An observational study in Migraine, sponsored by IRCCS National Neurological Institute "C. Mondino" Foundation. Completed at 1 site in Italy. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2020-07-20.
Sponsored by IRCCS National Neurological Institute "C. Mondino" Foundation · Observational
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.
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.
1,528 studies on the registry are indexed under Migraine Disorders; 299 are open to participants now.
This study's enrollment of 55 is below the median of 130 across 299 observational studies indexed under Migraine Disorders.
Browse Migraine Disorders studies →IRCCS National Neurological Institute "C. Mondino" Foundation is the lead sponsor of 57 studies on the registry; 20 are open to participants now.
Counted across the registry records on this site, refreshed daily.
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).
Inclusion Criteria for EM subjects:
Exclusion Criteria:
Inclusion criteria for CM-MO patients:
Exclusion Criteria:
Plasma levels of CGRP
In order to identify individual or a panel of potential biomarkers of migraine subtypes
Time frame: Day 0 at the enrolment
Expression of miRNAs in PBMCs
In order to identify individual or a panel of potential biomarkers of migraine subtypes
Time frame: Day 0 at the enrolment
Changes in CGRP levels
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.
Time frame: Day1 - Two months after Day 0
Changes in miRNAs levels
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.
Time frame: Day 1 - Two months after Day 0
Plan to share: No
This study is completed, as verified in Jul 2020. You cannot join it, but the record below documents what was studied.
Get an email when the registry record changes — status, dates, results — or when someone posts here.
Sign in to followQuestions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.
Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.
Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.
IRCCS National Neurological Institute "C. Mondino" Foundation