T. Kevin Murphy

The efficacy and safety of pregabalin in the treatment of neuropathic pain associated with chronic lumbosacral radiculopathy

&NA; We evaluated the efficacy of pregabalin in patients with chronic lumbosacral radiculopathy. This randomized, controlled, withdrawal trial included five phases: screening (4–18 days); run‐in (4–10 days) to screen out placebo responders; single‐blind (28 days) to identify pregabalin responders; double‐blind to randomize responders to pregabalin or placebo (35 days); and final study medication taper (7 days). The primary endpoint was time to loss of response (LOR) during the double‐blind phase (≥1‐point increase in pain, discontinuation, or rescue‐medication use). In the single‐blind phase, 58% of patients had ≥30% pain reduction. In the double‐blind phase, pregabalin (n = 110) and placebo (n = 107) groups did not differ significantly in time to LOR. Adverse events caused the discontinuation of 9.9% and 5.6% of pregabalin‐treated and placebo‐treated patients, respectively. Most patients with chronic lumbosacral radiculopathy responded to pregabalin therapy; however, time to LOR did not significantly differ between pregabalin and placebo. Considering the results of all phases of the study, it is difficult to draw definitive conclusions from it, suggesting a need for further work to understand the clinical potential of pregabalin treatment for lumbosacral radiculopathy.

Safety and efficacy of pregabalin in patients with central post-stroke pain.

&NA; Pregabalin has demonstrated efficacy in several forms of neuropathic pain, but its long‐term efficacy in central post‐stroke pain (CPSP) is unproven. We evaluated the efficacy and safety of pregabalin versus placebo in patients with CPSP. A 13‐week, randomized, double‐blind, multicenter, placebo‐controlled, parallel group study of 150 to 600 mg/day pregabalin was conducted in patients aged ⩾18 years with CPSP. The primary efficacy endpoint was the mean pain score on the Daily Pain Rating Scale over the last 7 days on study drug up to week 12 or early termination visit. Secondary endpoints included other pain parameters and patient‐reported sleep and health‐related quality‐of‐life measures. A total of 219 patients were treated (pregabalin n = 110; placebo n = 109). A mean pain score at baseline of 6.5 in the pregabalin group and 6.3 in the placebo group reduced at endpoint to 4.9 in the pregabalin group and 5.0 in the placebo group (LS mean difference = –0.2; 95% CI = –0.7, 0.4; P = 0.578). Treatment with pregabalin resulted in significant improvements, compared with placebo, on secondary endpoints including MOS‐sleep, HADS‐A anxiety, and clinician global impression of change (CGIC) P < 0.05. Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 9 (8.2%) of pregabalin patients versus 4 (3.7%) of placebo patients. Although pain reductions at endpoint did not differ significantly between pregabalin and placebo, improvements in sleep, anxiety, and CGIC suggest some utility of pregabalin in the management of CPSP. Pain reductions at endpoint did not differ significantly between pregabalin and placebo, but improvements in comorbid conditions suggest some utility of pregabalin in central post‐stroke pain management.

Evaluation of the safety and efficacy of pregabalin in older patients with neuropathic pain: results from a pooled analysis of 11 clinical studies

BackgroundOlder patients are typically underrepresented in clinical trials of medications for chronic pain. A post hoc analysis of multiple clinical studies of pregabalin in patients with painful diabetic peripheral neuropathy (DPN) or postherpetic neuralgia (PHN) was conducted to evaluate the efficacy and safety of pregabalin in older patients.MethodsData from 11 double-blind, randomized, placebo-controlled clinical studies of pregabalin in patients with DPN or PHN were pooled. Efficacy outcomes included change in Daily Pain Rating Scale score, ≥30% and ≥50% responders, and endpoint pain score ≤3. Safety was based on adverse events (AEs). Primary efficacy was analyzed by analysis of covariance with terms for treatment, age category, protocol, baseline pain, and treatment-by-age category interaction.Results2516 patients (white, n = 2344 [93.2%]; men, n = 1347 [53.5%]; PHN, n = 1003 [39.9%]; pregabalin, n = 1595) were included in the analysis. Patients were grouped by age: 18 to 64 years (n = 1236), 65 to 74 years (n = 766), and ≥75 years (n = 514). Baseline mean pain and sleep interference scores were comparable across treatment and age groups. Significant improvements in endpoint mean pain were observed for all pregabalin dosages versus placebo in all age groups (p ≤ 0.0009), except for the lowest dosage (150 mg/day) in the youngest age group. Clinically meaningful pain relief, defined as ≥30% and ≥50% pain response, was observed in all age groups. The most common AEs were dizziness, somnolence, peripheral edema, asthenia, dry mouth, weight gain, and infections. The relative risks for these AEs increased with pregabalin dose, but did not appear related to older age or type of neuropathic pain.ConclusionsPregabalin (150-600 mg/day) significantly reduced pain in older patients (age ≥65 years) with neuropathic pain and improvements in pain were comparable to those observed in younger patients. Titration of pregabalin to the lowest effective dose should allow for effective pain relief while minimizing AEs in older patients with neuropathic pain. Given the common use of polypharmacy in older patients, the absence of known drug-drug interactions makes pregabalin an important treatment option for older patients with pain of neuropathic origin.

The effect of pregabalin on pain-related sleep interference in diabetic peripheral neuropathy or postherpetic neuralgia: a review of nine clinical trials.

Abstract Objective: Postherpetic neuralgia and painful diabetic peripheral neuropathy are common chronic neuropathic pain conditions associated with sleep disturbances. Pregabalin is indicated in the treatment of neuropathic pain. The objective of this review is to summarize the efficacy and safety of pregabalin in painful diabetic peripheral neuropathy and postherpetic neuralgia and the effect of pregabalin on sleep interference in these patients. Methods: MEDLINE and ISI Web of Knowledge databases were searched for randomized double-blind, placebo-controlled clinical trials of pregabalin reporting sleep measures in addition to pain endpoints in patients with painful diabetic peripheral neuropathy and postherpetic neuralgia published from inception through March 2009. Results: Nine trials met the inclusion criteria, providing data for a total of 2399 patients with painful diabetic peripheral neuropathy or postherpetic neuralgia treated twice or three times per day with pregabalin (75–600 mg/day) or placebo on a fixed or flexible schedule. Interpretation of sleep outcomes in two studies may be limited by trial inclusion criteria which permitted benzodiazepines for sleep problems. Also, none of the studies reported objective sleep measures. Pregabalin was well tolerated. Pregabalin (150–600 mg/day) significantly reduced pain and improved pain-related sleep interference. Conclusions: In addition to an analgesic benefit, pregabalin may decrease pain-related sleep interference in patients with painful diabetic peripheral neuropathy and postherpetic neuralgia.

Characterizing and understanding body weight patterns in patients treated with pregabalin

Abstract Objective: We examined patterns of weight change among patients treated with pregabalin for up to 1 year. Methods: Patients with ≥1 pre-treatment weight measurement, ≥2 measurements in Period 1 (day 2–56), and ≥2 during Period 2 (day 57–356) were identified from pooled data of 106 studies including 43,525 patients. Seven patterns were developed and used for exploratory ‘change point’ analyses (day on-treatment when weight-change trend changed from initial trajectory) and to assess patterns of weight change by baseline weight/body mass index (BMI). Results: A total of 3187 patients (from 41 studies) were eligible. 98.9% of patients were described by three of the seven patterns. The majority of patients (2607/3187 [81.8%]) remained within ±7% of baseline weight (‘Pattern 4’). Fewer patients (463/3187 [14.5%]) were ‘delayed weight gainers’ (exceeded 7% weight gain in Period 2 but not Period 1 [‘Pattern 6’]), fewer still (82/3187 [2.6%]) were ‘early weight gainers’ (exceeded ≥7% baseline weight in Period 1 and remained above 7% or continued to gain weight in Period 2 [‘Pattern 7’]). Overall weight gainers (Patterns 6, 7) experienced 1-year weight gain (median [% change]) of +6.20 kg [+9.12%] and 5.46 kg [+13.9%] vs. 2.22 kg [+2.10%] for non-weight gainers (Pattern 4). Average baseline weight/BMI was lower for weight gainers (Patterns 6, 7) versus other patterns. Early weight gainers (Pattern 7) had change point day at day 40 versus day 54 for Pattern 4 and day 69 for Pattern 6. Use of concomitant medications and influence of comorbid conditions on weight should be considered as inherent variables when interpreting the study. Conclusions: The majority of patients treated with pregabalin (150–600 mg/day) for 1 year maintained weight within ±7% baseline weight. One in six patients gained ≥7% weight from baseline, and generally exceeded 7%, 2–12 months after treatment onset.

Safety Profile and Tolerability of Up to 1 Year of Pregabalin Treatment in 3 Open-Label Extension Studies in Patients With Fibromyalgia

BACKGROUND Pain relief and an acceptable safety profile have been reported in randomized controlled trials (RCTs) of pregabalin in the treatment of fibromyalgia (FM) for up to 14 weeks. OBJECTIVE To evaluate the safety profile and tolerability of pregabalin (75-300 mg BID) treatment for up to 1 year in patients with FM. METHODS Twelve-week data were pooled from 3 open-label extension studies of pivotal RCTs. Study 1 was a 1-year extension of a 13-week RCT, and studies 2 and 3 were 12-week extensions of 14-week RCTs. The 1-year data were separately evaluated. The open-label data are summarized using descriptive statistics. RESULTS Overall, 1206 patients (92.4% female) with a mean (SD) age of 48.8 (10.7) years received open-label extended pregabalin treatment. A total of 119 of 1206 patients (9.9%) permanently discontinued study participation due to treatment-emergent adverse events (all causality) at 12 weeks (pooled data) and 53 of 429 (12.4%) within 1 year. Consistent with previous RCTs, the most commonly reported treatment-emergent adverse events with open-label pregabalin treatment were dizziness, somnolence, headache, peripheral edema, and increased weight. The highest incidence rates in the pooled 12-week data were for dizziness (214 of 1206; 17.7%) and somnolence (96 of 1206; 8.0%). In ratings of severity (mild, moderate, severe), most were reported as mild to moderate. The mean (SD) change in patient-reported visual analog scale pain scores (0-100) from the open-label baseline to the end of treatment was -21 (30.5) in study 1 (1 year), -26.7 (28.8) in study 2 (12 weeks), and -20.1 (26.8) in study 3 (12 weeks). CONCLUSIONS The data from these extension studies suggest that the adverse event safety profile and tolerability of patients with FM treated with open-label pregabalin (75-300 mg BID) for up to 1 year were stable and were consistent with those of previous studies. ClinicalTrials.gov identifiers: NCT00151528 (A0081057 [study 1]), NCT00282997 (A0081078 [study 2]), and NCT00346034 (A0081101 [study 3]).

Long-term Maintenance of Response Across Multiple Fibromyalgia Symptom Domains in a Randomized Withdrawal Study of Pregabalin

Objective: To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). Methods: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (≥16-point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (≥15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (≥10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. Results: Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalin-treated patients. Discussion: The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM (ClinicalTrials.gov registry ID: NCT00151489).

Sensory Pain Qualities in Neuropathic Pain

UNLABELLED The qualities of chronic neuropathic pain (NeP) may be informative about the different mechanisms of pain. We previously developed a 2-factor model of NeP that described an underlying structure among sensory descriptors on the Short-Form McGill Pain Questionnaire. The goal of this study was to confirm the correlated 2-factor model of NeP. Individual descriptive scores from the Short-Form McGill Pain Questionnaire were analyzed. Confirmatory factor analysis was used to test a correlated 2-factor model. Factor 1 (stabbing pain) was characterized by high loadings on stabbing, sharp, and shooting sensory items; factor 2 (heavy pain) was characterized by high loadings on heavy, gnawing, and aching items. Results of the confirmatory factor analysis strongly supported the correlated 2-factor model. PERSPECTIVE This article validates a model that describes the qualities of neuropathic pain associated with diabetic peripheral neuropathy and postherpetic neuralgia. These data suggest that specific pain qualities may be associated with pain mechanisms or may be useful for predicting treatment response.