Psychological and Biological Markers of Refractory Migraine

September 13, 2021 updated by: IRCCS National Neurological Institute "C. Mondino" Foundation

Factors Associated With Migraine Refractoriness to Preventive Treatments: Psychological Aspects and Relationship With Components of the Endocannabinoid System

The term "refractory" migraine describes a particularly aggressive form of the disease in which the patient does not benefit from any of the preventive therapies with the various classes of drugs available, including treatment with monoclonal antibodies directed against Calcitonin Gene Related Peptide (CGRP).

Anxiety, depressive symptoms, somatization, and pain hypersensitivity are significantly more prevalent in refractory migraineurs than in non-refractory subjects who benefit from preventive therapies, suggesting that these symptoms may contribute to treatment refractoriness. Recently, in a preliminary study on the efficacy of a CGRP-targeting monoclonal antibody in Chronic Migraine (CM) patients with at least 3 failures to previous preventive treatments, the investigators showed a higher prevalence of psychological disturbances in those who did respond to the monoclonal antibody compared with the responders. These data, although preliminary, point to a more psychologically complicated picture in non-responder patients compared with responders. To date, however, no neurobiological evaluations are available to explain how psychological comorbidities may contribute to treatment refractoriness. Isolated clinical evidence and growing pre-clinical evidence suggests a role for the endocannabinoid system in migraine. Hence, the present study aims to identify psychological and biological factors associated with refractory migraine. The investigators' hypothesis is that patients presenting with psychological disorders may bear an associated dysfunction of the endocannabinoid system, which makes them more resistant to migraine preventive therapies, including monoclonal antibodies directed against CGRP.

Study Overview

Status

Not yet recruiting

Conditions

Detailed Description

Migraine is a common and highly disabling condition, representing the second-leading cause of disability in the global ranking of most disabling diseases . In the majority of individuals, the disease manifests as episodic (EM), with attacks recurring weekly or monthly. In a smaller (2-3% of the general population), but still significant portion of patients, migraine becomes chronic, i.e., occurring on at least 15 days per month (CM).

Previous studies have shown that CM patients are characterized by the presence of multiple psychiatric comorbidities compared with subjects with episodic migraine and healthy controls. In recent years, it has also been shown that among the neurobiological systems involved in the genesis and development of mental disorders, the endocannabinoid system (ES) appears to play an active role. In particular, patients with these disorders are characterized, at the level of peripheral cells, by a gene alteration of cannabinoid receptors.

Several studies reported the involvement of SE in immune responses, psychological processes, transduction of neurobiological signals and pain, including migraine pain. Recently it has been shown that the peripheral gene expression of enzymes involved in the metabolism of anandamide (AEA) and 2-aciglycerol (2-AG), the two best known endocannabinoids, is altered in migraine patients, but more markedly in the chronic subtype, suggesting a role for these lipid molecules not only in the pathophysiology of the disease, but also in its exacerbation. The role of CGRP in the pathophysiology of migraine has now been demonstrated, although the mechanism of action at both peripheral and central levels and its possible interactions with other pathways are not completely known.

The term "refractory" migraine describes a particularly aggressive form of the disease in which the patient does not benefit from any of the preventive therapies with the various classes of drugs available, including treatment with monoclonal antibodies directed against CGRP (Consensus document of the European Headache Federation).

Anxiety, depressive symptoms, somatization, and pain hypersensitivity are significantly more prevalent in refractory migraineurs than in non-refractory subjects who benefit from preventive therapies, suggesting that these symptoms may contribute to treatment refractoriness. Recently, in a preliminary study regarding the efficacy of monoclonal antibody targeting CGRP in CM patients refractory to at least three preventive therapies,the investigators showed a higher prevalence of personality disorders (77% vs 37%) in those who were not responding to treatment at 1 year (non-responders: reduction in migraine days <50%), compared with those who were responding (responders: reduction in migraine days ≥50%). Non-responders were also characterized by a higher prevalence of anxiety spectrum disorders and more stressful events than responders. These data, although preliminary, point to a more psychologically complicated picture in non-responder patients compared with responders. To date, however, no neurobiological data are available to explain how psychological comorbidities may contribute to treatment refractoriness.

In this frame, the present study aims to identify psychological and potential biochemical/molecular factors associated with refractory migraine. The investigators' hypothesis is that patients presenting with psychological disorders may bear an associated dysfunction of the endocannabinoid system, which makes them more resistant to migraine preventive therapies, including monoclonal antibodies directed against CGRP.

There will be a screening phase of one month in which patients will complete a daily headache diary in which they will note the occurrence, intensity and duration of attacks, as well as the use of symptomatic drugs. At baseline patients will undergo the psychological and biochemical/molecular evaluation. Subjects will then be treated with one of the three commercially available monoclonal antibodies targeting CGRP and will continue to record the characteristics of attacks and the use of symptomatic drugs in their headache diary. Follow-up visits are foreseen after 3 and 6 months of treatment. At 6 months, patients will be divided into 2 groups (responder or not responder to the treatment) depending on the reduction of monthly migraine days in the previous 3 months (>50% and <50%, respectively).

The patients who failed to respond to the treatment will be considered refractory.

Psychological evaluation: All patients will be evaluated by psychological interview and by adopting the DSM-V criteria for personality disturbances, anxiety and mood disorders. All patients will also be administered the Hospital Anxiety and Depression Scale (HADS) the Toronto Alexithymia Scale 20 (TAS-20), severity of dependence questionnaires (Severity Dependence Scale - SDS - and Leeds Dependence Questionnaire - LDQ), questionnaires related to Childhood trauma and Stressful life events.

Study Type

Observational

Enrollment (Anticipated)

80

Contacts and Locations

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

Study Contact

Study Contact Backup

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 to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Sampling Method

Non-Probability Sample

Study Population

Eighty participants with EM and CM will be recruited at the Headache Science and Neurorehabilitation Centre of the IRCCS Mondino Foundation. The diagnosis of EM and CM is formulated according to the guidelines of the ICHD-III version (EM or CM with previous failure to at least 3 of the following classes of antimigraine preventive drugs :beta-blockers, antidepressants, calcium antagonists and, for CM, onabotulinumtoxinA).

Description

Inclusion Criteria:

  1. Clinical characteristics that meet the criteria of the current International Headache Classification for Migraine or Chronic Migraine.
  2. Age >18, <65 years of both sexes
  3. At least 8 days of migraine/month and Migraine Disability Assessment Questionnaire (MIDAS) score greater than 11 at baseline*.

  4. Lack of benefit or intolerance or contraindication to at least three classes of drugs for the preventive therapy of migraine*.

    • Drug Italian Agency (AIFA) criteria for the prescription of monoclonal antibodies directed against CGRP.

Exclusion Criteria:

  1. dementia, psychosis, mental retardation
  2. women of childbearing age without contraceptive protection, pregnant and lactating women

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
Personality disorders
Time Frame: Change from baseline to 3-month to 6-month
To evaluate the association of refractory migraine with personality disorders (according to Diagnostic and Statistical Manual of mental disorders - DSM V criteria) in subjects with resistant migraine undergoing therapy with monoclonal antibodies directed against CGRP.
Change from baseline to 3-month to 6-month

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Hospital Anxiety and Depression Scale (HADS)
Time Frame: Baseline, pre-receiving the treatment
The HADS is a fourteen item scale that generates: seven of the items relate to anxiety and seven relate to depression. Each item on the questionnaire is scored from 0-3. Higher scores are worst outcomes
Baseline, pre-receiving the treatment
Toronto Alexitimia Scale 20 (TAS-20)
Time Frame: Baseline, pre-receiving the treatment
The TAS is a 20-item instrument that is one of the most commonly used measures of alexithymia. The TAS-20 uses cutoff scoring: equal to or less than 51 = non-alexithymia, equal to or greater than 61 = alexithymia. Scores of 52 to 60 = possible alexithymia.
Baseline, pre-receiving the treatment
Childhood traumas questionnaire
Time Frame: Baseline, pre-receiving the treatment
The Childhood Trauma Questionnaire (CTQ) is a retrospective, self-report measure that was developed to provide a brief, reliable, and valid assessment of a broad range of traumatic experiences in childhood. It contains 70 items arranged according to four factors: physical and emotional abuse, emotional neglect, sexual abuse, and physical neglect. Responses are quantified on a 5-point Likert-type scale according to the frequency with which experiences occurred, with 1 = "never true" and 5 = "very often true.
Baseline, pre-receiving the treatment
Stressful life events questionnaire (SLESQ)
Time Frame: Baseline, pre-receiving the treatment
SLESQ is a 13-item self-report measure for non-treatment seeking samples that assesses lifetime exposure to traumatic events. Eleven specific and two general categories of events, such as a life-threatening accident, physical and sexual abuse, witness to another person being killed or assaulted, are examined. For each event, respondents are asked to indicate whether the event occurred ("yes" or "no"), their age at time of the event, as well as other specific items related to the event, such as the frequency, duration, whether anyone died, or was hospitalization, etc.
Baseline, pre-receiving the treatment
The Leeds Dependence Questionnaire (LDQ)
Time Frame: Baseline, pre-receiving the treatment
The LDQ has been developed as part of a treatment evaluation package. The LDQ is a 10-item, self completion questionnaire designed to measure dependence upon a variety of substances. All items are scored 0-1-2-3.
Baseline, pre-receiving the treatment
Severity of Dependence Scale (SDS)
Time Frame: Baseline, pre-receiving the treatment
The Severity of Dependence Scale (SDS) is a 5-item self-administered questionnaire that provides a score indicating the severity of dependence on drugs. Higher scores are worst outcomes
Baseline, pre-receiving the treatment
Endocannabinoid System (ES)
Time Frame: Baseline, pre-receiving the treatment
Main components of the ES at the peripheral level
Baseline, pre-receiving the treatment

Collaborators and Investigators

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

Sponsor

IRCCS National Neurological Institute "C. Mondino" Foundation

Investigators

  • Principal Investigator: Cristina Tassorelli, Prof, Headache Science Center

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 (Anticipated)

September 15, 2021

Primary Completion (Anticipated)

September 15, 2024

Study Completion (Anticipated)

September 15, 2024

Study Registration Dates

First Submitted

September 2, 2021

First Submitted That Met QC Criteria

September 13, 2021

First Posted (Actual)

September 16, 2021

Study Record Updates

Last Update Posted (Actual)

September 16, 2021

Last Update Submitted That Met QC Criteria

September 13, 2021

Last Verified

August 1, 2021

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ReMi2021

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

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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