A Randomized controlled trial of
duloxetine in diabetic peripheral neuropathic pain

 

Background:  Noradrenergic and serotonergic neurons may be responsible for the pain of  diabetic peripheral neuropathy, a selective 5-HT and NE reuptake inhibitor such as duloxetine may be advantageous in the treatment of diabetic peripheral neuropathy.

 

Objective:  The goal of this study was to confirm the safety and efficacy of duloxetine in the reduction of pain severity in diabetic patients with diabetic peripheral neuropathic pain (DPNP).

 

Methods:  This was a multicenter, parallel, double-blind, randomized, placebo-controlled trial.  Patients were included in the study if they were 18 or older and presented with DPNP caused by Type I or Type II diabetes.  The pain must have been present for at least 6 months.  Patients were also required to have stable glycemic control.  Patients were excluded if they were pregnant or breast-feeding; had previous renal transplant or current renal dialysis; had serious or unstable cardiovascular, hepatic, renal, respiratory, or hematological illness, symptomatic peripheral vascular disease; had a diagnosis of MDD, dysthmia, generalized anxiety disorder, alcohol, or eating disorder; had previous exposure to drugs known to cause neuropathy or history of substance abuse or dependence; treatment with an MAOI or fluoxetine; had severe allergic reactions to multiple medications; or had prior participation in a study of duloxetine.  A total of 334 patients were enrolled in the study and randomized to treatment groups:  placebo, duloxetine 60 mg once daily, or duloxetine 60 mg twice daily.  The study lasted for 13 weeks.  The primary efficacy outcome measure was the reduction in weekly mean of the 24-hour average pain scores.  The secondary efficacy outcome measures were pain severity for worst pain and night pain, along with dynamic allodynia and various scales used to assess patient perception of pain, improvement, and depression.  Investigators also observed health outcomes, pharmacokinetic measures, and safety measures.  The power of this study was 90%.  Data was handled using intent-to-treat analysis.

 

Results:  A total of 248 patients completed the study:  placebo group n=85, duloxetine once daily n=85, duloxetine twice daily n=78.  Compared to placebo, duloxetine showed a decrease in mean pain scores of –1.32 (p<0.001; 95% CI –1.95 to –0.69) for duloxetine once daily, and –1.44 (p<0.001 95% CI –2.08 to –0.81) for duloxetine twice daily.  For secondary outcomes, both duloxetine groups showed significant differences compared with placebo except for the 17-item Hamilton Rating Scale for Depression (HAMD₁₇) and dynamic allodyania.  For 24-hour worst pain score, the mean difference from placebo was –1.27 (p<0.001) for duloxetine once daily and –1.45 (p<0.001) for duloxetine twice daily.  Compared to placebo, significantly more patients in the duloxetine groups achieved a 30% and 50% reduction in the 24-hour pain response.

 

Strengths:  This study was well designed in the fact that it was double-blind, randomized, and placebo-controlled.  The study had appropriate power for the primary outcome.  Investigators fully elucidated the reasons for study dropouts.

 

Weaknesses:  Compliance and unblinding were not addressed in this study.  Pain diaries and many subjective assessments were used to measure outcomes, which could greatly affect results, especially if unblinding or noncompliance occurred.  Many baseline characteristics showed large variability such as duration of diabetes and diabetic neuropathy.  Differences in acetaminophen use were reported as being significantly lower when compared to placebo, but dosages were low overall and were not clinically significant.  The occurrence of some adverse events such as nausea and somnolence may contradict the relative tolerability of duloxetine reported by investigators.  Many significant results appear skewed due to the reporting of standard error of the mean rather than standard deviation.  When standard deviation is calculated, results show more variability.  Results for primary outcome did not achieve the goal set by investigators for clinical relevance, which was a change from baseline to endpoint of approximately 2 points.  Finally, all investigators were affiliated with Eli Lilly in some way, and the study was funded by Eli Lilly, the manufacturer of duloxetine.

 

Conclusion:  Based on the results and findings of this study, duloxetine does appear to be relatively safe and may have some effect on DPNP.  However, the results should be interpreted with caution based on the limitations of the study.  Duloxetine should be reserved for patients who do not tolerate or fail other established and cost-effective therapies for DPNP.  Future studies focusing on duloxetine’s long-term safety would be appropriate, in addition to head-to-head trials comparing duloxetine to other established therapies for DPNP.

 

Wernicke JF, Pritchett YL, D’Souza DN, Waninger A, Tran P, Iyengar S, Raskin J.  A randomized controlled trial of duloxetine in diabetic peripheral neuropathic pain.  Neurology 2006;67:1411-1420.

 

Catherine M. Hathaway, Pharm.D. Candidate