The study, led by Matija Sošić and colleagues across institutions in Croatia, Bosnia and Herzegovina, and Italy-linked collaborations, examined 47 patients with chronic migraine and MOH treated at a tertiary headache clinic. The patients received both a structured deprescribing program, in which overused acute medications were stopped or restricted according to national expert recommendations, and preventive therapy with monoclonal antibodies targeting CGRP or its receptor. The results were striking. At six months, 85.1 percent of patients had achieved at least a 50 percent reduction in monthly migraine days. By twelve months, 78.7 percent had achieved a reduction of more than 75 percent, meaning nearly four out of five patients saw their migraine burden collapse to a fraction of what it had been when treatment began.

What makes these numbers remarkable is not just their magnitude but their trajectory. The proportion of patients achieving the deepest improvement, a reduction of more than 75 percent, rose from 19.1 percent at six months to 78.7 percent at twelve months, suggesting that the combined strategy does not merely stabilize patients but progressively dismantles the sensitized pain circuitry that had built up over years. Only one patient in the entire cohort remained in the lowest improvement category at the twelve-month mark. The authors analyzed changes across the three time points using the Friedman test and found a clear, statistically supported decline in monthly headache days from baseline through both follow-up intervals.

To understand why this combination works, it helps to look at what MOH actually is at the biological level. The traditional view framed it as a behavioral problem, essentially a consequence of taking too many pills. Contemporary neuroscience tells a very different story. Sustained exposure to acute headache medications, whether triptans, opioids, nonsteroidal anti-inflammatory drugs, or combination analgesics, induces maladaptive neuroplastic changes in the central nervous system. Repeated pharmacological exposure lowers nociceptive thresholds, facilitates central sensitization, and weakens descending inhibitory pain control, the system that normally keeps pain in check. Experimental models show that chronic exposure to acute migraine medications increases cortical excitability and susceptibility to cortical spreading depolarization while simultaneously upregulating CGRP and other neuropeptides within the trigeminovascular system.

CGRP sits at the center of this story for good reason. It is a key mediator of trigeminovascular activation, peripheral and central sensitization, and neurogenic inflammation, all processes that are amplified by repeated acute medication exposure. When a person with migraine overuses painkillers, the CGRP pathway becomes progressively more dysregulated, creating a feedback loop in which the medications that were meant to abort attacks end up reinforcing the very pronociceptive signaling that drives chronification. This is why withdrawal alone, while removing an important trigger, often fails to fully resolve the problem. The sensitized biology persists, and without a targeted intervention to quiet it, relapse is common.

This is where anti-CGRP therapies enter the picture with a distinct pharmacological advantage. Monoclonal antibodies targeting CGRP or its receptor, including erenumab, galcanezumab, fremanezumab, and eptinezumab, along with oral gepants such as atogepant and rimegepant, offer high target specificity, minimal interaction with hepatic medication-metabolizing enzymes, and stable pharmacokinetics that allow predictable exposure with infrequent dosing. Crucially, they do not engage central reward pathways or reinforce medication-seeking behavior, making them particularly suitable for patients with medication overuse. Unlike opioids or barbiturates, which can perpetuate the cycle of dependence and sensitization, anti-CGRP agents modulate the molecular pathways central to migraine pathophysiology without adding another layer of pharmacological reinforcement.

The clinical evidence supporting this approach has been building steadily. Systematic reviews and meta-analyses demonstrate that anti-CGRP monoclonal antibodies significantly reduce monthly migraine days, improve responder rates, and facilitate reversion from MOH to non-MOH status in patients with chronic migraine. Network meta-analytic evidence further indicates that combination strategies incorporating preventive therapy alongside medication restriction are superior to withdrawal alone in reducing headache burden and preventing relapse. Yet a recent real-world study of 200 patients by Silvestro and colleagues has challenged whether structured detoxification is even necessary when starting anti-CGRP therapy, finding no additional clinical benefit compared with preventive therapy alone. The authors of the new perspective acknowledge this debate, noting that while some cohorts show improvement without mandatory withdrawal, their own data suggest that combining deprescribing with targeted preventive therapy may offer particularly robust long-term outcomes in carefully managed clinical settings.

One intriguing observation from the single-center experience was that patients with long-standing overuse of combination analgesics tended to respond more slowly to treatment. Nearly half of the cohort, 49 percent, overused an over-the-counter combination analgesic containing paracetamol, propyphenazone, caffeine, and codeine, while 32 percent overused triptans and 19 percent overused paracetamol, ibuprofen, or a tramadol-paracetamol combination. The authors suggest that the complexity of combination analgesic overuse, which involves multiple pharmacological mechanisms acting simultaneously, may create deeper and more entrenched sensitization that takes longer to reverse. This finding carries practical implications for clinicians, who may need to counsel patients with complex medication overuse that meaningful improvement may take longer than the standard six-month assessment window.

Beyond the clinical data, the perspective raises important questions about access and reimbursement. Although evidence-based guidelines assign strong recommendations to multiple anti-CGRP agents in both episodic and chronic migraine, many healthcare systems still require patients to fail several conventional oral preventives before gaining access to anti-CGRP therapy. Such step-therapy requirements are driven largely by economic and administrative considerations rather than pathophysiological rationale. Only a limited number of European countries, including Croatia, Iceland, Lithuania, and Luxembourg, currently provide reimbursement for anti-CGRP monoclonal antibodies as a first-line preventive option. The authors argue that delayed access may inadvertently prolong exposure to overused acute medications, sustain central sensitization, and undermine deprescribing efforts, highlighting a disconnect between reimbursement frameworks and the underlying biology of the disorder.

The broader significance of this work lies in its reframing of MOH as a pharmacologically modifiable disorder rather than a purely behavioral one. Neuroimaging studies have shown partial normalization of abnormal metabolic activity following successful medication withdrawal, confirming that the neuroplastic changes are at least partly reversible. However, reversibility is often incomplete in patients with long-standing chronic migraine, underscoring the need for adjunctive preventive strategies that target persistent sensitization biology. By integrating mechanism-based preventive therapy with structured deprescribing, clinicians may be able to address both the medication-related drivers and the entrenched migraine pathophysiology simultaneously, potentially shortening disease duration, reducing relapse risk, and limiting further chronification. While randomized studies directly comparing detoxification strategies with immediate initiation of CGRP-targeted therapy remain limited, the substantial and progressive improvements observed in this real-world cohort suggest that the combined approach deserves serious consideration as a treatment paradigm for one of the most challenging complications of migraine.

Subject of Research: neuroscience

Article Title: Deprescribing and Anti-CGRP preventive therapy in medication-overuse headache associated with migraine: pathophysiological rationale and single-center real world evidence

Article References: Sošić, M., Rački, V., Fajkić, A., Jašić, M., & Belančić, A. (2026). Deprescribing and Anti-CGRP preventive therapy in medication-overuse headache associated with migraine: pathophysiological rationale and single-center real world evidence. Frontiers in Drug Safety and Regulation, 6, Article 1836444. https://doi.org/10.3389/fdsfr.2026.1836444

Image Credits: AI Generated

DOI: 10.3389/fdsfr.2026.1836444

Keywords: migraine, medication-overuse headache, CGRP, deprescribing, neuroplasticity, preventive therapy, monoclonal antibodies, headache, Anti-CGRP, preventive, therapy, medication-overuse