Available Norepinephrine Reuptake Inhibitors
The primary norepinephrine reuptake inhibitors (NRIs) currently available include atomoxetine, reboxetine, and certain SNRIs (serotonin-norepinephrine reuptake inhibitors) that have significant noradrenergic activity.
Selective Norepinephrine Reuptake Inhibitors
Atomoxetine
- FDA-approved selective norepinephrine reuptake inhibitor 1
- Primary indication: ADHD in children, adolescents, and adults 2
- Mechanism: Selectively inhibits the pre-synaptic norepinephrine transporter, increasing both norepinephrine and dopamine in prefrontal cortex synapses 3
- Dosing: Available in multiple strengths (10,18,25,40,60,80, or 100 mg) 1
- First non-stimulant medication approved by the FDA for ADHD treatment 4
Reboxetine
- Selective norepinephrine reuptake inhibitor with high affinity and selectivity for the human norepinephrine transporter 5
- Not FDA-approved in the United States but available in other countries
- Primary indication: Major depressive disorder 6
- Dosing: Typically administered twice daily (8-10 mg/day) 5
- Pharmacological profile: Minimal affinity for muscarinic, histaminergic H1, adrenergic alpha1, and dopaminergic D2 receptors 6
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)
SNRIs with significant noradrenergic activity include:
Venlafaxine
- Inhibits reuptake of both serotonin and norepinephrine 2
- Used for anxiety disorders, depression, and neuropathic pain 2
- Norepinephrine reuptake inhibition becomes more prominent at higher doses (150-225 mg/day) 2
- Available in both immediate and extended-release formulations 2
Duloxetine
- Blocks reuptake of both serotonin and norepinephrine 2
- FDA-approved for generalized anxiety disorder in children and adolescents (7+ years) 2
- Effective for diabetic polyneuropathic pain at daily doses of 60-120 mg 2
- Typical dosing: 60 mg once daily (appears as effective as 60 mg twice daily) 2
Desvenlafaxine
- Active metabolite of venlafaxine with noradrenergic activity 2
- Long elimination half-life allowing for once-daily dosing 2
Levomilnacipran
- SNRI with relatively balanced serotonin and norepinephrine reuptake inhibition 2
Other Medications with Norepinephrine Reuptake Inhibition
Tricyclic Antidepressants
- Several TCAs (particularly secondary amines like nortriptyline and desipramine) have significant norepinephrine reuptake inhibition 2
- Less selective than newer agents with more side effects due to anticholinergic, antihistaminergic, and alpha-adrenergic blockade 2
Other Agents with NRI Activity
- Bupropion: Norepinephrine and dopamine reuptake inhibitor 7
- Tapentadol: Opioid with norepinephrine reuptake inhibition 7
- Mazindol, viloxazine, maprotiline, and teniloxazine: Less commonly used NRIs 7
Clinical Considerations
Efficacy
- NRIs have demonstrated efficacy in:
Common Side Effects
- Dry mouth, constipation, sweating, insomnia 8
- SNRIs may cause nausea, particularly during initiation 2
- Cardiovascular effects (increased blood pressure and pulse) with SNRIs 2
- Atomoxetine may cause initial somnolence and gastrointestinal symptoms 2
Monitoring Considerations
- Blood pressure and pulse monitoring recommended with SNRIs 2
- Dosage reduction needed in renal insufficiency for gabapentin and pregabalin 2
- Reduced starting doses recommended for elderly patients and those with hepatic/renal impairment 5
Practical Selection Guidance
- For ADHD: Atomoxetine is the only FDA-approved selective NRI 2, 4
- For neuropathic pain: SNRIs (duloxetine, venlafaxine) are first-line options 2
- For depression with prominent noradrenergic symptoms: SNRIs or reboxetine (where available) 6, 8
- For anxiety disorders: SNRIs (particularly duloxetine for GAD) 2
When selecting a norepinephrine reuptake inhibitor, consider the specific indication, side effect profile, and patient comorbidities to determine the most appropriate agent.