Treating Migraine in Teenagers
Medications
Over-the-Counter Agents
The first-line medications for migraine in the pediatric and adolescent populations are over-the counter medications, including ibuprofen, acetaminophen, and naproxen sodium. Ibuprofen has been well studied in pediatrics and was found to be safe and effective in 2 studies [10,11]at doses of 7.5–10 mg/kg. Again, care should be taken to ensure timely administration of ibuprofen at onset of headache, or aura if present, with appropriate weight-based dosing. Naproxen sodium has not been studied in pediatrics for treatment of migraine. However in practice, it is often used in similar doses of 10 mg/kg, with good efficacy. Although ibuprofen and naproxen sodium are both nonsteroidal anti-inflammatory medications (NSAIDs), anecdotally many patients report successful treatment with one NSAID when another has failed. Aspirin has shown efficacy in adults for treatment of acute migraine [12].It is likely effective in the pediatric population as well, but it is generally avoided due to long-standing concerns for precipitation of Reye syndrome in children. In adolescents over 16 years old, however, it is a reasonable option if there are no contraindications.
In one study, acetaminophen was compared to ibuprofen and placebo for treatment of migraine in children and adolescents and found to be effective more frequently than placebo but not as frequently as ibuprofen [10],likely due to its only minimal anti-inflammatory effects. It is a reasonable option for children and adolescents, particularly in those who have contraindications to NSAIDs.
While these over-the-counter medications are generally safe and well tolerated, clinicians should not overlook the potential for toxicity as well as medication overuse headache, and patients should be counseled to avoid use of any of these medications for more than 2 to 3 headache days per week.
Triptans
Studies of efficacy of triptans in treatment of pediatric migraine have been limited and results conflicting, largely due to high placebo response rates. However, some have shown efficacy over placebo, and in the past few years have received FDA approval for use in the pediatric and adolescent populations. Clinicians should remember that these medications are vasoconstrictors, so they should not be used in patients with vascular disease or in patients with migraine with brainstem aura or hemiplegic migraine. Additionally, due to the risk of serotonin syndrome, they should not be used in patients on monoamine oxidase inhibitors. It is also important to educate patients to limit use of these medications to 4 to 6 times per month to avoid precipitation of medication overuse headache.
Almotriptan was approved by the FDA in 2009 for use in patients 12 years and older, based on a large randomized controlled trial comparing doses of 6.25, 12.5, and 25 mg with placebo in patients ages 12 to 17 years old. All doses resulted in statistically significant pain relief as compared to placebo, and interestingly, the 12.5-mg dose seemed to be the most effective [13].
Rizatriptan received FDA approval in 2012 for use in patients 6 years and older. In 2 randomized controlled trials in patients 6 to 17 years old, rizatriptan (5 mg for patients < 40 kg, 10 mg for patients ≥ 40 kg) was more effective than placebo in providing pain freedom at 2 hours [14,15].One earlier trial found efficacy only on some measures (weekend treatment, decrease in nausea and functional disability) but no statistically significant difference than placebo in terms of overall efficacy in achieving pain freedom at 2 hours [16].However, this trial had a higher placebo response rate than typically seen in adult triptan trials. In a recent long-term open-label study in patients 12 to 17 years old, rizatriptan was found to be generally safe and well-tolerated with consistent efficacy of 46% to 51% pain freedom at 2 hours over time [17].
A combination pill consisting of sumatriptan and naproxen (Treximet) received FDA approval in May 2015 for patients 12 years and older. This was based on a randomized controlled parallel-group trial in patients 12 to 17 years old using the sumatriptan/naproxen combination in various dose combinations: 10/60 mg, 30/180 mg, or 85/500 [18].All doses were found to be equally effective in providing pain relief at 2 hours as compared to placebo, with a higher chance of sustained pain relief at 24 hours in the group receiving the 85/500 dose. In this trial, and in a long-term open-label safety trial [19],all doses were generally well tolerated with minimal adverse reactions.
Most recently, in June 2015, zolmitriptan nasal spray was approved for patients 12 years of age and older. In the large “Double-Diamond” study, which used a novel design to attempt to minimize placebo effect, zolmitriptan nasal spray (5 mg) was found to have a significantly higher headache response rate at 1 hour than placebo, and was significantly superior to placebo with regard to multiple secondary end-points [20].Additionally, a long-term open-label trial in patients 12 to 17 years old using oral zolmitriptan (2.5 mg or 5 mg) found it to be generally effective and well tolerated [21].
No other triptans have been approved for children or adolescents, however, most are widely used in clinical practice. There is good evidence for the efficacy and tolerability of sumatriptan nasal spray [22–26]in adolescents, and it is approved for use in adolescents with migraine in Europe. Although oral sumatriptan was the first triptan available clinically in the United States and is very widely used, there is surprisingly little published evidence for its use in the pediatric and adolescent populations. In fact, 2 randomized controlled trials in adolescents failed to show efficacy of oral sumatriptan as compared to placebo [27,28].Despite this, given its availability it is a reasonable choice for adolescent patients and is often one of the first tried. There has been 1 randomized controlled trial in adolescents for eletriptan without significant differences in efficacy at 2 hours as compared to placebo, although similar to other trials the placebo rate was high and there were some differences seen in secondary outcomes measures [29].Similarly, one randomized controlled trial of naratriptan 12.5-mg tablets failed to show efficacy as compared to placebo in pain relief [30].At present time, for frovatriptan there has only been a study looking at the pharmacokinetics and safety in adolescents, which found that it was generally well tolerated and recommended adolescent dosing similar to adult dosing [31].
In choosing a triptan, clinicians should keep in mind availability of alternate forms of administration, absence or presence of significant emesis, and the age of the patient. For patients who are unable to swallow pills or who have significant emesis associated with their migraines, nasal sprays and oral dissolving forms (melts) are good options. The nasal sprays (zolmitriptan and sumatriptan) additionally have the benefit of a quicker onset (~15 minutes) in general than the oral formulations. The downside to these nasal formulations is bad taste, which is frequently reported by patients. Patients should be counseled in proper administration of these nasal sprays (ie, avoiding inhalation, which causes the medication to enter the mouth) to minimize the bad taste and maximize absorption through the nasal mucosa. Other alternatives are the oral dissolving forms (rizatriptan and zolmitriptan). Given the FDA approval, the rizatriptan melt tablets are often the first-line triptan for children under age 12, but zolmitriptan melts are an option as well.
Preventive Treatment
General Approach
The decision to place an adolescent on a daily preventive medication should be based on a combination of headache frequency, severity, ease of breaking headaches, and overall disability as established by a disability scale (such as the PedMIDAS). Any patient with headaches occurring one or more days per week, those whose headaches are not easily treated or tend to be prolonged, and those with a PedMIDAS score of 30 or more should be considered candidate for a daily preventive. It is particularly important to consider starting a preventive early in adolescent patients given the possibility of impacting overall disease progression at a young age. While the natural history of headaches that start in the young is still being investigated, a known risk factor for transformation of episodic to chronic migraine is frequent headaches [32].It is therefore imperative to attempt to intervene early to improve quality of life in the present and also to prevent a downward cycle into chronicity, potential medication overuse, and worsening disability.
At present, there are several classes of medications that are commonly used for migraine prevention, including antidepressants, antiepileptics, antihistamines, and antihypertensives. Patients should be educated regarding the medication’s typical use, the specific way in which it is used in migraine, potential side effects, and overall expectations of efficacy. Most preventives need to be titrated up slowly to maximize tolerability, and patients need to understand that it may take time before they start to see results. In general, we recommend titrating up over the course of 4 to 12 weeks (depending on medication and dose goal), and then a substantial trial of 4 to 6 weeks on a full dose of medication before determining efficacy. If a medication shows a trend towards improvement but the patient has not met treatment goals, medication can be titrated up further at that point as tolerated. Patients and families should also understand that these medications are not intended as a “cure” for migraine but rather as a tool for improvement, which should be used in conjunction with the rest of a detailed plan. Generally, if a patient is well controlled for 4 to 6 months (ie, 3 or less headaches/month that are easily broken with medications, and a PedMIDAS < 30), attempts should be made to wean off of medication.
Medications
First-line Therapies
Currently, topiramate is the only medication approved for prevention of migraine in patients 12 years and older (approved in March 2014). Three randomized double-blind placebo-controlled trials in children and adolescents have found topiramate to be superior to placebo in multiple endpoints [33–35].Doses in these trials were 2–3 mg/kg/day, 100 mg/day, and 50 or 100 mg/day, respectively. Notably, the 50 mg/day dose was not found to be superior to placebo. Multiple retrospective, open-label, and drug comparison trials have shown effectiveness and tolerability as well [36–42].We typically use a goal dose of 2 mg/kg/day, which is reached after titrating over 8 to 12 weeks, which minimizes side effects (most commonly paresthesias, memory/language dysfunction, appetite suppression, and drowsiness), but higher doses can be used if needed.
Amitriptyline has consistently shown efficacy in adult migraine trials and is therefore one of the most commonly used medications worldwide for prevention of migraine in children and adolescents. Surprisingly, there have been no published randomized controlled trials using amitriptyline in the pediatric population, although a trial comparing amitriptyline, topiramate, and placebo is currently underway (Childhood and Adolescent Migraine Prevention Study) [43].In 2 retrospective pediatric studies improvement with amitriptyline was reported in 84.2% and 89% of patients, respectively [44,45].We typically use a goal dose of 1 mg/kg/day, also with an 8- to 12-week titration. The most common side effects with amitriptyline are somnolence, dry mouth, and weight gain, but it is generally well tolerated in children and adolescents. There is also a risk of worsening depression and suicidal thoughts, so it is recommended to use caution if considering prescribing to a patient with underlying depression. It is typically administered in once daily dosing a few hours before bed to minimize morning drowsiness. There is also a concern for precipitation of arrhythmias, and while there are no guidelines recommending screening ECGs, this should be considered in patients with a family history of heart disease. Of note, many practitioners use nortriptyline in place of amitriptyline as it can be less sedating. It should be noted, however, that evidence for its efficacy is lacking. Additionally, it may carry a higher risk of arrhythmia [44].
Second-line Therapies
The second-line therapies typically considered are other antiepileptics, valproic acid, levetiracetam, and zonisamide, for which there is some evidence, although mostly in the form of open-label or retrospective studies [46–51]. Of note, despite the many promising retrospective and open-label studies for valproic acid [46–48], one randomized double-blind placebo control trial comparing various doses of extended release divalproex sodium with placebo in adolescent patients failed to show a statistically significant treatment difference between any dose and placebo [52].It is, however, frequently prescribed and anecdotally quite efficacious. Given concerns about potential for teratogenicity, and possible effects on ovarian function, as well as potential for weight gain and hair loss, it should be used with caution in adolescent females.
Antihypertensives (beta blockers and calcium channel blockers) have long been used for prevention of migraine in both the adult and pediatric population, but evidence for their use in the pediatric population is conflicting. An early double-blind crossover study of propranolol in patients 7 to 16 years old showed significant efficacy as compared with placebo [53].However, in 2 subsequent studies it failed to show efficacy as compared with placebo and self-hypnosis, respectively [54,55].Given the conflicting evidence and the potential for hypotension, depression, and exercise-induced asthma, use of propranolol has fallen out of favor by experts for use in pediatric and adolescent migraine prevention. Flunarizine, a nonselective calcium channel blocker, has demonstrated effectiveness in pediatric migraine prevention [56,57],and is actually approved in Europe for this indication, but it is not available in the United States.
Cyproheptadine is an antihistamine with antiserotonergic properties which is used frequently for migraine prevention in young children who are unable to swallow tablets, although evidence is limited to 1 retrospective study [45].However, given the propensity for weight gain with this medication, it is generally not recommended for use in adolescents.
In recent years, there has been a growing interest in nutraceuticals given their general tolerability and minimal side effects, as well as a comfort in using a more “natural” approach, particularly in pediatrics. Evidence is limited but some of the frequently used substances may be beneficial. Butterbur (petasites hybridus) has strong evidence in adults and is recommended by the AAN for migraine prevention in adults [58].There is one small pediatric RCT showing efficacy for butterbur as compared to music therapy [59],as well as one promising open-label trial [60]. Typical dosing ranges from 50–150 mg daily. However, butterbur contains pyrrolizidine alkaloids, which are hepatotoxic, and due to the concerns for inadequate monitoring of removal of these substances in the manufacturing of commercial butterbur, it has been generally avoided in the pediatric population. Coenzyme Q10 (CoQ10) is considered possibly effective for adult migraine prevention by the AAN [58].Pediatric evidence is limited to an open-label study showing improvement with supplementation of CoQ10 in deficient patients [61],and a subsequent double-blind placebo-controlled add-on study, which showed improvement in both the CoQ10 and placebo groups but faster improvement in the CoQ10 group [62].Typical pediatric dosing is 1–2 mg/kg/day. Magnesium is considered by the AAN to be a good option for migraine prevention in adults [58].One randomized controlled trial in children however had equivocal results [63],while one small prospective open-label study had positive results [64]. Magnesium supplementation may be more effective in patients who have low ionized magnesium levels, but this is difficult to measure reliably in the clinical setting. Doses of 9 mg/kg/day can be used with the most common side effects reported being gastrointestinal upset and diarrhea, generally dose dependent. Riboflavin is also considered by the AAN to be probably effective for prevention in adults [58],but again the evidence in children is limited to one positive retrospective study [65]and 2 equivocal randomized controlled trials [66,67],one of which had an unusually high placebo rate [66]. Appropriate dosing is also something of debate, as riboflavin is minimally absorbed and has a short half-life, so while studies were done using 200–400 mg daily, smaller more frequent dosing may be needed.
A potential approach to treatment with vitamins is to check for deficiencies, but currently only the study mentioned above in which CoQ10 levels were checked showed improvement with normalizing of low levels [61,62].Further research into this topic is needed to elucidate whether checking and repleting levels of specific vitamins would be beneficial in prevention of migraines in certain patients.
Healthy Habits
The importance of maintaining healthy lifestyle habits and modifying potentially detrimental ones should be stressed to patients and families, and counseling regarding these issues should be provided at every visit, as repetition is often key to patients understanding their importance. Skipping meals is a commonly reported migraine trigger [68,69].This is not an uncommon occurrence even in the most well-meaning of families; adolescents often report not feeling hungry in the morning, and in the rush to get to school will often skip breakfast. Many patients report not liking school lunches leading them to go most of the day without food. Adolescent girls may skip meals due to weight concerns. Patients need to be reminded that well-balanced meals throughout the day is imperative, and they often may need specific counseling on how to achieve this practically. Of note, unless a specific migraine trigger has been identified in a given patient, we do not generally recommend restricting any specific food lists.
Maintaining good sleep hygiene and a consistent sleep schedule is also often difficult for adolescent patients, with after-school activities, homework, and screen use (eg, television, electronic devices) often contributing to late bedtimes with then forced early morning waking for school. However, improvement in sleep hygiene has been shown to be effective in improving migraines in children and adolescents [70],and realistic plans for improvement in sleep should be discussed with patients.
Dehydration is also a common migraine trigger [8,9],so the importance of staying well hydrated should be stressed as well. Again, specific recommendations for how this can be achieved are often needed, especially given adolescents’ busy schedules. Additionally, many schools do not allow water bottles to be carried, and often a school note is needed so patients may be allowed to carry a water bottle at school and also be provided extra bathroom breaks as needed.
Also important is stressing maintenance of daily functioning throughout migraine treatment. By the time adolescents seek medical care, they may already be in a cycle of missing school due to headaches, and some may even be receiving home-schooling. The goals of staying in school and learning to function with headaches should be stressed, often with the help of coping skills, which will be discussed below, as it has been shown that functional disability generally improves before pain [71].
Behavioral Treatments
Psychological treatments are an important aspect of migraine management. Biobehavioral treatments such as relaxation training, biofeedback, and multimodal cognitive behavioral therapy (CBT) have been evaluated in randomized controlled trials and reviewed in meta-analyses in pediatric migraine populations and found to be efficacious [72–75].These treatments have been shown to reduce pain intensity and disability for children and adolescents with headaches and therapeutic gains appear to be maintained [72].
Relaxation training typically includes instruction in techniques such as diaphragmatic breathing, progressive muscle relaxation, and guided imagery. Relaxation training is most effective with children 7 years of age or older [76].Biofeedback is often used in conjunction with relaxation training to provide audio or visual feedback about normally unconscious physiological body responses associated with increased relaxation. Effective biofeedback parameters used with children and adolescents with migraine headache include electromyographic (EMG) activity and peripheral skin temperature [77].Biofeedback techniques can help children and adolescents become more aware of physical responses, better control these responses and generalize physical responses outside of therapy sessions to better cope with pain [76].CBT involves instruction in skills such as biofeedback-assisted relaxation training, activity pacing, distraction, and cognitive strategies for coping with pain. CBT was shown to be effective in a recent study comparing adolescent patients with chronic migraine receiving amitriptyline and CBT with patients receiving amitriptyline and standard headache education [78]. Patients who received CBT plus amitriptyline had greater reductions in days with headache and migraine-related disability compared with patients who received headache education plus amitriptyline [78].Hypnosis and acceptance and commitment therapy (ACT) are also psychological treatments used with children and adolescents with migraine headaches. ACT prioritizes the outcome of improved functioning above headache reduction and has broadly demonstrated efficacy for chronic pain [79]. Both treatments have shown promising benefit but there has been less evidence supporting the use of these therapies in pediatric headache than other well-established behavioral treatments.
The presence of comorbid psychiatric issues such as anxiety, depression, or ADHD can make the treatment of patients with migraine headaches more complex. A recent study found that approximately 30% of a sample of children and adolescents with chronic daily headache had a lifetime psychiatric diagnoses and having a lifetime psychiatric diagnosis was associated with poorer headache-related disability and quality of life [80].As a result, more intensive behavioral treatment for children and adolescents with a psychiatric comorbidity may be needed to focus on emotional and behavioral issues.
Pediatric psychologists can assess pain-related disability and coping difficulties and treat children and adolescents with migraine headaches. Children are often referred to a psychologist or other mental health professional if headaches are severe or impairing functioning. Unfortunately, access to this therapy is sometimes limited, but when available, should be offered to any migraine patients with significant disability requiring prevention, and specifically to patients with chronic migraine.
