The phenomenon of offset analgesia (OA) refers to a disproportionately large decrease in perceived pain following a slight reduction in the intensity of a noxious heat stimulus. This phenomenon is considered as an indicator of the activation of the endogenous pain modulation system, whose dysfunction is implicated in the pathophysiology of migraine and other chronic pain conditions. This study aims to investigate pain processing mechanisms using the OA paradigm in individuals with episodic migraine (EM) during different phases of the migraine cycle and in those with chronic migraine (CM), with and without medication overuse headache (CMwoMOH and CM-MOH, respectively). A population of healthy subjects matched by sex and age will also be enrolled

Migraine is a cyclic disorder marked by varying activity in different brain regions. It is generally believed that migraine involves a pronociceptive pain modulation pattern, likely due to impaired endogenous pain inhibitory systems. However, there are few studies in this respect, and different experimental approaches have produced mixed results, showing both normal and abnormal pain responses in migraine. Most research has focused only on episodic migraine (EM) during headache-free periods, leaving the role of pain modulation dysfunction in recurring migraines and the progression to chronic migraine unexplored. Conditioned Pain Modulation (CPM) tests, which measure the "pain inhibits pain" effect, are commonly used to assess inhibitory pain modulation. Studies comparing CPM responses in migraine sufferers and healthy individuals have yielded inconsistent findings, with some showing reduced inhibitory responses in migraineurs, while others found no difference. Offset Analgesia (OA) is another method used to study descending pain modulation systems in chronic pain conditions. Unlike CPM, OA examines temporal filtering of pain when dynamic noxious stimuli are applied and is characterized by a large reduction in pain sensation after a small decrease in a heat stimulus. Research indicates that central mechanisms, including the activation of descending pain modulatory and reward systems, play a significant role in OA. Only one study has explored the OA response in episodic migraine patients during headache-free intervals, finding no inhibitory pain modulation in the trigeminal area. This study aims to: 1) assess changes in pain modulation across the migraine cycle in EM patients, and 2) determine if different dysfunctional pain modulation patterns are present in chronic migraine, both with and without medication-overuse headache (CMwoMOH and CM-MOH).

Subjects and methods. The investigators will enroll 30 subjects with EM, 30 patients with CM (with and without MOH), and 30 healthy control subjects. Patients with EM during the preictal, ictal, and postictal phases will be also enrolled. All participants underwent an experimental paradigm consisting of three stimulus offset trials (OT) and three constant temperature trials (CT) applied to the forehead based on the individual heat pain threshold (HPT). All tests will be carried out by using a Q-sense CPM device (Medoc) and computerized visual analogue scale (CoVAS).

Experimental paradigms. All subjects will be assessed in a single experimental session. After obtaining written consent, participants will complete various questionnaires. The Heat Pain Threshold (HPT) will be then measured on the forehead (1st branch of the trigeminal nerve, V1), followed by three constant trials (CT) and three offset-analgesia trials (OT) in the same area. The following questionnaires will be administered: 12-item Allodynia Symptom Checklist (ASC-12), Migraine Disability Assessment (MIDAS), and Hospital Anxiety and Depression Scale (HADS).

Inclusion Criteria:

• patients affected by episodic or chronic migraine according to the International Headache Society (IHS) Classification (3rd edition), aged 18 to 70 years

Exclusion Criteria:

• any other headache diagnosis according to the IHS classification
• other acute or chronic pain conditions
• serious internal, psychiatric, or neurological systemic diseases
• pregnancy, breastfeeding, skin pathologies in the tested trigeminal nerve area (V1)
• poor sleep quality the night before testing
• alcohol consumption or intense exercise within 24 hours prior to examination
• women were not assessed during their menstrual cycle.
• Use of migraine prophylactic medication for patients with EM.