Duloxetine in Brief
- Generic name : Duloxetine hydrochloride
- Brand names: Cymbalta®, Xeristar®, Yentreve®
- Therapeutic class: Antidepressant
- Pharmacologic class: Serotonin-Norepinephrine
- 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,
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
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). Finaly, 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
- 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 have 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
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.
- 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,
- Antidepressant effects may be noticed after one week 13
- Convenience of once-daily dosing
- Low risk of duloxetine emergent hypomania, mania, or hypomanic-like
- Specifically studied for pain
- True "dual agent" -- increases levels of norepinephrine at lower doses than venlafaxine
- Relatively low cardiovascular risks 23
- Effective in elderly patients with recurrent major depressive
- Effective in the prevention of depression relapse 8
- High rates of nausea during treatment initiation 5
- Higher rates of insomnia compared to SSRIs (may be a persistant
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
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 by its antidepressant action, the data strongly suggest 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:
Duloxetine (Cymbalta) and weight gain
Short-term treatment is usually not associated with weight gain. Some
persons may experience minor weight loss. However, there is a risk of
waight gain with long-term treatment, and this risk increases with higher
doses 24, 26.
Duloxetine (Cymbalta) and alcohol
The combination of duloxetine with alcohol can lead to liver injury.
Duloxetine should be used with caution in patients with chronic
liver disease, and substantial alcohol use 29.
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Published: March 31, 2008
Last updated: May 25, 2015
- Eli Lilly's patent on Cymbalta has been expired on June 11, 2013.
- Duloxetine has become the first drug to gain FDA approval for treatment of painful diabetic neuropathy (PDN).