Combination Therapy Better Approach For Medication-Overuse Headache

Medication-overuse headache (MOH) is more likely to be relieved by restricting or withdrawing the causative medication when there is an additional complementary intervention, such as calcitonin gene–related peptide (CCRP) inhibitor therapy or greater occipital nerve block, according to a recent network meta-analysis of interventions (J Headache Pain 2025;26:43).

“Our results suggest that an abrupt withdrawal strategy alone may not be an effective treatment for MOH. For improved outcomes, it should be combined with other strategies,” said Prut Koonalintip, MD, in the Division of Neurology, Department of Internal Medicine, at the Prince of Songkia University, in Hatyai, Thailand.

The investigators found a relationship between the International Classification of Headache Disorders (ICHD) definition for MOH as the consequence of excessive use of analgesics for acute treatment of the primary headache, specifically in people who experience headaches on 15 or more days per month, and overuse of analgesics for acute treatment for more than 10 to 15 days per month over a period of three consecutive months (Cephalalgia 2018;38[1]:1-211).

In discussing the meta-analysis and seeking to rank strategies for MOH by effectiveness in reducing monthly headache days, Koonalintip told Pain Medicine News that he considers the best strategy is to prevent MOH from developing.

“However, raising awareness of MOH among both doctors and the general public remains challenging,” Koonalintip noted. “In my opinion, one practical and effective approach could be the implementation of guideline-based restrictions on the use of acute pain medications in specific settings.

“For example, in patients who have experienced a primary headache disorder for more than three months, by limiting the frequency and quantity of acute medication use in these patients, combined with patient education, clinicians can help reduce the likelihood of overuse and prevent the progression to MOH,” he said.

Koonalintip and his colleagues analyzed 16 randomized controlled trials (RCTs) of interventions for MOH, from 52 that had initially appeared to meet inclusion criteria. The trials were conducted between 2006 and 2023, and involved 3,000 subjects from cohorts ranging from 46 to 904. Most studies reported follow-up outcomes at eight to 16 weeks, with three extended to 24 weeks.

“The majority of patients included in this network meta-analysis had complex MOH, characterized by the predominant use of combination analgesics (44.3%) as well as simple analgesics (28.5%), triptans (25.5%), ergotamine (1%) and opioids (0.7%),” Koonalintip said.

“The mean duration of medication overuse was approximately 3.5 to four years, which likely contributed to the relatively modest benefit observed from abrupt withdrawal alone,” he added.

The strategies for managing MOH that were assessed in the trials were abrupt withdrawal; oral agents aimed at preventing the headache; botulinum toxin injection; anti-CGRP therapies; and combinations with greater occipital nerve block, education and drug restriction. The investigators found that combinations of strategies were more effective than any single intervention for reducing the number of monthly headache days. Abrupt withdrawal of the causative medication in combination with greater occipital nerve block and an oral prevention agent , and restriction of the causative medication with oral prevention and an anti-CGRP demonstrated the greatest efficacy. with reduction in monthly headache days of 10.6 (95% CI, 15.03-6.16) and 8.47 (95% CI, 12.78-4.15), respectively.

“In my opinion, withdrawal strategies—whether abrupt or restrictive—remain fundamental to the management of MOH and should be implemented in all patients with this condition,” Koonalintip said. “When combined with other interventions, withdrawal strategies are associated with an additional reduction of approximately one to two headache days per month.”

Although Koonalintip acknowledged that abrupt withdrawal alone may be effective in some cases of “simple” MOH, he emphasized the increased effectiveness of combination strategies demonstrated in the meta-analysis, as well as the importance of the patient’s shared decision-making and active involvement.

“Evidence from previous RCTs suggests that the greater efficacy observed when abrupt withdrawal is combined with education underscores the critical role of patient motivation and understanding in achieving successful outcomes,” Koonalintip noted.

Assessing Anti-CGRP Therapy

Stewart Tepper, MD, the vice president of The New England Institute for Neurology and Headache, in Stamford, Conn., and a professor of neurology in the Geisel School of Medicine at Dartmouth College in Hanover, N.H., considered the treatment options described and ranked in the meta-analysis from his perspective as an investigator of therapy with the CGRP inhibitor, erenumab (Aimovig, Amgen). His group recently published evidence on the effectiveness of anti-CGRP therapy for MOH (JAMA Neurol 2024;81[11]:1140-1149), and presented results from a trial extension up to one year (Headache 2024;64[suppl 1]:163 [abstract]).

“I believe the erenumab study, along with the analyses of the pivotal trials discussed in the Koonalintip et al meta-analysis, suggests a new and superior approach to treating nonopioid MOH: that is, beginning an anti-CGRP MAB [monoclonal antibody] without an explicit withdrawal, and allowing that treatment to work, expecting MOH remission,” Tepper commented.

“Only if the treatment fails at six months would I resort to other approaches, including behavioral treatments and consideration for infusions or hospitalization,” he added.

Tepper also referred to an ongoing trial that is comparing eptinezumab (Vyepti, Lundbeck) in combination with brief education on MOH and the education component alone. “If that trial confirms the erenumab results, then I believe that the new approach of using anti-CGRP MAB therapy with either brief education or none, without a formal withdrawal, will become the new standard for treatment of MOH,” he said.

Although the meta-analysis supported combining treatments for MOH, Koonalintip acknowledged that there is not a single best strategy, and that research could be expected to reveal additional options.

“Treatment decisions should be individualized, taking into account factors such as cost, potential side effects, patient preference and treatment accessibility,” Koonalintip said. “Future research should look into optimal management of MOH in terms of efficacy, disadvantages and long-term outcomes.”

—Kenneth Bender

Koonalintip reported no relevant financial disclosures. Tepper reported research funding, and consultant fees and honoraria, from Amgen and Novartis, the developers of erenumab.