Migraine Medication: A Complete Overview

Overview: the medication landscape in migraine

If you have migraine, medication is often the first thing you encounter. A family doctor prescribes paracetamol, a neurologist triptans or a preventive. And when nothing seems to work, you may hear about the newest CGRP inhibitors. But how exactly do all these drugs work? What are the risks? And when is medication not enough?

In this extensive overview we discuss all categories of migraine medication: from simple painkillers to the very newest biological therapies. We explain how each drug works, what the side effects are, and when it is sensible to look beyond medication alone.

Migraine medication is broadly divided into two groups:

• Acute medication - to break an attack (painkillers, triptans, gepants)
• Preventive medication - to reduce the number of attacks (beta-blockers, anti-epileptics, CGRP antibodies)

It is important to understand that no drug cures migraine. All of these work symptomatically: they reduce the pain or lower the attack frequency, but they do not address the underlying factors. That is no criticism of medication - it is a fact you take into account when making treatment choices.

Painkillers in migraine

Painkillers are the most commonly used first option in migraine. They are available over the counter, relatively cheap and often sufficient for mild to moderate attacks. But not all painkillers are equal, and the risk of overuse is strongly underestimated.

Paracetamol (acetaminophen)

Paracetamol (acetaminophen, sold as Tylenol or Panadol) is the most frequently recommended first option in migraine. It works centrally in the brain by raising the pain threshold. With mild migraine attacks it can be effective, especially when taken early in the attack.

• How it works: Raises the pain threshold in the central nervous system
• Advantages: Few side effects with correct use, available over the counter
• Disadvantages: Often insufficient for moderate to severe migraine, liver toxicity at high doses

What many people do not know: paracetamol uses up glutathione, your most important intracellular antioxidant. With frequent use this can raise the oxidative stress in your body - precisely one of the factors that makes your nervous system more sensitive to migraine attacks.

NSAIDs (anti-inflammatories)

NSAIDs (Non-Steroidal Anti-Inflammatory Drugs) such as ibuprofen (Advil, Motrin), naproxen (Aleve) and diclofenac (Voltaren) are more effective than paracetamol in migraine, because they not only inhibit pain but also address the neurogenic inflammation around the membranes of the brain.

• Ibuprofen: fast-acting, the most used NSAID in migraine
• Naproxen: longer duration of action (suitable for prolonged attacks)
• Diclofenac: powerful but more stomach complaints
• Aspirin: proven effective in migraine (comparable to sumatriptan in mild attacks)

The downside: NSAIDs inhibit the enzyme cyclooxygenase (COX), which also plays a role in protecting your stomach lining and the blood flow to your kidneys. With regular use (more than 10 days a month) the risk of stomach ulcers, kidney problems and - ironically - medication-overuse headache rises.

Combination painkillers

Combination products such as Excedrin Migraine (paracetamol + aspirin + caffeine) are marketed specifically for migraine. Caffeine enhances the effect of painkillers and narrows the blood vessels around the brain.

Although combination painkillers can be more effective, the risk of dependence is greater. Caffeine causes tolerance with regular use, so you need more for the same effect. This is an important route to medication-overuse headache.

Triptans

Triptans are the first drugs developed specifically for migraine. They were introduced in the 1990s and have since been the standard treatment for moderate to severe migraine attacks. Unlike ordinary painkillers, triptans act on the specific mechanism of a migraine attack.

How do triptans work?

Triptans are serotonin (5-HT1B/1D) agonists. They mimic the action of serotonin and work in three ways:

1. Vasoconstriction: they narrow the dilated blood vessels around the brain
2. Inhibition of neuropeptides: they prevent the release of CGRP and other inflammatory messengers
3. Blocking pain signals: they inhibit the transmission of pain signals in the trigeminal nucleus

Available triptans

There are seven triptans on the market, each with a slightly different profile:

• Sumatriptan (Imitrex) - the "mother" of all triptans, available as a tablet, nasal spray and injection
• Zolmitriptan (Zomig) - also as a melt tablet and nasal spray, good with nausea
• Rizatriptan (Maxalt) - fast-acting, popular as a melt tablet
• Eletriptan (Relpax) - strongly acting, higher success rates but more side effects
• Almotriptan (Axert) - well tolerated, fewer side effects
• Naratriptan (Amerge) - slow but long-acting, suitable for prolonged attacks
• Frovatriptan (Frova) - the longest half-life, useful in menstrual migraine

Effectiveness

Triptans are significantly more effective than ordinary painkillers in moderate to severe migraine. On average, 60-70% of patients are pain-free within 2 hours or have considerable relief. But that also means 30-40% respond insufficiently.

An important nuance: if one triptan does not work, another one may. It is therefore worth trying several triptans before concluding that they do not work for you.

Side effects and limitations

• Triptan sensations: tingling, a feeling of warmth, pressure on the chest, heaviness in the limbs (in about 15% of users)
• Fatigue and drowsiness after taking
• Rebound effect: with more than 10 days a month of use, a high risk of medication-overuse headache
• Contraindications: not to be used with cardiovascular disease, uncontrolled high blood pressure, basilar or hemiplegic migraine
• Serotonin syndrome: caution in combination with SSRIs and SNRIs (antidepressants)

From a cPNI perspective it is interesting that triptans work through the serotonin system. About 95% of your serotonin is made in your gut. If your gut microbiome is disrupted - which is the case for many people with migraine - this can influence your serotonin metabolism and thereby raise your sensitivity to migraine.

CGRP inhibitors: the newest generation

CGRP inhibitors are the first drugs developed specifically for the migraine mechanism. CGRP (Calcitonin Gene-Related Peptide) is a protein that plays a central role in the onset of migraine pain: it causes blood vessel dilation, neurogenic inflammation and central sensitization.

There are two categories of CGRP inhibitors with different mechanisms and applications.

Monoclonal antibodies (preventive)

These are proteins administered monthly or quarterly by injection. They bind to the CGRP molecule or the CGRP receptor, blocking the signal:

• Erenumab (Aimovig) - blocks the CGRP receptor, monthly subcutaneous injection
• Fremanezumab (Ajovy) - binds the CGRP molecule, monthly or quarterly
• Galcanezumab (Emgality) - binds the CGRP molecule, monthly
• Eptinezumab (Vyepti) - intravenous infusion every 3 months, fastest-acting

These drugs are generally reserved for people with episodic migraine (at least 4 migraine days a month) or chronic migraine (15+ headache days a month), usually on the condition that at least two earlier preventive treatments had insufficient effect.

Gepants (acute and preventive)

Gepants are small molecules in tablet form that block the CGRP receptor. They are a breakthrough because they can be used both acutely and preventively, and cause no vasoconstriction (so they are also safe with cardiovascular disease):

• Rimegepant (Nurtec ODT) - both acute and preventive (every other day), melt tablet
• Ubrogepant (Ubrelvy) - acute use only
• Atogepant (Qulipta) - daily preventive use

Effectiveness of CGRP inhibitors

• On average a 50% reduction in migraine days in about half of patients
• About 25-30% do not respond or barely respond
• In chronic migraine: on average 4-6 fewer migraine days a month
• The effect often begins within the first month

Side effects

CGRP inhibitors are generally well tolerated, but there are points of attention:

• Constipation - the most common side effect (10-15% of users)
• Injection-site reactions - redness, pain, swelling
• Fatigue and muscle pain
• Hair loss - reported in rare cases
• Unknown long-term effects - CGRP also plays a role in wound healing, heart protection and blood pressure regulation

The fundamental question from a cPNI perspective: why does your body produce so much CGRP? Elevated CGRP is a sign of an overloaded trigeminovascular system. If you address the cause of that overload - chronic inflammation, hormonal fluctuations, oxidative stress - then your CGRP level drops on its own.

Preventive medication

If you have more than 4 migraine attacks a month, or if acute medication works insufficiently, preventive medication comes into the picture. The goal is not to treat individual attacks, but to reduce the total number of attacks by at least 50%.

None of the classic preventive drugs was originally developed for migraine. They are medicines from cardiology, neurology or psychiatry that were found by chance to reduce migraine attacks. This is important to know, because it explains why the side effects are often considerable.

Beta-blockers

Beta-blockers were originally developed for high blood pressure and heart problems. They are most often prescribed as the first preventive drug in migraine.

• Propranolol (Inderal) - most prescribed
• Metoprolol (Lopressor) - alternative if propranolol causes side effects
• Atenolol (Tenormin) - less well-supported, sometimes used

Mechanism: Beta-blockers block beta-adrenergic receptors, which lowers the heart rate and blood pressure. The exact mechanism by which they reduce migraine is not fully clear, but it is thought to relate to stabilizing serotonin activity and inhibiting excessive sympathetic activation.

Effectiveness: The figures are sobering. A large meta-analysis (Jackson et al., 2019) calculated that you have to treat 5 to 6 patients before there is one who genuinely benefits from beta-blockers (the so-called NNT - number needed to treat). The average reduction is just 1.3 attacks a month - from 4.8 to 3.5. And "benefit" is already defined here as a halving of your attacks, not their disappearance. If you factor in dropout due to side effects, in practice only about 1 in 6 patients truly benefits.

Side effects:

• Fatigue, loss of energy and reduced stamina
• Cold hands and feet
• Sleep disturbances and vivid dreams
• Depressive complaints
• Weight gain
• Reduced libido
• Not to be combined with asthma

But the most underestimated side effect is not in the package insert: beta-blockers disrupt your melatonin production by 80 to 86%. That is no marginal effect - that is almost complete suppression. Research by Stoschitzky et al. (1999) showed that propranolol lowers nighttime melatonin production by 80%, and atenolol even by 86%. This happens because beta-blockers block the beta1 receptors needed for the production of melatonin in the pineal gland.

This is particularly problematic when you consider what melatonin does in migraine. Melatonin is not only your sleep hormone - it is one of the most powerful endogenous antioxidants your body makes, it inhibits neuroinflammation, it stabilizes your mitochondrial function and it modulates the CGRP system. Precisely the mechanisms that are dysregulated in migraine. Sleep itself is the moment when your brain recovers, clears waste through the glymphatic system, and brings your pain threshold back to level. Poor sleep is one of the most consistent migraine triggers in the scientific literature.

In other words: you are prescribed a drug to reduce your migraine that at the same time destroys the system your brain needs at night to recover. You fight the symptom while worsening the cause. This is one of the clearest examples of why symptom-focused treatment so often falls short in migraine.

Anti-epileptics

Anti-epileptics stabilize the excitability of nerve cells. In migraine, two drugs are used most:

Valproate (Depakote) - effective but with serious limitations: it is teratogenic (harmful to unborn children) and must not be prescribed to women of childbearing age unless strict contraception is followed. Given that 75% of people with migraine are women, this is a considerable limitation.

Topiramate (Topamax) - one of the most effective preventive drugs, but notorious for its cognitive side effects:

• Word-finding problems and difficulty concentrating (so frequent that the drug earned the nickname "Dopamax")
• Tingling in hands and feet
• Weight loss (sometimes wanted, sometimes not)
• Mood changes and depression
• Kidney stones with long-term use
• Also teratogenic - serious risk during pregnancy

Antidepressants

Certain antidepressants are used in low doses as migraine prophylaxis, not because of an antidepressant effect but because of their influence on the serotonergic and noradrenergic system.

• Amitriptyline (Elavil) - most well-supported, taken before sleep. Effective with comorbid tension and sleep problems
• Venlafaxine (Effexor) - SNRI, second choice

Side effects of amitriptyline:

• Drowsiness and grogginess (which is why it is taken in the evening)
• Dry mouth and constipation
• Weight gain
• Dizziness on standing up
• Heart rhythm effects at higher doses

Other preventive drugs

• Candesartan (Atacand) - an angiotensin receptor blocker (blood pressure drug), well tolerated and increasingly well-supported
• Flunarizine (Sibelium) - calcium antagonist, effective but can cause depression and weight gain
• Botox (onabotulinumtoxin A) - only in chronic migraine (15+ days a month), injections every 12 weeks into specific head muscles

Medication-overuse headache (MOH)

This is perhaps the most underestimated problem with migraine medication: the medication you take to get rid of your headache can actually cause more headache. Medication-overuse headache (MOH) is estimated to affect 1-2% of the general population and up to 50% of patients in specialized headache clinics.

When do we speak of MOH?

The official diagnosis MOH (ICHD-3) is made at 10-15 days of medication use a month, depending on the type of drug. But those thresholds are diagnostic criteria, not safety limits.

In practice we see that chronification begins much earlier. Every use of medication has systemic effects that worsen your migraine over time:

• Gut damage: NSAIDs damage the gut lining, which promotes leaky gut and chronic low-grade inflammation
• Immune suppression: painkillers suppress inflammatory processes your body actually needs to recover
• CGRP up-regulation: triptans structurally raise your CGRP production, making you more sensitive to the next attack
• Glutathione depletion: paracetamol uses up your most important intracellular antioxidant, increasing oxidative stress

In other words: you do not have to take medication half the month to chronify. The more often you reach for medication without addressing the underlying vulnerability, the faster that process gets going.

The vicious circle

Frequent medication use changes the way your brain processes pain. Your pain system becomes dysregulated: the pain threshold drops, sensitivity rises, and your brain "expects" medication. When the drug wears off, your body reacts with rebound headache, for which you take medication again. So a vicious circle arises that becomes harder and harder to break.

All categories of acute medication can cause MOH, but the risk is greatest with:

1. Combination painkillers (paracetamol + caffeine + codeine) - highest risk
2. Opioids (tramadol, codeine) - very high risk
3. Triptans - moderate risk, but reached sooner (already at 10 days a month)
4. Ordinary painkillers (paracetamol, ibuprofen) - risk at 15+ days a month

Out of the MOH spiral: the attack plan

The classic approach to MOH is detoxification: stopping the medication and sitting out the rebound period. That works, but it is also the reason so many people relapse. If you only remove the medication without giving your brain something better, you leave it helpless.

What does work is an attack plan: a protocol of lifestyle interventions, targeted interventions and techniques that structurally support your brain during and between attacks. Not symptom suppression, but restoration of the systems that drive your attacks.

Beyond medication: the cPNI perspective

At the Functional Migraine Clinic we do not work against medication - we work alongside it and behind it. The goal is to lower the need for medication by addressing the underlying factors of your migraine. This is where clinical psycho-neuro-immunology (cPNI) and orthomolecular therapy are complementary to conventional medicine.

What is cPNI?

Clinical psycho-neuro-immunology (cPNI) is a scientific discipline that studies the interplay between the psychological system, the nervous system, the immune system and the hormonal system. In migraine, all of these systems are involved.

Instead of only treating the symptom (headache), we look for the underlying factors that put your nervous system in a state of overexcitability:

• Chronic low-grade inflammation: often driven by gut problems, food intolerances or a disrupted immune system
• Hormonal imbalance: estrogen fluctuations, thyroid problems, cortisol dysregulation
• Mitochondrial dysfunction: reduced energy production in your cells, leaving your nervous system vulnerable
• Oxidative stress: an imbalance between free radicals and the antioxidant capacity of your cells, damaging nerve tissue
• Gut-brain axis disruptions: the microbiome directly influences your serotonin metabolism and neuroinflammation
• Stress response dysregulation: an overactive HPA axis, chronic sympathetic activation

How we work out which factors are at play for you - and what it takes to address them - you can read on our page about the cPNI approach.

Conclusion

Medication can give you breathing room. A triptan that breaks an attack, a beta-blocker that temporarily lowers the frequency, a CGRP inhibitor that flattens the worst peaks - that has value. But breathing room is not a solution. None of the drugs on this page address the underlying factors behind your migraine. They buy time - and you can use that time to find out what makes your nervous system so vulnerable.

Be critical about your medication use: keep a headache diary, stay alert to medication-overuse headache, and discuss regularly with your doctor or neurologist whether there is room to taper. And always look for the why behind your migraine - not only the how of pain relief.

Want to take a first step? The Building Block Analysis maps which building blocks play a role for you, and the DNA Migraine Blueprint adds what your genes say about them.

Curious why certain medication does not work for you? A migraine-focused DNA analysis maps how your body processes medication, from triptans and painkillers to preventive drugs. That way you find out sooner what has a chance of working for you and what you might better skip.

Sources

• Eigenbrodt, A.K. et al. (2021). "Diagnosis and management of migraine in ten steps." Nature Reviews Neurology, 17(8), 501-514.
• Ashina, M. et al. (2021). "Migraine: disease characterisation, biomarkers, and precision medicine." The Lancet, 397(10283), 1496-1504.
• Edvinsson, L. et al. (2018). "CGRP as the target of new migraine therapies." Nature Reviews Neurology, 14(6), 338-350.
• Goadsby, P.J. et al. (2017). "A Controlled Trial of Erenumab for Episodic Migraine." New England Journal of Medicine, 377(22), 2123-2132.
• Diener, H.C. et al. (2016). "Medication-overuse headache: risk factors, pathophysiology and management." Nature Reviews Neurology, 12(10), 575-583.
• Schoenen, J. et al. (1998). "Effectiveness of high-dose riboflavin in migraine prophylaxis." Neurology, 50(2), 466-470.
• Sandor, P.S. et al. (2005). "Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial." Neurology, 64(4), 713-715.
• Teigen, L. & Boes, C.J. (2015). "An evidence-based review of oral magnesium supplementation in the preventive treatment of migraine." Cephalalgia, 35(10), 912-922.
• Ramsden, C.E. et al. (2021). "Dietary alteration of n-3 and n-6 fatty acids for headache reduction in adults with migraine." BMJ, 374, n1448.
• Varkey, E. et al. (2011). "Exercise as migraine prophylaxis: a randomized study using relaxation and topiramate as controls." Cephalalgia, 31(14), 1428-1438.
• Charles, A.C. et al. (2024). "Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update." Headache, 64(4), 333-341.
• Loder, E. et al. (2013). "Choosing wisely in headache medicine: the American Headache Society's list of five things physicians and patients should question." Headache, 53(10), 1651-1659.
• Ailani, J. et al. (2021). "The American Headache Society Consensus Statement: Update on integrating new migraine treatments into clinical practice." Headache, 61(7), 1021-1039.
• Russell, F.A. et al. (2014). "Calcitonin gene-related peptide: physiology and pathophysiology." Physiological Reviews, 94(4), 1099-1142.
• Stoschitzky, K. et al. (1999). "Influence of beta-blockers on melatonin release." European Journal of Clinical Pharmacology, 55(2), 111-115.
• Jackson, J.L. et al. (2019). "Beta-blockers for the prevention of headache in adults, a systematic review and meta-analysis." PLOS ONE, 14(3), e0212785.

Disclaimer: This article is written for information purposes and does not replace medical advice. Always consult your doctor or neurologist before making changes to your medication. The Functional Migraine Clinic works complementary to conventional medicine and never advises stopping or changing medication on your own.