Carlsen LN, Munksgaard SB, Nelsen M, et al. Comparison of 3 Treatment Strategies for Medication Overuse Headache. JAMA Neurol 2020;77:1069–78.

The lead-up

Medication overuse headache (MOH) is a disease characterized by escalating headache frequency and progressive use of short-term medication.¹ MOH affects more than 60 million people globally and causes significant individual burden and reduced quality of life.² The disease has a socioeconomic impact as well; MOH is one of the most expensive neurological diseases on a cost-per-person basis.³ Improving MOH treatment could lead to reduced burden for individuals with the disease as well as reduced socioeconomic stress and healthcare costs.³

The question then becomes, as the authors of Carlsen et al. posed it: how should we treat MOH? Identifying the best strategy to alleviate the problems of individuals severely affected by MOH is crucially important. There is debate around this topic­—during withdrawal of frequently used symptomatic (acute pain-relieving) medication, should prophylactic treatment be initiated during withdrawal or after detoxification?⁴ Carlsen et al. sought to compare three different treatment strategies for MOH: withdrawal with preventive treatment from the start, preventive treatment without withdrawal, and withdrawal with postponed (optional) preventive treatment.

The approach

The study by Carlsen et al. was a prospective, longitudinal, open-label randomized clinical trial. Patients diagnosed with MOH were randomized 1:1:1 to three groups: preventive treatment, withdrawal, or withdrawal plus preventive treatment. All three strategies were outpatient treatments. Patients were excluded from the study if they had severe physical illness or psychiatric disorders, among other qualifiers.

After being advised by trained headache nurses, those in the withdrawal group as well as the withdrawal plus preventive group completely discontinued analgesics for two months. After withdrawal, patients in both of these groups could use short-term acute medication as often as nine days per month. Preventive treatment was given to the preventive group as well as the withdrawal plus preventive group throughout the study. Monoclonal antibodies targeting calcitonin gene-related peptide and its receptors, a class of preventive treatments that has emerged in recent years, was not available at the time of this trial.

The primary outcome of this study was the change in headache days per month from baseline to six months in the three treatment strategies. The secondary outcomes were comparison of the three treatment strategies on several parameters, including change in headache days per month, short‑term medication use, and headache intensity.

The findings

In total, 40 patients were randomized to each of the three treatment groups, and 102 completed the six-month follow-up. This corresponds to a 15% dropout rate for the study as a whole. Baseline characteristics of the patients were similar across all three groups. The withdrawal group, preventive group, and withdrawal plus preventive group had 30, 23, and 25 headache days per month, respectively.

After six months of implementing the three treatment strategies, headache days per month were reduced by 12.3 in the withdrawal plus preventive group, 9.9 in the preventive group, and 8.5 in the withdrawal group. Importantly, over 60% of patients in the withdrawal group elected to add a preventive treatment across months 4–6. There was no significant difference in reduction of headache days per month (P=0.20) between the three groups after six months or at any other point in the study. At six months, 96.8% of patients in the withdrawal plus preventive group were cured of MOH, compared with 74.3% in the preventive group and 88.9% in the withdrawal group (P=0.03). Additionally, 74.2% of patients in the withdrawal plus preventive group reverted to episodic headache from chronic headache, compared with 60.0% in the preventive group and 41.7% in the withdrawal group (P=0.03).

The scrutiny

All three treatment strategies were found to be effective for the treatment for MOH, with no significant difference between the strategies in the reduction of monthly headache days. Still, the withdrawal plus preventive group had the numerically largest reductions in headache days, migraine days, short-term medication use, and headache intensity. There was also a significantly better chance of being cured of MOH and a better chance of reverting to episodic headache in the withdrawal plus preventive group.

This study has high clinical relevance, as the results are easily applicable to most patients with MOH and the outpatient programs may also be feasible in primary and secondary care. The majority (75%) of individuals in the study had their MOH attributed to simple analgesics. Most of the patients excluded from the study had a more complex form of MOH, so these results may be less applicable for patients with more complex MOH.

The next questions

• What is the best strategy for persons with a more complex form of MOH, including those using combinations of triptans, ergots, and opioids?
• What new evidence needs to come forward for headache experts to reach a consensus on MOH treatment?
• Would migraine-specific preventive treatments targeting CGRP perform similarly to the preventive treatments used in this study?

The bottom line

This study compared three MOH treatment strategies: withdrawal, preventive treatment, and withdrawal plus preventive treatment. There was no difference between the three methods in reducing headache days per month. However, withdrawal plus preventive was found to be the most effective strategy according to several endpoints, such as having the best chance to cure MOH. The study concluded that all three strategies were effective and that withdrawal plus preventive was the most effective, providing evidence that could help settle the debate around MOH treatment. If patients are to be treated by withdrawal, more awareness and scrutiny should be given to start proper preventive treatment immediately after withdrawal.

References

1. Kristoffersen ES, Lundqvist C. Medication-overuse headache: epidemiology, diagnosis and treatment. Ther Adv Drug Saf 2014;5:87-99.
2. GBD 2016 Disease and Injury Incidence and Prevalence Collaborators. Global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet 2017;390:1211-59.
3. Jellestad PL, Carlsen LN, Westergaard ML, et al. Economic benefits of treating medication-overuse headache - results from the multicenter COMOESTAS project. Cephalalgia 2019;39:274-85.
4. Louter MA, Robbins MS, Terwindt GM. Medication overuse headache: An ongoing debate. Neurology 2017;89:1206–7.

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