Abstract & Commentary
Source: Kline KM, et al. Painful diabetic peripheral neuropathy relieved with use of oral topiramate. South Med J. 2003;96:602-605.
Topiramate may soon legitimately be added to the list of anticonvulsants useful for the control of painful diabetic peripheral neuropathy. In this case report, a 47-year-old woman, with a 6-year history of diabetes, had a 4-year history of severe peripheral neuropathy, confirmed by electrodiagnostic studies. Gabapentin (1200 mg/d) and ibuprofen (800 mg t.i.d.) failed to control her pain, and she was intolerant to amitriptyline. Topiramate, as her sole analgesic, was then quickly titrated upward from 25 mg b.i.d. to 100 mg b.i.d. but resulted in nervousness, jitteriness, and interference with sleep. Reduction to 25 mg b.i.d. followed by a slower increase, over several months, to 100 b.i.d. resulted in symptomatic improvement. Hypoglycemic episodes, which developed when topiramate was begun, were controlled by decreasing her oral hypoglycemic medication. Topiramate was consequently well tolerated and effective, blood glucose was better controlled, and the neuropathy did not progress over the ensuing 9 months. Topiramate may prove useful for the treatment of painful neuropathy.
Topiramate (2,3:4,5-bis-0-[1-methylethylidene]-ß-D-fructo-pyranose sulphamate) acts on neuronal transmission in several ways.1 It has a dose-dependent modulatory effect on voltage-gated sodium channels, decreasing the frequency and duration of epileptiform-like bursts of action potential firing. GABA (g-aminobutyric acid) activity at GABAA receptors is enhanced at concentrations of 10-100 mmol/L, with receptor desensitization at higher (> 100 mmol/L) concentrations. L-type voltage-gated calcium channels and kainate/AMPA (amino-3-hydroxy-5-methylisoxazole-4-propionic acid) receptors are selectively inhibited at low concentrations (10-100 mmol/L). Presynaptically, topiramate impairs glutamate release. Lastly, carbonic anhydrase isozymes II and IV are selectively inhibited, explaining the perioral and digital paresthesiae and nephrolithiasis, which occur as adverse effects.
These mechanisms presage a potential role for topiramate in pain control. Central sensitization, whereby central pain pathways are hypothesized to be altered secondary to peripheral influences, involves kainate/AMPA systems. This, in turn, brings NMDA into play, and topiramate may influence central sensitization by its effect on kainate/AMPA receptors. Descending inhibitory pathways to the dorsal horn also modulate pain input with GABAB receptors likely involved, although the role for GABAA receptors is less clearly defined. ß-endorphins are inhibited by GABAA antagonists, possibly implicating their involvement and supporting a role for topiramate, which potentiates GABAA activity. Carbonic anhydrase inhibition by topiramate may also be relevant at this level. Voltage-gated sodium channels undergo increased expression and translocation following nerve injury, and voltage-gated calcium channels modulate pain and alter opiate tolerance. Both of these effects may be influenced by topiramate, allowing it to be effective in the control of neuropathic pain. —Michael Rubin, Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus, Assistant Editor, Neurology Alert.
1. Chong MS, Libretto SE. Clin J Pain. 2003;19:59-68.