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

Hassan Jassar; Thiago D Nascimento; Niko Kaciroti; Marcos F DosSantos; Theodora Danciu; Robert A Koeppe; Yolanda R Smith; Marcelo E Bigal; Frank Porreca; Kenneth L Casey; Jon-Kar Zubieta; Alexandre F DaSilva

doi:10.1016/j.nicl.2019.101905

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

Neuroimage Clin. 2019:23:101905. doi: 10.1016/j.nicl.2019.101905. Epub 2019 Jun 18.

Authors

Affiliations

¹ Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA. Electronic address: hjassar@umich.edu.
² Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA.
³ Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; Department of Biostatistics, School of Public Health, University of Michigan, Ann Arbor, MI 48109, USA; Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48104, USA; Center for Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: nicola@umich.edu.
⁴ Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI 48104, USA.
⁵ PET Physics Section, Division of Nuclear Medicine, Radiology Department, University of Michigan, Ann Arbor, MI 48109-5030, USA.
⁶ Department of Obstetrics and Gynecology, Medical School, University of Michigan, Ann Arbor, MI 48109-0276, USA.
⁷ Ventus Therapeutics, Montreal, Canada.
⁸ Department of Pharmacology, University of Arizona, Tucson, AZ 85724-5050, USA.
⁹ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
¹⁰ Department of Psychiatry and Behavioral Heal, Stony Brook University, Stony Brook, NY 11794, USA.
¹¹ Headache & Orofacial Pain Effort (H.O.P.E.), Biologic & Materials Sciences Department, University of Michigan School of Dentistry, Ann Arbor, MI 48109, USA; Center for Human Growth and Development, University of Michigan, Ann Arbor, MI 48104, USA. Electronic address: adasilva@umich.edu.

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.

Publication types

Clinical Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Amygdala / diagnostic imaging
Amygdala / metabolism*
Analgesics, Opioid / pharmacokinetics
Caudate Nucleus / diagnostic imaging
Caudate Nucleus / metabolism
Chronic Disease
Female
Fentanyl / analogs & derivatives
Fentanyl / pharmacokinetics
Humans
Male
Middle Aged
Migraine Disorders / diagnostic imaging
Migraine Disorders / metabolism*
Migraine Disorders / physiopathology*
Nociception / physiology*
Pain Threshold / physiology*
Parahippocampal Gyrus / diagnostic imaging
Parahippocampal Gyrus / metabolism*
Physical Stimulation
Positron-Emission Tomography
Radiopharmaceuticals / pharmacokinetics
Receptors, Opioid, mu / metabolism*
Severity of Illness Index
Thalamus / diagnostic imaging
Thalamus / metabolism
Young Adult

Substances

Analgesics, Opioid
Radiopharmaceuticals
Receptors, Opioid, mu
carfentanil
Fentanyl

Associated data

ClinicalTrials.gov/NCT03004313