Anticonvulsants in SCI Pain

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 2x daily in combination with Amitriptyline 50 mg 3x 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) noted that neuropathic pain is ultimately generated by excessive firing of pain-mediating nerve cells, insufficiently controlled by segmental and non-sequential inhibitory circuits. Gabapentin and pregabalin work by increasing GABA and reducing the release of glutamate thereby suppressing the sensitivity of N-methyl-D-asparate (NMDA) receptor. This has been shown to reduce neuronal hyper-excitability 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).

Discussion

Gabapentin

Three studies found that gabapentin was no better than placebo in improving pain intensity post SCI (Rintala et al. 2007; Kaydok et al. 2014; Tai et al. 2002). While, Levendoglu et al. (2004) found gabapentin significantly reduced post SCI neuropathic pain compared to placebo. Three pre-post studies found gabapentin had a time effect in reducing pain post SCI (To et al. 2002; Ahn et al. 2003; Putzke et al. 2002).

Pregabalin

Six studies examined the efficacy of pregabalin on pain post SCI. Min et al. (2016) found pregabalin and oxcarbazepine were equally effective in relieving pain overall. However, was more effective in relieving burning pain, allodynia, and hyperalgesia. Kaydok et al. (2014) found no significant difference in pain reducing between gabapentin and pregabalin. Siddall 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).

Arienti et al. (2011) compared treatment of pain in three groups: 1) pregabalin only group; 2) pregabalin and osteopathy group; 3) osteopathy group. The study found significant improvement in pain perception and pain relief in the combined pregabalin and osteopathy group compared to the other two groups (p<0.01). Further, relief of pain was faster in the combined group compared to the pregabalin and osteopathy only groups.

In a RCT conducted by Vranken et al. (2008) 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.

Cardenas et al. (2013) studied 220 patients with neuropathic pain post SCI they were randomized to 150-600mg of pregabalin (108 patients) vs Placebo (112) patients. The patients in the treatment group experienced significant improvements in all primary and key secondary outcomes including duration adjusted average change in pain, change in mean pain scores,percentage of patients with greater that 30% reduction in pain and reduction in pain related sleep interference scores compared to placebo. The improvements were seen as early as one week after initiation of treatment and lasted for the duration of the 17 week study. As with previous studies the medication was generally well tolerated, somnolence and dizziness were the most common side effects. This study provided class 1 evidence for the effectiveness of pregabalin 150mg to 600mg in the treatment of neuropathic pain post spinal cord injury.

Lamotrigine

Two studies evaluated the effectiveness of lamotrigine in reducing pain post SCI. Agarwal and Joshi (2017) found lamotrigine resulted in similar reduction in pain compared to amitriptyline. Finnerup et al. (2002) studied 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 five weeks and then crossed over after a one 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 three 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.

Conclusion

There is level 1b evidence (Levendoglu et al. 2004) that the gabapentin improves neuropathic pain post SCI compared to placebo.

There is level 1b evidence (Rintala et al. 2007) that gabapentin is no more effective as an active placebo in improving neuropathic pain post SCI.

There is level 1b evidence (Kaydok et al. 2014) that gabapentin and pregabalin are equally effective at reducing neuropathic pain post SCI.

There is level 1b evidence (from one RCT: Arienti et al. 2011) that combined pregabalin and osteopathy treatment improves pain post SCI.

There is level 4 evidence (from one pre-post study: Ahn et al. 2003) that the anticonvulsant Gabapentin is more effective when SCI pain is<6 months than >6 months.

There is level 1b evidence (from one RCT: Finnerup et al. 2002) that lamotrigine improves neuropathic pain in incomplete spinal cord injury

There is level 1b evidence (from one RCT: Finnerup et al. 2009) that Levetiracetam is not effective in reducing neuropathic pain post SCI.

There is level 2 evidence (from one RCT: Drewes et al. 1994) that valproic acid does not significantly relieve neuropathic pain post SCI.