Expert Perspective

Understanding the pathophysiology of medication overuse headache

Alan M. Rapoport, MD, Clinical Professor of Neurology, The David Geffen School of Medicine at UCLA, Los Angeles, California

Dr. Rapoport has disclosed the following relevant financial relationships: Serve(d) as a consultant for: Allergan; Amgen; Biohaven; Cala health; Novartis; Satsuma; Teva Pharmaceuticals; Theranica; Xoc; Zosano. Serve(d) as a speaker for: Allergan; Amgen; Biohaven; Lundbeck and Teva Pharmaceuticals.


Last month’s column focused on medication overuse headache and pointed out an excellent review article by Sun-Edelstein and colleagues. Another fascinating topic also covered within that paper that warrants closer examination is pathogenesis. Developing a thorough knowledge of the pathophysiology of medication overuse headache and its underlying mechanisms positions clinicians to help patients better understand and manage this disorder.

Mechanisms impacting primary headaches

Let us start by detailing the various causes of primary headaches. Activation of the trigeminal nociceptive pathway is the last common step in headache generation. Peripheral sensitization exacerbates intracranial headache pain and leads to the pulsating nature of migraine pain. This severe discomfort is triggered by physical activity and movement. Calcitonin gene-related peptide (CGRP) is primarily responsible for this phenomenon. Increased sensitivity of central trigeminal neurons leads to central sensitization and causes scalp and forehead allodynia typically seen during a migraine attack. Sensitization of trigeminothalamic neurons is thought to be responsible for extensive cutaneous allodynia involving extracephalic regions, like face, arm, and leg.

Clinical clues

The pathogenesis of medication overuse headache includes chronic medication intake impacting an individual’s hypersensitive trigeminovascular nociceptive system. Physicians should be aware of the 4 factors required for this disorder to develop:

  1. Baseline activation of the trigeminovascular nociceptive pathways can cause migraine or tension-type headaches to transform into medication-induced headaches. This transformation typically develops in headaches with an accompanying inflammatory component, which might be related to mast cells in the dura.
  1. The discontinuation of acute care headache medication leads first to a worsening and then to an improvement in headaches. Interestingly, the regular use of analgesics for non-headache conditions is not linked to chronic headache development. Non-headache patients who take chronic opiates for cancer do not develop medication overuse headache. This suggests a cause-and-effect relationship, indicating that medication use causes transformation to medication overuse headache in patients with preexisting headache disorders—and is not the result of it. Culprits include migraine-specific drugs, such as triptans or ergots, or medications that are not migraine-specific, such as opioids, non-opioid analgesics, and nonsteroidal anti-inflammatory drugs. Lengthy exposure to these medications impacts a central pathway that controls nociceptive perception, thus causing medication overuse headache. It is important for patients to understand this paradoxical effect to break the cycle of medication overuse.
  1. The efficacy of anti-CGRP monoclonal antibodies in the treatment of medication overuse headache is better than that of the older preventive medication. As noted in the last installment, this class of drug is effective in patients with medication overuse headache who have not yet been weaned from the offending medication. The effect is thought to be a result of the decrease of nociception at peripheral perivascular areas, because anti-CGRP monoclonal antibodies do not cross the blood-brain barrier. It is known that CGRP increases transmission of pain signals and is also a vasodilator.
  1. The higher prevalence of psychiatric comorbidities, including depression, anxiety disorders, sleep disturbance, and non-cephalic body pain, suggest that they may either be causative or just comorbid. Additionally, individuals with medication overuse headache tend to experience poor general health and quality of life. This suggests that there is also an underlying alteration in neural pathways. Since brainstem aminergic systems are known to modulate mood, it is plausible that these systems impact medication overuse headache. The decrease in serotonin in these patients probably interferes with the brainstem’s descending antinociceptive system or diffuse noxious inhibitory control (DNIC). Increased risk of suicidal ideation is also seen in these individuals. Recently-published research shows that among 603 individuals with chronic migraine headache, the presence of medication overuse headache increased the risk of suicidal ideation by 75% and odds of previous suicide attempt by 88%, even after controlling for demographics, headache profile, disabilities, depression and anxiety symptoms, and sleep quality.

The bottom line: For medication overuse headache to develop, clinicians should see an underlying primary headache worsen with frequent acute care medication use as well as peripheral trigeminal nociceptor activation.

The role of low serotonin levels

Serotonin plays a key role in the pathogenesis of migraine headache. Research shows that in individuals who experience medication overuse headache, platelet serotonin is decreased and the density of serotonin receptors on platelets is increased, implying suppressed serotonin function, as mentioned above.

A recent study showed that individuals with medication overuse headache had higher intensity dependence of auditory evoked potentials (IDAP) levels than controls who did not suffer from headache. Investigators assessed 17 women who suffered from chronic migraine headache (12 of whom experienced medication overuse headache) and 19 healthy individuals as part of a study evaluating efficacy of bilateral betamethasone-lidocaine greater occipital nerve block (GON-B). At baseline, participants were assessed for habituation of visual evoked potentials (VEP) and IDAP. While baseline VEP habituation was similar in both groups, this was not the case for IDAP. Those values were significantly higher in headache sufferers, which implies lower serotonin levels.

Additionally, researchers found that IDAP was normalized in headache sufferers via the use of GON-B, and clinical improvement was seen. They concluded that altered serotonin levels and incoming trigeminal nociceptive input are important components of the pathogenesis of medication overuse headache.

The ‘2-hit model’

Though preliminary, an animal study lends credence to the so-called 2-hit model of medication overuse headache pathogenesis. Researchers hypothesized that abortive treatment, in the form of either migraine-specific medications or analgesics, can serve as a priming mechanism—a so-called first hit that facilitates central sensitization and increases responses to subsequent stimuli. Thus, the second hit occurs via enhancement of net descending facilitation in central pain modulatory pathways.

To test their hypothesis, investigators primed rats through continuous infusion of morphine or sumatriptan and assessed DNIC 7 days later and again 2 weeks after that, when sensory thresholds returned to baseline levels. Morphine-primed rats showed opioid-induced hyperalgesia and a loss of diffuse noxious inhibitory control on day 7, whereas sumatriptan-primed rats did not. Researchers concluded that acute nociceptive stimulation causes alterations in descending pain modulation that can last for long periods. Morphine’s detrimental effect reflects the clinical experience of higher medication overuse headache risk in individuals who use opioids for headache treatment. Thus, the authors noted, migraine medications along with repeated bouts of pain can amplify the consequences of nociceptor activation and increase the odds of future migraine attacks and risk of medication overuse headache. Clinically we see overuse of opioids causing more MOH than overuse of triptans, which can still cause MOH.

In a related animal study, rats underwent a similar priming process and were exposed to migraine triggers in the presence or absence of a humanized CGRP monoclonal antibody. The antibody significantly inhibited cutaneous allodynia in rats that had previously been primed with morphine or sumatriptan. A control protein that does not bind CGRP was ineffective. The authors concluded that acute migraine medications may promote medication overuse headache in susceptible headache sufferers via CGRP-driven mechanisms. Further, anti-CGRP monoclonal antibodies appear to be useful in the treatment of medication overuse headache.

Pain processing and addiction

A recent narrative review of imaging research studies revealed that medication overuse headache is linked with unusual structure and function of brain regions that process pain and other regions normally linked with addiction. Investigators looked at studies that evaluated abnormal structure and pain processing functionality in individuals with medication overuse headache. In addition to their primary findings regarding brain regions, researchers noted that several of the studies showed a return to normal structure and pain processing functionality after discontinuing overused medication; medication overuse headache resolved. Clinically we see this in patients that are detoxified from the offending overused medication. Interestingly, abnormalities in regions typically linked with addiction persisted, even after medication discontinuation. This suggests that individuals with medication overuse headache might have a brain trait that predisposes them to overuse medication.

Another study found that certain brain metabolites in key regions of the thalamocortical pathways differed between chronic migraine sufferers with and without medication overuse headache. Investigators conducted magnetic resonance spectroscopic imaging to map metabolites in specific regions of the brains of 48 participants: 16 migraine sufferers with medication overuse headache; 16 without overuse; and 16 healthy controls.

In patients with medication overuse headache, glutamate and glutamine levels were significantly higher in the right midcingulate cortex, and myo-inositol levels were significantly higher in the left anterior cingulate cortex, relative to those without medication overuse headache. These levels were similar to those seen in healthy controls. Additionally, in both groups of migraine sufferers, researchers observed a negative association between myo-inositol laterality index in the anterior cingulate cortices and the number of days per month with acute medication use. They concluded that individuals with medication overuse headache had a distinct concentration of myo-inositol in the anterior cingulate cortices that may be a result of medication overuse and might lead to the development of medication overuse headache.

Clinical implications

An understanding of these very complex pathophysiological findings in medication overuse headache serves as a foundation for neurologists and headache specialists. From there, evaluating the frequency, duration, and quantity of analgesic use in individuals with headache is an important and necessary next step. The time-tested treatment for medication overuse headache has always been patient education, detoxification, and starting preventive medications, which in the past have caused lots of side effects and not always been effective. Today, minimal education and starting a patient on a monoclonal antibody against CGRP is often quite effective, even without detoxification.

It should be noted that there is a new class of drug called the gepants, which block the CGRP receptor peripherally; 2 such gepants are approved by the FDA and are used as acute care medication (rimegepant and ubrogepant). They do not appear to cause medication overuse headache; one of them, rimegepant, was just approved by the FDA as the first headache medication to be used both as an acute treatment and a preventive treatment for migraine. Medication overuse headache understanding and treatment is changing right before our eyes.

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