Comparative Effectiveness: Strattera vs Guanfacine ER for ADHD
Strattera (atomoxetine) is more effective than guanfacine ER for treating ADHD based on effect sizes and clinical guidelines, though both are considered second-line agents after stimulants. 1
Evidence Hierarchy and Effect Sizes
The American Academy of Pediatrics explicitly ranks non-stimulant medications by strength of evidence: atomoxetine has "sufficient but less strong" evidence, while guanfacine ER has even weaker evidence ranking below atomoxetine in the treatment hierarchy. 1 This positioning reflects measurable differences in clinical efficacy:
- Atomoxetine demonstrates effect sizes of approximately 0.6-0.7 compared to placebo 1, 2
- Guanfacine ER shows effect sizes of approximately 0.7 compared to placebo 3
- Both fall substantially below stimulants (effect size ~1.0) 1, 3
Direct Comparative Evidence
A 2016 randomized controlled trial provides the most relevant head-to-head data, though it used placebo as the primary comparator. 4 In patients previously treated with methylphenidate:
- Atomoxetine showed minimal placebo-adjusted improvement (-1.8 points, effect size 0.15, not statistically significant) 4
- Guanfacine ER demonstrated significant placebo-adjusted improvement (-9.8 points, p<0.001, effect size 0.85) 4
However, this finding requires critical interpretation: the study specifically enrolled patients who had failed or discontinued prior stimulant treatment, creating a selection bias that may favor guanfacine. 4 In stimulant-naïve patients within the same trial, atomoxetine performed better (-5.0 points, p=0.022, effect size 0.43). 4
Clinical Guideline Positioning
Major clinical guidelines consistently position atomoxetine ahead of alpha-2 agonists (including guanfacine) in the treatment algorithm. 1 The 2022 Pharmacology and Therapeutics guideline states that "adverse effects of atomoxetine are considered to be less frequent and less pronounced compared to clonidine and guanfacine." 1
Onset of Action and Practical Considerations
Atomoxetine typically shows clinical benefits within 2-4 weeks, similar to guanfacine ER's delayed onset. 3, 2 Both require patience during titration, unlike stimulants which work immediately. 3
Guanfacine ER provides 24-hour coverage with once-daily dosing, which may offer advantages for evening/nighttime symptom control. 3, 5 Atomoxetine can be dosed once or twice daily with similar flexibility. 2
Adverse Effect Profiles
Atomoxetine carries fewer cardiovascular concerns compared to guanfacine, which causes predictable decreases in blood pressure (1-4 mmHg) and heart rate (1-2 bpm). 1, 3 Guanfacine requires:
- Baseline cardiovascular assessment 3
- Monitoring at each dose adjustment 3
- Mandatory tapering (1 mg every 3-7 days) to avoid rebound hypertension 3
Atomoxetine more commonly causes gastrointestinal upset, irritability, and fatigue (36% discontinuation rate in one study), while guanfacine primarily causes somnolence and sedation. 1, 6
Special Population Considerations
Both medications are preferred over stimulants in patients with:
- Substance use disorders (neither is a controlled substance) 1, 2
- Comorbid tic disorders (atomoxetine does not worsen tics; guanfacine may reduce them) 1
- Comorbid anxiety disorders (atomoxetine has supporting evidence) 1, 7
Guanfacine may be specifically preferred when:
- Sleep disturbances are prominent (can be dosed at bedtime) 1, 3
- Disruptive behavior disorders coexist 1
- Adjunctive therapy with stimulants is planned (FDA-approved indication) 1, 3
Practical Algorithm for Selection
Start with atomoxetine (0.5 mg/kg/day, target 1.2 mg/kg/day) as the first-line non-stimulant unless specific contraindications exist or comorbidities favor guanfacine. 1, 2
Switch to guanfacine ER (start 1 mg daily, titrate by 1 mg weekly to 0.05-0.12 mg/kg/day) if: 3, 5
- Atomoxetine causes intolerable GI effects or irritability
- Prominent sleep disturbances require evening dosing
- Adjunctive therapy with stimulants is planned
- Cardiovascular monitoring is feasible
Consider combination therapy (atomoxetine + guanfacine) only after optimizing monotherapy, though this lacks robust evidence. 3
Critical Caveats
Neither medication approaches stimulant efficacy for core ADHD symptoms. 1 If symptom control is inadequate after 4-6 weeks at optimal dosing of either non-stimulant, reassess whether stimulant therapy is truly contraindicated. 1
The 2016 study suggesting guanfacine superiority enrolled a highly selected population (prior stimulant failures), limiting generalizability. 4 In typical clinical practice with stimulant-naïve patients, atomoxetine demonstrates more consistent efficacy. 4
Recent evidence (2023) suggests viloxazine ER may outperform atomoxetine, though this represents a third option rather than resolving the atomoxetine-guanfacine comparison. 6