Keywords
Headache - Headache Disorders, Secondary - Migraine Disorders - Tension-Type Headache
- Therapeutics - Analgesics
INTRODUCTION
Concomitant medication overuse (MO) and medication overuse headache (MOH) classically
represent a significant challenge in migraine treatment. The management of these patients
has traditionally centered on discontinuation of overused medications concurrent with
initiating preventive therapy. However, the advent of calcitonin gene-related peptide
monoclonal antibodies (CGRP mAbs) has challenged this established paradigm. In recent
years, a growing body of evidence suggests that these innovative therapeutics can
effectively treat migraine prophylaxis without requiring prior analgesic discontinuation,
representing a significant shift in our approach and management. This sems to be a
pharmacological class effect as randomized clinical trials (RCTs) and real-world studies
demonstrated similar efficacy and tolerability of all these new medicines in chronic
(CM) and episodic migraine (EM), regardless of medication overuse (MO) and various
previous treatment failures.[1]
CLINICAL EFFICACY WITHOUT PRIOR DETOXIFICATION
CLINICAL EFFICACY WITHOUT PRIOR DETOXIFICATION
Supporting this approach, Pensato et al. conducted a comparative study to examine,
specifically, outcomes between patients who underwent detoxification and those who
did not before starting CGRP mAb therapy. Prospectively, they used data from 401 patients
with chronic migraine and MOHs who had utilized at least 28 days of analgesics monthly,
followed for 3 months. Their results revealed equivalent efficacy between groups,
providing strong evidence that prior detoxification is not essential for treatment
success.[2]
A multicenter study further validated this approach, showing significant improvements
in chronic migraine with MOH through CGRP mAb therapy, regardless of prior detoxification
status.[3] Over a 3-month follow-up period, patients exhibited a significantly greater reduction
in the number of headache days as well as in symptomatic medication intake compared
with the control group (p < 0.0001). Their findings suggest that the traditional emphasis on medication withdrawal
may be unnecessarily burdensome for patients.
REAL-WORLD EVIDENCE
An innovative real-world analysis by Scheffler et al. demonstrated remarkable success
rates in MOH resolution without mandatory detoxification. While this study was retrospective
and single-center, it found that 60.6 to 89% of patients successfully transitioned
from MOH to non-MOH status through CGRP mAb treatment alone.[4] This finding directly challenges the traditional requirement for medication withdrawal
before preventive treatment initiation.
In 2021, Caronna et al. provided additional real-world evidence through their 6-month
effectiveness study, demonstrating comparable improvement rates between medication-overuse
and non-overuse populations.[5] This was a prospective study conducted in chronic migraine patients with and without
medication overuse treated with monthly MAbs (erenumab/galcanezumab). This research
showed that patients naturally reduced their acute medication use as their migraine
frequency decreased under CGRP mAb therapy without requiring forced discontinuation.
EARLY TREATMENT RESPONSE AND SAFETY PROFILE
EARLY TREATMENT RESPONSE AND SAFETY PROFILE
Recent research by Ito et al. (2023) examined the early effects of CGRP mAbs (erenumab,
galcanezumab and fremanezumab) in MOH patients, documenting significant reductions
in monthly headache days as early as 1 month into treatment.[6] This rapid response occurred without mandatory analgesic discontinuation, suggesting
that delayed treatment initiation for detoxification may unnecessarily prolong patient
suffering.
The safety profile of this approach has been well-documented. De Luca et al., in a
prospective study on oxidative stress biomarkers, conducted a comprehensive safety
analysis, finding no significant increase in adverse events when CGRP mAbs were administered
alongside various acute medications.[7] This favorable safety profile has been consistently reported across multiple studies,
including long-term follow-up data.
PATIENT-CENTERED BENEFITS AND MANAGEMENT STRATEGIES
PATIENT-CENTERED BENEFITS AND MANAGEMENT STRATEGIES
Tanei and Saito (2024), aiming to evaluate the real-world clinical results of anti-calcitonin
gene-related peptide monoclonal antibody (CGRP mAb) treatment for migraine with MOH
without abrupt drug discontinuation and no hospitalization, demonstrated successful
outpatient management of MOH using CGRP mAbs without requiring hospitalization or
abrupt medication discontinuation.[8] This approach offers several advantages: a) improved treatment adherence, b) reduced
impact on daily activities, c) better patient acceptance of therapy, and d) lower
risk of withdrawal symptoms.
Another prospective study conducted at the University Hospital of Modena, provided
evidence that even severely impaired patients can benefit from direct CGRP mAb initiation.[9] Their work emphasized the importance of individualized treatment approaches rather
than rigid adherence to traditional detoxification protocols.
For cases with suboptimal response, Iannone et al. (2023) developed strategies for
switching between different CGRP mAbs, demonstrating that treatment can be optimized
without reverting to mandatory detoxification.[10] This flexibility in management approaches allows for better tailoring of therapy
to individual patient needs.
To measure treatment success, Sette et al. (2022) proposed a novel index for monitoring
acute medication use during CGRP mAb therapy. This index provides a structured approach
to tracking treatment success without requiring complete medication discontinuation.[11] This tool helps clinicians make informed decisions about treatment continuation
and modification.
UNDERSTANDING SUSTAINED EFFICACY DURING MEDICATION OVERUSE
UNDERSTANDING SUSTAINED EFFICACY DURING MEDICATION OVERUSE
Koumprentziotis and Mitsikostas (2022) explored the mechanistic basis for CGRP mAb
effectiveness in MOH, explaining why these treatments can succeed without prior detoxification.[12] Their work highlights how the specific targeting of the CGRP pathway remains effective
despite ongoing medication use.
GUIDELINES AND CLINICAL IMPLEMENTATION
GUIDELINES AND CLINICAL IMPLEMENTATION
The European Academy of Neurology's guidelines on MOH management have begun to acknowledge
the changing landscape of treatment options.[13] While not altogether abandoning the concept of medication withdrawal, these guidelines
recognize the potential for alternative approaches, particularly with newer therapeutic
options like CGRP mAbs.
Multiple observational studies provide additional support for this approach. Curone
et al. (2020)[14] and Di Cola et al. (2020)[15] documented successful outcomes in real-world settings without mandatory detoxification,
providing practical evidence for the feasibility of this approach.
In conclusion, the recent cumulative evidence strongly supports the position that
discontinuation of overused analgesics is not necessary before initiating CGRP mAb
therapy for migraine prophylaxis.
As demonstrated, multiple lines of evidence support this conclusion:
-
Equivalent efficacy in patients with and without prior detoxification;
-
Favorable safety profile regardless of concurrent medication use;
-
Improved patient acceptance and treatment adherence;
-
Natural reduction in acute medication use following successful treatment;
-
Practical advantages in real-world clinical settings.
This paradigm shift represents a significant advancement in migraine management, offering
a more patient-friendly approach without compromising treatment outcomes. The success
of CGRP mAbs in treating migraine with concurrent medication overuse suggests that
we should move away from rigid detoxification requirements and toward more flexible,
individualized treatment approaches.
Bibliographical Record
João José Freitas de Carvalho. Calcitonin gene-related peptide monoclonal antibodies
and medication overuse headache: is stopping excessive pain medication still necessary?.
Arq Neuropsiquiatr 2025; 83: s00451809658.
DOI: 10.1055/s-0045-1809658
