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Duloxetine (Cymbalta®)

Duloxetine in Brief

Generic name : Duloxetine hydrochloride
Brand names: Cymbalta®, Xeristar®, Yentreve®
Therapeutic class: Antidepressant
Pharmacologic class: Serotonin-Norepinephrine Reuptake Inhibitor
FDA Approved: August 3, 2004
Patent expiration date: June, 2013
Chemical Formula: C18H19NOS-HCl
Pregnancy Category: C
Habit forming? No
Originally discovered: 1988, Eli Lilly & Company, USA

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

History

The first publication of the discovery of the new potential antidepressant LY227942 was made in 1988 by Eli Lilly and Company researchers 30. LY248686 (Duloxetine hydrochloride, (+)-N-methyl-3-(1-naphthalenyloxy)-2-thiophenepropanamine) was synthesized for research purposes. LY227942 was the starting point for the development of duloxetine.

Duloxetine has been shelved in the early 1990s, in part because low doses had no effect on depression. But Lilly scientists discovered that higher doses relieved depression at least as well as Prozac. Subsequent testing proved the drug also curbed stress-related urinary incontinence. Eli Lilly originally patented duloxetine formula on June 11, 1991 (US patent No 5023269 "3-aryloxy-3-substituted propanamines").

Duloxetine was originally approved by the US FDA in August 3, 2004 for the treatment of depression under the trade name Cymbalta. Shortly after the approval for depression, duloxetine became the first and only officially indicated drug in the U.S. for the treatment of pain from diabetic peripheral neuropathy. In February 2007, the FDA approved Cymbalta for the treatment of generalized anxiety disorder (GAD). Finally, on November 2010, Cymbalta was licensed for chronic musculoskeletal pain.

FDA approved indications

Depression (MDD)
Diabetic peripheral neuropathic pain
Generalized anxiety disorder
Fibromyalgia 3, 18
Chronic musculoskeletal pain

Duloxetine for Fibromyalgia

Fibromyalgia is a chronic and painful musculoskeletal disorder. It affects 2 to 4 percent of the U.S. population. It is characterized by widespread pain and fatigue, sometimes to a disabling degree.

In a good-quality placebo-controlled trial, duloxetine (60 mg twice daily for 12 weeks) was shown to be moderately efficacious, safe, and well tolerated in the off-label treatment of patients with fibromyalgia 18. In clinical trials 3, 18 duloxetine treatment was associated with:

moderate reductions in the total score on the Fibromyalgia Impact Questionnaire
reductions in Brief Pain Inventory average pain severity and interference scores, number of tender points, and FIQ stiffness score
significant improvements in mean tender point pain threshold and several quality-of-life measures

However, significant improvement with duloxetine occurred in females only, whereas a treatment benefit was not shown in men.

The study has shown that Cymbalta's effect on fibromyalgia symptoms is independent of any effect on mood. There was no significant difference in response rates between patients with and without major depression 18.

Off-label & Investigational uses

Stress urinary incontinence (officially approved in Europe) 12
Chronic pain
Chronic fatigue syndrome 19
Low back pain33

Duloxetine "pros" and "cons"

Cymbalta appears to be an attractive option for MDD patients presenting with painful physical symptoms. This antidepressant may offer important benefits for postmenopausal women who have depression and menopause-related symptoms 21. Cymbalta is effective treatment in generalized anxiety disorder with significant pain symptoms 22.

Advantages:

Reduces painful physical symptoms of depression 11
Low risk of weight gain with short-term treatment 24
Lower rate of sexual side effects that with SSRIs 4, 10
Antidepressant effects may be noticed after one week 13
Convenience of once-daily dosing
Low risk of duloxetine emergent hypomania, mania, or hypomanic-like symptoms 25
Specifically studied for pain
True "dual agent" -- increases levels of norepinephrine at lower doses than venlafaxine (Effexor) 27
Relatively low cardiovascular risks 23
Effective in elderly patients with recurrent major depressive disorder 7
Effective in the prevention of depression relapse 8

Disadvantages:

High rates of nausea during treatment initiation 5
Higher rates of insomnia compared to SSRIs (may be a persistent side effect) 14, 16, 26
Making PTSD worse 28
Risk of weight gain with long-term treatment, the risk increases with higher doses 24
May cause severe withdrawal symptoms 2
Hepatic side effects. Duloxetine may cause aminotransferase increases. Patients with preexisting liver disease or excessive alcohol use are at a greater risk of duloxetine-induced liver injury 29.
Increases blood pressure 6
Potential for significant drug interactions between duloxetine and drugs that inhibit CYP1A2 enzymes or drugs that are metabolized by CYP2D6 enzymes.
May aggravate narrow-angle glaucoma.
Urinary retention
Rare cases of hyponatremia (low sodium level in the blood) have been reported31.
Very expensive.

Mechanism of action

Duloxetine is believed to exert its antidepressant effect through the potentiation of serotonergic and noradrenergic activity in the central nervous system.

Duloxetine is a potent inhibitor of serotonin and norepinephrine reuptake, with weak effects on dopamine reuptake. Duloxetine has no significant activity for muscarinic cholinergic, H1-histaminergic, or alpha2-adrenergic receptors, and does not possess MAO-inhibitory activity.

Analgesic effect of duloxetine
While some effects of duloxetine on painful symptoms can be accounted for its antidepressant action, the data strongly suggests that duloxetine also exerts a substantial direct analgesic effect over and above its antidepressant effects, in patients with major depressive disorder, diabetic peripheral neuropathic pain, and fibromyalgia syndrome 17.

Time to clear out of the system

The half-life of duloxetine is 10 to 15 hours. Steady-state is usually achieved after 3 days.

It may take 2 to 3 days for duloxetine to clear out of the system.

Onset of action

It usually takes 1-4 weeks to see improvements in symptoms and may take up to 4 to 7 weeks to achieve the remission. The symptoms showing improvements after 1-2 weeks of Cymbalta are depressed mood, guilt, suicidal ideation, work/activities, psychic anxiety, back pain and shoulder pain, retardation 13.

Efficacy rate: According to the studies that demonstrated efficacy of Cymbalta in the treatment of major depressive disorder the probabilities of remission range from 43% to 57% 15.

Weaning off Duloxetine

Most common duloxetine discontinuation symptoms include 9:

dizziness
nausea
headache
paresthesia
vomiting
irritability
nightmares