ELETRIPTAN (RELPAXA™) CAUSING FALSE POSITIVE ELEVATIONS IN URINARY METANEPHRINES

Abstract

Objective:

Pheochromocytoma is diagnosed biochemically by demonstrating an excessive production of catecholamines and their metabolites in the blood and urine. However, these tests are at times fraught with false-positive results due to drug effects. We report here a patient with markedly elevated urinary metanephrines associated with the use of eletriptan for migraine treatment.

Methods:

A literature search was conducted using the PubMed and Google Scholar databases for eletriptan and false positive metanephrine elevation. Urine and plasma metanephrine tests were performed via liquid chromatography/tandem mass-spectrometry.

Results:

A 29-year-old man with migraine recently started on eletriptan was evaluated for a worsening headache. Initially his blood pressure was 220/160 mm Hg with a creatinine of 1.9 mg/dL. He was treated with intravenous nicardipine. His lab tests showed normal aldosterone/plasma renin activity ratio, midnight salivary cortisol, thyroid function, and urinary drug screen. A 24-hour urine metanephrine level at 2,494 μg (normal, 45 to 290 μg) and normetanephrine level at 1,341 μg (normal, 82 to 500 μg) for secondary hypertension work-up were markedly elevated. In contrast, plasma metanephrines were at 27 pg/mL (normal, 0 to 62 pg/mL) and normetanephrines were at 255 pg/mL (normal, 0 to 145 pg/mL) were only mildly elevated. Adrenal CT and gallium-68 positron emission tomography/computed tomography showed no abnormalities. Within 1 week of eletriptan discontinuation, his urine and plasma metanephrine and normetanephrine levels completely normalized as well as a reduction of blood pressure (130’s/80’s mm Hg).

Conclusion:

The discrepancy between plasma and urine studies in our patient suggests the possibility of false positive tests. It is possible that eletriptan may affect the urine assays, but the exact mechanism causing elevated urine metanephrines/normetanephrines is not clear.

INTRODUCTION

Untreated or inappropriately treated patients with pheochromocytoma can have disastrous consequences. Given the nonspecific symptoms, it is important to confirm pheochromocytoma prior to initiating therapy. This is especially true for these neuroendocrine tumors as the management typically includes surgical resection (1–4). The diagnosis of pheochromocytoma is typically made by measurements of urinary and plasma fractionated metanephrines and catecholamines. Biochemical confirmation of the diagnosis is usually followed by radiologic evaluation to locate the tumor (5,6). Markedly elevated but false positive laboratory test results can potentially be avoided by careful selection of patients and tests. Drug interference should be considered in interpreting abnormal test results. There are several medications that result in falsely elevated normetanephrine and metanephrine levels so it is important to know the detailed medication history when working up a patient with a possible pheochromocytoma (5–8). Eletriptan, a relatively new medication (9,10) approved for migraine headaches causing falsely positive test results in a patient is herein reported.

CASE REPORT

A 29-year-old man with migraine headaches taking eletriptan was initially evaluated in the emergency room. He denied a history of palpitations, diaphoresis, pallor, or other symptoms consistent with pheochromocytoma. The patient had no previous history of hypertension. The patient presented to the emergency department complaining of worsening headaches. The initial triage revealed a blood pressure in the 220’s/160’s mm Hg with a heart rate of 90 beats/minute. He was admitted to the intensive care unit for the management of a hypertensive emergency. The patient was started on a nicardipine intravenous drip for 24 hours, then switched to oral nifedipine, chlorthalidone, and carvedilol. He had no clinical stigmata of Cushing syndrome. Laboratory evaluation for secondary causes of his hypertension revealed a plasma aldosterone of 3.1 ng/dL (normal, 0.0 to 30.0 ng/dL), plasma renin activity of 7.28 ng/mL/h (normal, 0.167 to 5.380 ng/mL/h), calculated aldosterone/plasma renin activity ratio of 0.4, and normal serum electrolytes (sodium 143 mmol/L [normal, 136 to 145 mmol/L], potassium 5.2 mmol/L [normal, 3.5 to 5.1 mmol/L], serum calcium 9.9 mg/dL [normal, 8.6 to 10.20 mg/dL]). However, there was a markedly elevated 24-hour urinary metanephrine and normetanephrine levels at 2,494 μg (normal, 45 to 290 μg) and 1,341 μg (normal, 82 to 500 μg), respectively (Table 1) were noted. In contrast, plasma metanephrines and normetanephrines were only mildly elevated (27 pg/mL [normal, 0 to 62 pg/mL], and 255 pg/mL [normal, 0 to 145 pg/mL], respectively). A urine drug screen was also negative. Computed tomography (CT) scan of the adrenals did not reveal a discrete nodule, however, a mild asymmetry was revealed. Since eletriptan is contraindicated in patients with severe hypertension, this drug was discontinued. Within a week of drug cessation, his hypertension was controlled on oral medications (nifedipine, chlorthalidone, and carvedilol). Follow-up laboratory evaluation revealed normalization of his plasma metanephrines and normetanephrines at 27 pg/mL and 101 pg/mL, respectively, on several occasions (Table 1). Similarly, urine metanephrine levels were also normal (metanephrine 76 μg/24 hours and normetanephrine 277 μg/24 hours) (Table 1). Both the urine and plasma tests were performed via liquid chromatography/tandem mass-spectrometry. The patient continues to be asymptomatic with excellent blood pressure control.

Table 1.

Urine and Plasma Normetanephrine and Metanephrine Levels While Taking Eletriptan and After Discontinuing Eletriptan

Urine
	Taking eletriptan	Eletriptan discontinued
Normetanephrine mg/24 h (normal, 82–500 mg/24 h)	1,341	277
Metanephrine mg/24 h (normal, 45–290 mg/24 h)	2,494	76
Plasma
	Taking eletriptan	Eletriptan discontinued
Normetanephrine pg/mL (normal, 0–145 pg/mL)	255	101
Metanephrine pg/mL (normal, 0–62 pg/mL)	27	27

Both the urine and plasma tests were performed via liquid chromatography/tandem mass-spectrometry (LC/MS).

DISCUSSION

It is recommended that patients showing signs or symptoms characteristic of catecholamine excess should be evaluated with biochemical testing independently of whether the patient has hypertension or not. Screening tests are also indicated in patients with unexplained variability of their blood pressures or those who show a paradoxic blood pressure response to surgery, anesthesia, or drugs that can precipitate symptoms of pheochromocytoma. When there is a discordance between the urine and the plasma metanephrine/normetanephrine levels, a false positive result should be suspected, especially due to a drug effect. It is important to note that our patient developed a hypertensive emergency following the administration of eletriptan since eletriptan may cause hypertension or a hypertensive crisis in susceptible patients. Our patient had a detailed evaluation to rule out pheochromocytoma based on a history of progressive headaches and markedly elevated systolic and diastolic blood pressures on several occasions along with markedly elevated urine metanephrines (than serum metanephrines). It has been shown that plasma and 24-hour urinary fractionated metanephrines have high diagnostic sensitivity (97%) and specificity (80 to 100%) (8–11), and are superior to other tests for the diagnosis of pheochromocytoma. Perry et al (11) recommended that measurement of 24-hour urinary fractionated metanephrines by tandem mass spectrometry also show excellent sensitivity (97%) and specificity (91%) for this diagnosis. The clonidine test is useful if the baseline metanephrine/normetanephrine levels are elevated; however, we did not perform it in our patient. The adrenal CT can be performed to confirm anatomic abnormality of the adrenal glands in more than 80% of patients with pheochromocytoma. Moreover, elevated levels of circulating chromogranin A have been generally associated with almost all types of neuroendocrine neoplasms, including pheochromocytomas (12). Plasma chromogranin A, measured by immunoassay, can be used as an appropriate additional test to metanephrine assays in the laboratory diagnosis of pheochromocytoma patients, especially in subjects with suspected or diagnosed nonfunctional pheochromocytoma (13). However we did not perform plasma chromogranin A level in this patient. Rechallenging the patient with eletriptan would have been ideal; however, we decided not to perform this due to safety concern.

It is important to perform a medication reconciliation in patients undergoing evaluation for pheochromocytoma. Phenoxybenzamine and tricyclic antidepressants are most frequently associated with false-positive results, together accounting for 41 to 45% of all elevated plasma levels of metanephrine and norepinephrine in patients without pheochromocytoma. Other medications reported to cause false-positive plasma or urine studies include labetolol, carvedilol, haloperidol, levodopa, tamsulosin, venlafaxine, hydrochlorothiazide, buspirone, lamotrigine, and aripiprazole (13–15). However, our patient was not taking any of these medications (including carvedilol) at the time of initial evaluation. Certain catecholamine rich food items such as plantain, walnut, and pineapple may also cause false positive results for urine catecholamines and rarely urine metanephrines (15). However, in our patient, a careful diet history excluded this possibility.

It is uncertain how eletriptan falsely elevated urine metanephrine and normetanephrine levels. Eletriptan binds with high affinity to 5-hydroxytryptamine/serotonin (5-HT)1B, 5-HT1D, and 5-HT1F receptors, has modest affinity for 5-HT1A, 5-HT1E, 5-HT2B, and 5-HT7 receptors, and exerts little or no affinity for 5-HT2A, 5-HT2C, 5-HT3, 5-HT4, 5-HT5A, and 5-HT6 receptors or alpha-1, alpha-2, beta adrenoceptors; dopaminergic D1 or D2; muscarinic; or opioid receptors. Eletriptan has no significant adrenoceptor activity (16). The N-demethylated metabolite of eletriptan is the only known active metabolite.

Eletriptan is metabolized primarily by the cytochrome P450 3A4 (CYP3A4) enzyme. Generally coadministration of potent CYP3A4 inhibitors was associated with relative tolerability. The margin of cardiovascular safety for eletriptan was also demonstrated previously. However, it is recommended that eletriptan may not be coadministrated with certain CYP3A4 inhibitors. This drug is also contra-indicated in patients with uncontrolled hypertension, ischemic heart disease, or other underlying cardiac disorders (9). However, it is also possible that the acute hypertension seen in this patient may not be related to eletriptan administration; it will also be interesting to investigate whether eletriptan or its metabolites interfere with metanephrine assays.

CONCLUSION

In conclusion, it is recommended that eletriptan should be added to the list of drugs causing false positive laboratory results affecting pheochromocytoma evaluation. Additional studies involving a large number of patients are needed.

Abbreviations

CYP3A4

cytochrome P450 3A4

5-HT

5-hydroxytryptamine