What is duloxetine (Serotonin-Norepinephrine Reuptake Inhibitor)?

Duloxetine: A Serotonin-Norepinephrine Reuptake Inhibitor

Duloxetine is a potent serotonin and norepinephrine reuptake inhibitor (SNRI) that works by inhibiting the reuptake of serotonin and norepinephrine in the central nervous system, used to treat multiple conditions including depression, anxiety disorders, and various chronic pain conditions. 1

Mechanism of Action

Duloxetine functions through:

• Potent inhibition of neuronal serotonin and norepinephrine reuptake 1
• Less potent inhibition of dopamine reuptake 1
• No significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, or GABA receptors 1
• No inhibition of monoamine oxidase (MAO) 1

This dual mechanism of action on both serotonergic and noradrenergic neurotransmission is believed to be responsible for its therapeutic effects in depression, anxiety, and pain conditions.

FDA-Approved Indications

Duloxetine is FDA-approved for:

• Major Depressive Disorder (MDD) 1
• Generalized Anxiety Disorder (GAD), including in children and adolescents 7 years and older 2
• Diabetic Peripheral Neuropathic Pain (DPNP) 1
• Fibromyalgia (FM) 1
• Chronic Musculoskeletal Pain due to:
  • Chronic Osteoarthritis Pain 1
  • Chronic Low Back Pain 1

Pharmacokinetics

Key pharmacokinetic properties include:

• Oral bioavailability: Well absorbed after oral administration 1
• Time to peak concentration: 6 hours post-dose (delayed to 10 hours with food) 1
• Elimination half-life: Approximately 12 hours (range 8-17 hours) 1
• Protein binding: Highly bound (>90%) to plasma proteins 1
• Metabolism: Extensive hepatic metabolism primarily through CYP1A2 and CYP2D6 1
• Excretion: 70% in urine as metabolites, 20% in feces 1

Dosing

• Standard dosing for most indications is 60 mg once daily 3
• For painful conditions, 60 mg daily has demonstrated efficacy with an NNT of 5 for diabetic neuropathy and 8 for fibromyalgia 4
• Lower doses (20 mg) are generally ineffective for pain conditions 4
• Dose adjustments may be needed in hepatic impairment 2

Contraindications

Duloxetine is contraindicated in:

• Patients taking MAOIs or within 14 days of stopping an MAOI 1
• Uncontrolled narrow-angle glaucoma 2
• Severe hepatic impairment 2
• Patients with QT prolongation risk factors 2

Adverse Effects

Common adverse effects include:

• Gastrointestinal: Nausea, dry mouth, constipation, vomiting, diarrhea, abdominal discomfort 2
• Neurological: Dizziness, headache, somnolence, tremor, insomnia 2

Serious but uncommon adverse effects include:

• Suicidal thinking and behavior (especially in children, adolescents, and young adults) 1
• Serotonin syndrome (when combined with other serotonergic agents) 2
• Hepatic failure 2
• Severe skin reactions 2
• Sustained clinical hypertension 2
• Abnormal bleeding 2

Drug Interactions

Important drug interactions to consider:

• MAOIs: Contraindicated due to risk of serotonin syndrome 1
• CYP1A2 inhibitors (e.g., fluvoxamine): Can increase duloxetine exposure by up to 460% 5
• CYP2D6 substrates: Duloxetine may increase levels of drugs metabolized by CYP2D6 5
• Smoking: Associated with 30% decrease in duloxetine concentration 5
• Benzodiazepines: Duloxetine may enhance their effects 5

Special Considerations

• Discontinuation: Requires tapering over 2-4 weeks after treatment longer than 3 weeks to prevent withdrawal symptoms 2
• Switching antidepressants: A cross-tapering approach is recommended 2
• Hepatic monitoring: Discontinue if jaundice or evidence of clinically significant liver dysfunction develops 2
• Cardiac effects: No clinically meaningful QT prolongation at therapeutic doses 1

Duloxetine's dual mechanism of action makes it particularly useful in patients with comorbid pain and mood disorders, offering potential benefits for multiple symptom domains with a single medication.