Etiology
The etiology of MOH is complex and involves multiple factors.[10] MOH typically arises when certain conditions are met:
The presence of a primary headache disorder (which is migraine and/or tension-type headache in up to 90% of cases but rarely can be cluster headache or posttraumatic headache)
Frequent use of acute headache medications (e.g., simple analgesics, triptans, opioids, or ergot derivatives), excluding oral calcitonin gene-related peptide (CGRP) antagonists (also known as gepants).
Additionally, several comorbidities have been found to be associated with medication overuse, including anxiety, depression, obsessive-compulsive disorder, chronic musculoskeletal complaints, gastrointestinal problems, metabolic syndrome, and insomnia. These comorbidities can contribute to the development or exacerbation of MOH.[4][9][17][18][19]
Pathophysiology
The pathophysiology of MOH is not completely understood. Genetic, behavioral/psychological, and sex-specific factors likely play a role.[10] MOH is not reported to occur in individuals who do not have an underlying headache disorder but overuse analgesia for other painful conditions, pointing to the hypothesis that MOH influences the neural pathways of the preexisting headache disorder.[10] Pathophysiologic mechanisms are thought to include altered descending pain modulation and central sensitization.[10]
Potential genetic factors involved in MOH include insertion or deletion polymorphisms in ACE (encoding angiotensin-converting enzyme), mutations in BDNF (brain-derived neurotrophic factor), and polymorphisms in COMT (catechol-O-methyltransferase) and SLC6A4 (serotonin transporter).[20] These genetic factors are associated with abnormalities in metabolic pathways, serotonergic or dopaminergic transmission, and drug dependence.
Behavioral and psychological factors may also play a part in development of MOH. Individuals with MOH have an increased familial risk of substance use disorder or drug dependence, suggesting a possible genetic predisposition.[10]
Female sex hormones may also be a factor, as suggested by the role of menstruation as a trigger for migraine.[21] The reduced effectiveness of triptans for menstrual migraines and the longer duration of such episodes might lead to vulnerability to medication overuse.[22]
Neuroimaging reveals structural brain differences in MOH, including altered pain-modulating regions such as the hippocampus, periaqueductal gray area, cingulate cortex, thalamus, orbitofrontal cortex, and limbic system, with changes in gray matter volume and metabolism.[23][24] Some of these differences have been found to normalize after medication withdrawal, although one study found persistent glucose hypometabolism in the orbitofrontal area. It is hypothesized that this may contribute to drug dependence and act as a risk factor for relapse in medication overuse and persistent MOH.[25]
Chronic exposure to analgesics may increase susceptibility to cortical spreading depression, promote central pain sensitization, alter descending pain modulation, and increase the susceptibility to developing cortical spreading depolarization.[26]
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