To assess efficacy of lamotrigine and Gabapentin as add on therapy by measuring seizure frequency, seizure free interval, pattern of seizures and responder rates
Author: Dr Anshu Sethi, who is working as a Senior resident in department of pharmacology, Maulana Azad Medical College New Delhi India. She has graduated from Lady Harding Medical College and has done her post Graduation from Maulana Azad Medical College, New Delhi. Her area of interest is research and clinical pharmacology. She also enjoys editing books, writing reviews and reading articles from various fields.
Seizure is a very common disorder. Robin(1988)1 estimated 10% of general population experiences at least one seizure in their life time and 4% of persons until 80 years of age will have a chronic seizure disorder. The incidence of seizures in developing countries was studied on a large population based survey in Ecuador reported by Placetia et al(1992),2 on behalf of International community based epilepsy research group (IEBECRG), who reported incidence of 12 to 19 per 1000 and a prevalence of 12.2 to 14.3 per 1000 per year. Sudharan and Murthy(1998)3 conducted a meta-analysis of various studies done in India and reported average incidence of seizures as 1.28-8.87 per 1000.
Epileptic seizures are classified by International League Against Epilepsy i.e. Epilepsia(1981)4 in to Generalized, partial and unclassified seizures. The classification provides not only the uniform definition of seizure type, aggregation of symptoms, but also the specific etiological classification and case assignment. Partial seizures are disturbances which apparently originate in more or less defined areas of brain and produce symptoms depending on epileptic focus. The hallmark of partial epilepsy is EEG discharge localized to focus on one cerebral hemisphere. Further it may sub-grouped as following on the basis of impairment of consciousness during the attack.
Simple partial seizures – where consciousness is not impaired. It may present with either motor or somatosensory signs with or without autonomic symptoms and psychic symptoms.
Complex partial seizures – These seizures are associated with impairment of consciousness, automatism and focal epileptic form discharges. It may present with simple partial seizures followed by unconsciousness or impairment of consciousness at the onset of seizures.
Secondary generalized seizures – It may be either simple partial or complex partial leading to generalized seizures. It can also present as simple partial evolving to complex partial and eventually to generalized seizures.
Anticonvulsant drugs are the mainstay of epilepsy management. The goal of pharmacological therapy for epilepsy is complete control seizures with minimum adverse effects. Unfortunately no single drug available currently has the ability to control all seizures types in all patients without causing adverse effects. Monotherapy with conventional antiepileptic agents is effective and is tolerated by a majority of epileptic patients. If the initial antiepileptic agent fails to control seizures or produce intolerable side effects, another drug can be added. However, as many as 30% patients require more than one agent as reported by Shovoron et al(1978)5. The drug of choice for partial seizures is carbamazepine followed by sodium valporate or sodium phenytoin. If the seizures continue despite of compliance, there is little evidence that more than 10% of patients with refractory epilepsy will benefit from treatment with two or more drugs. Moreover polypharmacy produce higher incidence of side effects and drug interactions, which influence the quality of life and well being of epileptic patients as cited by Brodie(1990)6. Schacter(1993)7 observed that 17 to 31% of all epileptic patients developed chronic intractable epilepsy even after treatment i.e. patients developed seizures refractory to available antiepileptics or to combination of standard antiepileptic drugs. The question as to how a patient develops refractoriness to treatment is still unanswered?
Jensen(1986)8 opined the patient with refractory epilepsy may be as one in whom acceptable seizure control has not been achieved despite of the effective drugs used in therapeutic or supratherapecutic range. Simultaneously the assessment of treatment failure has been designed by Schimdt et al(1986)9. He considered the seizure being intractable only when the optimum choice of drug, the most effective drug regimen and an adequate high daily doses have failed.
When a patient becomes refractory to first line drug, the newer antiepileptic agents i.e. lamotrigine and gabapentin which are broad spectrum can be given as add on therapy (Brodie, 1990)6. These agents provide adjunctive therapeutic options. The combination of these drugs with complementory modes of action may provide a rational pharmacological approach to manage epilepsy refractory to standard available antiepileptics. Various studies conducted earlier have reported the efficacy and safety of these newer antiepileptic drugs. Crawford et al(1987)10 suggested that 900mg of gabapentin as add on therapy produced a 45% reduction in seizure frequency in patients of partial seizures. Further, in a double blind placebo controlled study Sivenius et al(1994)11 in 43 subjects of refractory partial seizures reported that 1200mg/d gabapentin produced a 57% reduction in seizure frequency. Simultaneously International gabapentin study group (Anhut et al, 1994)12 reported median reduction in seizure frequency by 21.8 and 17.8% in the gabapentin group at doses of 1200mg and 900mg per day respectively as compared to 0.3% in the placebo group. The Responder rate i.e the number of patients showing atleast 50% reduction in seizure frequency) in placebo and gabapentin group were 10.1% and 23%, which was significantly higher. In Indian patients. Dhanraj and Velumurugendran(1996)13 reported the effect of gabapentin an add on therapy in 16 patients with partial seizures resistant to conventional antiepileptic drugs. The responder rate was 69%. Three(18.75%) patients had less than 50% reduction in seizure frequency and one patient (6.25%) showed an increased frequency of seizures. During 12 weeks period study, 9(56.25)% patients showed adverse effects which were mostly giddiness and sleepiness Simultaneously, Dixit et al reported the responder rate as 50% and the adverse effects reported were somolescence (24.4%), dizziness (20.3%) ataxia (17.4%), fatigue (14.7%) and tremor (15%).
Jawad et al(1989)15 conducted a double blind placebo controlled cross over study in 21 patients of refractory partial seizures. Only one patient was withdrawn because of the adverse events two patients showed no improvement while one patient reported an increase in frequency with lamotrigine. Of 17 patients 16 showed an improvement in simple and complex partial seizures. The median reduction in seizure count with lamotrigine as add on therapy was 59% indicating a significant reduction with lamotrigine in seizure frequency. In another study Cocito et al(1994)16 reported 50% reduction in seizures frequency at the end of a year with lamotrigine only in 6% of 16 patients suffering with refractory seizures. However, the safety and tolerability were fairly good but skin rashes were observed in 19% of patients.
In view of earlier studies the present study is a modest endeaveour to analyse the efficacy and safety to lamotrigine and Gabapentin as add on therapy in Indian patients of partial epilepsy refractory to carbamazepine and correlate these observation with serum carbazepine levels. The efficacy would be analysed by measuring seizure frequency, seizure free interval, pattern of seizures and responder rate. The safety would be assessed from subjective and objective adverse effects observed in patients and from information gathered from laboratory investigations.
AIMS AND OBJECTIVES
1. To assess efficacy of lamotrigine and Gabapentin as add on therapy by measuring seizure frequency, seizure free interval, pattern of seizures and responder rates.
2. To assess safety by measuring subjective and objective adverse effects observed in patients and from information gathered laboratory investigations i.e. Hb, TLC, DLC, LFT, KFT and serum carbamazepine levels.
3. To compare the efficacy and safety of lamotrigine and gabapentin as add on therapy groups with carbamazepine.
REVIEW OF LITERATURE
No disease is more intriguing and more pressing for solution than epilepsy. Epilepsy has been known for centuries and is probably as ancient as existence of man itself. In Indian Medicine, epilepsy has been defined as ‘Apsmara’ (Ape meaning negation or loss and smara means recollection or consciousness, Ramamurthi & Gurnathan(1969)17. The word ‘Epilepsy’ was derived from ancient Greek word meaning “something seizing the subject”. This was attributed to supernatural phenomenon and it was called ‘Sacred disease’ by Hippocrates (460-357 BC), the father of modern medicine. There has been a lot of stigma attached to epilepsy since ancient times. With the advent of more rational and scientific studies on epilepsy, the old superstitions and misunderstandings are fast disappearing. The credit of defining epilepsy goes to Taylor(1964)18 who expressed, “Epilepsy as a phenomenon, which scarcely warrants being called a symptom and not a disease.” It is not a specific disease, or even a single syndrome, but rather a broad category of symptom complexes arising from any number of disordered brain functions that might be secondary to a variety of pathologic processes. Wylle et al(1996)19 cited the term convulsive disorder or seizure disorder, which are synonymous with epilepsy, they all refer to disorder of brain function characterized by periodic recurrent and unpredictable occurrence of brain dysfunction manifested by stereotyped, synchronous and rhythmic firing a population of neurons.The seizures are classified into generalised, partial and unclassified seizures.
Pathophysiology of partial seizures
Local changes occurring in groups of cortical neurons produce spontaneous and repetitive neuronal discharges. Such discharges are recorded as localized spike foci on EEG periodically. The epileptic discharges may propagate to corresponding point in opposite hemisphere via corpus callosum forming a “Mirror focus” without any clinical change However, the continuous electrical bombardment initiated at primary site may permanently alter the excitability of a secondary site. Thus, the secondary site may begin independently to generate epileptic activity and eventually clinical seizures.
Table-I : The International Classification of seizure type
The patient with refractory epilepsy was defined by Schacter (1993)7 as one in whom acceptable seizure control has not been achieved, despite the use of effective drugs at adequate dosages and levels in therapeutic or supratherapeutic range. The treatment failures was scored according to scoring system designed by Schmidt (1986)9 after giving due consideration to optimum drug treatment with the most effective drug regimen and an adequate high daily dosage
SCHIMDT’S SCORING SYSTEM FOR ASSESMENT OF TREATMENT FAILURES
INDEX OF SEIZURE PERSISTING DESPITE
0 Other than primary drug regardless of daily dose.
1. Primary drug below the recommended daily dose.
2. Primary drug within recommended daily dose
3. Primary drug with in recommended therapeutic range.
4. Primary drug with the maximum clinically tolerated daily dose.
5. More than one drug with maximum clinically tolerated daily dose in subsequent single drug therapy.
Factor responsible for inadequate control of seizures are .
1. Antiepileptic drug
* Poor patient compliance with prescribed drug intake
* Inadequate drug dosage.
* Improper choice of drug.
* Inappropriate combination of drugs.
* Drug interactions.
2. Presence of seizure precipitating factor eg. stressful situations, sleep depreviation, menstruation, alcohol etc.
3. Eroneous classification of epileptic seizures
4. Misdiagnosed non epileptic seizures.
5. Unrecognized progressive neurological lesion.
Pharmacological Management of Epilepsy
The goal of pharmacological therapy for epilepsy is complete control of seizures with a minimum of adverse effects. Unfortunately, no single drug currently available has the ability to control all seizures types in all the patients without causing adverse effects. Monotherapy with conventional antiepileptic agent is effective and well tolerated by a majority of epileptic patients. Patients tolerate most adverse effects of antiepileptic drugs if they do not interfere significantly with daily activities. Serious complications can be avoided through preassessment of risk factors and monitoring of symptoms during treatment.
Selection of appropriate antiepileptic drug should be based on seizure type, pharmacokinetic profile of drug, its potential adverse effects and drug-drug interaction. Monotherapy can achieve goal of treatment i.e complete seizure control with tolerable side effects in 50 to 80% of patients as stated by Shovaron et al(1978)5. It has several important advantages. Treatment is initiated with a low dose, and the dose is increased slowly to a level where seizures are completely controlled or to a level just below that causes persistent and bothersome side effects. That dose of the drug is maintained until seizures recur or toxic reactions develop.
The drug of choice for partial seizures is carbamazepine followed by sodium valproate and phenytoin sodium. These drugs have been recommended as monotherapy for treatment of partial seizures. Despite of all reasonable attempt to control seizures with monotherapy some patient require an additional antiepileptic drug. Before a second agent is added, the serum levels of first drug should be measured to ensure complete compliance with prescribed regimen. If seizure continue despite compliance a second agent may be added to regimen. Initial dose, titration and monitoring may vary depending upon drug-drug interactions. Polytherapy is often problematic owing to a higher incidence of side effects and drug –drug -interactions. All these factors contribute to compromise the quality of life and well being of epileptic patients. Moreover, it has been realised that polytherapy offers no benefit over monotherapy. However, the standard goal of treatment of epilepsy is still that seizures must be controlled at any cost and that medication side effects and psychological problems are independent of medical care of patient with epilepsy still permeate current medical practice as cited by Schacter and Yerby (1997)20.
Patients with refractory epilepsy should be treated with high dose monotherapy, meaning highest dose tolerated by patient correlating with its blood levels. Shovoron et al(1978)5 stated high dose monotherapy is better tolerated with the development of less side effects than is polypharmacy. Combination of new drugs with complementary modes of action may provide a rational pharmacological approach to management of refractory epilepsy.
When a patient becomes refractory to first line drug of choice the newer antiepileptic agents i.e lamotrigine and gabapentin which are broad spectrum can be recommended as add on therapy. These two new agents provide adjunctive therapeutic options. These newer compounds are unrelated to standard antiepileptic drugs which helps to ensure minimum drug –drug interaction and good tolerability in patients.
Carbamazepine (CBZ), is a tricyclic compound that contains two benzene rings, one azepine ring with a double bond and one amide group
MECHANISM OF ACTION
Atleast two basic mechanisms of action, have been proposed
1. Enhancement of sodium channels inactivation by reducing high frequency repetitive firing of action potentials.
2. Action on syaptic transmission.
Peak plasma concentration of CBZ generally reached within 4-8 hrs after ingestion. The steady half live of CBZ ranges from 5-26 hours. The relationship between oral dose and plasma level appears to curvilinear, the smaller increments in plasma levels is related to oral dose (Sillapana 1996)21.
Volume of distribution of CBZ varies from 0.8 to 2/kg in humans. The apparent volume of distribution of the major metabolite CBZ epoxide (CBZ-E) is lower i.e ranges from 0.6 -1.5/Kg. This difference is consistent due to lower lipid solubility of the metabolite compared with parent drug (Sillapana 1996)21.
CBZ is highly bound to plasma protein. In patients the protein bound fraction ranged from 75%-78% but wide variability has been seen in children. Unbound CBZ concentration is inversely correlated with serum alpha 1-acid glycoprotein concentration. Disalle et al (1974)22 stated that unbound CBZ fraction range from 48-53%. Morselli et al (1997)23 detected a significant linear positive relationship between brain and plasma carbamazepine levels. Despite of variations in plasma levels of CBZ. A brain concentration of 4.5 to 5 mg/g were found to be the threshold values protecting electroshock therapy in humans.
The main pathways of biotransformation are epoxidation, hydroxylation, glucoronidation and sulfuration. CBZ is virtually completely metabolized in humans. The main metabolite CBZ-E is hydrolyzed to trans 10,11 dihydroxy carbamazepine epoxide. Faigle and Feldman (1975)24 reported 72% of carbamazepine was recovered in the urine and the remaining 28% in faeces. Considering only urinary excretion, the appropriate percentages of metabolites attributable to four major pathways of biotransformation were epoxidation 40%, hydroxylation 25%, glucuronidation 15%, and sulfuration 5%.
In CBZ treated patients relevant concentration of CBZ-E accumulate and may contribute to CBZ toxicity with unchanged CBZ concentration. Bertilsson and Tomson(1986)25 stated that the, blood concentration of CBZ–E appears to be lower in patients receiving monotherapy (10-20%) than in polytherapy (20-50%). It has been reported that CBZ-E :CBZ ratio is not dose related, suggesting that total plasma CBZ level can indicate sum effects of CBZ and CBZ-E independent of daily dosage.Analysis of serum CBZ maybe done in epileptic patients alongwith clinical judgement to assess seizure control and to confirm the toxicity. Bertilsson and Tomson(1986)25 employed the CBZ kinetics to correlate the CBZ concentration with anticonvulsant pharmacological activity and changes in CBZ half life with prolonged treatment. Inter individual differences in metabolism make it difficult to predict serum levels from administered dose particularly during concomitant therapy with other anticonvulsants .Serum levels monitoring helps to individualise dosage regimen and to assess safety and effectiveness of CBZ as it is effective and safe only in a narrow range of serum concentration. Autoinduction
CBZ markedly induces its own metabolism leading to increased clearance, shortened serum half life and a progressive decrease in serum levels. After a single dose the apparent elimination half life varies between 20 to 65 hours after multiple dosing for 10-20 days, it falls to approximately one half the elimination time. Because of autoinduction carbamazepine kinetics are time dependent clearance rates increase rapidly by second day after first dose. Increase in daily dosage are necessary to maintain plasma concentration. Autoinduction is usually completed within 20-30 days and is dependent on dose of CBZ. The metabolism of CBZ-E is induced more than CBZ turnover, indicating excessive carbamazepine induction compared with CBZ-E hydration (Sillapana, 1996)21.
Efficacy of CBZ in Partial Epilepsy
Numerous open and controlled studies have reported antiepileptic effects of CBZ especially in partial epilepsy. A study was conducted by Buttencourt et al (1993),26 in epileptic patients refractory to phenobarbital. The patients were randomized to add on treatment with carbamazepine or phenytoin. Those taking carbamazepine as add on therapy showed greater improvement and had frequent adverse effects than phenytoin .
In Complex partial seizures and secondary generalised seizures, CBZ remains to be the drug of choice. In other localization related epilepsies, CBZ is preferred to phenytoin, valporate and phenobarbital, which are as efficacious as CBZ but produces more cognitive, behavioral and sedative side effects.
Pereiera et al (1996) 27 in a study reported the use of high dose of CBZ for refractory partial seizures. A total of 48 patients with partial seizures were analysed during treatment with doses ranging between 1200 and 1900 mg/d. Thirty three patients were on monotherapy and fifteen on polytherapy. Seizure control was observed in 7 (14.48%) patients taking 1200 mg/d and in 2 (4.16%) taking 1400mg/d of CBZ. Thirty nine patient did not show any control of seizures despite higher doses .Ten (20.81%) patients had signs of intoxication. It was concluded that when patients had no improvement with 1400 mg/d it was difficult to obtain any control despite higher doses of CBZ, which frequently exposes the patient to side effects.
Jones(1991)28, reported the efficacy of CBZ in complex partial seizures by recording its influence on EEG. The study revealed the significant improved complex partial seizures with CBZ irrespective of the site of EEG focus. The patients with secondary generalised seizures were controlled for more than 1 year in 15 out of 19 patients having left focus and 3 of 11 patients having right focus EEG discharged.
Semah et al (1994)29, evaluated the efficacy, the development of side effects and correlation between CBZ and its major metabolites CBZ E in eighteen patients of refractory partial seizures out of which 5 were on monotherapy and 13 were on polytherapy. The dose of CBZ was increased till 50% reduction in seizure frequency or till adverse effects were observed. It was observed that a higher dose of CBZ can be used safely in patients of refractory seizures and CBZ‑E level was not a useful indicator of toxicity.
Antiepileptic drug selection may vary for special population. For children with symptomatic partial epilepsy, CBZ is considered as drug of first choice. It is especially desirable because of relative absence of neuropsychologic disturbances often encountered with barbiturates and the absence of cosmetic effects associated with phenytoin. In adults, it is a drug of choice for partial seizures because of good efficacy and tolerability. Among women using oral contraceptive pills, caution is advisable because of an increase risk for contraceptive failure resulting from increased clearance of female sex hormone. In pregnant female increased risk of congenital malformation i.e. spina bifida and neural tube closure have been reported with use of CBZ. In the elderly population CBZ use is complicated. These patients are often taking multiple drugs and CBZ may induce metabolism of other compounds i.e. warfarin, cyclosporin etc. The associated hyponatreamia and cardiac dysarrhythmias as well as absence of parenteral formulation makes CBZ less optimal drug for this population (Maughterton, 1997)30.
Cost benefit and Quality Analysis
Henke et al (1994) 31 calculated the cost of l year treatment with CBZ, phenytion and valproate. Cost consisted primarily of price of medication and the expense in managing side effects. Marked differences in cost were found among the drugs in adults with simple or complex partial seizures $1220 for phenytion, $ 1624 for carbamazepine and $ 2841 for valproate.
From various studies reported by Rodin et al (1974) 32; and Dodrill and Troupin (1977)33 it has been calculated that carbamazepine causes alteration of various psychological parameters :-
a) increase in psychic temperament in epileptic personality.
b) affective changes with reduction of dysphoric episodes, state of depression anxiety, irritability and aggressiveness.
Discontinuation of CBZ treatment causes an increase in anxiety which does not occur on withdrawal of phenytoin or valproate suggest a positive role of CBZ on mood and a better quality of life.
Though CBZ is relatively less toxic than other major antiepileptic drugs, but up to 50% experience CBZ related side effects which may be mild and reversible on treatment. Only 5% - 10% of patients require discontinuation of carbamazepine because of adverse effects mostly exanthemata. The following adverse effects have been reported by Sillpana et al 21.
Drowsiness, dizziness, ataxia, dyskinesia and visual disturbances are frequently reported but these signs are dose related and reversible in nature. These occur mostly at the beginning of CBZ treatment. Dystonic movements, choreoathetoid and other dyskinesia have been reported.
Serious heamatologic complications associated with carbamazepine therapy are extremely rare. However, thrombocytopenia, aplastic anemia, agranulocytosis and pancytopenia has been reported.
Tohen et al (1994)34 compared the incidence of hematologic side effects produced by carbamazepine and valproate. The risk of leucopenia (i.e. white blood counts less than 4000 cell /nm3) was 2.05% with CBZ and 0.32% with valproate. Time to develop 50% risk for leucopenia was 18 days and mean time to recovery was 3 days after discontinuation of CBZ therapy.
e) Dermatologic and other hypersensitivity reactions: Rashes have been reported in up to 17% of patients. Out of them 10% reactions were serious and potentially life threatening (eg. Steven Johnson Syndrome, Lyells Syndrome, or exfoliative dermatitis). In a study by Konishi et al (1993)35 the overall incidence of rash observed in epileptic patients was 9.9%, it increased with age, from 5% at 0-6 years to 15.4% at 7 years of age or older. Pellack (1987)36 observed in the study that most frequent side effects of CBZ treatment is not rash but drowsiness (23%) ataxia (10.4%), lecucopenia (10.4%) visual disturbances (9.2%) and elevated liver function test (9.1%).
Hypersensitivity reaction may take the form of lymphadenopathy, hepatomegaly, splenomegaly, pneumonitis, vasculitis, myocarditis or interstitial nephritis. Proliferation and activation of suppressor cytotoxic T cells induced by CBZ seems to be responsible for hypersensitivity.
Levels of hepatic enzyme are raised in 5% to 22% of patients. Mild elevations are insignificant and discontinuation of drug brings about normalisation of enzyme values. Adults are usually at greater risk than children. Successful desensitisation may be carried out by means of gradually increasing doses of CBZ.
a) Antidiuretic Hormone and Hyponatreania - CBZ role as vasopressor for controlling polyuria in patients with diabetes inspidus has been known. This drug causes hypernatremia, low serum calcium and chloride levels especially in patients with low baseline of sodium and high daily doses and high levels of CBZ.
b) Thyroid Hormones - A significant reduction in serum thyroxine levels has been reported in patients with long term CBZ therapy resulting in clinical goitre Decreased serum thyroxine hormones during CBZ therapy may result from drug induced peripheral metabolism of TSH hormones, or a depressed function at level of pituitary has been suggested.
c) Adrenocortical function - The free cortisol concentrations are increased in patients taking CBZ but does not clinically significant effects the circadian corticotrophin rhythm by long term treatment.
d) Sex Hormones - CBZ treatment may cause a rise in circulating sex hormone binding globulin and transient fall in testosterone fraction and androstenedione and continuous fall in dehydroepiandrosterone sulfate. The increase in sex hormone binding globulin and sex hormore catabolism are the result of CBZ induced sex hormone metabolism. These changes are involved in sexual dysfunction experienced in some patients.
Hyposexuality and reproductive dysfunction are commonly ascribed to decreased testosterone activity. Testosterone administration, however, had a moderate effect on restoration of sexual function. In a study on men with epilepsy treated with CBZ, Murialdo et al (1995)37 reported impotence in 8 out of 37 patients, and loss of libido in 2 patients. Hyposexuality was not associated with any specific epilepsy. Total testosterone level was normal, free testosterone and dihydrotestosterone were not significantly higher and estradiol level was lower than in controls.
Effect of CBZ on semen are controversial. There are studies which suggest no influence on sperm movements but only slight fructose elevation. In a study by (Sheeter et al, 1994)38 reported abnormalities in sperm count or motility.
e) Vitamin D and Calcium Metabolism - CBZ may effect metabolism of bone calcium although only a single case of overt osteomalacia has been reported and hypocalcemia, hypophosphataemia, elevated alkaline phosphatase and decrease in serum 25-hydroxy vitamin D have been observed.
Congenital anomalies have been reported in 0% to 2% of infants born to mothers with CBZ monotherapy compared with 9% - 15% for phenytoin and 14% for phenobarbital. Risk factors for congenital malformation in offspring of CBZ treated women include polythereapy and a subsequent higher concentration of CBZ-E. A low folate concentrations has been observed on CBZ therapy. Minor anomalies like finger nail and toe nail hypoplasia has been observed. An estimate of 1% for spinabifida has been reported with mega doses of CBZ (Sillapana, 1996)21.
Miscellaneous Side Effects-
a) Cardiac toxicity Occurs usually as a conduction disturbance in old patients. This warrants great caution in patients with pacemaker dysfunction and other adverse cardiac effects reported as aggravation of sick sinus syndrome and development of congestive cardiac failure.
b) Renal Effects - These are proteinuria, hematuria, oliguria or renal failure account for 3% of side effects.
c) Cholesterol levels - CBZ may affect cholesterol metabolism, resulting in elevation in high density lipoprotein (HDL) and cholesterol levels and increased HDL Cholesterol : total Cholesterol ratio.
d) Psychic disturbances: Asthenia, restlessness, eromania, agitation, anxiety, mania and psychosis has been reported.
e) Haeme biosynthesis is reportedly affected by CBZ and may be suppressed resulting in acute intermittent porphyria of non hereditary origin.
g) Gastrointestinal disorders - They comprise 3% to 6.5% of all reported side efforts the usual complaints are of diarrhoea, nausea, vomiting, stomatitis and glossitis may occur.
Massive Overdose and Intoxication :-
The maximum tolerable dose varies and depends on time elapsed since ingestion. Weaver et al (1988)39 identified 4 clinical stages of carbamazepine intoxication : (1) potential clinical deterioration (<11mg/l) (2) drowsiness, ataxia (11 - 15 mg I); (2) combativeness, hallucinations choreiform movements (15 - 25 mg/l); (4) coma and seizures (Levels more than 25 mg/l)
Serum level of 40 mg/l or higher are usually associated with life threatening complications such as seizures, coma, respiratory failure and cardiac conduction disorders. The measurement of serum level of CBZ is an accurate predictor of severity of toxic reaction in adults.
Pharmacokinetic studies by Bertilsson and Tomson (1986)25 have revealed prolonged CBZ half life, increased CBZ-E: CBZ ratio and emergence of CBZ-E as a significant toxic metabolite. Weaver et al (1988)39 reported the CBZ – E level were higher than the parent compound and were responsible for causing cardiac toxicity.
In addition to symptomatic treatment, carbamazepine intoxication should be managed with repeated gastric lavage, hemoperfusion and treatment of seizures with diazepam and phenytoin and forced diuresis, cathartics, and peritoneal haemodialysis.
Gabapentin is a newer antiepileptic drug apparently different from other antiepileptic agents. This drug also has some desirable pharmacokinetics like it does not bind with protein, does not get metabolised and does not induce liver enzymes, thus diminishing the likelihood of drug interactions with other antiepileptic agents and oral contraceptives (Mclean, 1996)40.
It is active in many standard animal seizure models and protect convulsions induced by Picrotoxcin, bicaculline, strychnine audiogenic and maximal electroshock. The profile of its anticonvulsant activity in animal thus may predicts its clinical efficacy in patients with partial seizures and secondarily generalisation of seizures by Goa and Sorkin (1993)41.
Mean maximum plasma gabapentin concentrations 2.7 to 2.99mg/l in health volunteers is attained in 2-3 hrs after oral 300mg dose. Absorption kinetics are dose dependent, possibly due to saturable transport system. Thus bioavailability of a single 300 mg oral dose of gabapentin is 60% but decreases with increasing dose (Goa and Sorkin, 1993)41. Gabapentin is lipophilic and relatively crosses blood brain barrier producing a CSF : plasma concentration ratio of 0.09 to 0.14mg/l.
Elimination of gabapentin is totally by renal clearance. Unabsorbed gabapentin is excreted in faeces and the absorbed fraction is excreted unchanged in urine. The urinary fraction decreases and the faecal fraction increases as oral dose increases. Following intravenous administration, plasma concentration verses time plots are filled by three compartment model with half lives of a, b and g phases of about 0.1, 0.6 and 5.3 hours respectively. Repeated administration does not affect elimination (Goa and Sorkin, 1993)41. The elimination half life ranges from 4 to 22 hours. Mclean (1996)40 stated a new steady state can be achieved in roughly 24-48 hours after initiation of therapy if renal function is normal. Dosage guidelines of gabapentin based on renal function have been generated from pharmacokinetic studies of gabapentin by Comstock et al (1990), 42 and Graves et al (1989)43; Handforth and Treiman et al (1997) 44.
Table 1: DOSAGE GUIDELINES FOR GABAPENTIN BASED ON RENAL FUNCTION
Mechanism of Action
Gabapentin possess unique yet undefined mechanism of antiepileptic action involving affinity for an undefined receptor in brain tissue primarily located only on neurons. Several mechanisms of action have been proposed for gabapentin. But mechanism most likely involved has been suggested by Chauhan et al (1993)45 that is its binding to undefined receptor site linked to L-system amino acid transporter. This site is stereoselective for S(+) – 3- isobutyl GABA, a gabapentin analogue which is also active in animal test for anticonvulsant activity. However, Goa and Sorkin (1993)41, Mclean (1996)40 have also proposed the other following mechanism:
1. Inhibition of GABA-aminotransferase
2. Increase of GABA synthesis rate
3. Reduction of monoamine neurotransmitter release
4. Inhibition of excitation due to excitatory amino acids and mediated by NMDA receptors.
Early evidence of efficacy and tolerability came from double blind cross over study by Crawford et al, (1987)10 in which gabapentin was given as add on therapy. The 25 enrolled subjects had atleast one partial seizures with or without secondary generalisation or primary generalised seizure per week. Each patient took 300, 600 and 900mg/d in random order for 2 months. The 900mg dose produced a 45% reduction in seizures,.
In another dose ranging study Bauer et al (1988)46 upto 1800mg/d of gabapentin as add on conventional antiepileptic drug regimen 31% with partial seizures and 35% of generalised tonic clonic seizures experienced a 50% reduction in seizure count. Further, in double blind placebo controlled study by Sivernius et al (1991)11. 43 patients with refractory partial seizures received placebo or 900 or 1200mg/d of gabapentin in addition to their other medications. The 900mg dose was ineffective while 1200mg/d resulted in 57% decrease in seizures, compared with the seizure frequency during a 3 months baseline period,.
In UK gabapentin, placebo controlled trial (1990)47 all participants had atleast one seizure per week during 12 week baseline before entering a 12 week double blind, add on period during which they received upto 1800mg/d of gabapentin in three doses Principal outcome measures were responder rate (percentage of patients whose seizure frequency decreased at least 50% from baseline), percent change in seizure frequency (PCB) and response ratio (RR). An RR ratio of –0.33 corresponds to a 50% decrease in number of seizures. They also compared 100mg/d of gabapentin with placebo against refractory partial seizures in 127 patients taking single or combination of standard antiepileptic drugs. A significantly greater percentage of patients responded to gabapentin than to placebo (25% vs 9.8%, p < 0.04). The median percent decrease in frequency was 29% with gabapentin and 12% with placebo. The RR of patients taking gabapentin was significantly more negative than that of patients taking placebo.
In US gabapentin study Group trial (1993)48 306 patients with predominantly refractory partial seizures and secondarily generalised tonic clonic seizures were randomised to receive placebo or 600, 1200 or 1800mg/d of gabapentin in double blind phase. In the 1800mg gabapentin group, 26.4% responded compared with 8.4% in the placebo group. The median decrease in seizure frequency was 32% vs about 6% in placebo group. The adjusted mean RR with higher doses of gabapentin were significantly more negative than RR with placebo 3% of all subjects dropped out because of side effects.
The International gabapentin study group reported by Anhut H et al(1994)12 enrolled 272 patients (245 evaluated) with refractory partial seizures taking one or two standard antiepileptic drugs. Responder ratio were 10.1% in placebo group, 22.9% in patients taking 900mg/d of gabapentin and 28% in those taking 1200mg/d of gabapentin. The median reduction in seizure frequency were 0.3%, 21.8% and 17.8% respectively in placebo group and gabapentin group with doses of 900mg/d and 1200mg/d. About 42% of patients with complex partial seizure responded to 1200mg/d in this study, compared with 26% of patients taking 1800mg/d of gabapentin in US study group.
Pooled data submitted by by US Trial group (1993)48 UK group trial (1990)47 International gabapentin study group (1994)12 cited by Goa and Sorkin(1993)41 for licensing by FDA revealed approximately 26% responder rates among patients with partial seizures and 54% among patients with secondarily generalised seizures.
Long term efficacy
In an open add by Ojemann et al (1992)49 on trial in 35 patients with partial epilepsy treated for 24 months, the gabapentin was given as add on therapy in doses ranging from 1200-2400mg/d. The combined seizures frequency decreased significantly within 3 months and significant decrease in simple and complex partial seizures were apparent at 12 and 24 months.
During the extension of multicentric US trial (1994) 50 against refractory partial seizures, 240 patients taking 600 to 2400mg/d of gabapentin were monitored for upto 2 years. After 2 years of trials 30% of patients had to withdraw because of lack of efficacy and 4% due to adverse effects. Median reduction in seizure frequency ranged from 33 to 60%, responder rate between 35 and 71% and RR ranged from - 0.226 to 0.554. Decrease of 45 to 100% in simple partial seizures 35 to 45% in complex partial seizures and 65 to 100% in secondarily generalised seizures were recorded. About 43% of patients considered themselves improved and 38.5% of patients were labelled improved by their physicians on subjective global evaluation scale.
Handforth and Treiman (1994) 51 reviewed the long term treatment of 23 patients who had participated in US gabapentin study. 16 of 23 patients tolerated up to 2400mg/d of gabapentin and other concominant antiepileptic medications upto 4 years. The gabapentin was withdrawn in 9 patients who experienced no benefit and rebound increase in seizure frequency after a year. Seizure frequency decreased by a 30% in 11 patients treated for a mean of 19 months. Out of 5 patients followed up for 48 to 54 months, 2 patients remained free of seizures for 12 to 18 months after the add on treatment began. One patient experienced a 90% reduction in seizures within 6 months of treatment initiation and remained free of seizures, 2 patients did not have more than 50% reduction in seizures but continued to take gabapentin for 4 years.
Sivenius and his colleagues (1991)11 monitored 25 patients with medication resistant partial and secondarily generalised tonic clonic seizures. Seven patients continued to take gabapentin and concomitant medications for an average of 54 months and five of these achieved better than 50% seizure reduction. gabapentin was well tolerated and safe in these patients.
Efficacy in other seizure types
Relatively little information is available about efficacy against other than partial seizures. Efficacy as add on therapy was studied by Garofalo E et al (1994)52 in 129 patients with refractory generalized tonic clonic seizures randomly to receive either placebo or 1200mg/d of gabapentin for 12 weeks following a 12 week baseline. Differences between two groups were not statistically significant although gabapentin group included 28% responders compared with 18% in the placebo group.
Adverse effects of Gabapentin
In the US trials 1993 and 199448,50, 88% of patients taking gabapentin and 72% of patients given placebo reported side effects generally rated as mild to moderate. Mostly gabapentin induced the central nervous system adverse effects within few days of therapy and lasted approximately 2 weeks without need for drug discontinuation. The frequent CNS adverse effects seen with gabapentin are : somnolence, dizziness, ataxia, nystagmus, headache, tremor, fatigue, rhinitis, diplopia, nausea and vomiting. Side effects were reported in 4% to 43% of patients but infrequently caused discontinuation. Dysphoria (aggression, irritability) and weight gain (>7% above baseline) were more prominent than in controlled trials.
Positive effect on mood and adjustment were greater with low dose of gabapentin and personality improved after 12 week at doses up to 2400mg/d.
Litzinger et al (1995)53 reported of adverse behavioural effects especially from mentally retarded patients given gabapentin as add on therapy. 20% of patients at one center and 16% at another experienced irritability, outburst of temper and even violence, impatience and other dysphoric situations. In a total of 110 mentally retarded institutionalized individuals, 16% exhibited increased aggressive behaviour, 15% increased seizure frequency and 9% ataxia or lethargy with gabapentin doses of 1000 to 1300mg/d.
This drug causes delayed ossification of long bones skull and vertebrae in some rodents foetus at doses up to 4 times the 3600mg/d human dose. Hydroureter and hydronephrosis has also been observed. There is no evidence of mutagenesis in vivo or in vitro. Little experience is available in the treatment of pregnant females. There is one evidence of an encephalic body born to a mother who took carbamazepine and gabapentin during first trimester cited by Goa and Sorkins (1993)41.
Despite its indication for adjunctive agents gabapentin has also been used in some trial as a first line drug for control of new onset partial seizures because of safety, tolerability and preliminary evidence of monotherapy. If monotherapy fails, another drug can be combined with or replace gabapentin without significant drug interactions.
The recommended schedule for initiation of gabapentin 300mg on day 1, 300mg twice daily on day 2 and 300mg three times a day therafter an increment of 300mg per day can be made till there is 50% reduction in seizure frequency or some adverse effects appears. Maintenance dose ranges from 900-6400 mg/d with variable seizure control has been established (Goa and Sorkins (1993)41. Slow titration allows identification of those likely to develop adverse effects and those who will achieve an optimal therapeutic response at low doses. Plasma level of more than 2 mg/ml is associated with a significant clinical improvement.
Lamotrigine is a phenyl triazine derivative chemically unrelated to other anticonvulsants. Though many mechanisms for its action has been postulated but the best studied mechanism of action of lamotrigine is its inhibitory effect on the voltage sensitve sodium and possibly calcium channels blocking release of the excitatory aminoacids glutamate and aspartate under conditions of substained repetitive, while the normal spontaneous release is unaffected (Messenheimer 1996)54.
Absorption, Distribution and metabolism
After oral administration, absorption is rapid and virtually complete with a bioavailability of 97.6% in healthy volunteers and peak plasma is achieved within 2 to 3 hours, food does not alter absorption. The plasma protein binding is reported to be constant at 50% over a concentration range of 1 to 4mg/l (cited by Messenheimer)54. A linear relationship has been observed between the dose administered and the peak concentration (Cmax) of lamotrigine over the dosage range of 50 to 400mg administered as single dose. This has also been noted for doses upto 700mg (Garnett 1997)55. The time to peak lamotrigine concentration (tmax) following oral administration is 1 to 3 hours and is not affected by dose. A second peak may occur between 4 and 6 hours after oral and intravenous dosing which suggests enterohepatic recycling ( stated by Garnett 1997)55.
Lamotrigine is widely distributed throughout all organs and tissues in test animals the tissue concentration were several fold higher than plasma concentration. The volume of distribution is 0.9 to 1.3 l/kg is human volunteers. It undergoes linear hepatic metabolism by glucuronidation. In humans the major metabolite is 2-N glucuronide; no active metabolites are produced. Approximately, 70% of a single oral or intravenous dose is recovered in the urine, glucuronide products constituting 90% and 5% as unchanged. Lamotrigine does not induce mixed function oxidase enzymes but slightly induces its own glucuronidation. In a study, Yau et al (1992)56 found the half life decreased by 25% from a mean of 32.8 hours to 25.4 hours in healthy volunteers maintained on 300mg/d for 14 days. The half life of lamotrigine is reduced to one half by enzyme inducing anticonvulsants and is increased two fold to three fold by valproic acid. The elimination rate of lamotrigine is increased by enzyme inducing drugs such as phenytoin, carbamazepine, primidone. The half life of lamotrigine is reduced to approximately 14 hours from 25 hours in patients taking enzyme inducers, whereas valproic acid doubles this half life to approximately to 55 hours. Age does not significantly alter the serum half life.
Efficacy of Lamotrigine in Epilepsy
The efficacy of lamotrigine as add on therapy has been analysed from four double blind randomized trial in patients of refractory partial epilepsy.conducted by Binnie et al (1989)57, Jawad et al(1989)15, Sander et al (1990)58 Loisseau et al(1990)59.. All the trials had similar phases; a baseline period of 8 weeks and two treatment period of 12 weeks with a washout period of 6 weeks each in between the two treatment periods. Binnie et al (1989)57 studied the effect of lamotrigine in 30 patients with refractory partial seizures. The patients were allowed to continue the receiving standard antiepileptic drug and the total daily lamotrigine dose ranged from 50 to 400mg. & 19 of the 30 patients showed an improvement on seizure frequency with lamotrigine .
In another study carried out in by Jawad and co-worker(1989)15 involved 21 outpatients with refractory partial seizures. Three patients did not complete the trial and one patient was withdrawn from the trial due to ataxia, diplopia, dyspnea, and tiredness while receiving lamotrigine. The patients continued to received standard antiepileptic drugs and the daily dosage of lamotrigine administered ranged from 75 to 400mg, producing a mean trough plasma lamotrigine concentration of 1.9 mg/ml, for the patients in the study. All 21 patients completed the study and 18 patients showed an improvement i.e. a significant reduction in total seizures (p<0.002) with lamotrigine treatment as compared to placebo
In a similar study at Chalfont by Sander et al(1990)58, 18 patients were included with refractory seizures. Patients continued the standard antibiotic drugs and the daily dose of lamotrigine ranged from 100 to 300mg. Twelve of 18 patients had fewer seizures during lamotrigine treatment period compared with placebo. Lossaeau et (1990) et al59 carried out a study in 23 patients with refractory partial seizures. Patients continued standard antiepileptic drugs. and the lamotrigine dosage prescribed ranged from 75 to 300mg. A total of 15 of 23 patients showed an improvement in seizure reduction with lamotrigine treatment and the incidence of rashes was 17% In the metanalysis of these trials, the differences of adverse events between the lamotrigine and placebo group were not significant.
Coccito et al (1994)16 reported a different observation on the long term use of lamotrigine as add on therapy ,in a open trial in 16 adult patients with refractory epilepsy . Lamotrigine was added to current antiepileptic medication at dosage of 200-400mg. Ten patients who completed one year treatment and were followed up for 15-38 months. Among these six patients (38%) had greater than 50% reduction in seizure frequency as compared to baseline but some efficacy decline was seen after an year , the responder rate dropped from 38% to 19% after 2 years and 13% after 3 years. The drop outs during first year were due to increased seizures in two patients, steven johnson syndrome (2 patients), macrocytic anaemia (one patient) and poor compliance (one patient).
CONCOMITANT LAMOTRIGINE AND CARBAMAZEPINE
The controlled trials of lamotrigine did not shown any significant systemic effect on plasma concentration on concurrent administration of standard antiepileptic drug (Yuen 1995)60. However, one report of nine patients suggested that Lamotrigine caused an increase in CBZ and CBZ-E levels(Warner et al, 1992)61. Still, another report of three patients suggested an increase in the plasma concentration of the CBZ -E, without an increase in the parent drug (Graves et al, 1991)62.
In another two placebo controlled trials of 11 and 22 patients, no significant difference in CBZ or CBZ-E concentrations (Schapel et al, 199263, Stolarek et al, 1993)64 was observed Eriksson et al (1996)65 found no clinically important changes in plasma concentration of CBZ in children and young adults who received lamotrigine as adjunctive therapy. Brodie et al(1992)66 demonstrated an increase in central nervous system side effects after lamotrigine was added to treatment regimen of patients already receiving CBZ, suggesting a pharmacodynamic interaction between lamotrigine and CBZ.
Brodie et al (1992)66, Graves et al (1991)62, Wolf et al(1992)68, Warner et al (1992)61 stated diplopia and dizziness as the sign of CBZ toxicity when lamotrigine was added to CBZ treatment . Whether these are the signs of lamotrigine toxicity or lamotrigine affected the plasma concentrations of CBZ and/or its pharmacologically active epoxide metabolite or there is a pharmacodynamic interaction between drugs which enhanced the adverse effects was studied by Besag and his co-workers (1995)67. Around 17 patients of epilepsy with ongoing CBZ treatment, lamotrigine was added as adjunctive therapy when seizures were not controlled. However, seven cases of toxicity consisting diplopia and dizziness occurred in patients whose initial CBZ concentration were >8mg/l. In none of 9 patients who developed CNS effects there was significant increase in CBZ epoxide levels.
Wolf (1992) 68 also observed neurotoxic adverse effect when lamotrigine was used in combination with CBZ but he drew a different conclusion regarding the nature of interaction. Nine of 12 patients studied were taking a sub toxic or just tolerated dose of CBZ and 8 developed signs of cerebellar toxicity when lamotrigine was added to achieve a plasma concentration of less than 4mg/l. No significant effect in serum CBZ concentrations occurred. There was slight increase in CBZ epoxide level upto 10% but this did not account for toxicity.
GABAPENTIN AND CARBAMAZEPINE
Concomitant administration of gabapentin 300 to 400mg 8 hourly for 4 to 8 days did not affect plasma concentration of CBZ or its active epoxide metabolite. Conversely, the standard antiepileptic drug carbamazepine does not affect pharmacokinetics of gabapentin. Mean steady state plasma CBZ/CBZ-E during and after gabapentin administration does not require any dosage adjustment. Thus, no pharmacokinetic interaction exists between CBZ and gabapentin (Radulovic et al, 1994)69.
MATERIALS AND METHODS
The study was conducted in Department of Pharmacology, Maulana Azad Medical College in association of Department of Neurology and Department of Biochemistry G.B Pant Hospital, New Delhi during the period of April 1999 to February 2000. The patients suffering with partial seizures taking maximum tolerated dose of carbamazepine (CBZ) were included in the study to compare the efficacy and safety of two newer antiepileptic agents lamotrigine and gabapentin as add on therapy to CBZ.
Selection of subjects
The patients with partial seizure who failed to respond to maximum tolerated dose of CBZ were eligible for the study. CBZ accounts for wide range of doses and substantial inter-individual variation in concentration which occurs with same dose in different individuals. Hence the maximum clinically tolerated doses of CBZ was defined as the dose which causes neurotoxic adverse effects especially nystagmus, diplopia, ataxia etc. Partial seizures were sub-classified according to the commission on classification and terminology of international league against epilepsy 19894 in to simple partial, complex partial and secondarily generalized seizures. The index of intractability was assessed by Schidmt’s scoring system9. All recruited patients had an average of at least 4 partial seizures during baseline period despite treatment with maximum clinically tolerated dose of CBZ. The treatment failures score designed by Schimdt2 is stated below:
SCHIMDT’S SCORING SYSTEM
INDEX OF SEIZURE PERSIST DESPITE TREATMENT WITH
0 Other than primary drug regardless of daily dose.
1. Primary drug below the recommended daily dose.
2. Primary drug within recommended daily dose
3. Primary drug with in the plasma concentration with in recommended therapeutic dose
4. Primary drug with the maximum clinically tolerated daily dose.
5. More than one drug with maximum clinically tolerated daily dose in subsequent single drug therapy.
1. Patients of either sex >12 years
2. Women of child bearing age group using adequate local barrier method of contraception.
1. Progressive or fresh CNS lesions like tuberculoma, neurocysticerosis stroke, infarct, tumors, hemiparesis or any other organic lesions.
2. History of hepatic renal and cardiovascular diseases
3. WBC counts less than 3000 cu.mm or neutrophils less than 1500 cumm
4. History of chronic alcoholism or drug ingestion and history of psychiatric illness.
5. Pregnant or lactating females
6. Other antiepileptic drugs,
7. Generalized seizures, or any history of non epileptic seizures.
8. Duration of epilepsy more than 2 years.
Written informed consent from each patient to participate in study was obtained. In case of patients less than 18 years the consent was obtained from the guardian of the patient. The characteristics of each patient viz. name, age, sex, occupation , registration number, detailed history of each patient i.e. duration of epilepsy, clinical presentation and number of seizures, drug treatment and any other history of concomitant illness, the general physical, systemic and detailed neurological examination including higher mental functions, reflexes, coordination etc. were recorded on a pre-designed patient sheet at every follow up.
The EEG findings and other investigations were carried out and any adverse reactions were noted at every follow up in the patient sheet.
The following investigation were done to confirm suitability of the patients for the study.
1. Blood : Haemoglobin & Total and differential leukocyte count
2. ECG (electrocardiogram) - To exclude cardiovascular disease
3. Liver function tests. S.bilirubin and liver aminotransferases i.e. SGOT, SGPT, to exclude liver damage
4. Blood urea and serum creatinine to exclude renal impairment.
5. Electroencephalogram (EEG) to record pattern of seizures, frequency, number of discharges and any secondary generalisation of seizures.
6. Serum carbamazepine levels
These investigations were carried out at the time of enrolment i.e. baseline, 6 and at 12 weeks of add-on therapy during treatment phase. The EEG findings if found abnormal (i.e. with epileptiform discharge, abnormal background activity, loss of anterioposterior gradient etc.) at onset of study would be recorded at two weekly follow up.
Based on inclusion and exclusion criteria the patients were enrolled. The baseline investigation were performed at time of onset of study. The patients were randomized equally into two groups.
Group I was administered gabapentin alongwith carbamazepine
Group II was administered lamotigine alongwith carbamazepine
Drug and its administration
In Group I, gabapentin was added after failure of CBZ therapy in patients of seizures. The schedule for intitiation of gabapentin was 300mg on day 1, 300mg twice daily on day 2 thereafter an increment of 300mg was added at every follow up till seizures were controlled or till the end point of treatment i.e ³ 50% reduction in seizure frequency was achieved (Mclean 1996)40, The maintenance dose ranging between 900 to 6400 mg/d has been considered for variable seizures control. Slow titration of drug was allowed for identification of encountered adverse effects and to identify patients, who achieved an optimal therapeutic response at low doses.
In group II, patients of partial seizures failing to CBZ therapy were administered lamotrigine 50mg everyday for 2 weeks as add on therapy followed by 50mg twice daily for 2 weeks. Subsequent every two weekly increase or titrations of 50 to 100mg/d were made until a maintenance dose of 500 to 700mg/d reached or the end point for control of seizure was achieved i.e. ³50% reduction in seizure frequency was obtained. In patients less than 16 years of age, (i.e. paediatric age group) the lamotrigine was started with 2 mg/kg per day for 2 weeks followed by 5mg/kg per day for 2 weeks, till a maintenance dose of 5-15mg/d, if the seizure were not controlled, Messenheimer (1996)54
Patients were evaluated at baseline, 6 and at 12 weeks of treatment using EEG and other investigations as mentioned earlier and at every two week interval to record primary outcome measures. i.e. seizure frequency and presentation of seizures, neurological examination and adverse effects which were recorded on a predesigned patient sheet. The patient who had a normal EEG at onset of study would be assessed with EEG at baseline, 6 and 12 weeks of active treatments. The patients with abnormal EEG i.e showing progressive epileptic form discharges at onset were reviewed with EEG at every 2 weekly interval. The patient or the attendent was given a diary for recording number of seizures and were asked about clinical presentation of seizures with or without loss of consciousness, rolling of eye balls, increased muscular tone of body, frothing in mouth, automatism etc. and the seizure free intervals at every follow up visit. The patients would be assessed using the following parameters:
A) SEIZURE FREQUENCY
It is defined as number of seizures occurring in periods of observation72. All activity would be recorded in patient daily diary.
The primary efficacy criteria would be percentage of change in frequency of partial seizures (PCH), relative to baseline response, response Response ratio and responder rate. These would be derived from the seizure frequency72,73.
a) Percentage of change in seizure frequency (PCH)
It would be defined as % of change in seizure frequency during treatment compared with baseline72. PCH = T-B/B x 100. T-frequency of seizures following completion of treatment; B-frequency of seizures at baseline.
Would be at least 50% reduction in seizure frequency during treattment as compared with base line72.
C) RESPONDER RATE
Would be expressed as % of patients classified as responder. i.e. with a 50% or greater reduction in seizure frequency during a specific 12 week treatment as compared with baseline72.
d) Response ratio (R Ratio)
R ratio would be calculated as the difference between the seizure frequency during a specified 12 week treatment period (T) and baseline seizure frequency (B) divided by the sum of two frequencies72 : R Ratio = T-B /T+B B-frequency of seizures at baseline, T-frequency of seizures at treatment period.
R Ratio varies between +1 and –1. Negative values indicate reduction in severity.
e) Secondary efficacy criteria
Would include R Ratio for all cases of partial seizures and its classification into 3 groups simple, complex and partial seizures progressing to secondarily generalised seizures.
PATTERN OF SEIZURES
Would be assessed from the location and nature of discharges and change in nature of existing seizure and would be analysed on electroencephalogram
SEIZURES FREE INTERVAL
Would be analysed from clinical history from patient or attendant and would be defined as duration of time in between two last seizures.
The major efficacy parameters would be seizure frequency, seizure free interval, responder rate and pattern of seizures
It would be evaluated based on information gathered from subjective and objective adverse effect experienced by the patient and any significant change in laboratory investigations i.e. LFT, KFT, TLC, DLC and serum carbamazepine levels.
ANALYSIS OF SERUM CARBAMAZEPINE LEVEL
The serum carbamazepine levels was estimated by using EMIT assay kit to have a quantitative analysis of carbamazepine in human serum, which was collected in non heparinised vial from the patients on CBZ monotherapy.
After an overnight fast, carbamazepine tablet was taken orally with water. No food was given for two hours to ensure proper absorption of the drug. Blood sample was collected in the morning at 9.00 A.M before morning dose of carbamazepine. Then blood was centrifuged for 5 minutes within two hours of collection and supernatant, was used for further study. The sera thus obtained was stored at 2-8o C until required for analysis. The concentration of the drug in serum was estimated following EMIT method.
The EMIT (Enzyme multiplied Immunoassay technique) assay is a homogeneous enzyme immunoassay technique. It is based on competition between drug in the sample and drug labelled with the enzyme glucose-6-phosphate dehydrogenase (G-6PD-H) for antibody binding sites. Enzyme activity decreases upon binding to the antibody. So the drug concentration in the sample can be measured in terms of enzyme activity. Active enzyme converts oxidized nicotinamide adenine dinucleotide (NAD) to NADH, resulting in an absorbance change that is measured spectrophotometrically (Endogenous serum G6PD-H) will not interfere with oxidation of NAD because the co-enzyme functions only with the bacterial (Leuconostoc mesenteroids) enzyme employed in the assay (Oellerich, 1980)70.
This EMIT carbamazepine assay measures the total (protein bound plus free) carbamazepine concentration in serum or plasma.
The kit71 (Syva Company, San Jose, CA 95161-9013) was used for estimation of drug and contains.
In the assay procedure 1 part sample, 6 parts reagent A, 6 parts reagent B, 6.4 parts buffer concentrate and 90 parts distilled water was taken. Buffer concentrate was diluted with 90 parts distilled water to form buffer solution. The working reagents were prepared by adding buffer solution to the reagent. Same volume of reagent A and reagent B were added to the sample (50ml). Then the absorbance was measured at 340nm.
A calibration curve was prepared using the calibrators. When calibrators were reconstituted, contain the following stated carbamazepine concentrations.
Concentrations of the calibrators were measured using the same procedure (as mentioned earlier in the case of sample) and a standard curve was plotted against concentration verses absorbance. Using the standard curve unknown concentration was concentration versus absorbance. Using the standard curve unknown concentration was calculated.
The factors that influence the relationship between carbamazepine concentration in serum and clinical response include the type and severity of seizures, age, general state of health and use of other drugs. The above assay method accurately quantitates carbamazepine concentration in human serum containing 2.0 to 20.0 mg/ml carbamazepine. Patients taking carbamazepine alone respond best in the range of 5.0 to 14.0mg/ml.
Monitoring serum carbamazepine concentration alongwith careful clinical assessment is an effective means of controlling seizure, reducing the risk of toxicity and minimizing the need for additional anticonvulsant medication.
The EEG is the principal investigation used in epilepsy. It detects, the brain’s electrical activity by sensitive sensors called ‘electrodes’ which are placed on the scalp. The recording technician first measures the patients head for correct placement of electrodes, which are placed according to an international system based on the patients head size and on measurements taken from bridge of nose and bony protrusion at back of neck. 20 electrodes are used in adults. Wires from each electrode are connected to junction box connected to amplifiers. After amplication the EEG machine records the signals on tape or disc or paper.
E.E.G was done for all the cases, while the patients were awake and during sleep under the effect of seconal sodium (100mg for adults and 4mg/kg body weight for children), hyperventilation was done for 3 minutes in all the cases. Methods of activation were used when required.
Techniques : All the electroencephalograph were done with an eight chanelled ink writing Galiles R 35f EEG machine. The patient was asked to avoid oil on the head 24 hours prior to the EEG and a thorough head wash was done with soap and lukewarm water 12 hours before the EEG. Anticonvulsant medication was stopped for 24 hours prior to the test. The hair must be completely dry. Bentonite paste was applied and rubbed over the scalp at various places where the surface silver electrodes were applied. Electrode placement was solely based upon Taspers 10-20 electrode system. 21 electrodes were used 19 on the scalp and 2 on the ears.
Various epileptic form discharges recorded would be spikes and sharp wave, typical spike wave paroxysms, slow spike wave paroxysm or rhythmic slow waves or generalized flattening of the EEG pattern. Various activation procedures are used for detection in provoking abnormalities in patients in whom EEG fail to detect abnormalities. Various activation procedures used were hyperventilation, sensory stimulation photic stimulation, sleep and sleep deprivation and drugs activation using methohexital, pentylenectetrazol (PTZ) or thiopental test or seconal sodium.
Typical EEG characteristics recorded in partial seizures4
OBSERVATION AND RESULTS
In the present study, fifty two patients of either sex i.e. 25 males and 27 females (see appendix Ia & B for details ) suffering with partial seizures despite of maximum tolerated dose of carbamazepine (CBZ) were included. Another seven patients ( 3 in gabapentin & 4 in lamotrigine group) discontinued the treatment.The distribution of these patients for different add on therapy has been shown in table-1 ,
Table 1 Showing the age range and the distribution of patients with different types of partial seizures on carbamazepine therapy with Gabapentin or lamotrigine as add on therapy
values are x±s.d
SPS – Simple partial seizures
CPS – Complex Partial seizures
Gen – Partial seizures with generalisation
A total of 30 patients were enrolled in the gabapentin add on therapy group and only 27 patients completed the study. The development of CBZ tolerance was more or less equal among males and females. Among these 19 males and 8 female patients received gabapentin as add on therapy with CBZ in the dose range of 600-2400 mg/d. while another 25 patients (6 males and 19 females) were given lamotrigine as an add on therapy with carbamzepine.
Table 2 : Comparison of Demographic profile of patients on Carbamazepine therapy in Gabapentin or Lamotrigine group with add on therapy
SPS-simple partial seizures
CPS-complex partial seizures
In the lamotrigine group 29 patients were included but only 25 completed the study and 2 patients dropped due to development of serious adverse effects with lamotrigine & another two because of poor compliance and pregnancy. In the gabapentin and lamotrigine group the Male : Female sex ratio were 19:8 and 6: 19 respectively. When these patients were subgrouped as simple partial seizures (SPS), complex partial seizures (CPS) and secondary generalized seizures (Gen), it was observed that the total number of patient in each subgroup were 17,15and 20 respectively, but the number of patients distributed under the gabapentin and lamotrigine group was variable ,In the gabapentin group there were 11,4 and 12 patients in SPS, CPS and Gen categories of partial seizures, while in lamotrigine 6,11 and 8 were in SPS,CPS and Gen subtypes of partial seizures. The average mean age was 22.33±7.17 years in gabapentin group and 24.8±11.33 years in lamotrigine group.
It could be further observed from table-2 that majority of patients i.e 41 were between the age group of 15-35 years distributed equally as males and females out of them approximately 50% i.e.21 patients were between age group of 15-20 years .The age group of 15-20 years showed a predominance of female population, the male and female ratio was 9:12.
All the 52 cases in the present study had atleast 4 recurrent seizures during baseline period of 4 weeks despite of treatment with maximum tolerated dose of carbamzepine at the point of enrolment in the study.
The efficacy of the drugs was determined on the basis of major parameters which were the seizure frequency i.e. the number of seizures, seizure free interval and pattern of seizures.
The average frequency of basal partial seizures as shown in table-3 were 6.26±3,86 and 5.04 ± 2.47in the groups selected for add on therapy with gabapentin and lamotrigine respectively which decreased significantly (p<.001) after 12 weeks to 1.75±2.16 and 1.68±2.94 with gabapentin or lamotrigine. (For details refer Table III- Appendix ) .Diagram 1and 2 shows the protective effect of add on therapy with gabapentin and lamotrigine on their respective seizure frequency.
Table 3 : Showing the efficacy of gabapentin or lamotrigine group as add on therapy using seizure frequency.
* significant p<0.001as compared to baseline values.
However, no significant difference in seizure frequency was observed either in baseline or after 12 weeks treatment with gabapentin and lamotrigine groups (p >0.5).
The primary efficacy criteria were PCB( percentage change in seizure frequency at baseline), percentage response (% reduction in seizure frequency), responder rate (% of patient showing atleast 50% reduction in the number of basal seizures) and response ratio (R.Ratio) for partial seizures in general which was calculated as the difference in no. of seizures at baseline and after treatment divided by the total no. of seizures during baseline and treatment period.(negative value for PCB and RRatio indicate reduction in seizures).The RRatio for different subgroups- SPS, CPS and Gen of partial seizures was also calculated as the secondary efficacy critiera which were derived from seizure frequency.
It could be observed from table-4 that the PCB values after 12 weeks of add on therapy in gabapentin group decreased to –72.81±34.92 and –76.22±29.68 in lamotrigine group respectively .The difference between the decrease in PCB values after add on therapy of gabapentin or lamotrigine groups was not significant.
Table 4 Showing the primary efficacy criteria derived from seizure frequency in gabapentin or lamotrigine as add on therapy
Values are mean±s.d.
Response percentage –An inadequate response < 50% i.e. patients who failed to treatment were observed in 5(18.7%) and 1(4%) patients treated with add on therapy with gabapentin and lamotrigine respectively as shown in table4&diagram 3and 4 . A 50-75% and 75-100% response was seen in 33.3% and 44.4% patients in gabapentin group and 32% and 60% in lamotrigine groups respectively. While, one patient in each group on the contrary experienced an increase in frequency of seizure and failed to respond to the given treatment with either of these drugs.
RESPONDER RATE- It was defined as the % of patients showing atleast 50% reduction in seizure frequency after treatment with add on therapy. As shown in table 2 in the gabapentin group 21 patients and in lamotrigine group 23 patients as add on therapy showed atleast 50% reduction in seizure frequency thus indicating the responder rate as 77.77% and 92% which appears a greater response in lamotrigine group .However, the difference in responder rates between gabapentin and lamotrigine groups was not significant ( p >0. 50).
Further, the effect of add on therapy with gabapentin and lamotrigine was evaluated on different types i.e. SPS,CPS and Gen partial seizures. It would be observed from table6 that in more than 75% patients of different types i.e.SPS,CPS and Gen partial seizures responded to either gabapentin or lamotrigine add on therapy. The number of patients in each subtype of partial seizures appears less suggesting to explore further the efficacy of these therapies in further details.
Table5- Showing the responders* and non responder*with different types of partial seizures with gabapentin or lamotrigine therapy on CBZ.
*Non responders i.e. < 50% of response after treatment
*responders showing>50% response.
Response ratio (R Ratio)= It could be observed from table 6 and diagram 5 that add on therapy with gabapentin the R Ratio was –0.66±0.35 and in lamotrigine group , it was –0.75±0.30. The RRatio of –0.33 is equivalent with 50% reduction in seizures and the greater negative value shows a greater reduction in seizures. On comparing the RRatio between two add on therapies the results were not significant( p >0.2). The RRatio for subgroup i.e. SPS, CPS and secondarily generalised seizures of partial seizure were -0.313, -0.123, ‑0.225 in gabapentin group and -0.189, -0.172,- 0.1408 in lamotrigine group respectively. Similar results are seen from table6 and diagram5.This suggested probably gabapentin is more effacious in SPS and Gen subtypes of partial seizures where all subtypes of partial seizures were well controlled with lamotrigine.
Table 6 : Showing the effect of gabapentin or lamotrigine as add on therapy on secondary efficacy criteria.
Values are mean +s.d.
*RRatio was analysed using ANOVA & results were insignificant.(p>0.2)
SEIIZURE FREE INTERVAL: It was defined as duration of time in days in between two last seizures. As shown in table8 and diagram6&7 the basal seizure free interval in was 9.69±5.32 days in group treated with gabapentin as add on therapy significantly increased(p<.001) to 54.24±34.79 days after 12 weeks of treatment. Similarly, the basal seizure free interval was 7.86±3.65 days and increased to 61.12±33.17 days after treatment with lamotrigine showing a significant increase(p<0.001). But on comparing seizure free interval between gabapentin group and lamotrigine group using unpaired ‘t’ test for independent variables. The results were not significant (p value > 0.2) statistically.
PATTERN OF SEIZURES : Pattern of seizures was assessed with the help of EEG to find out the location i.e. whether discharges were focal or diffuse, nature of discharge i.e.spike slow waves, sharp slow waves, delta and theta waves and any change in nature of existing seizures and also from clinical presentation of seizures.The normal pattern of seizures are shown in picture-1 &picture-2 shows the phase reversal phenomenon which is the earliest sign of epileptogenic foci.Pictures 3-8 shows the various recorded epileptiform discharges.
The abnormal EEG expression was recorded at baseline in 33.33% (9) patients of gabapentin group and 40%(10) patients of lamotrigine group But after treatment abnormal EEG was further recorded only in 3 i.e.(33.3%)out of 9 patients on gabapentin add on therapy and in 4 i.e. (40%) out of 10 patients in group with lamotrigine add on therapy. (Table IV A, B, C appendix)
The pattern of seizures in patients with abnormal EEG expression the secondarily generalised seizures i.e. diffuse discharges which were seen in 2 patients at baseline and was not seen in after treatment with gabapentin and similarly,the diffuse discharge seen in 3 patients at baseline was observed in only 1 patient after treatment with lamotrigine as add on therapy as observed from table 8.
Table-8 Pattern of seizure in patients with abnormal EEG expression
.(N)-denotes the EEG carried out
Group-1 indicate gabapentin add on therapy group
,Group-2 indicate lamotrigine add on therapy group
*Appears to be a decline in the initial values
In 5 patients out of 27 patients within gabapentin group a change in the clinical presentation of seizure was observed. The seizures altered to myoclonic in (3) patients, atypical absence in one patient and pseudoseizures in one patient. In group with gabapentin as add on therapy while on lamotrigine as add on therapy, 4 out of 25 patients had altered seizures two of them had atypical absence (2) and the other two developed pseudo seizures (2) .
SAFETY PROFILE OF PATIENTS
It was evaluated based on information gathered from subjective adverse effects experienced by patient and objective parameter recorded by us as observation or a significant change in laboratory investigations i.e. Hb, LFT, KFT, TLC, DLC and serum CBZ levels.On the basis of safety profiles of patients derived from laboratory investigation i.e. Hb, TLC, DLC LFT and KFT did not reveal any significant variation in above parameters at baseline and after treatment. (Refer table VI-Appendix ).The heamoglobin levels were 11.16+2.05 and 12.6+1.79 mg/l before the commencement of add on therapy with gabapentin or lamotrigine in respective groups, After 12 weeks of add on treatment, the Hb levels were with in the normal range in both groups i. e. 11.3+1.65 and 12.8+1.83 mg/l in gabapentin and lamotrigine groups respectively.The total leucocyte count were 7116+1454.21 and7076+1454.08 per cubic mm. in gabapentin group at baseline and after treatment while in lamotrigine group respective values were 6829+1458.08 and 6470+1421.37per cubic mm.The liver function test i.e. serum bilirubin,serum aminotransferases were also with in normal range in both groups at baseline and after treatment, No alteration of the kidney function was seen in either gabapentin or lamotrigine group before and after treatment.(Refer table-VI appendix)
Table 9 – Serum Carbamazepine level in the gabapentin and lamotrigine as add on therapy at groups at baseline and after treatment.
*Results were significant p <0.018 as compared to baseline value.
As observed from table 9 with baseline and treatment values of serum. CBZ levels in gabapentin group were 8.22+2.71 at baseline&9.11+3.32 mg/l after treatment and the results were not statistically significant (p = 0.285).
On analysis of serum CBZ level in lamotrigine group at baseline were 7.48+2.38 mg/l and 9.64+2.60 mg/l after 12 weeks of treatment ,the increase in the serum CBZ level were found to be significant (p<0.0156).The diagram 8and9 shows the effect of gabapentin and lamotrigine as add on therapy on CBZ on serum CBZ levels.
ADVERSE DRUG REACTION
Five patients out of 27 patients did not complain of any adverse reaction with gabapentin as adjuvant therapy.The common adverse effects have been shown in table 10 and diagram 19,11,12 &13.However, 7 patients did not report any adverse effect with lamotrigine .
In group with gabapentin as add on therapy, one patient had to be withdrawn because of poor tolerability, vomiting, nausea and dizziness and increased no. of seizures. Two patients were dropped because of poor compliance. So ,only 27 patients completed study. In gabapentin group, the adverse drug effects were mostly neurotoxic in nature and epigastric discomfort seen in 11.11% which were seen especially after 6 weeks of treatment with gabapentin as add on therapy but they were mild to moderate and reversible in nature.The common adverse effects reported were headache(25.9%), dizziness(22.2%), drowsiness(14.8%), weakness(14.8%)& tiredness(14.8%).
In group with lamotrigine as add on therapy, common adverse effects reported were either neurotoxic or due to hypersensitivity. Apart from the marked anxiety was seen in 16% of the patients.The common adverse events were diplopia(24%), weakness(24%), headache(20%), dizziness(28%), rashes(16%) & phobia of getting another seizures in 12% of patients. In lamotrigine group 29 patients were enrolled but only 25 patients completed the study. Two patients had to be withdrawn due to adverse effects. One patient developed steven Johnson syndrome and another patient developed anxiety neurosis with hydrophobia and increased frequency of seizures. The other two patients were withdrawn due to pregnancy, and poor compliance. The rashes observed were maculopapular, cutaneous or mucosal in nature. They subsided either with reduction in dose or with treatment spontaneously. They were commonly observed at 0-2 weeks of initiation of therapy and were self limiting in nature.
Table –10 : Adverse Drug Reaction in the study group
*ADR-adverse drug reaction
Epilepsy remains one of the most commonly prevalent diseases in society. It predominately affects the young population of society. The stigma attached to it, it becomes imperative to treat the disorder as effectively as possible. Although several medications are in use to treat such seizures, in approximately one third of patients they cannot be adequately controlled with any single drug or combination of drug (Schmidt, 1986)9. On the basis of various clinical trials, CBZ has been considered to have the best overall combination of efficacy and freedom from adverse effects during treatment of partial seizures (Mattson et al 198674, Mattson, 1989)75. Though conventional antiepileptic drug i. e. CBZ is effective and well tolerated in majority of cases but 30% of treated patients require therapy with more than one drug (Schaeter CS and Yerby, 1997)20. Polytherapy in such uncontrolled patients is often problematic due to higher incidence of side effects and drug-drug interactions. When a patient becomes refractory to first line drug of choice, the newer antiepileptic drugs lamotrigine or gabapentin which are broad spectrum can be recommended as add on therapy it may improve quality of life of refractory patients. As these drugs are unrelated to standard antiepileptic drugs, this minimises drug-drug interaction and ensures good tolerability in patients. On the basis of results from various clinical trials (Jawad et al, 198915, Richen and Yuen 199176) lamotrigine has become a well established adjunctive drug for partial seizures. So far no Indian study has reported the efficacy of lamotrigine in resistant partial seizures. The safety and efficacy of gabapentin has also been reported in patients of refractory partial seizures (Crawford et al, 198710, UK Gabapentin study group 199047, Sivneus 199111, US gabapentin study group 199348) where gabapentin was added after failure to a existing combination of standard antiepileptic drugs.
The present study was undertaken to assess the efficacy and safety of gabapentin and lamotrigine as first add on therapy in Indian patients of partial seizures refractory to CBZ. In group , with gabapentin as add on therapy in the dose range from 600mg-2400 mg/d controlled seizures in 21 of 27 patients receiving CBZ therapy yielding a responder rate of 77. 77% These results are consistent with previous reports from indian studies by Dhanraj et al (1998)13 and Dixit etal (1996)14. who observed the responder rate as 66, 6% and 50% in refractory partial seizures. Clinical studies with gabapentin as an add on therapy byAnhut et al 199412, Ojeman et al 199249 demonstrated a dose response effect at dosage ranging 600-1800 mg/d, these studies indicated increasing efficacy with increasing dose but in the present study no such relationship was observed. But it is difficult to conclude any relationship between dose response and efficacy from the present study as the sample size was very small. The drug was well tolerated at all dosages upto 2400mg/d, though a rebound increase in number of seizures was seen at 2400 mg/d in only one patient whereas UK Gabapentin group1990 reported an increase in seizure frequency in 19 % patients with gabapentin compared to 33% with placebo.
The efficacy was studied in each group using the primary and secondary efficacy critieria derived from seizure frequency, pattern of seizures and seizure free interval. The basal seizure frequency of 6. 26+3. 86 declined to 1. 75+2. 16 i. e. 56% after treatment with gabapentin for 12 weeks in comparison to 32% reported by Bauer et al 198846 & 57% by Sivineus et al 199111. The present study suggested probably gabapentin anticonvulsant action was more pronounced on simple partial seizures and secondarily generalised partial seizures than on complex partial seizures these results are consistant with Crawford et al(1987)10 but contrary to those by US gabapentin group 199348 which showed this drug to be more efficaeous in partial seizures . The responder rate of various sub types of partial seizures-SPS, CPS and Gen were 90. 9% i. e. 10 out of 11 patients, 75% i. e. 3out of 4 patients and 66. 7% i. e. 8 out of 12 patients. In contrast to 13. 3% for SPS, 24. 3% for CPS and 61. 4% for generalised partial seizures by Maeyer etal 199977. A significant increase (p<. 001) in seizure free interval was seen after 12 weeks of treatment with gabapentin as reported by Maeyer etal 199977. An improvement was seen clinically as well on EEG on the pattern of seizures. About 9 patients (33. 33%) reported an abnormal interictal EEG at onset and 6 patients showed improvement in the pattern in the form of disappearance of focal discharges or diffuse discharges, ablation or reduction in rate of epileptiform discharge during 12 week follow up after commencement of add on therapy. This has not been reported from previous studies i. e. US (1993)48, UK (1990)47 and International gabapentin study group (1994)12 etc. reported in literature. A difference in the clinical presentation of seizures was noted especially during treatment period. Myclonic Jerks, psychomotor seizures or atypical absence seizures which constitute a generalised epilepsy was observed. in 5 patients This may be either due to provoking of precipitating factors i. e. sleeplessness, fever etc which can cause convulsions or due to the fact that partial seizures may occur in association with other types of seizures in a seizure syndrome complex and gabapentin may be less efficacious in seizures other than partial seizures . The efficacy of gabapentin was not associated with any significant changes in serum concentration of CBZ. Such interaction was unexpected as this drug does not bind to plasma proteins or nor in an enzyme inducer (Vollmer 1986)78. These results are consistent with experience of gabapentin and CBZ reported by Graves et al, 199143, Radulovic 1994)69 . Overall a higher responder of 77. 7% was seen with treatment with gabapentin as add on therapy than of 32% reported by Anhut et al, (1994)12. A complete control of seizures were seen in 8(29. 6%) out of 27 patients during the course of study whereas Brauni et al (1998)79eported 53 out of 141 patients (46%) achieved complete remission of seizures during last 8 weeks of treatment of gabapentin as adjuvant therapy. A significant improvement (p<0. 001) in seizure free interval was seen after treatment with gabapentin, this was similarly observed by Anhut et al (1994)12 and Sivineus et al (1991)11. The dose regimen were not interval (fixed and adjustment were permitted in response to inadequate seizure control or side effects during the period of study.
The common adverse effects reported with gabapentin were mainly neurotoxic in nature i. e. headache, diplopia, dizziness. drowsiness and weakness. But these were mild in nature and discontinuation of drug was noted only in one patient due to poor tolerability. These results support those reported by Mclean MJ et al, (1999)80 US gabapentin study group (1993)48, Anhut H et al, (1994)12. No derangement in laboratory parameters was seen. This study thus demonstrates the short term safety and tolerability of gabapentin as adjunctive therapy to achieve the adequate seizure control in patients with partial epilepsy
In another group, lamotrigine was given as first add on therapy in dose range from 50-300mg/day. This study was a parallel design study than the previous cross over studies which report efficacy of lamotrigine (Jawad et al (1989)15, Binne et al (1989)57, Sander et al, (1990)58. In this study lamotrigine was given add on therapy to 25 patients of partial seizures refractory to CBZ and the efficacy of this drug was assessed using same measures as mentioned above with gabapentin add on therapy.
The maximum response of 100% was seen in 11(44%) out of 25 patients on lamotrigine as add on therapy. The mean reduction in the number of seizures at baseline and after treatment were statistically significant (p<0. 001) and similar to those reported by Jawad et al (1989)15 &Loisseau et al (1990)59. The use of lamotrigine as adjunctive therapy was effective in reducing seizures freuqencey ³ 50% in 23 out of 25 patients achieving a responder rate of 92% which is greater than 66. 6% reported by Jawad and co-workers 1989 in patients of resistant partial seizures. All subtypes of partial seizures were controlled effectively though Binnie et al(1987)57 and Loisseau et al (1990)59 reported better control of SPS and CPS than Gen partial seizures, One patient (4%) experienced an increase in seizure frequency during treatment phase with lamotrigine as add on therapy, the reason of which has been illustrated in gabapentin group. A statistically significant (p<0. 001) prolongation was seen in seizure free interval after treatment with lamotrigine as shown by Jawad etal (1989)15. An improvement was also seen in pattern of seizures which was analysed with help of EEG and clinical presentation, A little information is available about the action of lamotrigine on paraoxysmal EEG abnormalities. Marcini et al (1998)81 and Marcini et al (1996)82 reported a reduction in epileptiform discharges but no dissappearence of focal discharges was observed but in present study, focal discharges diminished and persisted in 3out of 7patients and diffuse discharges which depict genralisation was seen in none out of 3 patients after 12 weeks of add on therapy. Apart from this there was reduction in rate of discharges. This proved that there was a benefit with lamotrigine on the pathogenesis of seizures. There was also an alteration in clinical presentation of seizures the partial seizures were altered to atypical absense (2 patients) and pseudo seizures in 2 patients. The explanation for this has been quoted in gabapentin group. The safety of this drug was assessed from laboratory parameters and adverse drug reactions observed during treatment. Around 25% of patients did not complain of any adverse effects. 2 patients were dropped due to poor compliance and due to pregnancy. 2 patients terminated the study due to severe adverse reactions i. e. Stevan Johnson syndrome and anxiety neurosis with hydrophobia and increased frequency of seizures. The incidence of steven Johnson syndrome and severe hypersensitivity syndrome has been reported by Guberman et al (1999)83 from a large multicentric trials was 0. 3% (3 patients per 1000 adult patients) and 1 per 100 epileptic children, in this study the reported incidence was 4% (one patient). Further, investigation is required in this matter to elucidate the incidence of such severe condition in indian patients. Anxiety neurosis has not been reported till date from literature in any clinical study with lamotrigine as add on therapy.
The other neurotoxic adverse effects reported were headache, drowsiness, diplopia dizziness and dysphoria, these have been reported by Malsero et al, (1993)84 and Messenheimer et al (1994)85 but ataxia was not reported in any patient. A greater incidence of hypersensitivity reaction were reported in 16% of patients especially rashes which were mild, benign and self limiting in nature in 2-4 weeks of treatments with lamotrigine. These effects were mild and did not require discontinuation of drug. The other adverse effects reported were anxiety, marked phobia of getting recurrent sieuzres and epigastric discomfort. No derangement in laboratory parameters was seen. No abnormality in EEG findings was seen. An interaction between (p<0. 01) lamotrigine and CBZ levels were seen after treatment with lamotrigine as add on therapy with CBZ but whether this was dose related could not be assessed from the study. Such interaction has been reported by Besag et al (1996)67, Warner et al (1992)61 & Wolf et al (1992)68 which was responsible for neurotoxic adverse effects but in the present study since estimation of lamotrigine was not done in serum whether there was a pharmacokinetic or pharmcodynamic cannot be established on the basis of this study, so we suggest that further studies should be carried out to verify this interaction.
On comparing the two groups it was observed though seizure frequency declined significantly with in these groups after treatment with gabapentin or lamotrigine however no significant difference in basal or after 12 weeks of treatment with gabapentin or lamotrigine in seizure frequency was seen. The seizure free interval also successfully prolonged equally with 12 week of treatment with gabapentin and lamotrigine. An increase in number of seizures was observed in one patient in each group, this effect has already been reported with CBZ due to attenuation of sodium channels by Mattson 1996 whether similar mechanism operates with gabapentin or lamotrigine needs to be explored on the basis of further studies. 5 patients and one patient in gabapentin and lamotrigine group respectively failed to achieve desirable response of 50% reduction in seizure frequency. Abnormal EEG expression was recorded in 33. 3% and 40% patients in gabapentin and lamotrigine group at point of enrolment in the study. An improvement was seen in the pattern of seizures in the form of disappearence of epileptiform discharges, generalisation focus and reduction in rate of discharges. 5 patients were observed to have an additional phenomenon in gabapentin group-myoclonic(3), atypical absense(1) and pseudo seizure. while in lamotrigine group 2 patients experienced pseudo seizures and 2 patients had atypical absense seizures. The development of this new phenomenon may be either due to natural history of disease or due to any precipitating factor fever, sleeplessness etc. This point should be further clarified with a large clinical study and the effect of both drugs on mood elevation and reducing anxiety especially with lamotrigine (Gilliam et al (1993)86 was not observed in our study. Both drugs were found to be equally efficacious and well tolerated in epileptic patients.
To summarise, it was observed that the development of tolerance to CBZ was distributed equally in gabapentin and lamotrigine add on therapy groups. Both drugs gabapentin and lamotrigine were highly effiaceous in reducing seizure frequency, prolonging the seizure free interval and improved the pattern of seizures clinically as well as on EEG, The responder rate in gabapentin and lamotrigine group were 77. 7% & 92% respectively. However, treatment with gabapentin or lamotrigine did not differ on evaluating the various efficacy parameters mentioned earlier, both drugs are equally efficacious in controlling seizures for a short period upto 3 months. Though neurotoxic adverse effects were observed in both groups but they were mild and self limiting in nature. A precaution is indicated in using lamotrigine due to development of hypersentivity reactions so a gradual titration of dose is advised.
SUMMARY AND CONCLUSIONS:
1. The present study was conducted in 52 patients (25 males and 27 females) suffering with various subtypes of partial seizures viz simple partial seizures, complex partial seizures and secondarily generalized seizures. They were labeled refractory to the maximum tolerated dose of CBZ or produced intolerable adverse effects which were mostly nystagmus, ataxia, diplopia, etc. All the selected patients had atleast four seizures during basal period of four weeks.
2. After selection, patients were randomly divided into two group. Group I received gabapentin as add on therapy with CBZ, while group receiving lamotrigine as adjuvant therapy with CBZ for twelve weeks. The two groups were studied for efficacy and safety of gapapentin or lamotrigine. The efficacy was analysed from seizure frequency responder rate, seizure free interval and pattern of seizures. The safety was assessed from adverse events reported either by patients or information gathered from laboratory parameters i.e. Hb, TLC, DLC, LFT, KFT and serum CBZ levels.
3. The majority of patients i.e. 20 out of 52 were in the age range of 15-20 years. The female patients were predominant in the lamotrigine group (6 males and 19 females. The number of patients distributed under the sub categories of partial seizures in gabapentin or lamotrigine group were variable. In the gabapentin group, there were 11, 4 and 12 patients in SPS, CPS, and Gen subtypes of partial seizures. While in lamotrigine group 6, 11 and 8 patients were in SPS, CPS and Gen subtypes of partial seizures.
4. The average frequency of partial seizures despite of CBZ were 6.26±3.86 and 5.04±2.47 in the groups with gabapentin as add on therapy which declined significantly (p<0.001) to 1.68±2.94 and 1.75±2.16 after 12 weeks of treatment with these drugs. However, no significant difference was observed at baseline or after 12 weeks treatment in between the gabapentin or lamotrigine groups (p > 0.5). An inadequate response i.e. <50% reduction in basal seizures was seen in 18.7% and 4% patients in gabapentin and lamotrigine group respectively and an adequate response was seen in 21 out of 27 patients in gabapentin group and 23 out of 25 patients in lamotrigine group giving a responder rate of 77.77% and 92% respectively. While one patient in each group on the contrary experienced an increase in seizure frequency.
5. A better control of SPS and Gen. seizures was probably seen in gabapentin group whereas in lamotrigine group all subtypes of partial seizures were almost equally controlled.
6. There was a significant increase (p<0.001) in seizure free interval after 12 weeks of add on therapy with gabapentin or lamotrigine at baseline and after 12weeks of add on therapy with in these groups. But on comparing the groups with either gabapentin or lamotrigine no significant results were seen (p >0.05) after treatment with 12 weeks of add on therapy.
7. Pattern of seizures was recorded as any change in the nature of existing seizures as depicted from EEG as well as from the clinical presentation of seizures. Abnormal EEG expression was noted at baseline in 33.3% (9) patients and 40% (10) patients in gabapentin and lamotrigine group respectively. But after treatment abnormal EEG expression was seen in 3 out of 9 patients and in 4 out of 10 patients in group with gabapentin and lamotrigine add on therapy group. An improvement was recorded in the from of disappearance of focal discharges, ablation of epileptiform discharges decrease in rate of discharges, and no generalization of discharges. In 5 out of 27 patients within gabapentin group and in 4 out of 25 patients a change in clinical presentation of seizures was seen. The seizures were altered from partial seizure to myoclonic, atypical absence and pseudoseizures.
8. On analyzing serum CBZ levels after treatment with either gabapentin or lamotrigine at baseline, no significant change was observed in gabapentin group, however, in lamotrigine group, 16 patients showed an increase in the basal serum CBZ level after 12 weeks of treatment and the results were significant when compared to basal values of serum CBZ levels (p<0.015). But since no analysis of lamotrigine was done or any relationship of such interaction to dose of lamotrigine was studied so, it is difficult to conclude whether this is a pharmacodynamic or pharmockinetic interaction.
9. No derangement in the investigated laboratory parameters was observed after treatment with gabapentin or lamotrigine groups.
10. The common adverse effect reported in the gabapentin group were mainly neurotoxic in nature whereas in the lamotrigine group, they were mostly neurotoxic or hypersensitivity reaction, though gastritis was seen in both groups. Two patients were withdrawn due to development of Steven Johnson syndrome and anxiety neurosis in lamotrigine group but in gabapentin group only one patient was withdrawn due to poor tolerability. The other adverse effects in both the group were self limiting in nature and were mild to moderate.
11. On comparing these drugs in terms of efficacy, gabapentin and lamotrigine were equally efficacious and none of the drug showed superiority over the other. Both the drugs were well tolerated and safe, though a precaution is indicated due to development of hypersensitivity reactions with lamotrigine.
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Table 1 : Comparison of Demographic profile of patients on Carbamazepine therapy in Gabapentin or Lamotrigine group with add on therapy
SPS-simple partial seizures
CPS-complex partial seizures
Table 2 : Showing the efficacy of gabapentin or lamotrigine group as add on therapy using seizure frequency.
* significant p<0.001as compared to baseline values.
Table 3- Showing the primary efficacy criteria derived from seizure frequency in gabapentin or lamotrigine as add on therapy
Values are mean±s.d.
Table 4 - Showing the responders* and non responder*with different types of partial seizures with gabapentin or lamotrigine therapy on CBZ.
*Non responders i.e. < 50% of response after treatment
*responders showing>50% response.
Table 5- Pattern of seizure in patients with abnormal EEG expression
.(N)-denotes the EEG carried out
Group-1 indicate gabapentin add on therapy group
,Group-2 indicate lamotrigine add on therapy group
*Appears to be a decline in the initial values
Table 6 – Serum Carbamazepine level in the gabapentin and lamotrigine as add on therapy at groups at baseline and after treatment.
*Results were significant p <0.018 as compared to baseline value.
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