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Predictors of placebo response in peripheral neuropathic pain: insights from pregabalin clinical trials.

ABSTRACT: BACKGROUND:Greater understanding of factors associated with the high placebo-response rates noted in recent neuropathic pain trials may improve trial design. This study investigated placebo response and its predictors in pregabalin trials in patients with diabetic peripheral neuropathy (DPN) or postherpetic neuralgia. PATIENTS AND METHODS:Individual patient data from 16 randomized, placebo-controlled, double-blind trials of pregabalin in 3,053 patients with DPN and 1,460 patients with postherpetic neuralgia were pooled (by condition and all together) in order to investigate the placebo response and its predictors. Univariate and multivariate analyses were performed across all 16 trials to identify predictors of change in pain score in patients. Trials with a >2-point mean reduction in pain score at endpoint with placebo were designated high placebo response and were compared with low placebo-response trials (those with a ?2-point mean reduction) with respect to patient and study characteristics. RESULTS:Three high placebo-response studies were identified, with all in DPN patients and all conducted postapproval of pregabalin. Younger age, higher mean baseline pain score, longer study duration, higher ratio of patients on active treatment to placebo, and study conducted postapproval were all significantly associated with a higher placebo response (P<0.05). There was a trend towards an increased placebo response in all studies over time without any corresponding change in the response to pregabalin. CONCLUSION:Consideration of the factors identified here as contributing to a higher placebo response could help improve the sensitivity and accuracy of clinical trials in patients with neuropathic pain.

SUBMITTER: Freeman R

PROVIDER: S-EPMC4459620 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Predictors of placebo response in peripheral neuropathic pain: insights from pregabalin clinical trials.

Freeman Roy R Emir Birol B Parsons Bruce B

Journal of pain research 20150601

<h4>Background</h4>Greater understanding of factors associated with the high placebo-response rates noted in recent neuropathic pain trials may improve trial design. This study investigated placebo response and its predictors in pregabalin trials in patients with diabetic peripheral neuropathy (DPN) or postherpetic neuralgia.<h4>Patients and methods</h4>Individual patient data from 16 randomized, placebo-controlled, double-blind trials of pregabalin in 3,053 patients with DPN and 1,460 patients ...[more]

PMID: 26082659

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Project description:BACKGROUND:Pregabalin is an effective treatment option for many patients with neuropathic pain. Higher doses of pregabalin have been shown to be more effective in improving pain outcomes but, in practice, failing to appropriately increase the dose can leave patients under-treated. METHODS:This was a pooled analysis of 6 flexible-dose clinical trials of pregabalin in patients with neuropathic pain (diabetic peripheral neuropathy, peripheral herpetic neuralgia, posttraumatic pain, or postsurgical pain). Patients were divided into "dose pathway" groups based on their weekly pregabalin dose from the start of their trial to the first week of their maintenance phase. These were: 150 mg/day only; 150 to 300 mg/day; 150 to 300 to 450 mg/day; 150 to 300 to 450 to 600 mg/day; 150 to 300 to 600 mg/day; 300 to 600 mg/day. Pain outcomes assessed for each group at each new dose were proportion of 30% and 50% responders (?30% or ?50% reduction in mean pain score from baseline) and mean change in pain score. Percent change in mean pain score from baseline was assessed using a marginal structural model. RESULTS:Seven hundred and sixty-one patients treated with flexible-dose pregabalin were included in the analysis. For each dose pathway group, there was a notably greater proportion of 30% and 50% responders and change in pain score, at each escalating dose. As assessed by the marginal structural model, higher doses of pregabalin were estimated to result in a significantly greater change in mean pain score at each week. This dose response with flexible-dose pregabalin was consistent with that previously observed with fixed-dose pregabalin. CONCLUSION:Many patients who do not respond to lower doses of pregabalin will respond with notable improvements in pain outcomes when the dose is escalated. These data should encourage physicians treating patients with neuropathic pain to escalate pregabalin to the dose that delivers optimal analgesia and tolerable side effects.

Project description:BackgroundCharacterizing relationships between pain relief and function can inform patient management decisions. This analysis explored graphically the relationship between pain relief and functional improvement in patients with neuropathic pain associated with spinal cord injury in two clinical trials of pregabalin.MethodsThis was a post hoc analysis of two randomized, double-blind, clinical trials in patients who were treated with pregabalin (n=181) or placebo (n=172) for neuropathic pain associated with spinal cord injury. The bivariate relationship between percent pain relief and absolute change in the functional outcomes with placebo and pregabalin was evaluated graphically using scatter plots, and loess curves illustrated the extent of the relationship between pain and function. Linear trend analysis evaluated the statistical significance of these relationships using Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT)-based thresholds of pain reduction (<15%, 15% <30%, 30% to <50%, and ≥50%). Outcome measures included modified Brief Pain Inventory pain interference with function in one of the studies and the Medical Outcomes Study Sleep Scale (an 11-point Numeric Rating Scale) and the Hospital Anxiety and Depression Scale (HADS) for the pooled studies.ResultsData ellipses showed a shift with pregabalin relative to placebo toward greater improvement with increasing pain relief for all outcome measures except HADS. Loess curves suggested a relationship between increased pain relief and improved function except for HADS, with the clearest relationship observed for sleep. Linear trend analysis showed significant relationships between pain and Medical Outcomes Study Sleep Scale (P<0.0001) and between pain and function on the modified Brief Pain Inventory Interference Index and most individual items (P<0.05).ConclusionGreater functional improvements were generally achieved at higher levels of clinically significant pain reduction. Pregabalin resulted in shifts from placebo toward greater functional improvement with greater pain relief.

Project description:Placebo response in the clinical trial setting is poorly understood and alleged to be driven by statistical confounds, and its biological underpinnings are questioned. Here we identified and validated that clinical placebo response is predictable from resting-state functional magnetic-resonance-imaging (fMRI) brain connectivity. This also led to discovering a brain region predicting active drug response and demonstrating the adverse effect of active drug interfering with placebo analgesia. Chronic knee osteoarthritis (OA) pain patients (n = 56) underwent pretreatment brain scans in two clinical trials. Study 1 (n = 17) was a 2-wk single-blinded placebo pill trial. Study 2 (n = 39) was a 3-mo double-blinded randomized trial comparing placebo pill to duloxetine. Study 3, which was conducted in additional knee OA pain patients (n = 42), was observational. fMRI-derived brain connectivity maps in study 1 were contrasted between placebo responders and nonresponders and compared to healthy controls (n = 20). Study 2 validated the primary biomarker and identified a brain region predicting drug response. In both studies, approximately half of the participants exhibited analgesia with placebo treatment. In study 1, right midfrontal gyrus connectivity best identified placebo responders. In study 2, the same measure identified placebo responders (95% correct) and predicted the magnitude of placebo's effectiveness. By subtracting away linearly modeled placebo analgesia from duloxetine response, we uncovered in 6/19 participants a tendency of duloxetine enhancing predicted placebo response, while in another 6/19, we uncovered a tendency for duloxetine to diminish it. Moreover, the approach led to discovering that right parahippocampus gyrus connectivity predicts drug analgesia after correcting for modeled placebo-related analgesia. Our evidence is consistent with clinical placebo response having biological underpinnings and shows that the method can also reveal that active treatment in some patients diminishes modeled placebo-related analgesia. Trial Registration ClinicalTrials.gov NCT02903238 ClinicalTrials.gov NCT01558700.

Project description:BackgroundPregabalin is approved by the US Food and Drug Administration for the treatment of fibromyalgia (FM), diabetic peripheral neuropathy (DPN), postherpetic neuralgia (PHN), and neuropathic pain due to spinal cord injury (SCI). Approval was based on clinical trial data demonstrating statistically significant differences in pain scores versus placebo. However, statistically significant pain relief may not always equate to clinically meaningful pain relief. To further characterize the clinical benefit of pregabalin, this analysis examined shifts in pain severity categories in patients with FM, DPN/PHN (pooled in this analysis), and SCI treated with pregabalin.MethodsData were pooled from 23 placebo-controlled trials in patients with FM (1,623 treated with pregabalin, 937 placebo), DPN/PHN (2,867 pregabalin, 1,532 placebo), or SCI (181 pregabalin, 175 placebo). Pain scores were assessed on an 11-point numeric rating scale and categorized as mild (0 to <4), moderate (4 to <7), or severe (7 to 10). Only patients with mean score ≥4 at baseline were randomized to treatment. The percentage of patients shifting pain category from baseline to endpoint for pregabalin and placebo was analyzed using a modified ridit transformation with the Cochran-Mantel-Haenszel procedure.ResultsA higher proportion of patients shifted to a less severe pain category at endpoint with pregabalin compared with placebo. With flexible-dose pregabalin, the percentage of patients improving from: severe to mild (pregabalin versus placebo) was 15.8 versus 13.4 in FM patients, 36.0 versus 16.6 in DPN/PHN patients, 14.3 versus 7.7 in SCI patients; severe to moderate was 28.7 versus 28.2 in FM patients, 32.5 versus 28.2 in DPN/PHN patients, 35.7 versus 28.2 in SCI patients; and moderate to mild was 38.3 versus 26.4 in FM patients, 59.5 versus 41.4 in DPN/PHN patients, 38.6 versus 27.2 in SCI patients.ConclusionCompared with placebo, pregabalin is more often associated with clinically meaningful improvements in pain category in patients with FM, DPN, PHN, or SCI.

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Predictors of placebo response in peripheral neuropathic pain: insights from pregabalin clinical trials.

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Predictors of placebo response in peripheral neuropathic pain: insights from pregabalin clinical trials.

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