Duloxetine - Drug Monograph

Introduction

Duloxetine hydrochloride is a serotonin-norepinephrine reuptake inhibitor (SNRI) approved by the FDA in 2004. It is a widely prescribed psychotropic medication with multiple therapeutic applications spanning psychiatric and pain disorders. Duloxetine represents an important option in the management of major depressive disorder, various chronic pain conditions, and anxiety disorders.

Mechanism of Action

Duloxetine exerts its therapeutic effects through potent inhibition of serotonin (5-HT) and norepinephrine (NE) reuptake transporters. The drug has approximately 10-fold greater affinity for serotonin transporters compared to norepinephrine transporters. This dual mechanism enhances neurotransmission in both serotonergic and noradrenergic pathways in the central nervous system.

Unlike many other antidepressants, duloxetine has minimal affinity for muscarinic, histaminergic, or adrenergic receptors, resulting in a more favorable side effect profile regarding anticholinergic effects and sedation. The analgesic effects are mediated through both central pain modulatory pathways and direct action on descending inhibitory pathways in the spinal cord.

Indications

FDA-approved indications include:

• Major Depressive Disorder (MDD)
• Generalized Anxiety Disorder (GAD)
• Diabetic Peripheral Neuropathic Pain (DPNP)
• Fibromyalgia
• Chronic Musculoskeletal Pain

Non-FDA approved uses (off-label):

• Stress urinary incontinence
• Chemotherapy-induced peripheral neuropathy
• Osteoarthritis pain
• Chronic low back pain

Dosage and Administration

• Depression: 40-60 mg/day (initiate at 30 mg/day for one week, then increase to 60 mg/day)
• Anxiety: 60 mg/day (initiate at 30 mg/day for one week)
• Diabetic neuropathy: 60 mg/day
• Fibromyalgia: 60 mg/day
• Chronic pain: 60 mg/day

• Administer whole capsule orally, with or without food
• Do not crush, chew, or open capsules (enteric-coated)
• Swallow capsule whole to prevent exposure to acidic environment

• Hepatic impairment: Avoid in chronic liver disease
• Renal impairment: Not recommended in severe renal impairment (CrCl <30 mL/min)
• Elderly: Initiate at lower doses (20-30 mg/day)
• Pediatrics: Safety and effectiveness not established under age 7

Pharmacokinetics

Contraindications

• Concomitant use with MAOIs or within 14 days of discontinuing MAOI therapy
• Uncontrolled narrow-angle glaucoma
• Hypersensitivity to duloxetine or any component of the formulation
• Severe hepatic impairment
• Concomitant use with linezolid or intravenous methylene blue

Warnings and Precautions

• Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults

• Hepatotoxicity: Cases of liver failure reported
• Orthostatic hypotension and syncope
• Serotonin syndrome
• Abnormal bleeding: Increased risk of bleeding events
• Activation of mania/hypomania
• Seizures
• Hyponatremia
• Discontinuation syndrome: Taper gradually
• Urinary hesitation and retention

Drug Interactions

• MAOIs: Risk of serotonin syndrome (contraindicated)
• Other serotonergic drugs: Triptans, tramadol, tryptophan (increased serotonin syndrome risk)
• Strong CYP1A2 inhibitors: Fluvoxamine (increase duloxetine levels 5-fold)
• Anticoagulants: Warfarin (increased bleeding risk)
• NSAIDs, aspirin: Increased bleeding risk
• CYP2D6 substrates: Reduced metabolism of drugs metabolized by CYP2D6

• Alcohol: Increased risk of liver damage
• CNS depressants: Enhanced sedative effects
• Antihypertensives: Potential additive effects

Adverse Effects

• Nausea (20-30%)
• Dry mouth (15-20%)
• Fatigue (10-15%)
• Constipation (10-15%)
• Dizziness (10-15%)
• Insomnia (10-15%)
• Sweating (10%)

• Suicidal ideation
• Hepatotoxicity
• Serotonin syndrome
• Severe skin reactions
• Angle-closure glaucoma
• Orthostatic hypotension
• Hyponatremia
• Urinary retention

Monitoring Parameters

• Comprehensive metabolic panel (including LFTs)
• Blood pressure and heart rate
• Renal function
• Screening for bipolar disorder
• Suicide risk assessment

• Blood pressure (regularly, especially during dose changes)
• LFTs (periodically, more frequently in high-risk patients)
• Symptoms of bleeding
• Weight changes
• Mood changes, suicidal ideation
• Signs of serotonin syndrome
• Urinary function

Patient Education

• Take medication at the same time each day
• Do not stop abruptly due to withdrawal symptoms
• Report any worsening depression or suicidal thoughts immediately
• Avoid alcohol during treatment
• Be cautious when driving or operating machinery until effects are known
• Report signs of liver problems (yellowing skin, dark urine, right upper quadrant pain)
• Inform all healthcare providers about duloxetine use before any procedures
• Use effective contraception during treatment
• Report any unusual bleeding or bruising
• Rise slowly from sitting/lying position to prevent dizziness

References

1. FDA Prescribing Information: Cymbalta (duloxetine) [2023] 2. Stahl SM. Essential Psychopharmacology. 4th ed. Cambridge University Press; 2013. 3. Sansone RA, Sansone LA. Serotonin norepinephrine reuptake inhibitors: a pharmacological comparison. Innov Clin Neurosci. 2014;11(3-4):37-42. 4. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;(1):CD007115. 5. American Psychiatric Association. Practice Guideline for the Treatment of Patients with Major Depressive Disorder. 3rd ed. 2010. 6. Product Information: Cymbalta(R) oral delayed release capsules, duloxetine hydrochloride oral delayed release capsules. Lilly USA, LLC; 2022.