Time to onset of neuropathic pain reduction: A retrospective analysis of data from nine controlled trials of pregabalin for painful diabetic peripheral neuropathy and postherpetic neuralgia.

These retrospective analyses of daily mean pain scores from nine placebo-controlled trials of pregabalin at 150, 300, or 600 mg/day (pregabalin, n = 1205; placebo, n = 772) examined time to significant reduction of pain during the first 2 weeks of treatment of painful diabetic peripheral neuropathy and postherpetic neuralgia. Time to onset of reduction in pain-defined as the first day for which patients treated with pregabalin had significant reductions (P < 0.05) in mean pain score compared with the placebo group for that day and the subsequent day-was calculated for all treatment groups demonstrating statistically significant reduction in pain at trial end point. The time to a 1-point or greater improvement in mean pain score was measured for each patient who was a responder at end point (30% or greater improvement in mean pain score). In seven of the nine trials (representing 11 of 14 pregabalin arms), significant reduction in pain was achieved at end point. The time to onset for reduction in pain was treatment Day 1 or 2 in nine of these successful treatment arms. Individual responder analysis confirmed that responders in the pregabalin groups reported a 1-point or greater pain reduction earlier than responders in placebo groups (P < 0.0001). However, this analysis is not a direct estimate of the likelihood that an individual patient would experience noticeable pain relief by the end of the second day. Overall, for patients who will respond to pregabalin, statistically significant and sustained reduction of pain associated with diabetic peripheral neuropathy and posttherapeutic neuralgia occurs early, usually by the end of 2 days of pregabalin treatment.

Long-term add-on pregabalin treatment in patients with partial-onset epilepsy: pooled analysis of open-label clinical trials.

PURPOSE: To evaluate the safety, tolerability, and efficacy of long-term pregabalin as add-on therapy for patients with poorly controlled partial seizures. METHODS: Analysis of data from six long-term clinical trials involving 2,061 patients receiving open-label pregabalin 75-600 mg/day adjunctive therapy for partial onset epilepsy refractory to multiple antiepileptic drugs. RESULTS: Total pregabalin exposure was 3,877 person-years. The mean duration of pregabalin treatment was 534 days (range 0.3-8 years) and 59% completed 1 year. One-third of patients discontinued for lack of efficacy. The most common dose was >or=300 mg/day; over half took >or=450 mg/day. There was a mean reduction in the 28-day seizure rate of 25-40%, and more than 40% of all patients had a >or=50% reduction in seizures from baseline during the last 3 months of treatment. Twelve percent of all patients had a 6-month period continuously free of seizures. In the last year, 6% were seizure-free for the entire year. Pregabalin was generally well-tolerated and the safety profile favorable in patients treated for up to several years, with an adverse event (AE) profile similar to short-term placebo-controlled trials. Common AEs included CNS symptoms (dizziness, somnolence, headache, and asthenia), accidental injury, and weight gain. CNS AEs tended to be mild and transient. Rates of sudden unexpected death in epilepsy (SUDEP), mortality, cancer, and status epilepticus were within the expected range for this population. CONCLUSIONS: Adjunctive pregabalin was effective, generally well tolerated, and safe in the long-term treatment of partial seizures, and provided clinically meaningful seizure reduction and freedom without evidence of tolerance over 2 years of follow-up.

Reliability, validity, and responsiveness of the daily sleep interference scale among diabetic peripheral neuropathy and postherpetic neuralgia patients.

To evaluate the psychometric characteristics of the Daily Sleep Interference Scale (DSIS) in patients with painful diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN), a post hoc secondary analysis of data from eight randomized clinical trials (four DPN and four PHN) was performed. Data were pooled within patient populations when assessment weeks were the same. The DSIS was completed by 1,124 DPN and 1,034 PHN patients. Patient-reported outcomes, including a Daily Pain Diary, the Short-Form McGill Pain Questionnaire, SF-36 Health Survey, Profile of Mood States, MOS-Sleep Scale (MOS-SS), EQ-5D, and Patient Global Impression of Change, were used to validate the DSIS. Test-retest reliability was high for both samples (intraclass correlation coefficient>0.90). The DSIS showed good construct validity, with moderate to high correlations between the DSIS and weekly mean pain scores (r=0.48-0.80), MOS-SS sleep disturbance subscale (r=0.45-0.64), MPQ-SF Pain Experience (r=0.37-0.61), and VAS (r=0.42-0.72). The DSIS showed good discriminant validity in both groups; high and low MOS-SS sleep disturbance groups had significantly different DSIS scores (P<0.001). DPN patients who improved minimally on the Patient Global Impression of Change and in pain scores improved 1.5-2 DSIS points on average; for PHN, patient scores improved an average of 1-2 points. The DSIS demonstrated robust test-retest reliability, good construct and discriminant validity and responsiveness in painful DPN and PHN patients. A 1-2 point change on the DSIS might be interpreted as an important difference.

Pregabalin in the treatment of refractory neuropathic pain: results of a 15-month open-label trial.

OBJECTIVE: Neuropathic pain associated with postherpetic neuralgia (PHN) and painful diabetic peripheral neuropathy (DPN) can be intractable and may not respond to commonly used treatments, such as tricyclic antidepressants (TCAs) and opioids. This long-term, open-label study was a preliminary evaluation of pregabalin for patients whose pain had been judged refractory to other treatments for neuropathic pain. DESIGN: Patients had previously participated in double-blind, placebo-controlled, randomized trials of pregabalin in DPN and PHN. They had moderate to severe neuropathic pain despite treatment with gabapentin, a TCA, and a third medication (e.g., other anticonvulsants, opioid, selective serotonin reuptake inhibitor, tramadol). Flexible-dosage pregabalin 150-600 mg/day was taken for 3-month periods followed by 3- to 28-day pregabalin "drug holidays," with an analysis up to 15 months (five treatment cycles). Pain intensity was measured using the visual analog scale of the Short-Form McGill Pain Questionnaire. RESULTS: In total, 81 patients were included in this analysis. Pregabalin 150-600 mg/day was associated with clinically meaningful and sustained pain reduction during each treatment cycle. During pregabalin "drug holidays," pain quickly returned to baseline levels; it was reduced again when pregabalin was reinstated. CONCLUSIONS: These results suggest that pregabalin may be beneficial in patients with neuropathic pain who have had an unsatisfactory response to treatment with other medications.

Efficacy of pregabalin in neuropathic pain evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible- and fixed-dose regimens.

Pregabalin binds with high affinity to the alpha2-delta subunit protein of voltage-gated calcium channels and, thereby, reduces release of excitatory neurotransmitters. This 12-week randomised, double-blind, multicentre, placebo-controlled, parallel-group study evaluated the efficacy and safety of pregabalin in patients with chronic postherpetic neuralgia (PHN) or painful diabetic peripheral neuropathy (DPN). Patients were randomised to placebo (n=65) or to one of two pregabalin regimens: a flexible schedule of 150, 300, 450, and 600 mg/day with weekly dose escalation based on patients' individual responses and tolerability (n=141) or a fixed schedule of 300 mg/day for 1 week followed by 600 mg/day for 11 weeks (n=132). Both flexible- and fixed-dose pregabalin significantly reduced endpoint mean pain score (primary outcome) versus placebo (P=0.002, P<0.001) and were significantly superior to placebo in improving pain-related sleep interference (P<0.001). The most common adverse events (AEs) for pregabalin-treated patients were dizziness, peripheral oedema, weight gain (not affecting diabetes control), and somnolence. These results are consistent with previous studies' demonstrating pregabalin's efficacy, tolerability, and safety for treatment of chronic neuropathic pain associated with DPN or PHN. Pregabalin dosing aimed at optimal balance of efficacy and tolerability provides significant pain relief and may reduce risks for AEs and therapy discontinuation.