What Is Combination Treatment in Migraine? Moving Toward a Uniform Definition of a Familiar Principle

Migraine is a multifactorial neurologic disease influenced by genetic, epigenetic, hormonal, and environmental components, and their interactions [1, 2]. Therapeutic modalities for migraine can be divided into three groups: pharmacologic therapy (e.g., oral medications and injectable options such as monoclonal antibodies and nerve blocks), neuromodulatory devices (e.g., transcranial magnetic stimulation and noninvasive vagus nerve stimulation), and behavioral interventions (e.g., cognitive behavioral therapy [CBT], progressive muscle relaxation [PMR], and motivational interviewing). These modalities rest on the foundation of lifestyle modifications, which are highly accessible and should be included as part of any migraine management plan. Lifestyle modifications include proper nutrition and sleep, reduction of exposure to migraine triggers, adequate hydration, exercise, stress management, and use of a migraine diary (Fig. 1) [3].

Fig. 1.

Migraine treatment: foundation, modalities, and strategies [3]

Treatment via these modalities is deployed using a variety of strategies, including intervention at the time of migraine attack (e.g., acute treatment) or intervention at set intervals whether or not an attack is present, intended to reduce the frequency or severity of attacks (preventive treatment). Given the multiplicity of modalities and treatment strategies, concise language is needed to communicate the array of therapeutic approaches and improve implementation of these strategies, particularly in regions where different terminologies and treatments are used.

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Strategies Within Treatment Modalities

Monotherapy within a given modality can be inadequate in a subset of people, often those with greater migraine-related burden. For these individuals, achievement of individualized therapeutic goals may require the combination of multiple acute or multiple preventive treatments that target different pathogenic aspects of migraine, a multimodal management approach [4].

Combination Treatment

Combination treatment in the context of migraine management can be defined as the concomitant use of two or more acute treatments or two or more preventive treatments. The use of two preventive treatments would be termed “combination preventive treatment,” while the use of two acute treatments would be “combination acute treatment.” Use of a single acute treatment and a single preventive treatment would not be considered combination treatment under this definition. Furthermore, the concomitant use of multiple acute and multiple preventive treatments would be referred to as “combination acute and combination preventive treatment.” It is important to distinguish combination treatment as defined above from another common form of pharmacologic treatment, delivering two or more active treatments in a single tablet or capsule. To avoid confusion, we recommend use of the terms (1) “combination treatment” to describe the coadministration of two or more separate tablets or capsules, each containing a different active pharmacologic agent at a specific dose and (2) “fixed-combination treatment” to refer to a single tablet or capsule containing two or more active treatments for migraine at fixed doses.

Factorial studies provide empirical evidence of the effectiveness of combining treatments. A factorial study design evaluates each treatment alone and then in combination looking for incremental benefits of the combination. Fixed-combination products, for example with two active ingredients, require factorial studies to prove that the combination of the two agents in a single tablet is more effective than either agent given alone. In the absence of factorial studies, combination acute treatment is often based on real-world evidence or clinical experience.

Acute Combination Treatment and Fixed Combinations

Nonsteroidal anti-inflammatory drugs (NSAIDs) and triptans—commonly used acute treatments for migraine—target different mechanisms in the inflammatory and neural process underlying migraine and have been shown to have incremental benefits when used as combination treatment. Sumatriptan and naproxen sodium administered as combination treatment (separate tablets) [5, 6]) or as a fixed combination (i.e., sumatriptan/naproxen sodium [7]) have benefits. Other examples of fixed combinations in migraine include the investigational acute migraine treatment AXS-07/MoSEIC (meloxicam/rizatriptan) [8], acetaminophen/aspirin/caffeine [9], which is available over the counter, and products that contain butalbital, caffeine, and either aspirin or acetaminophen [10–12]. Combination therapies using triptans together with NSAIDs and/or antiemetics may also provide incremental benefits (e.g., frovatriptan plus dexketoprofen [13]), but additional randomized controlled trials are needed to establish their efficacy versus monotherapies [14, 15]. In the emergency department (ED) setting, combination treatment is often recommended as a first-line approach, with marked and consistent improvement in pain outcomes in patients who present with a migraine attack [12, 16–18]. A combination treatment algorithm using ketorolac, an antiemetic (e.g., metoclopramide), magnesium sulfate, sodium valproate, and dexamethasone, each administered intravenously, was developed for patients in the ED presenting with an intractable migraine attack [19, 20].

Preventive Combination Treatment

Preventive treatment for migraine may also include monotherapy or combination treatment. Unlike with acute treatments, preventive treatments lack rigorous factorial studies showing that the combination of two preventive medications is more effective than either preventive medication alone. The Chronic Migraine Treatment Trial (NCT00772031) was a randomized, double-blind, placebo-controlled trial to investigate combination treatment for the management of chronic migraine [21]. The combination of topiramate ≤ 100 mg/day with add-on propranolol ≤ 240 mg/day was no more effective than the addition of placebo in decreasing the rate of moderate to severe headaches (at least moderate intensity and lasting ≥ 4 h or treated with triptans or ergots) over 28 days [21]. However, other clinical trials and real-world evidence support combination therapy in preventive treatment within the modalities of pharmacologic (e.g., onabotulinumtoxinA/erenumab [22] and topiramate/greater occipital nerve block [23]), behavioral interventions (e.g., combinations of PMR [24], CBT [25], motivational interviewing [26], and other behavioral techniques provided by health psychologists), and in multimodal approaches (e.g., CBT/amitriptyline [27]). Devices are not usually used in combination with other devices but given their different mechanisms of action, there may be a rationale for development of combination treatments that include devices.

Putting Together a Management Plan

The selection of appropriate therapy for combination treatment for migraine should begin with identifying a baseline treatment. If combination treatment is deemed appropriate, subsequent treatments can be layered on the baseline treatment in a stepwise manner with continuous monitoring. This approach is analogous to pharmacologic principles used for other chronic diseases such as diabetes and epilepsy.

The combination of treatments is built over time using a stepwise process in which an initial medication is established, and subsequent medication layers are built onto this baseline treatment with regular evaluation for migraine control, tolerability, and adherence. When the baseline treatment is first selected, it is evaluated to determine whether dose adjustment is needed or whether an alternative baseline treatment should be tested instead. After the baseline treatment is optimized, treatment should be assessed to determine if the current treatment is meeting all goals in alignment with the individual’s concept of migraine freedom. If significant migraine-related burden remains, a subsequent treatment can be identified and layered onto the baseline treatment based on the individual patient’s characteristics and disease burden. Comorbidities, mechanisms of action of drugs, and drug interactions should be considered, as they may drive decisions about what medications to layer and at what dose level.

Once a layered medication is selected and initiated, treatment optimization for the combination of treatments must also be evaluated in a similar manner. Regular clinical evaluations may be used to evaluate the effect of the layered treatment in combination with the baseline treatment. Discontinuing treatment based on efficacy and tolerability should be considered. Detailed guidelines for the practice of combining treatments are beyond the scope of this article, but any implementation of combination treatment should include regular evaluation and communication between the clinician and patient.

Combination treatment can be a rational approach to addressing the multifactorial etiology of migraine and the larger picture of disability. However, ambiguity in the terminology used is a potential barrier in the field. Establishing a standardized lexicon among clinicians and researchers is a necessary step for improving communication and elevating the quality of patient care.

Author Contributions

Richard B. Lipton, Jessica Ailani and Andrew M. Blumenfeld contributed equally to the development of this article.

Funding

This work was supported by AbbVie, which had no participation in the development of this publication aside from a final medical accuracy review. The journal’s Rapid Service Fee was funded by AbbVie.

Declarations

Conflict of Interest

Richard B. Lipton, MD, serves on the editorial boards of Neurology and Cephalalgia and is a senior advisor for Headache. He has received research support from the National Institutes of Health. He also receives support from the Migraine Research Foundation and the National Headache Foundation. He has reviewed for the National Institute on Aging and National Institute of Neurological Disorders and Stroke; serves as consultant, advisory board member, or has received honoraria or research support from AbbVie, Aeon, Amgen, Biohaven, Dr. Reddy’s Laboratories, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Teva, Vector, and Vedanta Research. He receives royalties from Wolff’s Headache, 8th edition (Oxford University Press, 2009), and Informa. He holds stock or options in Axon, Biohaven, CoolTech, Manistee, and Wizermed. Jessica Ailani, MD, has served as a consultant for AbbVie, Aeon, Amgen, Biohaven, Dr. Reddy, Eli Lilly, GlaxoSmithKline, Gore, Impel, Ipsen, Linpharma, Lundbeck, Merz, Miravo, Nesos, Neurolief, Pfizer, Scilex, Satsuma, Teva, Theranica, and Tonix; received stock options from Ctrl M; provided editorial services to Current Pain and Headache Reports, SELF, and Medscape; and received clinical trial support from AbbVie, Biohaven, Eli Lilly, Parema, Satsuma, and Zosano. Andrew M. Blumenfeld, MD, has served on advisory boards for, consulted for, and/or been a speaker or contributing author for AbbVie, Aeon, Alder, Allergan, Amgen, Axsome, Biohaven, Equinox, Lilly, Lundbeck, Novartis, Revance, Teva, Theranica, and Zosano. He has received grant support from AbbVie and Amgen.

Ethical Approval

This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.