Psychological and Biological Markers of Refractory Migraine

NCT05046119 | Unknown

• 1 other identifier: ReMi2021
• Study Type: observational
• Target: 80
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Migraine

Keywords

Migraine; Refractoriness; Monoclonal antibodies directed against CGRP; Psychological disturbances; Endocannabinoid system

Outcome Measures

Primary Outcomes (1)

• Personality disorders

  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 Outcomes (7)

• Hospital Anxiety and Depression Scale (HADS)

  Baseline, pre-receiving the treatment

• Toronto Alexitimia Scale 20 (TAS-20)

  Baseline, pre-receiving the treatment

• Childhood traumas questionnaire

  Baseline, pre-receiving the treatment

• Stressful life events questionnaire (SLESQ)

  Baseline, pre-receiving the treatment

• The Leeds Dependence Questionnaire (LDQ)

  Baseline, pre-receiving the treatment

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• 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).

You may qualify if:

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

You may not qualify if:

• dementia, psychosis, mental retardation
• women of childbearing age without contraceptive protection, pregnant and lactating women

Sponsors & Collaborators

• IRCCS National Neurological Institute "C. Mondino" Foundation: lead

Study Sites (1)

Headache Science Center

Pavia, 27100, Italy

Location

Related Publications (13)

• Ashton CH, Moore PB. Endocannabinoid system dysfunction in mood and related disorders. Acta Psychiatr Scand. 2011 Oct;124(4):250-61. doi: 10.1111/j.1600-0447.2011.01687.x. Epub 2011 Mar 9.

  PMID: 21916860 BACKGROUND

• Bottiroli S, Galli F, Viana M, De Icco R, Bitetto V, Allena M, Pazzi S, Sances G, Tassorelli C. Negative Short-Term Outcome of Detoxification Therapy in Chronic Migraine With Medication Overuse Headache: Role for Early Life Traumatic Experiences and Recent Stressful Events. Front Neurol. 2019 Mar 7;10:173. doi: 10.3389/fneur.2019.00173. eCollection 2019.

  PMID: 30899242 BACKGROUND

• Bottiroli S, Galli F, Viana M, Sances G, Tassorelli C. Traumatic Experiences, Stressful Events, and Alexithymia in Chronic Migraine With Medication Overuse. Front Psychol. 2018 May 14;9:704. doi: 10.3389/fpsyg.2018.00704. eCollection 2018.

  PMID: 29867669 BACKGROUND

• Bottiroli S, Viana M, Sances G, Ghiotto N, Guaschino E, Galli F, Vegni E, Pazzi S, Nappi G, Tassorelli C. Psychological factors associated with failure of detoxification treatment in chronic headache associated with medication overuse. Cephalalgia. 2016 Dec;36(14):1356-1365. doi: 10.1177/0333102416631960. Epub 2016 Feb 15.

  PMID: 26879321 BACKGROUND

• Cupini LM, Bari M, Battista N, Argiro G, Finazzi-Agro A, Calabresi P, Maccarrone M. Biochemical changes in endocannabinoid system are expressed in platelets of female but not male migraineurs. Cephalalgia. 2006 Mar;26(3):277-81. doi: 10.1111/j.1468-2982.2005.01031.x.

  PMID: 16472333 BACKGROUND

• Cupini LM, Costa C, Sarchielli P, Bari M, Battista N, Eusebi P, Calabresi P, Maccarrone M. Degradation of endocannabinoids in chronic migraine and medication overuse headache. Neurobiol Dis. 2008 May;30(2):186-9. doi: 10.1016/j.nbd.2008.01.003. Epub 2008 Feb 1.

  PMID: 18358734 BACKGROUND

• De Icco R, Greco R, Demartini C, Vergobbi P, Zanaboni A, Tumelero E, Reggiani A, Realini N, Sances G, Grillo V, Allena M, Tassorelli C. Spinal nociceptive sensitization and plasma palmitoylethanolamide levels during experimentally induced migraine attacks. Pain. 2021 Sep 1;162(9):2376-2385. doi: 10.1097/j.pain.0000000000002223.

  PMID: 33587406 BACKGROUND

• Iani L, Lauriola M, Costantini M. A confirmatory bifactor analysis of the Hospital Anxiety and Depression Scale in an Italian community sample. Health Qual Life Outcomes. 2014 Jun 5;12:84. doi: 10.1186/1477-7525-12-84.

  PMID: 24902622 BACKGROUND

• Ibarra-Lecue I, Pilar-Cuellar F, Muguruza C, Florensa-Zanuy E, Diaz A, Uriguen L, Castro E, Pazos A, Callado LF. The endocannabinoid system in mental disorders: Evidence from human brain studies. Biochem Pharmacol. 2018 Nov;157:97-107. doi: 10.1016/j.bcp.2018.07.009. Epub 2018 Jul 17.

  PMID: 30026022 BACKGROUND

• Sacco S, Braschinsky M, Ducros A, Lampl C, Little P, van den Brink AM, Pozo-Rosich P, Reuter U, de la Torre ER, Sanchez Del Rio M, Sinclair AJ, Katsarava Z, Martelletti P. European headache federation consensus on the definition of resistant and refractory migraine : Developed with the endorsement of the European Migraine & Headache Alliance (EMHA). J Headache Pain. 2020 Jun 16;21(1):76. doi: 10.1186/s10194-020-01130-5.

  PMID: 32546227 BACKGROUND

• Sarchielli P, Pini LA, Coppola F, Rossi C, Baldi A, Mancini ML, Calabresi P. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007 Jun;32(6):1384-90. doi: 10.1038/sj.npp.1301246. Epub 2006 Nov 22.

  PMID: 17119542 BACKGROUND

• Tassorelli C, Greco R, Silberstein SD. The endocannabinoid system in migraine: from bench to pharmacy and back. Curr Opin Neurol. 2019 Jun;32(3):405-412. doi: 10.1097/WCO.0000000000000688.

  PMID: 30883435 BACKGROUND

• Viana M, Bottiroli S, Sances G, Ghiotto N, Allena M, Guaschino E, Nappi G, Tassorelli C. Factors associated to chronic migraine with medication overuse: A cross-sectional study. Cephalalgia. 2018 Dec;38(14):2045-2057. doi: 10.1177/0333102418761047. Epub 2018 Apr 10.

  PMID: 29635935 BACKGROUND

Biospecimen

Retention: SAMPLES WITH DNA

A sample of peripheral blood (30ml) for the evaluation of gene expression of enzymes involved in the synthesis (arachidonoylphospatidylethanolamine phospholipase D (NAPE-PLD) and diacylglycerol lipase α (DAGL-α)) and degradation (Fatty acid amide hydrolase (FAAH) or monoacylglycerol lipase (MAGL)) of endocannabinoids and their receptors (CB1 and CB2) in peripheral mononuclear cells (PBMC), through rtPCR method. In addition, in the same subjects we will evaluate plasma levels of AEA and its congener Palmitoylethanolamide, known to be altered in chronic migraine. The outcomes at 3 and 6 months will be analyzed cross-sectionally.

MeSH Terms

Conditions

Migraine Disorders

Condition Hierarchy (Ancestors)

Headache Disorders, Primary; Headache Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Study Officials

• Cristina Tassorelli, Prof

  Headache Science Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Cinzia Fattore

CONTACT

0039 (0)382380385; cinzia.fattore@mondino.it

Sara Bottiroli, PhD

CONTACT

0039 (0)382380390; sara.bottiroli@unipv.it

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 2, 2021
• First Posted: September 16, 2021
• Study Start: September 15, 2021
• Primary Completion: September 15, 2024
• Study Completion: September 15, 2024
• Last Updated: September 16, 2021

Record last verified: 2021-08

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)