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Anesth Analg 2003;96:1700-1706 © 2003 International Anesthesia Research Society
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Abstract |
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We studied the ability of zonisamide (ZonegranTM) to relieve thermal hyperalgesia and/or mechanical allodynia in the chronic constriction injury model of neuropathic pain. Zonisamide (25, 50, or 100 mg/kg) or saline was administered in a blinded, randomized manner by intraperitoneal injection on postoperative days (PODs) 4, 5, and 6. Paw withdrawal latency (PWL) to heat, paw withdrawal response to von Frey monofilaments, and pain scores based on weight-bearing were tested: before surgery; before and after zonisamide or saline (PODs 4, 5, and 6); and on POD 9. Systemic zonisamide relieved thermal hyperalgesia in a dose-dependent manner. All PWLs were significantly increased after zonisamide administration compared with pre-zonisamide measurements, except with the 100 mg/kg dose on POD 5. After zonisamide 100 mg/kg administration, there was a sustained increase in PWL on PODs 5 and 9, with significant carryover effect from the previous dose. However, zonisamide had little effect on mechanical allodynia, except at the 100 mg/kg dose, which was sedating in the rat. At the 100 mg/kg dose, paw withdrawal response was increased on PODs 4 and 5, whereas pain scores were reduced on PODs 4, 5, and 6. Pain scores were inconsistently reduced after 50 mg/kg or 25 mg/kg doses.
IMPLICATIONS: Zonisamide causes a dose-related decrease in heat sensitivity in a rat model of neuropathic pain, but relieves mechanical sensitivity only in a dose that is sedating to the rat. Zonisamide may be useful in the treatment of some types of neuropathic pain.
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Introduction |
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Neuropathic pain can result from a variety of heterogeneous conditions, with multiple etiologies and anatomic lesions (1). Patients with neuropathic pain frequently demonstrate thermal and mechanical hyperalgesia and allodynia (2). Different pain mechanisms may account for these symptoms, and these different mechanisms may occur alone or together in the individual patient (2,3). These mechanisms may account for the variability in response to treatment seen among patients with neuropathic pain. Factors involving hyperexcitability of the peripheral and central nervous systems have been proposed to explain neuropathic pain (3). Consequently, drugs that reduce hyperexcitability have been investigated for their effectiveness in treating neuropathic pain.
Anticonvulsant drugs are often used in the treatment of chronic pain in humans. They apparently exert their effect by suppressing or limiting the spread of aberrant neuronal discharges (4). The anticonvulsant most often used in the United States for chronic pain is gabapentin (5). Gabapentin’s mechanism of action in neuropathic pain is unknown, but it seems to be effective in both diabetic neuropathy and postherpetic neuralgia (PHN) and was recently approved by the United States Food and Drug Administration for these indications (4,6). Gabapentin is thought to modulate 
-aminobutyric acid activity by binding to voltage-gated calcium channels in the brain (7,8). These channels may have an important role in controlling the excitability of neurons. The major side effect of gabapentin is sedation.
Carbamazepine is the most studied of the anticonvulsants and, until recently, it has been the only one approved by the Food and Drug Administration for treatment of any type of neuropathic pain. It is effective in the treatment of diabetic neuropathy and trigeminal neuralgia and has been shown to decrease spontaneous activity in experimental neuromas (4,6,9–11). Carbamazepine’s mechanism of action seems to be through sodium channel blockade, modulating voltage-dependent sodium channels, stabilizing membranes, and reducing neuronal excitability. It has infrequent, but life-threatening, potential complications and has lost favor despite its efficacy (5,12). The sodium channel blocker, mexiletine, has also been used for the treatment of neuropathic pain, and is particularly effective in diabetic and other peripheral neuropathies (13,14).
Zonisamide (ZonegranTM) is a novel anticonvulsant currently available for clinical use in the treatment of seizure disorders. Zonisamide blocks sodium channels and T-type calcium channels. It binds to but does not modulate -aminobutyric acid receptors. It is also a carbonic anhydrase inhibitor, but this action does not seem to be related to its anticonvulsant action. Thus, the activity profile for zonisamide seems to be favorable for the treatment of neuropathic pain (15). A preliminary study in a rat diabetic neuropathy model showed dose-related efficacy in relieving mechanical allodynia (data on file, Elan Pharmaceuticals). The objective of this study was to determine whether parenteral zonisamide relieves mechanical allodynia and/or thermal hyperalgesia in rats with neuropathic pain caused by chronic constriction injury (CCI) of the sciatic nerve.
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Materials and Methods |
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The study was approved by the Institutional Animal Care and Use Committee of Emory University. Male Sprague-Dawley (Harlan, Indianapolis, IN) rats weighing 250–350 g were used. Animals were housed in clear plastic cages with solid floors and soft, loose, absorbent bedding. Animals were housed in groups of two to three and allowed free access to food and water. Animals underwent surgery to produce a CCI of the left sciatic nerve and a sham condition of the right sciatic nerve, and each was anesthetized with an intraperitoneal (IP) dose of 40 mg/kg pentobarbital. Subsequent doses of pentobarbital (2–4 mg/kg) were administered as necessary to maintain adequate anesthetic depth. Aseptic technique was used. The surgical technique is described by Bennett and Xie (16). Zonisamide (sodium salt), supplied by Elan Pharmaceuticals, was dissolved in normal saline and administered IP to rats at doses of 25, 50, and 100 mg/kg. Control rats received saline IP. Rats were administered single injections of saline or zonisamide on postoperative days (PODs) 4, 5, and 6. The injection volume for each treatment was 1 mL/kg. The effects of zonisamide on thermal hyperalgesia and mechanical allodynia were evaluated in 48 animals. During the week before surgery, each animal was acclimated to the environment in the cage and to the paw withdrawal testing procedures during three separate sessions on different days. After completion of these three, preoperative paw withdrawal latency (PWL), paw withdrawal response (PWR), and pain score testing sessions, each rat underwent surgery to produce the CCI of the left sciatic nerve and the sham condition of the right sciatic nerve.
Thermal hyperalgesia and mechanical allodynia were evaluated postoperatively by performance of PWL, PWR, and pain score testing. Each rat underwent this testing on POD 4, after which it was randomly assigned to 1 of 4 experimental groups: zonisamide 25, 50, 100 mg/kg, or saline. Each experimental group contained 12 rats. Each rat received an IP injection of the appropriate randomly assigned treatment at each postoperative testing session. Thirty minutes after being treated, the rat was again tested for PWL, PWR, and pain score. The testing and treatment were repeated on each of the next two PODs, 5 and 6. On POD 9, which was 3 days after the last treatment, each rat was tested for PWL, PWR, and pain score for the final time. The observer performing the testing was blinded to the treatment that the animal received.
The sedative effects of zonisamide were evaluated using another 48 animals, studied in the activity cage. After the initial monitoring in the activity cage, 12 rats were randomly assigned to 1 of 4 groups: zonisamide 25, 50, 100 mg/kg, or saline. Activity was tested for 30 min after the treatment dose to determine whether zonisamide had a sedating effect on the rat that might have potentially confounded the behavioral testing.
Thermal hyperalgesia was evaluated by measuring PWL using a radiant heat source. PWL testing was performed using a device (Ugo Basile, Italy) that was similar to that described by Hargreaves et al. (17) PWL was measured as the time from the initial exposure to the heat source until paw withdrawal. A cut-off time of 22.5 s prevented tissue damage. At each measurement session, the PWL test was performed five times on each hindpaw, and the average of these five tests was used as the PWL measurement for each paw for that measurement time. A minimum of 2 min elapsed between testing the same paw on each animal.
Mechanical allodynia (punctate) was evaluated by measuring PWR using application of progressive force with von Frey monofilaments (18). Responses to mechanical stimulation were determined using calibrated von Frey monofilaments applied from underneath the cage through openings in the steel mesh floor. Each filament was applied once to an area approximately 1 cm from the heel, starting with a force of 4.08 g and continuing until a withdrawal response occurred or the force of 6.65 g was reached. At each measurement session, the PWR test was performed three times on each hind limb. The lowest force (bending force) from the three tests producing a response was considered the withdrawal threshold for each paw. A cumulative pain score was used to assess pain behavior, as described by Brennan et al. (18). Each animal was placed on the steel mesh table (1-cm grid) for 15 min. The paw was viewed from below by use of a mirror. Weight-bearing was assessed on a scale from 0 to 2. A score of 0 was given if the paw was blanched or distorted by the mesh. A score of 1 was given if the paw rested on the mesh without blanching or distortion. A score of 2 was given if the foot was held completely off the floor. The cumulative pain score was the sum of 12 scores for each animal at each measurement session. Sedative effects were evaluated by measuring total and ambulatory movements. Before monitoring, each animal was placed in a Plexiglas cage with air holes, food, and water. The rat could move freely in the cage and was left for 5 min to acclimate to the environment. The animal was then monitored for 25 min in the activity cage. An array of 12 photoelectric cells was used to measure both ambulatory movement and total movement. Ambulatory movement was determined by the breaking of two adjacent photoelectric beams in succession, and total movement was determined by the breaking of any one photoelectric beam (e.g., scratching or ambulation).
The grand mean of the test results from the 3 preoperative sessions was used as the control value (time 0) for data analysis when comparisons were made between the preoperative and postoperative PWL results. PWL measurements were analyzed using a t-test for repeated measures or a repeated-measures analysis of variance (ANOVA) followed by a Tukey test for multiple comparisons (because n = 12 in each group) as appropriate. Because they were noncontinuous, medians were determined for PWR and pain score test data. von Frey (PWR) and pain score measurements were analyzed using a Wilcoxon’s signed rank test or a nonparametric repeated-measures ANOVA with a Dunnett’s multiple comparison test as appropriate. In all cases, a P value < 0.05 was considered significant.
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Results |
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Effects on Thermal Hyperalgesia: PWL
The presence of thermal hyperalgesia after CCI was demonstrated by a highly significant (P < 0.01) decrease in PWL in all groups postoperatively, before treatment with zonisamide, compared with preoperative control values (Table 1, Fig. 1). Zonisamide produced a dose-dependent improvement in thermal hyperalgesia. All doses of zonisamide caused a significant (P < 0.005) improvement in PWL when comparing pre- and postinjection values, except the 100 mg/kg dose on POD 5. Repeated-measures ANOVA suggested that there was a significant effect of dose (P < 0.01) and number of injections (P < 0.025) on PWL values and that there was a significant (P < 0.05) interaction between dose and number of injections.
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The effects of a dose of 100 mg/kg zonisamide on PWL were long lasting, because the response from treatment on POD 4 was still evident at the pretreatment measurement on POD 5. For the 100 mg/kg dose of zonisamide, the pretreatment value on POD 5 was significantly (P < 0.025) larger than the pretreatment PWL value on POD 4, indicating a significant carryover effect of zonisamide from POD 4 to 5. The large pretreatment PWL value on POD 5 left little room for improvement after treatment with zonisamide. The same carryover effect was seen in the 100 mg/kg group on POD 9, 3 days after the last treatment with zonisamide, in which the PWL value on POD 9 was significantly more than pretreatment PWL on PODs 4, 5, and 6 (P < 0.05). PWL changes on the sham side were not statistically significantly different (P = 0.114) compared with preoperative or postoperative preinjection values. Saline administration had no apparent effect on PWL (P > 0.05). Animals in the saline group did not show any improvement in PWL postinjection.
Effects on Mechanical Allodynia: PWR and Pain Score
Mechanical allodynia caused by CCI was demonstrated by a significant (P < 0.01) decrease in PWR in all groups at all measurement times compared with preoperative control values (Fig. 2). Zonisamide produced improvement in mechanical allodynia only at the largest dose tested. Zonisamide at a dose of 100 mg/kg produced a significant increase in bending force required at POD 4 (P < 0.002) and POD 5 (P < 0.02). Zonisamide at 25 or 50 mg/kg produced no significant changes in von Frey responses between pre- and postinjections. No carryover effect was seen on POD 9 or any other testing day. There was no improvement in von Frey values after saline on any treatment day.
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CCI produced a significant (P < 0.001) increase in pain scores related to weight-bearing behavior in all groups and at all measurement times compared with preoperative control values (Fig. 3). Treatment with zonisamide produced significant improvement in pain scores. On POD 4, zonisamide at all 3 doses produced significant (P < 0.025) improvement in pain scores. On POD 5, only the 100 mg/kg dose of zonisamide produced a significant (P < 0.025) reduction in pain score. On POD 6, zonisamide at both the 25 (P < 0.05) and 100 mg/kg (P < 0.025) doses produced significant reductions in pain scores. The large variability in the pain scores for rats treated with 50 mg/kg probably prevented the posttreatment pain scores from being statistically significant for that dose. No changes in pain scores were noted for the saline group after any of the injections.
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Effect on Ambulatory and Total Activity
Zonisamide produced significant sedative effects at the largest dose tested (Fig. 4). Zonisamide at a dose of 100 mg/kg produced significant (P < 0.01) reductions in both ambulatory and total movements compared with saline.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Zonisamide inhibits neuronal voltage-dependent sodium and T-type calcium channels, both of which have a pivotal role in membrane excitability. Neuronal injury, such as that produced by CCI, results in changes in sodium channel numbers and types, which contribute to the hyperexcitability (19–21). T-type calcium channels may regulate the rate of repetitive neuronal firing, further contributing to the hyperexcitability (22). Blockade of sodium channels suppresses sodium-dependent action potentials, and inhibition of T-type calcium channels attenuates the sharp depolarization of the membrane potential underlying sodium-dependent action potentials (15).
In the current experiment, zonisamide caused a dose-related reduction in the thermal hyperalgesia induced by CCI and had a sustained effect at the 100 mg/kg dose, with effects seen at 3 days after the final drug administration. This result is important because zonisamide is the first drug tested in our laboratory that had such a prolonged effect. The reason for this prolonged carryover effect is not clear, but may be related to the long half-life of the drug in rats. After a single oral dose of 20 mg/kg in rats, the half-life of zonisamide is 8 hours in plasma and 21 hours in red blood cell fraction (data on file, Elan Pharmaceuticals). Because we did not test for sedation at 24 hours or 3 days after administration, we cannot exclude that the prolonged effect from the 100 mg/kg dose was not associated with sedation.
Sodium channel blockers reduce mechanical allodynia (23). Sodium channel blockade suppresses the abnormal discharge originating in nerve injury by increasing membrane stability, leading to decreased spontaneous and evoked neural activity. Because zonisamide has sodium channel blocking properties, it was expected to significantly improve mechanical allodynia. However, zonisamide seems to be less effective in reducing superficial cutaneous mechanical allodynia than in reducing thermal hyperalgesia. It produced a partial reversal of the CCI-induced mechanical allodynia to a punctate stimulus (monofilaments), but this effect was only robust at the 100 mg/kg dose. Zonisamide consistently reduced mechanical allodynia caused by the touch of a smooth object (cage floor) at the 100 mg/kg dose and inconsistently did so at the smaller doses. Unlike the effect of zonisamide on thermal hyperalgesia, the effect on mechanical allodynia was not prolonged. Hyperalgesia to deep tissue pressure has been reported in humans with complex regional pain syndrome and in animal models of neuropathic pain, but was not measured in this study. Moreover, the effect of zonisamide on mechanical allodynia may just have been from sedation. The results of the activity testing showed that zonisamide at 100 mg/kg significantly decreased both ambulatory and total movements, evidence of a sedating effect. This effect was not unexpected, because anticonvulsants typically cause sedation (15).
The pathogenetic mechanisms responsible for thermal hyperalgesia and mechanical allodynia are probably not the same, either in the rat CCI model or in human neuropathic pain (24,25). Differences in the response of hyperalgesia and allodynia to the same therapy have been seen (26). Therefore, the different effects of zonisamide on thermal hyperalgesia and mechanical allodynia seen in the present study are not surprising and are consistent with the presumed different etiologies for these two neurologic phenomena.
Different types of neuropathic pain, such as that associated with diabetic neuropathy, PHN, and rat CCI, can be caused by different pathogenetic mechanisms, and can also exhibit different pathological characteristics (27). For example, comparison of the rat CCI model used in this study to the diabetic rat neuropathy model shows that the CCI model has more large-fiber than small-fiber damage, although small-fiber damage is significant. The diabetic neuropathy model has been characterized in some studies primarily by loss of small A-
and C-fibers (23,28–30). Sodium channel blockers have been effective in patients with diabetic neuropathy, a condition in which mechanical allodynia is uncommon (11,14,28). Thus, the response to zonisamide in the diabetic neuropathy model is clinically consistent with a sodium channel-blocking effect.
By comparison, PHN is associated with mechanical allodynia and greater loss of large fibers compared with small fibers, and mechanical allodynia is a frequent finding. Sodium channel blockers may be more effective with small-fiber than large-fiber damage (2,5,12,31). In this study of a model with predominant large-fiber damage, zonisamide had minimal effect on mechanical allodynia. These findings suggest that diabetic neuropathy patients may respond better to treatment with zonisamide than would PHN patients.
Because different mechanisms are responsible for different pain symptoms and pain syndromes, the mechanisms responsible for pain in the individual patient should be identified (3,6,27), and treatment aimed at altering those mechanisms (3). Different drugs may affect different symptoms (e.g., allodynia versus hyperalgesia; mechanical versus thermal). The clinical situation with neuropathic pain is often complex, with many unknown mechanisms accounting for the patient’s disease. When testing zonisamide in humans with neuropathic pain, consideration should be given to the mechanism of nerve injury as it relates to the properties of zonisamide demonstrated in animal models. In the CCI model, zonisamide was effective in relieving thermal hyperalgesia, and partially effective in reducing mechanical allodynia. The type of pain testing used for evaluation of patients is important because zonisamide may show different results depending on whether testing is done for mechanical- or thermal-induced pain.
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Acknowledgments |
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Supported by an unrestricted educational grant from Elan Pharmaceuticals.
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