Description of the condition

Epilepsy is one of the most common chronic, non‐contagious, neurological disorders, affecting more than 50 million people globally (Banerjee 2009; De Boer 2008; Goldenberg 2010; World Health Organization 2016). Epilepsy makes a 0.75% contribution to the global burden of disease, which shows years of life lost due to premature death and time spent living in less than full health (World Health Organization 2016). Brief recurrent episodes of involuntary movements and sensations or loss of consciousness, or both, characterise epilepsy. Recurrent seizures may be focal (partial), involving only a part of the body, or generalised, involving the entire body. Loss of consciousness and control of autonomic functions or involuntary actions, which are not under conscious control, in particular those of the bowel or bladder, or both, may accompany seizures. Epilepsy is a heterogeneous group of disorders, as classified by the International League Against Epilepsy (ILAE Commission 1998): excessive electrical discharges in epileptic focus (a group of damaged brain cells, located in various parts of the brain) may trigger most seizure episodes, while some may be generalised at onset (idiopathic generalised epilepsy) (Marson 2007b). The latter include generalised onset tonic‐clonic seizures, absence seizures, and myoclonic seizures, which could be due to genetic predisposition, and are characterised by specific generalised spike‐wave abnormalities in an electroencephalogram (Marson 2007b).

Seizures vary substantially in their form, duration, frequency, and implications for the affected individual; they may be as short as the briefest lapses of attention or muscle jerks, but may be severe prolonged convulsions, from less than one episode per year to several per day. It is important to note that one seizure alone cannot result in diagnosis of epilepsy since up to 10% of the general population worldwide experience one seizure in their lifetime. Epilepsy is defined as having two or more unprovoked seizures (Fisher 2014). Despite massive research in the field of epilepsy and advances in its management, still, in many parts of the world, people with epilepsy and their families suffer from stigma and discrimination, with nearly 80% living in low‐ and middle‐income countries (World Health Organization 2016). Epilepsy presents a significant burden of disease with profound socioeconomic consequences both for the individual and for society as a whole (Jennum 2011; Megiddo 2016; World Health Organization 2016). A 2011 study found that in Europe, people with epilepsy had lower employment rates and lower income compared with people without epilepsy, with direct net annual healthcare and indirect costs of €14,575 (Jennum 2011). In a 1998 study conducted in India, the cost of treatment per person with epilepsy was 88.2% of the country's per capita gross national product (GNP), and epilepsy‐related costs, including lost work time, exceeded $2.6 billion per year (Megiddo 2016). According to the World Health Organization (WHO) fact sheet, approximately three fourths of people with epilepsy who live in low‐ and middle‐income countries do not receive adequate treatment (World Health Organization 2016).

Description of the intervention

Pharmacotherapy is the mainstay in the management of epilepsy. Antiepileptic drugs (AEDs) can successfully treat epilepsy, with complete seizure control rates of up to 70% in children and adults (World Health Organization 2016), or 70% of people with epilepsy enter remission, which is defined as five or more years of seizure freedom while being on drug treatment (Goldenberg 2010). According to the WHO estimates, treatment with antiepileptic drugs is affordable, with daily medication costs of US$5 per year (World Health Organization 2016). Complete treatment withdrawal can be successfully achieved in 75% of seizure‐free people with epilepsy who have been on drug treatment for two to five years (Goldenberg 2010), or in about 70% of children and 60% of adults without subsequent relapse (World Health Organization 2016).

There is an expanding number of new antiepileptic drugs (AED) approved for epilepsy treatment either as monotherapy or as add‐on treatment. Despite the diversity of chemical structures and variations in the mode of action of antiepileptic drugs, the problem of epilepsy resistant to pharmacotherapy remains a challenge. Approximately 30% of people with epilepsy may be resistant to antiepileptic medicines and experience seizures (Bazil 2005; Cockerell 1995; Kwan 2000; Walker 1997; World Health Organization 2016). The strategy to overcome resistance and to minimise adverse effects includes slow‐dose titration of an AED, used as monotherapy until seizure control is achieved or side effects of AEDs preclude further dose increments, and combination therapy, i.e. addition of one antiepileptic agent to another, known as add‐on therapy (Bazil 2005; Goldenberg 2010; St. Louis 2015).

Gabapentin, 1‐ (aminomethyl)cyclohexaneacetic acid, which is structurally related to gamma‐aminobutyric acid (GABA) (Goldenberg 2010; Marson 1997; Morris 1999), is a "newer" antiepileptic drug (Goldenberg 2010). It has been licensed in the UK as an add‐on therapy for epilepsy since 1993 (Pitkanen 2005). Currently, the U.S. Food and Drug Administration (FDA) recommends gabapentin use for postherpetic neuralgia in adults, and as an adjunctive therapy in the treatment of partial onset seizures with and without secondary generalisation in adults and paediatric patients three years of age or older with epilepsy (U.S. Food and Drug Administration 2016), while the European Medicines Agency (EMA) in its harmonisation documents of the summaries of product characteristics (SmPCs) labelling and package leaflet for gabapentin (Neurontin) and associated names included uses of gabapentin as adjunctive therapy in the treatment of partial seizures with and without secondary generalisation in adults and children aged six years and above; as monotherapy in the treatment of partial seizures with and without secondary generalisation in adults and adolescents aged 12 years and above; and as treatment of peripheral neuropathic pain, such as painful diabetic neuropathy and postherpetic neuralgia in adults (European Medicines Agency 2006). The Russian regulator, the Ministry of Health of the Russian Federation, recommends its use both as an add‐on therapy and as monotherapy for epilepsy, as well as for neuropathic pain (MoH 2016).

Like other antiepileptic medicines, multiple adverse effects, which regulatory and manufacturer's documents describe, characterise gabapentin (MoH 2016; Pfizer 2016; U.S. Food and Drug Administration 2016). Among them are suicidal thoughts or actions. On the basis of the analysis of reports of suicidal behaviour or ideation from placebo‐controlled trials of drugs used to treat epilepsy, the FDA require that all manufacturers of antiepileptic drugs included a warning in their labelling and developed a medication guide for people to inform them of the risk of suicidal thoughts or actions while taking antiepileptic drugs. The requirement was based on the finding that the increased risk of suicidal behaviour or thoughts was consistent among 11 drugs with varying mechanisms of action and across a range of indications, including epilepsy. Gabapentin was on the list of the 11 drugs (U.S. Food and Drug Administration 2008). The latest instruction for gabapentin (Neurontin) use in the Russian Federation, approved by the national regulator (the Ministry of Health of the Russian Federation), describes its adverse effects: gabapentin causes serious, life‐threatening allergic reactions; severe withdrawal syndrome ‐ rebound seizures with abrupt cessation of treatment; acute pancreatitis; myopathy; hepatitis; jaundice; renal failure; sleepiness and dizziness; lack of co‐ordination resulting in injuries and falls; whole body swelling; acute increase in body mass; laboratory test changes; sexual dysfunction; swelling of breasts; and many other adverse effects ‐ of particular note are pains in various parts of the body, including acute chest pain. Cases of the sudden deaths of people on gabapentin were reported (MoH 2016). The manufacturer lists the following among the most common side effects: lack of or difficulty with co‐ordination; viral infections; feeling drowsy; nausea and vomiting; difficulty with speaking; tremors; swelling (usually of legs and feet); feeling tired; fever; jerky movements; double vision; and unusual eye movement (Pfizer 2016).

Direct comparison of gabapentin versus other antiepileptic drugs used for treatment of partial epilepsy showed that it was most likely to be associated with treatment failure due to inadequate seizure control and that carbamazepine was the least likely to be associated with treatment failure (gabapentin verus carbamazepine: hazard ratio (HR) 2.45, 95% confidence interval (CI) 1.81 to 3.32). At the same time, gabapentin was the least likely to result in treatment failure due to unacceptable adverse events (gabapentin versus carbamazepine: HR 0.60, 95% CI 0.44 to 0.81) (Marson 2007a).

Likewise, the recent Cochrane Review looking at monotherapy treatment of epilepsy in pregnancy and congenital malformation outcomes in the child found that there was no increased risk of major malformation for gabapentin, along with a few other antiepileptic medicines (lamotrigine, levetiracetam, oxcarbazepine, primidone, zonisamide), though the authors noted that there were substantially fewer data for these medicines (Weston 2016).

Obviously, the trade‐off between effectiveness and safety of gabapentin in monotherapy of epilepsy needs to be systematically evaluated, for example, it might be an acceptable alternative for some fraction of pregnant women with partial epilepsy.

How the intervention might work

The precise mechanism of action of gabapentin is not fully understood (McClean 1995; Morris 1999; Pfizer 2016). By its chemical structure, gabapentin is related to the neurotransmitter gamma‐aminobutyric acid (GABA). However, in vivo and in human body gabapentin is not metabolised into GABA or a GABA agonist; it does not inhibit GABA re‐uptake or degradation. Gabapentin does not modify GABA_A or GABA_B radioligand binding (Goldenberg 2010; Pfizer 2016). According to the manufacturer, gabapentin binds with high affinity to the α2δ subunit of voltage‐activated calcium channels in in vitro studies; however, the relationship of this binding to the therapeutic effects of gabapentin is unknown (Pfizer 2016).

Why it is important to do this review

This review is needed to clarify whether gabapentin is of any benefit for epilepsy treatment as monotherapy. This is particularly important and timely since gabapentin is heavily promoted in Russia and other post Soviet countries for various neurologic and psychiatric disorders, including epilepsy. The pattern of off‐label illegal promotion of gabapentin in the US in the 1990s for a wide range of unapproved conditions, all of which were off‐label uses according to the FDA labelling at that time, became a classical example in drug promotion literature (Steinman 2006; Steinman 2007). For these promoted uses, gabapentin has not been adequately tested, and its potential benefits may not outweigh its potential harm (Steinman 2006). The Study of Neurontin: Titrate to Effect, Profile of Safety (STEPS) trial without a control group provided an example of inadequate testing of gabapentin in a low‐quality trial with high risk of bias, which had the marketing objective to increase its dose and market share, involving 772 physicians who treated four participants each on average (Krumholz 2011). In this study, gabapentin salespeople collected data and were directly involved in suggesting to the doctors which people to enrol while being present in the doctors' offices. The participants of this study were not informed about its true marketing purpose, while the actual study subjects were the doctors, since the effect of their participation in the study on gabapentin sales was closely monitored (Gøtzsche 2013; Krumholz 2011).

There is discrepancy between FDA‐approved uses and those approved by the EMA and Russian drug regulator. The FDA recommends gabapentin use only as an adjunctive therapy in the treatment of partial seizures with and without secondary generalisation in people over three years of age with epilepsy (U.S. Food and Drug Administration 2016), while the EMA (European Medicines Agency 2006) and Russian regulator, the Ministry of Health of the Russian Federation (MoH 2016) recommend it both as adjunctive therapy and as monotherapy for epilepsy.

Guidelines are not completely unanimous in their recommendations of gabapentin as monotherapy for epilepsy. For example, the Scottish Intercollegiate Guidelines Network (SIGN) recommends gabapentin as an adjunctive treatment of drug‐resistant focal epilepsy, drug‐resistant generalised or unclassified epilepsy, and as an alternative monotherapy or adjunctive therapy option in older people with epilepsy (Scottish Intercollegiate Guidelines Network 2015). The National Institute for Health and Care Excellence (NICE) recommends gabapentin only as adjunctive treatment for refractory focal seizures in children, young people, and adults and for treatment of children and young people with benign epilepsy with centrotemporal spikes, Panayiotopoulos syndrome, or late‐onset childhood occipital epilepsy (Gastaut type). NICE specifically emphasises that gabapentin should not be used in people who have generalised tonic‐clonic seizures (GTC); if absence or myoclonic seizures or juvenile myoclonic epilepsy is suspected; in people with tonic or atonic seizures; in people with Dravet syndrome and Lennox–Gastaut syndrome; and in children, young people, and adults with idiopathic generalised epilepsy (IGE) syndromes (NICE 2016). The International League Against Epilepsy (ILAE) recommended gabapentin as initial monotherapy of newly diagnosed, not yet treated focal seizures in adults; for focal seizures in the elderly; and for idiopathic focal epilepsy in children (Glauser 2006; Glauser 2013). The American Academy of Neurology (AAN) recommends gabapentin only as adjunctive treatment for epilepsy, referring to insufficient evidence to recommend gabapentin as monotherapy for refractory partial epilepsy (American Academy of Neurology 2016). Russian Federal guidance on the use of medicines recommends gabapentin as monotherapy for partial seizures with or without secondary generalisation in adults and adolescents aged 12 years and above (Federal guideline 2016).

There is a Cochrane Review of gabapentin as an add‐on treatment for drug‐resistant partial epilepsy (Al‐Bachari 2013), which concluded that gabapentin was effective as an add‐on treatment versus placebo. However, the studies included in the review were of relatively short duration and provided no evidence for the long‐term effects of gabapentin beyond three months of follow up. The results of this review cannot be extrapolated to gabapentin monotherapy. Furthermore, the authors did not find any difference between gabapentin and placebo in global effectiveness; treatment withdrawal rates during the course of treatment, used as the secondary outcome measure, were the same in gabapentin and placebo add‐on groups. Treatment withdrawal is an outcome to which participants make their contribution; it is the primary outcome measure recommended by the Commission on Antiepileptic Drugs of the International League Against Epilepsy (Glauser 2013). The Cochrane Review found that adverse effects were significantly associated with gabapentin compared with placebo, with risk ratios at around two for ataxia, dizziness, fatigue, and somnolence (Al‐Bachari 2013). A systematic review needs to assess the use of gabapentin as a monotherapy treatment.