Effect
of topiramate and gabapentin on neuropathic pain induced in rats by sciatic
nerve ligation

(Final
report)

Submitted by:

    Abdullatif
Obaidallah alharbi

ID:321102889

 

Supervision  by

Dr. Hossam El
sisi and Dr. Ibrahim Awwad

College of Pharmacy

Qassim University

DEC 2017

CERTIFICATE

This is to certify that this graduation
project report entitled “Effect
of topiramate and gabapentin on neuropathic pain
induced in rats by sciatic nerve ligation” is submitted to the College of Pharmacy, Qassim University in partial
fulfilment of the requirements for the degree of Doctor of Pharmacy (Pharm.D)
by Abdullatif Obaidallah alharbi under the supervision of Dr.Hossam Elsisi &
Dr.Ibrahim Awwad. I hereby confirm that the work submitted in this project is
my own. I have not violated the college’s policy on plagiarism.

 

Dr.Hossam
Elsisi

Signature:

 

Dr.Ibrahim Awwad

Signature:

 

Abdullatif Alharbi

Signature:

 

Table
of contents

                                                                                                Page
Number

Acknowledgment                                                               
   4List of Figures and Tables                                                 
   4List of Abbreviations                                                         
   4Abstract                                                                                            5Keywords                                                                              
5Introduction and Review of literature                                  6Aims of the Study                                                                            6        Materials and Method                                                           7        Results                                                                                   10      

10.                       
Discussion                                                                             
13

11.                       
 conclusion                                                               
             13

12.                       
 References                                                                                               13          

 

 

 

 

 

 

Acknowledgment:

I would like to thank my supervisors
Dr.Hossam Elsisi and Dr.Ibrahim Awwad for their tremendous help, support and
time that they had spent with me in the lab and outside lab from the first day
of graduation project. Also, I would like to thank Dr.Sultan Sajid for his help
in lab. Last but not least, I would like to thank my friend Waleed Alharbi for
his help and support.

 

Figures and Tables

                                                                                          Page Number

Figure  1                                                                        
         8         

Figure 
2                                                                                 10

Table 1                                                                                     
 11

Table 2                                                                                      
11

Table 3                                                                                      
12

Figure 3                                                            
                     12

 

 

Abbreviations :

 (GBP) Gabapentin ,(TPM)
Topiramate , (TPM) Thiopental,(CBZ) carbamazepine.

 

 

Abstract:

Objectives:

To study the effect of
topiramate and gabapentin on neuropathic pain induced in rats by sciatic nerve
ligation.

To compare the effect of topiramate and gabapentin on neuropathic pain
induced in rats by sciatic nerve ligation

Hypothesis:

The hypothesis of this study is that topiramate and gabapentin is effective to treatment
neuropathic pain.

Methodology:

§    
Study design: Experimental study

§    
Sampling: rats

§    
Equipments  : Analgesia
Meter

§    
Drugs: Gabapentin ,Topiramate ,Thiopental.

Results :

There is significance effect (p<0.05) of Gabapentin and Topiramate regarding analgesic effect on the rat . Conclusions : Both Gabapentin and topiramate showed significant results regarding analgesic effect , but Gabapentin superior to topiramate in their analgesic effect .   Keywords: neuropathic pain, Antiepileptic drugs, Gabapentin, Topiramate.   Introduction and review of literature: Neuropathic pain have a tendency to be chronic and may be present for months or years. the International Association for the Study of  Pain (IASP) defined neuropathic pain as "pain initiated or caused by a primary lesion or dysfunction in the nervous system"(1). Neuropathic pain is may be caused by damage or injury of the nerve , and is often followed by changes in either the peripheral or the central nervous system (CNS)(2). Ibuprofen or paracetamol maybe ineffective in treatment of neuropathic pain,while drugs that are primarily used to treatment depression or status epilepsy may be can be effective in some people with neuropathic pain. Antiepileptic medications that currently used to treat neuropathic pain include   topiramate, phenytoin,gabapentin ,CBZ, lamotrigine,clonazepam, levetiracetam, lacosamide, pregabalin, and valproate. (3)   Different antiepileptic drugs will have different mechanisms of action, not all of which are likely to be well understood, especially in terms of how a particular drug produces pain relief in any particular individual with any particular chronic pain condition(4) Antiepileptics in general are thought to reduce the ability of the neuron to ?re at high frequency(7).Topiramate has been shown to blocks voltage-gated Na  channels, may act at glutamate (NMDA) sites,Increase frequency of Cl- channel opening by binding to GABA receptor and Reduces high-voltage Ca currents (âL type CC) (5) . On the other hand gabapentin acts by binding to calcium channels and by modulating calcium in?ux(6).   Aims of the Study:                              Aims of the research is to study and to compare the effects of topiramate and gabapentin on neuropathic pain induced in rats by sciatic nerve ligation.   Materials and Methods: Materials             I.      Animals:   Albino-rats weighing 200-350gm were used in this study. They were They were kept in cages with free access to water and food.            II.      Drugs: ·        Gabapentin (GBP) 60mg/kg (10). ·        Topiramate (TPM) 40mg/kg (11). ·        Thiopental (TPM) 40mg/kg .           All the above drugs were dissolved in distilled water just before intraperitoneal injection.   METHODS: Induction of chronic neuropathic pain in rats:           In this method neuropathic pain is induced in experimental animals by unilateral ligation of the sciatic nerve in the thigh under general anesthesia with 40 mg/kg thiopental (8). The right sciatic nerve is exposed and isolated at the mid thigh and one third to one half of the nerve is ligated tightly with 5-0 silk suture. Within few hours after the operation and for several months thereafter, the rats develop a guarding behavior of the ipsilateral hind paw and lick it. The cause of this behavior is development of hyperalgesia. The plantar surface of the foot became highly sensitive to non-noxious and noxious stimuli and a sharp decrease in the reaction time measured by analgesia meter in response to thermal stimulation is noticed (9).      Sham operated rat model: Animals of this group were subjected to all procedures of sciatic nerve ligation. The nerve was dissected and isolated at the midthigh then left without ligation to evaluate the effect of surgical intervention on the reaction time.   Measurement of the reaction time         The reaction time which indicate the tolerability of the animals to thermal pain, is measured using Analgesia Meter 11TC Model 390 Paw Stimulator "figure 1" {Woodland hills, C.A., U.S.A}  Figure (1): Analgesia Meter.           This instrument allows the user to apply heat stimulation (infra red) to the experimental animals (with intensity and brightness of 50%) without any physical contact between the test subject and the heat source. Experiment model:       After 10 days of Induction of chronic neuropathic pain the animals were divided into three groups. The number of animals in each group were 4 (n=4). For the first group ; treated with normal saline as a control group and we noted the reaction time of animals on the hot plate at 30,60,90 minutes after drug administration. For the second group ; treated with Gabapentin (GBP) 60 mg/kg. and we noted the reaction time of animals on the hot plate at 30,60,90 minutes after drug administration. For the third group ; treated with Topiramate (TPM). 40mg/kg and we noted the reaction time of animals on the hot plate at 30,60,90 minutes after drug administration.   Statistical analysis:       Data are reported as means ± SEM and were analyzed statistically by ANOVA (one-way analysis of variance). where (p<0.05) considered as significant results.   Results Induction of chronic neuropathic pain test      We initially started by Induction of chronic neuropathic pain in rats ,so to ensure that we measured the postoperative reaction time. the results of postoperative reaction time was decrease As explained in Figure 2 .                    Figure 2 Hot- plate analgesia test      In the hot- plate analgesia test showed the average latency of the control group was between 11.17 and 11.4  sec ( Table 1 ). And The animals treated with Gabapentin (60 mg/kg) increased the latency reaction on 30,60  and 90 min (p<0.05) as compared with the control group ( Table 2 ). Also The animals treated with topiramate (40 mg/kg) increased the latency reaction on 30,60  and 90 min (p<0.05) as compared with the control group (Table 3)   S. No. Drug Body wt.(g) Dose, in  ml by I.P Reaction time  in seconds 30 60 90 1   Control Normal saline 246g 0.24 11.9 11.1 11.3 2 286g 0.28 11.2 11.3 11.6 3 252g 0.25 10.9 11.9 11.2 4 232g 0.23 11.3 11.4 11.1 Mean score 11.17 11.4 11.32 Table 1   S. No. Drug Body wt.(g) Dose, in  ml by I.P Reaction time  in seconds 30 60 90 1   Gabapentin (GBP) 290g      60 (mg/kg) 12.3 13.6 16.6 2 250g 12.5 13.5 16.0 3 262g 12.3 13.8 16.2 4 241g 12.2 13.3 16.1 Mean score 12.32 13.54 16.22 Table 2       S. No. Drug Body wt.(g) Dose, in  ml by I.P Reaction time  in seconds 30 60 90 1   Topiramate (TPM) 281g      40 (mg/kg) 12.1 12.9 14.2 2 255g 11.9 13 14.1 3 248g 11.8 12.8 13.9 4 221g 12 13.1 14.3 Mean score 11.95 12.95 14.125 Table 3     Figure 3   In figure (3) figure shown analgesic effect among three intervention groups. Gabapentin and topiramate showed significant results (P<0.05 ) #P<0.05 as compared to control group.   Discussion      Gabapentin showed analgesic effect because it increases the latency of reaction at 30,60,90 min in the anelgesic test. So this experiments confirmed the analgesic effect of gabapentin using the analgesic test following sciatic nerve ligation. support  the beneficial gabapentin role for neuropathic pain. Camara  et al (2013) using the same model. (12)                  Topiramate is anticonvulsant that maybe used for treating neuropathic pain, but there is lack of evidence that support the use of topiramate to treating neuropathic pain. In present study we find that topiramate showed analgesic effect because it increases the latency of reaction at 30,60,90 min in the analgesic test , but the analgesic effect of topiramate less than analgesic effect of gabapentin (13)   Conclusions      Both drugs Gabapentin and topiramate showed significant results regarding analgesic effect , but Gabapentin superior to topiramate in their analgesic effect .