Drug Criteria & Outcomes

Duloxetine (Cymbalta) Formulary Evaluation

Part 2: Clinical Trial Summary, Treatment of Peripheral Neuropathy, Conclusion/Recommendation

By Andrea Pierce, PharmD Candidate
McWhorter School of Pharmacy
Samford University, Birmingham, AL

Clinical trial summary

Duloxetine has been studied in several randomized, placebo-controlled clinical trials. The following three trials determine duloxetine to be efficacious in the treatment of major depressive disorder (MDD) in adults. Duloxetine also has been approved to treat peripheral neuropathy. At the present time, there have not been any studies evaluating duloxetine’s efficacy compared to other agents such as selective serotonin reuptake inhibitors (SSRIs) or serotonin/norepinephrine (SNRIs) reuptake inhibitors. All the trials addressed both efficacy and safety issues. The trials compared duloxetine to placebo to determine efficacy. The following fourth study also evaluates its use in peripheral neuropathy.

Trial 1: Detke MJ, Lu Y, Goldstein DJ, et al. Duloxetine, 60 mg, once daily, for major depressive disorder: A randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002;63:308-315.

This was a prospective, placebo-controlled clinical trial involving 245 patients with diagnosed MDD according to the DSM-IV criteria, who were randomly chosen to receive either placebo or duloxetine 60 mg for a total of nine weeks. The primary efficacy tool used was the Hamilton Rating Scale for Depression (HAM-D) score and was measured at each visit. Other tests used to measure secondary endpoints were the Clinical Global Impressions-Severity Scale (CGI-S), the Patient Global Impressions-Improvement Scale (PGI-I), the Visual Analog Scale (VAS), and the Quality of Life in Depression Scale.

The probability that patients will go into remission is higher in the duloxetine group than in the placebo group (44% vs. 16%). The duloxetine patients also had less painful physical symptoms such as headache and backaches than those patients receiving placebo. There were more duloxetine-treated patients to withdraw from the study than placebo-treated patients (13.8% vs. 2.5%). The main adverse effect reported was nausea (occurring mainly during the first week of treatment) in 46.3% of duloxetine patients, compared to 9% in placebo.

The strengths of the study included randomization, double-blind design, lead-in and lead-out phases, and use of several tests to determine efficacy. The weaknesses include lack of titration schedule, short duration, and the use of a placebo control rather than an active control. In conclusion, duloxetine was shown to be safe and effective in the treatment of MDD and in the reduction of painful symptoms associated with depression.

Trial 2: Goldstein DJ, Mallinckrodt C, Lu Y, et al. Duloxetine in the treatment of major depressive disorder: A double-blind clinical trial. J Clin Psychiatry 2002;63:225-231.

This trial was a prospective, double-blind placebo-controlled study of the efficacy and safety of duloxetine in the treatment of MDD. This study involved 173 patients randomized to receive duloxetine, placebo, or fluoxetine 20 mg per day (2:2:1 ratio). The fluoxetine arm served as an internal control group; this study was not designed to be a comparison of fluoxetine and duloxetine. The duloxetine patients were titrated from 40 mg to 120 mg per day during the first three weeks of treatment. The primary endpoint was the HAM-D score with secondary endpoints being the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S, the PGI-I, and the Hamilton Rating Scale for Anxiety (HAM-A).

The results of the study showed a significant decrease in HAM-D scores in the patients treated with duloxetine compared to placebo. The estimated probability of remission after eight weeks of therapy was 56% in the duloxetine group, 32% in the placebo group, and finally 30% in the fluoxetine group. The estimated response rate was 64%, 52%, and 48% for duloxetine, fluoxetine, and placebo, respectively. Duloxetine also was shown to be more efficacious in most of the secondary endpoints than fluoxetine and placebo.

The number of patients who discontinued the study was higher in the duloxetine group than in the placebo group (10% vs. 4.3%). The side effects also were similar to those reported in other studies. The strengths of this study include randomization, double-blind design, and lead-in and lead-out phases.

The weaknesses include the use of a placebo control rather than an active control, forced titration to 120 mg/day with the maximum dose not reached until the fourth week of the eight-week study, and 2:2:1 ratio of agents used with the fluoxetine dose not maximized, perhaps in some cases allowing efficacy to be similar to placebo. The investigators concluded that duloxetine is an effective treatment in patients diagnosed with MDD with little risk of serious side effects.

Trial 3: Raskin J, Goldstein DJ, Mallinckrodt CH, et al. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry 2003; 64:1,237-1,244.

The study was an open-label, 52-week study to determine the long-term safety of duloxetine in doses up to 120 mg per day for patients with MDD as determined by the DSM-IV criteria. Patients who could not tolerate 80 mg per day of duloxetine were not included in the study. The primary endpoint was determined by the CGI-S, HAM-D, Beck Depression Inventory (BDI-II), and the PGI-I scales with quality of life determined by the patients using the Sheehan Disability Scale.

Of the 1,279 patients beginning the study, only 553 completed it, with 17% discontinuing due to adverse effects. The estimated probabilities of response at 6, 28, and 52 weeks were 62.9%, 84.3%, and 89.1%, respectively. The probabilities of remission were 50.8%, 75.6%, and 81.8% at weeks 6, 28, and 52 weeks, respectively.

The strengths of this study include the length of the study, use of appropriate tests to determine efficacy, and appropriate timing of measurements. The weaknesses in this study include the open-labeled single-arm design, high dropout rate, and the exclusion of patients who were unable to tolerate 80 mg duloxetine per day. In conclusion, duloxetine was well tolerated and efficacious during the 52-week trial in patients who could tolerate the drug at the beginning of their treatment period.

Treatment of peripheral neuropathy

Trial 4: Goldstein DJ, Lu Y, Iyengar S, et al. Duloxetine in the treatment of the pain associated with diabetic neuropathy. AAPM presentation from Eli Lilly & Co.; March 3, 2004.

This was a prospective, randomized, placebo-controlled trial to determine the efficacy of duloxetine in the treatment of peripheral neuropathy. Patients received duloxetine 20 mg, 60 mg, 120 mg, or placebo. The primary efficacy endpoint was the decrease in the 24-Hour Average Pain Severity Score. Doses of 60 mg to 120 mg per day were proven to be the most efficacious. The use of concomitant acetaminophen also was lower in the duloxetine-treated patients than the placebo. The results also showed that the patients taking the 60 mg dose had similar efficacy to the 120 mg group with fewer adverse events occurring.

The strengths of the study include randomization, prospective, intent-to-treat, and appropriate measurement tools used. The weaknesses include the use of a placebo control, short duration, and lack of titration schedule. The results of the study determined that duloxetine was efficacious in the treatment of the pain associated with neuropathies with the dose of 60 mg being as effective as the 120 mg dose.

Conclusion/recommendation

Duloxetine appears to be an efficacious treatment for patients suffering from MDD, especially in patients suffering from painful physical symptoms. Its use is limited to the lack of clinical trials comparing it to other SSRIs or SNRIs, but studies currently are under way. Duloxetine also is FDA-approved to treat diabetic peripheral neuropathies. The occurrence of adverse effects appears to be rather low in patients treated with duloxetine. There is a risk of increased blood pressure, but it does not increase the blood pressure as much as venlafaxine. The risk of sexual side effects and weight gain also do not appear to occur as frequently as with other agents used to treat depression. Greater clinical experience with the drug will better define its adverse effect profile. At the present time, the addition of duloxetine to the formulary would be beneficial to several patient populations.

Resources

  • Clinical Pharmacology web site. Available at http://cp.gsm.com/. Assessed Oct. 10, 2004.
  • Cymbalta web site. Available at www.cymbalta.com. Assessed Oct. 19, 2004.
  • Detke MJ, Lu Y, Demitrack MA. Duloxetine, 60 mg, once daily, for major depressive disorder: A randomized double-blind placebo-controlled trial. J Clin Psychiatry 2002:63:308-315.
  • Goldstein DJ, Mallinckrodt C, Lu Y, et al. Duloxetine in the treatment of major depressive disorder: A double-blind clinical trial. J Clin Psychiatry 2002;63:225-231.
  • Goldstein DJ, Lu Y, Iyengar S, et al. Duloxetine in the treatment of the pain associated with diabetic neuropathy. AAPM presentation from the Eli Lilly & Co. March 3, 2004.
  • Raskin J, Goldstein DJ, Mallinckrodt CH, et al. Duloxetine in the long-term treatment of major depressive disorder. J Clin Psychiatry 2003;64:1,237-1,244.
  • USPDI Updates On-line, Vol. 122. Thomson Micro-medex web site. Available at www.micromedex.com. Assessed Oct. 18, 2004.
  • Wyeth-Ayerst web site. Available at: www.wyethayerst.com. Assessed Oct. 25, 2004.