Researchers Find Potential Diagnostic for Migraine in Sinuses

In a small study, researchers identified high nasal-paranasal sinus nitric oxide and carbon monoxide levels as potential migraine biomarkers.

High levels of nitric oxide (NO) and carbon monoxide (CO) suctioned out from the nasal-paranasal sinuses can be used to distinguish migraineurs from healthy controls, according to study results published in BMC Neurology.

Although no pathophysiological origin of migraine has been identified, numerous theories have been proposed, including the sinus hypoxic nitric oxide hypothesis, which purports that diffused sinus NO (dsNO) in the nasal mucosa causes migraine, researchers explained.

“Hypoxia leads to increase production of NO and CO, which have vasodilatory and anti–inflammatory actions,” they added, while “administration of intranasal NO scavengers has been proven to neutralize nasal NO and reduce migraine attacks and the severity.”

In the current analysis, investigators in Sri Lanka studied the levels of NO and CO in the air sucked out from the nasal-paranasal sinuses in migraine patients and healthy individuals.

All study participants were between ages 16 and 19 years. Those with migraine underwent the procedure during an acute episode and all samples were taken within 6 hours of headache onset. None had taken acute treatment for migraine prior to the procedure.

“Three normal oral breathings were taken before the breath test for NO and CO to wash out paranasal gases. Then, after maximal oral inspiration, subjects were instructed to exhale into the device mouthpiece of the NO and CO analyzer,” authors wrote.

A normal exhaled NO level was defined as 5 to 10 ppb, and 1.01 ± 0.12 ppm was considered normal for CO. A total of 20 migraineurs and 22 healthy participants completed the study. Participants also reported their general headache pain before and after suction using a standard pain rating scale (0 being pain free and 10 being severe pain).

Analyses revealed:

  • Patients had comparatively high values compared with controls for paranasal NO (both left and right sides), paranasal CO (both left and right sides), fraction exhaled NO (FeNO), and fraction exhaled CO (FeCO).
  • Patients had median paranasal NO contents of 132.5 ppb and 154 ppb on left and right sides, respectively, compared with 36 ppb and 34.5 ppb corresponding values in controls (P < .0001).
  • A similar pattern was observed with paranasal CO (P < .0001).
  • FeNO and FeCO content were also higher in migraineurs (P < .0001).
  • Receiver operating characteristic curves of all gas measurements showed that they all could classify patients and controls effectively and NO was the most effective followed by paranasal CO.
  • With paranasal sinus NO, all patients had values above 50 ppb and controls had values below 50 ppb.
  • With paranasal sinus CO, all patients had values of 1 ppm or above, but all controls had this value less than 1 ppm but recorded as 1 ppm.
  • After air suction, the mean pain scores of general headache and tenderness dropped by a very large margin in migraine patients (P < .0001).

Overall, “these data strongly indicated that migraine patients in general have comparatively 4-5 times higher values of NO in paranasal air compared to controls,” the authors wrote. They continued, “CO concentration in paranasal air was also very high (P < .0001) in migraine patients than controls, where patients had a median CO level of 2 ppm (both left and right sides) compared to 1 ppm (both left and right sides) in controls.”

Currently, no specific laboratory test has been established for the diagnosis of migraine, and researchers suggest that these exhalation tests may help aid diagnosis in difficult situations—for instance, when headache symptoms overlap with other.

As the study was only carried out among those aged 16 through 19, results may not be generalizable to the wider adult population, marking a limitation.

“Further studies are needed to conclude that NO and CO can be a causative molecule for migraine headache,” researchers concluded.


Bandara SMR, Samita S, Kiridana AM, and Herath HMMTB. Elevated nitric oxide and carbon monoxide concentration in nasal-paranasal sinus air as a diagnostic tool of migraine: a case – control study. BMC Neurol. Published online October 26, 2021. doi:10.1186/s12883-021-02434-y