Levetiracetam as an antiepileptic, neuroprotective, and hyperalgesic drug
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.193801
Source of Support: None, Conflict of Interest: None
The main purpose of this review was to expound upon the mechanism of action of Levetiracetam (LEV) as an antiepileptic, neuroprotective, and hyperalgesic drug. LEV is a second-generation anti-epileptic drug (AED) that is approved for clinical use as monotherapy and may also be used for adjunctive treatment of patients with seizures. Several researchers have recommended LEV as a treatment option in different diseases causing neuronal damage, and recently, LEV has been used as an antihyperalgesic drug. LEV exhibits favorable characteristics, including a low potential for interaction, a short elimination half-life, and has neither active metabolites nor major negative effects on cognition. This has generated many new research avenues for the utilization of this drug. However, the precise mechanism of action of LEV has not been fully elucidated. In this review, a search was conducted on PubMed, ProQuest, EBSCO, and the Science Citation index for studies evaluating the effects of LEV as an antiepileptic, neuroprotective, and hyperalgesic drug. A total of 32 studies related to the use of LEV suggested different mechanisms of action, such as binding to the synaptic vesicle glycoprotein 2A (SV2A) protein, inhibition of Ca2+ N-type channels, and its presence as a neuromodulator. These studies concluded that the pharmacodynamics of LEV should be viewed as a single pathway, and should not be based on specific molecular targets that depend on the physiological or pathological conditions prevalent at that time.
Keywords: Antiepileptic drug; epilepsy; hyperalgesic; levetiracetam; mechanism of action; neuronal damage
Levetiracetam (LEV) is a second-generation anti-epileptic drug (AED) belonging to the pyrrolidone family, a class of drugs with a wide spectrum of action. LEV possesses a unique pharmacological profile compared with the traditional anticonvulsants, and it is chemically unrelated to other antiepileptic drugs.
It was synthesized in the early 1980s during a chemical follow-up program aimed at identifying a second-generation nootropic drug, and the initial pharmacologic studies with LEV explored its ability to facilitate cholinergic neurotransmission. LEV was approved by the U.S. Food and Drug Administration (FDA) in 1999, and was also approved in Europe in 2000 for use in adult patients with myoclonic seizures, for juvenile myoclonic epilepsy, or for primary generalized tonic-clonic seizures. It was approved in India in 2005 as an adjunctive therapy in the treatment of partial-onset seizures in adults with epilepsy. However, it was not until 2012 that the FDA approved LEV for use as an adjunctive therapy for partial-onset seizures in infants and children, 1 month of age and older. LEV exhibits an excellent pharmacokinetic profile and has been used in a wide range of clinically complex situations.
LEV has proven to be effective in the prevention of various forms of epilepsy, has been employed as monotherapy,,, and adjunctive treatment,,,, for the prevention of early post-traumatic seizures.,,, More recently, in neonatal seizures, the safety of LEV and its efficacy has been widely reported.,, Moreover, studies have proposed that LEV possesses considerable neuroprotective properties in non-epileptic,, and epileptic,,,,,, disorders and even in ischemia-related epilepsy. Experimental evidence suggests that LEV provides antihyperalgesic effects in inflammatory pain,,, chronic pain, and neuropathic pain,,, models. However, the specific mechanism of action of LEV has not been fully clarified. The main purpose of this review was to summarize the current understanding of the mechanism of action of LEV as an antiepileptic, neuroprotective and hyperalgesic drug.
Epilepsy comprises a group of disorders characterized by two or more unprovoked seizures. Epilepsy is classified, based on the seizure source, into partial and generalized seizures. LEV entails convenient twice-daily dosing, a wide margin of safety, no requirement for serum drug monitoring, and no interactions with other anticonvulsants. This advantageous pharmacological profile renders LEV an attractive first-line or adjunctive therapy for epileptic seizures [Table 1].
Preclinical trial with LEV in epilepsy treatment
In the past, it was observed that LEV is virtually ineffective in acute-seizure animal models (i.e., maximal electroshock and pentylenetetrazole (PTZ)-induced seizures), which are routinely utilized to screen for potential new AEDs. In contrast, recent studies have suggested that LEV provides seizure protection in various animal seizure models and displays a favorable safety margin. LEV also produces an anti-epileptogenic effect; it delays the acquisition of audiogenic kindling in Krushinsky–Molodkina rats and inhibits the development of hippocampal hyperexcitability following pilocarpine-induced status epilepticus in rats. LEV has been shown to be active in animal models in terms of what are thought to represent generalized seizures. Expression of seizure activity was prevented in both audiogenic-susceptible mice and rats. Furthermore, a single dose of LEV administered 30 min after the onset of behavioral status epilepticus was adequate for transiently attenuating seizure activity in animals treated with LEV at 800 mg/kg or higher.
Clinical trial with LEV in epilepsy treatment
According to Phase IV trial conducted by Lambrechts et al., LEV was effective and safe when added on to therapy in partial epilepsy in adults. LEV reduced seizure frequency of partial seizures (Type I) by 62.2%, of all seizure types combined (Types I + II + III) by 61.7%, and 56.6% subjects had a reduction in seizure frequency of ≥50%.
The efficacy and tolerability of adjunctive LEV in patients with uncontrolled generalized tonic-clonic seizures associated with idiopathic generalized epilepsies was studied by Berkovic et al. A greater mean reduction was observed in about 56.5% subjects in the frequency of generalized tonic-clonic seizures weekly over the treatment period, when compared to the placebo treatment, where the mean reduction in seizure frequency was 28.2%. During the evaluation period, the percentage of patients free from generalized tonic-clonic seizures was 24.1% for LEV vs. 8.3% for placebo (P<0.009). Brodie et al., compared the efficacy of LEV versus carbamazepine on epilepsy. They showed that remission rates at the end of 6 months to 1 year were 80.1% with LEV and 85.4% with carbamazepine.
Pediatric trials with LEV in epilepsy treatment
The efficacy of LEV in children with epilepsy intractable to treatment with existing antiepileptic drugs (with a mean follow-up period of 13 months and maximal follow-up period of 21 months), was studied by Lee et al. They observed, in 48% of patients, a seizure reduction of ≥50%, and 22% of patients became seizure-free. Also, in reports on seizure reduction and adverse events in 130 children with intractable epilepsy treated with LEV adjunctive therapy, there was a reduction in seizures of ≥50% in 52% of children with partial seizures, and in 44% of children with generalized seizures. The efficacy, safety, and tolerability data in children from 1 month of age with partial-onset seizures were reviewed by Cormier et al., who concluded that LEV may be a safe and effective treatment option for children and infants with partial seizures occurring due to a variety of etiologies. Moreover, the efficacy and tolerability of LEV as an add-on therapy in patients with startle epilepsy was studied by Gurses et al., who found that 60% of patients responded to LEV.
In an open-label study that included >300 investigators in clinical practice conducted by Morrell et al., the authors investigated the safety and tolerability of LEV and the medication's efficacy as an add-on therapy for partial-onset seizures. 57.9% of patients under the administration of LEV experienced at least a 50% reduction in the frequency of partial-onset seizures. Also, 40.1% of patients experienced at least a 75% reduction, and 20% demonstrated a 100% seizure reduction.
Monotherapy trial with LEV in epilepsy treatment
The efficacy and tolerability of LEV administered at a dosage of 1,500 mg twice daily as monotherapy was evaluated in a multicenter, randomized, double-blind, parallel-group, responder-selected study conducted by Ben-Menachem et al. These authors concluded that in the LEV monotherapy group, the median percentage of reduction in partial-seizure frequency compared with baseline was 73.8%, with a response rate of 59.2%. Conversion to LEV monotherapy (1,500 mg twice daily) is effective and well-tolerated in patients with refractory partial seizures who responded to 3,000 mg/daily LEV as an add-on therapy. In an open study by Alsaadi et al., two third of the patients had the same or better seizure control while one third of the non-seizure free group at 6 months of follow-up had worse seizure control at 12 months. Therefore, LEV can be an effective and well- tolerated medication in adult patients with either new or difficult-to-control epilepsy.
LEV in epilepsy treatment caused by brain injuries
Limited studies have proven the efficacy of LEV in traumatic brain injuries and in the prophylactic therapy of postoperative seizures. In a comparative study of LEV monotherapy versus phenytoin in seizure prophylaxis in severe traumatic brain injury performed Jones et al., the authors concluded that LEV is as effective as phenytoin in preventing early post-traumatic seizures. However, LEV monotherapy was associated with increased frequency of abnormal electroencephalographic findings.
The retrospective study investigating the efficacy and tolerability of LEV for peri-operative seizure prophylaxis in patients with supratentorial brain tumors by Zachenhofer et al., demonstrated the perioperative effectiveness of LEV in patients with brain tumors, leading to a lower frequency of peri-operative seizures (2.6% in the first postoperative week), accompanied by the occurrence of minor and reversible side-effects (in 6.4% of patients). Furthermore, the advantage of LEV's inability to cause cytochrome P450 enzyme induction allowed for an early initiation of an effective postoperative chemotherapy in patients with malignant glioma.
A pilot study was conducted by Lim et al., in which the main purpose was to assess the safety and feasibility of conversion from phenytoin to LEV monotherapy after a craniotomy for glioma resection in patients with a history of tumor-related seizures. It concluded that it is safe and feasible to switch patients from phenytoin to LEV monotherapy after performance of a craniotomy for excision of a supratentorial glioma.
In an open-label, prospective, single-arm pilot study by Bahr et al., the authors assessed the efficacy and tolerability of intravenous and per oral LEV in patients with suspected primary brain tumors and tumor-related seizures. They concluded that oral and intravenous LEV was safe and effective in the perioperative treatment of tumor-related seizures. Treatment failure occurred in three patients even after dose escalation to 3,000 mg/day.
The use of AEDs for a possible neuroprotective strategy is receiving increasing attention. Moreover, several studies have proposed that LEV possesses considerable neuroprotective properties in both epileptic and non-epileptic disorders. In this section, we evaluate the studies investigating the use of LEV in the treatment of neuronal damage [Table 2].
Preclinical trial with LEV in the treatment of neuronal damage
A preclinical study by Hanon et al., in the rat middle cerebral artery occlusion model of focal cerebral ischemia, reported that LEV possessed neuroprotective properties as it reduced the infarct volume. LEV, therefore, induced significant neuroprotection in the rat model of focal cerebral ischemia. Furthermore, this supports the finding that the neuroprotective properties of LEV may also be relevant to its antiepileptogenic action.
Experimental observations have demonstrated that LEV protects against kainic acid-induced neurotoxicity through inhibition of the lipid peroxidation process and the inflammatory cascade in rat brain. Intravenous administration of LEV in murine models that followed closed head injury and subarachnoid hemorrhage was studied by Wang et al.. The authors observed that administration of LEV (54 mg/kg) was neuroprotective against traumatic brain injury in clinically relevant animal models. Moreover, Gibbs and Cock conducted a study to assess the protective effects of LEV on mitochondrial function and cellular antioxidant-reduced glutathione production, when the medication was administered after status epilepticus in rats. The final conclusion was that LEV does not possess the same protective effects on mitochondrial dysfunction and cellular antioxidant-reduced glutathione production as when administered during established status epilepticus.
The potential effect of LEV on neuronal apoptosis in neonatal rat models of hypoxic–ischemic brain injury was studied by Kilicdag et al., who found that LEV administration after hypoxic ischemia results in a significant decrease in the number of apoptotic cells in the hippocampus and cerebral cortex when compared with the placebo group (P <0.006).
In a recent study by Lee et al., the authors examined the efficacy of LEV as an add-on treatment with diazepam in status epilepticus-induced (SE) neuronal death. They suggested that LEV may negatively interact with diazepam and be more effective in preventing SE-induced neuronal death as a first-line drug than as a second-line therapy after benzodiazepine treatment. Furthermore, LEV alone is more efficacious for preventing the SE-induced neurodegeneration in hippocampus than other AEDs, such as diazepam or valproate.
Clinical trial with LEV in the treatment of neuronal damage
A prospective, single-center, randomized, single-blinded comparative trial of LEV versus intravenous phenytoin in patients with severe traumatic brain injury by Szaflarski et al., found that LEV may be a suitable alternative to intravenous phenytoin in seizure prevention in patients with severe traumatic brain injury. LEV results in fewer undesirable side effects and better long-term effects. However, a prospective, single-blinded, comparative trial that randomized 52 patients with traumatic brain injury or subarachnoid hemorrhage to receive prophylactic LEV or fosphenytoin was conducted by Steinbaugh et al. Its goal was to assess, utilizing the collected clinical trial data, whether or not continuous electroencephalography findings predict both short- and long-term outcomes in a well characterized patient cohort with a defined seizure prophylaxis regimen. The conclusion was that more severe slowing of the electroencephalographic activity was associated with worse outcomes, and that LEV appears to be better that fosphenytoin in controlling this phenomenon. Furthermore, Madeja et al., conducted a study to assess the effect of LEV on voltage-operated potassium channels and concluded that LEV exerts moderate inhibition of delayed rectifier potassium currents in the isolated hippocampal neurons, in vitro. Oliveira et al., also reported, in a study in a pilocarpine model of SE, that LEV pretreatment could counteract the oxidative stress (OS) through maintenance of lipid peroxidation, nitrite-nitrate levels, catalase activity, and glutathione at normal levels in the hippocampus. LEV displays activity against pilocarpine-induced OS in the hippocampus, which might contribute to the drug's ability to be a possible neuroprotective agent.
LEV is a novel anticonvulsant with proven analgesic properties. Its antinociceptive/antihyperalgesic effects have been demonstrated in animal models [Table 3].
Preclinical trial with LEV in the treatment of hyperalgesia
The effects of two-drug combinations of LEV with ibuprofen/aspirin/paracetamol in the study of a mouse model of painful diabetic neuropathy was conducted by Micov et al. These authors evaluated, by means of the radiant heat tail-flick test, the effect of these medications on the thermal nociceptive responses in both diabetic and non-diabetic mice. They reported a synergism between LEV and ibuprofen/aspirin/paracetamol in this model of painful diabetic neuropathy.
Shannon et al., compared a broad range of clinically utilized anticonvulsant drugs in a persistent pain model with the formalin test, and reported that carbamazepine, oxcarbazepine, lamotrigine, gabapentin, and ethosuximide produced statistically significant analgesic effects in the formalin test, whereas phenytoin, topiramate, zonisamide, phenobarbital, tiagabine, valproate and LEV did not. These results suggestrd that the effects of these drugs may be due to different pharmacologic mechanisms.
The antinociceptive efficacy of LEV in a mice model for painful diabetic neuropathy employing the 'hot-plate test' was investigated in a study by Ozcan et al. The results indicated that LEV induces an antihyperalgesic effect (P <0.001). Furthermore, the authors' results illustrate that a mouse is a good experimental model for studying the prospective agents that may be utilized for neuropathic pain.
The effect of LEV and its mechanism of action, investigated by examining the involvement of the GABAergic, opioidergic, 5-hydroxytryptaminergic (5-HTergic), and adrenergic systems in a study of inflammatory pain, was conducted by Micov et al. They reported that LEV produced an antihyperalgesic effect that is, at least in part, mediated by GABAA, opioid, 5-HT, and α2-adrenergic receptors. Therefore, activation of the opioidergic system, in addition to that of the noradrenergic and 5-HT systems, might indicate that the analgesic effect of LEV depends on the interaction of the descending inhibitory system. Stepanovic-Petrovic et al., compared the anti-hyperalgesic and anti-edematous effects of LEV administered peripherally by local injection and the potential role of opioid, adrenergic, adenosine, 5-HT, and GABA receptors and their subtypes, in the local peripheral antihyperalgesic action of LEV. Their data suggest that LEV produces local peripheral anti-hyperalgesic and anti-edematous effects as well.
The effects of the two-drug combinations of LEV with non-steroidal analgesics (ibuprofen, celecoxib, and paracetamol) and caffeine on controlling hyperalgesia in localized inflammation, measured by a modified ''paw-pressure'' test, was a preclinical study conducted by Tomic et al. The aim in this study was to determine the type of interaction among the components. Its data showed that the two-drug combination of LEV and nonsteroidal analgesics/caffeine could be useful in a treatment of inflammatory pain.
Clinical trial with LEV in the treatment of hyperalgesia
The effect of LEV on patients with central neuropathic pain due to multiple sclerosis was investigated in a randomized, double-blind, placebo-controlled, cross-over trial by Falah et al. Its objective was to investigate the independent effects of LEV and concomitant treatments in the management of neuropathic pain. The authors reported that the anticonvulsant LEV exerted no effect in a non-selected group of patients with central neuropathic pain due to multiple sclerosis.
Rossi et al., reported the effects of LEV on central neuropathic pain in multiple sclerosis subjects; they performed a single-center, prospective, randomized, single-blind, placebo-controlled study in a sample of patients who were non-responsive or intolerant to the conventional medications. Their data suggests that LEV is a well- tolerated drug, and acts beneficially against central pain, thereby improving the quality of life of patients with multiple sclerosis.
The efficacy of LEV in the prophylactic treatment for migraine was a small open-label trial conducted by Brighina et al., in which the patients were treated with LEV at a dosage of 1000 mg/d for 6 months. They found that LEV was generally well tolerated and was effective in the treatment of migraine.
Mechanisms of action
A total of 32 studies focused on studying the use of LEV as a drug for the treatment of epilepsy, neuronal damage, and hyperalgesia were included in this review. These studies suggest different mechanisms of action for LEV; however, the pharmacodynamics of this drug has not been fully elucidated. These studies provide evidence of the following three major molecular targets: SV2A protein; inhibition of Ca2+ N-type channels, and the neuromodulator action on GABA, 5HT, α2-adrenergics, and μ-opioidergic pathways. The pharmacokinetic properties, effectiveness, high tolerability, low interaction with other drugs, and various mechanisms of action proposed for LEV have generated great interest and have opened up novel avenues for clinical research.
LEV binds to a unique binding site in the brain, the protein SV2A, which is an integral membrane protein present in synaptic vesicles and some neuroendocrinal cells. The expression of SV2 isoforms has been mapped at several sites within the central nervous system (CNS) and is particularly abundant in subcortical areas, such as the thalamus, basal ganglia, cortex and hippocampus. The exact role of SV2A in synaptic vesicle cycling and neurotransmitter release remains uncertain. However, it is proposed that SV2A protein could act as a transporter or could modulate the exocytosis of transmitter-containing synaptic vesicles and modify synaptic function. In animal models, Kaminski et al., concluded that SV2A deficiency may lead to an increased seizure vulnerability and accelerated epileptogenesis, and the effectiveness of LEV in seizure models is mediated by the SV2A protein. LEV does not appear to affect normal brain physiology; thus, it is possible to modulate SV2A function only under pathophysiological conditions. However, Nowack et al., found a correlation between increased SV2A expression and changes in synaptic functioning, and suggested that too much SV2 is as detrimental to neuronal function as too little of it. On the other hand, Lynch et al., conducted a study in patients with a confirmed diagnosis of epilepsy, where in the main purpose was to correlate the genetic variations in the SV2A, SV2B, and SV2C proteins to LEV administration; the authors found there was no relationship between the common genetic variations of SV2A, SV2B, or SV2C and the response to LEV during the assessment of susceptibility to epilepsy.
In addition, LEV inhibits Ca2+ N-type channels, reverses the inhibition of negative allosteric modulators such as zinc and beta-carbolines of GABA and glycine-gated currents, and reduces calcium release from intraneuronal stores. These mechanisms of action suggest that LEV possesses neuroprotective properties. LEV's action could also be related to its ability to hyperpolarize membrane potential via K+ channel activation and the inhibition of Ca2+ entry into the cells. Vogl et al., concluded that the SV2A ligand, LEV, attenuates Ca2+ current density in the superior cervical ganglion neurons without exerting effects on the voltage dependence of activation and inactivation. LEV increases the presynaptic inhibitory effect of GABAergic neurons and reduces the excitotoxic effect of glutaminergic neurons by blocking N-methyl-D-aspartate (NMDA) receptors. Kilicdag et al., reported that LEV demonstrated the regulation of amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated excitatory synaptic transmission in the dentate gyrus of the hippocampus by acting on the presynaptic P/Q-type voltage-dependent Ca2+ channel, thereby reducing glutamate release and inhibiting the amplitude of excitatory postsynaptic current in the dentate gyrus. Moreover, LEV possesses neuroprotective properties through its ability to upregulate the expression of glial Glutamate (Glu) transporters EAAT1/GLAST and EAAT2/GLT-1.
The antihyperalgesic effect of LEV and its mechanism of action was studied by examining the involvement of GABAergic, opioidergic, 5-hydroxytryptaminergic (5-HTergic) and adrenergic systems in a rat model of inflammatory pain in a study conducted by Micov et al. The authors reported that the effect of LEV in antihyperalgesia involves the indirect activation of central and/or peripheral GABA pathways by augmenting GABAergic neurotransmission, decreasing noradrenaline levels via its α2-adrenergic action, as well by modulating 5-HT levels utlizing various 5-HT receptors. LEV also influenced the μ-opioidergic receptors because these also inhibit N-type Ca2+ channels in a voltage-dependent manner. These results suggest that LEV possesses a broad spectrum of molecular targets, rendering it difficult to elucidate its mechanism of action.
We think that the mechanism of action of LEV comprises a cascade of effects, that in the first instance, is exerted by binding to protein SV2A, by modulating neuronal excitability, and by generating various changes in the CNS. The different effects of the administration of LEV lead us to think that its pharmacodynamics involves various molecular targets, but that these must be integrated into a single mechanism of action by a single pathway. We need to generate new avenues of research that is conducted with the main purpose of clarifying the pharmacodynamics of LEV. This would be of immense use in supporting the administration of this antiepileptic drug as an alternative treatment to neuronal damage and hyperalgesia.
LEV has been widely employed as an antiepileptic drug, and novel new research avenues have proposed the use of LEV as a neuroprotective and antihyperalgesic medication. However, till date, its mechanism of action has not been fully elucidated. This review proposes that the pharmacodynamics of LEV should be viewed as a single pathway and not as specific molecular targets that are utilized depending on the physiological or pathological conditions. We need further research to clarify the mechanism of action of LEV in order to support the utilization of this drug for various novel indications.
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Conflicts of interest
There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]