Duloxetine

Generic Name

Duloxetine

Brand Names

Cymbalta

Yentreve

Ariclaim

Duzela

Sympta

Other local/international names depending on country of marketing

Drug Class

Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)

Antidepressant and anxiolytic

Also classified as a central-acting pain modulator

Mechanism of Action

Duloxetine is a potent and selective inhibitor of serotonin (5-HT) and norepinephrine (NE) reuptake at the presynaptic cleft

It increases the synaptic concentration of these neurotransmitters in the central nervous system, enhancing neurotransmission

By modulating pain perception pathways, especially descending inhibitory pathways in the spinal cord, duloxetine also contributes to analgesic effects

Negligible affinity for dopaminergic, histaminergic, cholinergic, or adrenergic receptors

No significant monoamine oxidase (MAO) inhibitory activity

Indications

Psychiatric Indications

Major Depressive Disorder (MDD) in adults

Generalized Anxiety Disorder (GAD) in adults and children over 7 years

Panic disorder (off-label in some countries)

Pain-Related Indications

Diabetic Peripheral Neuropathic Pain (DPNP)

Fibromyalgia

Chronic musculoskeletal pain (e.g., chronic lower back pain, osteoarthritis of the knee)

Stress Urinary Incontinence (Yentreve brand in some countries, e.g., Europe only)

Off-Label Uses

Chemotherapy-induced peripheral neuropathy

Urinary incontinence not responsive to other treatments

Postherpetic neuralgia

Tension-type headaches

Hot flashes in menopausal women

Selective serotonin reuptake inhibitor (SSRI)-induced sexual dysfunction

Chronic fatigue syndrome

Radiculopathy and neuropathic pain syndromes

Dosage and Administration

Major Depressive Disorder (MDD)

Initial: 30–60 mg orally once daily

Maintenance: 60 mg once daily

Max: 120 mg/day, though no added benefit >60 mg for depression

Generalized Anxiety Disorder (GAD)

Initial: 30 mg once daily

Maintenance: 60–120 mg/day

Adjust based on tolerability and response

Diabetic Peripheral Neuropathic Pain

Start: 60 mg once daily

No titration required

Some patients may benefit from 120 mg/day

Fibromyalgia / Chronic Musculoskeletal Pain

Initial: 30 mg/day

Increase to 60 mg/day after 1 week

120 mg/day may be used if needed and tolerated

Stress Urinary Incontinence (Yentreve)

European dose: 40 mg twice daily

Titrate up from 20 mg BID to minimize nausea

Not approved for urinary incontinence in USA

Pediatric Dosing (GAD)

Age 7–17 years: Start with 30 mg/day

Titrate to 60 mg/day after 2 weeks

Administration Notes

Capsules should be swallowed whole

Do not open, crush, chew, or sprinkle contents

Can be taken with or without food

Administer at the same time each day to maintain stable blood levels

Pharmacokinetics

Absorption: High oral bioavailability (~50%)

Peak plasma concentration: 6 hours

Protein Binding: ~95% (mainly albumin)

Metabolism: Extensive hepatic metabolism via CYP1A2 and CYP2D6

Elimination: Renal (70%) and fecal (20%) as metabolites

Half-life: ~12 hours

Steady state: achieved in 3 days with once-daily dosing

Contraindications

Hypersensitivity to duloxetine or any component of the formulation

Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of stopping MAOIs

Uncontrolled narrow-angle glaucoma

Severe hepatic impairment

CrCl <30 mL/min (due to accumulation and increased exposure)

Caution with potent CYP1A2 inhibitors (e.g., ciprofloxacin)

Warnings and Precautions

Suicidal thoughts and behavior in children, adolescents, and young adults especially during initiation or dose changes

Monitor closely for agitation, hostility, or unusual behavioral changes

May cause orthostatic hypotension and syncope especially in elderly

Risk of serotonin syndrome when used with other serotonergic agents (e.g., SSRIs, triptans, tramadol, St John’s Wort)

May impair platelet aggregation and increase bleeding risk especially when used with NSAIDs or anticoagulants

May increase blood pressure or heart rate

Hyponatremia/SIADH (especially in elderly, volume-depleted patients, or those on diuretics)

Discontinuation syndrome if stopped abruptly (dizziness, headache, paresthesia, insomnia, irritability)

Hepatotoxicity reported in some patients

Mydriasis reported – caution in patients with elevated intraocular pressure or at risk for angle-closure glaucoma

May worsen glycemic control in diabetes patients

Caution in patients with seizure disorders

Adverse Effects

Very Common (>10%)

Nausea

Dry mouth

Somnolence

Headache

Dizziness

Fatigue

Constipation

Decreased appetite

Increased sweating

Common (1–10%)

Insomnia

Blurred vision

Tremor

Sexual dysfunction (libido decrease, erectile dysfunction, anorgasmia)

Palpitations

Increased blood pressure

Diarrhea

Vomiting

Weight loss

Anxiety

Urinary hesitation or retention

Uncommon to Rare (<1%)

Hepatitis, elevated liver enzymes

Orthostatic hypotension

Hyponatremia

Serotonin syndrome

Rash, angioedema, urticaria

Stevens-Johnson syndrome

Seizures

Glaucoma

Suicidal ideation

Tinnitus

Mania or hypomania (in bipolar patients)

Anaphylaxis (rare)

Pregnancy and Lactation

Pregnancy

Category C (USA)

Use only if benefits outweigh risks

Neonatal complications including respiratory distress, irritability, and feeding difficulties reported with late pregnancy exposure

Avoid third-trimester use if possible

Lactation

Excreted in human milk

Caution advised—use only if clearly needed

Monitor infant for sedation, weight loss, irritability

Drug Interactions

MAOIs

Contraindicated due to risk of hypertensive crisis and serotonin syndrome

Other serotonergic drugs

Additive risk of serotonin syndrome (SSRIs, SNRIs, triptans, tramadol, lithium, fentanyl, linezolid)

CYP1A2 inhibitors (e.g., ciprofloxacin, fluvoxamine)

May increase duloxetine serum concentrations

Consider dose adjustment or avoid

CYP2D6 substrates (e.g., desipramine, risperidone, metoprolol, tamoxifen)

Duloxetine inhibits CYP2D6 and may increase serum levels of co-administered drugs

Alcohol

May enhance CNS depression and hepatotoxicity

Anticoagulants / Antiplatelets

Increased risk of bleeding due to inhibition of platelet aggregation

Diuretics

Additive risk of hyponatremia

Beta-blockers

Possible pharmacodynamic interactions (e.g., bradycardia, hypotension)

Monitoring Parameters

Mood and behavioral changes especially in first few months

Suicidal ideation or unusual behavior

Blood pressure and heart rate

Hepatic function in patients with hepatic risk factors

Serum sodium levels in elderly or at-risk patients

Blood glucose in diabetic patients

Symptoms of serotonin syndrome

Withdrawal symptoms if stopped suddenly

Counseling Points

Take consistently at the same time daily

May take several weeks to see full benefit

Do not stop abruptly—dose should be tapered

Inform healthcare provider if planning pregnancy or becoming pregnant

Report any unusual mood changes, suicidal thoughts, or serotonin syndrome signs (agitation, confusion, muscle twitching)

Avoid alcohol and other CNS depressants

Do not use with MAOIs or within 14 days of stopping either drug

Notify provider about any liver-related symptoms (jaundice, dark urine) or urinary retention

Comparative Notes

Duloxetine vs Venlafaxine

Both are SNRIs

Duloxetine has more evidence for pain syndromes

Venlafaxine may be more effective for severe depression but more likely to cause withdrawal symptoms

Duloxetine has fewer effects on blood pressure at low doses

Duloxetine vs SSRIs (e.g., fluoxetine, sertraline)

Slightly more effective in severe depression and painful physical symptoms

Higher risk of nausea and liver-related adverse events compared to SSRIs

SSRIs better tolerated in some individuals

Duloxetine vs Amitriptyline

Both used in neuropathic pain

Duloxetine better tolerated and safer in elderly

Amitriptyline more sedating and anticholinergic

Legal and Regulatory Status

Prescription-only medication

Approved by FDA, EMA, and other regulatory bodies

Included in national guidelines for depression, anxiety, neuropathic pain, and fibromyalgia

Listed on WHO Model List of Essential Medicines