Can concurrent use of Celebrex (celecoxib), Buspirone, Depakote (valproate), and Duloxetine cause syncope?

From the Guidelines

Taking Celebrex, buspirone, Depakote, and duloxetine together can potentially cause syncope due to their combined effects on blood pressure regulation and central nervous system function. This combination of medications may increase the risk of syncope through several mechanisms, including additive effects on blood pressure and central nervous system function. Each of these medications individually lists syncope or dizziness as possible side effects, and when combined, they may exacerbate orthostatic hypotension (blood pressure drop when standing) or affect heart rhythm, further increasing fainting risk 1.

Mechanisms of Syncope Risk

• Celebrex can affect blood pressure in some patients, potentially contributing to orthostatic hypotension 1.
• Buspirone, Depakote, and duloxetine all act on the central nervous system and can cause drowsiness, dizziness, or hypotension, which may increase the risk of syncope 1.
• Depakote and duloxetine may interact to increase serotonin levels, potentially causing serotonin syndrome in severe cases, which can include syncope among its symptoms 1.

Clinical Considerations

• If you're taking this combination and experience dizziness, lightheadedness, or fainting, contact your healthcare provider immediately 1.
• Do not suddenly stop taking any of these medications without medical supervision, as abrupt discontinuation could cause withdrawal effects 1.
• According to the 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope, it is essential to evaluate the patient's history, physical examination, and ECG to determine the underlying cause of syncope 1.

Management of Syncope

• The management of syncope depends on the underlying cause, and treatment should be tailored to the individual patient's needs 1.
• Physical counterpressure maneuvers, such as leg crossing or handgrip, may be effective in preventing syncope in some patients 1.
• Medications such as midodrine or fludrocortisone may be used in certain cases, but their effectiveness is not well established 1.

From the FDA Drug Label

Orthostatic hypotension, falls, and syncope have been reported in patients treated with the recommended duloxetine delayed-release capsules dosages. The risk of BP decreases may be greater in patients taking concomitant medications that induce orthostatic hypotension (such as antihypertensives) or are potent CYP1A2 inhibitors Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). The concomitant use of duloxetine delayed-release capsules with MAOI antidepressants is contraindicated. Duloxetine delayed-release capsules should also not be started in a patient who is being treated with MAOIs such as linezolid or intravenous methylene blue

Key Points:

• The use of duloxetine with other medications that may induce orthostatic hypotension may increase the risk of syncope.
• Buspirone is a serotonergic agent that may increase the risk of serotonin syndrome when used concomitantly with duloxetine.
• The combination of celebrex (an NSAID), buspirone, depakote, and duloxetine may increase the risk of syncope due to the potential for orthostatic hypotension and serotonin syndrome.
• Patients taking these medications together should be closely monitored for signs of orthostatic hypotension, falls, and syncope, as well as serotonin syndrome 2, 2.

From the Research

Interaction Between Celebrex, Buspirone, Depakote, and Duloxetine

• The combination of these medications may lead to increased risk of adverse events due to potential drug interactions.
• Duloxetine, an antidepressant, can increase the risk of hemodynamic adverse events when combined with certain medications, such as β-blockers, due to its inhibition of the CYP2D6 enzyme 3.
• The combination of duloxetine and bupropion has been studied for treatment-resistant major depressive disorder, with reports of significant decrease in symptom severity, but also potential side effects such as nausea, dry mouth, and increased blood pressure 4.
• Buspirone, a serotonin 5-HT1A receptor partial agonist, can potentiate the effects of duloxetine and fluoxetine on dopamine and noradrenaline levels in the frontal cortex of rats, but not serotonin levels 5.
• There is no direct evidence on the combination of celebrex, buspirone, depakote, and duloxetine, but the potential for drug interactions and increased risk of adverse events, such as syncope, cannot be ruled out.
• The mechanism of action of each medication and potential interactions should be considered when evaluating the risk of syncope or other adverse events 3, 4, 5.