What is the best course of action for a patient with a history of polycystic ovary syndrome (PCOS) and insulin resistance, controlled on metformin, who is experiencing projectile vomiting, intermittent flushing, nausea, headaches, and slightly elevated white blood cell count (WBC) and C-reactive protein (CRP), while taking spironolactone, doxazosin, Adderall (amphetamine and dextroamphetamine) for attention deficit hyperactivity disorder (ADHD), and venlafaxine for anxiety?

Immediate Diagnostic Workup for Carcinoid Syndrome

This patient's constellation of projectile vomiting, intermittent flushing, headaches, and persistent nausea with elevated inflammatory markers warrants urgent evaluation for carcinoid syndrome or neuroendocrine tumor, particularly given the failure of standard treatments and the episodic nature of symptoms.

Critical Red Flags Requiring Immediate Investigation

The symptom pattern described—projectile vomiting, episodic flushing, headaches, and persistent nausea—does not fit typical metformin gastrointestinal intolerance, which presents as transient symptoms that resolve with dose adjustment or extended-release formulation 1, 2. The chronicity and severity suggest an alternative diagnosis.

Key Distinguishing Features

• Projectile vomiting is not characteristic of metformin-induced nausea, which typically presents as mild-to-moderate nausea with gradual onset 1, 2
• Intermittent flushing combined with gastrointestinal symptoms raises concern for carcinoid syndrome or other neuroendocrine pathology 3
• Persistently elevated CRP and WBC suggest ongoing inflammatory or neoplastic process rather than medication side effect 3
• The patient reports "just feeling unwell" with random vomiting episodes, indicating systemic illness beyond drug intolerance 3

Essential Diagnostic Testing

First-Line Laboratory Studies

• 24-hour urine 5-HIAA (5-hydroxyindoleacetic acid) to screen for carcinoid syndrome 3
• Serum chromogranin A as a neuroendocrine tumor marker 3
• Fasting gastrin level to evaluate for gastrinoma (Zollinger-Ellison syndrome) 3
• Comprehensive metabolic panel including calcium to assess for multiple endocrine neoplasia 3
• Thyroid function tests (TSH, free T4) as thyroid disorders can cause nausea and vomiting 3

Second-Line Imaging Studies

• CT abdomen/pelvis with contrast to evaluate for neuroendocrine tumors, particularly in the small bowel and pancreas 3
• Upper endoscopy if gastric pathology suspected, especially given NSAID use 3

Medication Review and Adjustment

Immediate Medication Considerations

While investigating the underlying cause, address potential medication-related contributions:

• Temporarily discontinue metformin to assess if symptoms improve, though this is unlikely the primary cause given the atypical presentation 1, 2
• Review Adderall (amphetamine/dextroamphetamine) as stimulants can cause nausea, vomiting, and flushing, particularly at higher doses or with prolonged use 3
• Evaluate venlafaxine which can cause nausea and, rarely, serotonin syndrome when combined with other serotonergic agents 3
• Assess NSAID use as chronic use increases risk of peptic ulcer disease and gastritis, which could explain vomiting 3

Metformin Management If Continued

If metformin is to be continued during workup:

• Switch to extended-release formulation (metformin XR) which minimizes GI side effects 1, 2
• Reduce dose temporarily to 500 mg daily with gradual escalation if symptoms are partially metformin-related 1, 2
• Ensure adequate renal function (eGFR ≥45 mL/min/1.73 m²) before continuing metformin 1, 2
• Check vitamin B12 levels given long-term metformin use in PCOS management 1, 2

Critical Pitfalls to Avoid

• Do not attribute projectile vomiting to metformin without excluding serious pathology, as metformin causes mild nausea, not severe projectile vomiting 1, 2
• Do not overlook drug interactions between venlafaxine (SNRI) and Adderall (sympathomimetic), which can potentiate adverse effects 3
• Do not dismiss the flushing episodes as benign, as this is a hallmark of carcinoid syndrome when combined with GI symptoms 3
• Do not continue NSAIDs without gastric protection (PPI) given the vomiting symptoms 3

Symptomatic Management During Workup

Antiemetic Therapy

• Ondansetron (serotonin antagonist) 4-8 mg every 8 hours as needed for acute symptom control 3
• Metoclopramide (dopamine antagonist) 10 mg before meals if gastroparesis suspected, though use cautiously with other psychiatric medications 3
• Avoid prolonged antiemetic use without identifying underlying cause 3

Supportive Care

• Maintain hydration with oral rehydration solutions or IV fluids if severe 3
• Small, frequent meals rather than large meals 3
• Avoid trigger foods that exacerbate symptoms 3

PCOS-Specific Considerations

The combination of metformin and spironolactone is appropriate for PCOS management and does not increase adverse effects compared to metformin alone 4, 5, 6. However, this patient's symptoms exceed typical medication side effects:

• Metformin plus spironolactone reduces BMI and testosterone more effectively than metformin alone without increasing nausea or vomiting 4, 5
• Spironolactone alone does not cause significant GI symptoms in PCOS patients 7, 5
• Continue PCOS medications unless diagnostic workup reveals contraindication 4, 5

Follow-Up Timeline

• Urgent evaluation (within 1-2 weeks) for neuroendocrine workup given severity of symptoms 3
• Reassess in 3-5 days if metformin discontinued to determine if symptoms improve 1, 2
• Gastroenterology referral if initial workup negative but symptoms persist 3