Chronic lumbar radicular pain is the most common neuropathic pain syndrome. This was a double-blind, randomized, 2-period crossover trial of topiramate (50 to 400 mg) and diphenhydramine (6.25 to 50 mg) as active placebo to assess the efficacy of topiramate. Each period consisted of a 4-week escalation, a 2-week maintenance at the highest tolerated dose, and a 2-week taper. Main outcome was the mean daily leg pain score on a 0 to 10 scale during the maintenance period. Global pain relief was assessed on a 6-level category scale. In the 29 of 42 patients who completed the study, topiramate reduced leg pain by a mean of 19% (P = .065). Global pain relief scores were significantly better on topiramate (P < .005). Mean doses were topiramate 200 mg and diphenhydramine 40 mg. We concluded that topiramate treatment might reduce chronic sciatica in some patients but causes frequent side effects and dropouts. We would not recommend topiramate unless studies of alternative regimens showed a better therapeutic ratio. PERSPECTIVE: The anticonvulsant topiramate might reduce chronic lumbar nerve root pain through effects such as blockade of voltage-gated sodium channels and AMPA/kainite glutamate receptors, modulation of voltage-gated calcium channels, and gamma-aminobutyric acid agonist-like effects.
OBJECTIVES: To evaluate the efficacy and tolerability of topiramate in patients with painful diabetic polyneuropathy.
MATERIALS AND METHODS: Patients with moderate to extreme pain (0-4 Categorical Pain Scale score > or = 2) were randomized to placebo or topiramate (100, 200, or 400 mg/day) in three similar double-blind trials. The primary efficacy analysis was pain reduction from final visit to baseline in the 100-mm Visual Analog Scale (VAS) for the intent-to-treat populations.
RESULTS: After 18-22 weeks of double-blind treatment, pain reductions were numerically greater with topiramate in two studies but differences between topiramate and placebo in VAS scores or in the secondary efficacy endpoints did not reach statistical significance in any of the three studies. Across all studies, 24% of topiramate-treated patients and 8% of placebo-treated patients discontinued due to adverse events; groups did not differ in the occurrence of serious adverse events.
CONCLUSION: These studies did not find topiramate to be significantly more effective than placebo in reducing pain scores in patients with painful diabetic polyneuropathy. Several design features may have precluded the studies from having sufficient sensitivity to differentiate effective and ineffective treatments. The study design and results are instructive for other investigators designing future clinical studies in neuropathic pain.
<b>BACKGROUND: </b>Using identical methods, three simultaneous placebo-controlled trials of topiramate for painful diabetic neuropathy (PDN) did not reach significance. This independent yet concurrent placebo-controlled trial used different methods to assess topiramate efficacy and tolerability in PDN.<b>METHODS: </b>This 12-week, multicenter, randomized, double-blind trial included 323 subjects with PDN and pain visual analog (PVA) score of at least 40 on a scale from 0 (no pain) to 100 (worst possible pain). Topiramate (n = 214) or placebo (n = 109) was titrated to 400 mg daily or maximum tolerated dose. Short-acting rescue analgesics were permitted only during the first 6 weeks.<b>RESULTS: </b>Baseline characteristics were comparable between groups except for mean body weight (topiramate, 101.4 kg; placebo, 95.7 kg; p = 0.028). Twelve weeks of topiramate treatment reduced PVA scale score (from 68.0 to 46.2 mm) more effectively than placebo (from 69.1 to 54.0 mm; p = 0.038). Fifty percent of topiramate-treated subjects and 34% of placebo-treated subjects responded to treatment, defined as >30% reduction in PVA scale score (p = 0.004). Topiramate monotherapy also reduced worst pain intensity (p = 0.003 vs placebo) and sleep disruption (p = 0.020 vs placebo). Diarrhea, loss of appetite, and somnolence were the most commonly reported adverse events in the topiramate group. Topiramate reduced body weight (-2.6 vs +0.2 kg for placebo; p < 0.001) without disrupting glycemic control.<b>CONCLUSIONS: </b>Topiramate monotherapy reduced pain and body weight more effectively than placebo in patients with painful diabetic neuropathy.
Chronic lumbar radicular pain is the most common neuropathic pain syndrome. This was a double-blind, randomized, 2-period crossover trial of topiramate (50 to 400 mg) and diphenhydramine (6.25 to 50 mg) as active placebo to assess the efficacy of topiramate. Each period consisted of a 4-week escalation, a 2-week maintenance at the highest tolerated dose, and a 2-week taper. Main outcome was the mean daily leg pain score on a 0 to 10 scale during the maintenance period. Global pain relief was assessed on a 6-level category scale. In the 29 of 42 patients who completed the study, topiramate reduced leg pain by a mean of 19% (P = .065). Global pain relief scores were significantly better on topiramate (P < .005). Mean doses were topiramate 200 mg and diphenhydramine 40 mg. We concluded that topiramate treatment might reduce chronic sciatica in some patients but causes frequent side effects and dropouts. We would not recommend topiramate unless studies of alternative regimens showed a better therapeutic ratio.
PERSPECTIVE:
The anticonvulsant topiramate might reduce chronic lumbar nerve root pain through effects such as blockade of voltage-gated sodium channels and AMPA/kainite glutamate receptors, modulation of voltage-gated calcium channels, and gamma-aminobutyric acid agonist-like effects.
