Medication-overuse headache (MOH) is a significant health concern affecting over 60 million people worldwide (1, 2). According to the International Headache Society (ICHD-3) guidelines (3), MOH is classified as a secondary headache disorder in patients who are overusing headache medication for treating a primary headache disorder. MOHs are classified as headaches occurring at least 15 days per month and overuse of headache medication is defined by the regular intake (>3 months) of medication for more than 10 days per month or more than 15 days per month, depending on the medication that is being overused. It is estimated that over 50% of patients in headache clinics who suffer from chronic forms of headache are overusing headache medication and develop MOH (4–7). The overuse of medication can lead to worsening of headache and the transition from episodic to chronic migraine. For patients with MOH, discontinuation of the medication that is being overused can result in a significant improvement of headache symptoms including a reduction in headache frequency (8–10); however, it is of note that the success rate of medication withdrawal varies widely among studies and likely depends on the medication that was being overused (11).

Although the neuropathology of MOH is still incompletely understood, research imaging of brain structure and function has helped our understanding of the involved neuromechanisms underlying MOH. This review will focus on studies that have used the following research neuroimaging techniques for evaluating brain structure, including T1-weighted MRI for interrogating gray and white matter structure, diffusion tensor imaging, for estimating integrity of white matter tracts, functional magnetic resonance imaging (fMRI) using resting-state paradigms to estimate the functional connectivity of brain networks, task-based fMRI to assess brain responses to specific stimuli, and positron emission tomography (PET) to evaluate the metabolic changes in glucose uptake in the brain. Studies are highlighted that have evaluated structural and functional imaging findings in patients with MOH compared to migraine patients without MOH, have assessed associations between brain changes and disease burden, and have examined brain mechanisms of recovery subsequent to medication withdrawal. Lastly, research neuroimaging differences between patients with MOH and patients with migraine are compared to neuroimaging differences between patients with post-traumatic headache relative to healthy controls in order to better understand neuropathological similarities and differences between MOH and post-traumatic headache, which are both discussed within this review series.

For this review, PubMed was queried for English language articles using the following search terms: “Medication-overuse headache” and “magnetic resonance imaging” or “resting-state” or “diffusion tensor imaging” or “positron emission tomography.” Database search results were then limited to articles with relevance to the topic that were published between January 2000 and July 2019. Single-subject studies and studies that included <6 patients with MOH were excluded. Included in this review were 17 structural and functional imaging studies of patients with MOH (see Table 1).

Frequent medication overuse associates with exacerbated changes in regions of the pain matrix as well as with changes in structure and function of regions within mesocortical-limbic circuit. There is evidence of potential brain “traits” (higher occipital gyrification and less orbitofrontal cortex volume and thickness), which may contribute to the development of MOH or which may be a vulnerability factor for unsuccessful withdrawal.

Although the topic of “post-traumatic headache” (PTH) is part of another comprehensive review, entitled “Structural and Functional Brain Alterations in Post-traumatic Headache Attributed to Mild Traumatic Brain Injury,” the potential similarities and differences in neuropathology between primary headaches (migraine) and secondary (MOH and PTH) headaches are intriguing.

Migraine, MOH, and PTH show overlapping pathophysiology in regions associated with the cognitive-affective, sensory, and modulatory components of the “pain-matrix,” yet compared to migraine, patients with MOH and PTH have exacerbated changes within regions involved in multisensory integration (19, 21, 36, 37). MOH and PTH show additional neuropathology in brain systems that are not part of the pain matrix such as the visual cortex and specifically the lingual gyrus where hyperexcitability or sensitization is evident in both MOH and PTH (15, 36). Specifically, MOH has distinct structural and functional changes within regions of the mesocortical-limbic circuit implicated in addiction but also in reward, memory, motivation, and emotional response. Although there are currently no studies that have directly compared MOH to PTH, alterations within the mesocortical-limbic circuit and specifically the orbitofrontal cortex appear to be unique to MOH. There are some data suggesting rapid reorganization of cortical structure and function for both MOH and PTH. For example, several brain circuits demonstrate signs of brain normalization (or adaptation) weeks following successful withdrawal of patients with MOH. Similarly, patients with PTH at 1 week post-concussion show early alterations in brain structure. However, it is yet insufficiently understood whether these changes reflect mechanisms of neuronal repair, adaptation, or degeneration (38).

Although statements about the generalizability of neuroimaging findings in patients with MOH are premature, the number of studies published over the past few years has continued to increase our understanding of the neuropathology underlying MOH. Some of the current study discrepancies are likely due to between-study differences in sample sizes, the types of medications that were being overused (opiates vs. simple analgesics), the time frame over which overuse persisted (months vs. years), and whether patients experienced successful vs. unsuccessful withdrawal (headache relief vs. no headache relief, or relapse to MOH), which are important and often overlooked variables of the complex MOH disease mechanism (11) that will need to be better investigated and controlled for in future studies.

The most conclusive evidence of brain changes associated with MOH is derived from studies that have compared (i) patients with chronic migraine and MOH to patients with chronic migraine without MOH relative to cohorts of healthy controls; or assessed (ii) patients before and subsequent to medication withdrawal. Such studies are uniquely designed to interrogate and extract the disease pathology distinctive to medication overuse. Data from other studies that have compared MOH to healthy controls although informative are by design unable to extrapolate the pathology distinctive to medication overuse, as the migraine pathology and medication-overuse pathology are entangled.

Compared to patients with migraine, patients with MOH have exacerbated changes in brain structure and function in regions of the pain-matrix and in areas of the mesocortical-limbic circuit. Some of the brain structural alterations (i.e., changes in brain gyrification patterns) could indicate “brain traits” that contribute to the development of MOH. Additionally, the relationship between brain changes and medication overuse (i.e., number of pills overused) or the association between brain recovery and discontinuation of medication overuse suggest “state-dependent” brain adaption patterns. In summary, these findings of state and trait-like changes suggest modification of brain structure and function in patients with MOH, some of which are likely reversible as patients recover from headache. Lastly, the neuropathological similarities of patients with MOH and post-traumatic headache may indicate common disease pathways that need to be further investigated.

The author confirms being the sole contributor of this work and has approved it for publication.