovered following screening in an animal model—much as was phenytoin. However, the chemical family was then explored using systematic chemistry—with thousands of products each analyzed and again screened in the same models. In this way, the basic chemical structures necessary for clinical action were elucidated. Such a program was only possible in the research factories of the major pharmaceutical companies. The story of the benzodiazepines opened a new chapter in the history of drug development (Sternbach, 1980).

The value of these drugs in human epilepsy was rapidly recognized. The anticonvulsant effect of Librium was first reported in 1960 (Rosenstein, 1960). In 1962, a series of cases of epilepsy treated with Librium (Ro 5-0690) and Valium (Ro 5-2807) were presented by Hernandez at the second Latin American Congress on Psychiatry in Mexico and by Madalena in Brazil in 1963. Madalena also mentioned the use of clonazepam in epilepsy, which he considered superior to diazepam owing to its lower dosage, almost complete absence of side effects (an extraordinary assessment from the today’s perspective), better effects on the behavioral disorders associated with epilepsy, safety, and more favorable efficacy in petit mal than either Valium or Librium. These drugs were beginning to be widely used in epilepsy. In 1965 Henri Gastaut weighed in with a laudatory report of the use of Valium in status epilepticus (Gastaut et al., 1965), and 6 years later was even more enthusiastic about the new agent clonazepam (Ro 05-4023 (Gastaut et al., 1971; Neligan & Shorvon, 2009) (Fig. 6).

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Figure 6.   An early advertisement for clonazepam—one of the first advertisements to advise the use of drug based clearly on the modern classification of seizures.

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Browne and Penry (1973) published a major review of the use of the benzodiazepines in the treatment of epilepsy. (Penry’s colleague Ewart Swinyard had published reviews of the experimental effects in 1966 and 1969.) This review was a definitive statement on the position of these drugs after a decade of use, and its main purpose was surely to persuade the regulatory agency of the need to license these drugs, which were now widely available in Europe and elsewhere but not in the United States (Penry and colleagues had written similar reviews of carbamazepine and valproate for similar reasons—see preceding text). The review covered clinical pharmacology and toxicology, effects on EEG, and clinical effects, and summarized the status of the benzodiazepines 10 years after the first licensing of Valium. By then there were 28 open studies of benzodiazepines in patients with refractory petit mal and one of new cases—dating from 1961; Browne and Penry were scathing about the methodology, but noted that the results were uniformly encouraging. They concluded that controlled studies were needed “to establish definitively the role of benzodiazepines in the treatment of absence attacks.” In 1977 they reported one such study, a double-blind comparison of clonazepam and ethosuximide, and also found the drug useful in photosensitive epilepsy, myoclonic epilepsy, West syndrome, akinetic seizures, alcohol withdrawal seizures, and eclamptic seizures. However, the results of treatment in grand mal and focal epilepsies were generally less promising, and indeed, grand mal seizures could be exacerbated. On the question of status epilepticus, Penry was more lukewarm than Gastaut had been. He reviewed 35 articles on the effectiveness of diazepam in various types of status epilepticus but failed to mention Gastaut’s article, and noted lasting control of the status in between 20–89% of cases depending on the seizure type. The principal objection to diazepam was its respiratory depressant and hypotensive side effects. In addition, because of the propensity for tolerance to develop on continuous oral medication, the drugs were most useful in their parenteral formulations. It is difficult to disagree with any of the conclusions in Penry’s review, which still largely apply today.

The mechanism of action of the benzodiazepines was the subject of intensive study in the 1960s and 1970s. The importance of γ-aminobutyric acid (GABA) as the main cerebral inhibitory transmitter was established by 1975, and shortly after this the main site of action of the benzodiazepines was shown to be at the GABA receptor. The benzodiazepines still used in long-term oral therapy for epilepsy now are clobazam and clonazepam, and occasionally nitrazepam and diazepam. None are currently considered first-line therapy. Only clobazam is widely used worldwide (although not licensed in the United States), and clonazepam is used extensively in France. Enthusiasm for their antiepileptic effect has been tempered by the occurrence of tolerance and the problems of dependency and sedation. Rectal diazepam, buccal and intranasal midazolam, and intravenous diazepam and lorazepam, however, are still the drugs of choice in first-line therapy for convulsive status epileptics and in generalized absence status epilepticus.

Clobazam (Frisium)

Clobazam is an outsider in the benzodiazepine family. It is the only benzodiazepine that has been extensively studied clinically in which the diazepine ring is substituted by a nitrogen atom in the positions 1 and 5 of the benzene ring and no imine group at positions 4 and 5. It has distinctive properties that set it apart from the other benzodiazepines, and that are probably explicable by its different differential action on subtypes of the GABAA receptor. This structural change results in an 80% reduction in its anxiolytic activity and a 10-fold reduction in its sedative effects when compared with diazepam in animal studies. It has been licensed in Europe since 1975, Canada since 1988, but is unavailable in the United States. It is widely used in specialist epilepsy clinics, where this underdog of a drug has many champions.

The antiepileptic effects were reported in mice in 1973 and then in baboons (Chapman et al., 1978). The first human trials were reported in 1979 by Gastaut and Low (1979). It has since then been the subject of at least two international conferences and is the most widely used of the benzodiazepine drugs in chronic epilepsy, at least outside of the United States. It was discovered in 1984 that its main effects are due to its active metabolite, N-desmethylclobazam, which has a longer half-life and greater serum levels than the parent drug. Clobazam was first trialed as an anxiolytic and was licensed for this purpose, although it was withdrawn in recent years for this indication as it has few advantages over the 1,4-benzodiazepine drugs. Its antiepileptic properties were discovered a few years later when clobazam was made available, in October 1977, to the Marseilles group of Gastaut. It was tested first for a few days in 140 patients with frequent seizures, and then continued in patients who showed a response at a dose of 0.5 mg/kg/day. Its effects were dramatic initially, as has been confirmed many times since. Seventy-six percent of the patients with severe epilepsy showed a marked and potent response, although this was maintained in only 52% after a matter of months. Side effects were slight, and good results were obtained in patients with all types of seizure, in reflex epilepsy, and in the Lennox-Gastaut syndrome. Since then, its strong antiepileptic effects have been confirmed in numerous open and also eight double-blind placebo-controlled studies carried out between 1982 and 1991, four from the United Kingdom, and one each from France, Germany, Canada, and one multicenter European study (reviewed in Shorvon, 1995). The study from Canada found clobazam to have efficacy equivalent to that of carbamazepine and phenytoin as monotherapy for childhood epilepsy (Canadian Study Group for Childhood Epilepsy 1998).

The major problem with clobazam, as noted immediately by Gastaut, is the propensity for tolerance to develop in 50–80% of patients, sometimes within days or weeks of its initiation. Maneuvers such as drug holidays, initiation at very low doses, the use of partial benzodiazepine agonists, and the use of very high doses have all failed to circumvent this problem. Other side effects, such as drowsiness, dizziness, weakness, restlessness, and aggression, are either less common or less marked than with any of the 1,5-benzodiazepine drugs. It is, in routine practice, very well tolerated. Its mild anxiolytic effect is also useful in some patients with epilepsy.

It also has a useful role as one-off prophylactic therapy on special occasions when it is particularly important to prevent a seizure (e.g., on days of travel, interview, examinations and so on) or in catamenial epilepsy (Feely et al., 1982; Shorvon, 1989; Shorvon, 1995). Its availability in Canada, but not the U.S.A., is said to have resulted in a lucrative cross-border trade.

Progabide (Gabrene)

As might be surmised from its name, this drug was designed as a prodrug of GABA, and was manufactured and developed by the French company Synthelo Laboratory. It was a direct product of the GABA wave (described later) of neurochemical research, and in animal studies, progabide was shown to have a wide spectrum of anticonvulsant actions (Worms et al., 1982). This was furthermore also one of the first drugs to be identified in the NIH Antiepileptic Drug Development (ADD) program. Although it is a GABA prodrug, its exact mode of action is still not entirely clear. It may act at the GABAB receptor (subunit 1) and regulate the availability of functional GABA-B-R1A/GABA-B-R2 heterodimers by competing for GABA-B-R2 dimerization. It certainly is not a direct GABA agonist in the same way as vigabatrin. Its effectiveness is complicated by the fact that it elevates phenytoin concentrations and enhances the metabolism of carbamazepine to the epoxide. Some clinical studies showed positive effects and others were negative, both in partial and absence seizures. It was also trialed in a head-to-head comparison against valproate, which was terminated prematurely, as it caused elevated levels of liver enzymes and was less efficacious than valproate. There have remained persisting anxieties about its hepatic toxicity. It has been extensively studied as a drug that improves tardive dyskinesia in Parkinson’s disease, although it has never been licensed for this use and has been found to have mild psychotropic effects. Progabide (a French drug) was licensed in France first in 1985, and by 1992 was reported to have been used in more than 2,500 persons. It is now licensed in France for use in monotherapy and also as adjunctive therapy for generalized tonic–clonic, myoclonic, partial seizures, and for Lennox-Gastaut syndrome, in both children and adults. It is not licensed in any other European country nor in the United States.

Other drugs

Corticosteroids and particularly adrenocorticotropic hormone (ACTH) were also introduced into clinical epilepsy practice in 1950. Prior to this, steroids were thought to be proconvulsant, although ACTH and cortisone were both known to normalize the EEG (Friedlander & Rottgers, 1951). The first report of efficacy in childhood epilepsy was in 1950 (Klein & Livingston, 1950) and then in 1958, when Sorel and Dusaucy-Bauloye (1958) demonstrated the dramatic effect in infantile spasms. Thereafter, ACTH rapidly became, and remains, first-line therapy for this indication. ACTH and cortisone were shown in the 1950s also to have value in occasional cases of other types of childhood epilepsy and in status epilepticus. Paraldehyde became another drug widely used in status epilepticus and in alcohol withdrawal seizures in the mid-century. It had been introduced into clinical practice in 1882, and the first report of its anticonvulsant action was by Wechsler in 1940. Its intravenous use in status epilepticus required a complex series of glass tubing (as it degrades plastic), had the appearance of a chemistry lesson, and is still seared in the memory. It continues to be used as a rectal instillation, particularly as out-of-hospital use in patients with severe epilepsy (for instance in epilepsy institutions). Its undoubted safety and efficacy make it a popular choice, although few who have observed the effects of paraldehyde will forget its lingering odor, a madeleine of institutional practice. The first report of the use of chlormethiazole in status epilepticus was in 1963 (Poiré et al., 1963), and a number of uncontrolled studies were reported in the next 10 years, all showing that the drug rapidly controls seizures in most patients, including those unresponsive to diazepam infusion (Harvey et al., 1975). It became a standard second-line therapy in the 1970s, especially in Britain, and I remember many cases of status treated by chlormethiazole infusions well into the 1980s. It has a tendency to accumulate dangerously though, and by the 1990s was only occasionally used, as other safer alternatives entered clinical practice and protocols for the therapy of status become more standardized.

The Drug Treatment of Epilepsy 1989–2009

  1. Top of page
  2. Summary
  3. The Drug Treatment of Epilepsy 1959–1988
  4. The Drug Treatment of Epilepsy 1989–2009
  5. Therapy of Epilepsy in 2009
  6. Acknowledgments
  7. References

The last 25 years of this history have been dominated by the introduction of 13 new antiepileptic drugs. This has undoubtedly improved therapy and indeed the prognosis of epilepsy, although none of the drugs is a panacea, and for a significant number of patients, epilepsy remains uncontrolled. Some of these drugs derive from the great advances in neurochemistry and neurobiology that had their foundations in the 1970s, particularly in relation to GABA, which was then found to be the major inhibitory neurotransmitter in the brain. This “GABA wave” was followed by the “glutamate wave,” a period of intense research into excitatory transmission, but the yield of clinically useful pharmaceuticals from the study of glutaminergic transmission has been disappointing. Furthermore, most of the new antiepileptics were found essentially by chance (via random screening) or by manipulating the structure of existing drugs. Although there were major advances in pharmacology, the principles of epilepsy therapy hardly changed, and as we shall see, the approach to a patient and to clinical therapeutics today is essentially the same as that of 30 years ago.

This period, too, saw the strengthening of the position of the ILAE as the central organization in epilepsy. It became much more international, and through its journal (Epilepsia), its conferences, and its commissions, and through the production of ILAE guidelines—for instance, the important ILAE treatment guidelines for antiepileptic drug monotherapy (Glauser et al., 2006)—now largely sets the professional epilepsy agenda in relation to therapy.

Another important trend has been the rise in power and profits of the pharmaceutical industry—and the reaction to the rise of regulation and governmental intervention. Both have become considerable, and because of both, the focus of work has moved from the clinic and from the patient to the markets and the legal offices. This has been a striking change in perspective and culture (Table 5).

Table 5.   Drugs licensed in Europe and the United States since 1989
Year of first licenceProprietary nameCountry in which first licensedManufacturer
  1. aZonisamide was licensed in the 1989 in Japan and South Korea as Excegran (manufacturered by Dainippon Pharmaceuticals).

1990LamotrigineIrelandBurroughs-Wellcome
1990OxcarbazepineDenmarkNovartis
1989VigabatrinUnited KingdomMarion Merrill Dow
1993FelbamateU.S.A.Carter Wallace
1994GabapentinU.S.A., United KingdomParke-Davis
1995TopiramateUnited KingdomJohnson and Johnson
1996TiagabineFranceNovo-Nordisk
1999LevetiracetamU.S.A.UCB Pharma
2000ZonisamideaU.S.A.Elan pharmaceuticals
2004PregabalinEuropean UnionPfizer
2007StiripentolEuropean UnionLaboratoires Biocodex
2007RufinamideEuropean UnionEisei
2008LacosamideEuropean UnionUCB Pharma

Epilepsy therapy in 1989

To determine the overall progress made in epilepsy therapeutics between 1960 and 1989, it is revealing to compare Lennox’s (1960) with the third edition (1989) of Antiepileptic Drugs, both the standard epilepsy therapy textbooks of their time. A number of interesting points emerge from this comparison. First, the introduction of carbamazepine and valproate, and to a lesser extent the benzodiazepine drugs, had a rapid and enormous impact on epilepsy practice. By the mid-1970s, carbamazepine and valproate dominated therapy in Europe and, 10 years later, were doing the same in the United States. Their advent pretty well marked the end of all prescriptions of bromide, the virtual end of the routine use of phenobarbital, at least in Europe (for instance in my own practice in 1980, this had now largely disappeared), and a marked reduction in the use of phenytoin in Europe and less so in the United States.

The rise of clinical pharmacokinetics was the second major development in this period—with most of the advance in this area made between 1960 and 1972. The principles of absorption, distribution, metabolism, excretion, and drug interactions were described in a way in the 1972 book, which has since hardly changed, and most of the major parameters were established then. The advances in pharmacokinetics written into the third edition were related to the characterization of the P450 system (emphasizing particularly the various genetic phenotypes—nota bene those who think pharmacogenomics is a new subject), the influences on this system, and in particular the importance (and mechanisms) of drug interactions. The first mention of teratogenicity appeared in 1972 (as recorded in the 1989 edition: “during the last decade, reports … appeared which indicate that some of the drugs used as anticonvulsants may be teratogenic”); this was a topic not found in Lennox’s book.

By the third edition, the selection of antiepileptic drug therapy was firmly linked to seizure type, using the new ILAE classification, and there was also a chapter by Roger Porter (then ILAE secretary-general) titled “How to Use Antiepileptic Drugs.” This chapter demonstrates how the principles of the science of clinical pharmacokinetics have been translated into clinical practice, and the impact of the science on the clinical process. The therapeutic framework and approach described by Porter is essentially unchanged today (Table 6).

Table 6.   “How to use antiepileptic drugs” (from the chapter by Roger Porter in Antiepileptics Drugs, 3rd edition, 1989)—an approach that has hardly changed today
Diagnosis
 Etiologic
 Seizure
 Syndrome
Which patients to treat
 Epilepsy is not homogeneous
 Single seizures
 Etiology
How to initiate therapy
 Timing of drug administration
 Timing of drug intake intervals
 Timing of changes in drug dose
 Reaching steady state
 Value of monitoring plasma drug levels
 Limited importance of free drug levels
Monotherapy and multiple drug regimens
Compliance and noncompliance
When the proper medical regimen fails
 25% of patients
 Consider nonepileptic seizures
 Video-EEG monitoring
Refer difficult patients to an epilepsy center
Surgical intervention
 Is a patient’s epilepsy intractable?
 Does the patient really want an operation?
 How well localized is the epileptogenic lesion?
 Types of surgery and outcome

The introduction of carbamazepine and valproate and the rise of clinical pharmacokinetics in the period between 1959 and 1989 had other, less obvious, consequences. One was the much greater interest in “epilepsy” as a subject. In most advanced neurologic units, by 1910 epilepsy had fallen from its position as “queen” of neurology to a rather peripheral subject. It remained in the doldrums at least until 1940, with a reputation as a tiresome condition (with the inference of having tiresome patients), which neither challenged the intellect nor stimulated the interest of the neurologic establishment. Neurology had the reputation of being an essentially diagnostic subject, which required high intelligence and a rigorous approach based on interpretation of the clinical examination. Epilepsy was not generally a diagnostic challenge, nor did the patients need a sophisticated neurologic examination. The attractions of the topic though progressively grew in the second half of the 20th century with the introduction of diagnostic aids, notably EEG, TDM, and neuroimaging, and particularly with the introduction of novel therapy. Few neurologic specialties had such a range of effective therapies. Furthermore, the establishment of specialized epilepsy units, of which the most celebrated was Lennox’s Seizure Unit in Boston, was an important step in raising the profile of the disorder. Similar units open in 1970s and 1980s in Europe. The example of the National Hospital at Queen Square illustrates this point well. In 1975, for instance, there was no particular epilepsy interest, no research, and no specialized clinics. Epilepsy was considered a subject of little interest, despite the illustrious role the institution had played in the history of epilepsy. In 1983, an epilepsy group was formed and epilepsy became progressively, again, one of the hospitals leading specialties in both clinical and research fields. This new dynamism in the field of epilepsy was partly stimulated by financial support from the pharmaceutical industry. This was a period in which Ciba-Geigy, which manufactured carbamazepine and Sanofi-Labaz, which manufactured valproate (Epilim, Depakine), provided sponsorship in increasing quantities to many educational activities. Consequently, the ILAE conferences grew in size and ambition, and in this period the modern conference, with satellites and a commercial exhibition, was born.

Eilat conferences on antiepileptic drugs

On May 31, 1992, the first conference in what was going to turn out to be a very important series was held in Jerusalem as a satellite of the 2nd Jerusalem Congress on Pharmaceutical Sciences and Clinical Pharmacology. The conferences were conceived by two clinical pharmacologists—Meir Bialer from the Hebrew University in Jerusalem and Rene Levy from the University of Washington, Seattle—and have become very influential in the field of epilepsy therapeutics, than the ILAE international congresses.

Bialer and Levy put together an excellent program for the first conference, which included speakers such as Paul Leber, then director of the FDA Division of Neuropharmacological Drug Products; Roger Porter; Harry Meinardi, then ILAE president; and Harvey Kupferberg, chief of National Institute of Neurological Diseases and Stroke (NINDS)’s preclinical pharmacology section. This was the start of a remarkable partnership and a series of conferences that have occurred every 2 years since, and have become known as the Eilat Conferences on Antiepileptic Drugs. Each conference brings together medical academics and members of the pharmaceutical industry for high-level scientific debate about many aspects of antiepileptic drug use. A major element of the congress is the session devoted to in-depth progress reports on new drugs in different stages of development. The program throughout has been innovative and lively, and the presence of figures from the FDA was an important element.

Since 1994, Epilepsy Research has carried summaries of the progress reports on new drugs, and these are highly cited (Bialer et al., 1995; Stables et al., 1995; Bialer et al., 1996, 1999, 2001, 2002, 2004, 2007). A list of the drugs in development discussed at each conference since 1994 is shown in Table 7 and is a good indication of the state of the “pipeline” during these years. All drugs licensed in this period had been the subject of presentations at the conferences. The list also shows how long it takes an antiepileptic to reach the stage of licensing and the height of the regulatory hurdle now required for licensing, with more than two-thirds of drugs discussed failing to reach a licensing stage even after entering clinical trials (Table 7).

Table 7.   The drugs in development discussed at the Eilat conferences from 1994 to 2006
Eilat II, 1994Eilat III, 1996Eilat IV, 1998Eilat V, 2000
TopiramateTiagabineADCIAWD 131–138
TiagabineRemacemideAWD 131–138DP-VPA (DP16)
Remacemide hydrochlorideRufinamide (CGP 33101)DP16 (DP-VPA)Harkoseride (SPM 92 7)
StiripentolLevetiracetam (ucb L059)Ganaxolone (CCD 1042)LY 300164
CGP33 101D-23129Levetiracetam (ucb LO59)NPS 1776
ucb L059 (levetiracetam)TV 1901LosigamoneNW-1015
DezinamideDezinamidePregabalin (CI-1008; isobutyl GABA)Pregabalin (CI-1008)
LosigamoneaRalitolineRemacemide hydrochlorideRemacemide
  Retigabine (D-29129) 
  Rufinamide (CGP 33101)Retigabine (D-23129)
  Soretolide (D2916)Rufinamide
  TV 190112Valrocemide (TV 1901)
  534U87 
Eilat VI, 2002Eilat VII, 2004Eilat VIII, 2006Eilat IX, 2008
  1. aLosigamone was mentioned in program but not the publication.

  2. bRWJ-333369 was mentioned in program but not the publication.

  3. cNS1209 was mentioned in the publication but not the program.

Carabersat (SB-204269)AtipamezoleBrivaracetam (ucb 34714)Brivaracetam (ucb 34714)
CGX-1007 (Contantokin-G)BIA 2-093Eslicarbazepine acetate (BIA 2-093)Carisbamate (RWJ-333369)
PregabalinFluorofelbamateFluorofebamate2-Deoxy-glucose
RetigabineNPS 1776GanaxoloneEslicarbazepine acetate (BIA 2-093)
SafinamidePregabalinHuperzine AFluorofebamate
SPD421 (DP-VPA)RetigabineJZP-4Ganaxolene
SPM 927SafinamideLacosamideHuperzine
TalampanelSPM 927NS1209cLacosamide (SPM 927)
Valrocemide (TV 1901)StiripentolPropylisopropyl acetamide (PID)NAX 5055
 TalampanelRetigabineRetigabine
 ucb 34714RufinamideT2000
 ValrocemideRWJ-333369Tonabersat
 RWJ-333369bSeletracetam (ucb 44212)Valrocemide
  StiripentolJZP-4
  TalampanelPropylisopropyl acetamide (PID)
  ValrocemideValnoctamide
   YKP3089

Drugs introduced into clinical practice between 1989 and 1994

In this 5-year period, five major antiepileptic drugs were licensed in Europe and introduced into clinical practice—vigabatrin, oxcarbazepine, lamotrigine, felbamate, and gabapentin (also in this period, Zonisamide was licensed in Japan and South Korea). This was a pace of expansion not experienced before, and it generated a great deal of excitement and promotional activity. Two of the drugs have now largely disappeared from routine practice due to serious toxicity discovered after marketing (felbamate and vigabatrin), and one has fallen out of favor due to a perceived lack of efficacy (gabapentin). Lamotrigine and oxcarbazepine, though, remain in widespread use.

Vigabatrin (Sabril)

The results of the GABA wave were initially disappointing and rather conflicting. Several potent GABA agonists, for example 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) and muscimol, had proepileptic effects when tested in baboons (Meldrum & Horton, 1978; Pedley et al., 1979). GABA itself could not be used as an antiepileptic as it does not cross the bloodbrain barrier, so methods had to be developed to overcome this problem. The first was an attempt to devise what was hoped would be a GABA prodrug, progabide. The second method was more successful. GABA is catabolized at the GABAergic synapse by the enzyme GABA transaminase (GABA-T) and a compound was devised at the Centre de Recherche Merrell International in Strasbourg, which proved to be an irreversible inhibitor of GABA-T. This compound was gamma-vinyl GABA and soon was shown to raise GABA levels in the brain in rodents and in mice (Lippert et al., 1977; Schechter et al., 1977) and then to afford protection in mice against audiogenic seizures. A year later, Meldrum and Horton (1978) reported the effect of this new compound in the photosensitive baboon model. They demonstrated protection at an intravenous dose of 450–950 mg/kg against generalized myoclonus or seizure responses induced by photic stimulation in baboons without or with priming with subconvulsant doses of allylglycine. The protection became maximal 1–3 h after injection, and continued for 7–24 h. Other animal models were studied, and by the early 1980s, 3 years after the discovery of its neurochemical action, vigabatrin (as it was then known) was being used in human studies.

The first reported short-term phase II single-blind efficacy studies were carried out in 1983 by Lennart Gram et al. (1983). About half of 15 patients had a 50% or more reduction in median seizure frequencya finding that was to be replicated over and over again in more definitive studies. By 1989, four short-term single-blind and six double-blind crossover studies had been carried out in a total of 133 and 141 patients (the crossover studies were reported by Rimmer & Richens, 1984; Gram et al., 1985; Loiseau et al., 1986; Tartara et al., 1986; Remy et al., 1986; Tassinari et al., 1987a sufficient number and development program in those days for the drug to be licensed in Europe. It was launched in 1989 first in the United Kingdom and then in Denmark, and soon after in 60 countries, although not in the United States. In 1992, Ring and Reynolds (1992) wrote: “The introduction of vigabatrin into clinical practice may prove to be a milestone in the treatment of epilepsy, not only because it is the first novel antiepileptic drug since valproate in the 1970s, but because it appears to be the first successful rational approach to the treatment of epilepsy.” As things turned out, the case of vigabatrin was certainly a milestone, but not in the manner envisaged. Monotherapy trials were quickly carried out and also showed effectiveness (for instance Kälviäinen et al., 1995; Chadwick, 1999).

The rapidity of licensing was perhaps surprising, for there were toxicologic concerns about this drug from the onset. Dose-dependent intramyelinic vacuolation was noticed early on in the initial toxicologic studies of vigabatrin in the 1970s in mice, rats, and dogs, but not in monkeys. And although subsequent studies in humans have not shown any similar effects, the suspicion of neurotoxicity hung over the drug in many quarters right through the 1990s. The mechanism of this unusual effect remains obscure. Over the years, histopathologic examination was carried out in 76 temporal lobe specimens removed at epilepsy surgery, evoked potential examinations in several hundred patients, and serial magnetic resonance imaging (MRI) scans performed in more than 670 patients—without abnormalities being found. Psychosis and other severe psychiatric symptoms were then reported (Sander et al., 1991), and the propensity of the drug to cause marked psychiatric reactions (and aggression) became well established (although, part of this effect was wrongly attributed to forced normalization). The psychiatric effects were hinted at in the double-blind studies but were overlooked. By the mid-1990s, the drug was widely used and was being heavily marketed in Europe—despite unease about neurotoxicity. In the United States, however, the FDA refused initially to license the drug.

Early on in its development, the manufacturers of vigabatrin alighted on the concept that the GABA agonist action was a “rational” design. This became a slogan at the center of a lavish marketing campaign for vigabatrin, the success of which was one reason for the prominent position the drug assumed in the antiepileptic drug market. At that time, few medical meetings were not sponsored by the company, whose hospitality and largesse were overwhelming and whose influence seemed to be everywhere. The claim to be the “first rational antiepileptic” was as illogical then as now, but vigabatrin was certainly “clean” in the sense that its neurochemical effects were seemingly restricted to its binding to GABA-T. By the middle of the 1990s, a rash of papers, supported largely by funding from the manufacturers, appeared showing no human neurotoxicity; an example was the definitive study on CNS conduction times (including visual evoked potentials) of 109 patients followed for 12 months (Mauguière et al., 1997). Then, in January 1997, Mark Lawden and colleagues from Leicester reported severe visual field constriction in three patients taking vigabatrin therapy (Eke et al., 1997). This appeared just as the FDA had decided to issue an approvable letter for the use of vigabatrin the United States. The decision was rapidly retracted; later, the FDA complimented itself on not licensing the drug. A rash of further cases were discovered, and by 1999 it was recognized that vigabatrin causes visual field constriction in around 30–50% of users and that the effects are irreversible. In October 1999, Marion Merrell Dow sent a letter to all prescribers warning of the effect, and sales of the drug began to plummet. In fact, a prescription event monitoring study of vigabatrin conducted between 1991 and 1994 had identified four cases of bilateral, persistent visual field defects for which there was no alternative cause, but this seems to have been neither well publicized nor followed up. The inevitable lawsuits took place to determine whether the company knew or should have known about the risk to vision, and were settled for undisclosed sums.

Once visual field constriction was acknowledged, the licensing authorities heavily restricted the use of vigabatrin, although it remains available for use as adjunctive therapy in partial epilepsy where other options have failed and where the risks of therapy are outweighed by the benefits. In subsequent years, a niche indication in West syndrome, especially where this is caused by tuberous sclerosis, was established (incidentally, one of the few examples where the etiology of an epilepsy syndrome dictates choice of medication). At the time of writing, vigabatrin has become the drug of choice in infantile spasms. And yet in a further twist, in 2006, MRI changes strongly suggestive of intramyelinic edema were observed in the basal ganglia and cerebellum of infants treated with the drug (da Rocha et al., 2006). Further investigation has confirmed this effect in about 11% of all infants (up to the age of 3 years) treated for infantile spasms with high doses of vigabatrin. This was the effect long searched in adults but not found. The changes appear to be reversible, and their significance is currently unclear.

Lamotrigine (Lamictal)

In 1966, Ted Reynolds published a paper postulating that, as some anticonvulsant drugs caused folate deficiency (notably phenytoin and phenobarbitone, an effect noted in the 1950s), perhaps the antifolate effect was also responsible for their antiepileptic effect (Reynolds et al., 1966). Actually, the hypothesis was incorrect, and the antifolate effects of the two drugs have no relevance to the antiepileptic action. Nevertheless, researchers in the Wellcome Research Laboratories in Beckenham, Kent, decided to examine the antiepileptic effect of some antifolate drugs. It was a wild goose chase in terms of mechanism; but the goose laid a golden egg. The phenyltriazine derivatives were among a whole series of compounds studied, and of these, one—BW430C—looked promising, although ironically it too turned out not to have a strong antifolate action. BW430C was then tested in a number of conventional animal models, including the PTZ and MES models. Lamb et al. (1985) within the Wellcome Research Laboratories published comparisons of lamotrigine with the major contemporary drugs: phenytoin, phenobarbital, valproate, carbamazepine, diazepam, troxidone, and ethosuximide, and found lamotrigine to have more effect in abolishing hind-limb extension in the MES than any of these comparators. Inhibition of hind-limb extension is not the same as a human antiepilepsy effect, and indeed, the clinical efficacy of lamotrigine did not seem to match this experimental promise. The drug was then studied in other animal models (thousands of mice, rats, and marmosets participating in the studies) with variable success, and then in human volunteers (Cohen et al., 1985). Toxicology was slow, and consequently the initial clinical studies had to be short-lived. Hemmed in by regulatory restrictions, the company focused on single-dose effects on interictal EEG abnormalities and photosensitivity, and these were interesting and innovative designs (Binnie et al., 1986, 1987). When toxicology was completed, the drug moved into phase III trials—using a crossover design (Binnie et al., 1987; Jawad et al., 1989; Loiseau et al., 1990; Sander et al., 1990; Schapel et al., 1993; Messenheimer et al., 1994). This was an erratic clinical development program, but ultimately successful, and the drug was licensed first in Ireland in 1990, in the United Kingdom in 1991, and then in other countries in Europe. A parallel group study was completed in the United States (216 patients; Matsuo et al., 1993), and the drug was then licensed there as well (the biggest and most lucrative market) in December 1994 as adjunctive treatment for partial seizures with or without secondary generalization in adults.

The crossover designs in this lamotrigine program were used probably for the last time in definitive drug studies, as the FDA began to favor the parallel group formula. Crossover designs have the singular advantage of needing fewer exposed patients to demonstrate efficacy by reducing variance, and remarkably the initial clinical trial program of lamotrigine comprised only 221 patients. In fact, as it turned out, the results of the crossover studies were very similar to those of the parallel group studies, and one wonders whether this cheaper and quicker method of assessment should again be reconsidered.

There have been at least 11 placebo-controlled studies as adjunctive therapy in patients with refractory partial epilepsy, with the early studies using doses guided by blood levels but usually not in excess of 300 mg/day. Several of these early studies showed no significant difference in efficacy between lamotrigine and placebo, but a meta-analysis of all six studies showed a modest effect (an approximately 25% reduction in seizures) in the usual refractory partial-onset epilepsies. This was not a particularly exciting result, but it sufficed to allow licensing. The side-effect profile of lamotrigine was also studied, and the drug proved to be reasonably well-tolerated, with relatively low frequencies of the usual neurotoxic effects. One problem though, not identified in the short-term studies but soon to become very apparent, was the propensity of the drug to cause an allergic rash. This rash occurred in a surprisingly high proportion of initial patients (over 10% in the placebo-controlled trials). Later cases of severe rash were also reported, including Stevens-Johnson reaction, which were occasionally fatal. Several years later the high rash rate was shown to be partly due to the rapid introduction of the drug and could be reduced by slow titration, especially when the drug was used in combination with valproate, which elevated its levels. Nevertheless, serious rash was reported to occur at a rate of about 0.3% even in 1999 (Rzany et al., 1999). The rash was also found to be commoner in children, and this resulted in the regulatory requirement for complex dosing regimens depending on age and co-medication.

Despite what was considered by many to be an initially relatively poor performance, lamotrigine was very heavily marketed as a novel and exciting antiepileptic drug. The marketing was more efficacious than the clinical trials, and there was a rapid growth of sales, especially in Britain and later in Europe. It was approved for use in the United States in 1993, and by 1994 had been used by more than 80,000 people in 40 different countries. Lamotrigine was welcomed as a replacement for the less-marketed older drug leaders—carbamazepine, valproate and phenytoin—at a time when there were few new compounds. Indeed, the introduction of lamotrigine resulted slowly in significant falls in the share of the market occupied by phenytoin (but less so in the United States where fashion dictated support for phenytoin long after it was abandoned in Europe). For over 10 years, from the early 1990s, Wellcome and then in turn its successors GlaxoWellcome and GlaxoSmithKline, dominated medical sponsorship, for instance, in medical meetings (including the ILAE meetings) and in medical journal advertising and sponsored supplements.

There were several other facets of lamotrigine’s development, which at a distance now of 20 years are interesting to reflect on. First, several years after its launch, it became apparent that the drug had value in the treatment not only of the partial epilepsies, its licensed indication, but also in the generalized epilepsies, both primary and secondary. The marketing departments were not slow to exploit this new information, and soon the drug was being hailed as a broad spectrum anticonvulsant. The treatment of generalized epilepsy was dominated by valproate, and an aggressive advertising battle was launched with negative messages made about valproate. In 1993, it was then suggested that valproate caused polycystic ovarian syndrome, a claim based largely on Finnish studies (Isojärvi et al., 1993) and not confirmed in others. Another development was the discovery in the mid-1990s that valproate caused significant teratogenicity. Lamotrigine was then profiled in a new advertising campaign as the drug “for women with epilepsy”—no weight gain, no ovarian cysts, no teratogenicity (in contrast to valproate), and for good measure no interactions with the contraceptive pill (in contrast to carbamazepine). Women with epilepsy became a hot topic, and a remarkable number of publications and conferences were subsequently devoted to the subject. Martha Morrell in New York became a champion and leader in the field. It took another 10 years before the polycystic ovarian story was put into perspective, the remarkable fall in lamotrigine levels in late pregnancy was noted along with interaction with the contraceptive pill, and the drug’s teratogenic potential fully recognized. In fact, at high doses the effects of lamotrigine are probably not dissimilar from those of median doses of valproate. As the patent lapsed, the topic faded from the conference timetables, journals, and bookshops.

In the 1990s, a number of new drugs were licensed, and sales of lamotrigine faltered—not least because of the perception that the drug was a relatively weak antiepileptic. In December 1998, it was licensed for use as monotherapy in the United States, when converting from an enzyme-inducing antiepileptic drug, and in 2004 as monotherapy when converting from valproate. The monotherapy licenses were based on randomized comparative trials in partial-onset seizures, generalized tonic–clonic seizures in adults, the elderly, in children, in Lennox-Gastaut syndrome, and in newly diagnosed patients (Brodie et al., 1995; Reunanen et al., 1996; Besag et al., 1997; Eriksson et al., 1998; Motte et al., 1998; Brodie et al., 1999; Duchowny et al., 1999; Nieto-Barrera et al., 2001;Brodie et al., 2002). An influential double-blind monotherapy comparison with carbamazepine in 260 patients showed lamotrigine to be of equal efficacy but better tolerated (Brodie et al., 1995) and since then lamotrigine has been increasingly used as first-line monotherapy, particularly for generalized epilepsy as an alternative to valproate.

In 2005, as the patent and exclusivity licensing ended, generics moved into the market with a product from TEVA. Since then GlaxoSmithKline sponsorship rapidly diminished, with for instance no satellite symposiums in the recent international and regional congresses. A patent battle between TEVA and Glaxo was initiated in the United States courts, an example of the many internecine legal battles that rage in the pharmaceutical industry.

In 2007, the SANAD study (Marson et al., 2007b), a large-scale pragmatic comparison of initial monotherapy, found lamotrigine to be superior to carbamazepine in partial-onset epilepsy. The results were surprising and contentious, and the pages of the medical journals were filled with critical comment, but it remains to be seen whether this will revive the fortunes of the drug for use in epilepsy at a time when the main thrust of industrial-sponsored research and marketing is directed at its effects in bipolar disease. By December 2007, lamotrigine was licensed in 130 countries and reported to have more than 8.6 million patient-years of experience, and at the time of writing there are 63 current clinical trials in various indications. In terms of unit sales, lamotrigine remains third in the United Kingdom at least after carbamazepine and valproate, with lamotrigine still the most prescribed drug among female teenagers.

Felbamate (Felbatol)

The NIH ADD program early on identified one important compound: 2-phenyl-1,3-propanediol dicarbamate (felbamate). It was synthesized in the Wallace Laboratories in the 1950s as a relative of meprobamate in their search for new sedative drugs. It appeared to have little promise as a sedative and so was shelved for many years. Screened by the NIH program, the drug was found to have very low toxicity (“This drug does not kill rats,” as Harvey Kupferberg put it) and had a unique profile of antiepileptic drug activity in both rats and mice (Swinyard et al., 1986). Its pharmacokinetics were rapidly defined, and it soon progressed into clinical trials. In 1991, the first phase II studies, funded by NIH, were reported (Leppik et al., 1991) and were soon followed by two monotherapy studies in 1992–1993. Novel study designs were agreed with the FDA, including studies of felbamate versus no therapy in presurgical patients, and the first regulatory studies in Lennox-Gastaut syndrome. By the mid-1990s, eight major double-blind placebo-controlled studies had been carried out, four with a parallel group add-on design, one a crossover design, and two monotherapy studies. In two studies, an “active control” (low-dose valproate) was employed, with the rationale that it would prevent serious seizure exacerbation yet the superiority of felbamate to be clearly demonstrated. It was a controversial program, but the drug was recommended for approval by the FDA in December 1992. This was the first new antiepileptic drug approved in the United States for 15 years (although in Europe, vigabatrin, clobazam, lamotrigine, oxcarbazepine, and gabapentin, and in Japan zonisamide, had all been licensed), and the move was clearly influenced by general pressure to get an “American” drug to market. The launch of the drug in July 1993 was followed by a massive advertising campaign. The basic message was that here was a new, highly effective American drug, with a remarkable lack of toxicity. Advertisements of a pretty women walking in a flower-strewn meadow with the caption “Seizure control that is easy to live with” appeared in the national press and were highly influential. The culmination, in August 1993, was a Time magazine feature article about a 38-year-old Connecticut homemaker and mother of two boys, named Tiscia, whose uncontrolled seizures and life were dramatically improved by felbamate. Tiscia was quoted “I’m back ! It’s me …. My sister tells me she finally likes me again, She even lent me her car. My mother yells at me again. It’s great.” The campaign was very effective; as Tiscia signed off, the sales of felbamate took off.

In the clinical trials, 1,600 people were exposed to felbamate, over half for 9 months or more, and no significant hematologic or hepatic changes were noted. Within the first year of launch, by August 1994, more than 110,000 patient exposures had resulted. In January 1994, the first cases of aplastic anemia was recorded, and by the end of 1994, 34 cases were reported of which in retrospect 23 were definitely related to felbamate, with 14 deaths. Eighteen patients also developed hepatic failure, with five deaths definitely attributable to felbamate. By August 1994, Wallace laboratories and the FDA recommended suspending use of the drug. The manufacturers then wrote to 240,000 physicians advocating withdrawal unless absolutely necessary. Status epilepticus was precipitated in some cases withdrawing the drug. The planned launch of the drug, about to take place in Europe with a major conference planned in Spain by the European licensee Schering Plough, was cancelled at the last minute. In September 1994 the FDA committee voted (by 6:1) to allow felbamate to remain on the market for restricted cases, with careful monitoring and surveillance and with a black box warning. Since then, the drug has continued to be prescribed, but only in very selected patients. It is currently thought that between 10,000 and 13,000 patients are taking the drug, and since 1995, two new cases of aplastic anemia and two cases of hepatic necrosis have been recorded. The U.S. courts were swamped with more than 100 lawsuits, mostly from people without any bad reaction to the drug but claiming emotional distress or damages for the forced withdrawal. Carter Wallace went out of business, but the drug continued to be manufactured, unpromoted, by MedPoint and now Media Pharmaceuticals. This was an unhappy episode in the recent history of antiepileptic drug therapy. As it turns out, the overall risk of marrow depression is between 27 and 300 per million patients treated (Bialer et al., 2007), and of hepatic failure between one in 26,000–34,000 persons—a risk greater, but not orders of magnitude, so than that of carbamazepine. There are a number of lessons from this debacle. First, the full toxicologic risk of a drug may not be evident on licensing. This is of course obvious, and there are numerous other examples in the antiepileptic drug field where patients take regular therapy for many years and thus where side effects which are rare or which develop only after a long period of exposure or in certain circumstances only (e.g., pregnancy) come to light, sometimes years after licensing. Licensing in this sense must be seen as a balance between allowing undefined risks in order to make available the benefits in terms of seizure control. In the case of felbamate, the short-lived and difficult-to-identify atropalderhyde metabolite of felbamate is probably the causative agent, and susceptible individuals lack the enzyme to metabolize it. It is notable that rodents do not share this metabolic pathway, and so animal toxicology did not detect the risk. Second, it is irresponsible to promote a novel therapy with incautious claims and aggressive advertising—this takes risks with people’s lives. The place of a new antiepileptic may take years to establish, and the excessive marketing of felbamate in its first year resulted in severe restriction and the loss of opportunity to study what might have proved to have been a useful drug in selected circumstances.

Gabapentin (Neurontin)

Gabapentin is an analog of GABA, the structure of which has been twisted deliberately in the laboratory to make it more lipophilic than the parent compound and thus hopefully able to cross the blood–brain barrier more easily. This was the theory when G. Satzinger, the medicinal chemist working in the company of Goedecke, a subsidiary of Parke-Davis, in Germany first produced the compound. It was developed as a GABA analog, but in fact its antiepileptic effects are due to an entirely different mechanism: to its binding to the α2δ subunit of the neuronal voltage-dependent calcium channel (a fact discovered a decade or more after licensing and launch). Animal and initial patient experience was positive, and in 1984, a clinical development plan was devised in Germany by Bernd Schmidt, who was recruited by Parke-Davis to set up a European clinical research network for the study of the compound. The initial clinical studies were in the field of spasticity and rigidity, as the toxicologic information allowed at this time only 4 weeks of exposure, but later three proof-of-concept (phase IIa) studies were completed in Zurich, Austria/Germany, and in Liverpool, which demonstrated antiepileptic activity. Schmidt recalls that Parke-Davis was at that time uninterested in the drug, partly it was felt at least in Germany because it was “non-NIH” (it was known apparently internally as the Black Forest medication), and partly because they were also handling zonisamide at the time, which took precedence.

The drug “died three times” according to Schmidt, but was resuscitated and then entered into definitive double-blind randomized clinical studies. (UK Gabapentin Study Group 1990; Silvenius et al., 1991; The US Gabapentin Study Group No. 5, 1993;Anhut et al., 1994; Chadwick et al., 1998). These were notable for innovative statistical approaches, and in 1994 gabapentin was licensed in the United States and United Kingdom for use in partial seizures. The drug was also trialed in eight nonepilepsy indications, including major areas such as bipolar disease, mood disorders, and neuralgic pain. over a period of a few years, Neurontin became one of Pfizer’s best-selling products, By 2003 gabapentin was one of the 50 most-prescribed drugs in the United States (its sales rose from $97.5 million in 1995 to nearly $2.7 billion in 2003). According to some estimates, nonepilepsy use accounted for up to 90% of all sales. In 2004, a generic formulation of gabapentin, manufactured by TEVA, was licensed and launched in the United States. In recent years, the drug has been trialed for use in a diverse range of other indications, ranging from the therapy of menopausal hot flushes to the alleviation of drug abuse. In epilepsy, gabapentin has gained a reputation as a rather weak antiepileptic, although well-tolerated, and seems to have a particular role in the elderly, where its gentle nature and lack of drug interactions are particular advantages. It has also been trialed in children (Appleton et al., 1999), but does not seem to have gained much popularity. Its place in the therapy of both pain and epilepsy has to a large extent been superseded by the newer drug pregabalin.

Oxcarbazepine (Trileptal)

This compound was first synthesized in 1966 and is a keto derivative of carbamazepine, in which an extra oxygen atom is added on the dibenzazepine ring. This difference avoids the epoxidation stage of metabolism and thus reduces the risk of interactions. It also has a much lower risk of bone marrow suppression and hepatic dysfunction. Like carbamazepine, it acts by inhibiting the neuronal sodium channel, and its clinical effects are very similar to those of carbamazepine. It was approved for use as an anticonvulsant first in Denmark in 1990, then Spain in 1993, Portugal in 1997, all other EU countries in 1999, and the United States in 2000. Its early use in Demark was partly due to the championship of the drug by Mogens Dam, previous ILAE president, who conducted the first double-blind randomized study, and who was deeply committed to the compound (Dam et al., 1989). By 1989, the main features of oxcarbazepine compared to carbamazepine were well-established by the work of Dam and others—similar efficacy, somewhat better tolerability, lower risk of drug interaction, lower risk of allergy, but greater incidence of hyponatremia. Its clinical trial program is unusual in that it was directly compared to other drugs rather than placebo, trialed early in monotherapy and in children (Bill et al., 1997; Christe et al., 1997; Guerreiro et al., 1997; Schachter et al., 1999; Beydoun et al., 2000; Glauser et al., 2000; Sachdeo et al., 2001), and the drug attained a monotherapy license early on. Oxcarbazepine has continued to be used widely, but perhaps surprisingly has not generally superseded carbamazepine.

Drugs introduced between 1995 and 2009

In this 15-year period, a further nine new antiepileptic drugs were licensed in either Europe or the United States. It is too early to place these drugs in a historical perspective and they will be briefly listed here.

Topiramate (Topamax), a monosaccharide derived from fructose, was developed initially to be an antidiabetic drug (it has only weak action in this regard) and was then found to have antiepileptic action after routine screening. It has multiple mechanisms of action, including carbonic anhydrase inhibition, and exerts a relatively broad spectrum activity in animal models. It rapidly developed the reputation of being a very powerful antiepileptic drug but which has a high rate of side effects (a reputation which derived I remember initially from a presentation made at the Oslo ILAE International Epilepsy Congress in 1993 by Olaf Henriksen, who showed a slide of a single patient with 13 different side effects). In the celebrated meta-analysis of antiepileptic trials by Marson et al. (1997), topiramate was found to be the drug with the greatest antiepileptic effect. This action has been demonstrated repeatedly in a large variety of controlled studies in various countries, in partial and generalized epilepsy and in adults and children, and in Lennox-Gastaut syndrome (Ben-Menachem et al., 1996; Faught et al., 1996; Sharief et al., 1996; Tassinari et al., 1996; Biton et al., 1999; Elterman et al., 1999; Korean Topiramate Study Group 1999; Sachdeo et al., 1999; Yen et al., 2000). Its poor side-effect profile, though, remains a drawback for the drug. One unusual effect is the non-infrequent development of word-finding difficulties, and other troublesome sequelae include a wide range of other CNS effects, the risk of renal calculi, carbonic anhydrase effects, and weight loss. As a result of findings from dosage studies, the general tendency now is to employ much lower doses than were used in the initial trials (see for instance Gilliam et al., 2003; Wheless et al., 2004), and at the lower doses, side effects are much less troublesome. Nevertheless, the drug is usually reserved, at the time of this writing, as a second-line therapy for resistant cases. Recently topiramate was licensed for migraine, and it may end up being used more often for this condition than for epilepsy.

Tiagabine (Gabitril) is a selective GABA-reuptake blocker that was licensed first in France and then widely in Europe in 1996 and in the United States in 1997, on the basis of positive controlled trial evidence (Richens et al., 1995; Kälviäinen et al., 1996, 1998; Sachdeo et al., 1997;Uthman et al., 1998). It has a pure GABAergic action, but unlike vigabatrin does not affect the retina. It was initially much in favor in northern Europe, but then sales began to founder largely because of the drug’s propensity to cause transient CNS side effects if taken before meals and to induce nonconvulsive seizures or an encephalopathy. It is now little used. At one stage it was suggested that the tiagabine is especially effective in lesional epilepsy, but that seems not to have been borne out in wider practice.

Levetiracetam (Keppra) is, at the time of writing, the most successful of all the newer antiepileptic drugs introduced in this last period of our history. It is one of a large family of pyrrolidone drugs, a drug class pioneered by the chemist Gurgea at UCB (Shorvon, 2001), and has a very close structural similarity to piracetam. Early studies in other indications used the racemic mixture, etiracetam. Levetiracetam is the L-enantiomer of etiracetam (the R-enantiomer being an inactive substance in models of epilepsy) and was known in those early days by the code name ucb-L059. It was first investigated in the early 1980s as a drug with cognitive-enhancing and anxiolytic effects. More than 2,000 patients were included in these early studies, the majority receiving doses ranging from 250–1,000 mg/day, but the findings were disappointing. Attention then switched to the field of epilepsy and studies were initiated, not in the MES and PTZ models, which were the usual screening tests employed for instance by the NIH ADD program, and in which the drug has no positive action, but in the amygdala kindling and photosensitivity models. In these alternative models, the drug had excellent efficacy, and clinical trials as adjunctive therapy in the treatment of partial-onset seizures were begun in 1991. I remember its first trials at the Chalfont Centre for Epilepsy, where as principal investigator I was struck by how novel and effective this drug seemed—and substantially better than others being also trialed. The trials were concluded slowly (Ben-Menachem & Falter, 2000;Cereghino et al., 2000; Shorvon et al., 2000), but were eventually completed and were positive. On the basis of these, levetiracetam was licensed in 1999 in the United States and 2000 in Europe. It was marketed under the trade name Keppra (named after the Egyptian sun god; the launch of the compound took place in Cairo, with a conference full of razzmatazz, dinners in tents in the desert, and camel rides). Its mode of action was initially unclear, but in 2004, it was found to bind selectively and with high affinity to a synaptic vesicle protein known as SV2A, which is involved in synaptic vesicle exocytosis and presynaptic neurotransmitter release. This is a novel binding site (shared only by other pyrrolidone drugs, including piracetam), and exactly how binding confers antiepileptic action is unknown. What is clear though is that this is a new and powerful antiepileptic compound whose clinical effects are distinctive—it has action against many types of generalized as well as partial seizures and controls seizures in many patients in whom other drugs are ineffective. It has a generally alerting rather than sedative action—and it is this latter property that is probably the reason for its popularity. Its main side effect is its tendency to induce irritability and occasionally severe aggression and marked behavioral changes. What role the drug will eventually have in the therapy of epilepsy is unknown. But on its current form, it seems likely to this author at least to become a first-line therapy, challenging valproate and carbamazepine; the discovery of new side-effects of toxicity, though, could easily challenge this position. A range of other pyrrolidone drugs are now being studied for antiepileptic effect, and it is also possible that these will at some stage supersede the place of levetiracetam. For UCB, a relatively small Belgian pharmaceutical company, levetiracetam has proved to be an enormous money-spinner, making over 1 billion Euros in 2008, and propelling the company into the big league.

Zonisamide (Excegran, Zonegran) is currently available worldwide but has had a rather erratic clinical development. It was discovered by Uno and colleagues in 1972 (Shah et al., 1972) and approved for licensing in Japan and South Korea in 1989, manufactured by Dainippon Pharmaceuticals (which in 2005 merged to become Dainippon Sumitomo Pharma) as Excegran. An attempt to license the drug in Europe or the United States failed at that time, on the basis of a clinical trial program that was felt to be inadequate by the licensing authorities and also anxieties about the risk of renal calculi. Following a new series of randomized clinical trials in the United States, it was approved there for licensing in 2000, in 2005 in the United Kingdom, and Germany in 2005, and then in many other countries as adjunctive treatment of partial seizures in adults, under the trade name Zonegran. It had in the meantime proved a popular drug in Japan, where it is said now to occupy about 15% of the Japanese antiepileptic drug market, and where it is licensed as adjunctive and monotherapy in partial seizures and generalized seizures. It shows a strong effect in clinical trials (Schmidt et al., 1993; Faught et al., 2001), although side effects are not infrequent. The mechanism by which the drug exerts its antiepileptic action is not entirely clear, and zonisamide has been shown to be an inhibitor of carbonic anhydrase inhibitor, to block repetitive firing of voltage-gated sodium channels, to reduce T-type calcium channel currents, to bind to GABA receptors, and to increase levels of the glutamate transport protein. Its use seems likely to increase.

Pregabalin (Lyrica) was discovered in 1989 by the medicinal chemist Richard Silverman working at Northwestern University. Like gabapentin, pregabalin binds to the α2δ subunit of the neuronal voltage-dependent calcium channel, reduces calcium influx into the nerve terminals, and decreases glutamate release, but it binds much more tightly than gabapentin. Its effect in epilepsy, anxiety, and pain were studied at the Northwestern University and by Pfizer, which licensed pregabalin for manufacture, and the drug was approved for use in the European Union in 2004 for epilepsy, in the United States for epilepsy, diabetic neuropathy pain, and postherpetic neuralgia pain in June 2005, and then in 2007 for fibromyalgia. Its effects in neuropathic pain have been exceptionally profitable, and within 2 years of its launch in the United States, it had brought in $1.2 billion in sales. Interestingly, both Silverman and Northwestern accrued huge sums from the royalties, and pregabalin is a striking example of a drug discovered in an academic rather than industrial setting. This raised the university from 71st to 11th in the league of U.S. Universities’ industrial earnings and has financed a large academic expansion. Universities often led in drug discovery pre-1940, when royalties were modest, but the massive value of the sales of the drug demonstrates how profitable the pharmaceutical industry had become, and now most drug discovery is conducted in-house by the industry; pregabalin is a striking exception. Pregabalin’s effectiveness in epilepsy across the recommended dose range of 150–600 mg daily was shown in three pivotal double-blind, placebo-controlled randomized trials, with higher doses being more effective (Arroyo et al., 2004; Beydoun et al., 2005; Elger et al., 2005). It has the potential for CNS side effects, and its relative place in epilepsy therapy is at present ill- defined.

Stiripentol (Diacomit) has a long history. It is an aromatic alcohol identified as an antiepileptic in 1978. Its initial trials in adults with partial epilepsy were relatively disappointing, complicated by its potent inhibition of the CYP3A4, CYP1A2, and CYP2C19 isoenzymes of the cytochrome P450 system, resulting in marked effects on the levels of other antiepileptic drugs. The first clinical trials were reported in 1984, and the drug mouldered in the background of epilepsy therapy for many years while studies continued largely in France. Interest has been revived by the discovery that stiripentol has a rather marked and seemingly specific action in severe myoclonic epilepsy in infancy (Dravet’s syndrome). As soon as this was established, Biocodex laboratories submitted the drug for approval under the newly created orphan drug scheme of the European Medicines Agency, and stiripentol was licensed in the European Union in 2007 for use, in conjunction with clobazam and valproate, as adjunctive therapy for refractory generalized tonic–clonic seizures in patients with severe myoclonic epilepsy in infancy. This is the first antiepileptic drug to be licensed for such a narrow indication or for a specific syndrome, and it remains to be seen what its ultimate place in therapy will turn out to be.

Rufinamide (Inovelon) was discovered and initially developed in the early 2000s by Novartis, and then certain rights relating to its epilepsy indications were licensed in 2004 to Eisei. It is a triazole derivative, which probably acts by blocking sodium channels. It was initially trialed in adults with partial epilepsy with rather disappointing results. Then a double-blind, placebo-controlled study in children with Lennox-Gastaut syndrome showed a marked clinical benefitin particular for drop attacks, which are a major source of disability and morbidity in this severe form of epilepsyand the drug was approved for use in this syndrome under the orphan drug scheme in the European Union in 2007. It is too early to say how useful rufinamide will turn out to be. But Synosia Therapeutics, an American drug development company, signed an exclusive, worldwide licensing agreement (outside Japan) with Novartis to develop and commercialize rufinamide for the treatment of anxiety disorders and bipolar mood disorders, and this may prove to be the major market for the drug. By early 2008, more than 2,500 patient-years of exposure to the drug had been gained in epilepsy studies, and the good safety profile was one reason for commercial interest in pursuing an anxiety indication.

Lacosamide (Vinpat) was initially developed by Schwartz Pharma (under the names SPM 927, ADD 234037, harkeroside, erlosamide) as a drug for the treatment of partial seizures and status epilepticus. It is a synthetic derivative of the amino-acid D-serine. Schwartz was taken over by UCB Pharma in 2006, and in 2008 the drug was licensed in the European Union for adjunctive therapy in partial seizures following a large multicenter, international study (Ben-Menachem et al., 2007). It acts at the sodium channel, but by a different mechanism from carbamazepine or phenytoin. It is also under investigation for the much bigger indication of diabetic neuropathic pain. It was launched in Europe in September 2008.

Other antiepileptic drugs

A number of other drugs are currently in active development. Some are derivatives of existing drugs, hoping to replace the older drugs with their shorter patent life and also to improve features—examples are brivaracetam (ucb 34714) and seletracetam (ucb 44212)—structurally similar to levetiracetam; eslicarbazepine acetate (BIA 2-093) and JZP-4—structurally similar to carbamazepine; valprocemide and propylsopropyl acetamide—structurally similar to valproate; T-2000—structurally similar to phenobarbital; and fluorofelbamate—structurally similar to felbamate. Others are novel structures—examples are 2-deoxy-D-glucose, ganaxolone, Huperzine A, ICSC 700-008, NAX-5055, NS1209, talampanel, tonabersat, and YKP3089. Many of these act at the glutamate receptor (including talampanel, which is an AMPA antagonist). There are few new drugs currently designed for totally new targets, although ganaxolone is a neurosteroid and Huperzine A (derived from a Chinese herbal remedy and classified by the FDA as a dietary supplement) has a number of known actions on transmitters not normally associated with epilepsy. In many cases, the exact mechanisms of action are not known. This is an active pipeline that holds promise for the future, although currently none of the drugs in development looks so strikingly good that a paradigm shift in epilepsy therapy looks likely. The promise of the molecular age of personalized medicine, pharmacogenetically determined therapy, stem cell therapy, or drugs designed for action at completely novel targets is still far away.

Of these drugs, four (retigabine, carisbamate, eslicarbazepine, and brivaracetam) seem likely to be licensed in the next few years. In addition, as in previous decades, there are other compounds that were investigated in the period under study as antiepileptic drugs, and which entered early human studies, but which have not progressed (examples are dezinamide, nafimidone, ralitoline, milacemide, loreclezole, and losigamone). These are also briefly discussed in subsequent text.

Retigabine: (N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester) is a truly novel drug directly activating as it does the voltage-gated potassium channels that conduct the M-type potassium current. No other current antiepileptic drug does this, and it has entered phase III clinical trials and shows promise. It seems to be extremely effective in some patients who are intractable to other compounds, and its wider use is, accordingly, awaited with interest. By the same token, the currently disclosed side-effect profile is depressingly similar to that of other antiepileptic drugs.

Carisbamate, previously known as YKP 509; RWJ-333369, is due to be licensed in Europe for the treatment of refractory partial seizures in 2009. It is a carbamate derivative, developed in South Korea by SK Pharma and licensed in 1998 to Johnson & Johnson. Its proposed advantages include very good tolerability at least up to 300 mg, a broad spectrum of activity in preclinical testing, including the GAERS model, action in human photosensitivity, and little effect on the blood levels of other drugs. Importantly, it is also the first licensed compound shown to prevent epilepsy in an experimental post–status epilepticus model. However, it has relatively limited efficacy in clinical trials, and phenytoin greatly increased its clearance.

Eslicarbazepine acetate is a derivative of carbamazepine that produces structurally different metabolites and avoids the 10,11-epoxide stage, which it is hoped will improve tolerability without lowering efficacy. This bold aspiration seems to be realized in the preliminary clinical trials. Studies are ongoing.

Brivaracetam: The enormous success of UCB Pharma with levetiracetam stimulated a search for further—racetam derivatives. Two were found that show great promise—brivaracetam (UCB 34714) and seletracetam (UCB 44212). The company decided to pursue the former, which binds more strongly to the SV2A protein than levetiracetam and also has sodium-channel blocking action. In animal models it appears more potent than levetiracetam but, because it is extensively metabolized in the liver, it has its own pharmacokinetic interactions. It seems in early clinical studies to be highly effective and well tolerated and is an exciting prospect for the future.

Remacemide is an interesting compound, manufactured by AstraZeneca, which was in clinical development for many years and initially showed promise. It, and its active metabolite (F12495AA, FPL12925, AR-12495AA), are N-methyl-d-aspartate (NMDA) receptor antagonists. The drug also blocks voltage-gated sodium channels. It was developed first as an antiepileptic drug, then in two well-conducted and well-controlled randomized clinical trials in newly diagnosed epilepsy, an unusual but welcome departure from the traditional clinical trial route (Brodie et al., 2002; Whitehead et al., 2002). Unfortunately, a Cochrane Review in 2002 concluded that in the two clinical trials of 514 patients there was only a modest effect on seizures and the drug was more likely to be withdrawn than placebo. Its potential as a neuroprotectant in epilepsy has not been pursued, but it is being studied after stroke in an attempt to minimize cerebral damage, and in Parkinson’s disease and Huntington’s disease.

Dezinamide was the name chosen for AHR-11748, the desmethyl metabolite of fluzinamide, manufactured by A. H. Robins Company and developed by Athena Neurosciences. Experimental findings indicate that it has antiepileptic properties, and its pharmacokinetic properties were assessed in healthy volunteers and in phase II studies. But it was not further trialed clinically. Dezinamide had a promising and unusual profile in the NIH ADD program, but it nevertheless probably acts as a sodium-channel blocker. However, it can cause neurotoxic side effects, including hypomania and rash. Its development ceased in the 1990s, although for financial rather than scientific reasons.

Nafimidone was an imidazole derivative, developed by Syntex Research Laboratories and supported by the Epilepsy Branch of NINDS. Early studies showed striking efficacy, and the experimental and clinical profile of the compound was similar to that of phenytoin and carbamazepine. However, it was said to have a very poor therapeutic/toxicity ratio, and further clinical development was abandoned in the early 1990s.

Ralitoline is a thiazolidinone derivative and manufactured by Warner-Lambert. Experimentally, it resembled phenytoin and carbamazepine and was thought to act on the sodium channel. The major problem identified early in development was its very short half-life, and possibly largely for this reason, and despite a rather promising efficacy profile, its clinical development stopped in the early 1990s.

Milacemide was designed as a glycine agonist and sponsored by Monsanto-Searle. Although open studies showed effectiveness, early double-blind studies found little antiepileptic efficacy and the drug was abandoned as an antiepileptic. Its development continued in other indications, including myoclonus, but was effectively abandoned by the year 2000.

Loreclezole: This triazole derivative, sponsored by Janssen Pharmaceutical, has an experimental profile similar to that of the barbiturates and benzodiazepines, and was found to have promising results, both in monotherapy and as add-on therapy in phase II trials. It binds to the same site as the active ingredient, valerenic acid, of the valerian plant, which is a well-established traditional herbal remedy for epilepsy. Loreclezole has been a valuable, indeed almost cult, compound used to elucidate the functioning of the GABA receptor because of its unique binding properties. Although it continues to be studied experimentally, it seems not to be entering any large-scale clinical development program.

Losigamone was developed by Willmar Schwabe in the late 1980s, in conjunction with the NIH ADD program. It has continued to be investigated in a low-level way, and is now in phase III studies; whether it will ever be licensed after such a long gestation remains to be seen. It has been postulated that it blocks seizure spread by acting on voltage-gated ion channels. Uniquely for an antiepileptic, the drug is a β-methoxy-butenolides and exists as a racemic mixture of two enantiomers (AO-242 and AO-294). In clinical trials, the enantiomer AO-242 seems to be more potent than AO-294 or racemate, and is apparently effective against partial and secondary generalized seizures. A particular advantage is its good tolerability.

Therapy of Epilepsy in 2009

  1. Top of page
  2. Summary
  3. The Drug Treatment of Epilepsy 1959–1988
  4. The Drug Treatment of Epilepsy 1989–2009
  5. Therapy of Epilepsy in 2009
  6. Acknowledgments
  7. References

In 2009, the third edition of the reference book Treatment of Epilepsy (Shorvon et al., 2009a) was published. It provides a summary of the contemporary approaches to medical and surgical therapy in 2009. The second section of the book of 21 chapters covers the principles of therapy, and the third section contains 29 chapters, each devoted to an individual drug or group of drug therapies. These drug chapters are listed in Table 8, and show the range of therapies used in advanced clinical practice in 2009. A comparison with the situation in 1989 is instructive.

Table 8.   Drug treatment in 2009 (based on the list of drug chapters in the reference book The Treatment of Epilepsy, see text)
  1. In addition, a chapter on antiepileptic drugs in clinical development included the following drugs in early development: Fluorofelbamate; ganaxolone; JZP-4; safinamide (FCE 26743; PNU-151774E; NW-1015); seletracetam (ucb 44212); T2000; talampanel (LY300164; GIKY 53773); tonabersat (SB-220453); valrocemide (N-valproyl-glycinamide; TV 1901); YKP3089.

  2. aDrugs in final stages of clinical trial and which look likely to be licensed by 2012.

ACTH and corticosteroids
Brivaracetama
Carisbamatea
Carbamazepine
Clobazam, clonazepam, nitrazepam, clorazepate
Midazolam, lorazepam, diazepam
Eslicarbazapinea
Ethosuximide
Felbamate
Gabapentin
Lacosamide
Lamotrigine
Levetiracetam
Oxcarbazepine
Phenobarbital
Phenytoin
Piracetam
Pregabalin
Retigabinea
Rufinamide
Stiripentol
Tiagabine
Topiramate
Valproate
Vigabatrin
Zonisamide
Other drugs rarely used: Allopurinol, bromide, ethotoin, furosemide, mephenytoin, phenacemide, trimethadione (oral use)

In relation to therapeutic principles, there is little fundamental change. Knowledge has increased incrementally in all areas, but the similarities of approach are much greater than the differences. The field of genetics has advanced most, and has influenced mainly classification, etiology, and experimental pharmacology and physiology. The impact of genetics on clinical therapeutics has to date been relatively limited, although this may change in the next decade. More knowledge has also accrued in relation to the side effects of therapy—including a better understanding of teratogenicity and idiosyncratic reactions. Given the similarity of the antiepileptic power of the available drugs, in this period, side effects have become a predominant factor in differentiating therapies. There is also a better understanding of the management of specific syndromes. The quality of clinical assessment of therapy also improved in these two decades, with the strong emphasis on controlled and randomized studies and statistical methods (including the use of meta-analysis). Knowledge of the mechanisms of pharmacokinetic interactions has also increased, particularly at the level of hepatic enzyme action.

Although general therapeutic approaches have not changed very much in the 20-year period from 1989, the number of effective drugs available for use has greatly increased. Thirteen new drugs were licensed between 1989 and 2009, and the undoubted effectiveness of each was confirmed in randomized trials compared against placebo, although unfortunately with few head-to-head comparisons. These drugs have cleared regulatory hurdles, which greatly increased in these decades, an impressive record unmatched except perhaps only by the decade after 1938. The greater range and choice of therapy is an improvement over previous times, although none of the drugs has proved strikingly superior to any other, or to the first-line therapies (in 1989) or carbamazepine, valproate, phenytoin, or phenobarbital. This point is taken further below.

The antiepileptic drug market and the rise of the pharmaceutical industry

The postwar period was marked by an enormous rise in the power and profits of the pharmaceutical industry and the intense commercialization of this therapeutic area (as of many others in medicine). Initially this was a period of great optimism. The drugs developed in the 1950s and marketed in the 1960s included the first oral contraceptives, cortisone, antihypertensives, monoamine oxidase (MAO) inhibitors, chlorpromazine, haloperidol, and Valium (the latter drug becoming at one point the most prescribed drug in history). The profits of the drugs companies soared in the 1960s, and for many years, for instance, the U.S. pharmaceutical sector was judged the most profitable of all industrial sectors in terms of rate of return (2006–17% on revenue). The antiepileptic drugs now bring in billions of dollars annually, and the massive financial rewards have changed the balance of power in medicine in several ways. First, the leadership of drug development has moved away from the university academic environment to the in-house laboratories of the companies. The research is now much more focused and more applied, and this move is probably the fundamental reason for the rapid increase in the number of compounds being brought forward for clinical testing. The move has had some negative effects, not least the fact that transparency has diminished and drug development has become more secretive. The later stages of development particularly have become a ruthless commercial enterprise kept under conditions of tight secrecy to protect commercial interests. Epilepsy therapeutics also has experienced a transfer of influence away from the academic neurologic community to the marketing departments of pharmaceutical companies. This latter change was first noticeable in the 1960s, and has been especially prominent in the last 10 years. The relationship between the two continues to be at the still center.

Particularly since the mid-1980s, the value of the antiepileptic drug market has increased dramatically. The total sales of antiepileptic drugs in the United States, for instance, rose from $400 million in 1990 to $3 billion in 2000. In 2001, the total world market for epilepsy was valued at around $5 billion. The global market is large partly because, according to WHO estimates, up to 42 million people are affected by epilepsy and there are approximately 3.5 million new cases each year. However, the traditional antiepileptic drugs are extremely inexpensive, and although total sales have increased in part due to a rise in prescription numbers, a much greater influence on the market value is the staggering increase in the price of the newer drugs. Based on the British National Formulary 2008 figures, a year’s supply of phenobarbital (the least expensive drug) in the United Kingdom in 2008, at a standard dose range (60–180 mg/day) costs the National Health Service £9.12–27.36 (in 60-mg tabs). This compares with a cost of £1,255.20 and £4,852,90 for a standard-dose range of levetiracetam (1,000 mg/day in 500 mg tablets to 4,000 mg/day in 1,000 mg tablets), a 138–177-fold difference. The large increase in price (and profits) has attracted the large pharmaceutical companies, and for instance five of the six largest (Pfizer, Sanofi-Aventis, GlaxoSmithKline, Johnson & Johnson, and Novartis) market antiepileptic drugs; and five companies (Pfizer, Johnson & Johnson, Abbott, GlaxoSmithKline, and Novartis) account for approximately 75% of the global antiepileptic market in monetary terms. Furthermore, a major attraction of the antiepileptic drug market is the fact that the drugs, once licensed for epilepsy, also then tend to acquire value in other indications, notably pain and bipolar disease, which are even larger markets in monetary terms. Pfizer, for instance, the largest pharmaceutical company in the world, generated around one-third of its total sales with Neurontin, first launched in 1994, up to June 2004.

This is all the more remarkable given that none of the newer expensive antiepileptics have proven to be any more efficacious in clinical trials than the older drugs in controlled studies, nor generally have they resulted in a paradigm-shift in side-effect profile. Some, however, have fewer interactions and cleaner pharmacokinetics than, say, phenytoin or carbamazepine. The price difference is justified by the pharmaceutical industry as a return for research and investment. However, the difference is so high that most governments and health care providers now actively seek to limit prescriptions of expensive therapy. At the time of writing this is one of the most important health care issues facing many societies, both in the West and the developing world.

The large profits and lack of clear-cut scientific evidence to justify costs are probably also one reason for the enormous rise in marketing budgets within the pharmaceutical industry. The recognition that “a brand is simply a perception” has led the industry to spend large sums of money on changing perceptions. In the early post-war years, marketing was limited and restrained. But since the 1980s, increasingly sophisticated and powerful methods have been used to target doctors, and more recently patients and patient organizations. Details are often difficult to determine, but two examples are in the public domain.

The first concerns gabapentin, which was the subject of a lawsuit in 2004 in which Warner-Lambert paid $430 million in fines to settle civil and criminal charges related to illicit means of marketing the epilepsy drug gabapentin for off-label uses. Because of the legal proceedings, details of the marketing budget and marketing strategy were made public, and this included the epilepsy-related activities. These documents were analyzed in detail in a seminal article by Steinman et al. (2006), from which the following information is taken. In 1998, the draft total advertising and promotion budget of gabapentin by Parke-Davis, the manufacturer, was $40 million. Several strategies were employed by the company. These included the use of advisory boards that cultivated relationships and of educational activities, some directly arranged by the company and others indirectly through medical communication companies. Some were luxury trips to Hawaii, Florida, and the 1996 Olympics in Atlanta, and the speakers received large honoraria (one doctor almost $308,000 to speak about Neurontin in various conferences). Nineteen million dollars was spent in such professional education. Another highly criticized activity was the use of medical journals. The company contracted with medical education companies to expand the literature on gabapentin by developing review and original articles and letters—paying up to $18,000 per article. These were also often ghost-written by the medical communication companies in conjunction with the manufacturers, and failed to acknowledge company sponsorship (although they did acknowledge support by the medical education company). Finally, criticism was made of sponsored research such as STEPS (Study of Neurontin: Titration to Effectiveness and Profile of Safety), an uncontrolled open-label study in which more than 700 physicians were each paid $300 per enrolled patient. Indicators of success for the study included increases in market share and use of higher doses of gabapentin. At least six of nine authors of the published report had substantial financial relationships with Parke-Davis and had participated in a total of 263 activities sponsored by the company between 1993 and 1997, with payments ranging from $11,450 to $69,000 per author. It should be emphasized that these events occurred before Pfizer became the owner of the drug, and Pfizer had no responsibility whatsoever for these events. Indeed, the marketing and promotion of the drug since Pfizer became its owner have been of the highest ethical standard.

A second example of the sophistication of marketing is the “integrated segmentation strategy.” This shows the subtlety and detail with which pharmaceutical companies make their pitch to the medical profession (their customers) and is described in detail by Kumar and Brand (2003). Such sophisticated marketing practices are now widespread in most large pharmaceutical companies and seem to have developed only in recent times. They are backed up by huge marketing budgets and reflect the extent to which the center of gravity of clinical therapeutics has shifted.

The rise of regulation

The increasing influence and power of the pharmaceutical industry has been paralleled by, and has no doubt contributed to, an increase in governmental regulation and restriction. This reflected the growing public interest, and concern, in drug therapy in many areas of medicine. In fact, it was a series of well-publicized debacles which led to incremental changes in governmental regulation.

The example of the legislation in the United States is instructive, although similar legislation tended to follow the American example in other countries. Prior to 1906, there was almost no regulation of drugs or medicines in the United States, which lagged behind Europe in this regard. The first major legislation was the Federal Pure Food and Drugs Act, passed by the U.S. Congress in 1906, in response to public concern about excessive misbranding and adulteration of food. This act required, for the first time, simply “accurate” labeling, but there was no obligation to provide any real evidence of either toxicity or efficacy. By the 1930s, the nascent consumer movement raised the awareness of the U.S. public (if not their doctors), who became increasingly concerned about the quality of medicines. Efforts were made to tighten regulatory control, for instance through the ill-fated Tugwell bill of 1933, but such efforts never made it to the legislature, partly because of the powerful industrial lobby. However, in the 1930s, the deaths of more than 100 people caused by “elixir of sulfanilamide,” a liquid form of sulfanilamide, dissolved in diethyleneglycol, ignited public anger. In response to this, in 1938, a new act—the Food, Drug and Cosmetic Act—was passed into legislation. This required, among other things, evidence of safety to be submitted to the FDA prior to marketing. Between 1938 and 1962, no other major tightening was made to the laws concerning drugs and medicines (although there were changes to laws concerning foodstuffs), but this changed with the thalidomide tragedy. Thalidomide was a drug very widely sold during the late 1950s and early 1960s to pregnant women to alleviate morning sickness and to assist sleep. It was inadequately tested, and between 1956 and 1962, approximately 10,000 children were born with severe malformations in Europe and elsewhere (not, however, in the United States, where the drug had not been licensed). In response to the massive public outcry, new laws were drafted, and in 1962, the Drugs Amendment Act (the Kefauver–Harris Amendment) was signed into law by John F. Kennedy. These amendments were a milestone in medical history, and for the first time required evidence of efficacy as well as safety of medicines, and also the continuing evaluation of drugs already on the market and the retrospective evaluation of efficacy of all drugs introduced between 1938 and 1962. The Kefauver–Harris Amendment also required drug advertising to disclose accurate information about side effects and efficacy of treatment and placed on the FDA an obligation to establish guidelines for testing all classes of drugs, including antiepileptics. A new system of licensing was devised by which the FDA required each company to obtain an IND (Investigational New Drug, a notice of claimed investigational exemption for a new drug) before it was permitted to use the drug in human subjects. Complete chemical and manufacturing information, preclinical screening, and animal investigation, including toxicology, teratogenicity, and safety, had to be submitted to the FDA before the IND was granted. Once an IND was granted, clinical testing could begin and was divided into phase I (healthy volunteers); phase II (controlled studies in seizure patients); and phase III (broad and varied clinical studies). After completion of these studies, a “New Drug Application” (NDA) could be filed. If approved, the drug could then be licensed.

These new regulations no doubt protected the public from dangerous compounds, but there were also immediate negative consequences. The cost of developing antiepileptic drugs increased greatly due to the huge increase in the number of animals and procedures needed in preclinical testing, and in the complexity and scope of this testing. Large controlled clinical trials were also required, and gone were the days when a few short open studies were sufficient (as applied for instance for phenytoin or ethosuximide). This led to a rapid fall-off in the number of drugs being developed, and the U.S. companies in particular largely withdrew from the field of epilepsy, engendering considerable concern in epilepsy and ILAE circles. Responding to these concerns, in 1972, the U.S. NINDS set up an Ad Hoc Committee on Anticonvulsant Drugs to translate the new rules into practice, and in conjunction with the ILAE Commission on Antiepileptic Drugs and the FDA a detailed document was produced outlining the approved design, patient selection, and protocols for new drug trials (Penry, 1973). This new schema became the framework for drug development right up until the present day.

However, in the early 1980s, the FDA again began to tighten its regulations in relation to antiepileptic and other drugs. This was not driven by legislation, but rather the agency itself raising the bar and initiating more scientifically valid methods of assessment. By now, epilepsy had entered the era of the randomized controlled trial (RCT), which had for some time already been introduced in other areas of medicine. In epilepsy, the FDA made the momentous decision that the new drugs had to demonstrate superiority in RCTs over a comparator compound rather than equivalence, and so almost all the subsequent regulatory studies compared the new drug with placebo rather than a conventional therapy. This decision was based on the perceived difficulties of interpreting the finding of noninferiority, but resulted in a lamentable lack of head-to-head RCTs. The initial trials were of small numbers of patients in a crossover design, and these were soon replaced by the early 1990s by the requirement to carry out parallel group studies in increasingly large numbers of patients (largely arbitrarily chosen by the FDA). Over the last decades, the laws have been interpreted with increasing stringency, and the bar for new drug licensing was further raised, with larger numbers needed and higher levels of side effect surveillance.

The levels of evidence of efficacy and lack of toxicity are, therefore, now far more stringent than even 20 years ago. In the 1980s, the European authorities tended to take a more pragmatic approach, and licensed drugs on the basis of comparative studies against an active control. Getting the regulatory balance right is difficult. Drugs tended in this period to be licensed in Europe years before licensing in the U.S.A., and American patients were therefore denied potentially lifesaving therapies. Conversely, patients in Europe were exposed to the serious hazards of vigabatrin, which was licensed there for 8 years before the recognition of these problems, and was never licensed in the U.S.A. (although the reverse was true of felbamate). In the mid-1990s, however, European regulations became more closely aligned with those of the FDA. Whether the balance between protecting the public and stimulating new therapies is appropriate is a matter of opinion, although there is a strong sense that the development of antiepileptic drugs is now again hampered by overregulation.

A final complication is the recent proliferation of additional bodies seeking to limit prescribing of new therapy on a national basis. Some are government-inspired (for instance NICE—the National Institute for Clinical Excellence in the United Kingdom) and some based in regions or hospitals (formulary committees). These produce “guidelines” for therapy that restrict use of new drugs, largely on the grounds of cost. The “health economic” argument is often based on shaky foundations, and the guidelines can be inconsistent and indeed contradictory (Shorvon, 2006). Guidelines are not regulations but often are treated as such, and this has raised new issues of clinical freedom. A doctor ringed by restrictive guidelines may not be able to deliver what he considers optimal advice. The overbearing use of guidelines is part of an increasing tendency to bureaucratize medicine, and a major change in the last decade in countries with government-subsidized health services has been the increasing tendency to view clinical decisions simply as issues of resource allocation.

Basic science and antiepileptic drug development

We are now, in 2009, firmly in the molecular age. The waves of interest first in GABAergic mechanisms (in the 1970s and 1980s) and then glutaminergic mechanisms (1980s and 1990s), and in sodium and calcium channel blockade, which are the traditional drug targets, have partly given way to a still limited but more diverse list of potential drug mechanisms. Currently, research targets not only these three classical mechanisms but also blockade of potassium channels, gap junctions, synaptic vesicle proteins, and neuronal adenosine, nicotinic acetylcholine, and serotonin receptors. In addition, much more is known about the chemistry, structure, and functioning of channels and receptors, and their regional cerebral and microscopic distribution. Drugs can now be targeted at specific isoforms and genetic variants—this at least is the theory, but it has to be admitted that progress has been limited. Despite this explosion of research into the mechanisms of action of antiepileptic drugs, almost all of the currently licensed drugs were discovered either by pure chance, the manipulation of the structure of existing compounds (with resulting “me-too drugs”), or by random screening. It is disappointing to note that the increase in knowledge of neurochemistry and pharmacology has not been translated into any really successful new therapy, and the promise of the molecular age—with the production of designer drugs targeting novel mechanisms—has yet to deliver a licensed therapy.

At the time of this writing there are at least a further 22 compounds that have reached the stage of clinical testing. Some of these are designed for novel mechanisms, but the process of testing is slow and arduous. Many drugs are in the end not licensed. Of the 24 drugs in clinical testing in 1996, for instance, only two have (by 2008) been licensed, two are still in testing but close to licensing, and five are in development but not making much progress. Fourteen are either now discontinued or not being actively studied. Furthermore, of those close to licensing, none has targeted a new mechanism, and the indications are that their advantages over current therapy, if any at all, will be incremental.

The cost to the pharmaceutical industry of developing an antiepileptic and the time taken to license a drug are also a serious concern. The cost is currently estimated to exceed $100 million, and the time taken from first clinical testing to licensing usually about 10–15 years. This means that only the largest pharmaceutical companies can now compete. The increasingly rigorous and restrictive regulations are as worrying as they were in 1970, and there are also the additional risks of expensive lawsuits, over side-effects and patents, which seem to plague the industry.

From the point of view of the industry, though, several changes in recent years provide encouragement: more animal models are now characterized than in the past, and these are relatively reliable in predicting antiepileptic effect; substantial public funding is available for drug discovery (through grants, government programs, the ADD program, and the orphan drug programs for rare epilepsy conditions); universities are increasingly willing to cooperate with industry in basic drug discovery; large commercial opportunities are afforded by the fact that drugs often are useful for other major indications such as pain and bipolar disease. Nevertheless, the lack of any truly innovative “designed” therapy and the hurdles inhibiting this development are disappointing and worrying (Table 9).

Table 9.   Discovery of the the antiepileptic effects of contemporary therapy
DrugAntiepileptic action found byComments
CarbamazepineManipulation of existing structure and random screeningFound by chance in an attempt to develop drugs for bipolar disease
BenzodiazepinesRandom screening initially and then manipulation of existing structures 
EslicarbazapineManipulation of existing structure 
EthosuximideManipulation of existing structure 
FelbamateRandom screening 
GabapentinAttempted rational design, but wrong mechanismDesigned as a GABAergic drug, but mechanism is actually non-GABAergic
LamotrigineAttempted rational design, but wrong mechanismFound in a screen of antifolate drugs, on the erroneous assumption that antiepileptic action could be due to antifolate properties
LevetiracetamManipulation of existing structure 
OxcarbazepineManipulation of existing structure 
PhenobarbitalPure chanceObservation that phenobarbital given as a human sedative also controlled seizures
PhenytoinRandom screening 
PiracetamPure chanceObservation that piracetam given as a cognitive enhancer also controlled myoclonus
PregabalinAttempted rational design, but wrong mechanismDesigned as a GABAergic drug, but mechanism is actually non-GABAergic
TiagabineAttempted rational design, but wrong mechanismDesigned as a GABAergic drug, but mechanism is actually non-GABAergic
TopiramateRandom screeningDesigned initially as an antidiabetic drug
ValproatePure chance 
VigabatrinRational designDesigned to be a GABA agonist

Seizure control in 2009: Have the improvements in therapy in the last 100 years translated into a better prognosis for epilepsy?

This, of course, is the fundamental question—and prolonged seizure control is the measure against which the success of therapy ultimately should be judged. We can, and should, ask to what extent the advances in neurochemistry, neurophysiology, pharmacology, and pharmacokinetics, and the introduction of a raft of new drugs have actually improved the chances of seizure control. This may seem a strange question, as surely—it might be argued—the introduction of better therapy will lessen the impact of the condition. Unfortunately, evidence of substantial improvement is relatively slight, at least in the last 40 years. Comparisons are made difficult by selection pressures and population differences and temporal changes, but it is notable that even the results Turner reported with bromides in 1907 do not sound so very different from the results of a novel therapy today.

The picture, though, is complex. First, it is clear at an anecdotal level that the introduction of first phenobarbital and then particularly of phenytoin had a large impact. I remember well my mentor, Dr. C. J. Earl, in the 1970s telling me how impressive it was to see in the case records of patients with chronic epilepsy at the National Hospital, after years and years of careful documentation of relentless seizures, sudden seizure freedom with the introduction of phenytoin. There are numerous similar anecdotal reports of many patients rendered seizure-free by these drugs after years of uncontrolled epilepsy. Similarly, the introduction of valproate and carbamazepine changed prognosis again, although to a lesser extent.

Seizure control depends very much on the stage that the epilepsy has reached. Turner (1907) recognized that new patients were likely to enter remission (50% in his series), whereas patients with established chronic epilepsy were much less likely to achieve seizure control. This pattern is similar today, and large-scale prospective population- and hospital-based studies carried out between 1980 and 2006 have demonstrated long-term seizure control (equivalent to “cure”) in about 60% of new patients starting therapy. As was pointed out in 1984 (Shorvon, 1984), one of the most important pointers to prognosis is the temporal stage the epilepsy had reached (the length of time it had been active). The first-line antiepileptics most commonly prescribed in newly diagnosed epilepsy are valproate and carbamazepine. In almost every head-to-head comparison of these two drugs, no differences in efficacy have been found either against phenytoin or phenobarbital or any of the newer drugs (Heller et al., 1995; de Silva et al., 1996; Beghi & Tognoni, 1988; Cockerell et al., 1997; MacDonald et al., 2000; Sillanpaa & Schmidt, 2006; Wang et al., 2006; Marson et al., 2006, 2007a,b).

It is in chronic epilepsy that the improvements of the last few decades can be most easily detected. It is possible that the newer drugs have terminated seizures in a greater proportion of cases, thereby lessening the prevalence of chronic epilepsy, leaving only the more intractable cases. This effect might introduce selection bias and explain the apparent similarity in response to new and ancient therapy. Turner viewed therapy (bromides) as having no useful effect, and the 1984 review (Shorvon, 1984) concluded that once epilepsy has become chronic, the chances of subsequent remission are relatively slight (in the order of 1–5% per year). However, the clinical trials of the newer drugs have all shown—albeit in the short term—50% reductions in seizures in 30–50% of patients and seizure freedom in a small percentage of patients (<8%). If improvement is maintained, one would, therefore, expect, with the wider range of therapies, marked improvement in cases of previously chronic epilepsy. This appears to be the case. In one recent study of 155 patients with chronic epilepsy (often chronic and severe), drug changes resulted in seizure remission (defined as a 12-month or more period without seizures) in 28% (Luciano & Shorvon, 2007). It is likely that this encouraging response is due at least in part to the greatly increased range of different antiepileptic drugs now available. Indeed, in this group, over an observation period of 3 years or so, 14% of second drug changes resulted in seizure freedom in those who failed a first change, and 15% after a third change in those who failed a first and second change. There have been no recent population-based surveys of prognosis, which is a pity, but one would expect the proportion of patients with uncontrolled seizures to have shrunk—at least to some extent.

The challenge for the future is to license a drug that will have a major impact on prognosis in chronic epilepsy. If a drug successfully controlled seizures in even 20% of all patients with chronic epilepsy, there would be 2,000 fewer cases per million of the population—a major health care breakthrough. It is difficult to know whether the current hybrid system of research carried out in universities and pharmaceutical companies can produce the best results. Certainly, one should be shocked by the futility of huge amounts of university research (I would guess 95% of all clinical and basic medical research is, in terms of advancing therapy, totally pointless) and similarly be suspicious that commercial research is driven by strategies that take little notice of health care needs. The ILAE, and similar organizations, are in a good position to lobby for better therapy and to facilitate its production. But there has been a conspicuous absence of strategic thinking on such points.

Acknowledgments

  1. Top of page
  2. Summary
  3. The Drug Treatment of Epilepsy 1959–1988
  4. The Drug Treatment of Epilepsy 1989–2009
  5. Therapy of Epilepsy in 2009
  6. Acknowledgments
  7. References

The text in this chapter, with permission, is based upon and borrows heavily from the preface of the third edition of Treatment of Epilepsy by the same author (Shorvon et al., 2009).

Disclosure: The author has acted as a member of an Advisory Board and/or has received honoraria for speaking from UCB Pharma, Eisei, and Johnson & Johnson.

References

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  2. Summary
  3. The Drug Treatment of Epilepsy 1959–1988
  4. The Drug Treatment of Epilepsy 1989–2009
  5. Therapy of Epilepsy in 2009
  6. Acknowledgments
  7. References
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