Predictors of placebo response in pooled lamotrigine neuropathic pain clinical trials.

OBJECTIVES: One limitation of neuropathic pain clinical trials is the often large and variable extent of response in the placebo group, possibly obscuring true medication effects. We pooled data from 252 individuals in the placebo arms of 3 clinical trials of lamotrigine in patients with neuropathic pain to examine the relationship of baseline patient and study site characteristics with 12-week change in the Pain Intensity Numerical Rating Scale score (DeltaPI-NRS). The 574 patients in the pooled lamotrigine treatment arms were used as a replication dataset. MATERIALS AND METHODS: We performed univariable and multivariable regression analysis of predictors of DeltaPI-NRS. Clinical factors examined were baseline pain intensity score (mean daily PI-NRS over the week prior to randomization), age, sex, diagnosis, prior and concurrent gabapentin use, prior and concurrent tricyclic antidepressant use, pain duration, variability of daily pain scores during the baseline week, and slope of daily pain scores over the baseline week. Site factors evaluated were study site, US geographic region, recruitment rate, and recruitment period. RESULTS: Baseline PI-NRS and site recruitment rate were independent predictors of the 12-week DeltaPI-NRS in the last observation carried forward, observed case, and repeated measures analyses. Patients with higher baseline PI-NRS scores had a significantly greater 12-week reduction in pain intensity than patients with lower baseline scores. Patients within sites with a faster recruitment rate also had a significantly greater reduction of pain intensity than those in sites with slower recruitment. DISCUSSION: These results suggest that both patient and study site characteristics can influence the response in the placebo arms of neuropathic pain studies.

Double-blind, placebo-controlled trial of lamotrigine in combination with other medications for neuropathic pain.

This randomized, double-blind, placebo-controlled study was undertaken to evaluate the efficacy and tolerability of lamotrigine added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic in patients whose neuropathic pain was inadequately controlled with these medications. Patients with neuropathic pain from diabetic peripheral neuropathy, postherpetic neuralgia, traumatic/surgical nerve injury, incomplete spinal cord injury, trigeminal neuralgia, multiple sclerosis, or HIV-associated peripheral neuropathy, who had a mean weekly pain score > or =4 on an 11-point numerical rating scale, were randomized to receive a flexible dose of lamotrigine 200, 300, or 400mg daily (n=111) or placebo (n=109) for up to 14 weeks (including eight weeks of dose escalation) in addition to their prestudy regimen of gabapentin, a tricyclic antidepressant, or a nonopioid analgesic. No statistically significant difference in the mean change in pain-intensity score from baseline to Week 14 (primary endpoint) was detected between lamotrigine and placebo (P=0.67). Differences between lamotrigine and placebo were not statistically significant for secondary efficacy assessments, including mean changes from baseline in the Short-Form McGill Pain Questionnaire, the Neuropathic Pain Scale, rescue medication use, and the percentages of patients rated as much improved or very much improved at the end of treatment on the Clinician Global Impression of Change scale and the Patient Global Impression of Change scale. Lamotrigine was generally well tolerated. Lamotrigine (up to 400 mg/day) added to gabapentin, a tricyclic antidepressant, or a nonopioid analgesic did not demonstrate efficacy as an adjunctive treatment of neuropathic pain but was generally safe and well tolerated.

Lamotrigine for treatment of pain associated with diabetic neuropathy: results of two randomized, double-blind, placebo-controlled studies.

To assess the efficacy and tolerability of lamotrigine in pain associated with diabetic neuropathy, two replicate randomized, double-blind, placebo-controlled studies were conducted. Patients (n=360 per study) with painful diabetic neuropathy were randomized to receive lamotrigine 200, 300, or 400 mg daily or placebo during the 19-week treatment phase, including a 7-week dose-escalation phase and a 12-week, fixed-dose maintenance phase. The mean reduction in pain-intensity score from baseline to week 19 (primary endpoint) was greater (p < or = 0.05) in patients receiving lamotrigine 400 mg than placebo in Study 2 (observed scores, -2.7 versus -1.6 on a 0- to 10-point scale). This finding was not replicated in Study 1. Lamotrigine 200 and 300 mg did not significantly differ from placebo at week 19 in either study. Lamotrigine 300 and 400 mg were only occasionally more effective than placebo for secondary efficacy endpoints. The 200-mg dose did not separate from placebo. In a post hoc analysis of pooled data including only patients who reached their target dose, lamotrigine 400 mg conferred greater (p0.05) mean reduction in pain-intensity score from baseline to week 19 than placebo (-2.5 for 300 mg and -2.7 for 400mg versus -2.0 for placebo). Adverse events were reported in 71-82% of lamotrigine-treated patients compared with 63-70% of placebo-treated patients. The most common adverse events with lamotrigine were headache and rash. Compared with placebo, lamotrigine (300 and 400 mg daily) was inconsistently effective for pain associated with diabetic neuropathy but was generally safe and well tolerated.