Impact of Disease Characteristics on the Efficacy of Duloxetine in Diabetic Peripheral Neuropathic Pain

Ziegler, Dan; Pritchett, Yili; Wang, Fujun; Desaiah, Durisala; Robinson, Michael J.; Hall, Jerry A.; Chappell, Amy S.

doi:10.2337/dc06-2009

Cited by 73 publications

(42 citation statements)

References 21 publications

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“…Registration studies of pregabalin (Lyrica, Pfizer, New York, NY), duloxetine (Cymbalta, Eli Lilly, Indianapolis, IN), and gabapentin (Neurontin, Pfizer) had a placebo change in pain severity by PI-NRS or PI-VAS (cm) from À 0.3 to À 1.7 at 8 to 12 weeks for PDN or postherpetic neuralgia [(last observation carried forward (LOCF)]. [2][3][4][5][6][7][8][9][10][11][12] Fourteen to 22 week clinical trials of lamotrigine (Lamictal, GlaxoSmithKline, London, UK), topiramate (Topamax, Johnson and Johnson, New Brunswick, NJ), and oxcarbazepine (Trileptal, Novartis, Basel, Switzerland) that failed to demonstrate a consistent treatment effect in PDN and neuropathic pain had a placebo change in PI-NRS from À 1.5 to À 2.2 (LOCF). [13][14][15][16][17][18] Large and variable improvement of pain scores in the placebo group may make it more difficult to detect true medication effects.…”

mentioning

confidence: 99%

Predictors of Placebo Response in Pooled Lamotrigine Neuropathic Pain Clinical Trials

Irizarry

Webb²,

Ali

et al. 2009

The Clinical Journal of Pain

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confidence: 99%

Predictors of Placebo Response in Pooled Lamotrigine Neuropathic Pain Clinical Trials

Irizarry

Webb²,

Ali

et al. 2009

The Clinical Journal of Pain

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“…This result is consistent with an analysis of 3 clinical trials of painful DPN that suggested that medication vs placebo differences were greater in subjects with greater baseline pain intensity. 31 Considered together, these data suggest that neuropathic pain RCTs should use a pain inclusion criterion of at least 40 on a 0 to 100 scale (alternatively 4 on a 0-10 scale) to decrease the likelihood that studies of efficacious treatments will have falsely negative outcomes. We also found that age was associated with assay sensitivity, with greater subject age being associated with larger effect sizes.…”

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confidence: 99%

Assay sensitivity and study features in neuropathic pain trials

et al. 2013

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Objective: Our objective was to identify patient, study, and site factors associated with assay sensitivity in placebo-controlled neuropathic pain trials. Methods:We examined the associations between study characteristics and standardized effect size (SES) in a database of 200 publicly available randomized clinical trials of pharmacologic treatments for neuropathic pain.Results: There was considerable heterogeneity in the SESs among the examined trials. Univariate meta-regression analyses indicated that larger SESs were significantly associated with trials that had 1) greater minimum baseline pain inclusion criteria, 2) greater mean subject age, 3) a larger percentage of Caucasian subjects, and 4) a smaller total number of subjects. In a multiple metaregression analysis, the associations between SES and minimum baseline pain inclusion criterion and age remained significant. Conclusions: Our analyses have examined potentially modifiable correlates of study SES andshown that a minimum pain inclusion criterion of 40 or above on a 0 to 100 scale is associated with a larger SES. These data provide a foundation for investigating strategies to improve assay sensitivity and thereby decrease the likelihood of falsely negative outcomes in clinical trials of efficacious treatments for neuropathic pain. Multiple efficacious medications have been identified for the treatment of patients with neuropathic pain.1-4 However, these treatments have significant limitations. For example, in placebocontrolled randomized clinical trials (RCTs), no more than 60% of patients with neuropathic pain experience clinically important pain reductions.5 In addition to modest efficacy, there are appreciable side effects and safety risks. These limitations of existing medications for neuropathic pain provide a compelling impetus for the development of treatments with improved efficacy, safety, and tolerability.A major challenge in developing improved treatments for neuropathic pain is that a number of recent neuropathic pain RCTs have found that the medications being evaluated did not significantly differ from placebo in conditions in which their efficacy was previously demonstrated and for which they had been approved by regulatory agencies. [6][7][8] Assuming that previous evidence of efficacy was valid and that patients and outcome measures in these studies were comparable, such results may reflect a failure of the RCTs themselves to demonstrate analgesic effects.Failure to demonstrate statistically significant evidence of efficacy can reflect limited assay sensitivity, which has been defined as the ability of a clinical trial "to distinguish an effective treatment from a less effective or ineffective treatment." 9 Identifying patient, research design,

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“…In several large trials, P Ͻ 0.10 has been interpreted as a significant test for treatment effect modification in subgroup analysis (interaction), despite increasing the chance of type I error, 21,22 yet cautious interpretation of the interaction terms is required for the NASCET results. The seeming benefit may be in part due to chance variation in the rates of stroke at 2 yr among surgically treated patients with CKD compared with those with preserved renal function (5.6 versus 9.5% respectively; Table 2).…”

Section: Discussionmentioning

confidence: 99%

Carotid Endarterectomy Benefits Patients with CKD and Symptomatic High-Grade Stenosis

Mathew¹,

Eliasziw²,

Devereaux³

et al. 2010

Journal of the American Society of Nephrology

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Endarterectomy is generally recommended for symptomatic high-grade (70 to 99%) stenosis of the internal carotid artery, but whether this procedure is beneficial among patients with chronic kidney disease (CKD) is unknown. In this re-analysis of data from the North American Symptomatic Carotid Endarterectomy Trial, we included patients with symptomatic stenosis and either stage 3 CKD (n ϭ 524) or preserved kidney function (n ϭ 966; estimated GFR Ն 60). For medically treated patients with high-grade stenosis, risk for ipsilateral stroke at 2 yr was significantly higher in patients with CKD than in those with preserved renal function (31.6 versus 19.3%; P ϭ 0.042); carotid endarterectomy significantly reduced this risk by 82 and 51%, respectively. To prevent one ipsilateral stroke, the number needed to treat by endarterectomy was four for patients with CKD and 10 for patients with preserved renal function. Compared with patients with preserved renal function, those with CKD had similar rates of perioperative stroke and death but higher rates of cardiac events. In conclusion, patients with stage 3 CKD and symptomatic high-grade carotid stenosis gain a large benefit in stroke risk reduction after endarterectomy. Approximately 795,000 people in North America have a stroke every year, 185,000 of whom have recurrent strokes. 1 As a secondary prevention strategy, current practice guidelines recommend carotid endarterectomy for patients with symptomatic high grade (70 to 99%) carotid stenosis. 2 Endarterectomy is also offered to patients with moderategrade (50 to 69%) stenosis, after considering factors such as age, gender, comorbidities, and severity of recent symptoms. 2 It is estimated that Ͼ15 million Americans have chronic kidney disease (CKD), and the prevalence is increasing. 3 Patients with CKD are at high risk for cardiovascular 4 -6 and cerebrovascular disease, including stroke 7,8 ; however, patients with CKD are less likely than others to undergo invasive procedures to reduce this risk, 9 a phenomenon sometimes called "renalism." 10 Although patients with CKD are prone to adverse events from procedures and treatments, 11,12 in some situations patients with CKD derive larger absolute benefits than others because of their high baseline risk. [13][14][15][16]

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Impact of Disease Characteristics on the Efficacy of Duloxetine in Diabetic Peripheral Neuropathic Pain

Cited by 73 publications

References 21 publications

Predictors of Placebo Response in Pooled Lamotrigine Neuropathic Pain Clinical Trials

Predictors of Placebo Response in Pooled Lamotrigine Neuropathic Pain Clinical Trials

Assay sensitivity and study features in neuropathic pain trials

Carotid Endarterectomy Benefits Patients with CKD and Symptomatic High-Grade Stenosis

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