Anticonvulsant medications are often utilized in treating neurogenic or deafferent pain following SCI based on the theory that these drugs alter sodium conduction in uncontrolled hyperactive neurons (“convulsive environment”) in the spinal cord. Carbamazepine has been reported as being somewhat effective in the paroxysmal, sharp, shooting pain of trigeminal neuralgia (Swerdlow 1984).  Gibson and White (1971) described relief resulting from carbamazepine treatment in two cases of L2 and T8 SCI with intractable pain below the level of SCI.  A similar effect of Carbamazepine (200 mg 2 x daily in combination with Amitriptyline 50 mg 3 x daily) was reported in a complete C8 patient with dysesthesia below the level of the  injury (Sandford et al. 1992).  Again, controlled studies utilizing these drugs in SCI pain are lacking with the exception of gabapentin and pregabalin.

Gabapentin and pregabalin are now regarded as first-line treatments of neuropathic pain (Ahn et al. 2003; Moulin et al. 2007). Gabapentin and pregabalin have been recommended as first line treatments for neuropathic pain in Canadian and international guidelines (Gajraj 2007). The mechanism of action for Pregabalin and Gabapentin is through binding the alpha-2 delta receptors in the central nervous system. These receptors are present on the presynaptic nerve terminals. When bound by gabapentin or pregabalin they decrease the influx of calcium into the presynaptic terminal there by decreasing the release of excitatory neurotransmitters. Gabapentin and pregabalin appear to potentiate GABA effects centrally through enhancement of GABA synthesis and release.  Levendoglu et al. (2004) note that neuropathic pain is ultimately generated by excessive firing of pain-mediating nerve cells, insufficiently controlled by segmental and nonsequental inhibitory circuits.  Gabapentin and pregabalin work by increasing GABA and reducing the release of glutamate thereby suppressing the sensitivity of N-metyl-D-asparate (NMDA) receptor. This has been shown to reduce neuronal hyperexcitability recorded at the spinal dorsal horn near the level of injury (Ahn et al. 2003).  Gabapentin and pregabalin are relatively well tolerated with only a few transient side effects, lack of organ toxicity, and no evidence of significant interaction with other medications (Levendoghu et al. 2004, Gajraj 2007).

Table: Anticonvulsants for SCI Pain

Discussion

Gabapentin

To et al. (2002)studied the impact of gabapentin on pain in a case series of 44 SCI patients with neuropathic pain and reported a significant decrease (p<0.001) in visual analogue pain scale (VAS) in 76% of subjects. Tai et al. (2002) studied the impact of gabapentin for pain treatment in a small RCT of only 7 patients.  There was a significant reduction of “unpleasant feeling” with gabapentin vs. placebo (p=0.028) while “pain intensity” and “burning pain” only trended to significance (p=0.094 and 0.065, respectively) and no differences were detected for other pain descriptors such as “sharp”, “dull”, “cold”, “sensitive”, “itchy”, “deep”, “surface”.  Levendoglu et al. (2004) in a cross-over design of 20 paraplegics with neuropathic pain > 6 months found that Gabapentin was more effective (p<0.05) than placebo in reducing neuropathic pain.  Ahn et al. (2003) in a before and after trial found that Gabapentin was effective (p<0.05) in decreasing neuropathic pain which was refractory to conventional analgesics for SCI patients with pain < 6 months and > 6 months and that the impact was greater for those patients with pain < 6 months in the most recent pain group. Putzke et al. (2002) found that, among the 21 patients who answered their questionnaire, 67% (n=14) reported a reduction in pain while on gabapentin. 

Rintala et al (2007) was the only study to report Gabapentin to have no benefit over placebo in the treatment of pain in spinal cord injury. This study may have been complicated by the fact  that the placebo treatment was dimenhydramine and not a true inert placebo and the number of subjects was only twenty two.

Pregabalin

Pregabalinis an analogue of the neurotransmitter gamma-aminobutyric acid (GABA) with demonstrated analgesic, anxiolytic, and anticonvulsant activity.  It’s mechanism of action is similar to gabapentin, but it has a higher affinity for the alpha-2-delta receptor and has linear pharmacokenetics. Sidall et al (2006) published the results of a double blind randomized control  trial evaluating the use of flexible dose pregabalin in the treatment of neuropathic pain in spinal cord injury. A total of 137 subjects with central neuropathic pain post spinal cord injury participated. The primary outcome was the VAS pain scale and secondary outcomes included sleep interference and anxiety scales. Seventy patients were randomized to receive pregabalin and 67 patients received placebo. At the end of the trial the pregabalin treated patients had significantly more pain relief. The pregabalin treated subjects also reported significantly improved sleep and anxiety. Side effects were mild and transient and included dizziness, drowsiness and edema (similar to gabapentin).

In a RCT conducted by Vranken et al. (2007) patients in the treatment group received escalating doses of pregabalin (150-600 mg daily), while those in the control group received a placebo. Subjects in the treatment group reported a significant decrease in pain (p<0.01), along with improvements in the EQ-5D VAS and utility scores (p<0.01), as well as the Bodily Pain subscale of the SF-36 (p<0.05), relative to the control group.

Lamotrigine

Finnerup et al. in 2002 studies the effects of lamotrigine on post SCI pain. Although the overall result showed no difference between placebo and lamotrigine, there was a significant reduction in pain in the incomplete spinal cord group.

Levetiracetam

Finnerup et al. (2009) conducted a randomized, double blind, crossover trial of levetiracetam in SCI individuals with pain. Participants were placed in either the levetiracetam or placebo group for 5 weeks and then crossed over after a 1 week washout period. This study found no significant difference between the levetiracetam and the placebo treatment group in improving pain intensity (p=0.46).

Valproate

In a double-blind cross-over study (n=20), Drewes et al. (1994) examined the effects of a 3 week treatment course of valoproic acid on chronic central pain in individuals who had sustained a SCI. Overall, they found no significant differences between the control and treatment groups; however, there was a trend towards improvement in the treatment group.

Table 18 Summary of Anticonvulsant Pain Treatment Post SCI

Conclusion

• There is level 1 evidence that the Gabapentin and pregabalin improve neuropathic pain post SCI.
• There is level 4 evidence that the anticonvulsant Gabapentin is more effective when SCI pain is <6 months than >6 months.
• There is level 2 evidence that lamotrigine improves neuropathic pain in incomplete spinal cord injury
• Based on one Level 1 study, Levetiracetam is not effective in reducing neuropathic pain post SCI.
• There is Level 1 evidence that valproic acid does not significantly relieve neuropathic pain post SCI.

• Gabapentin and pregabalin improve neuropathic pain post SCI.
• Lamotrigine may improve neuropathic pain in incomplete spinal cord injury
• Levetiracetam is not effective in reducing neuropathic pain post SCI.
• Valproic acid does not reduce neuropathic pain post SCI.