Pharmacology Update

Duloxetine Hydrochloride Capsules (Cymbalta)

By William T. Elliott, MD, FACP, and James Chan, PharmD, PhD

The FDA has approved duloxetine for the treatment of depression and the management of the pain associated with diabetic peripheral neuropathy. The drug is a selective serotonin and norepinephrine reuptake inhibitor (SSNRI) similar to venlafaxine (Effexor). Duloxetine is marketed by Eli Lilly and Company as Cymbalta.


Duloxetine is indicated for the treatment of major depressive disorder (MDD). Effectiveness has not been studied in hospitalized patients with MDD.1 Duloxetine is also indicated for the management of pain associated with diabetic peripheral neuropathy.


The recommended dose for depression is 40 mg (20 mg twice daily) to 60 mg daily (60 mg once daily or 30 mg twice daily). It may be taken without regard to meals. The recommended dose for neuropathy is 60 mg daily. The capsule contains enteric-coated pellets therefore it should be swallowed whole, not chewed or crushed nor sprinkle on food or liquid. It is not recommended for patients with liver dysfunction or patients with end stage renal disease.1

Duloxetine supplied as 20 mg, 30 mg, and 60 mg capsules.

Potential Advantages

Duloxetine is the first drug approved for the management of diabetic peripheral neuropathy. It is also reported to be effective in relieving painful physical symptoms in depressed patients. Improvements in pain severity were associated with higher remission rates.2

Potential Disadvantages

Duloxetine has been associated with increased risk of mydriasis. Therefore it should be avoid in patients with uncontrolled narrow angle glaucoma. Common side effects associated with duloxetine are nausea, somnolence, insomnia, headache, dry mouth, constipation, dizziness, and diarrhea.1,3 These tend to be more common earlier in therapy.3 Increase in blood pressure, symptoms of urinary hesitation, sexual dysfunction in males, and elevation of serum transaminase levels have also been reported. Other frequent (at least 1/100) side effects observed during premarketing evaluations include gastritis, irritability, lethargy, nervousness, nightmare, restlessness, dysuria, night sweats, pruritus, and rash.1 Duloxetine is metabolized by CYP1A2 and CYP2D6. Potent inhibitors of these isoenzymes result in increase levels of duloxetine. Duloxetine is also a moderate inhibitor of CYP2D6 and intermediate between paroxetine and sertraline.4 Due to the risk of serious ventricular arrhythmias and sudden death the co-administration of thioridazine and duloxetine in contraindicated.1


Duloxetine is a SSNRI with high affinity for these transporters and with little affinity for other central nervous system neural transmitters.5 Efficacy in MDD was shown in randomized placebo controlled studies of 8-9 week duration1,2,5,6 The primary end point was the 17-item Hamilton Depression Rating Scale (HAMD-17). In comparative trials with placebo and an active control, Duloxetine 40 mg was found to similar to paroxetine 20 mg in terms of response rate and remission rate although the primary goal of the study was not to compare active treatments,7 However, in a long-term open-label (n = 1279) the drug was reported to be effective, safe, and well tolerated.3 Mechanistically, duloxetine is most similar to venlafaxine. There are currently no published comparative trials between these SSNRIs. Venlafaxine is metabolized by CYP2D6 while duloxetine is metabolized by 2D6 and 1A2 isoenzymes. Side effects of duloxetine appear to be similar to venlafaxine and other SSRIs. The efficacy of duloxetine for the management of diabetic neuropathy was established in 2 randomized 12-week, controlled studies in about 1000 non-depressed subjects.8 Fifty eight percent (58%) achieved a 30% reduction in pain compared to 34% for placebo.

Duloxetine is being investigated for treating urinary incontinence.9 Duloxetine is priced similar to venlafaxine.

Clinical Implications

Duloxetine is the first drug to be approved for the management of diabetic peripheral neuropathy. It is not known how it compares with other drugs (ie, antidepressant, anticonvulsants) currently being used for this condition with limited success.

Duloxetine joins the crowded antidepressant market with several SSRIs and one other SSNRI. It is most similar to venlafaxine with no clear clinical advantage over other antidepressants.

Dr. Elliott is Chair, Formulary Committee, Northern California Kaiser Permanente; Asst. Clinical Professor of Medicine, University of California, San Francisco. Dr. Chan is Pharmacy Quality and Outcomes Manager, Kaiser Permanente, Oakland, CA. Both are associate editors of Internal Medicine Alert.


1. Cymbalta Product Information. Eli Lilly and Company. August 2004.

2. Fava, M, et al. J Clin Psychiatry. 2004;65(4):521-530.

3. Raskin J, et al. J Clin Psychiatry. 2003;64:1237-1244

4. Skinner MH, et al. Clin Pharmacol Ther. 2003; 73(3):170-177.

5. Karpa KD, et al. CNS Drug Rev. 2002;8(4):361-376.

6. Detke MJ, et al. J Clin Psychiatry. 2002;63(4):308-315.

7. Goldstein DJ et al. J Clin Psychopharmacol 2004; 24:389-399.

8. Lilly press release. September 7, 2004.

9. Millard RJ et al. BJU Int. 2002;93(3):311-318.