CGRP Antagonism and MOH Withdrawal

Medication-overuse headache (MOH) is a secondary headache associated with regular overuse of acute headache medication in people with a pre-existing primary headache; management has traditionally emphasized education, reduction or withdrawal of overused medication, and preventive treatment. The therapeutic landscape changed as calcitonin gene-related peptide (CGRP) emerged as a migraine-specific target within the trigeminal pain system, leading first to small-molecule CGRP receptor antagonists and then to monoclonal antibodies directed against CGRP or its receptor. CGRP-targeted monoclonal antibodies subsequently became established preventive treatments for chronic migraine, including populations with medication overuse or MOH, creating a clinically important question: whether effective CGRP antagonism can reduce medication overuse and induce MOH remission without requiring withdrawal as an obligatory first step. This question has attracted substantial clinical interest because withdrawal can be difficult, while uncontrolled migraine itself can sustain frequent acute-medication use. CGRP antagonism acts directly on a pathway central to migraine biology. CGRP is a trigeminal sensory neuropeptide, and therapies that block CGRP signaling were specifically developed to act on the trigeminal pain system^[1][2][3].

Fremanezumab, galcanezumab, and eptinezumab target the CGRP ligand, whereas erenumab targets the CGRP receptor; small-molecule gepants also antagonize the CGRP receptor. Clinical evidence connects this mechanism to reduced headache burden and medication use. In a randomized phase 4 trial of adults with chronic migraine and nonopioid MOH, erenumab 140 mg produced MOH remission in 69.1% at month 6 versus 52.6% with placebo and reduced monthly acute headache medication days by 9.4 days from baseline. Fremanezumab similarly reduced headache days in Japanese chronic migraine patients with medication overuse, while 46.3% receiving monthly treatment and 44.4% receiving quarterly treatment reverted from medication overuse to no overuse, compared with 29.7% receiving placebo. Galcanezumab phase 3 subgroup analyses also showed reductions in migraine headache days and medication-overuse rates among patients overusing acute medication at baseline^{[2][3][4][5][6]}.

These findings position CGRP antagonism as a preventive strategy that can simultaneously suppress migraine burden and facilitate transition away from medication overuse. Current MOH guidance supports patient education and migraine prophylaxis, identifies CGRP or CGRP-receptor monoclonal antibodies as effective in chronic migraine with medication overuse, and reserves medication pauses for patients in whom education and prophylaxis are insufficient; opioid overuse remains a setting in which inpatient withdrawal is recommended. A network meta-analysis of 28 randomized trials further found beneficial responder effects for fremanezumab and galcanezumab and improvement in reversion to non-overuse with eptinezumab and fremanezumab. Important uncertainties nevertheless remain: available studies differ in MO versus formal MOH populations, post-hoc subgroup analyses were not necessarily designed or powered for these subgroups, and trials commonly excluded or restricted opioid and barbiturate use. Direct comparative studies are still needed, particularly to establish whether structured withdrawal adds benefit to CGRP-targeted prevention and to define which patients can safely transition from mandatory detoxification toward preventive-first management.^{[1][3][4][5][6][7]}.