Prediction of Differential Pharmacologic Response in Chronic Pain Using Functional Neuroimaging Biomarkers and a Support Vector Machine Algorithm: An Exploratory Study.

OBJECTIVE: There is increasing demand for prediction of chronic pain treatment outcomes using machine-learning models, in order to improve suboptimal pain management. In this exploratory study, we used baseline brain functional connectivity patterns from chronic pain patients with fibromyalgia (FM) to predict whether a patient would respond differentially to either milnacipran or pregabalin, 2 drugs approved by the US Food and Drug Administration for the treatment of FM. METHODS: FM patients participated in 2 separate double-blind, placebo-controlled crossover studies, one evaluating milnacipran (n = 15) and one evaluating pregabalin (n = 13). Functional magnetic resonance imaging during rest was performed before treatment to measure intrinsic functional brain connectivity in several brain regions involved in pain processing. A support vector machine algorithm was used to classify FM patients as responders, defined as those with a ≥20% improvement in clinical pain, to either milnacipran or pregabalin. RESULTS: Connectivity patterns involving the posterior cingulate cortex (PCC) and dorsolateral prefrontal cortex (DLPFC) individually classified pregabalin responders versus milnacipran responders with 77% accuracy. Performance of this classification improved when both PCC and DLPFC connectivity patterns were combined, resulting in a 92% classification accuracy. These results were not related to confounding factors, including head motion, scanner sequence, or hardware status. Connectivity patterns failed to differentiate drug nonresponders across the 2 studies. CONCLUSION: Our findings indicate that brain functional connectivity patterns used in a machine-learning framework differentially predict clinical response to pregabalin and milnacipran in patients with chronic pain. These findings highlight the promise of machine learning in pain prognosis and treatment prediction.

Efficacy and Safety of Pregabalin for Fibromyalgia in a Population of Chinese Subjects.

PURPOSE: Fibromyalgia (FM) may go underdiagnosed and untreated in China in part due to a lack of awareness and understanding of the condition, and limited available treatments. PATIENTS AND METHODS: This randomized, double-blind, Phase III local registration trial compared the efficacy and safety of pregabalin (flexibly dosed 300-450 mg/day) versus placebo for the management of pain in Chinese adults diagnosed with FM according to American College of Rheumatology 1990 criteria, across 22 centers within China. Patients reported pain score of ≥40 mm on 100-mm scale (from 0 "no pain" to 100 "worst possible pain"). The primary efficacy endpoint was change from baseline to Week 14 in mean pain score (MPS). Secondary endpoints included measures of sleep and sleep interference. Safety and tolerability were monitored throughout. RESULTS: Median pregabalin dose was 335 mg/day. A significant reduction from baseline to Week 14 in weekly MPS was seen for patients treated with pregabalin (n=170) versus placebo (n=164) (least-squares mean difference [95% confidence interval]: -0.73 [-1.10 to -0.36]; P=0.0001). Significantly greater proportions of patients experienced ≥30% and ≥50% reductions in MPS at Week 14 with pregabalin versus placebo. Pregabalin-treated subjects demonstrated improvements in measures of sleep and sleep interference. Pregabalin was generally well tolerated. The most common adverse events were dizziness and somnolence; no serious adverse events (SAEs) occurred in pregabalin-treated subjects. Nine placebo-treated subjects experienced SAEs. CONCLUSION: Pregabalin (300-450 mg/day) is a safe and effective treatment for reducing pain and improving sleep in native Chinese subjects with FM. CLINICALTRIALSGOV IDENTIFIER: NCT01387607.

An evidence-based review of pregabalin for the treatment of fibromyalgia.

OBJECTIVES: Pregabalin, an α2-δ agonist, is approved for the treatment of fibromyalgia (FM) in the United States, Japan, and 37 other countries. The purpose of this article was to provide an in-depth, evidence-based summary of pregabalin for FM as demonstrated in randomized, placebo-controlled clinical studies, including open-label extensions, meta-analyses, combination studies and post-hoc analyses of clinical study data. METHODS: PubMed was searched using the term "pregabalin AND fibromyalgia" and the Cochrane Library with the term "pregabalin". Both searches were conducted on 2 March 2017 with no other date limits set. RESULTS: Eleven randomized, double-blind, placebo-controlled clinical studies were identified including parallel group, two-way crossover and randomized withdrawal designs. One was a neuroimaging study. Five open-label extensions were also identified. Evidence of efficacy was demonstrated across the studies identified with significant and clinically relevant improvements in pain, sleep quality and patient status. The safety and tolerability profile of pregabalin is consistent across all the studies identified, including in adolescents, with dizziness and somnolence the most common adverse events reported. These efficacy and safety data are supported by meta-analyses (13 studies). Pregabalin in combination with other pharmacotherapies (7 studies) is also efficacious. Post-hoc analyses have demonstrated the onset of pregabalin efficacy as early as 1-2 days after starting treatment, examined the effect of pregabalin on other aspects of sleep beyond quality, and shown it is effective irrespective of the presence of a wide variety of patient demographic and clinical characteristics. CONCLUSIONS: Pregabalin is a treatment option for FM; its clinical utility has been comprehensively demonstrated.

Efficacy and safety of pregabalin for painful diabetic peripheral neuropathy in a population of Chinese patients: A randomized placebo-controlled trial.

BACKGROUND: Limited information exists regarding the efficacy of pregabalin in Chinese patients with painful diabetic peripheral neuropathy (pDPN). METHODS: An 11-week double-blind placebo-controlled trial was performed in Chinese pDPN patients randomized (1 : 1) to 300 mg/day pregabalin or placebo. The primary outcome was change from baseline to endpoint in mean pain score (MPS; 0, no pain; 10, worst possible pain; using the mean of the last seven daily pain scores). Secondary outcomes included weekly MPS and responder status (MPS reduced by ≥30% or ≥50% vs baseline). Subgroup analysis assessed patients with severe (≥7) baseline MPS. Adverse events (AEs) were reported. RESULTS: In all, 620 patients were randomized (pregabalin, n = 313; placebo, n = 307). Improvement in MPS with pregabalin versus placebo was not significant (P = 0.0559). Post hoc sensitivity analyses, excluding one patient/site due to Good Clinical Practice (GCP) non-compliance, showed pregabalin significantly improved MPS when excluding the patient (P = 0.0448) or site (P = 0.0142). Pregabalin significantly improved weekly MPS (P = 0.0164) and ≥50% responders at endpoint (P = 0.0384). Improvement in proportion of ≥30% responders, impression of change, pain intensity, and sleep did not differ significantly between the treatment groups. In the severe pDPN subpopulation, pregabalin significantly improved MPS versus placebo (P = 0.0040). The most commonly reported AE was dizziness (9.6% vs 3.9% with placebo). CONCLUSIONS: Pregabalin did not significantly improve the primary measure of pain in the trial. Significant reductions in MPS were observed when excluding the GCP non-compliant patient/site and in the severe pDPN subpopulation. Pregabalin was well tolerated in Chinese pDPN patients.

Effect of Baseline Characteristics on the Pain Response to Pregabalin in Fibromyalgia Patients with Comorbid Depression.

Objective: To evaluate the effect of baseline characteristics on the treatment response to pregabalin in fibromyalgia (FM) patients with depression. Design: Post hoc analysis from a randomized, double-blind, placebo-controlled, two-way crossover study of pregabalin (300 or 450 mg/day, twice daily). Subjects: A total of 193 FM patients taking an antidepressant for comorbid depression. Methods: The effect of patient baseline characteristics on the treatment response to pregabalin vs placebo was assessed for the primary efficacy end point (mean pain score on an 11-point numeric rating scale). Variables were analyzed using a linear mixed effects model with sequence, period, and treatment as fixed factors, and subject within sequence and within subject error as random factors. Results: Pregabalin significantly improved mean pain scores vs placebo irrespective of age, duration of FM, number of prior FM medications, depression diagnosis, shorter-term depression (<10 years), prior or no prior opioid use, pain severity, anxiety severity, and sleep disruption severity (all P < 0.05). Compared with placebo, pregabalin did not significantly affect mean pain scores in patients with comorbid insomnia, irritable bowel syndrome, or gastroesophageal reflux disease; severe FM; a diagnosis of depression before FM, longer-term depression (≥ 10 years), more severe depression, or who were taking a high dose of antidepressant. Conclusions: Pregabalin significantly improved mean pain scores when compared with placebo for the majority of baseline characteristics assessed in FM patients taking an antidepressant for comorbid depression.

Normalizing fibromyalgia as a chronic illness.

Fibromyalgia (FM) is a complex chronic disease that affects 3-10% of the general adult population and is principally characterized by widespread pain, and is often associated with disrupted sleep, fatigue, and comorbidities, among other symptoms. There are many gaps in our knowledge of FM, such that, compared with other chronic illnesses including diabetes, rheumatoid arthritis, and asthma, it is far behind in terms of provider understanding and therapeutic approaches. The experience that healthcare professionals (HCPs) historically gained in developing approaches to manage and treat patients with these chronic illnesses may help show how they can address similar problems in patients with FM. In this review, we examine some of the issues around the management and treatment of FM, and discuss how HCPs can implement appropriate strategies for the benefit of patients with FM. These issues include understanding that FM is a legitimate condition, the benefits of prompt diagnosis, use of non-drug and pharmacotherapies, patient and HCP education, watchful waiting, and assessing patients by FM domain so as not to focus exclusively on one symptom to the detriment of others. Developing successful approaches is of particular importance for HCPs in the primary care setting who are in the ideal position to provide long-term care for patients with FM. In this way, FM may be normalized as a chronic illness to the benefit of both patients and HCPs.

Dose-response of pregabalin for diabetic peripheral neuropathy, postherpetic neuralgia, and fibromyalgia.

OBJECTIVES: The pregabalin dose-response for pain, Patient Global Impression of Change (PGIC), and sleep quality measures in painful diabetic peripheral neuropathy (pDPN), postherpetic neuralgia (PHN), and fibromyalgia (FM) is relevant for physicians treating these patients. This analysis aimed to demonstrate the dose-response of pregabalin for each indication and describe the onset (incidence), onset/continuation (prevalence), and resolution of adverse events (AEs) occurring during treatment. METHODS: Data from 14 placebo-controlled, fixed-dose pregabalin trials in pDPN, PHN, and FM were pooled within each indication. Patients had mean baseline pain scores ≥6 on an 11-point numeric rating scale. A hyperbolic Emax dose-response model examined the dose-response of pregabalin for pain, PGIC, and sleep quality. Safety assessments included onset and prevalence of common AEs each week, and resolution in the first 2 months of treatment. RESULTS: In all indications, the likelihood of patients experiencing pain relief and improvements in PGIC and sleep quality increased in a dose-dependent manner with increasing doses. In all indications, new incidences of dizziness and somnolence were highest after 1 week of treatment, with few subsequent new reports at a given dose. Prevalence rates decreased steadily after 1 week of treatment. In FM, new onset weight gain emerged 6-8 weeks following treatment; prevalence rates generally increased then remained steady over time. With the exception of weight gain, many AEs resolved in month 1. CONCLUSION: The dose-response of pregabalin for pain, PGIC, and sleep quality was demonstrated, highlighting the benefit of achieving the maximum recommended dose of 300 mg/day for pDPN, 300-600 mg/day for PHN, and 300-450 mg/day for FM. Common AEs are generally seen within 1 week of starting treatment, with few subsequent new reports at a given dose. New onset weight gain occurs after 6 weeks of treatment, reinforcing the need for regular monitoring of weight.

Safety and efficacy of pregabalin in adolescents with fibromyalgia: a randomized, double-blind, placebo-controlled trial and a 6-month open-label extension study.

BACKGROUND: Fibromyalgia (FM) is a common pain condition characterized by widespread musculoskeletal pain and tenderness. Pregabalin is an approved treatment for adults in the United States, but there are no approved treatments for adolescents with FM. METHODS: This was a 15-week, randomized, double-blind, placebo-controlled study and 6-month open-label safety trial of flexible-dose pregabalin (75-450 mg/day) for the treatment of adolescents (12-17 years) with FM. Primary outcome was change in mean pain score at endpoint (scored from 0-10, with 24-h recall). Secondary outcomes included global assessments and measures of pain, sleep, and FM impact. RESULTS: A total of 107 subjects were randomized to treatment (54 pregabalin, 53 placebo) and 80 completed the study (44 pregabalin, 36 placebo). Improvement in mean pain score at endpoint with pregabalin versus placebo was not statistically significant, treatment difference (95 % CI), -0.66 (-1.51, 0.18), P = 0.121. There were significant improvements with pregabalin versus placebo in secondary outcomes of change in pain score by week (P < 0.05 for 10 of 15 weeks); change in pain score at week 15 (1-week recall), treatment difference (95 % CI), -0.87 (-1.68, -0.05), P = 0.037; and patient global impression of change, 53.1 % versus 29.5 % very much or much improved (P = 0.013). Trends toward improvement with pregabalin in other secondary outcomes measuring pain, sleep, and FM impact were not significant. Safety was consistent with the known profile of pregabalin in adults with FM. CONCLUSION: Pregabalin did not significantly improve the mean pain score in adolescents with FM. There were significant improvements in secondary outcomes measuring pain and impression of change. TRIAL REGISTRATIONS: NCT01020474 ; NCT01020526 .

Pregabalin Improves Pain Scores in Patients with Fibromyalgia Irrespective of Comorbid Osteoarthritis.

OBJECTIVE: Fibromyalgia (FM) is a chronic pain disorder with patients frequently suffering from comorbid conditions, including osteoarthritis (OA). Data on how FM patients with comorbid OA respond to recommended therapies (such as pregabalin) could help their treatment. DESIGN: This was a pooled exploratory analysis of three randomized placebo-controlled clinical trials of pregabalin in FM patients to assess the impact of comorbid OA on the response to pregabalin. METHODS: Patients were divided into those with and without comorbid OA. Difference in change in least squares (LS) mean pain score at endpoint (assessed by 0-10 numeric rating scale, controlled for baseline pain score) with pregabalin (300 mg/day and 450 mg/day) vs placebo was assessed. Changes in Patient Global Impression of Change (PGIC) responders and Fibromyalgia Impact Questionnaire (FIQ) total score were also assessed. RESULTS: There were 1665 patients in the analysis set (558, placebo; 552, pregabalin 300 mg/day; 555, pregabalin 450 mg/day), including 296 with comorbid OA. Pregabalin 450 mg/day significantly improved the LS mean (95% confidence interval) difference in pain score vs placebo in patients with (0.99 [0.44, 1.55], P < 0.001), and without (0.64 [0.39, 0.89], P < 0.001) OA. Improvements with pregabalin 300 mg/day with (0.31 [-0.25, 0.86], P = 0.276) and without (0.51 [0.25, 0.76], P < 0.001) OA were not consistently significant. Improvements in PGIC and FIQ total score were observed in patients with and without comorbid OA. CONCLUSIONS: FM patients with or without comorbid OA respond to treatment with pregabalin 450mg/day with significant improvements in pain intensity scores. These data could provide guidance to healthcare professionals treating these patients.

Burden of illness in fibromyalgia patients with comorbid depression.

OBJECTIVES: To assess the burden of fibromyalgia (FM) in patients with FM taking antidepressant medication for comorbid depression. METHODS: Symptom burden, impact on work and activity, and healthcare resource utilisation (HCRU) was examined at randomisation in patients enrolled in a clinical trial. Symptom burden was estimated based on self-reported health status measures. The Work Productivity and Activity Impairment: Specific Health Problem scale adapted to FM and a separate HCRU questionnaire were completed. The relationship between FM severity and burden was evaluated. RESULTS: The total population analysed comprised 193 patients; 71 (36.8%) had moderate FM and 119 (61.7%) severe FM. Patients had moderate pain, severe impairment in functioning due to FM, sleep disruption, mild anxiety, and mild depression. In the 7 days preceding randomisation, an average of 58.0% overall work impairment was reported, with 15.2% of working hours missed and 54.0% productivity while at work. In the 3 months preceding randomisation, on average, 5.0 visits per patient were made to healthcare professionals. Physical treatments were used by 34.7% and supplements by 31.6% of patients. Prescription and non-prescription medications, as well as professional services providing help with activities of daily living (ADL) that are impacted by FM, were used by >75% of patients. In addition, 50.4 hours of unpaid help was provided for ADL assistance. Total out-of-pocket expenditures were US$307.1, €410.4, or C$211.3, depending on location. FM burden worsened with increasing FM severity. CONCLUSIONS: This study demonstrates the significant burden of FM in patients with comorbid depression treated with an antidepressant.

The Pharmacokinetics of Pregabalin in Breast Milk, Plasma, and Urine of Healthy Postpartum Women.

BACKGROUND: Limited data exist on the presence of pregabalin in human breast milk of nursing mothers. OBJECTIVES: This study aimed to determine pregabalin concentrations in breast milk, estimate the infant daily pregabalin dose from nursing mothers, and evaluate pregabalin pharmacokinetic data in lactating women (≥ 12 weeks postpartum). METHODS: In this multiple-dose, open-label, pharmacokinetic study, 4 doses of pregabalin 150 mg were administered orally at 12-hour intervals. Urine, blood, and breast milk samples were collected up to 12, 24, and 48 hours, respectively, following the fourth dose. Pharmacokinetic parameters were estimated using noncompartmental methods. Adverse events were monitored throughout. RESULTS: Ten healthy lactating women (age 24-37 years) received pregabalin. Geometric mean pregabalin Cmaxss and AUCτ values in breast milk were approximately 53% and 76%, respectively, of those for plasma. The mean amount of pregabalin in breast milk recovered in a 24-hour period after the last dose was 574 µg (range, 270-1720 µg), which is approximately 0.2% of the administered daily maternal dose of 300 mg. The estimated average daily infant dose of pregabalin from breast milk was 0.31 mg/kg/day, which would be approximately 7% (23% coefficient of variation) of the body weight normalized maternal dose. Approximately 89% of the dose administered was recovered in urine. Renal clearance averaged 68.2 mL/min. Adverse events were of mild or moderate severity. CONCLUSION: Lactation appears to have had little influence on pregabalin pharmacokinetics. Overall, the estimated dose of pregabalin in breastfed children of women receiving pregabalin is low. Pregabalin was well tolerated in lactating women. DECLARATION OF CONFLICTING INTERESTS: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Peter A. Lockwood, Lynne Pauer, Joseph M. Scavone, Maud Allard, Laure Mendes da Costa, Tanja Alebic-Kolbah, Anna Plotka, Christine W. Alvey, and Marci L. Chew were all full-time employees of Pfizer at the time the study was completed and hold stock and/or stock options in Pfizer. FUNDING: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by Pfizer, which was involved in the study design, the collection, analysis, and interpretation of the data, the writing of the report, and the decision to submit the paper for publication. Medical writing support was provided by Penny Gorringe, MSc, of Engage Scientific Solutions and funded by Pfizer.

Association of Alterations in Gray Matter Volume With Reduced Evoked-Pain Connectivity Following Short-Term Administration of Pregabalin in Patients With Fibromyalgia.

OBJECTIVE: Pregabalin (PGB) is an α2 δ calcium-channel subunit ligand that has previously been shown to reduce chronic pain in multiple conditions. Preclinical studies indicate that PGB may down-regulate brain glutamate release while also inhibiting astrocyte induction of glutamatergic synapse formation, and recent clinical findings support the notion that PGB modulates glutamatergic activity and functional brain connectivity in order to produce analgesia. The present study was undertaken to examine concurrent changes in brain gray matter volume (GMV) or evoked-pain connectivity in humans receiving PGB. METHODS: Sixteen female fibromyalgia patients participated in a randomized double-blind 2-period crossover study of PGB versus placebo. Before and after each period, patients underwent high-resolution structural and evoked pressure-pain functional brain imaging. GMV was analyzed using voxel-based morphometry, and functional connectivity during evoked pressure-pain was assessed. RESULTS: PGB administration significantly reduced GMV within the posterior insula bilaterally, whereas there were no significant changes in insular GMV following placebo treatment. GMV reductions in the medial frontal gyrus were also observed when comparing PGB versus placebo treatment, and were associated with reduced clinical pain. These reductions in insular GMV were associated with concomitant reductions in connectivity to the default mode network, which was also associated with reduced clinical pain. CONCLUSION: Short-term PGB treatment altered brain structure and evoked-pain connectivity, and these decreases were associated with reduced clinical pain. We speculate that these fairly rapid changes in GMV may be related to brain neuroplasticity. It is unknown whether these effects are generalizable to other chronic pain states.

Pregabalin in Patients With Painful Diabetic Peripheral Neuropathy Using an NSAID for Other Pain Conditions: A Double-Blind Crossover Study.

OBJECTIVES: To evaluate pregabalin's efficacy and safety versus placebo to reduce pain in patients with diabetic peripheral neuropathy (DPN) using a concomitant nonsteroidal anti-inflammatory drug. MATERIALS AND METHODS: In a randomized, double-masked, 14-week, 2-period, crossover study, patients with painful DPN using a nonsteroidal anti-inflammatory drug for non-DPN-related pain received 150 to 300 mg/d pregabalin or placebo (period 1); 14-day washout; then, the opposite therapy (period 2). Endpoints included weekly change in DPN pain score, sleep interference, adverse events, and patient-reported outcomes. RESULTS: Patients with similar baseline characteristics were randomized (period 1) to 1 of the 2 following possible sequences: pregabalin→placebo (n=154) or placebo→pregabalin (n=147). Results of the primary efficacy measure, mean weekly DPN pain at endpoint, showed no significant difference between pregabalin and placebo. However, 1 sensitivity analysis (mixed-model repeated measures) found greater pain score reductions with pregabalin than placebo at weeks 2 to 4 and overall (all P<0.05). One secondary endpoint analysis, mean treatment difference in DPN-related sleep interference, favored pregabalin over placebo (P=0.0009). Other sensitivity and secondary analyses were nonsignificant. Treatment-emergent adverse events were consistent with the known safety profile of pregabalin. DISCUSSION: Pregabalin (vs. placebo) showed overall improvements in sleep, pain reduction in 1 sensitivity analysis, and was well tolerated. Potential factors that may have confounded the ability to detect a treatment difference in DPN pain reduction (high placebo response, carryover effect, short washout period, or pregabalin dose) are discussed in the context of future studies.

Prior Opioid Use Does Not Impact the Response to Pregabalin in Patients With Fibromyalgia.

OBJECTIVE: Fibromyalgia (FM) is a chronic pain disorder for which pregabalin is an approved treatment in the United States. Although opioids are not a recommended treatment option, they continue to be used by many FM patients. The impact of patients' prior opioid use on their subsequent response to pregabalin has not been assessed. METHODS: This was a pooled analysis of 4 clinical trials to assess the efficacy of pregabalin in FM patients both with and without prior opioid use. Patients were divided into those using opioids prior to the trial and those who were not. The change in least squares mean pain score (assessed by 0 to 10 numeric rating scale) with pregabalin compared with placebo was assessed together with FM symptoms, anxiety, and depression. RESULTS: There were 2062 patients in the analysis set, including 371 patients with prior opioid use. Equal numbers of patients were treated with placebo, pregabalin 300 mg/d, and pregabalin 450 mg/d. Pregabalin significantly improved the least squares mean (95% confidence interval) difference in pain score compared with placebo in patients both with and without prior opioid use 0.87 (0.34-1.41) and 0.41 (0.17-0.65), respectively, at 300 mg/d and 0.91 (0.39-1.44) and 0.72 (0.48-0.96) at 450 mg/d (P≤0.001 for all). FM symptoms, anxiety, and depression were also improved with pregabalin compared with placebo, regardless of prior opioid use. DISCUSSION: FM patients respond to treatment with pregabalin with significant improvements in pain scores irrespective of prior opioid use. These data could inform treatment decisions for FM patients with prior use of opioids.

Efficacy and Safety of Pregabalin in Patients with Fibromyalgia and Comorbid Depression Taking Concurrent Antidepressant Medication: A Randomized, Placebo-controlled Study.

OBJECTIVE: To assess pregabalin efficacy and safety in patients with fibromyalgia (FM) with comorbid depression taking concurrent antidepressant medication. METHODS: This randomized, placebo-controlled, double-blind, 2-period, 2-way crossover study was composed of two 6-week treatment periods separated by a 2-week taper/washout phase. Patients with FM (aged ≥ 18 yrs) taking a stable dose of a selective serotonin reuptake inhibitor (SSRI) or a serotonin/norepinephrine reuptake inhibitor (SNRI) for depression were randomized 1:1 to receive pregabalin/placebo or placebo/pregabalin (optimized to 300 or 450 mg/day). Antidepressant medication was continued throughout the study. The primary efficacy outcome was the mean pain score on an 11-point numerical rating scale. Secondary efficacy outcomes included measures of anxiety, depression, patient function, and sleep. RESULTS: Of 197 patients randomized to treatment, 181 and 177 received ≥ 1 dose of pregabalin and placebo, respectively. At baseline, 52.3% of patients were taking an SSRI and 47.7% an SNRI, and mean pain score was 6.7. Mean pain scores at endpoint were statistically significantly reduced with pregabalin (least squares mean difference from placebo -0.61, 95% CI -0.91 - -0.31, p = 0.0001). Pregabalin significantly improved Hospital Anxiety and Depression Scale-Anxiety (difference -0.95, p < 0.0001) and -Depression (difference -0.88, p = 0.0005) scores, Fibromyalgia Impact Questionnaire total score (difference -6.60, p < 0.0001), and sleep quality (difference 0.57, p < 0.0001), but not EuroQol 5-Dimensions score (difference 0.02, p = 0.3854). Pregabalin safety was consistent with previous studies and current product labeling. CONCLUSION: Compared with placebo, pregabalin statistically significantly improved FM pain and other symptoms in patients taking antidepressant medication for comorbid depression. ClinicalTrials.gov identifier: NCT01432236.

Efficacy and Safety of Pregabalin in the Treatment of Patients With Painful Diabetic Peripheral Neuropathy and Pain on Walking.

OBJECTIVES: This randomized, double-blind, placebo-controlled, multicenter, 2-period crossover study (two 6-week treatment periods separated by a 2-week washout period) evaluated the efficacy and safety of pregabalin (150 to 300 mg/d) for treatment of pain and pain on walking in patients with painful diabetic peripheral neuropathy (DPN) who experienced pain while walking. METHODS: Co-primary efficacy endpoints were: (1) mean pain score (last 7 daily pain diary scores, 0 to 10 numeric rating scale at end of each treatment period) and (2) DPN pain on walking (0 to 10 numeric rating scale immediately after walking 50 feet [15.2 m] on flat surface). Secondary endpoints included other pain parameters, patient-reported sleep, health-related quality of life, and safety measures. RESULTS: Two hundred three patients were treated (pregabalin, n=198; placebo, n=186), with no statistically significant treatment difference for pregabalin versus placebo in the co-primary efficacy endpoints, mean DPN pain (P=0.0656) and mean DPN pain on walking (P=0.412). A carryover effect was observed. Analysis of co-primary endpoints for period 1 showed significant treatment difference for DPN pain (P=0.034) and DPN pain on walking (P=0.001). Treatment with pregabalin resulted in significant improvements versus placebo on prespecified patient global impression of change (end of period 1; P=0.002), and sleep interference rating scale (end of period 2; P=0.011). Adverse events were more frequent with pregabalin than with placebo and caused discontinuation in 13 (6.6%) pregabalin patients versus 5 (2.7%) placebo patients. DISCUSSION: Failure to meet the co-primary objectives may be related to carryover effect from period 1 to period 2, lower pregabalin dose (150 to 300 mg/d), and/or placebo response in painful DPN.

Time to improvement of pain and sleep quality in clinical trials of pregabalin for the treatment of fibromyalgia.

OBJECTIVE: To determine the time to immediate and sustained clinical improvement in pain and sleep quality with pregabalin in patients with fibromyalgia. DESIGN: A post hoc analysis of four 8- to 14-week phase 2-3, placebo-controlled trials of fixed-dose pregabalin (150-600 mg/day) for fibromyalgia, comprising 12 pregabalin and four placebo treatment arms. PATIENTS: A total of 2,747 patients with fibromyalgia, aged 18-82 years. METHODS: Pain and sleep quality scores, recorded daily on 11-point numeric rating scales (NRSs), were analyzed to determine time to immediate improvement with pregabalin, defined as the first of ≥2 consecutive days when the mean NRS score was significantly lower for pregabalin vs placebo in those treatment arms with a significant improvement at endpoint, and time to sustained clinical improvement with pregabalin, defined as a ≥1-point reduction of the baseline NRS score of patient responders who had a ≥30% improvement on the pain NRS, sleep NRS, or Fibromyalgia Impact Questionnaire (FIQ) from baseline to endpoint, or who reported "much improved" or "very much improved" on the Patient Global Impression of Change (PGIC) at endpoint. RESULTS: Significant improvements in pain and sleep quality scores at endpoint vs placebo were seen in 8/12 and 11/12 pregabalin treatment arms, respectively (P < 0.05). In these arms, time to immediate improvements in pain or sleep occurred by day 1 or 2. Time to sustained clinical improvement occurred significantly earlier in pain, sleep, PGIC, and FIQ responders (P < 0.02) with pregabalin vs placebo. CONCLUSIONS: Both immediate and sustained clinical improvements in pain and sleep quality occurred faster with pregabalin vs placebo.

Once daily controlled-release pregabalin in the treatment of patients with fibromyalgia: a phase III, double-blind, randomized withdrawal, placebo-controlled study.

OBJECTIVE: Safety and efficacy of a once daily controlled-released (CR) formulation of pregabalin was evaluated in patients with fibromyalgia using a placebo-controlled, randomized withdrawal design. RESEARCH DESIGN AND METHODS: This multicenter study included 6 week single-blind pregabalin CR treatment followed by 13 week double-blind treatment with placebo or pregabalin CR. The starting dose of 165 mg/day was escalated during the first 3 weeks, up to 495 mg/day based on efficacy and tolerability. Patients with ≥50% reduction in average daily pain score at the end of the single-blind phase were randomized to continue pregabalin CR at the optimized dose (330-495 mg/day) or to placebo. The primary endpoint was time to loss of therapeutic response (LTR), defined as <30% pain reduction relative to single-blind baseline or discontinuation owing to lack of efficacy or adverse event (AE). Secondary endpoints included measures of pain severity, global assessment, functional status, tiredness/fatigue, and sleep. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01271933. RESULTS: A total of 441 patients entered the single-blind phase, and 63 were randomized to pregabalin CR and 58 to placebo. The median time to LTR (Kaplan-Meier analysis) was significantly longer in the pregabalin CR group than placebo (58 vs. 22 days, p = 0.02). By trial end, 34/63 (54.0%) pregabalin CR and 41/58 (70.7%) placebo patients experienced LTR. Significantly more patients reported 'benefit from treatment' (Benefit, Satisfaction, and Willingness to Continue Scale) in the pregabalin CR group; no other secondary endpoints were statistically significant. Most AEs were mild to moderate in severity (most frequent: dizziness, somnolence). The percentage of pregabalin CR patients discontinuing because of AEs was 12.2% and 4.8% in the single-blind and double-blind phases, respectively (placebo, 0%). CONCLUSIONS: Time to LTR was significantly longer with pregabalin CR versus placebo in fibromyalgia patients who initially showed improvement with pregabalin CR, indicating maintenance of response. Pregabalin CR was well tolerated in most patients. Generalizability may be limited by study duration and selective population.