2025 Highlights in medication overuse and medication overuse headache

The recent update of the Global Burden of Disease study on headache disorders (1) demonstrated that more than 20% of the headache-attributed burden could be mitigated or completely avoided if people with migraine and tension-type headache did not overuse medication. Medication overuse headache (MOH) is a condition associated with medication overuse, and in individual patients frequent intake of acute medication may reflect a deterioration of migraine rather than the cause, or conversely, may itself contribute to worsening headache. This underscores the need to raise awareness, among both people with headache and health-care providers, about the risks associated with the overuse of acute medication and the different implications.

However, awareness needs to be supported by novel insights into the pathophysiology, treatment, and overall management of MOH, which remains understudied despite its impact and is often undermined by stigma.

In the last years, research has moved forward our knowledge of MOH. In 2025, a new series of studies published in Cephalalgia significantly contributed to show that MOH encompasses a greater complexity than previously recognized. Clinical, neurofunctional, and genetic studies characterize MOH as a multidimensional, neurological biobehavioral disease, finally reconsidering traditional assumptions about treatment and management.

The withdrawal of acute medication is considered the cornerstone of MOH management, sometimes supported by steroids or antiemetics. Historically, it was viewed as a necessary step to revert MOH (2,3). However, real-world evidence suggests that this paradigm may no longer completely apply in the era of CGRP-targeted therapies, if available (4). In a recent study including 200 patients with chronic migraine (CM) and MOH (4), participants were stratified into simple and complex MOH, the latter defined by psychiatric comorbidities, prior relapse, or near-daily intake of multiple acute medications. Regardless of whether acute medication withdrawal was undertaken, treatment with CGRP-targeting monoclonal antibodies (erenumab, fremanezumab, or galcanezumab) had similar and substantial reductions in headache frequency, intensity and duration, as well as acute medication use. The absence of an added benefit from withdrawal was consistent even in complex MOH (4). These results align with the only randomized clinical trial conducted to date, which demonstrated that monthly erenumab (140 mg) was effective in inducing MOH remission in adults with CM and non-opioid MOH without the use of any withdrawal strategies (5).

This shift toward a model in which acute withdrawal may no longer be required, could have an impact beyond therapeutic implications. Withdrawal, so often miscalled detoxification, carried undertones associated with dependency or addiction, perpetuating stigma (6). Recognizing MOH as a complex neurological, biobehavioral condition rather than a reward-seeking disorder may help transform both clinical practice and patient perceptions toward a more scientifically grounded and patient-centered approach. In line with this, terminology should evolve according to emerging evidence. In the future, the term “withdrawal” would be appropriate for patients overusing opioids or barbiturates, whereas “pausing medication” should be used for those overusing simple analgesics or triptans. These changes would allow more precise and clinically accurate definitions.

The biobehavioral nature of MOH also highlights the relevance of non-pharmacological interventions. Mindfulness-based strategies have shown particular promise. A study involving six weekly 90-min mindfulness sessions emphasizing meditation practice and the development of awareness and acceptance (7). This intervention is thought to influence functional connectivity within key central neural circuits. In a randomized clinical trial of 34 patients with CM and MOH, participants received either treatment as usual with or without mindfulness training. All subjects underwent functional imaging at baseline and after one year. Mindfulness training induced enhanced serotonin-enriched connectivity in the caudate and nucleus accumbens and increased dopamine-enriched connectivity in the right insula, all regions associated with affect regulation, reward processing, cognitive pain control, and pain modulation. These findings suggest that mindfulness may modulate neurochemical networks implicated in pain regulation and medication use (7). By restoring serotonergic and dopaminergic balance, mindfulness may help weaken the learned association between pain expectation and medication intake, a neural correlate of the “pain-pill cycle”. Integrating such non-pharmacological approaches may therefore offer complementary pathways for MOH management and, indirectly, understanding its pathophysiology.

The endocannabinoid system (ECS) represents another potentially important component in MOH. Widely distributed throughout the body, the ECS plays a key role in endogenous pain modulation. A cross-sectional study analyzed ECS-related gene expression with a focus on fatty acid amide hydrolase (FAAH), the enzyme responsible for degrading anandamide, a principal endogenous cannabinoid. Reduced FAAH activity correlates with elevated anandamide concentrations, potentially enhancing pain inhibition and emotional regulation through cannabinoid receptor activation. In this study (8), patients with MOH demonstrated higher FAAH protein levels than those with episodic migraine, while FAAH gene expression was significantly lower. This inverse pattern suggests possible compensatory mechanisms or dysregulation within the ECS and indicates that chronic medication exposure may trigger molecular adaptations affecting endocannabinoid balance. FAAH gene expression also showed a strong negative correlation with psychiatric comorbidity scores and disability reinforcing the view of MOH as a biobehavioral disorder integrating neurochemical and psychological dimensions (8).

Another long-standing question in headache medicine concerns whether MOH is exclusive to migraine and tension type headache (TTH) or can develop on other pre-existent primary headache disorders. On one hand, evidence from the SPARTACUS study (9), involving more than 16,500 individuals (8), showed that all 239 identified patients with medication overuse had migraine or migraine-related headache phenotypes, suggesting a strong link between migraine biology and susceptibility to medication overuse (9). On the other hand, Lund et al. conducted the largest study to date evaluating whether cluster headache (CH) can co-occur with MOH (10). Among 433 CH patients, approximately 16% met criteria for probable MOH, and notably, 60% of these individuals did not have coexisting migraine. Although causality cannot be inferred from the cross-sectional design, CH patients with probable MOH exhibited poorer responses to both acute and preventive therapies, paralleling patterns observed in MOH (10). These findings raise important questions on the nature of MOH itself and longitudinal studies are necessary to clarify the causal relationship between CH and MOH development. Moreover, it remains uncertain whether current ICHD-3 diagnostic criteria adequately capture MOH in non-migraine disorders, a topic likely to influence discussions during the forthcoming ICHD-4 revision.

MOH and medication overuse are global problems, not restricted to high-income countries, and novel anti-CGRP drugs are not globally available, raising concerns about shared treatments consensus. Continued research will be essential to further refine MOH conceptualization, diagnostic framework, pathophysiology, and management across the full spectrum of headache disorders and guarantee equal recognition and treatment worldwide.