Open questions — migraine¶
Last audited: 2026-08-30. IDs are stable: revise wording or status without renumbering. Tier 1 questions are practice-changing and prospectively testable now; Tier 2 questions need enabling cohorts, methods or longer follow-up.
Tier 1 — practice-changing, designable now¶
OQ-1 — What is the best first preventive strategy?¶
Question. In prevention-eligible adults, how do a conventional oral preventive, a CGRP antibody, a preventive gepant and—where chronic migraine is present—onabotulinumtoxinA compare in a pragmatic, preference-aware sequence?
Why open. Placebo-controlled efficacy is established, and erenumab and atogepant each outperformed topiramate on tolerability and response in direct trials. The live search through 2026-08-30 still identified no general multi-class sequence comparing oral drugs, antibodies, gepants and toxin while jointly measuring effectiveness, harms, cost and access (Reuter 2022, PMID 34743579; Reuter 2026, PMID 42492556; Lampl 2023, PMID 37208596).
OQ-2 — When should prevention start to avert chronic migraine?¶
Question. Among people with rising attack frequency, does early effective prevention produce a sustained reduction in chronic-migraine transition after treatment is withdrawn?
Why open. Frequency, overuse, obesity, mood and sleep predict progression, but predictor modification is not proof of disease modification; current trials mainly measure on-treatment symptom suppression (May 2016, PMID 27389092; Buse 2019, PMID 30589090).
OQ-3 — Withdrawal, prevention or both for MOH?¶
Question. Which drug- and patient-specific strategy—withdrawal first, immediate prevention, or both—maximizes sustained remission while minimizing withdrawal burden and relapse?
Why open. Combined withdrawal and early prevention performed best in one randomized strategy trial, while CGRP trials show improvement without formal detoxification; opioid/barbiturate dependence creates a distinct problem (Carlsen 2020, PMID 32453406; Sirilertmekasakul 2024, PMID 38564060).
OQ-4 — What should happen after the first acute treatment fails?¶
Question. After an adequate NSAID or triptan trial, which within-person sequence best delivers sustained pain freedom and function per cost and adverse event?
Why open. Network evidence ranks licensed oral agents, but cross-trial averages cannot estimate within-person response consistency, route effects or the best switch sequence (Karlsson 2024, PMID 39293828).
OQ-5 — Does combination prevention add enough benefit?¶
Question. In refractory chronic migraine, what is the incremental benefit, harm and cost of CGRP-pathway therapy plus onabotulinumtoxinA versus optimized monotherapy?
Why open. Both classes have efficacy, and a 2026 meta-analysis estimated benefit across observational combination cohorts, but it found no controlled comparative designs and substantial methodological limitations. A recruiting randomized active-comparator trial provides the direct route to an answer (Dodick 2010, PMID 20487038; Sarvari Soltani 2026, PMID 41721358; NCT07040813).
OQ-6 — Can patient-weighted endpoints change treatment choice?¶
Question. Do treatment rankings change when outcomes weight consistency, cognition, interictal burden, family function and patient priorities rather than mean MMD or a single two-hour endpoint?
Why open. Qualitative and measurement studies document priorities not fully represented in registration endpoints, but these outcomes have not been applied across treatments in a common comparative trial (Mangrum 2023, PMID 37140142; Hubig 2022, PMID 35941572).
OQ-7 — Which paediatric prevention package works best?¶
Question. In children and adolescents, how do CBT-first, drug-first and combined stepped-care pathways compare on headache, school participation, family burden and harms?
Why open. CHAMP found amitriptyline and topiramate no better than placebo with more harms, while CBT added benefit when both arms received amitriptyline; the optimal sequence remains unresolved (Powers 2017, PMID 27788026; Powers 2013, PMID 24368463).
OQ-8 — Which pregnancy-compatible pathway has the best balance?¶
Question. For people planning pregnancy or breastfeeding, which acute and preventive sequence minimizes maternal disability without avoidable fetal or infant risk?
Why open. Triptan observational data are comparatively mature, but newer CGRP therapies lack adequately powered prospective exposure data, and untreated disease carries its own harms (Marchenko 2015, PMID 25644494; Burch 2020, PMID 31579938).
Tier 2 — enabling science and longer-horizon questions¶
OQ-9 — Can a biomarker predict relative treatment response?¶
Why open. CGRP provocation, imaging, EEG, CSF and polygenic signals are mechanistically informative, but no locked multisite test predicts relative response to one preventive over another; REFORM's negative baseline suPAR result shows why prospective candidate testing matters (Al-Khazali 2024, PMID 38859744; Karlsson 2025, PMID 40275185; Hautakangas 2022, PMID 35115687).
OQ-10 — What initiates and terminates the migraine attack?¶
Why open. Trigeminovascular, hypothalamic, brainstem and cortical changes are all documented, but observed activation does not identify the causal ordering or the switch that restores the interictal state (Ashina 2021, PMID 33773610).
OQ-11 — How does cortical spreading depolarization connect to headache?¶
Why open. CSD is the leading aura substrate, yet aura and headache dissociate and the exact junction from cortical event to meningeal/trigeminal pain remains incomplete. A 2026 lamotrigine cohort adds uncontrolled aura-day data but not a controlled CSD-targeted test (Fraser 2019, PMID 31847045; Uzun 2026, PMID 42591364).
OQ-12 — Does migraine treatment modify vascular risk?¶
Why open. Migraine with aura is associated with ischemic stroke. A 2026 active-comparator cohort offers limited reassurance against a large CGRP-antibody hazard relative to onabotulinumtoxinA, but few events and no untreated comparison leave shared causation and treatment-mediated protection unresolved (Zhang 2022, PMID 35451664; Gül 2026, PMID 42390441).
OQ-13 — Is high-frequency gepant exposure free of MOH liability?¶
Why open. The live search through 2026-08-30 found expanding high-frequency and medication-overuse studies but no prospective exposure-threshold study demonstrating whether long-duration frequent gepant use causes, prevents or is neutral for MOH. Current reviews therefore support mechanistic reassurance, not proof of zero liability (Negro 2019, PMID 31081399; Ashina 2023, PMID 36732518).
OQ-14 — Why does migraine become sex-skewed after puberty?¶
Why open. Estrogen fluctuation explains an important attack trigger but not the full prevalence ratio; developmental, genetic, CGRP, social and recognition pathways remain entangled (Nappi 2022, PMID 35456034; Burch 2020, PMID 31579938).
OQ-15 — What is the biological meaning of the chronic threshold?¶
Why open. The ≥15-day line is operational, while disability, genetics and frequency vary continuously and people cross the boundary in both directions (IHS 2018, PMID 29368949; Adams 2015, PMID 25304766).
OQ-16 — Which global care-cascade intervention recovers most disability?¶
Why open. Diagnosis, consultation, acute treatment, prevention and follow-up gaps coexist; comparative implementation trials across resource settings are scarce (Katsarava 2018, PMID 29392600; Steiner 2018, PMID 29445880).
Dots not yet connected¶
| # | Dot A | Dot B | The missing junction | Powers |
|---|---|---|---|---|
| 1 | Early frequency rise predicts chronification | Targeted preventives rapidly reduce MMD | Withdrawal-after-remission trial testing persistent disease modification | Preventive timing and duration |
| 2 | CGRP infusion can provoke attacks | CGRP antibodies/gepants work on average | Prospective provocation-stratified head-to-head response study | Precision prescribing |
| 3 | GWAS shows neuronal and vascular loci | Aura carries vascular association | Ancestry-diverse genotype × aura × adjudicated vascular-outcome cohort | Risk stratification without overmedicalization |
| 4 | CSD explains aura | Trigeminal/CGRP signaling explains pain | Simultaneous cortical, meningeal and symptom time-series during spontaneous aura | Mechanistic bridge from aura to headache |
| 5 | Interictal burden exists on headache-free days | Trials optimize MMD | Comparative trial measuring whether interictal recovery is independent of MMD | Patient-centred treatment ranking |
| 6 | Cognitive symptoms span attack phases | Preventives and topiramate can alter cognition | Objective within-person cognitive testing before and after prevention | Separate disease benefit from drug harm |
| 7 | Stigma predicts disability/HRQoL | Structured education improves headache management | Randomized anti-stigma + care-navigation intervention with clinical outcomes | Care seeking and accommodation |
| 8 | Family burden is measurable | Pediatric/parent treatment targets individuals | Dyadic intervention and family-spillover endpoint trial | Household-level benefit |
| 9 | CHAMP shows large paediatric placebo/context response | CBT has incremental benefit | Dismantling trial of expectancy, monitoring, CBT skills and medication | Efficient paediatric stepped care |
| 10 | Menstrual attacks are longer and recurrence-prone | Short-term triptan prevention works | Head-to-head diary-based intermittent versus continuous strategy trial | Minimize total treatment and overuse days |
| 11 | Pregnancy exposure data are sparse | Trial registries now include exposure cohorts | Harmonized prospective registry with untreated-migraine comparator and infant follow-up | Reproductive decisions |
| 12 | Devices depend on credible sham | Blinding can be guessed from sensation | Sham-validation study embedded before efficacy testing | Trustworthy neuromodulation effects |
| 13 | MOH reflects disease severity and exposure | CGRP prevention can reduce overuse without detox | Drug-class-stratified causal strategy trial including dependence outcomes | Non-stigmatizing, safer MOH care |
| 14 | Stroke association is strongest for aura | Prevention can suppress aura/attacks | Long-term treated cohort with time-varying aura and vascular confounders | Determine whether risk is modifiable |
Governance¶
- Close an OQ only when direct evidence answers the stated comparison, population and outcome; adjacent efficacy evidence is insufficient.
- Preserve IDs when a question is narrowed or moved between tiers.
- Promote a dot to a numbered OQ when a feasible design and decision consequence are explicit.