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REVIEW ARTICLE
Year : 2014  |  Volume : 41  |  Issue : 3  |  Page : 227-231

Lacosamide: A novel antiepileptic and anti-nociceptive drug on the block


1 Department of Anaesthesiology and Intensive Care, Gian Sagar Medical College & Hospital, Banur, Punjab, India
2 Department of Anaesthesiology and Intensive Care, Government medical college and hospital, Chandigarh, India

Date of Web Publication19-Sep-2014

Correspondence Address:
Sukhminder Jit Singh Bajwa
House No. 27-A, Ratan Nagar, Tripuri, Patiala, Punjab
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0974-5009.141256

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  Abstract 

With an increasing demand for newer anti-epileptic agents having a better pharmacological profile, many newer agents are being investigated. Lacosamide is a newer functional amino acid being developed as an adjunctive therapy for resistant partial-onset seizures owing to its activity of enhancing the slow inactivation of voltage-gated sodium channels thereby reducing pathologic hyperactivity in neurons. It has also being investigated for its role as anti-nociceptive in variety of pain scenarios specifically in diabetic neuropathic pain. It is well-absorbed orally, metabolized in liver and excreted by the kidneys. It has a favorable pharmacologic profile in having minimal drug interactions. The adverse effects include mild dizziness, behavioral changes and dose dependent prolongation of PR interval. This review is directed toward the development of lacosamide and its potential usefulness as an anti-epileptic and an anti-nociceptive drug.

Keywords: Diabetic neuropathy, lacosamide, osteoarthritis, partial-onset seizures


How to cite this article:
Bajwa SS, Kulshrestha A. Lacosamide: A novel antiepileptic and anti-nociceptive drug on the block. J Sci Soc 2014;41:227-31

How to cite this URL:
Bajwa SS, Kulshrestha A. Lacosamide: A novel antiepileptic and anti-nociceptive drug on the block. J Sci Soc [serial online] 2014 [cited 2020 Jul 10];41:227-31. Available from: http://www.jscisociety.com/text.asp?2014/41/3/227/141256


  Introduction Top


With an ever increasing incidence of epilepsy and addition of more than 100,000 new cases of epilepsy every year in US and much higher in developing countries, the need to develop better pharmacological agents has become even more intense. [1],[2] It has been observed that about 70% of patients achieve control of seizures by a single anti-epileptic drug but 30% may progress to a chronic form which is refractory to the conventional anti-epileptic drugs and can result in intractable seizures. [3] Most of the existing anti-epileptic drugs are effective in controlling seizures but are often associated with clinically significant side-effects diminishing the quality-of-life in many patients. Several newer anti-epileptic drugs have been introduced recently, which are effective in treating these refractory cases besides having a favorable pharmacologic profile. [4] Many of these drugs are able to effectively modify the course of disease in patients who are refractory to current medications. It is also an established fact that these anti-epileptic drugs which usually act by depressing membrane excitability have potential to act as anti-nociceptives for chronic pain syndromes. [5]

Lacosamide is a newer anti-epileptic developed by Conley and Kohn in 1987, which is structurally a novel functionalized amino acid. [6] It was approved for use as an adjunctive therapy in treatment of complex-partial epilepsy by both Food and Drug Administration and European Medicines Agency in 2008. It has also shown to be beneficial in neuropathic pain as evidenced by animal studies and some clinical trials but it is not approved by regulatory authorities for use in pain clinics.


  Clinical pharmacology Top


It is chemically (R)-2-acetamido-N-benzyl-3-methoxypropionamide with the chemical structure as shown:



It has been found that only the (R) - isomer of this class of chemicals is pharmacologically active.

Pharmacodynamics

The exact mechanism of action of lacosamide is still not conclusively established but the animal studies suggest enhancement of slow inactivation of voltage-gated sodium channels without interacting with fast inactivation gating. [7],[8],[9] It has also been suggested that enhancement of slow inactivation can selectively reduce pathologic hyperactivity in neurons without affecting physiologic activity. Lacosamide binds to and modulates collapsing response mediator protein 2, a phosphoprotein involved in neuronal differentiation and control of axonal outgrowth but its role in control of seizures is still not known. [10] It has been found by various studies that lacosamide does not bind to specific targets or modulate calcium and potassium currents nor any specific receptor binding sites have been identified. [11] It has been found to reduce both generalized and partial seizures but is inactive against clonic seizures. [12],[13] Lacosamide also has been found to reduce pain behavior in animal studies involving bone cancer pain, diabetic neuropathic pain, central and trigeminal neuropathic pain, muscular pain and osteoarthritic pain. [14],[15],[16],[17],[18]

Pharmacokinetics

Lacosamide is available in oral as well as in parenteral preparation owing to its water solubility. Oral bioavailability is approximately 100% and time to peak concentration being 1-5 h after oral administration and at the end of intravenous infusion. [19] The rate or extent of absorption is not influenced by the presence of food for oral intake. [20] Lacosamide shows little protein binding of less than 15% and the elimination half-life is approximately 13 h.

It undergoes hepatic metabolism by CYP2C19 and is primarily excreted by kidneys. Approximately 40% of the drug is excreted unchanged in urine while 30% is excreted as O-desmethyl metabolite and the remaining 20% is excreted as structurally unknown polar fraction. The major metabolite is O-desmethyllacosamide which is inactive and has elimination half-life of 15-23 h.

The rate of renal excretion is reduced to about 25% in mild to moderate renal impairment (creatinine clearance of 30-80 ml/min) and about 60% in severe renal impairment (creatinine clearance of less than 30 ml/min) with unchanged peak concentrations. Dosage adjustments are required in patients with severe renal failure, end-stage renal disease and in mild to moderate hepatic impairment. Dosage adjustments are however not required in patients older than 65 years while pharmacokinetics in children is not studied.

Safety profile

The exposure to doses about 3 times the clinical dose results in reversible changes in liver manifesting in the form of hypertrophy of hepatocytes with no other histopathological changes.

There is insufficient data on the potential embryotoxic and fetotoxic effects of lacosamide. However, animal studies have shown that it freely crosses the placenta into the fetal circulation. It has also been found in animal studies that it affects the neonatal and juvenile development of brain leading to decreased brain weights and long term neurobehavioral changes. As such, potential adverse effects on nervous system cannot be ruled out.

Adverse-effects

As the story goes with other drugs, even lacosamide is also not absolutely free from side-effects. However, the side-effect profile still seems to be a favorable one when compared with other anti-epileptics. These side-effects can be summarized as.

Behavioral changes

Patients on lacosamide should be monitored for the emergence or worsening of depression, suicidal ideation and mood changes and it has been advised to discontinue the long-term therapy gradually.

Dizziness

It can cause dizziness (25%), ataxia (6%) or syncope with varying degrees. Patient should be advised to exercise caution while driving or operating machinery.

Cardiac rhythm and conduction

Lacosamide have been found to prolong PR interval and thus should be used with caution in patients with known conduction abnormalities (second or higher degree AV block, sick sinus syndrome) and patients with severe cardiac disease (myocardial infarction or heart failure). Patients taking drugs, which are known to prolong the PR interval, should be used cautiously along with lacosamide.

Drug interactions

Lacosamide does not induce or inhibit cytochrome enzyme systems and thus does not alter the concentrations of variety of drugs such as carbamazepine, clonazepam, gabapentin, lamotrigine, levetiracetam, phenobarbital, phenytoin, topiramate, valproate, local anesthetics, alternative medicines, digoxin, omeprazole. [21],[22] Lacosamide also did not altered pharmacokinetics of oral contraceptives. [23],[24],[25]


  LACOSAMIDE AS AN ANTI-EPILEPTIC Top


Lacosamide has been found to be effective as an adjunctive therapy in partial-onset seizures by its slow inactivation of voltage-gated sodium channels involved in generating the neuronal action potential thereby inhibiting the repetitive neuronal firing. Its anti-epileptic activity was demonstrated in three randomized, double-blind, placebo-controlled, multi-center studies spreading over 3 weeks and enrolling adult patients with uncontrolled simple or complex partial-onset seizures on two conventional anti-epileptic drugs. Lacosamide was given at an oral dose of 50 mg twice a day initially which was increased in an increment of 100 mg/day to the target doses of 200, 400 and 600 mg/day. [26],[27],[28] All these studies showed significant reductions in seizure frequency with the most beneficial being observed at the doses of 400 and 600 mg/day.

In an extension study enrolling 370 patients, 76.8% of the patients had more than 12 months of exposure with lacosamide, 60.5% had more than 24 months of exposure, 55.7% had more than 30 months of exposure and 37.8% had more than 36 months of exposure with lacosamide. The median dosage used was 400 mg/day while 30.8% had a median dose between 600 and 800 mg/day. The median reduction in 28-day seizure frequency was 45.9% while a 50% or greater response was achieved in about 46.6% of the patients suggesting a pivotal role of lacosamide in partial-onset seizures. [29],[30]

Intravenous lacosamide was also compared with oral preparation in an open-label study enrolling 160 patients receiving oral lacosamide as an adjunctive therapy in a dose range of 200-800 mg/day. The intravenous preparation was given twice daily for 2-5 days as a 30 min infusion in 40 patients, 15 min infusion in 100 patients and 10 min infusion in 20 patients. It was observed that administration times did not affect the adverse reactions and also the seizure patterns were unchanged with the use of intravenous preparation. [31],[32]

Lacosamide has also been investigated for its role in treatment of resistant status epilepticus based on some experimental models and has shown usefulness as first-line therapy when other agents are not suitable. [33],[34] Recently, intravenous lacosamide has been found to be efficacious and safe in managing patients with refractory non-convulsive status epilepticus as an adjunctive therapy. [35],[36]


  LACOSAMIDE AS AN ANTI-NOCICEPTIVE Top


The frequency of diabetic patients has been on rise in operative and critical care settings. [37],[38],[39] As such, many patients are presenting with varying symptoms and pathologies which require surgical or conservative interventions. [40],[41] The frequency of development of painful diabetic neuropathy in patients with long-term diabetes is very high and it results in significant morbidity and impaired quality-of-life. [42] With the ever increasing demand for newer treatment modalities, lacosamide have recently been investigated for its role in treatment of painful diabetic neuropathy. However, there is no literary evidence that it can cause hypoglycemia when simultaneously being administered with other anti-diabetic drugs.

Lacosamide has been found to attenuate mechanical hyperalgesia in some animal models for acute and chronic inflammatory pain. [43],[44],[45],[46] Its efficacy as an anti-nociceptive agent was further validated by an 18 weeks long placebo-controlled, double-blinded, randomized multi-center study which showed that monotherapy at a dose of 400 mg daily significantly reduced the pain in diabetic peripheral neuropathy. [44] There was reduction in mean pain scores by 38.5% in the group receiving lacosamide when compared with a reduction by 27.3% in the placebo group. This reduction in mean pain scores started after 4 th week of therapy and persisted throughout the study period of 18 weeks.

Another randomized, double-blind, placebo-controlled study enrolling 119 patients with pain of diabetic neuropathy and a score of at least 4 on a 11 point Likert pain scale received oral lacosamide in a dose titrated from 100 to 400 mg/day. The primary end point taken was a change in pain score on Likert pain scale. It was observed that lacosamide produced a 2 or more point reduction in pain scores in 60% of the patients as compared to only 50.8% of patients in the placebo group. Approximately 50% reduction in visual analog scale pain scores was observed in patients taking lacosamide as compared to 36% reduction in patients on placebo. Besides, an 18% increase in pain free days was observed with lacosamide when compared to 7.5% with placebo. [45]

An open-label extension study of lacosamide in 451 patients with diabetic neuropathy with 314 patients (69.6%) who received the long term lacosamide therapy showed a mean duration of exposure of 216 days and a maximum of 516 days of exposure. The doses used were 400 mg/day (26.4%) and 600 mg/day (22%). There was a reduction in mean pain scores from a baseline of 6.35 to pain scores of 2.78 at the end of titration phase, 2.16 after 6 months, 2.33 after 12 months and 2.28 after 18 months. More than 95% of the patients receiving lacosamide felt better after 6, 12 and 18 months of maintenance therapy. [46]

Another randomized, double-blind, placebo-controlled study enrolled 549 patients with diabetic neuropathic pain. The oral lacosamide administered was either in a standard titration of 100 mg/week (181 patients) or a fast titration of reaching the target dose of 400 mg/day in 1 week (189 patients). Comparable reductions in the pain scores were observed with standard titration group (₋2.34 points) as compared to the fast titration group (₋2.12 points) however, the median days to sustainable pain relief observed were 10 days in standard titration group, 11 days in fast titration group and 31 days in the placebo group, thus no advantage of fast titration was observed. [47]

Recently, lacosamide was investigated in a rat model of osteoarthritis induced by injection of monosodium iodoacetate into the joint which causes inhibition of activity of glyceraldehyde-3-phosphate leading to death of chondrocytes. Lacosamide in doses of 3, 10 and 30 mg/kg was used and was compared with subcutaneous morphine (3 mg/kg) and diclofenac sodium (30 mg/kg) with the pain assessment done at 3, 7 and 14 days. It was observed that lacosamide at all doses significantly reduced secondary mechanical allodynia and hyperalgesia at days 3, 7 and 14 after induction of arthritis similar to morphine while diclofenac was only able to reduce secondary mechanical hyperalgesia. [14]

The potential advantages of lacosamide as an anti-nociceptive agent include lack of sedative effect, availability of intravenous preparation, minimal drug interactions and no effect on hemoglobin A1c values making it a suitable therapy in diabetes. However, the administration of lacosamide should follow the principles of logical empiricism as data and evidence accumulates from newer research studies in the field of endocrine anesthesia. [48],[49],[50]


  Conclusion Top


Based on the above study it can be concluded that lacosamide, a newer functionalized amino acid, is a novel drug in the armamentarium of anti-epileptic drugs for uncontrolled partial seizures. There are numerous studies in literature suggesting its anti-epileptic activity and also anti-nociceptive abilities have been suggested especially in diabetic neuropathic pain. Due to non-availability of additional data on the adverse drug reaction, it is recommended for an adjunctive therapy in epileptic patients. Lacosamide is a novel anti-epileptic as well as anti-nociceptive drug with minimal drug interactions and controllable adverse reactions. However, many more randomized trials are needed to establish the potential benefits of lacosamide in other painful neuropathies as well.

 
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