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Am Fam Physician. 2005;72(6):1099-1101

Synopsis

Duloxetine (Cymbalta) is a serotonin and norepinephrine reuptake inhibitor in the same class as venlafaxine (Effexor). It is approved by the U.S. Food and Drug Administration (FDA) for use in the treatment of major depressive disorder and of diabetic peripheral neuropathic pain. In Europe it is marketed for the treatment of stress urinary incontinence; it is not approved for that indication in the United States.

NameStarting dosageDose formApproximate monthly cost*
Duloxetine (Cymbalta)20 to 30 mg twice daily or 60 mg once daily20−, 30−, and 60-mg capsules$100 for 30 60-mg capsules; $180 for 60 20-mg capsules

Safety

Duloxetine is considered to be safe. In one open-label study1 there were seven suicide attempts among 1,279 patients in one year (one suicide attempt per 115 patient-years of drug exposure) and no cases of fatal acute overdose. Duloxetine should not be used in patients taking a monoamine oxidase inhibitor (MAOI), including a period of five days before initiation of the MAOI and 14 days after its discontinuation.2 Duloxetine is metabolized extensively by cytochrome P450 enzymes 1A2 and 2D6. Duloxetine plasma concentrations may be increased significantly by some antidepressants, quinidine, and quinolone antibiotics. Duloxetine may increase the plasma concentrations of other antidepressants, antipsychotics, and type 1C antiarrhythmics such as propafenone (Rythmol) and flecainide (Tambocor).

Serum alanine transaminase levels increased to more than three times the upper limit of normal in about 1 percent of patients taking duloxetine in placebo-controlled trials2; alcohol may increase this risk. However, there have been no reports of hepatic failure. Duloxetine is not recommended in patients with end-stage renal disease or severe renal impairment because of the increased plasma concentrations of the drug and its metabolites. Duloxetine is FDA pregnancy category C based on negative animal studies; there have been no trials assessing its use in pregnant women.

Tolerability

In clinical trials for depression, the discontinuation rate in patients receiving duloxetine was significantly higher than in patients receiving placebo (approximately 10 percent and 4 percent, respectively).2 Nausea, somnolence, insomnia, and dizziness are the main side effects, reported by about 10 to 20 percent of patients.2 Anticholinergic-type side effects can occur. Changes in heart rate, blood pressure, and weight are not clinically significant.3 In four studies of depression, there was a higher rate of sexual dysfunction in men receiving duloxetine compared with those receiving placebo, based on the Arizona Sexual Experience scale.2 Men receiving duloxetine, 80 mg daily, found it more difficult to achieve orgasm than men receiving placebo.4 Rates of sexual dysfunction based on voluntary reporting range from 3 to 6 percent, although underreporting is likely.2 No effect on sexual function in women has been reported. There are no data comparing duloxetine with other anti-depressants in terms of their impacts on the rates of sexual dysfunction.

Effectiveness

Four studies involving a total of 1,059 patients with major depression have demonstrated the superiority of duloxetine over placebo based on the Hamilton Depression Rating Scale.2 Three of these studies,46 however, used duloxetine at higher-than-labeled dosages (80 to 120 mg daily). In an eight-week study4 of patients with mild to moderate depression, duloxetine, 40 mg daily, produced a response rate of 44 percent, compared with 31 percent for placebo (number needed to treat [NNT] = 8) and 40 percent for paroxetine (Paxil), 20 mg daily. In a study3 of patients given the maximum daily dose of 60 mg, the response rates were 45 percent for duloxetine and 23 percent for placebo (NNT = 5). There are no data regarding the effectiveness of duloxetine for preventing recurrence of symptoms.

Although duloxetine is marketed for the treatment of painful physical symptoms associated with depression, research results do not support its effectiveness for this use. In manufacturer-conducted studies, patients with low baseline pain scores had clinically insignificant changes in pain scores, with no significant improvement in overall pain or functional status.5 A study7 involving patients who had fibromyalgia with or without major depressive disorder showed a modest improvement (five-point difference on an 80-point scale) in those taking duloxetine compared with those taking placebo, which is unlikely to be clinically significant.

In the treatment of painful diabetic neuropathic pain, studies involving 791 patients showed duloxetine, 60 mg once or twice daily, to be more effective than placebo.2 The primary outcome measure—a reduction in the 24-hour average pain severity on the 11-point Brief Pain Inventory—decreased by about one point more with duloxetine than with placebo. A change in pain intensity of two points or more is considered clinically relevant. Functional outcomes were not assessed. There are no published studies, other than the trials mentioned above,2 of duloxetine’s efficacy in the treatment of diabetic neuropathy. Duloxetine has not been compared with other treatments for diabetic neuropathy.

Although not labeled for the treatment of stress urinary incontinence, duloxetine has been compared with placebo for this use in four studies worldwide.8 Duloxetine, 40 to 80 mg daily for 12 weeks, was shown to decrease the median incontinence episode frequency in 2,188 women by 50 to 64 percent, significantly better than placebo (reduction of 27 to 41 percent). Duloxetine has not been compared with other drugs for incontinence.

Price

A one-month supply of duloxetine, 60 mg daily, costs approximately $100. This is comparable to or lower than the price of extended-release venlafaxine (Effexor XR), depending on the dose, and more expensive than paroxetine and escitalopram (Lexapro). Generic fluoxetine is much less expensive at $9 to $25 per month.

Simplicity

The usual dosage of duloxetine is 40 to 60 mg once daily, without regard to food. It may be divided and given in a 20− to 30-mg dose twice daily to decrease nausea. The maximum daily dose is 60 mg.

Bottom Line

Duloxetine is safe and effective for the treatment of major depressive disorder. Because of its expense and the lack of data supporting its superiority over other antidepressants, it should be used as an alternative if other agents are ineffective or are not tolerated. The manufacturer has launched an aggressive marketing campaign targeting the use of duloxetine for the painful physical symptoms of depression, although there is insufficient evidence to support the choice of duloxetine for this indication over any other antidepressant. Duloxetine causes a modest reduction in pain in patients with diabetic neuropathy but is more expensive than amitriptyline (Elavil) and desipramine (Norpramin), and evidence showing benefit over these older agents is lacking.

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