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

INTRODUCTION: Migraine 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. DISCUSSION: This 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.