Report Description Table of Contents Introduction and Strategic Context The Global Refractory Chronic Migraine (Post-CGRP Failure) Market was valued at USD 432 million in 2025 and is projected to reach USD 660 million by 2030 and USD 870 million by 2035, confirms Strategic Market Research. This is not the “overall migraine” story. It’s a narrower, higher-intensity slice of care that starts once CGRP-targeted preventives have already been tried and the patient still isn’t under control. In real-world specialist settings, that usually means ongoing high-frequency disease, repeated cycling across preventives, and a growing reliance on combination strategies that don’t always translate into durable stability. What makes this market strategically important in 2025–2035 is the mismatch between innovation headlines and late-line reality. CGRP therapies changed prevention. But a meaningful subset of treated patients still fails to reach adequate or durable control, and that persistent non-responder pool becomes its own “care economy” with higher touchpoints, higher administrative friction, and more escalation discussions over time. The commercial foundation is also unusually “gated.” In 2025, SMR estimates roughly ~130,000 actively treated post-CGRP failure patients globally, concentrated in specialist care. The United States alone accounts for ~70,000 of these patients, followed by the EU5 at ~30,000, with Japan at ~8,000 and other developed markets adding ~12,000. That concentration matters because it shapes how quickly escalation pathways can scale: if the patient flow is specialist-led, the market is too. From a modality perspective, the revenue base in 2025 is still dominated by pharmacologic spend, with USD 388 million tied to pharmacologic therapies versus USD 44 million in non-invasive neuromodulation. By 2035, the mix broadens as escalation deepens: pharmacologic therapies rise to USD 560 million, non-invasive neuromodulation reaches USD 210 million, and implantable/interventional approaches expand to USD 100 million. In plain terms: growth here is less about “more patients,” and more about “more intensity per patient,” plus a shift toward modalities used when non-invasive ceilings show up. Key stakeholders in this market include headache specialists and neurologists, tertiary headache centers, payers and utilization management teams, pharmaceutical manufacturers, non-invasive neuromodulation providers, and implantable/interventional platform developers. If you’re making investment or commercial decisions, the real question isn’t whether CGRP remains important. It’s what happens after CGRP benefit plateaus—and who owns that next decision point. Market Segmentation and Forecast Scope For the Refractory Chronic Migraine (Post-CGRP Failure) Market, segmentation has to be built around “failure depth” and “escalation behavior,” not broad migraine categories. That’s the only way to reflect how this cohort actually moves through care once CGRP-based prevention hasn’t delivered durable control. By Preventive Failure Depth This market is explicitly anchored to how many preventive classes a patient has already failed. In 2025, the global actively treated post-CGRP failure pool is ~130,000 patients, and the failure-depth split is: 1 failed preventive (~20%), 2 failed preventives (~35%), and ≥3 failed preventives (~45%). The practical takeaway: value concentrates in the multi-failure end of the spectrum. “Refractory” here isn’t a label. It’s a proxy for recurring escalation conversations and repeated care touchpoints. By Type of CGRP Exposure Within post-CGRP failure, patients are segmented based on whether “failure” followed a CGRP monoclonal antibody versus a preventive gepant, including real-world patterns like partial response, discontinuation, switching, and treatment cycling. This matters because clinicians don’t treat “CGRP failure” as a single event. They treat it as a sequence problem, and switching behavior becomes part of the market’s persistence. By OnabotulinumtoxinA (Botox) Exposure and Combination Use A major segmentation layer is whether Botox is already in the regimen, and whether the patient is being managed through combination escalation (CGRP + Botox, then additional adjuncts). This is central to late-line reality because post-CGRP failure rarely returns to monotherapy. By Acute Medication Burden and MOH Risk Segmentation also accounts for acute medication dependence and medication-overuse headache (MOH) risk, because this becomes a structural constraint on “just adding more drugs.” In 2025, the post-CGRP failure cohort shows mean monthly headache days of 18–22 days, acute medication use ≥10 days/month in 55–65%, and patients meeting MOH criteria at 30–40%. This is where a lot of the economic logic comes from. As MOH risk rises, both clinicians and payers become more sensitive to drug-sparing approaches. By Escalation Pathway The market is ultimately segmented by escalation modality: Pharmacologic, Non-Invasive Neuromodulation, and Implantable / Interventional approaches. This is also how the forecast is structured. By Regional scope The ~130,000 actively treated post-CGRP failure patients in 2025 are geographically concentrated: United States (~70,000), EU5 (~30,000), Japan (~8,000), Other Developed Markets (~12,000), and Rest of World (~10,000). This concentration is why commercialization tends to start with specialist-heavy systems first. The patient funnel is gated, and so is the revenue pool. Forecast scope The forecast window is 2025–2035, with market sizing expressed in USD million, and growth driven mainly by escalating treatment intensity and mix shift rather than a large expansion in underlying patient counts. In 2025, total market value is USD 432 million, split across Pharmacologic (USD 388 million), Non-Invasive Neuromodulation (USD 44 million), and Implantable / Interventional (—). That means Pharmacologic therapies account for ~89.8% of 2025 value, while Non-Invasive Neuromodulation contributes ~10.2%. So yes, the base is still drug-led. But the strategic story is the migration of high-disability patients beyond non-invasive ceilings, which is why the interventional pool becomes visible by 2030 and scales by 2035 Market Trends and Innovation Landscape Innovation in the Refractory Chronic Migraine (Post-CGRP Failure) Market is moving in two directions at once. On one side, drug developers are trying to “solve” the non-responder problem with new biology. On the other, clinicians are quietly building a more durable playbook around escalation tools that don’t depend on adding yet another systemic preventive. That tension is exactly what shapes this market between 2025–2035. Trend 1 The market is becoming more failure depth driven, not product driven Post-CGRP failure care is starting to look less like a broad migraine algorithm and more like a narrowing decision tree. After failure, neurologists tend to repeat a small set of actions rather than endlessly branching out. In 2025, treatment actions in post-CGRP failure patients cluster around Botox initiation or optimization (45–55%), CGRP switching or recycling (20–30%), preventive gepant use (15–20%), and a sharp rise in increased acute medication reliance (60–70%). Non-invasive neuromodulation add-on (8–15%) sits as an early escalation layer. What’s telling here is how “repeatable” the pathway is. The market behaves like a system with guardrails, not an open playground of choices. Trend 2 Neuromodulation is shifting from optional add-on to a planned escalation layer SMR’s view is that neuromodulation adoption deepens over time inside a relatively stable refractory population. Estimated escalation adoption within post-CGRP failure patients rises from 8–15% in 2025, to 22–28% in 2030, reaching 30–40% by 2035. That adoption curve is consistent with the revenue mix shift already visible in the forecast by modality: the total market grows from USD 432 million in 2025 to USD 660 million by 2030 and USD 870 million by 2035, with non-invasive neuromodulation expanding from USD 44 million (2025) to USD 120 million (2030) and USD 210 million (2035), while implantable/interventional becomes commercially meaningful at USD 35 million (2030) and USD 100 million (2035). In plain terms: escalation is becoming more “scheduled” in the care journey, especially when drug-based control hits a ceiling. Trend 3 Pipeline innovation is targeting CGRP non-responders, but it doesn’t erase the escalation need Pipeline development for CGRP non-responders is increasingly oriented toward PACAP-pathway modulation and other exploratory non-CGRP mechanisms. The report also flags that response is likely to remain heterogeneous, with partial efficacy expected to preserve a residual uncontrolled group. Critically, the pipeline does not structurally address issues that dominate late-line reality like acute medication dependence, medication-overuse headache, and long-term functional impairment. So even with new biology, the market still needs non-systemic options that can sit alongside drugs rather than trying to replace them. Trend 4 Payer mechanics are shaping innovation priorities, not just access outcomes Utilization management adds friction that influences sequencing and persistence. Policies commonly include step therapy, renewal thresholds (often requiring ≥50% reduction in monthly migraine days), and guardrails against “CGRP stacking.” Beyond the policy text, SMR notes measurable access friction, including 20.6% of actively treated patients experiencing “payer blocking” (defined as ≥2 denials). This pushes innovation toward solutions that can be positioned as reducing acute utilization and downstream costs, not just improving a symptom score. Competitive Intelligence and Benchmarking Competition in the Refractory Chronic Migraine (Post-CGRP Failure) Market (2025–2035) doesn’t behave like a classic “brand share” fight. In late-line chronic migraine, clinicians are usually comparing escalation paths, not choosing between two near-identical options. The more realistic battleground is whether a neurologist escalates at all, and if yes, whether they escalate with more pharmacologic cycling, short-cycle procedures, non-invasive neuromodulation, or an implantable/interventional step. Below is how the most relevant players benchmark in this setting. Salvia BioElectronics BV Salvia is positioned around implantable/interventional neuromodulation as a late-line infrastructure play. The strategic pitch is durability for patients who have exhausted systemic options, with the key competitive comparison being against continued cycling and repeated short-term interventions rather than direct device-to-device rivalry. If Salvia wins, it’s because it becomes the “next step” once the non-invasive ceiling and pharmacologic fatigue show up. AbbVie AbbVie sits on the pharmacologic side of the escalation stack. In post-CGRP failure practice, drug leaders retain relevance because neurologists often preserve partially effective therapies and layer rather than replace. AbbVie’s advantage is scale in specialist channels and experience navigating payer controls. The limitation is structural: drug-based approaches face diminishing marginal benefit and growing scrutiny when acute medication dependence and MOH risk rise. Amgen Amgen’s positioning is similar: maintain presence through biologic depth and established neurology access. In refractory care, the “product” isn’t just efficacy, it’s predictability of reimbursement and renewal. So the benchmark here is operational: who can minimize the admin churn that accelerates discontinuation and switching fatigue. Eli Lilly and Company Lilly competes through breadth in migraine care pathways and the ability to stay in the regimen via combination logic. The real benchmark is persistence in a market where “post-failure” is rarely a clean stop, and where clinicians retain partially helpful therapies. In practical terms, late-line value often comes from staying on the chessboard, even if you’re not the final move. Teva Pharmaceutical Industries Teva’s relevance in this segment is partly commercial: coverage reach, formulary positioning, and the ability to remain a viable option in cost-sensitive treatment ladders. In post-CGRP failure, cost-to-continue matters because high-frequency patients generate repeated utilization and repeated payer review. electroCore electroCore is a benchmark name in non-invasive neuromodulation, which is increasingly treated as an adjunctive layer in refractory pathways rather than a niche add-on. The competitive lever is “fit” in specialist workflow: how easily it can be prescribed, supported, and justified as drug-sparing when acute reliance climbs. Theranica Bio-Electronics Theranica represents the broader class of non-invasive platforms that compete on usability, patient adherence, and real-world outcomes capture. The benchmark isn’t just adoption. It’s whether the platform can hold up as patients progress toward higher disability tiers where implantable/interventional consideration starts to appear. Overall, this market is not a “winner takes all” category. The durable advantage comes from use-case dominance: being the option neurologists trust at a specific escalation moment, and being the option payers can rationalize when drug cycling is no longer defensible. Regional Landscape and Adoption Outlook The post-CGRP failure segment is global in footprint, but it is not global in “commercial gravity.” Value concentrates where three things exist at the same time: dense specialist care, mature escalation pathways, and reimbursement mechanisms that can tolerate repeat sequencing. That’s why the actively treated pool in 2025 is heavily clustered in a few developed regions: United States (~70,000), EU5 (~30,000), Japan (~8,000), Other Developed Markets (~12,000), and Rest of World (~10,000), totaling ~130,000 globally. North America North America is the core value engine because it combines biologic maturity with earlier escalation behavior and higher treatment intensity. In fact, the United States alone contributes ~55–60% of global market value, driven by faster adoption of adjunctive strategies and greater willingness to progress beyond drug-only management. Practically, this region is where combination therapy becomes “normal” in clinic, but still runs into administrative pressure. Utilization management commonly includes step therapy, preferred-agent rules, renewal thresholds (often ≥50% reduction in monthly migraine days), and restrictions around combination preventive use. So adoption isn’t blocked. It’s shaped. Companies win here by fitting the documentation workflow and making escalation defensible to payers, not by relying on awareness building. Europe Europe behaves differently. Care is more guideline-driven, and reimbursement tends to be structured through national systems with formal evidence expectations. The report frames Europe as “guideline-driven care with persistent unmet need,” with cross-country variability in access and escalation pathways. What that means commercially is slower but steadier escalation. Botox remains a long-standing backbone in advanced chronic migraine, while CGRP access is heterogeneous and preventive gepant availability can be constrained depending on country. Europe can be attractive, but it’s rarely “one launch.” It’s a sequence of country-level proof points, often led by centers that can generate evidence and influence adoption. Asia Pacific Asia Pacific is described as a large-population region with selective interventional upside. The practical divide is between developed markets (where specialist care, CGRP access, and escalation infrastructure exist) and emerging markets (where diagnosis gaps and access disparities dominate). The report highlights CGRP adoption in Japan, South Korea, and Australia, alongside limited preventive gepant access outside select markets. So the upside isn’t “everywhere at once.” It’s concentrated in a handful of countries where refractory cohorts are visible, documentable, and managed in centers that can support escalation. LAMEA / Rest of World In Rest of World, the segment exists, but it is structurally constrained. The report flags low diagnosis rates, limited access to advanced care, and heavy reliance on acute pharmacologic management, with minimal preventive escalation and higher risk of acute medication overuse. Neuromodulation relevance is more niche here, mainly in private and tertiary centers, with “long-term potential rather than near-term scale.” This region is less about immediate revenue and more about optionality—building footholds where private specialty care is expanding and where refractory patients are starting to surface as a distinct group. End-User Dynamics and Use Case End-user behavior in the Refractory Chronic Migraine (Post-CGRP Failure) Market (2025–2035) is shaped by one big reality: this cohort is not managed in primary care. Decision authority sits with headache specialists and neurologists, and the workflow is heavily tied to documentation-heavy access steps like headache-day tracking and prior authorization narratives . So even when the science is clear, adoption still depends on who can “carry the paperwork” and who has the clinic structure to keep patients stable over time. Headache Specialists Headache specialists are the primary end users in this segment because they see the highest density of multi-failure patients and control escalation sequencing. They’re also the clinicians most likely to treat post-CGRP failure as a repeatable pathway, not a one-off “non-response.” Their behavior is predictable in 2025: they often attempt incremental steps like Botox initiation or optimization (45–55%), CGRP switching or recycling (20–30%), and preventive gepant use (15–20%), while acute reliance rises (60–70%) and non-invasive neuromodulation add-on (8–15%) begins to show up as an adjunct rather than a last resort . The “end-user” story here is really about managing the pharmacologic ceiling without letting acute dependence take over. General Neurologists General neurologists participate, but their role is narrower. They are more likely to follow payer-driven sequencing and refer out when complexity rises. The referral threshold tends to show up when the patient profile starts to match the escalation-ready clinical characteristics in 2025: 18–22 mean monthly headache days, acute use ≥10 days/month in 55–65%, and MOH in 30–40% . At that point, “try another preventive” starts to feel less like progress and more like churn. Tertiary Headache Centers and Centers of Excellence Tertiary headache centers act as market multipliers because they absorb the most refractory patients, standardize escalation pathways, and influence broader practice patterns through training and evidence generation . They also tend to be the first to operationalize neuromodulation pathways as an integrated part of late-line management, especially when non-invasive strategies reach a functional ceiling and interventional escalation becomes rational . In practice, centers of excellence don’t just “treat.” They create the documentation, follow-up cadence, and multidisciplinary framing that makes escalation approvable and sustainable. Hospitals and Emergency Care Settings Hospitals aren’t the primary decision makers for long-term prevention, but they’re part of the downstream consequence loop. The report notes that access frictions and interruptions are associated with higher acute care utilization, including emergency department visits and short-term procedural escalation . This is why payers and providers both become more sensitive to options framed around reducing acute utilization and avoiding care re-routing. Use Case Highlight A tertiary headache center managing a post-CGRP failure cohort noticed many patients were stuck in a loop: persistent >15 monthly headache days, rising acute use, and repeated payer friction for further pharmacologic layering. The center standardized an “escalation-ready” pathway using documented headache-day tracking and MOH screening, reflecting the typical 2025 profile of 18–22 mean monthly headache days, acute use ≥10 days/month in 55–65%, and MOH in 30–40% . Once patients hit that threshold, clinicians added non-invasive neuromodulation as a drug-sparing adjunct rather than waiting for another failed cycle, aligning with the observed adoption layer of 8–15% in 2025 . The operational benefit wasn’t just symptom control. It was smoother documentation for renewals, fewer “infinite cycling” debates, and a clearer clinical justification when escalation beyond non-invasive management was eventually considered . Recent Developments + Opportunities & Restraints Recent Developments (Last 2 Years) In March 2024, the American Headache Society updated its treatment guidelines to formally recommend CGRP-targeted preventives as first-line therapy for chronic migraine management. Between 2023 and 2025, U.S. and EU5 payers have shown inconsistent alignment with updated clinical guidelines, maintaining legacy access hurdles such as step therapy, preferred drug lists, and documentation thresholds. Neuromodulation vendors have advanced real-world integration pilots with tertiary headache centers, enabling device-based escalation earlier in care sequencing. Several companies in implantable neuromodulation received regulatory pathway clarification in late 2023, marking a shift from experimental to commercial pathway readiness. New CGRP-adjacent pipeline candidates, including PACAP-pathway modulators, began early-phase trials aimed at non-responders and partial responders, adding interest in adjunct, not replacement, positioning. Opportunities Non-invasive neuromodulation is moving from niche adjunct to a planned escalation tool, with market value forecasted to grow from USD 44 million in 2025 to USD 210 million by 2035. The implantable/interventional segment becomes a formal category by 2030 and is projected to reach USD 100 million by 2035, driven by structured escalation in patients with ≥3 preventive failures. Specialist-driven care enables high-yield commercialization with focused outreach. With just ~130,000 actively treated patients globally in 2025, companies can build efficient go-to-market strategies around a gated prescriber base. Payer engagement opportunities are increasing, particularly for solutions that reduce acute medication use, address MOH risk, and improve treatment durability without cycling. Restraints Utilization management controls remain a key friction point. Step edits, prior authorization renewals, and rules against CGRP stacking continue to delay or block escalation. Roughly 20.6% of patients in this segment experience “payer blocking”, defined as two or more coverage denials during their escalation pathway. Clinical stabilization is difficult, with patients averaging 18–22 headache days/month, acute medication use ≥10 days/month in over 55%, and MOH criteria met in 30–40%—limiting clean outcome wins and raising churn risk. The segment is inherently specialist-constrained, with access bottlenecks and high documentation burdens slowing adoption of advanced options, even when supported by strong clinical rationale. 7.1. Report Coverage Table Report Attribute Details Forecast Period 2025 – 2035 Market Size Value in 2025 USD 432 Million Revenue Forecast in 2030 USD 660 Million Revenue Forecast in 2035 USD 870 Million Overall Growth Rate CAGR of 7.5% (2025 – 2035) Base Year for Estimation 2025 Historical Data 2020 – 2024 Unit USD Million Segmentation By Escalation Modality, By CGRP Exposure, By Preventive Failure Depth, By Geography By Escalation Modality Pharmacologic Therapies, Non-Invasive Neuromodulation, Implantable / Interventional By CGRP Exposure Type CGRP mAbs, Preventive Gepants, Combination Exposure By Preventive Failure Depth 1 Failed Preventive, 2 Failed Preventives, ≥3 Failed Preventives By Region North America, Europe (EU5), Asia (Japan + Others), Other Developed Markets, Rest of World Country Scope U.S., Germany, France, U.K., Italy, Spain, Japan, Canada, Australia, Others Market Drivers - Persistent unmet need in post-CGRP failure care - Specialist-led escalation behaviors - Shift toward neuromodulation and implantable modalities Customization Option Available upon request Frequently Asked Question About This Report Q1. How big is the refractory chronic migraine (post-CGRP failure) market? A1. The global refractory chronic migraine (post-CGRP failure) market was valued at USD 432 million in 2025 and is projected to reach USD 870 million by 2035, growing at a CAGR of 7.5%. Q2. What defines the "post-CGRP failure" segment in this market? A2. This segment refers to chronic migraine patients who have tried CGRP-targeted preventives (monoclonal antibodies or gepants) but still experience persistent, high-frequency migraines requiring further escalation in care. Q3. Who are the leading companies in this market? A3. Key players include Salvia BioElectronics, AbbVie, Amgen, Eli Lilly and Company, Teva Pharmaceutical Industries, electroCore, and Theranica Bio-Electronics. Q4. Which treatment modalities are driving market growth? A4. Growth is driven by intensifying reliance on non-invasive neuromodulation and implantable/interventional strategies, especially for patients with ≥3 preventive failures. Drug-based therapies remain dominant but show signs of plateauing. Q5. What makes this market commercially unique? A5. It’s a gated, specialist-led care economy with high patient concentration in the U.S., EU5, and Japan. Value scales not through volume but through deeper escalation intensity per patient. TABLE OF CONTENTS 1. EXECUTIVE SYNTHESIS — THE POST-CGRP FAILURE OPPORTUNITY 1.1. Emergence of Post-CGRP Failure as a Distinct Market Segment Transition from CGRP breakthrough to residual uncontrolled disease Scale and visibility of persistent non-responders in chronic migraine care 1.2. Refractory Chronic Migraine as a High-Burden, High-Value Sub-Population Persistent disability despite advanced pharmacologic management Clinical, economic, and system-level burden concentration in multi-failure patients 1.3. Escalation Dynamics Across Drugs, Non-Invasive Devices, and Implantable Interventions Stepwise progression in refractory chronic migraine management Severity, disability, and exhaustion thresholds driving interventional escalation Positioning of implantable neuromodulation within late-line care pathways 1.4. Global Market Size Snapshot and Growth Outlook (2025–2035) Size and durability of the post-CGRP failure population Revenue contribution by pharmacologic therapy, non-invasive neuromodulation, and implantable neuromodulation Structural sustainability of the opportunity over the forecast period 1.5. Strategic Implications for Implantable Neuromodulation Platforms Value capture beyond pharmacologic and non-invasive ceilings Role of implantable neuromodulation in refractory chronic migraine infrastructure Long-term relevance as disease complexity and treatment fatigue increase 2. MARKET DEFINITION & SEGMENTATION — A FAILURE-CENTRIC FRAMEWORK 2.1. Clinical Definitions in Advanced Migraine Care Resistant vs refractory chronic migraine in specialist practice Commercial relevance of refractory designation 2.2. Real-World Interpretation of CGRP Failure in Neurology Practice CGRP monoclonal antibody non-response and discontinuation Preventive gepant limitations in high-frequency chronic migraine Partial responders, treatment cycling, and therapy fatigue 2.3. Operational Definition Applied in This Analysis Minimum exposure and duration assumptions Headache-day thresholds and functional impairment criteria 2.4. Segmentation Framework for the Post-CGRP Failure Market By number of preventive therapy failures By type of CGRP exposure (mAb vs gepant) By Botox exposure and combination use By acute medication burden and MOH risk By escalation pathway (drug-only → non-invasive → implantable intervention) 2.5. Structural Persistence of the Post-CGRP Failure Market Biological, behavioral, and therapeutic constraints Ongoing progression toward interventional care in high-disability patients 3. EPIDEMIOLOGY & PATIENT FUNNEL — FROM PREVALENCE TO ESCALATION READINESS 3.1. Global Chronic Migraine Prevalence and Diagnosis Landscape Diagnosed vs undiagnosed populations Regional variability in access to advanced care 3.2. Treated Population and Preventive Therapy Penetration Traditional preventive use vs modern biologics CGRP positioning within chronic migraine algorithms 3.3. CGRP-Exposed Patient Pool Monoclonal antibody exposure Preventive gepant exposure Overlap, sequencing, and switching patterns 3.4. Post-CGRP Outcomes and Failure Drivers Non-response, partial response, and discontinuation dynamics Persistence of disability despite multiple therapeutic attempts 3.5. Size of the Post-CGRP Failure Population by Escalation Readiness Drug-refractory but non-invasive eligible Implantable-eligible high-disability subgroup Sensitivity ranges by definition stringency 3.6. Patient Funnel Evolution and Forward Trajectory (2025–2035) Impact of CGRP saturation on refractory pool size Stability of late-line, intervention-ready populations 4. CURRENT STANDARD OF CARE AFTER CGRP FAILURE 4.1. OnabotulinumtoxinA as the Backbone of Advanced Chronic Migraine Management Role in multi-failure patients Combination use with CGRP therapies Limitations in severe, long-standing disease 4.2. CGRP Monoclonal Antibodies in the Multi-Failure Setting In-class switching and recycling behavior Diminishing returns in refractory populations 4.3. Preventive Gepants in Advanced Chronic Migraine Adjunctive positioning Constraints in sustained disease control 4.4. Acute Therapy Dependence in Post-Preventive Failure Escalation patterns and loss of control Early indicators of medication overuse 4.5. Structural Gaps in Current Refractory Migraine Management Persistent functional impairment Cumulative drug burden without durable control Escalation dead-ends prior to interventional consideration 5. THE PHARMACOLOGIC CEILING IN REFRACTORY CHRONIC MIGRAINE 5.1. Limits of CGRP Pathway Modulation in High-Frequency Disease Central sensitization and non-CGRP mechanisms Plateau effects in advanced chronic migraine 5.2. Long-Term Constraints of Drug-Based Disease Control Injection fatigue, adherence erosion, and burnout Access, authorization, and persistence barriers 5.3. Diminishing Returns from Sequential Preventive Escalation CGRP cycling fatigue Gepants as partial rather than definitive solutions 5.4. Limitations of Late-Line Pharmacologic Escalation Neurologist perspectives in multi-failure patients Transition toward non-pharmacologic strategies 5.5. Interventional Escalation as a Structural Outcome of Refractory Chronic Migraine Pharmacologic saturation Non-invasive neuromodulation ceiling Implantable neuromodulation as late-line, high-impact intervention 6. MEDICATION OVERUSE HEADACHE (MOH) — A STRUCTURAL ESCALATION CONSTRAINT 6.1. MOH Prevalence and Burden in Post-CGRP Failure Patients Incidence and concentration within multi-failure chronic migraine Association with loss of long-term disease control 6.2. Acute Therapy Escalation Patterns After Preventive Saturation Triptans, NSAIDs, and combination analgesic utilization Gepant and ditan use in high-frequency populations 6.3. Pharmacologic Escalation Constraints in MOH-Prone Patients Cycles of acute dependence Clinical hesitation toward further medication intensification 6.4. Neuromodulation as a Drug-Sparing Modality Role in acute symptom control without medication escalation Alignment with MOH mitigation objectives 6.5. Health-System and Payer Implications of MOH Reduction Cost-of-care concentration in uncontrolled patients Emergency care utilization, repeat consultations, and productivity impact 7. NEUROMODULATION IN REFRACTORY CHRONIC MIGRAINE — MODALITY POSITIONING 7.1. Neuromodulation Modalities Across the Refractory Migraine Spectrum Non-invasive neuromodulation platforms Implantable neuromodulation approaches (occipital, trigeminal, multi-site) Acute, preventive, and hybrid therapeutic intent 7.2. Mechanistic Alignment of Neuromodulation with Refractory Disease Biology Complementarity to pharmacologic therapies Central pain modulation in high-frequency chronic migraine 7.3. Clinical Use-Case Coverage in Refractory Chronic Migraine Acute intervention Preventive support Combination use with Botox and CGRP-based therapies 7.4. Structural Fit of Neuromodulation in Multi-Failure Patients Drug fatigue and tolerance considerations Adherence, durability, and long-term safety profile 7.5. Disease-Severity Gradient and Neuromodulation Uptake Escalation patterns in high-disability patients Prescriber behavior in late-line settings 7.6. Non-Invasive vs Implantable Neuromodulation — Severity-Based Stratification Patient profiles appropriate for non-invasive use Transition thresholds toward implantable intervention Complementary, not competitive, modality roles 8. NEUROMODULATION LANDSCAPE — CATEGORY STRUCTURE AND ROLE DIFFERENTIATION 8.1. Non-Invasive Neuromodulation Landscape Prescription and non-prescription platforms Indication scope and chronic migraine applicability 8.2. Implantable Neuromodulation Platforms Therapeutic intent and patient selection logic Role in high-disability, late-line refractory populations 8.3. Operational and Care-Delivery Considerations Procedural intensity and center-of-excellence dependence Referral pathways and specialist concentration 8.4. Comparative Framework Across Neuromodulation Modalities Acute vs preventive applicability Chronic migraine eligibility Access pathways and reimbursement posture Durability of effect and real-world utilization 8.5. Strategic Role of Implantable Neuromodulation in Post-CGRP Failure Care Value concentration in the most refractory segments Positioning within long-term migraine management infrastructure 9. REAL-WORLD EVIDENCE, DIGITAL SIGNALS & LONG-TERM CONTROL 9.1. Evidence Generation Limitations in Advanced Chronic Migraine Under-representation of multi-failure patients in RCTs Disconnect between trial endpoints and real-world control 9.2. Real-World Evidence as the Dominant Decision Input Functional outcomes vs headache-day reduction Persistence, adherence, and discontinuation patterns Patient-reported outcome relevance 9.3. Digital Monitoring and Behavioral Reinforcement Role of digital interfaces in therapy adherence Feedback loops in chronic disease management 9.4. Digital Biomarkers in Refractory Migraine Attack frequency, severity, and temporal patterns Acute medication utilization signals Early indicators of MOH and loss of control 9.5. Strategic Implications for Neuromodulation Platforms Evidence requirements for access expansion Long-term value of longitudinal data capture 10. CLINICAL AND COMMERCIAL ALTERNATIVES TO NEUROMODULATION 10.1. In-Class CGRP Switching as a Default Late-Line Strategy Behavioral and systemic drivers Impact on treatment timelines and disease control 10.2. Pipeline Anticipation and Treatment Deferral PACAP-targeting therapies Opportunity cost of prolonged uncontrolled disease 10.3. Acute Therapy Escalation as a Competing Care Path Short-term symptom relief vs long-term deterioration Reinforcement of MOH risk 10.4. Escalation Delay and Therapeutic Inertia Inaction as an implicit competitor Deferred transition to interventional solutions Timing gaps before implantable consideration 10.5. Commercial Implications for Neuromodulation Platforms Entry points within real-world treatment pathways Importance of escalation timing over modality comparison Relevance of implantable solutions in late-line decision-making 11. PIPELINE INNOVATION TARGETING CGRP NON-RESPONDERS 11.1. PACAP-Targeting Therapies — The Leading Post-CGRP Drug Class Late-stage PACAP programs and clinical status Differentiation versus CGRP-pathway modulation Expected positioning within refractory migraine algorithms 11.2. Emerging Non-CGRP Pharmacologic Approaches Central sensitization and downstream pathway targets Development stage, scope, and anticipated clinical role 11.3. Impact of Pipeline Innovation on the Refractory Patient Pool Clinical, biological, and behavioral constraints on full disease control Persistence of multi-failure populations despite innovation 11.4. Drug Innovation and Interventional Demand Dynamics Interaction between novel drugs and combination therapy adoption Coexistence trajectories for drugs and neuromodulation through 2035 11.5. Strategic Implications for Implantable Neuromodulation Pipeline progress as a complement, not a substitute Reinforcement of late-line interventional relevance 12. MARKET SIZE & FORECAST — THE POST-CGRP FAILURE OPPORTUNITY 12.1. Market Modeling Framework Bottom-up patient funnel construction Eligibility, adoption, and persistence assumptions by escalation tier 12.2. Global Market Size and Growth Outlook (2025–2035) Total market value (USD) Growth trajectory and inflection points 12.3. Revenue Mix by Therapy Modality Pharmacologic therapies Non-invasive neuromodulation Implantable neuromodulation 12.4. Combination-Therapy Penetration Scenarios Conservative, base-case, and upside scenarios Sensitivity to CGRP and PACAP uptake 12.5. Neuromodulation Adoption Scenarios Share of refractory patients by modality Influence of reimbursement, access, and center-of-excellence concentration 12.6. Market Sustainability and Long-Term Value Distribution Durability of the implantable-eligible population Implications for long-horizon investment and platform strategy 13. NORTH AMERICA — CORE MARKET FOR POST-CGRP FAILURE INTERVENTION 13.1. Regional Treatment Landscape and Escalation Context CGRP saturation and biologic maturity Entrenched role of Botox in chronic migraine Acceptance of combination and interventional strategies 13.2. Post-CGRP Failure Patient Pool — North America Chronic migraine prevalence and treatment depth Size of CGRP-exposed and CGRP-failed populations Persistence of refractory burden despite innovation 13.3. Standard of Care Following CGRP Failure CGRP switching and recycling dynamics Botox and combination use patterns Preventive gepant utilization constraints 13.4. Neuromodulation Adoption Environment Prescriber readiness for interventional escalation Role in MOH-prone and high-disability patients Real-world utilization in refractory chronic migraine 13.5. Pricing, Reimbursement, and Access Landscape Private versus public payer dynamics Evidence thresholds for device reimbursement Role of longitudinal outcomes and real-world data 13.6. Market Size and Forecast — North America (2025–2035) Total post-CGRP failure market value Drug versus neuromodulation revenue mix Implantable neuromodulation penetration scenarios 13.7. Strategic Considerations for Implantable Neuromodulation Platforms North America as the primary value anchor Key growth enablers and structural constraints 14. EUROPE — GUIDELINE-DRIVEN CARE WITH PERSISTENT UNMET NEED 14.1. Regional Care Pathway Structure Step-therapy discipline and guideline adherence Cross-country variability in access and escalation 14.2. Post-CGRP Failure Patient Pool — Europe CGRP access heterogeneity Refractory burden persistence under conservative treatment paradigms 14.3. Standard of Care Following CGRP Failure Botox as a long-standing backbone CGRP monoclonal antibody utilization patterns Preventive gepant access constraints 14.4. Neuromodulation Landscape Physician perception of interventional therapies Country-level adoption variability Alignment with non-drug treatment philosophies 14.5. Reimbursement and Access Considerations HTA evidence expectations Role of national health systems Barriers to rapid interventional scale-up 14.6. Market Size and Forecast — Europe (2025–2035) Regional value contribution Drug versus neuromodulation mix evolution Adoption sensitivity by country cluster 14.7. Strategic Considerations for Implantable Neuromodulation Platforms Priority markets versus deferral markets Evidence-led access strategy signals 15. ASIA PACIFIC — LARGE POPULATION, SELECTIVE INTERVENTIONAL UPSIDE 15.1. Regional Migraine Management Landscape Diagnostic variability and access disparities Differences between developed and emerging APAC markets 15.2. Post-CGRP Failure Dynamics — Asia Pacific CGRP penetration gradients Refractory population emergence in developed APAC Under-treated chronic migraine burden 15.3. Standard of Care Following CGRP Failure Botox availability and utilization CGRP adoption in Japan, South Korea, and Australia Limited preventive gepant access outside select markets 15.4. Neuromodulation Adoption Potential Cultural acceptance of non-drug interventions Digital health readiness Reimbursement and scalability constraints 15.5. Market Size and Forecast — Asia Pacific (2025–2035) Developed versus emerging market split Concentration of neuromodulation upside Long-term growth drivers 15.6. Strategic Considerations for Implantable Neuromodulation Platforms Priority countries versus watchlist markets Role of center-led and evidence-first entry strategies 16. REST OF WORLD — LONG-TERM OPTIONALITY 16.1. Regional Overview and Structural Constraints Low diagnosis rates and limited access to advanced care Heavy reliance on acute pharmacologic management 16.2. Post-CGRP Failure Presence in ROW Small but emerging CGRP-exposed populations Refractory burden in select private and urban settings 16.3. Standard of Care Constraints Minimal preventive escalation High risk of acute medication overuse 16.4. Neuromodulation Relevance Niche applicability in private and tertiary centers Long-term potential rather than near-term scale 16.5. Market Size and Forecast — Rest of World (2025–2035) Modest contribution to global value Conservative growth assumptions 16.6. Strategic Role of ROW in a Global Implantable Neuromodulation Strategy Future expansion optionality Portfolio relevance outside the base-case horizon 17. PRICING, ACCESS & REIMBURSEMENT DYNAMICS 17.1. Cost-of-Care Profile in Refractory Chronic Migraine Cumulative cost concentration in multi-failure patients Preventive, acute, and combination-therapy cost stacking Economic burden associated with persistent disease activity 17.2. Payer Perspectives in the Post-CGRP Failure Segment Willingness-to-pay gradients in high-disability populations Preference for add-on versus replacement interventions Openness to non-pharmacologic and interventional solutions 17.3. Reimbursement Pathways for Neuromodulation Coverage status of prescription neuromodulation devices Private versus public payer dynamics Specialty pharmacy, DME, and procedural access channels 17.4. Evidence Requirements for Coverage Expansion Clinical and functional endpoints prioritized by payers Role of real-world evidence alongside randomized data Relevance of MOH reduction and acute medication sparing 17.5. Pricing Strategy Considerations for Implantable Neuromodulation Value-based positioning in late-line refractory care Framing against cost-of-failure rather than drug benchmarks Durability and long-term economic justification 18. PRESCRIBER AND CENTER-OF-EXCELLENCE LANDSCAPE 18.1. Prescriber Segmentation in Advanced Chronic Migraine Headache specialists General neurologists Limited primary care spill-over 18.2. Treatment Philosophy by Prescriber Segment Escalation behavior following CGRP failure Comfort with combination and interventional approaches Adoption thresholds for implantable solutions 18.3. Role of Tertiary Headache Centers Early adoption of interventional modalities Influence on treatment guidelines and community practice Centers as hubs for refractory care innovation 18.4. Centers of Excellence as Market Multipliers Referral concentration and patient funnel effects KOL-driven diffusion of advanced treatment paradigms Importance for longitudinal evidence generation 18.5. Commercial Implications for Implantable Neuromodulation Platforms Priority prescriber profiles Sequencing of engagement across care settings Center-led scale versus broad-based promotion 19. STRATEGIC IMPLICATIONS FOR IMPLANTABLE NEUROMODULATION PLATFORMS 19.1. Positioning Within the Post-CGRP Treatment Continuum Role in late-line escalation Integration with pharmacologic and non-invasive modalities Contribution to durable disease control 19.2. Priority Patient Segments High-disability, multi-failure chronic migraine patients MOH-prone populations Drug-intolerant or treatment-fatigued patients 19.3. Competitive Context and Pipeline Interaction Interaction with PACAP and other post-CGRP drug innovations Coexistence versus displacement dynamics Strategic insulation from pharmacologic cycle risk 19.4. Geographic Prioritization Framework Core value markets versus long-horizon expansion markets Evidence-first versus commercialization-first sequencing 19.5. Long-Term Role of Implantable Neuromodulation in Migraine Care Transition from adjunctive therapy to care infrastructure Increasing relevance as disease complexity accumulates 19.6. Strategic Roadmap Considerations Evidence-generation priorities Market-access sequencing Platform expansion and indication adjacency 20. APPENDICES 20.1. Research Methodology Secondary and primary research inputs Clinical, commercial, and epidemiologic triangulation 20.2. Market Modeling Assumptions Patient funnel construction Adoption, persistence, and pricing logic Scenario definitions 20.3. Data Sources Clinical guidelines and consensus statements Regulatory and trial databases Real-world evidence publications 20.4. Definitions and Abbreviations Clinical terminology Commercial and modeling terms 20.5. Scope Limitations and Interpretation Notes