What is duloxetine (Serotonin-Norepinephrine Reuptake Inhibitor)?

Duloxetine: A Serotonin-Norepinephrine Reuptake Inhibitor (SNRI)

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

Mechanism of Action

Duloxetine functions through:

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

The exact mechanisms of its antidepressant, pain inhibitory, and anxiolytic actions are not fully understood but are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS 1.

FDA-Approved Indications

Duloxetine is FDA-approved for:

• Major Depressive Disorder (MDD)
• Generalized Anxiety Disorder (GAD) - including in children and adolescents 7 years and older 2
• Diabetic Peripheral Neuropathic Pain (DPNP)
• Fibromyalgia (FM)
• Chronic Musculoskeletal Pain due to:
  • Chronic Osteoarthritis Pain
  • Chronic Low Back Pain 1, 3

Pharmacokinetics

• Absorption: Well absorbed orally with a 2-hour lag time before absorption begins 1
• Distribution: Highly protein bound (>90%), primarily to albumin and α1-acid glycoprotein 1
• Metabolism: Extensive hepatic metabolism primarily through CYP1A2 and CYP2D6 1
• Elimination: Half-life of approximately 12 hours (range 8-17 hours) 1
• Excretion: About 70% excreted in urine as metabolites, 20% in feces 1

Dosing Considerations

• Available in 20mg, 30mg, and 60mg delayed-release capsules 1
• Food delays time to peak concentration from 6 to 10 hours but only marginally decreases absorption 1
• Can be taken with or without food 1
• Extended-release formulations allow for once-daily dosing 2
• Typical effective dose for most conditions is 60mg once daily 3

Efficacy in Various Conditions

Anxiety Disorders

Duloxetine is effective for generalized anxiety disorder, with significant improvements in anxiety symptoms compared to placebo 4. It is the only SNRI with FDA approval for treating generalized anxiety disorder in children and adolescents 7 years and older 2.

Neuropathic Pain

For diabetic peripheral neuropathic pain, duloxetine 60mg daily shows significant efficacy with a number needed to treat (NNT) of 5 for achieving ≥50% pain reduction at 12 weeks 5.

Fibromyalgia

Duloxetine 60mg daily is effective for fibromyalgia over both 12-week and 28-week periods, with an NNT of 8 for achieving ≥50% pain reduction 5.

Chronic Musculoskeletal Pain

Studies support duloxetine 60mg once-daily dosing as effective for chronic osteoarthritis pain and chronic low back pain 3.

Adverse Effects

Common adverse effects include:

• Gastrointestinal: Nausea, dry mouth, constipation, vomiting, diarrhea, abdominal discomfort 2, 1
• Neurological: Dizziness, headache, somnolence, tremor, insomnia 2
• Other: Diaphoresis, decreased appetite, weight loss, fatigue 2

Serious but uncommon adverse effects include:

• Suicidal thinking and behavior (particularly in those under 24 years) 2
• Behavioral activation/agitation
• Hypomania or mania
• Sexual dysfunction
• Seizures
• Abnormal bleeding
• Serotonin syndrome 2
• Hepatic failure (presenting as abdominal pain, hepatomegaly, elevated transaminases) 2
• Severe skin reactions including erythema multiforme and Stevens-Johnson syndrome 2
• Sustained clinical hypertension, increased blood pressure, and increased pulse 2

Contraindications and Precautions

• Absolute contraindication: Concomitant use with MAOIs due to risk of serotonin syndrome 1
• Severe hepatic impairment 2
• Uncontrolled narrow-angle glaucoma 6
• QT prolongation risk factors 6
• Requires tapering over 2-4 weeks when discontinuing after treatment longer than 3 weeks to prevent withdrawal symptoms 6

Drug Interactions

• MAOIs: Contraindicated within 14 days of MAOI use 1
• CYP1A2 inhibitors: Concomitant use should be avoided 4
• CYP2D6 substrates: Use with caution, particularly those with narrow therapeutic index 4
• Anticoagulants/antiplatelets: Increased bleeding risk 1
• CNS depressants: Possible additive effects 1

Clinical Pearls

• Duloxetine is the only SNRI with FDA approval for treating generalized anxiety disorder in children and adolescents 7 years and older 2
• The 60mg once-daily dose is generally considered the optimal therapeutic dose for most indications 3
• Duloxetine should be discontinued and not restarted if jaundice or other evidence of clinically significant liver dysfunction develops 2
• When switching antidepressants, a cross-tapering approach is recommended to minimize discontinuation symptoms 6
• Duloxetine's dual mechanism of action makes it particularly useful in patients with comorbid pain and depression or anxiety 7

Duloxetine represents an important therapeutic option with demonstrated efficacy across multiple conditions, particularly when pain syndromes coexist with mood or anxiety disorders.