Safety and tolerability of duloxetine in the acute management of diabetic peripheral neuropathic pain: analysis of pooled data from three placebo-controlled clinical trials

Abstract

Objective: Summarize safety and tolerability of duloxetine in treating diabetic peripheral neuropathic pain.

Research design and methods: Pooled data from three double-blind, randomized studies with 12-week, placebo-controlled (acute) and 52-week, routine-care-controlled (extension) phases.

Main outcome measures: Frequency/discontinuations due to treatment-emergent adverse events (TEAEs).

Results: There were 1139 (placebo, n = 339; duloxetine, n = 800) and 867 (routine-care, n = 287; duloxetine, n = 580) patients in the acute and extension phases, respectively. Patient details were as follow: 60 years (mean age); Caucasian, 84%; and male, 57%. In the acute phase, there were significantly more TEAEs, duloxetine versus placebo (p = 0.001), the most common being nausea and somnolence. Discontinuations due to adverse events were significantly greater (12.5 vs 5.6%, p < 0.001), with similar outcomes in the extension phase. Baseline-to-endpoint aspartate transaminase/alanine transaminase were significantly increased and fasting plasma glucose was increased for duloxetine (0.67 mmol/l) versus decreased in routine-care (-0.64 mmol/l, p < 0.001). HbA1c was significantly increased, duloxetine vs routine-care, in the extension phase (52 vs 19%, p < 0.001). Endpoint measures neuropathy, nephropathy and retinopathy indicated no disease progression.

Conclusions: Duloxetine was generally safe and well tolerated, with the three most commonly reported TEAEs being nausea, somnolence and constipation. Modest changes in glycemia were associated with duloxetine. Aspartate transaminase/alanine transaminase increases were transient and not considered predictive of more severe outcomes.

Keywords::

• diabetes
• duloxetine
• neuropathy
• pain

Acknowledgments

All authors are current employees of Eli Lilly and Company (with the exception of JA Hall, a former Lilly USA employee and current Abbott Laboratories employee) and meet the ICMJE conditions for authorship. All authors have read and approved the final version of the manuscript. In addition, JA Hall, TM Myers Oakes, F Wang, A Crucitti and N Acharya were involved in the analysis and interpretation of the study data and drafting and review of the manuscript; F Wang was also involved in the design of the trials. BG Utterback was involved with the interpretation of the data and drafting of the manuscript.

The authors would like to thank M Wohlreich, A Meyers, S Mellinger, J Ahl and S Shoemaker for their critical review of this manuscript.

Clinical trial registry summaries for the trials included here are posted at: http://www.clinicalstudyresults.org with the ID numbers 4097aa, 4097ab, 4097ba, 4097bb, 4098a and 4098b.

Two of the three trials that comprise this manuscript were registered at http://clinicaltrials.gov. As these two trials were identical, they were registered under the same ID number: NCT00322621. The third trial opened prior to the requirement for study registration.