Treating acute migraine attacks with medication such as triptans, NSAIDs (anti-inflammatory drugs) and paracetamol (acetaminophen) can be effective in the short term. Frequent use of these drugs, however, can lead to what we call “medication overuse headache”. This means your body responds less well to the medication, and you may even get more frequent and more intense migraine attacks. In this blog I give an overview of the most commonly used painkillers and explain why they can contribute to medication overuse headache.
Anti-inflammatory drugs (NSAIDs)
NSAIDs such as ibuprofen, naproxen and diclofenac are anti-inflammatory drugs that are often used to relieve migraine pain. Excedrin also contains an NSAID (acetylsalicylic acid, or aspirin).
Although NSAIDs can reduce inflammation acutely, repeated use can lead to side effects. They can disrupt the function of the mitochondria in the brain, which can affect the energy production in your brain. They can also affect the blood vessels, which can ultimately cause more headache once the medication wears off.
NSAIDs can also damage the protective mucus layer of the stomach, which can lead to stomach problems. That is why NSAIDs are often combined with stomach protectors, but with frequent use these can cause problems with the gut barrier. This in turn can result in low-grade inflammation that can make migraine worse.
Frequent use of acid blockers also inhibits the absorption of vitamin B12. This vitamin is vital for detoxification and for the insulating layer (myelin) around nerves. The trigeminal nerve can become hypersensitive when the myelin sheath is not strong enough, making you more susceptible to migraine.
There is a deeper reason why NSAIDs encourage medication overuse headache. Your body contains a detoxification enzyme called SULT1A1 that neutralises irritating substances around your nerves. This enzyme is found not only in your gut and liver, but also locally in your trigeminal nerve, the facial nerve that becomes active during migraine. NSAIDs are themselves broken down by this enzyme, and at the same time they inhibit it. With frequent use, its capacity becomes exhausted, and recent research (Topa et al., Journal of Headache and Pain, 2025) shows that the amount of this enzyme in the trigeminal nerve itself drops after long-term NSAID exposure. As a result, irritating substances build up around the nerve endings and the threshold at which a new migraine attack starts goes down.
Paracetamol
Paracetamol, like all medication, is broken down by the liver. This process costs energy and uses specific helper substances in the body. While the liver is busy breaking down paracetamol, other metabolic processes, such as processing toxins from food, air and skin, can run less efficiently. That is why extra support for the liver may be needed with long-term or frequent paracetamol use.
How paracetamol works is still largely unclear and seems broad. Partly it has an effect similar to the NSAIDs, so it counters inflammation. That is only a (limited) part of how it works, though. Among other things, it is also thought to keep endocannabinoids (painkillers made by our own body) active for longer. However, when more of these endocannabinoids stay active, our brain simply gets used to a higher amount. This may create a dependency, so that we feel more pain once the paracetamol wears off.
Triptans
Triptans come in several variants, such as sumatriptan, rizatriptan, almotriptan and others. Among other things, they work by narrowing the blood vessels, countering the vasodilation that goes with a migraine attack. They do this by acting on the serotonin receptors. However, the more often this happens through medication, the less sensitive these receptors become. This could make it increasingly difficult to keep vasodilation under control without medication.
They are also thought to inhibit CGRP, a neuropeptide that is produced during a migraine attack and contributes to inflammation and vasodilation.
Interaction with food triggers
Do you also have the impression that you become more sensitive to migraine after red wine, aged cheese, chocolate or citrus? These foods all contain substances that are broken down by the same SULT1A1 enzyme that processes your NSAID. When the enzyme is overloaded by medication, there is less capacity left for the food triggers, and a glass of wine or a piece of chocolate suddenly does trigger an attack where it didn’t before.
Some people are more sensitive to this and slip into a medication-dependent pattern faster than others. There is an inherited variant of this detoxification enzyme with a lower innate capacity (Sandler’s research, Lancet 1982). People with that variant start with a thinner buffer and run into trouble sooner when medication and food triggers have to be broken down at the same time. Clinically, this means that temporarily avoiding phenol-rich foods while tapering off medication helps to take the load off the enzyme, so it can recover and the migraine threshold can rise again.
Natural support for migraine
The good news is that the SULT1A1 enzyme can recover when the medication load decreases. That is not a matter of stopping suddenly, which could actually cause a rebound effect, but of tapering off gradually under guidance, combined with a temporary restriction of phenol-rich foods (red wine, aged cheese, chocolate, citrus) so the enzyme isn’t loaded from two sides at once.
There are also targeted interventions for the other underlying causes: food that supports the mitochondria, magnesium and B vitamins for nerve health, stress regulation through biofeedback, and restoring the gut barrier. Together, these approaches give your trigeminal nerve room to find its balance again.
