Impact of chronic migraine attacks and their severity on the endogenous μ-opioid neurotransmission in the limbic system

Abstract

Objective: To evaluate, in vivo, the impact of ongoing chronic migraine (CM) attacks on the endogenous μ-opioid neurotransmission.

Background: CM is associated with cognitive-emotional dysfunction. CM is commonly associated with frequent acute medication use, including opioids.

Methods: We scanned 15 migraine patients during the spontaneous headache attack (ictal phase): 7 individuals with CM and 8 with episodic migraine (EM), as well as 7 healthy controls (HC), using positron emission tomography (PET) with the selective μ-opioid receptor (μOR) radiotracer [¹¹C]carfentanil. Migraineurs were scanned in two paradigms, one with thermal pain threshold challenge applied to the site of the headache, and one without thermal challenge. Multivariable analysis was performed between the μ-opioid receptor availability and the clinical data.

Results: μOR availability, measured with [¹¹C]carfentanil nondisplaceable binding potential (BP_ND), in the left thalamus (P-value = 0.005) and left caudate (P-value = 0.003) were decreased in CM patients with thermal pain threshold during the ictal phase relative to HC. Lower μOR BP_ND in the right parahippocampal region (P-value = 0.001) and right amygdala (P-value = 0.002) were seen in CM relative to EM patients. Lower μOR BP_ND values indicate either a decrease in μOR concentration or an increase in endogenous μ-opioid release in CM patients. In the right amygdala, 71% of the overall variance in μOR BP_ND levels was explained by the type of migraine (CM vs. EM: partial-R² = 0.47, P-value<0.001, Cohen's effect size d = 2.6SD), the severity of the attack (pain area and intensity number summation [P.A.I.N.S.]: partial-R² = 0.16, P-value = 0.031), and the thermal pain threshold (allodynia: partial-R² = 0.08).

Conclusions: Increased endogenous μ-opioid receptor-mediated neurotransmission is seen in the limbic system of CM patients, especially in right amygdala, which is highly modulated by the attack frequency, pain severity, and sensitivity. This study demonstrates for the first time the negative impact of chronification and exacerbation of headache attacks on the endogenous μ-opioid mechanisms of migraine patients. ClinicalTrials.gov identifier: NCT03004313.

Keywords: Central pain; MRI; Migraine; Opioid; PET; Thermal pain threshold.

Graphical abstract

Fig. 1

Migraine headache severity and endogenous μ-opioid ictal activation during PET. (A) Schematic of individual recorded migraine headaches and facial P.A.I.N.S from the 7 CM and 8 EM patients after the ictal PET session, using the GeoPain mobile application. Sequence of participants follows Table-1, from top left to lower right. The curved white arrows indicate that the head of this patient was flipped to show the most intense headache on the left side. The 3D head images at the center represent the average rating of P.A.I.N.S. Headache color scale: Mild (1 – light red), Moderate (2 – red), and Severe (3 – dark red). (B) PET images with the endogenous μ-Opioid activation during migraine headache attack and trigeminal thermal pain threshold in the left thalamic (MNI_[-10,-14,8]) and left caudate (MNI_[-14,18,-8]) for 7 CM vs. 7 HC (P-values = 0.005 and 0.003, respectively) (top), as well as in the right amygdala (MNI_[22,2,-16]) and the right parahippocampal gyrus (MNI_[26,4,-36]) for 7 CM vs. 8 EM during attack (P-values = 0.002 and 0.001, respectively) (bottom). Both indicate a higher release of endogenous μ-opioid during CM attack and thermal pain threshold. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Altered μOR of the right amygdala regarding type of migraine, attack severity, and thermal pain threshold. (A) Pie graph illustrating the relative percentages of variance (R²) explained by μOR BP_ND level in the right amygdala (MNI_[22,2,-16]), during the attack, in response to migraine type, P.A.I.N.S, and cutaneous thermal pain threshold (overall R² = 71%). Amygdala μOR BP_ND is mostly affected by the type of migraine (partial-R² = 47%) compared to P.A.I.N.S (partial-R² = 16%) and thermal pain threshold sensitivity (partial-R² = 8%). P.A.I.N.S and thermal pain threshold sensitivity were set at their mean value (85.47 and 43.04 respectively). (B–D) Scatterplot analysis of amygdala μOR BP_ND in response to each of the three variables shown in (A), adjusted for the other two. (B) Type of migraine: significant lower amygdala μOR BP_ND for CM vs. EM (P-value<0.001). (C) Attack severity: adjusted linear regression model indicating a significant negative linear correlation between P.A.I.N.S. and amygdala μOR BP_ND levels (P-value = 0.031). (D) Thermal pain threshold: adjusted linear regression model showing a marginal positive linear correlation between amygdala μOR BP_ND and cutaneous STPT (P-value = 0.1).

Fig. 3

Illustration summarizes the finding for endogenous μ-Opioid release. (A) Stable levels of endogenous μ-Opioid for HC. (B) Illustration of a participant suffering severe headache attacks during CM (≥15 attacks/month) and exposed to a cutaneous STPT challenge. (C) Sudden increase in endogenous μ-opioid release in the limbic system (right amygdala) of CM patients during the ongoing headache attacks and allodynia relative to EM.