Role of Endo-opioid and Endo-cannabinoid Systems in Migraine and Medication-overuse Headache

Abstract

Objective: The endo-opioid and endo-cannabinoid systems are important in regulating pain and have been implicated in migraine pathophysiology. Patients with frequent attacks, such as patients with chronic migraine (CM), frequently develop medication overuse headache (MOH). Not all patients with chronic headache develop MOH, the reason for which is not exactly known. We aimed to assess the involvement of these neurotransmitter systems in episodic and CM and in MOH.

Materials and Methods: Patients with (episodic migraine; n=29), (CM; n=15), MOH (n=16) and 31 healthy controls were recruited and blood levels of nociceptin and anandamide (AEA) were compared between groups, as well as their levels with headache parameters.

Results: AEA levels were significantly lower in the combined migraine groups compared to controls (p=0.009), but head to head comparison of the groups revealed no significant difference (p=0.062). Median nociceptin levels were found to be very high in CM (235.76 ng/l) group and very low in MOH (30.08 ng/l) group, but the difference was not statistically significant.

Conclusion: Our finding of low AEA levels in migraine supports the hypothesis of a dysfunctional endocannabinoid system in migraine. Although our results failed to reveal any differences between episodic and CM, an interpretation of findings reported in the literature suggested that this low endocannabinoid inhitory tone might contribute to nociceptive facilitation resulting in maintained central sensitization and therefore sustained pain in CM. Although not significant, nociceptin levels were much higher in CM group and the lowest levels were found in MOH group. It is possible that in CM, the opioid system tries to counterbalance the endocannabinoid dysfunction and if the opioid levels fail to rise, the patient is driven to an excessive use of analgesics and MOH develops. Although we were unable to prove this hypothesis we think it would be worthwhile studying this hypothesis in a larger group of patients.

The study protocol was approved by the Local Ethics Committee of Akdeniz University (decision no: 148, date no: 21.02.2018).

Informed consent from all participants was obtained.

Externally peer-reviewed.

Surgical and Medical Practices: G.H., Concept: D.D-D., S.Ö., B.D., Design: D.D-D., S.Ö., B.D., Data Collection or Processing: G.H., S.Ö., Analysis or Interpretation: G.H., B.D., Literature Search: G.H., B.D., Writing: G.H., S.Ö., B.D.

No conflict of interest was declared by the authors.

This study was funded by the Akdeniz University Scientific Research Project Unit.

We wish to thank Prof. Mehmet Ziya Fırat from the Akdeniz University Faculty of Agriculture Division of Zoometry, Department of Biometry and Genetics for his kind help in statistical analysis of the data.