In this discussion, Matija Sošić, PhD, MD, a neurologist and headache specialist at Juraj Dobrila University of Pula in Croatia, explores medication overuse in headache care. Here, he highlights the pathophysiology of medication overuse in headache, the rationale for combining structured deprescribing with anti-calcitonin gene-related peptide preventive (anti-CGRP) therapy, broader insights into the role of CGRP signaling across headache medicine, and more.
Neuro Therapy Today: Please introduce yourself to our audience by including your name, title, and affiliation as well as your role in the study.
Dr. Sošić: My name is Matija Sošić, PhD, MD, a neurologist and headache specialist. I am affiliated with the Special Hospital for Orthopedics and Rehabilitation “Martin Horvat” in Rovinj-Rovigno–Headache Clinic and the Faculty of Medicine at Juraj Dobrila University of Pula in Croatia. For this study, I am the corresponding author. I am responsible for conceptualizing the project, designing the methodology, collecting the clinical data, writing and supervising the analysis, and writing together with my coauthors Valentino Rački, Almir Fajkić, Mladen Jašić, and Andrej Belančić.
Neuro Therapy Today: Your paper challenges the traditional view of medication-overuse headache (MOH) as primarily a consequence of excessive acute medication use, instead highlighting the roles of central sensitization, maladaptive neuroplasticity, and CGRP signaling. What do you hope clinicians take away from this evolving understanding of MOH pathophysiology?
Dr. Sošić: For a long time, medication-overuse headache has been framed almost as a self-inflicted problem, where a patient takes too many painkillers or triptans, and the headache worsens as a result. This paper highlights that this view is incomplete. Repeated exposure to acute headache medications appears to reshape how the nervous system processes pain actively. It lowers nociceptive thresholds, weakens the brain’s own descending pain-inhibitory pathways, activates glial cells and low-grade neuroinflammation, and upregulates CGRP signaling within the trigeminovascular system. In other words, MOH looks less like a behavioral side effect and more like a biologically driven, partly pharmacologically induced disorder. What I hope clinicians take from this is a shift in mindset: rather than treating medication overuse purely as something to correct through restriction or willpower, we should recognize that these patients have measurable, partly reversible changes in central pain processing that need direct attention. That reframing has real clinical consequences. It explains why simply stopping the overused medication so often fails to bring lasting relief, especially in patients with long-standing chronic migraine, and it argues for treating these patients with the same mechanism-based approach we would use for any other neurobiological pain condition, rather than viewing withdrawal as a purely disciplinary measure.
Neuro Therapy Today: A central theme of your study is that withdrawal of overused medications may not fully address the biological mechanisms underlying migraine chronification. What was the rationale for combining structured deprescribing with anti-CGRP preventive therapy, and how do you believe these strategies complement one another in clinical practice?
Dr. Sošić: Our rationale was fairly straightforward once you accept that MOH has two components that don’t necessarily resolve together. Deprescribing removes the external driver, the repeated pharmacological exposure that keeps reinforcing sensitization, but on its own it does nothing to correct the neuroplastic and CGRP-mediated changes that have already taken hold, particularly in patients with a long history of overuse. Anti-CGRP therapies, by contrast, act directly on that biology: they target the CGRP pathway that drives trigeminovascular activation and central sensitization, and, importantly, they do not engage central reward pathways or reinforce medication-seeking behavior the way some acute treatments can. In practice, the two strategies cover each other’s blind spots. Deprescribing removes the trigger, while anti-CGRP therapy stabilizes the underlying migraine biology and, in our experience, makes the withdrawal period considerably more tolerable by reducing the exacerbation and rebound headache that so often derail withdrawal attempts when they are done in isolation. We see it less as choosing between the two approaches and more as using each to support the other.
Neuro Therapy Today: In your single-center cohort, most patients achieved clinically meaningful reductions in monthly headache days, with nearly 80% experiencing greater than a 75% reduction after 12 months. Which findings were most notable to you, and how might they influence the management of patients with chronic migraine and MOH?
Dr. Sošić: A few findings stood out to us. The first is simply the scale and trajectory of improvement: by six months, 85% of our patients had already reached at least a 50% reduction in monthly headache days, and by twelve months, nearly 80% had reached a reduction of more than 75%, while almost no one remained below that 50% threshold. That trajectory- continued improvement between six and twelve months rather than a plateau- suggests that sustained CGRP blockade may progressively reverse some of the sensitization mechanisms we discussed earlier, and it is a strong argument for giving this combined approach enough time before judging whether it has worked. The second finding that stood out was that patients who had been overusing combination analgesics containing paracetamol, propyphenazone, caffeine, and codeine tended to respond more slowly than those overusing triptans or simple analgesics.
For clinical practice, I think this means two things: first, that twelve months, not three or six, may be the more meaningful checkpoint for judging treatment success in this population, and second, that clinicians should set realistic expectations with patients who have a long history of overusing combination or opioid-containing analgesics, since their path to improvement may take longer without that necessarily meaning the treatment has failed.
Neuro Therapy Today: Your findings add to a growing body of evidence supporting therapies that target the CGRP pathway. How do these results contribute to our understanding of where injectable CGRP-targeting therapies fit within the treatment paradigm for patients with chronic migraine, particularly those with medication overuse?
Dr. Sošić: I think these results reinforce something the field has been moving toward for a while now, which is that anti-CGRP monoclonal antibodies are not just one more option on a long list of preventive medications for chronic migraine with medication overuse, but that they address a pathway that appears to be central to how the disorder is sustained in the first place. That has practical implications for where they sit in the treatment sequence. In many healthcare systems, patients are still required to fail several conventional oral preventives before they can access anti-CGRP therapy, largely for administrative or cost reasons rather than because the underlying biology supports waiting.
Our findings, together with the broader evidence base, support moving these therapies earlier in the treatment pathway for patients with chronic migraine and medication overuse, rather than reserving them as a last resort. A small number of European countries, including Croatia, already allow first-line reimbursement for anti-CGRP monoclonal antibodies based on disease burden rather than prior treatment failures, and our data support extending that kind of access more broadly, particularly for patients whose migraine has already been complicated by medication overuse.
Neuro Therapy Today: Although this study focused on migraine-associated MOH, CGRP-targeting therapies have also expanded treatment options in other headache disorders, including episodic cluster headache. Do the mechanisms discussed in your paper provide broader insights into the role of CGRP signaling across headache medicine, and what lessons might clinicians draw from that overlap?
Dr. Sošić: Our paper focuses on migraine-associated MOH, but CGRP itself is not migraine-specific. It is a shared mediator of trigeminal activation across several primary headache disorders, including cluster headache, where anti-CGRP therapies have already shown efficacy in the episodic form. The broader lesson I would draw is that it may be more useful to think about chronic or frequent headache less in terms of a fixed diagnostic label and more in terms of which biological pathway drives symptom persistence in a given patient. CGRP happens to be one of the most well-validated and pharmacologically tractable of those pathways, which is part of why these therapies have expanded so quickly into other headache disorders beyond migraine.
That said, I urge some caution about extrapolating too far. The evidence base for anti-CGRP therapy is far more mature in migraine than in cluster headache or other headache types, and the specific questions we raise in this paper around deprescribing, medication overuse, and treatment sequencing were studied specifically in a migraine population. Whether the same logic applies in the same way to other headache disorders deserves its own dedicated research rather than assumption.
Neuro Therapy Today: Some emerging studies have questioned whether formal detoxification is always necessary when initiating anti-CGRP therapy. Based on the available evidence and your own findings, what are the most important questions future research should address regarding treatment sequencing, deprescribing strategies, and long-term outcomes?
Dr. Sošić: This is one of the more actively debated questions in the field right now, and our own data speak to it only indirectly, since we studied a combined approach rather than directly comparing detoxification against no detoxification. Other real-world evidence, including a cohort of two hundred patients reported by Silvestro and colleagues, found that structured detoxification did not add measurable benefit over preventive therapy alone. Our own patients showed substantial and progressive improvement using deprescribing combined with anti-CGRP therapy, which tells me that a combined approach remains a reasonable and effective strategy, without necessarily proving that formal withdrawal is required for everyone.
Looking ahead, the field needs a few things. First, we need randomized trials that directly compare immediate initiation of anti-CGRP therapy without withdrawal, combined deprescribing plus anti-CGRP therapy, and detoxification followed by preventive therapy so that we can move beyond observational comparisons. Second, we need to identify which patients still benefit most from structured withdrawal; our own data hint that people who have long overused combination analgesics containing agents such as caffeine and codeine respond more slowly, and they may be a subgroup where a more structured approach still has real value. Third, we need longer follow-up than most current studies provide to understand relapse rates, the durability of MOH reversion, and whether preventive therapy can eventually be tapered once the underlying sensitization has resolved. And finally, we should reconsider some of our language in this space. Terms like “detoxification” carry a stigmatizing connotation that may not reflect what we now understand to be a biologically driven, treatable condition. That framing is itself worth revisiting as the evidence evolves.