Comparison of the efficacy of carbamazepine, gabapentin and lamotrigine for neuropathic pain in rats.

BACKGROUND: Neuropathic pain in cancer patients remain a treatment challenge. Many of the anticancer drugs have to be abandoned because patients develop neuropathic pain. Several antiepileptic drugs like carbamazepine, phenytoin, lamotrigine, felbamate are effective in neuropathic pain and trigeminal neuralgia. However, their efficacy varies. AIM: The aim of this study is to compare the efficacy of antiepileptic drugs in neuropathic pain induced by anticancer drugs.
MATERIALS AND METHODS: Neuropathic pain was induced in rats by injecting 4 doses of paclitaxel. The rats were divided into four groups of six animals each. Group I was treated with oral carbamazepine (cbz) 100 mg/kg, group II received oral gabapentin (gbp) 60 mg/kg, and group III was treated with oral lamotrigine (lam) 40 mg/kg and group IV was the control group. Behavioural testing for thermal hyperalgesia and mechanical hyperalgesia was assessed from 26(th) day of paclitaxel administration to next five days by hot plate method and Randall Siletto test, respectively, in all the four groups. One way analysis of variance followed by Scheffe's post hoc test was used for statistical analysis.
RESULTS: In thermal hyperalgesia lam treated group was found to be significantly (P < 0.001) superior to cbz and gbp treated group. In mechanical hyperalgesia, lam group showed significant response (P < 0.05) as compared to gbp group. However, the gbp treated group showed a significant (P < 0.01) improvement after three days of treatment.
CONCLUSIONS: In paclitaxel induced neuropathic pain, lamotrigine appears to be a promising drug. The difference in responses shown by different antiepileptics' depends on the etiology of the underlying mechanisms in neuropathic pain.

Introduction

Neuropathic pain results from injury to the central or peripheral nerves and is difficult to treat. Allodynia (innocuous stimulation evokes intense and prolonged pain) and hyperalgesia (noxious stimulation evokes intense and prolonged pain) are prominent symptoms of neuropathic pain.[1] About 20% of cancer patients develop neuropathic pain and are at risk for terminating an otherwise successful treatment.[2] It restricts therapy to doses that are suboptimal for killing tumor cells and have a significant impact on the patient's quality of life.[3]

Drugs from different groups are used to treat neuropathic pain. With the development of animal models and improved understanding of pathophysiology of neuropathic pain, the efficacy of different groups of drugs is being assessed. Tricyclic antidepressants (TCAs), often the first choice have significant side effects[4] and antiepileptics are partially effective.[5] So it is difficult to select a right drug in different types of neuropathic pain. With this background, a study has been undertaken to compare the efficacy of antiepileptics carbamazepine (cbz), gabapentin (gbp) and lamotrigine (lam) in neuropathic pain induced by anticancer drug (paclitaxel) in rats.

Materials and Methods

Animals

Adult male Wistar rats weighing between 150-200 g were used. Animals were acclimatized to the laboratory environment for 5-7 days before initiating in the study. They were allowed free access to water and were maintained on standard rat diet under laboratory conditions. 12-hour light/dark cycle was maintained. All procedures were carried with approval of Institutional Animal Ethics Committee (IAEC).

Drugs

Carbamazepine (100 mg/kg),[6] gabapentin (60 mg/kg),[7] lamotrigine (40 mg/kg)[8] were used in the doses as per the previous study. Carbamazepine and lamotrigine were dissolved in 2% gum acacia and gabapentin in distilled water. All the drugs were administered by oral gavage.

Experimental Protocol

Paclitaxel induced neuropathy pain model was used. Paclitaxel was dissolved in saline in the concetration of 2 mg/ml and injected intraperitoneally (2 mg/kg) on four alternate days (day 0-day 6).[9] The pain was first detected on day 15 and reached the peak severity on day 26.[9] Behavioural testing started on day 26 of paclitaxel administration. Animals were divided into four groups of six in each group. After taking baseline values, the drugs were administered once a day orally. The first group was treated with cbz (100 mg/kg), the second group with gbp (60 mg/kg), third group was administered lam (40 mg/kg) and the fourth group received distilled water as the control group. Hot plate latency and antihyperalgesic effects of the drugs were assessed 24 hours after administration of drug.

Thermal Hyperalgesia

Thermal hyperalgesia was assessed by hot plate method suitable for evaluation of analgesics having central action. The animal was placed on a hot plate maintained at a temperature of 55-56°C. Latency to either licking of hindpaw or vertical jumping was determined. The observer was blind to the drug treatment. The response was tested three times and the mean calculated.

Mechanical Hyperalgesia

Mechanical hyperalgesia, suitable for evaluation of central and peripheral analgesics, was assessed by Randall Selitto test as described by Randall and Selitto.[10] Analgesymeter (Ugo-Basile pressure apparatus) was used to assess the pressure pain threshold. The observer was blind to group treatment. The rat's hind paw was placed into the pressure applicator and steadily increasing pressure was applied to dorsal surface of paw until the rat withdrew. The force (in grams) needed to produce paw withdrawal is regarded as pain threshold.

Statistical Analysis

Statistical analysis among different groups was done using univariate method by one way analysis of variance followed by Scheffe's post hoc test. P < 0.05 was considered statistically significant.

Results

Effect of Drugs on Thermal Hyperalgesia

Lam (P < 0.001) and cbz significantly (P < 0.05) increased the hot plate latency as compared to the control group. However, gbp did not show any difference on hot plate latency as compared to control. In intergroup comparison lam significantly (P < 0.001) increased hotplate latency as compared to cbz and gbp. Figure 1 shows the withdrawal latencies in lam, cbz, gbp and control group in hot plate method.

Figure 1

The withdrawal latency in rats treated with lamotrigine, carbamazepine and gabapentinin hot plate method. Where, values are in mean ± Standard error (SE) (n = 6); lam = lamotrigine, gbp = gabapentin, cbz = carbamazepine. Average = mean of day 1-5

Effect of Drugs on Mechanical Hyperalgesia

Lam, cbz and gbp showed a significant (P < 0.01, P < 0.01, P < 0.05 respectively) analgesic effect as compared to control. On comparing the three groups using ANalysis Of Variance (ANOVA), a statistically significant (P < 0.05) difference was obtained. Post hoc tests revealed that anti hyperalgesic effect of lam was significant (P < 0.05) as compared to gbp. However, the anti hyperalgesic effect of lam was not different from cbz. Analysis of the analgesic effect of drug on different days showed that in gbp group, there was a significant (P < 0.01) attenuation in hyperalgesia over a span of 5 days [Figure 2].

Figure 2

Pain threshold in animals treated with lamotrigine, carbamazepine and gabapentin. Values are in mean ± Standard error (SE) (n = 6); lam = lamotrigine, gbp = gabapentin, cbz = carbamazepine

Discussion

Neuropathic pain related to chemotherapeutic agents is often resistant to standard analgesics. Anticonvulsants have been utilized as adjuvant analgesics from 1960.[11] They act by potentiation of gamma- aminobutyric acid ( GABA) transmission, reduction of glutamate mediated excitatory transmission, and blockade of voltage-activated ion channels. This study compared the efficacy of carbamazapine, lamotrigine and gabapentin in neuropathic pain induced by paclitaxel. Studies show that treatment with paclitaxel 2 mg/kg produces long lasting heat hyperalgesia, mechanical allodynia and cold allodynia in mice.[12] The present study demonstrated that lam significantly increased withdrawal latency in hot plate method as compared to gbp and cbz. Lam is a novel antiepileptic and its antihyperalgesic effect is postulated mainly due to inhibition of glutamate release rather than sodium channel blockade.[13] Gbp has no effect on normal afferent fibre activity but inhibits the ectopic discharge activity associated with peripheral nerve injury[14] and for this reason its effect was not significantly different from control group on thermal hyperalgesia. Lam, cbz and gbp produced a significant analgesia as compared to control in paclitaxel induced peripheral neuropathic pain. In an earlier study, it has been shown that cbz, lam and gbp showed anti allodynia in vincristine induced peripheral neuropathy.[15]

Comparing the three drugs in Randall Selitto test, lam produced statistically significant analgesia as compared to gbp, but there was no difference between the analgesic action of lam and cbz. Some of the earlier studies demonstrated that gbp significantly reversed mechanoallodynia with 70 mg/kg dose[15] while others found no action against mechanoallodynia with 50-300 mg/kg doses.[16] Gbp has been found to be effective in diabetic models after single dose administration.[16] Majority of clinical evidence supports analgesic efficacy of gbp in diabetic neuropathy and postherpetic neuralgia, but limited evidence supports its efficacy in other types of neuropathies.[17] Gbp increased the threshold of mechanical hyperalgesia over five days and the effect reached peak by 4th dose [Figure 2]. Similar results have been put forth in other study in which paclitaxel treated rats showed significant decrease in allodynia only after third injection of gbp.[9] Similarly, delay in onset of gabapentin analgesia was reported in traumatic nerve injury model.[18]

The small sample size and short duration of follow up are limitations of this study. Also Randall Selitto test is not a very sensitive test and can have observer bias which has been partly overcome by blinding the observer. To conclude, lam is an effective analgesic in anticancer drugs’ induced neuropathic pain. Though gbp is very effective in diabetic neuropathic pain, it is lamotrigine which is superior to gbp in cancer chemotherapy induced neuropathic pain. This may be probably due to difference in the analgesic action of different antiepileptics. Also, the underlying mechanisms of neuropathic pain of different etiologies need to be understood.