Duloxetine (Cymbalta®)

Volume VII, Number 5 | September/October 2004
Ian Hollis, Pharm.D. Candidate

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Duloxetine (Cymbalta®; Eli Lilly and Co.) is classified as a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). It was approved by the Food and Drug Administration (FDA) in August 2004 for the treatment of major depressive disorder (MDD) and one month later received an indication for the treatment of peripheral neuropathic pain associated with diabetic neuropathy (DN).

Major Depressive Disorder (MDD)

MDD is characterized by a depressed mood or loss of interest in activities for a minimum of 2 weeks.1,2 At least four other symptoms must be experienced by the patient and may include fatigue, change in sleep patterns or appetite, impaired concentration, feelings of guilt, or periodic thoughts of death or suicide.1 MDD may manifest as unipolar depression, referring only to the periodic occurrence of depressive symptoms, or as bipolar depression, where depressive symptoms alternate with manic episodes consisting of a combination of increased psychomotor activity, decreased need for sleep, and delusional, grandiose, paranoid, or psychotic behavior.1,2

Approximately 15% of the general population will experience a major depressive event at some point in their lives. A depressive event occurs more often in women than in men.2 A possible cause of depression is a medical illness, either through psychological stress, the disease itself, or the pharmacological treatment. Neuroendocrine hormonal variations can also contribute to the etiology of MDD, especially when combined with environmental stressors (e.g., death of a relative, assault, or severe relationship issues).2

Pharmacotherapy for depression includes a variety of treatment options. The monoamine oxidase inhibitors (MAOIs), such as phenelzine (Nardil™), increase the concentration of serotonin (5-HT), norepinephrine (NE), and dopamine (DA) within the neuronal synapse through inhibition of the monoamine oxidase enzyme.3,4 The potential for hypertensive crisis, a severe and potentially life-threatening side effect, makes the use of these agents undesirable. Tricyclic antidepressants (TCAs), such as amitriptyline (Elavil®) and imipramine (Tofranil®), block the reuptake of 5-HT and NE. This class of drugs has shown good efficacy but has a burdensome adverse effect profile including anticholinergic, neurologic, and cardiovascular adverse effects.4 The selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac®), sertraline (Zoloft®), paroxetine (Paxil®), fluvoxamine (Luvox®), citalopram (Celexa®), and escitalopram (Lexapro®), were developed to achieve efficacy comparable to existing categories of antidepressants while maintaining an improved safety profile.4-6 This category of agents inhibits 5-HT reuptake and exhibits very little of the unwanted results of the aforementioned agents that also block NE and/or DA.

Venlafaxine (Effexor®) became the first agent in a category of antidepressants known as the SSNRIs. It lacks the adverse effects of TCAs while implementing the combined antagonism of 5-HT and NE. This mechanism may lead to a more rapid onset of therapeutic effect.7 Unfortunately, venlafaxine has the potential to increase blood pressure in a dose-dependent manner in approximately 3-13% of patients.8 Duloxetine is a new addition to the SSNRIs, and it appears to exhibit a greater balance in the relative reuptake inhibition of 5-HT and NE.7,9

Diabetic Neuropathy (DN)

DN is a set of clinical syndromes that affect distinct regions of the nervous system and may be precipitated by various pathologic mechanisms.10 It may involve somatic and/or autonomic aspects of the peripheral nervous system. DN may present focally, involving dysfunction of a single nerve or group of nerves, or diffusely, involving a larger group or area of nerves.10 DN occurs in approximately half of all patients with long-term diabetes mellitus (DM), both type 1 and type 2.2 The likelihood of its presence, like most chronic complications of DM, is dependent on the duration of time with DM and the degree of glycemic control.

One of the most common neuropathies related to DM is diffuse sensory neuropathy, which is gradual in onset and first presents with pain and loss of temperature and pressure sensation in the lower limbs. The pain is burning and superficial and may be accompanied by poor autonomic function such as sweating, dry skin, and decreased blood flow.2 Pain becomes constant for up to 10% of patients with DN, and it may occur independently or in response to a stimulus and may result in mood and sleep disorders.

Pharmacotherapy for DN-associated pain is determined by the type of fibers that are involved (e.g., C-fiber and A-delta fiber).10 Pharmacotherapy for C-fiber pain includes topical capsaicin or topical/oral clonidine (Catapres®). Pharmacotherapy for A-delta fiber pain includes insulin, intravenous lidocaine, tramadol (Ultram®), dextromethorphan, and anticonvulsants such as carbamazepine (Tegretol®), phenytoin (Dilantin®), gabapentin (Neurontin®), lamotrigine (Lamictal®), and topiramate (Topamax®). Each of these agents has limitations, including method of administration and adverse effects.10


Duloxetine has been shown to be a potent inhibitor of 5-HT and NE reuptake and a weak inhibitor of DA reuptake.9 In an in vitro study, duloxetine was shown to have a higher affinity for 5-HT transporters than NE transporters when compared with venlafaxine.7 Duloxetine has been shown to have little affinity for adrenergic, cholinergic, histaminergic, dopaminergic, opioid, γ-amino butyric acid (GABA), or glutamate receptors, nor does it inhibit monoamine oxidase.9


The elimination half-life for duloxetine is approximately 12 hours, with a range of 8-17 hours. Administration with food may delay the maximum concentration (Cmax) by approximately 4 hours (from 6 to 10 hours), and it may also decrease the extent of absorption (AUC) by 10%. Duloxetine is highly protein bound (>90%). It is metabolized by hepatic oxidation through the cytochrome P450 (CYP) 2D6 and 1A2 isoenzymes. The majority (70%) of the metabolites are eliminated in the urine and only 20% are excreted in feces. Unchanged duloxetine represents only 1-3% of the total excreted products.9,11

Select Clinical Studies


Goldstein and colleagues conducted an 8-week randomized, double-blind, placebo-controlled trial evaluating duloxetine for the treatment of MDD. Patients included in this study had a HAM-D-17 score of at least 15 and a CGI-S score >4. Patients (n=173) were randomized to one of the following treatment groups: placebo, duloxetine 40-60 mg twice daily, or fluoxetine 20 mg daily.5 Fluoxetine was present as a qualitative control arm for detection of efficacy and was not compared to duloxetine. The primary efficacy endpoint was the HAM-D-17 score. Secondary measures included the CGI-S and PGI-I. A response rate was defined as a >50% reduction in HAM-D-17 score from baseline, and a remission rate was defined as a HAM-D-17 score <7. Safety measures were also assessed and included discontinuation rates and blood pressure monitoring. Duloxetine demonstrated a greater mean change in the HAM-D-17 score from baseline to week 8 compared to placebo, -9.73 and -6.61, respectively (p=0.009). Estimated probabilities of response for placebo, duloxetine, and fluoxetine were 48%, 64%, and 52%, respectively and estimated probabilities of remission were 32%, 56%, and 30%, respectively. Select secondary measures can be located in Table 1. There were no statistically significant differences between duloxetine and placebo in discontinuation rates (10% vs. 4.3%) and adverse events except for asthenia (17.1% vs. 4.3%) and insomnia (20% vs. 7.1%). Hypertension was reported in 4.3% and 5.7% of the duloxetine-treated and placebo-treated patients, respectively. The majority of the duloxetine patients (75%) were titrated to 120 mg/day. The authors concluded that duloxetine is efficacious for the treatment of MDD and is safe and well-tolerated.5

Detke and co-workers conducted a 9-week randomized, double-blind, placebo-controlled trial evaluating duloxetine for the treatment of MDD in 245 patients.12 Inclusion criteria (e.g., baseline disease severity) were similar to the Goldstein study. Patients were randomized to duloxetine (60 mg once daily) or placebo. The primary efficacy measure was the HAM-D-17 score. Secondary measures included the VAS and CGI-S, and PGI-I scale as well as safety assessments.15 Response and remission rate definitions were the same as in the Goldstein trial. Duloxetine demonstrated a significantly greater mean change in the HAM-D-17 score from baseline to week 9 compared to placebo, -10.91 and -6.05, respectively (p<0.001). Select secondary measures can be located in Table 1. Nausea, dry mouth and somnolence were the most common adverse events in duloxetine-treated patients. Furthermore, no clinically significant incidence of hypertension was noted. Adverse events caused 17 duloxetine-treated patients and three placebo-treated patients to discontinue therapy. The authors concluded that duloxetine 60 mg administered once daily was safe and effective for the treatment of MDD.12

In a second trial by Detke and colleagues, duloxetine demonstrated a greater mean change in the HAM-D-17 score from baseline to week 9 compared to placebo, -10.46 and -8.29, respectively (p=0.024).6 Estimated probabilities of response and remission were 65% and 43%, respectively for duloxetine compared with 42% and 28%, respectively for placebo. Other secondary measures are detailed in Table 1. Discontinuation rates were more frequent in duloxetine-treated patients and the most frequent adverse events were nausea, dry mouth, dizziness, and constipation. Additionally, there was not a significant incidence of hypertension. The authors concluded that duloxetine is safe and effective for the treatment of MDD when dosed at 60 mg daily.6

Table 1: Select Primary and Secondary Efficacy Measures for Duloxetine in the Treatment of MDD
Efficacy Measures Goldstein5 Detke12 Detke6
  Mean Change from Baseline    
HAM-D-17 D: -9.73
P: -6.61(p=0.009)
D: -10.91
P: -6.05 (p<0.001)
D: -10.46
P: -8.29 (p=0.024)
CGI-S D: -1.67
P: -1.07 (p=0.007)
D: -1.87
P: -0.97 (p<0.001)
D: -1.74
P: -1.51 (p=0.15)
PGI-I D: +2.92
P: +2.27 (p=0.006)
D: +3.27
P: +2.48 (p<0.001)
D: +2.59
P: +3.00 (p=0.014)

P = Placebo
D = Duloxetine
Definition of scales14-17
HAM-D-17 (Hamilton Rating Scale for Depression-17): Most widely used rating scale for depression. Ratings to assess symptoms of depression done by clinician through clinical interview on a 0 to 4 spectrum (0 = none, 4 = most severe).14
CGI-I, CGI-S (Clinical Global Impressions): Three-item scale which measures overall illness factors. Severity of Illness (CGI-S) rated by clinician on a 1 to 7 scale (1 = normal, 7 = among the most severely ill patients). Global Improvement (CGI-I) rated by clinician on a 1 to 7 scale (1 = very much improved, 7 = very much worse). Designed to be used to assess change over time.14
PGI (Patient Global Impressions - Improvement): A scale used by the patient to rate their own improvement based on a 0 to 7 scale (0 = not assessed, 7 = very much worse).


The efficacy of duloxetine was studied in two randomized, double-blind, placebo-controlled trials that were conducted in adult patients (n=791) with DN.9 Both trials were 12 weeks in length and included patients with a 6-month minimum history of DN. Both trials compared duloxetine 60 mg administered once or twice daily to placebo. In addition, one trial evaluated duloxetine 20 mg administered daily compared to placebo. The primary efficacy measure was the weekly mean of the 24-Hour Average Pain Severity score on an 11-point Likert Scale (0=no pain, 10=worst pain; baseline pain score >4). Treatment with duloxetine 60 mg once or twice daily improved the mean pain scores from baseline in a statistically significant manner compared to placebo and increased the proportion of patients with at least a 50% reduction in pain score from baseline.9


Duloxetine is contraindicated in patients with a known hypersensitivity to any of the active or inactive ingredients. It is also contraindicated for concomitant use with MAOIs and in patients with narrow-angle glaucoma.9 Duloxetine should be avoided in patients with known hepatic disease, and it may be necessary to reduce the dose in patients with known hepatic insufficiency.9 Additionally, due to the extent of renal clearance (70%) of both the parent drug and its metabolites, duloxetine is also not recommended for use in patients with end-stage renal disease (ESRD) requiring dialysis (estimated creatinine clearance <10 mL/min) or in patients with severe renal impairment (estimated creatinine clearance <30 mL/min).9 Finally, small increases (1-2 mm Hg) in blood pressure have been noted and therefore baseline values and periodic monitoring of blood pressure may be warranted in patients with pre-existing hypertension or cardiac disease.9

Antidepressive agents that block 5-HT uptake can induce mania in a predisposed subset of patients; therefore, duloxetine should be used with caution in patients with a past medical history or family history of mania.9 All patients should be closely monitored during initiation of antidepressant therapy, especially if there is a personal or family history of suicidal ideation.9,18

Adverse Reactions

The most common adverse events (incidence of 5% or greater and at least twice the incidence compared to placebo patients) for patients being treated with duloxetine for MDD include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating.9

Table 2. Incidence of Adverse Events in Duloxetine-Treated MDD Patients9
  Percentage of Patients Reporting Event
  Duloxetine N=1139 Placebo N=777
Nausea* 20 7
Dry Mouth 15 6
Constipation 11 4
Insomnia 11 6
Dizziness 9 5
Diarrhea 8 6
Fatigue 8 4
Decreased Appetite 8 2
Somnolence 7 3
Increased Sweating 6 2

Duloxetine vs. Placebo
*Nausea was the only common adverse event that led to discontinuation and is considered to be drug-related.

The most commonly observed adverse events (incidence of 5% or greater and at least twice the incidence in placebo patients) in duloxetine-treated DN patients were nausea, somnolence, dizziness, constipation, dry mouth, hyperhidrosis, decreased appetite, and asthenia.9

Table 3. Incidence of Adverse Events in Duloxetine-Treated DN Patients9
  Percentage of Patients Reporting Event
  Duloxetine 60 mg once daily Placebo
Nausea* 22 9
Constipation 11 3
Dry Mouth 7 4
Decreased appetite 4 <1
Somnolence* 15 5
Dizziness* 14 6
Fatigue* 12 5
Increased Sweating 6 2

Duloxetine vs Placebo
*Nausea, somnolence, dizziness, and fatigue were the most common adverse events that led to discontinuation and are considered to be drug-related.

Drug Interactions

Duloxetine is a substrate of CYP2D6.9 Duloxetine metabolism was decreased by coadministration with paroxetine, a known CYP2D6 inhibitor.19 Duloxetine is also a substrate of CYP1A2.8 Coadministration of duloxetine with fluvoxamine a strong CYP1A2 inhibitor, increased the Cmax of duloxe-tine 2.5-fold and the AUC 5-fold.9 Combination of duloxetine and any strong CYP1A2 inhibitors (e.g., ketoconazole [Nizoral®]) should be avoided.9

Data from clinical studies indicate that duloxetine is also an inhibitor of CYP2D6.19 Duloxetine increased the Cmax and AUC of desipramine (Norpramin®), a drug almost exclusively metabolized by CYP2D6, by 1.7- and 2.9-fold, respectively.19 Drugs that are principally metabolized by CYP2D6 and have a narrow therapeutic index should be cautiously co-administered with duloxetine.8 Plasma protein interactions are possible, as duloxetine is highly protein bound and may cause dissociation of other highly bound drugs from serum proteins.

Patients currently taking other medications with substantial serotonergic activity should be monitored closely due to an increased risk of serotonin syndrome. MAOIs should be discontinued 14 days before initiation of duloxetine therapy to prevent this from occurring. Additionally, a minimum of 5 days should separate the discontinuation of duloxetine and the initiation of MAOIs.9


Duloxetine is categorized as a pregnancy-risk category C, meaning reproductive studies conducted in animals have shown adverse effects on the fetus and there are no controlled studies in women.8,9 Neonates exposed to SSRIs and SSNRIs, late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding.9 These symptoms (e.g., respiratory distress, seizures, hypoglycemia, tremor, and temperature instability) can occur upon delivery and may be classified as toxicity, discontinuation syndrome, or even serotonin syndrome. Since there are no adequate and well-controlled studies in pregnant women, duloxetine should be utilized only when the potential benefit to the mother outweighs the potential risk to the fetus.

Duloxetine has been detected in the breast milk of lactating rats, but it is currently unknown whether the parent drug or its metabolites enter human breast milk. Therefore, duloxetine is not recommended for use by breastfeeding mothers.9

Dosing and Administration

The recommended oral dose for initiation of therapy in MDD is 40 mg/day (administered as 20 mg twice daily) to 60 mg/day (administered either as once daily or as 30 mg twice daily). The recommended dose for diabetic peripheral neuropathic pain is 60 mg daily. Although doses up to 120 mg/day have been utilized, no clinical superiority has been demonstrated when compared to 60 mg/day and an increase of adverse events were noted at higher doses.9

Abrupt discontinuation of duloxetine should be avoided if possible. Withdrawal symptoms such as headache, nausea, dizziness, abnormal dreams, sensory disturbances, and agitation have been reported in patients stopping therapy with this class of antidepressants.9

Investigational Uses

Arnold and colleagues conducted a randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of duloxetine in subjects (n=207) with primary fibromyalgia with or without MDD.21 Primary outcomes measures were the Fibromyalgia Impact Questionnaire (FIQ) total score and FIQ pain score. Duloxetine-treated patients, regardless of MDD history, showed improvement in fibromyalgia symptoms and pain severity. The female cohort (89%) demonstrated significantly greater improvement on most efficacy measures compared to the male cohort. Patients were steadily titrated from 20 mg/day to 120 mg/day of duloxetine by the second week of the therapy phase (12 weeks). Insomnia, dry mouth, and constipation were significantly greater in the duloxetine group compared to the placebo group. There were no statistically significant differences in discontinuation rates between the groups and most adverse events were of mild or moderate severity. The authors concluded that duloxetine 60 mg twice daily is safe and well-tolerated in fibromyalgia patients. Furthermore, duloxetine demonstrated efficacy for the majority of outcome measures, particularly in women and irrespective of MDD status.21

Studies have also been conducted to evaluate duloxetine's efficacy in treating stress urinary incontinence (SUI). One of these trials compared duloxetine 20-, 40-, and 80-mg daily to placebo in women (n=553) with >4 incontinence episodes per week.22 The primary efficacy measurements were incontinence episode frequency (IEF), incontinence quality of life (I-QOL), PGI-I, and mean time between voids (MTBV). There was a statistically significant improvement compared to placebo in all efficacy variables when using the 80 mg dose. The most common adverse events included nausea, fatigue, headache, dizziness, dry mouth, insomnia, and constipation; however, nausea was the most common adverse event leading to duloxetine discontinuation. The authors concluded that duloxetine was safe and efficacious at a dose of 80 mg/day.

Additional trials have evaluated the efficacy and safety of duloxetine 80 mg/day in female patients with SUI.22 Specifically, three of these trials (n=1635) assessed the median percentage change in IEF and the mean change in total I-QOL over 12 weeks. The median percentage reduction in weekly IEF was 50-54% with duloxetine and 28-40% with placebo (p significant). The mean improvement I-QOL score was 5.5-11.1 points with duloxetine and 4.1-6.8 points with placebo (p significant for 2 out of 3 trials). The most common adverse events included fatigue, insomnia, nausea, constipation, dizziness, headache, and dry mouth. Fatigue and dizziness, however, were the most common adverse events leading to duloxetine discontinuation. These data suggest that duloxetine is safe and effective for women with SUI.22

Duloxetine will most likely be marketed under a separate brand name, Yentreve, by Eli Lilly and Co., for the treatment of SUI. The manufacturer is projecting a first-half 2005 FDA-approval and market launch. Currently, there is discussion at the FDA regarding the drug interaction labeling for Yentreve. In SUI, patient medication profiles may include long-term potent 2D6 and 1A2 inhibitors and may increase the risk of duloxetine-related drug interactions.23


Cymbalta® is available as 20-, 30-, and 60-mg capsules. At this time, there are no pharmacoeconomic studies evaluating duloxetine therapy for MDD or DN.

Table 4. Cost Comparison24
Drug Formulary Status Strength Cost (AWP)/Tablet
Duloxetine (Cymbalta®) F 20 mg $3.05
30 mg $3.42
60 mg $3.42
Venlafaxine (Effexor®) F 25 mg $1.83
37.5 mg $1.88
50 mg $1.94
75 mg $2.06
100 mg $2.18
Venlafaxine (Effexor® XR) F 37.5 mg $3.04
  75 mg $3.41
  150 mg $3.71
Fluoxetine (generic) F 10 mg $2.60
  20 mg $2.67
  40 mg $5.34

F = FormularyAWP = Average Wholesale Price

Formulary Status

Cymbalta® was added to The Cleveland Clinic Foundation Formulary of Accepted Drugs in October 2004.


Duloxetine is a new member of the SSNRI class of antidepressants. It is FDA-approved for the treatment of MDD and DN and is currently being evaluated for women with SUI. Duloxetine has been shown to be efficacious in the treatment of MDD and DN without clinically significant blood pressure elevations. The most common adverse drug events include nausea, constipation, and fatigue. The recommended dose for MDD is 40-60 mg daily and for DN-associated pain is 60 mg/day. The cost of duloxetine is similar to venlafaxine. Duloxetine is a novel therapeutic modality with a unique mechanism of action, good efficacy and safety profile, and has the potential to be utilized in a variety of pharmacological areas.

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Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124