As described above, MOH is a disorder with headache for ≥15 days per month in a patient with pre-existing headache, while taking acutely acting medication for ≥3 months according to certain requirements [
3]. From a clinical perspective, MOH is present in about 1% of the general population, and develops mainly in patients with pre-existing migraine (ca. 70% of all MOH cases), or tension-type headache [
24,
45] with chronic migraine (CM) being a form of migraine with especially high prevalence of MOH [
45]. All classes of acutely acting antimigraine drugs are able to cause development of MOH [
22,
23], although clinical differences, such as different mean duration until onset of MOH, remain [
22]. MOH patients exhibit, in general, several behavioral characteristics that are also seen in substance abuse or drug addiction [
46,
47]. This seems to be in accordance with observations regarding the relapse rate after successful treatment. Although this rate is variable across studies from various countries investigating different separate populations (e.g. populations with triptan overuse, opioid overuse, and / or comorbid psychiatric disorders), the majority shows a relapse rate of 25–35% [
45,
48]. Research on the pathophysiology of MOH has, until now, developed in mainly two directions. The first being epidemiological and clinical research on MOH patients, the second pertaining to animal models of MOH. Animal models of CM and MOH usually (repeatedly) administer acutely acting antimigraine drugs (e.g. sumatriptan, paracetamol, opioids) to induce MOH [
9,
25,
49‐
51], or apply nitroglycerin (NO donor) [
52‐
54] or an inflammatory soup on the dura mater [
55,
56] to induce CM (with features similar to MOH). These models exhibit several phenotypes that relate to CM as well as MOH, such as mechanical hyperalgesia, photophobia, nociceptive behavior, and facial grooming. However, these models are obviously an imperfect representation of the clinical characteristics. For example, a major critique is that these models cause similar phenotypes, but through a completely different mechanism. Although this may be a strong point, it seems to fit with observations in the clinical situation where diverse classes of drugs may cause similar features of MOH. An obvious difference is that MOH only develops in patients with pre-existing headaches, while in the MOH models naïve mice are exposed to the MOH-inducing drugs. Similarities with the clinical disorders and shortcomings of the animal models are extensively reviewed elsewhere [
57]. Utilizing an animal model for MOH, it was shown in 2010 that triptans can induce central sensitization in rats, which could possibly function as a basis for MOH [
9]. Since then, ample studies have confirmed that chronical application of drugs like paracetamol [
51] and opiates [
29,
58,
59] have similar effects, which could possibly underlie the pathogenesis of MOH. Two common observations in MOH models are that CGRP expression increases [
9,
25,
28,
30] and 5-HT
1B/D receptor expression decreases [
60,
61] upon prolonged exposure to antimigraine drugs in animal models. Clinical research has shown that 5-HT levels are decreased in patients with MOH [
8,
26,
62]. This decrease in 5-HT levels might subsequently upregulate the pronociceptive 5-HT
2A expression [
63]. Such an upregulation of 5-HT
2A expression is also observed in animal models of MOH [
51]. Additionally, reduced 5-HT concentrations in animal models resulted in increased amount of CSDs and hyperexcitability in the cortex and the nucleus caudalis of the trigeminal tract [
64‐
66], mimicking clinical observations in patients with migraine and decreased 5-HT levels. Furthermore, these lower 5-HT levels may also increase CGRP expression [
45,
63], providing a possible connection between the increased CGRP and decreased 5-HT levels observed in MOH patients. Blocking CGRP receptors with a monoclonal antibody (mAb) has shown to reduce the risk for cutaneous allodynia, which was used as a proxy for MOH in an animal model utilizing nitroglycerin as inducer [
27]. This is in accordance with the concept that increased CGRP levels may be involved in the pathogenesis of MOH [
67], although it should be kept in mind that other recent studies did not confirm that systemic CGRP levels are increased in medication overuse headache [
68,
69]. In conclusion, decreased 5-HT, increased 5-HT
2A receptor level and possibly increased CGRP expression seem to be involved in the pathophysiology of MOH, based upon animal research models.