Evidence supports prophylactic treatment for migraine

Table, part 1

Table, part 2

Table, part 3

Migraine is one of the most common neurologic disorders in children and adolescents with a prevalence of 7.7%. The prevalence is actually higher in boys compared with girls prior to puberty. However, after puberty, the incidence and prevalence of migraine increase more rapidly in girls than boys with girls ultimately having a higher prevalence after age 11 years.¹ Given this prominence, the American Academy of Neurology and the American Headache Society have standard practice guidelines for the pharmacologic treatment for pediatric migraine prevention. These guidelines were most recently updated and published in 2019.²

The goal of this article is to discuss pharmacologic treatment for pediatric migraine prophylaxis in a succinct and evidence-based approach for the general pediatrics provider. Although outside the scope of this article, it is important to remember that lifestyle modifications, such as sleep hygiene, hydration, a consistent well-balanced diet, exercise, and stress management, cannot be overlooked as these are the foundation to all other migraine prevention including pharmacologic therapies. Additionally, complementary therapies such as physical therapy, biofeedback, and acupuncture often are used as an adjunct to migraine prevention.

Adults with migraine headache for more than 6 days in a month are at risk for progression to chronic migraine. Medication overuse also contributes to this progression. The guidelines note that there is no available data on this topic in Pediatrics. However, it is hypothesized that there are similar relationships between frequent headache, medication overuse, and progression to chronic migraine in children. Therefore, it is suggested that clinicians consider preventive treatment in these populations.

What clinical trials revealed

In the clinical trials regarding preventive treatment agents, the inclusion criteria for headache frequency were variable and included a minimum of 4 headache days per month with no maximum and 3 to 4 migraine attacks per month for at least 3 months.² It is also worth noting that certain populations are at increased risk of migraine-related disability and may need additional consideration for preventive therapy. For instance, teenagers with migraine who had a Pediatric Migraine Disability Assessment Score (PedMIDAS) over 30 (indicating moderate to severe migraine-related disability) had a higher risk of mood and anxiety disorders and increased severity and frequency of headache.

The Table highlights some migraine preventive options.^2-10

The majority of randomized controlled trials that have studied the efficacy of preventive medications for pediatric migraine were not able to demonstrate superiority to placebo. In the Childhood and Adolescent Migraine Prevention (CHAMP) study, the largest double-blind, placebo-controlled pediatric migraine prevention study funded by the National Institutes of Health to date, it was found that most patients showed a marked improvement in their migraines whether treated with amitriptyline, topiramate, or placebo.¹¹ A more recent network meta-analysis published in JAMA Pediatrics determined that only 2 treatments were significantly more effective than placebo when data were combined: propranolol and topiramate. However, the 95% prediction intervals for this study were nonsignificant.¹ Despite results not being superior to placebo, what the majority of studies to date have in common is the fact that patients experienced improvement in their migraines with treatment.

Additionally, general headache education was shown to be beneficial, highlighting the importance of not solely focusing on pharmacologic therapies. What the studies, including the CHAMP study, show is that patients tended to do markedly better whether a conventional drug or placebo was used. This supports the notion that to treat, in general, is more important than selecting a specific drug therapy.

When selecting an agent, it is reasonable to consider the age of the patient, their comorbidities, and the adverse-effect profile that would be most tolerable. At times, the adverse effects can be used to the patient’s benefit. For instance, topiramate has a possible adverse effect of weight loss and can be used not only for migraine prevention but weight management in obese patients. It is important to discuss all the medication options, their benefits, and their potential adverse effects with the patient and family. When the treatment plan is agreed on by all parties, there is a much greater chance of success. The art of preventing migraines is choosing an agent that is individualized for the patient rather than picking a perfect treatment based on superior evidence.

Given that migraine is a chronic disorder with remissions and relapses and that many of the medications listed in the Table have adverse effects, duration of therapy can be tricky as there is not a definitive length of time to continue treatment. The randomized controlled trials to date have followed patients only for a limited follow-up period. Therefore, there is little data to guide when to stop therapy and the risk of relapse when doing so. Some publications support stopping medication as early as 4 to 6 weeks after good control is established whereas others recommend 12 months. The current guidelines recommend periodically monitoring medication effectiveness and adverse effects while patients are on therapy.² Patients and families also should be counseled about the risk and benefits of stopping a medication once good migraine control is established.

Future clinical trials

Looking toward the future of pediatric migraine prevention, there are several open clinical trials that are investigating new therapies. The calcitonin gene-related peptide (CGRP) inhibitors erenumab and galcanezumab have trials openly recruiting patients. As providers caring for patients with migraines, clinicians are eagerly awaiting new data.

Summary

In conclusion, there are several options available to prevent migraines in the pediatric and adolescent populations. Available data cannot not claim whether one medication is better than another. However, the evidence supports treatment of some kind in order to reduce migraine frequency and severity. This should be paired with lifestyle modifications and consideration of alternative therapies as a multitiered approach that generally leads to better migraine management. Ultimately, treatment regimens need to be selected and tailored to fit each individual patient for the greatest chance of success.

Note from Dr Lee

Pediatric migraine prevention continues to be a challenge with the associated complexities of the disorder and lack of significant positive outcomes from randomized controlled drug trials. The investigation and application of precision medicine techniques may provide improved patient outcomes for defining individualized therapies that are efficacious and safe.

-Carlton Lee, PharmD, MPH, FASHP, FPPAG

References:

1. Locher C, Kossowsky J, Koehlin H, et al. Efficacy, safety, and acceptability of pharmacologic treatments for pediatric migraine prophylaxis: a systematic review and network meta-analysis. JAMA Pediatrics. February 10, 2020. Epub ahead of print.

2. Oskoui M, Pringsheim T, Billinghurst L, et al. Practice guideline update: Pharmacologic treatment for pediatric migraine prevention. Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology and the American Headache Society. Published October 2019. Accessed April 17, 2020. https://www.aan.com/Guidelines/home/GetGuidelineContent/978

3. Winner P, Pearlman EM, Linder SL, et al; Topiramate Pediatric Migraine Study Investigators. Topiramate for migraine prevention in children: a randomized, double-blind, placebo-controlled trial. Headache. 2005; 45(10):1304-1312.

4. Lewis D, Ashwal S. Hershey A, et al; American Academy of Neurology Quality Standards Subcommittee; Practice Committee of the Child Neurology Society. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004;63(12):2215-2224.

5. Caruso JM, Brown WD, Exil G, Gascon GG. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache. 2000;40(8):672-676.

6. Yatham LN, Kennedy SH, Parikh SV, et al. Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society of Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder. Bipolar Disord. 2018;20(2):97-170.

7. Hershey AD, Powers SW, Bentti AL, Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache. 2000;40(7):539-549.

8. Sorge F, De Simone R, Marano E, Nolano M, Orefice G, Carrieri P. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebo-controlled, crossover study. Cephalgia. 1988;8(1):1-6.

9. Orr SL The evidence for the role of nutraceuticals in the management of pediatric migraine: a review. Curr Pain Headache Rep. 2018;22(5):37.

10. Condò M, Posar A, Arbizzani A, Parmeggiani A. riboflavin prophylaxis in pediatric and adolescent migraine. J Headache Pain. 2009;10(5):361-365.

11. Powers SW, Coffey CS, Chamberlin LA, et al; CHAMP Investigators. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med. 2017;376(2):115-124.