Plasma Levels of CGRP and Expression of Specific microRNAs in Blood Cells of Episodic and Chronic Migraine Subjects (CGRP-RNA)

July 16, 2020 updated by: IRCCS National Neurological Institute "C. Mondino" Foundation

Plasma Levels of CGRP and Expression of Specific microRNAs in Blood Cells of Episodic and Chronic Migraine Subjects: Toward the Identification of a Panel of Peripheral Biomarkers of Migraine?

Migraine can manifest with an episodic or chronic pattern in a continuum of disease severity. Multiple factors are associated to the transformation of the pattern form episodic to chronic. Of these, the most consistently reported is the overuse of medications (MO) for the acute treatment of attacks. Knowledge of the mechanisms through which MO facilitates the transformation of episodic migraine (EM) into chronic migraine (CM) is very limited. In order insights into these mechanisms, the present study was aimed at identifying possible peripheral biomarkers associated to the 2 forms of migraine and to the presence of MO.

The investigators evaluated CGRP plasma levels and the expression of miR-34a-5p and miR-382-5p in peripheral blood mononuclear cells of subjects with episodic migraine (EM, n=27) and CM-MO (n=28). CM-MO group was also tested 2 months after an in-hospital detoxification protocol.

Study Overview

Status

Completed

Conditions

Detailed Description

Chronic migraine (CM) is a highly disabling condition that frequently manifests as a negative evolution of episodic migraine (EM) taking place over years. In a recent meta-analysis on the predictors of migraine chronification, a number of monthly headache days >10 showed the strongest level of evidence, with depression and low household income being supported by moderate evidence. In the same meta-analysis, medication overuse (MO) was associated to the highest risk ratio in a random-effects model (RR 8.82; 95% Confidence Interval (CI), 2.88-27) but the strength of evidence was rated 'very low'due to substantial heterogeneity among studies.

It is likely that CM is the result of the dynamic interaction of multiple co-factors acting on a substrate represented by a more aggressive type of migraine. This hypothesis would explain why as many as 75% of CM subjects can spontaneously fluctuate around chronicity and episodicity. On the other hand, multiple pieces of evidence show that withdrawal from overuse medications induces a clinically meaningful improvement in a large percentage of subjects, with rates of benefit that are too high to be ascribed to a simple placebo effect.

The mechanisms underlying the negative effect of MO in migraine outcome are largely unknown. Neural mechanisms including a combination of nociceptive facilitation with weakened descending pain inhibition, associated with trigeminal hyperexcitability, may be involved. The loss of diffuse descending inhibition has been demonstrated in a preclinical model of CM with MO. In this frame, it is worth noting that the investigators have recently reported a marked derangement of the endocannabinoid system in subjects with CM and MO (CM-MO), which was more marked when compared with subjects suffering from episodic migraine (EM). Interestingly, detoxification induced in CM-MO subjects the normalization of pain thresholds paralleled by the reduction in headache frequency. Pre-clinical studies show that triptans, the specific symptomatic migraine drugs, induce a condition of hyperalgesia when administered chronically. Thus, it is possible that acute migraine medications taken in repeated episodes of pain may amplify the consequences of nociceptor activation and increase the probability of subsequent migraine attacks, together with the risk of medication overuse.

In this context of multiple concurrent causes, it seems extremely important to investigate in more depth the mechanisms that may be involved in CM and MO. Calcitonin gene-related peptide (CGRP) undoubtedly plays an important, though not exclusive, role in the generation of migraine headaches. CGRP receptors are localized in the sites involved in migraine pathogenesis. CGRP is involved in mast cell degranulation, neurogenic inflammation, and vasodilation. It has been shown that CGRP induces InterLeukin-6 (IL-6) gene expression in macrophages by upregulation of circular RNA_007893, a modulator of MicroRNA-485-5p. MicroRNAs (miRNAs) are involved in the generation and maintenance of chronic pain and several lines of evidence suggest that specific miRNAs may play a role in migraine pain. In a previous clinical study, Andersen and colleagues found an increased expression of miR-34a-5p during migraine attacks, while miR-382-5p levels increased also in the attack-free phase. In addition, the peripheral expression of miR-34a-5p decreased in the saliva of young migraineurs patients under drug treatment, thus suggesting a possible role in the prediction of therapeutic response. At present, no reliable individual biomarker of migraine and its subtypes has been identified, though multiple molecules have been proposed and supported by promising results.

In this study, the investigators assayed the plasma levels of CGRP and the expression of miRNAs in PBMCs of patients with EM and CM-MO in order to identify individual or a panel of potential biomarkers of migraine subtypes. As secondary outcome, the investigators evaluated the changes in CGRP and miRNAs levels after detoxification in the subjects with CM-MO in order to gather more insights into the mechanisms that are involved in the improvement of migraine pattern following the withdrawal of the overused medications.

This is a cross-sectional observational controlled study with 2 groups (EM and CM-MO), integrated with a prospective open label interventional trial to assess the effect of detoxification in the CM-MO group on the biomarkers of interest. Samples were labeled with numerical codes and all biochemical determinations were performed by researchers who were blind to the diagnosis.

At baseline (Day 0), all patients underwent a visit with a neurologist of the Headache Science Centre during which clinical/demographical data were recorded and inclusion/exclusion criteria were checked. If the criteria were met, subjects underwent peripheral venipuncture for the evaluation of CGRP, miR-382-5p, and miR-34a-5p levels.

Patients with CM-MO were hospitalized for a 7-day standardized detoxification protocol, consisting in abrupt withdrawal of overused drugs associated to intravenous therapy twice daily (08:00 a.m. and 4:00 p.m.) with isotonic 0.9% Sodium Chloride (NaCl) saline 500 ml + cyanocobalamin 2500 mcg + folic acid 0.70 mg + nicotinamide 12 mg + ascorbic acid 150 mg + sodic glutathione 600 mg + delorazepam 0.5 mg. Two months after hospital discharge (Day 1), the CM-MO patients returned for a follow-up visit, during which clinical data were recorded and a second venous blood sample obtained from their ante-cubital vein.

Study Type

Observational

Enrollment (Actual)

55

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Italy
      • Pavia, Italy, 27100
        • Headache Science Center

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (ADULT, OLDER_ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Twenty-seven subjects with EM and 28 subjects with CM-MO were consecutively enrolled among patients attending the outpatient clinics of the Headache Science Centre of the IRCCS Mondino Foundation of Pavia (Italy).

Description

Inclusion Criteria for EM subjects:

  • diagnosis of migraine without aura according to The International Classification Headache Disorders 3rd edition (ICHD-3) criteria;
  • documented history of EM for at least 10 years before enrollment;
  • negative life-time history of CM.

Exclusion Criteria:

  • headache or headache with migraine features and mild intensity (less than 4 on 0 to 10 visual analogue scale) in the 24 hours before blood sampling;
  • intake of acute anti-migraine medications in the 24 hours before blood sampling.

Inclusion criteria for CM-MO patients:

  • diagnosis of CM and MO according to ICHD-3 criteria;
  • documented pattern of stable CM in the 5 years prior to enrollment, without any remission period. This latter point was verified with a high degree of confidence combining the information obtained from the patients' history with their medical records, including their headache diaries.

Exclusion Criteria:

  • headache or headache with migraine features and mild intensity (less than 4 on 0 to 10 visual analogue scale) in the 24 hours before blood sampling;
  • intake of acute anti-migraine medications in the 24 hours before blood sampling.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma levels of CGRP
Time Frame: Day 0 at the enrolment
In order to identify individual or a panel of potential biomarkers of migraine subtypes
Day 0 at the enrolment
Expression of miRNAs in PBMCs
Time Frame: Day 0 at the enrolment
In order to identify individual or a panel of potential biomarkers of migraine subtypes
Day 0 at the enrolment

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Changes in CGRP levels
Time Frame: Day1 - Two months after Day 0
In the subjects with CM-MO after detoxification in order to gather more insights into the mechanisms that are involved in the improvement of migraine pattern following the withdrawal of the overused medications.
Day1 - Two months after Day 0
Changes in miRNAs levels
Time Frame: Day 1 - Two months after Day 0
In the subjects with CM-MO after detoxification in order to gather more insights into the mechanisms that are involved in the improvement of migraine pattern following the withdrawal of the overused medications.
Day 1 - Two months after Day 0

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

IRCCS National Neurological Institute "C. Mondino" Foundation

Collaborators

University of Pavia

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

December 15, 2017

Primary Completion (ACTUAL)

April 15, 2019

Study Completion (ACTUAL)

June 15, 2019

Study Registration Dates

First Submitted

July 13, 2020

First Submitted That Met QC Criteria

July 15, 2020

First Posted (ACTUAL)

July 16, 2020

Study Record Updates

Last Update Posted (ACTUAL)

July 20, 2020

Last Update Submitted That Met QC Criteria

July 16, 2020

Last Verified

July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CGRP-microRNA2020

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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