Headache Drugs: Medications That Cause or Treat Headaches

How Headaches Are Classified and Why Drug Choice Depends on It

The International Headache Society (IHS) divides headaches into primary disorders (migraine, tension-type, cluster) and secondary headaches caused by another condition, including drug exposure. This classification system, the International Classification of Headache Disorders, 3rd edition (ICHD-3), is the diagnostic foundation that determines which medication a clinician should prescribe [1].

Primary headaches account for over 90% of all headache presentations. Tension-type headache is the most common, affecting roughly 40% of adults in any given year according to Global Burden of Disease data [2]. Migraine follows at approximately 12% prevalence, but generates disproportionate disability. The World Health Organization ranks migraine as the second leading cause of years lived with disability worldwide. Cluster headache is rarer, affecting fewer than 1 in 1,000, but produces some of the most severe pain known in medicine.

Drug selection tracks directly to these categories. A triptan works for migraine but does nothing for tension-type headache. Oxygen therapy is effective for cluster headache but irrelevant for the other two. Prescribing errors frequently stem from misclassification, which is why the American Headache Society consensus statement emphasizes accurate diagnosis before pharmacotherapy [3].

First-Line Drugs for Treating Acute Headaches

For tension-type headache, simple analgesics remain the standard. Ibuprofen 400 mg achieves at least 50% pain relief in roughly 1 out of every 2.5 patients treated, according to a Cochrane systematic review of 12 trials covering over 3,100 participants [4]. Acetaminophen 1 to 000 mg is also effective, though with a slightly higher number needed to treat (NNT) of 3.6. Aspirin 900-1 to 000 mg performs comparably to ibuprofen for episodic tension-type headache.

Migraine acute therapy is more nuanced. The AHS 2021 consensus statement recommends triptans as first-line for moderate-to-severe migraine attacks [3]. Sumatriptan 100 mg oral achieves pain freedom at 2 hours in approximately 32% of patients versus 11% with placebo, based on a meta-analysis of 133 trials published in The Lancet [5]. Subcutaneous sumatriptan 6 mg raises that figure to roughly 59%.

Not all triptans perform identically. Rizatriptan 10 mg and eletriptan 80 mg have shown slightly higher 2-hour pain-free rates than sumatriptan in head-to-head comparisons, though individual response varies. "The best triptan is the one that works for the individual patient," noted Dr. Peter Goadsby, a leading headache researcher, in a 2017 review in The New England Journal of Medicine [6].

Newer options include the gepants (ubrogepant, rimegepant), small-molecule CGRP receptor antagonists approved for acute migraine. These avoid the vasoconstrictive effects of triptans, making them suitable for patients with cardiovascular risk factors. The ACHIEVE-I trial (N=1,672) showed ubrogepant 50 mg achieved 2-hour pain freedom in 19.2% versus 11.8% placebo [7].

For cluster headache, high-flow oxygen at 12 L/min via nonrebreather mask and subcutaneous sumatriptan 6 mg are first-line, per European Headache Federation guidelines [8].

Preventive Medications That Reduce Headache Frequency

Patients experiencing 4 or more migraine days per month, or those with attacks that respond poorly to acute therapy, should be considered for preventive treatment. Traditional oral preventives include topiramate, propranolol, amitriptyline, and valproate.

Topiramate 100 mg daily reduced monthly migraine days by approximately 1.8 days more than placebo in the MIGR-002 trial (N=469) [9]. Propranolol 80-240 mg daily has similar efficacy but a different side-effect profile: fatigue and exercise intolerance versus the cognitive dulling and weight loss seen with topiramate.

The CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, eptinezumab) changed migraine prevention beginning in 2018. In the STRIVE trial (N=955), erenumab 140 mg monthly reduced migraine days by 3.7 per month versus 1.8 for placebo [10]. The REGAIN trial demonstrated galcanezumab's efficacy even in chronic migraine, with roughly 28% of patients achieving a 50% or greater reduction in monthly migraine days versus 15% placebo [11].

For chronic tension-type headache, amitriptyline 25-75 mg at bedtime is the best-studied preventive, per a Cochrane review [12]. Venlafaxine and mirtazapine may also work, though evidence is thinner.

Cluster headache prevention relies primarily on verapamil 240-960 mg daily (requiring ECG monitoring for PR prolongation) and short-term bridging with corticosteroids. Lithium is a second-line option for chronic cluster headache, requiring serum level monitoring.

Drugs That Cause Headaches as a Side Effect

The same pharmacology that treats one headache type can trigger another. This bidirectional relationship is clinically significant because patients frequently do not connect a new medication with a new headache pattern.

Nitrates and nitric oxide donors are the most studied headache-inducing drugs. Nitroglycerin causes headache in up to 82% of users, according to a study in the European Journal of Neurology [13]. Isosorbide mononitrate and isosorbide dinitrate carry similar risk. The mechanism involves nitric oxide-mediated vasodilation and activation of trigeminal nociceptors.

PDE5 inhibitors (sildenafil, tadalafil, vardenafil) produce headache in 16-28% of users across clinical trials. Sildenafil's FDA label lists headache as the most common adverse event [14]. The mechanism overlaps with nitrate-induced headache since PDE5 inhibition increases downstream cGMP, potentiating nitric oxide signaling.

Hormonal preparations are frequent headache triggers. Combined oral contraceptives containing ethinyl estradiol can worsen migraine, particularly during the placebo week when estrogen drops. The WHO medical eligibility criteria classify combined hormonal contraceptives as category 4 (unacceptable health risk) for women with migraine with aura due to increased stroke risk [15].

Proton pump inhibitors such as omeprazole are underrecognized headache triggers. A large Danish cohort study found PPI use associated with a 24% increased risk of incident migraine [16].

Other common offenders include dipyridamole (up to 34% headache incidence), nifedipine and other dihydropyridine calcium channel blockers, caffeine withdrawal after chronic use, and histamine-releasing drugs.

Medication-Overuse Headache: When the Cure Becomes the Cause

Medication-overuse headache (MOH) is one of the most clinically important drug-headache relationships. It affects an estimated 1-2% of the general population, but up to 50-80% of patients seen in tertiary headache clinics [17]. ICHD-3 defines MOH as headache occurring on 15 or more days per month in a patient with a pre-existing headache disorder who has been overusing acute headache medication for more than 3 months [1].

The thresholds differ by drug class. Triptans, ergots, opioids, and combination analgesics carry a 10-day-per-month threshold. Simple analgesics (NSAIDs, acetaminophen) carry a 15-day threshold. "Patients often escalate their analgesic use gradually, and neither the patient nor the clinician recognizes the overuse pattern until the headache has become daily," wrote Dr. Hans-Christoph Diener in a 2019 Lancet Neurology review [18].

The pathophysiology involves central sensitization and downregulation of endogenous pain modulation. Opioids carry the highest MOH risk. Butalbital-containing combinations are also particularly problematic.

Treatment requires withdrawal of the overused medication, which typically worsens headaches for 2-10 days (longer with opioids or barbiturates). Bridge therapy with naproxen 500 mg twice daily, corticosteroids (prednisone taper), or nerve blocks can ease the transition. Starting a preventive medication simultaneously improves outcomes. A randomized trial comparing abrupt withdrawal to continued use found that stopping the overused drug was associated with a 42% reduction in headache days at 8 weeks [19].

Which Drug Classes to Try Based on Headache Pattern

Matching the medication to the headache type and frequency is where clinical decision-making earns its value. A patient with 2 migraines per month needs acute treatment only. A patient with 10 migraine days per month needs both acute and preventive therapy.

For episodic migraine (fewer than 15 days per month), acute-only management with triptans, NSAIDs, or gepants may suffice. The AHS position statement recommends considering prevention when acute treatment is needed more than 2 days per week, acute treatments fail or are contraindicated, or attacks cause significant disability [3].

For chronic migraine (15 or more headache days per month with at least 8 having migraine features), onabotulinumtoxinA (Botox) 155 units every 12 weeks is FDA-approved based on the PREEMPT trials (N=1,384), which showed a reduction of 8.4 headache days per month versus 6.6 for placebo [20]. CGRP antibodies are the other main option for chronic migraine prevention.

For new daily persistent headache (NDPH), treatment is less evidence-based. Clinicians often trial the same preventives used for chronic migraine, but response rates are lower. This remains one of the most treatment-resistant headache disorders.

Patients with cardiovascular disease who cannot use triptans should receive gepants or lasmiditan (a 5-HT1F agonist without vasoconstrictive properties). The SAMURAI trial (N=1,856) showed lasmiditan 200 mg achieved 2-hour pain freedom in 32.2% versus 15.3% placebo [21].

Red-Flag Headaches That Require Urgent Evaluation, Not a Prescription

Not every headache should be treated with medication before evaluation. Certain features ("red flags") signal a secondary headache requiring urgent workup. The SNOOP mnemonic, widely taught in neurology training, captures the key warning signs: Systemic symptoms (fever, weight loss), Neurological signs, Onset sudden ("thunderclap"), Older age at onset (after 50), and Pattern change (progressive worsening) [22].

A thunderclap headache reaching peak intensity within 60 seconds demands emergent CT followed by lumbar puncture if imaging is negative, to rule out subarachnoid hemorrhage. The sensitivity of non-contrast CT for subarachnoid hemorrhage is approximately 98% within 6 hours of onset but drops to 93% by 24 hours, per a study in The BMJ [23].

Headache with papilledema suggests raised intracranial pressure (idiopathic intracranial hypertension, mass lesion). New headache in an immunocompromised patient requires imaging and possible CSF analysis. Headache after trauma, particularly with anticoagulant use, warrants CT to exclude intracranial hemorrhage.

Drug therapy without appropriate evaluation in these scenarios can delay diagnosis of life-threatening conditions. The correct first step is always clinical assessment.

Emerging Therapies and Pipeline Drugs for Headache

Several new drug classes are in late-stage development. Atogepant, an oral CGRP antagonist, received FDA approval in 2021 for episodic migraine prevention. In the ADVANCE trial (N=910), atogepant 60 mg daily reduced mean monthly migraine days by 3.7 versus 2.5 for placebo [24].

Eptinezumab, the only intravenous CGRP antibody, offers rapid onset. In the PROMISE-2 trial (N=1,072), 100 mg IV achieved a 50% responder rate of 57.6% for months 1-3 versus 38.8% placebo in chronic migraine [25]. The IV route may benefit patients who have difficulty with self-injection.

Pituitary adenylate cyclase-activating peptide (PACAP) receptor antagonists represent a novel target distinct from CGRP. Early-phase trials are underway. Nitric oxide synthase inhibitors and glutamate receptor modulators are also in the pipeline, though none have reached phase III yet.

Neuromodulation devices (single-pulse transcranial magnetic stimulation, supraorbital transcutaneous nerve stimulation, noninvasive vagus nerve stimulation) provide drug-free options for patients who prefer or require non-pharmacological approaches. These are FDA-cleared and supported by randomized trial data [26], though effect sizes are generally smaller than pharmacotherapy.

Patients who have failed at least two oral preventives and one CGRP-targeted therapy should be referred to a headache specialist or multidisciplinary headache center. The American Academy of Neurology quality measure set considers referral after three preventive failures a performance benchmark [27].