Development Of Medication Overuse Headache Research Articles

The role of personality factors in development of medication-overuse headache in patients with primary cephalalgia

The role of personality factors in development of medication-overuse headache in patients with primary cephalalgia

Refractoriness to drugs in migraine may be the result of developing anti-drug antibodies

IntroductionMigraine is a common neurological disease and is listed second among the most disabling health conditions worldwide. Refractory migraine (RM) is a term used to emphasize the unresponsiveness of migraine to various treatment options, encompassing both episodic refractory and chronic refractory migraine. In this paper we discuss various known and possible mechanisms of pharmacological refractoriness in RM, such as possible involvement of the gut microbiome, the blood-brain barrier, migraine genetics and various mechanisms of pharmacokinetic and pharmacodynamic tolerance. Development of medication-overuse headache as a secondary disorder following migraine is also considered. We argue that the available literature is insufficient to fully explain the mechanisms of refractoriness and we present our hypothesis.HYPOTHESIS. Refractoriness to drugs in migraine may be the result of developing anti-drug antibodies. Most migraine drugs are small molecules, which cannot elicit an immune response on their own due to their size. However, such molecules can bind to peptide carriers in their vicinity, greatly increasing their immunogenicity. A small molecule possessing this binding ability is called a hapten. Haptens form hapten-carrier complexes (HCCs), which can evoke powerful immune responses. Immune reactions to HCCs are known to be predominantly ‘drug allergies’ or type 1 drug hypersensitivity reactions’, usually resulting from IgE or non-IgE mediated mast cell degranulation. We argue that the immune reaction to HCCs can take shape in developing neutralizing anti-drug antibodies (ADA) in the form of IgG and IgA class antibodies. Since biological therapeutics, such as various monoclonal antibodies, face the issue of ADA-induced drug tolerance, HCCs, being similar in the sense that they carry peptide antigens, are of sufficient size and may be considerably immunogenic, can be responded to in a similar way by producing neutralizing ADA. Furthermore, we argue that such responses are expected to happen more frequently than is thought, due to IgG and IgA being prevalent antibodies, which utilize their neutralizing capabilities on regular basis. Finally, it is important to consider that neutralization reactions in normal immune responses are typically asymptomatic, with the only clinical expression being progressive drug tolerance. These cases may be overshadowed by the life-threatening cases of drug allergy induced anaphylaxis, possibly leading to neutralization reactions being underrecognized. DiscussionThis hypothesis aims to stimulate more research regarding drug resistance, and if it receives support from empirical evidence, it may help further elucidate the mechanisms underlying refractory diseases and contribute to the development of more effective treatment of many disorders.

The role of personality, disability and physical activity in the development of medication-overuse headache: a prospective observational study

BackgroundFactors associated with development of medication-overuse headache (MOH) in migraine patients are not fully understood, but with respect to prevention, the ability to predict the onset of MOH is clinically important. The aims were to examine if personality characteristics, disability and physical activity level are associated with the onset of MOH in a group of migraine patients and explore to which extend these factors combined can predict the onset of MOH.MethodsThe study was a single-center prospective observational study of migraine patients. At inclusion, all patients completed questionnaires evaluating 1) personality (NEO Five-Factor Inventory), 2) disability (Migraine Disability Assessment), and 3) physical activity level (Physical Activity Scale 2.1). Diagnostic codes from patients’ electronic health records confirmed if they had developed MOH during the study period of 20 months. Analyses of associations were performed and to identify which of the variables predict onset MOH, a multivariable least absolute shrinkage and selection operator (LASSO) logistic regression model was fitted to predict presence or absence of MOH.ResultsOut of 131 participants, 12 % (n=16) developed MOH. Migraine disability score (OR=1.02, 95 % CI: 1.00 to 1.04), intensity of headache (OR=1.49, 95 % CI: 1.03 to 2.15) and headache frequency (OR=1.02, 95 % CI: 1.00 to 1.04) were associated with the onset of MOH adjusting for age and gender. To identify which of the variables predict onset MOH, we used a LASSO regression model, and evaluating the predictive performance of the LASSO-mode (containing the predictors MIDAS score, MIDAS-intensity and –frequency, neuroticism score, time with moderate physical activity, educational level, hours of sleep daily and number of contacts to the headache clinic) in terms of area under the curve (AUC) was weak (apparent AUC=0.62, 95% CI: 0.41-0.82).ConclusionDisability, headache intensity and frequency were associated with the onset of MOH whereas personality and the level of physical activity were not. The multivariable LASSO model based on personality, disability and physical activity is applicable despite moderate study size, however it can be considered as a weak classifier for discriminating between absence and presence of MOH.

Polymorphism of the Glutamate Transporter Protein EAAT2 and Migraine Transformation into Chronic Daily Headache

Background and PurposeThe progression of migraine into chronic daily headache involves multiple risk factors, but the main contributor is not known. Glutamate is the major excitatory neurotransmitter in central sensitization, which is an important process in the pathogenesis of migraine transformation. The glutamate transporter protein excitatory amino acid transporter 2 (EAAT2) is the primary modulator of glutamatergic neurotransmission, and genetic polymorphisms of its gene, EEAT2, have been identified. The aim of this study was to determine the effect of EAAT2 polymorphisms on migraine transformation into chronic daily headache.MethodsWe included 74 migraine patients with episodic attack (M-E) and 59 migraine patients with chronic daily headache (M-CDH). After amplifying EAAT2 by polymerase chain reaction, we assessed its genotype frequencies based on restriction fragment length polymorphisms. We reclassified all migraine patients into two groups according to their EAAT2 genotype, either with the A allele (n=62) or without it (n=71), and compared the clinical variables between the two groups.ResultsThe genotype frequencies of EAAT2 polymorphisms did not differ between the M-E and M-CDH groups. Comparison between EEAT2 genotypes revealed that the frequency of analgesic usage was significantly higher among migraine patients with the A allele (12.9±1.6 days/month) than in those without the A allele (8.1±1.2 days/month; p=0.019). The other clinical variables of migraine did not differ between the two groups.ConclusionsThe results suggest that EEAT2 polymorphism contributes to the tendency toward frequent analgesic usage in migraine patients. This implies a potential genetic influence on the progression of migraine into chronic daily headache through the development of medication-overuse headache.