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ORIGINAL ARTICLE
Year : 2013  |  Volume : 3  |  Issue : 4  |  Page : 341-346

Comparative study of effects of gabapentin, vigabatrin and sodium valproate on psychomotor performance in healthy volunteers


Department of Pharmacology, Government Medical College, Nagpur, Maharashtra, India

Date of Submission25-Jun-2013
Date of Acceptance29-Jul-2013
Date of Web Publication15-Oct-2013

Correspondence Address:
Kavita M Jaiswal
Lal Imali Chowk, Gandhibagh, Nagpur, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2231-0738.119841

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   Abstract 

Context: The cognitive and psychomotor functions may become impaired in epileptic patients due to underlying etiology, effect of seizures and side-effects of antiepileptic drugs. It is desirable for the drug to have a minimal effect on cognitive abilities. Few studies have evaluated the psychomotor effects of newer antiepileptic agents and hence do not have the proper evidence base for their psychomotor adverse effects. Aims: The aim of this study is to evaluate the effects of gabapentin (GBP), vigabatrin (VGB), valproate (VAL) on psychomotor functions. Settings and Design: Randomized, prospective, double-blind, placebo (PLB) controlled crossover study. Subjects and Methods: A total of 24 healthy volunteers were included to administer single oral doses of GBP 300 mg, VGB 500 mg, sodium valproate 200 mg and PLB following a Latin square design. The objective parameters - six-digit cancellation test, digit symbol substitution test, critical flicker fusion test, arithmetic ability test, digit span test, hand steadiness test and subjective parameters like visual analog scale (VAS) were tested at 0, 1, 2 and 3 h. Statistical Analysis Used: Repeated measures ANOVA was used to compare the difference in mean score. Fisher's exact test was used for statistical analysis of adverse effects. Results: Sodium valproate impaired all subjective and objective psychomotor functions while GBP, VGB did not show any impairment when compared with PLB. GBP when compared with VGB, no difference was observed in any test, but when both the drugs were compared with sodium valproate, statistically significant difference at the end of third hourwas observed. Conclusions: VGB and GBP have few adverse cognitive and psychomotor effects as compared with sodium valproate, therefore are safe as add on therapy or monotherapy.

Keywords: Antiepileptic drugs, gabapentin, psychomotor performance, vigabatrin


How to cite this article:
Jaiswal KM, Gaikwad AV, Pimpalkhute SA, Bajait CS, Sontakke SD. Comparative study of effects of gabapentin, vigabatrin and sodium valproate on psychomotor performance in healthy volunteers. Int J Nutr Pharmacol Neurol Dis 2013;3:341-6

How to cite this URL:
Jaiswal KM, Gaikwad AV, Pimpalkhute SA, Bajait CS, Sontakke SD. Comparative study of effects of gabapentin, vigabatrin and sodium valproate on psychomotor performance in healthy volunteers. Int J Nutr Pharmacol Neurol Dis [serial online] 2013 [cited 2019 Jul 21];3:341-6. Available from: http://www.ijnpnd.com/text.asp?2013/3/4/341/119841


   Introduction Top


In patients with epilepsy, any derangement in psychomotor and cognition process added to the one that already exists is a matter of great concern. [1] The cognitive and psychomotor functions may become impaired in patients of epilepsy due to underlying etiology of epilepsy, the effect of seizures and the side-effects of anti-epileptic drug treatment. [2] Therefore, it is desirable for the drug to have minimal or no effect on cognitive abilities such as perception, processing, learning, reasoning, judgment, memory and mathematical and analytical skills so that the productivity of the patient is retained without any social and academic maladjustment. Valproate (VAL) is the drug of choice in generalized tonic clonic seizure, myoclonic seizure, clonic seizures and absence seizure. Vigabatrin (VGB) is used as add on therapy in treatment of epilepsy and also as a monotherapy as a drug of choice in the treatment of infantile seizures. Gabapentin (GBP) in addition, to its use as an add on therapy in treatment of epilepsy is also used as a monotherapy in various neuralgic pain syndromes like the diabetic neuralgia and neuropathic pain. [3] Majority of the studies in which the cognitive effects of antiepileptic drugs were assessed are comparative studies with other antiepileptic drugs in treated patients. This makes the interpretation about the cognitive and psychomotor adverse effects difficult. Hence, studies on individual drugs are needed to have more conclusive evidence and data from such single drug studies will provide initial information for carrying out studies using different doses and for longer duration. Evidence on cognitive impairment by phenobarbitone, phenytoin and carbamazepine is present in the literature. [4],[5] Several new antiepileptics have been introduced into clinical practice in the last few years few studies were published on the new antiepileptic medications and hence do not have proper evidence base for their cognitive and psychomotor adverse effects.

Hence, the present study was undertaken with the following aims and objectives:

  • To evaluate the effects of GBP, VGB, VAL on psychomotor effects in healthy volunteers with the help of battery of the subjective and objective psychomotor tests
  • To perform inter-drug comparative study of the effect of these drugs on psychomotor performance
  • To study any other side effects of the drugs.

   Subjects and Methods Top


This study was a randomized, prospective, double-blind, placebo (PLB) controlled, crossover study carried out in 24 healthy volunteers from September 2010 to November 2011 in the Department of Pharmacology, Government Medical College, Nagpur after approval from the Institutional Ethics Committee. A written informed consent was taken from each subject after explaining them the nature of the study.

Healthy volunteers from either gender aged 18 to 30 years with minimum education up to secondary school certificate. were included in the study. Patients having a history of smoking, tobacco chewing, seizure, renal, hepatic, cardiovascular, neurological illness, allergy, hypersensitivity or reaction to any medication, receiving chronic medications for any type of illness were excluded from the study. Pregnant and lactating women and volunteers with decreased visual acuity were also excluded. The general and systemic examination was done of each subject and was selected in the study only if he/she was declared fit by the examining physician. Before the study, volunteers received training until a performance plateau was reached.

A single oral dose of GBP 300 mg (Aventis), VGB 500 mg (Sanofi), sodium valproate 200 mg (Intas) and PLB was administered following a Latin square design. The parameters were tested at 0, 1, 2 and 3 h. After a wash out period of 1 week, the participants were again called and the same procedure was repeated for the second drug and similarly for the third and fourth drug respectively with wash out period of 1 week. The volunteers were asked to note any side-effects experienced by them during the study.

All formulations were packed in inert gelatine capsules of the same color and dimensions and given specific codes by a person other than investigator and subject. The drugs GBP, VGB and sodium valproate were purchased from a local pharmacy and the empty gelatine capsules used were obtained from a pharmaceutical industry on request.

Tests for psychomotor functions: A sensory component

Test for perception

Six-digit cancellation test (6DCT): [6] Volunteers were required to cancel as many target digits as possible in a sheet consisting of 1200 randomized digits in 3 min.

Test for recognition and recoding

Digit symbol substitution test (DSST): [6],[7] Volunteers were required to insert the corresponding symbol in the space above each digit in a sheet consisting of 200 randomized digits in 2 min.

Test for central integration

Critical flicker fusion test (CFFT) [8],[9] is a reliable psychometric test as there is no learning curve effect. The apparatus consists of a viewing tube at the end of which a red circle of light flickers at the rate of 550 cycls/s. The critical fusion frequency was determined by increasing the frequency from 5 Hz until a steady light source was seen and the critical flicker frequency by decreasing the frequency from 50 Hz until flickering was seen.

Test for central processing

Arithmetic ability test (AAT): [6] The subjects had to solve simple mathematical problems, i.e., addition, subtraction, multiplication and division (five of each) within 2 min.

Test for memory and learning

Digit span test (DST): [6] The subject were asked to write down a nine digit sequence after 10 seconds of hearing it within 30 seconds (five different sequences were repeated).

Motor component

Test for steadiness

This was tested by steadiness tester, which consists of holes of different sizes and subjects had to insert stylus into the hole without touching its sides. [10]

Subjective component

Visual analog scale

The volunteers were asked to indicate the state of their current feeling by marking on a 100 mm horizontal line. The opposite mood-related adjectives at each end were as follows [11],[12],[13]

  • Wide awake - Extreme sleepy
  • Alert - Dull
  • Active - Tired.
Statistical analysis

Sample size was calculated by using a level of significance (α) 5% and Power 80%. Graph prism version 5 was used for statistical analysis. Repeated measures ANOVA was used to compare the difference in mean score from baseline to 1, 2 and 3 h for all drugs. P < 0.05 was taken as significant. Fisher's exact test was used for statistical analysis of adverse effects.


   Results Top


In various psychomotor performance test (DSST, 6-DCT, AAT, CFFT, DST, HST) statistically significant difference in the scores was observed at the end of third hour 3 rd h in sodium valproate group. No difference was observed either in the GBP or VGB group when compared with baseline suggesting that the drugs have no detrimental effect on the scores of psychomotor performance test.[Table 1] When compared with PLB, statistically significant difference was observed in sodium valproate group at the end of third hour. No difference was observed with VGB and GBP when compared with PLB. When GBP was compared with VGB, no difference was observed at any point of time in any test. GBP when compared with sodium valproate, statistically significant difference at the end of third hourwas observed suggesting that sodium valproate caused a decrease in scores than GBWhen compared with VGB, statistically significant difference was observed in sodium valproate group at the end of third hour suggesting that sodium valproate caused reduced scores than VGB.[Table 2]
Table 1: Effects of gabapentin, vigabatrin, valproate at 0, 1, 2 and 3 h on subjective parameters of psychomotor performance as compared with baseline

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Table 2: Inter-drug comparison of gabapentin, vigabatrin, valproate at 1, 2 and 3 h on objective parameters of psychomotor performance

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[Figure 1], [Figure 2] and [Figure 3] shows Effects of gabapentin, vigabatrin and valproate at 0, 1, 2 and 3 h on sedation, alertness and concentration respectively using visual analog scale.
Figure 1: Effects of gabapentin, vigabatrin, valproate at 0, 1, 2 and 3 h on sedation using VAS (***P < 0.001; VAL: Sodium valproate; VGB: Vigabatrin; GBP: Gabapentin)

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Figure 2: Effects of gabapentin, vigabatrin, valproate at 0, 1, 2 and 3 h on alertness using VAS (***P < 0.001; VAL: Sodium valproate; VGB: Vigabatrin; GBP: Gabapentin)

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Figure 3: Effects of Gabapentin, Vigabatrin, Valproate at 0, 1, 2 and 3 h on concentration using VAS (VAS-3)

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Adverse events

Nausea and abdominal pain observed in the sodium valproate group was statistically significant when compared with PLB. These side-effects are expected and also reported in the literature. [12] The adverse effects with GBP and VGB group are similar as compared to PLB at the dose used in the study.


   Discussion Top


All conventional antiepileptic drugs have been reported to be associated with cognitive and psychomotor adverse effects. [14],[15] Newer antiepileptic drugs have more favorable adverse effect profile with minimum psychomotor impairment. [16] However, there are fewer reports in the literature on acute psychomotor effect of newer antiepileptic drugs. In our study, no significant difference was found between GBP and VGB in any of the psychomotor and cognitive functions as compared with PLB at any duration of the study. However, with sodium valproate, there were statistically significant detrimental effects on performance on all six objective tests at the end of third hour when compared to PLB, GBP and VGB.

These results are consistent with and support other studies both on healthy volunteers and epileptic patients suggesting that VGB and GBP have minimal effect on cognitive and psychomotor performance. The finding in our study is in accordance with findings obtained in other studies like Salinsky. (2005) [17] evaluated the cognitive effects of topiramate and GBP concluded that topiramate impaired cognitive test performance, whereas GBP had minimal effects. A study [18] on 34 healthy senior volunteers comparing the cognitive effects of carbamazepine and GBP concluded that overall tolerability and side-effect profile of carbamazepine were poorer than those of GBP. Martin (1999) [19] compared GBP, lamotrigine and topiramate and demonstrated cognitive adverse effects for topiramate, whereas minimal effects were displayed for either GBP or lamotrigine in young healthy adults. Similar findings were reported by Meador . (1999) [20] and Leach . (1997). [21] The finding in our study in VGB group is in accordance with findings obtained in other studies by Thomas and Trimble (1996), [22] Dodrill . (1995), [23] Gillham et al. (1993) [24] and McGuire . (1992). [25] In all these studies, VGB was compared with PLB. In spite of the extensive literature search, we couldn't find any study comparing VGB with GBP and sodium valproate for their effect on psychomotor performance. However in one study VGB was associated with a significant reduction in measure of motor performance and learning test. [26]

In subjective scales using VAS for sedation, alertness and concentration, in sodium valproate group volunteers rated increased sedation, reduced alertness and concentration at the end of third hour. While no statistically significant changes were observed in GBP and VGB group in VAS rating alertness and concentration. Sedation was observed in all three groups at the end of third hour (also at second hour in sodium valproate group), but this was statistically not significant in GBP and VGB group. The probable reason for this may be related to the plasma concentration of the drug, which peaks at the end of 2-3 h for the drugs. [27] The above finding is in accordance with studies reported in healthy human volunteers and newly diagnosed epileptic patients [21] as in initial period, sedative effect with these antiepileptic drug is reported in the literature.

In this study, we studied the drugs acting through gamma-aminobutyric acid (GABAergic) mechanism i.e., GBP that increases GABA release and VGB that inhibits GABA transaminase, both leads to increase in the synaptic concentration of GABA. VAL is among the older antiepileptic drug, which has multiple mechanism of action including an increase in the synaptic concentration of GABA. [27] The present study observed that drugs acting through purely GABAergic mechanism such as GBP and VGB did not have any detrimental effect on the cognitive and psychomotor performance in contrast to VAL, which may help to reduce the impact on everyday life in school or at the workplace.

While it would be more informative and useful to study the effect of higher doses in patients of epilepsy on long term basis, in the present study, effect of a single dose of antiepileptic drug was tested in healthy volunteers as higher doses for longer duration require appropriate set up for monitoring and other facilities. In the present study, the molecular and receptor mechanism by which the drug affects psychomotor performance could not be commented upon.


   Conclusion Top


To conclude, VGB and GBP have fewer adverse cognitive and psychomotor effects as revealed in this study and therefore are safe as add on therapy or monotherapy. The finding from this study has clinical implications and may help to reduce the impact on everyday life in school or at the workplace and will also assist physician and their patients on making a treatment decision. The clinicians' goal for the individual patient is to balance a variety of factors in order to obtain seizure control, minimize the adverse effects and maintain the quality-of-life of patients. However, further studies measuring serum concentration of the drug using dose variation and studying the molecular mechanism of cognitive and psychomotor impairment of the drug are required.

 
   References Top

1.Motamedi G, Meador K. Epilepsy and cognition. Epilepsy Behav 2003;4 Suppl 2:25-38.  Back to cited text no. 1
    
2.Aldenkamp AP. Antiepileptic drug treatment and epileptic seizures-Effects on cognitive functions. In: Trimble M, Schmitz B, editors. The Neuropsychiatry of Epilepsy. New York: Cambridge University Press; 2002. p. 256-67.  Back to cited text no. 2
    
3.Aldenkamp AP, De Krom M, Reijs R. Newer antiepileptic drugs and cognitive issues. Epilepsia 2003;44 Suppl 4:21-9.  Back to cited text no. 3
    
4.Smith WL, Lowrey JB. Effects of diphenylhydantoin on mental abilities in the elderly. J Am Geriatr Soc 1975;23:207-11.  Back to cited text no. 4
    
5.Devinsky O. Cognitive and behavioral effects of antiepileptic drugs. Epilepsia 1995;36 Suppl 2:S46-65.  Back to cited text no. 5
    
6.Stone BM. Pencil and paper tests - Sensitivity to psychotropic drugs. Br J Clin Pharmacol 1984;18 Suppl 1:15S-20.  Back to cited text no. 6
    
7.Workshop on clinical pharmacology. Manual on Clinical Pharmacology. Chandigarh: Postgrad Inst Med Ed Res (PGIMER); 2000.  Back to cited text no. 7
    
8.Turner P. Critical flicker frequency and centrally-acting drugs. Br J Ophthalmol 1968;52:245-50.  Back to cited text no. 8
    
9.Parkin C, Kerr JS, Hindmarch I. The effects of practice on choice reaction time and critical flicker fusion threshold. Hum Psychopharmacol 1997;12:65-70.  Back to cited text no. 9
    
10.Seth GS. Manual pharmatech. Techniques in Pharmacology. Mumbai: Med Coll and KEM Hosp; 1996.  Back to cited text no. 10
    
11.Aitken RC. Measurement of feelings using visual analogue scales. Proc R Soc Med 1969;62:989-93.  Back to cited text no. 11
    
12.Nicholson AN. Visual analogue scales and drug effects in man. Br J Clin Pharmacol 1978;6:3-4.  Back to cited text no. 12
    
13.Maxwell C. Sensitivity and accuracy of the visual analogue scale: A psycho-physical classroom experiment. Br J Clin Pharmacol 1978;6:15-24.  Back to cited text no. 13
    
14.Trimble MR. Anticonvulsant drugs and cognitive function: A review of the literature. Epilepsia 1987;28 Suppl 3:S37-45.  Back to cited text no. 14
    
15.Desai JD. Epilepsy and cognition. J Pediatr Neurosci 2008;3:16-29.  Back to cited text no. 15
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16.Morris GL. Gabapentin. Epilepsia 1999;40 Suppl 5:S63-70.  Back to cited text no. 16
    
17.Salinsky MC, Storzbach D, Spencer DC, Oken BS, Landry T, Dodrill CB. Effects of topiramate and gabapentin on cognitive abilities in healthy volunteers. Neurology 2005;64:792-8.  Back to cited text no. 17
    
18.Martin R, Meador K, Turrentine L, Faught E, Sinclair K, Kuzniecky R, et al. Comparative cognitive effects of carbamazepine and gabapentin in healthy senior adults. Epilepsia 2001;42:764-71.  Back to cited text no. 18
    
19.Martin R, Kuzniecky R, Ho S, Hetherington H, Pan J, Sinclair K, et al. Cognitive effects of topiramate, gabapentin, and lamotrigine in healthy young adults. Neurology 1999;52:321-7.  Back to cited text no. 19
    
20.Meador KJ, Loring DW, Ray PG, Murro AM, King DW, Nichols ME, et al. Differential cognitive effects of carbamazepine and gabapentin. Epilepsia 1999;40:1279-85.  Back to cited text no. 20
    
21.Leach JP, Girvan J, Paul A, Brodie MJ. Gabapentin and cognition: A double blind, dose ranging, placebo controlled study in refractory epilepsy. J Neurol Neurosurg Psychiatry 1997;62:372-6.  Back to cited text no. 21
    
22.Thomas L, Trimble M. The effects of vigabatrin on attention, concentration and mood: An investigation in healthy volunteers. Seizure 1996;5:205-8.  Back to cited text no. 22
    
23.Dodrill CB, Arnett JL, Sommerville KW, Sussman NM. Effects of differing dosages of vigabatrin (Sabril) on cognitive abilities and quality of life in epilepsy. Epilepsia 1995;36:164-73.  Back to cited text no. 23
    
24.Gillham RA, Blacklaw J, McKee PJ, Brodie MJ. Effect of vigabatrin on sedation and cognitive function in patients with refractory epilepsy. J Neurol Neurosurg Psychiatry 1993;56:1271-5.  Back to cited text no. 24
    
25.McGuire AM, Duncan JS, Trimble MR. Effects of vigabatrin on cognitive function and mood when used as add-on therapy in patients with intractable epilepsy. Epilepsia 1992;33:128-34.  Back to cited text no. 25
    
26.Grünewald RA, Thompson PJ, Corcoran R, Corden Z, Jackson GD, Duncan JS. Effects of vigabatrin on partial seizures and cognitive function. J Neurol Neurosurg Psychiatry 1994;57:1057-63.  Back to cited text no. 26
    
27.Porter RJ, Meldrum BS. Antiseizure drugs. In: Katzung BG, editor. Basic and Clinical Pharmacology. 11 th ed. McGraw Hill. New Delhi; 2009. p. 399-422.  Back to cited text no. 27
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

  [Table 1], [Table 2]


This article has been cited by
1 Psychomotor safety differs between antiepileptics
Reactions Weekly. 2013; 1477(1): 4
[Pubmed] | [DOI]



 

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