In a patient with back pain and markedly elevated prolactin who is taking Nurtec (rimegepant), Cymbalta (duloxetine), bupropion, and Zofran (ondansetron), could these medications be causing the prolactin elevation?

Medication Contributions to Elevated Prolactin

Among the medications this patient is taking, only Zofran (ondansetron) has a documented mechanism to elevate prolactin levels, though the elevation is typically mild and transient. Nurtec (rimegepant), Cymbalta (duloxetine), and bupropion are not established causes of clinically significant hyperprolactinemia. 1, 2, 3

Medication-Specific Analysis

Zofran (Ondansetron)

• Ondansetron is classified as a prokinetic/antiemetic agent that can increase prolactin levels through serotonergic pathways, as medications that increase bowel motility are recognized causes of drug-induced hyperprolactinemia. 2, 3, 4
• However, the prolactin elevation from ondansetron is typically mild and may not fully explain markedly elevated levels. 1

Cymbalta (Duloxetine)

• Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), and while some antidepressants with serotoninergic activity—particularly SSRIs, MAO inhibitors, and certain tricyclics—can cause hyperprolactinemia, SNRIs like duloxetine are not prominently listed among the common culprits. 2, 3
• The risk appears lower than with pure SSRIs or tricyclic antidepressants. 2

Bupropion

• Bupropion is notably absent from the literature on medication-induced hyperprolactinemia and works primarily through dopamine and norepinephrine reuptake inhibition—mechanisms that would theoretically lower rather than raise prolactin. 2, 3, 4
• This medication is extremely unlikely to contribute to elevated prolactin. 1

Nurtec (Rimegepant)

• Rimegepant is a CGRP receptor antagonist used for migraine, and there is no established association between CGRP antagonists and hyperprolactinemia in the medical literature reviewed. 1, 2, 3

Diagnostic Approach for This Patient

Essential Initial Steps

• Review the degree of prolactin elevation: Mild elevation (<100 μg/L or <2000 mU/L) is more consistent with medication effects, stalk compression, or stress, whereas marked elevation (>4000 mU/L or >188 μg/L) strongly suggests a prolactinoma. 1, 5
• Exclude macroprolactinemia through polyethylene glycol (PEG) precipitation testing, as this accounts for 10–40% of all hyperprolactinemia cases and represents biologically inactive prolactin complexes. 1, 6
• Screen for hypothyroidism (TSH and free T4), as primary hypothyroidism causes hyperprolactinemia in 43% of affected women and can produce pituitary hyperplasia mimicking a prolactinoma. 1, 5
• Assess renal and hepatic function, since chronic kidney disease (30–65% prevalence) and severe liver disease are associated with elevated prolactin. 1

Imaging Considerations

• Obtain high-resolution pituitary MRI with and without contrast if prolactin remains elevated after excluding secondary causes, particularly given the patient's back pain, which could represent mass-effect symptoms if a large adenoma is present. 1, 5
• If a large pituitary mass is found but prolactin seems paradoxically normal or only mildly elevated, request manual serial dilutions to rule out the "hook effect," which occurs in approximately 5% of macroprolactinomas. 1, 5

Management Strategy

If Medication-Induced Hyperprolactinemia Is Confirmed

• Temporarily discontinue ondansetron (in consultation with the prescribing physician) to determine if prolactin levels normalize, which would confirm the medication as the cause. 3, 4
• If ondansetron cannot be stopped and hyperprolactinemia is symptomatic (menstrual disturbances, galactorrhea), consider switching to an alternative antiemetic that does not affect prolactin. 3, 4
• Do not routinely add a dopamine agonist for drug-induced hyperprolactinemia unless a structural lesion has been definitively excluded and symptoms are severe, as this approach may be dangerous without proper evaluation. 7, 4

If a Prolactinoma Is Identified

• Cabergoline is first-line therapy for both micro- and macroprolactinomas, with superior effectiveness and tolerability compared to bromocriptine, achieving prolactin normalization in approximately 74% of patients. 6, 5, 7
• For macroadenomas, repeat MRI 3–6 months after initiating cabergoline to verify tumor shrinkage and assess for resolution of mass effects. 5, 7

Critical Pitfalls to Avoid

• Do not assume the medications are responsible without measuring the actual prolactin level and excluding structural lesions, as the back pain could indicate a large pituitary tumor with mass effect. 1, 3
• Do not overlook hypothyroidism, which is a reversible cause of hyperprolactinemia and must be excluded in every case. 1, 5
• Do not miss macroprolactinemia, especially if the patient is asymptomatic or has only mild elevation, as 20% of these patients may still have concurrent true hyperprolactinemia or pituitary adenomas. 1, 6
• Do not start dopamine agonist therapy for mild, asymptomatic, medication-related hyperprolactinemia without first confirming the absence of a structural lesion. 5, 4