: The primary objective of this prospective, randomized, double-blind, placebo-controlled clinical trial is to evaluate whether repetitive bilateral greater occipital nerve (GON) blockade administered with a local anesthetic (0.5% bupivacaine) significantly reduces headache severity, attack duration, and the number of pain days in female patients with menstrual migraine compared to a placebo group (normal saline). Patients will receive injections twice a month for three months (seven days before the expected onset of menstruation and on the first day of menstruation).

Menstrual migraine (MM) is a highly prevalent and challenging migraine subtype triggered by fluctuations in estrogen and progesterone levels, particularly estrogen withdrawal during the perimenstrual period

• This hormonal withdrawal sensitizes the trigeminovascular system and promotes the release of neuropeptides such as calcitonin gene-related peptide (CGRP)
• Currently, there are no licensed prophylactic medications specifically developed for MM, making alternative and non-systemic treatments necessary

This study investigates the efficacy of a targeted peripheral neuromodulation approach using bilateral greater occipital nerve (GON) blockade. The underlying clinical rationale is that GON blockade timed to the perimenstrual period can modulate nociceptive transmission at the trigeminocervical complex (TCC) and decrease peripheral nerve excitability, thereby limiting the impact of cyclic hormonal fluctuations on the trigeminovascular system

. In this trial, a Latin square experimental design is utilized to ensure balanced randomization between the active treatment and placebo groups

• Unlike single-injection protocols, the intervention is specifically synchronized with the patients' menstrual cycles, involving injections twice a month over a three-month period (seven days before menstruation and on the first day of menstruation)
• By evaluating this specific timing and repetitive protocol, the study aims to establish whether perimenstrual-targeted GON blockade can serve as an effective, non-systemic, short-term prophylactic strategy for patients suffering from this refractory migraine subtype.

Inclusion Criteria:

• Diagnosed with pure menstrual migraine or menstrually related migraine according to the International Classification of Headache Disorders, 3rd edition (ICHD-3) diagnostic criteria.
• A documented history of migraine attacks during the perimenstrual period (between days -2 and +3 relative to the onset of menstruation) in at least two of the last three menstrual cycles.

Exclusion Criteria:

• Diagnosis of chronic migraine.
• Presence of an additional primary or secondary headache disorder.
• Pregnant or lactating.
• Known hypersensitivity to local anesthetics.
• Received an occipital nerve blockade within the last three months.
• Presence of a significant neurological or systemic disease that could affect the outcome evaluation.

The data supporting the findings of this study is available from the corresponding author upon reasonable request.

Data will become available immediately following the publication of the study results and will remain accessible indefinitely.

De-identified individual participant data that underlie the results reported in this article will be shared. Data will be available to researchers who provide a methodologically sound proposal to achieve aims in the approved proposal. Requests should be directed to the corresponding author via email. Access may require signing a data access agreement.

The treatment allocation was known only to the investigational pharmacist and the study coordinator; the patients, administering physicians, and outcome assessors were kept blind throughout the study.