What happens if droxidopa (Northera) is abruptly stopped in a patient with neurogenic orthostatic hypotension (NOH)?

Abrupt Discontinuation of Droxidopa

When droxidopa is abruptly stopped in patients with neurogenic orthostatic hypotension, symptoms of orthostatic hypotension will return, including dizziness, lightheadedness, and increased risk of falls, though this represents a return to baseline disease state rather than a withdrawal syndrome.

Evidence from Withdrawal Studies

The most direct evidence comes from a randomized withdrawal trial that specifically examined what happens when droxidopa is stopped:

• In a 14-day withdrawal study, patients who were responding to droxidopa were randomized to either continue treatment or switch to placebo 1
• Patients who withdrew to placebo experienced worsening of orthostatic hypotension symptoms, though the primary endpoint (dizziness/lightheadedness score) did not reach statistical significance between groups 1
• Four of five symptom scores and all four symptom-impact scores favored continued droxidopa treatment over withdrawal to placebo, with statistically significant differences in the ability to perform activities requiring standing 1
• A composite score of all symptoms demonstrated significant benefit for continuing droxidopa versus withdrawal (p=0.013) 1

Clinical Implications of Stopping Droxidopa

The return of symptoms upon discontinuation reflects the underlying disease pathophysiology rather than a true withdrawal syndrome, as droxidopa works by increasing norepinephrine levels to compensate for autonomic failure 2:

• Patients experience recurrence of orthostatic symptoms including dizziness, lightheadedness, and impaired ability to stand 1
• Fall risk may increase when droxidopa is discontinued, as exploratory analyses suggest droxidopa reduces fall rates by approximately 50% compared to placebo 3
• Standing blood pressure decreases return to pre-treatment levels when the medication is stopped 1

Duration of Effect After Discontinuation

• The symptomatic effects of droxidopa discontinuation become apparent within days, as evidenced by the 14-day withdrawal period used in clinical trials 1
• Since droxidopa is a prodrug that requires conversion to norepinephrine, its effects dissipate relatively quickly once administration stops 2

Treatment Persistence Data

Real-world evidence suggests that when patients do discontinue droxidopa, it is typically due to tolerability issues rather than loss of efficacy:

• Median treatment persistence with droxidopa in real-world practice is 303 days, significantly longer than midodrine (172 days) 4
• Patients using droxidopa monotherapy are 16% more likely to remain on treatment at any time point compared to those using midodrine 4

Management Recommendations

If droxidopa must be discontinued, the ACC/AHA/HRS guidelines recommend implementing alternative management strategies for neurogenic orthostatic hypotension 2:

• Consider switching to midodrine as an alternative pharmacologic agent for neurogenic orthostatic hypotension 2
• Maximize non-pharmacologic measures including compression garments (at least thigh-high, preferably including abdomen), physical counter-pressure maneuvers (leg crossing, squatting), and acute water ingestion (≥480 mL for maximum effect) 2
• Increase salt intake (6-9 g daily) to expand plasma volume, unless contraindicated by hypertension, renal disease, or heart failure 2
• Consider fludrocortisone or pyridostigmine for refractory cases 2

Important Caveats

• There is no evidence of a dangerous rebound effect or withdrawal syndrome from abruptly stopping droxidopa—the concern is simply return of the underlying orthostatic hypotension symptoms 1
• Patients with Parkinson's disease using carbidopa may have already experienced decreased droxidopa effectiveness, making discontinuation less impactful 2
• The primary risk of stopping droxidopa is the return of fall risk and orthostatic symptoms, which can significantly impact quality of life and safety 1, 3