Evaluating the effectiveness of atomoxetine for the treatment of primary orthostatic hypotension in adults

1. INTRODUCTION

Orthostatic hypotension (OH) is a common condition characterized by a reduction in systolic blood pressure (SBP) of at least 20 mm Hg and/or in diastolic blood pressure (BP) of at least 10 mm Hg within 3 minutes of standing.1, 2, 3, 4, 5, 6 It is often accompanied by symptoms of dizziness/lightheadedness, fatigue, vision disturbance, and loss of concentration, which can greatly hinder quality of life.2 The prevalence of OH increases with age, affecting approximately 5% of patients younger than 50 years, 30% of patients older than 70 years, and up to 50% of nursing home patients older than 80 years.3, 4 Generally, OH is a result of autonomic failure and abnormal BP regulatory mechanisms. In normal situations, standing induces baroreceptor unloading, which leads to increased venous return and regulation of resting BP. Patients with OH show increased resistance to this regulatory mechanism, leading to abnormal BP.1, 5

Nonpharmacological interventions remain first‐line strategies for OH, followed by pharmacological therapy if nondrug treatments are unsuccessful.1, 2, 5, 6, 7 Current guidelines list midodrine and droxidopa as the primary pharmacological agents to treat OH.8 However, several studies have shown that atomoxetine, a selective norepinephrine reuptake inhibitor, increases seated and standing SBP and improves orthostatic symptoms when given in a pediatric dose of 18 mg.1, 2, 3, 5, 9, 10, 11, 12, 13 This evidence demonstrates the benefit of atomoxetine as an alternative pharmacological agent in the treatment of OH. Through a pharmacotherapy review, this report aims to justify the need for updated OH guidelines, including atomoxetine as a viable treatment option.

2. METHODS

An electronic literature review was performed using the following MEDLINE databases, EBSCOhost and PubMed. Key search terms included orthostatic hypotension, atomoxetine, blood pressure, autonomic failure, cardiovascular, postural, essential, and severe. Articles were limited to human studies published in English from January 2000 to May 2017. Articles were eligible for inclusion if they were randomized or observational studies, cohort or crossover studies, case series or case reports, or literature reviews that addressed atomoxetine use in OH in adults 18 years and older. Information on nonpharmacological and pharmacological interventions were included. Additional primary literature and guidelines were referenced for information on pathophysiology. Articles addressing children and adolescents or diagnoses other than OH were excluded.

3. CURRENT THERAPY RECOMMENDATIONS

Symptom relief is the main focus in treating primary OH.5 Nonpharmacological interventions have been recommended as a first‐line approach to treating OH.1, 2, 5, 6, 7, 14 Pharmacological therapy may be immediately added to these interventions in cases of severe OH.5, 6, 7, 14 Any potential offending medications (eg, α‐blockers, antihypertensives, tricyclic antidepressants, and alcohol) should be discontinued. Patients should be educated about physical maneuvers that reduce venous pooling such as gradual elevation from the supine position, squatting, and tensing leg muscles. Abdominal binders and/or compression stockings may also provide symptom relief. Increased salt (up to 6–10 g of sodium chloride daily) and water (up to 1.5–2 L) consumption and exercise should be encouraged.5, 14

When starting pharmacological therapy, presence of hypertension should be considered in order to select the appropriate agent.5 The 2006 European Federation of Neurological Societies guidelines for OH recommends fludrocortisone as a valuable first‐line drug and sympathomimetics such as midodrine, ephedrine, or dihydroxyphenylserine as second‐line drugs.14 The 2013 American Society of Hypertension position paper on OH proposes an initial trial of fludrocortisone or midodrine in patients with nonhypertensive OH.5 The 2017 American College of Cardiology/American Heart Association/Heart Rhythm Society Guideline for the Evaluation and Management of Patients With Syncope recommends midodrine or droxidopa for OH.8

Midodrine and droxidopa are approved by the US Food and Drug Administration (FDA) for OH treatment. Midodrine initiated with a single starting dose of 2.5 mg is a short‐acting α₁‐adrenergic agonist. It is preferred when OH is accompanied with supine hypertension or heart failure. It is favorably administered on an as‐needed basis, usually 30 to 45 minutes before upright activities. Evening doses are to be avoided because of increased risk of causing supine hypertension.5 Side effects of midodrine include scalp tingling, piloerection, and urinary retention.8 Droxidopa has been approved for patients with OH as a result of Parkinson disease, pure autonomic failure, and multiple system atrophy. It may reduce falls; however, its use is limited by supine hypertension, headache, dizziness, and nausea.8

Alternative agents include fludrocortisone, pseudoephedrine, pyridostigmine, and octreotide.3, 6, 7, 8, 14, 15 Fludrocortisone has been recommended for patients with nonhypertensive OH.5 It has also been shown to prevent OH in astronauts after space flight when taken regularly.8, 16 Higher doses of >0.3 mg/d should be avoided as they may result in corticosteroid‐like effects. Common side effects encountered are hypokalemia, headaches, supine hypertension, and heart failure; hence, heart failure is a relative contraindication.5 Pseudoephedrine was found to be effective for autonomic failure OH according to a previous study.5, 17 Even though pyridostigmine has been less effective in severe forms of OH, 60 mg has been shown to improve OH symptoms without significantly increasing supine BP. Its use has been limited by gastrointestinal side effects.5, 8, 14, 18 Octreotide is the agent of choice when other options have failed. However, its use has been limited because of required parenteral administration and gastrointestinal side effects.5, 8, 14, 19 Combination therapy (eg, combined use of fludrocortisone [0.1–0.3 mg each morning] and midodrine [5–10 mg]; combined use of midodrine [5–10 mg] or pseudoephedrine [30 mg]; and water bolus [16 ounces]) is a considerable option for patients refractory to conventional therapy.5

4. ATOMOXETINE IN OH

Atomoxetine is a selective norepinephrine reuptake inhibitor, which is approved by the FDA for treating attention deficit hyperactivity disorder.13 It increases norepinephrine levels peripherally and, when given in pediatric doses (18 mg), can increase BP in patients with autonomic failure, manifesting as OH.10, 14 It is a nonstimulant drug with no potential for abuse.9 Atomoxetine is metabolized by the cytochrome P450 system, specifically CPY2D6. Side effects of atomoxetine include headache, abdominal pain, nausea, vomiting, decreased appetite, weight loss, irritability, insomnia, and sedation. Common cardiovascular side effects include increase in heart rate, sinus tachycardia, increase in SBP in adults, and palpitations.20

The 1 summarizes the literature surrounding atomoxetine in OH. When compared with placebo in a randomized, single‐blind, crossover study of 21 patients, atomoxetine in extremely low doses induced hypertension in patients with central autonomic failure, with an increase of 54 (±26) mm Hg in seated SBP and 45 (±23) mm Hg in standing SBP. In patients with peripheral autonomic failure, atomoxetine showed a minimal increase in BP. These findings show that atomoxetine has therapeutic potential in patients with central lesions, but an intact peripheral system is essential to avoiding hypertension caused by atomoxetine.7, 12 Recently, atomoxetine has been compared with the standard of care for OH.7 When compared with midodrine in a randomized, single‐blind, crossover study of 65 patients, atomoxetine increased upright SBP by 20 mm Hg and diastolic BP by 11 mm Hg compared with an increase of upright SBP by 12 mm Hg and diastolic BP by 7 mm Hg, but there was no difference in seated BP between both drugs. Atomoxetine increased heart rate to a greater extent as compared with midodrine. Overall, atomoxetine and not midodrine improved OH‐related symptoms in patients compared with placebo.7, 9

Table 1.

Review of the literature on atomoxetine in OH

Study purpose	Methods	Main results	Study implications
To compare atomoxetine and midodrine in improving upright SBP in patients with neurogenic orthostatic hypotension	Randomized, single‐blind, crossover study9	Atomoxetine improves upright blood pressure to a greater extent than midodrine (mean difference, 7.5 mm Hg; 95% CI, 0.6–14.5 [P = .03]) Only atomoxetine improved orthostatic hypotension–related symptoms (for atomoxetine vs placebo, improvement in quartile 1 (0.6 SQRT points; 95% CI, −0.1 to 1.7 [P = .03]), while for midodrine vs placebo, no improvement in quartile 1 (0.6 SQRT point; 95% CI, −1.6 to 0.5 [P = .29])	Additional studies are required to address the long‐term efficacy of atomoxetine Atomoxetine, when given at pediatric doses, may be an alternative therapy for patients who do not experience symptom relief with midodrine
To assess atomoxetine use for 10 wk in an elderly patient with primary orthostatic hypotension	Case report10	Variability in SBP readings significantly improved along with symptoms	For patients in whom other hypotensive therapies have failed, atomoxetine may be considered as an alternative Clinicians should be aware that a low dosage of atomoxetine is effective and safe for symptom improvement and blood pressure control in orthostatic hypotension Large prospective randomized trials are needed to explore the efficacy and safety of atomoxetine use in primary orthostatic hypotension, especially in younger patients
To test the pressor effect of 18 mg of atomoxetine in 21 patients with damage of the central (10 patients) and peripheral (11 patients) autonomic nervous system	Randomized, crossover, placebo‐controlled design12	Atomoxetine significantly increased seated and standing SBP in patients with central autonomic failure as compared with placebo (slope difference 0.92; 95% CI, 0.73–1.11 [P ≤ .001]) At the end of the observation period, the mean seated SBP in the atomoxetine group was in the hypertensive range (149 ± 26, range 113–209 mm Hg) In patients with peripheral autonomic failure, atomoxetine did not elicit a pressor response (slope difference 0.16; 95% CI, −0.02 to 0.34 [P = .08])	These findings suggest that a functional central sympatholytic pathway is essential to avoid hypertension in patients treated with this drug Caution should be exercised when this medication is used in patients with milder forms of autonomic impairment

CI, confidence interval; OH, orthostatic hypotension; SBP, systolic blood pressure; SQRT, square‐rooted transformed.

Furthermore, an intriguing case report on an elderly patient has demonstrated success of atomoxetine in the management of OH symptoms after failing fludrocortisone, midodrine, and pyridostigmine both as single and combination treatment for more than 7 years. The 84‐year‐old patient showed time‐dependent improvement in OH symptoms with no more than two doses of 18 mg atomoxetine per day over a period of 10 weeks. SBP significantly improved, with a variability between 0 and 60 mm Hg. Additionally, any incidence of clinical side effects such as changes in weight, liver function tests, and heart rate were not reported throughout the study period. This report suggests that continued use of atomoxetine for more than 1 month in elderly patients is safe and effective.

In patients who have OH in whom other treatment options have failed, atomoxetine may be a reasonable alternative. Atomoxetine raises BP dramatically at small doses.3, 7, 10, 12 It is recommended that atomoxetine be taken at least 60 minutes before standing and to avoid the supine position for at least 4 hours after taking.7 Atomoxetine has also been proposed as a pharmacological tool to determine whether a patient has a central or peripheral autonomic disorder based on the response in BP from atomoxetine. In patients with intact central autonomic pathways, this dramatic increase in BP with the use of atomoxetine is counteracted by a sympatholytic effect of norepinephrine reuptake. This is an important distinction between central and peripheral autonomic disorders.12

5. CONCLUSIONS

In patients who have OH and in whom other treatment options have failed, atomoxetine may be a viable alternative. Atomoxetine raises BP dramatically at small doses, specifically doses at 18 mg. Atomoxetine significantly raises seated and standing SBP when compared with placebo and current standards of care such as midodrine. Atomoxetine has been shown to raise SBP only in patients with an intact central nervous system. Atomoxetine can be useful in patients with severe symptoms of OH or in patients with refractory OH. It is important that clinicians are aware of atomoxetine as a promising agent for the symptomatic management of patients with primary OH in whom conventional therapies have failed. It has been proven to be safe and effective, even in the elderly population.

CONFLICT OF INTEREST

The authors report no conflicts of interest to disclose.

Patel H, Simpson A, Palevoda G, Hale GM. Evaluating the effectiveness of atomoxetine for the treatment of primary orthostatic hypotension in adults. J Clin Hypertens. 2018;20:794–797. 10.1111/jch.13260