Authors: Holshouser B, Ferguson M.
Pract Pain Manag. 2022 September/October;22(5).
Guidelines on Preventive Migraine Treatment in Adults
First-line drug therapies for migraine prophylaxis in adults include valproate, metoprolol, propranolol, timolol, frovatriptan, and topiramate. The American Academy of Neurology defines first-line treatments as those with established efficacy in 2 or more class I trials. (A class I trial is defined as an RCT with objective assessment that was conducted in a representative population.)
Clinical trials found topiramate to be more effective than placebo and equivalent to propranolol and valproate.³˒⁴ While efficacy is comparable between these options, safety is not. Valproate has boxed warnings for hepatotoxicity, fetal neural tube defects, and pancreatitis.
Topiramate and propranolol do not have boxed warnings, but they carry risks of their own. For example, topiramate, at doses of 200 mg/day or higher can decrease the efficacy of hormonal contraceptives. All patients concurrently taking these two medications should be counseled on this potential interaction and recommended folic acid supplementation.
While efficacy endpoints are discussed, current pediatric guidelines do not list any treatment as first-line. Guidelines have different recommendations regarding topiramate. While clinical trials in adults found that topiramate showed efficacy over placebo for migraine prophylaxis, this was not the instance for pediatric patients.
Evidence regarding the use of topiramate in children includes:
- probably more likely than placebo to decrease the frequency of migraine days
- possibly similar to placebo in decreasing migraine-related disability
- insufficient evidence to prove at least a 50% reduction in headache frequency vs. placebo2
Clinicians may also consider prescribing pediatric patients amitriptyline in combination with cognitive behavioral therapy (CBT). One study showed that this approach decreased the frequency of migraine days, reduced headache frequency by at least 50%, and decreased migraine-related disability. However, amitriptyline alone does not have sufficient evidence for any of the previously listed endpoints.
Table I provides more details.
|Children (0 to 17 years)||Adults (18+ years)|
|amitriptyline + CBT||Beta-Blockers|
Drug Delivery Challenges in Migraine Prevention
When Solid Oral Dosage Forms Are Not Doable
The drug therapies recommended for migraine prevention in both adults and children have been on the market for decades but largely as solid oral dosage forms. The guidelines provide minimal guidance regarding route of administration or how it is impacted by patient-specific factors.
A 2015 survey found that of 100 participants, 54% experienced trouble swallowing pills and 61% of those individuals reported this issue due to physical properties of the pill itself such as size, shape, and texture.⁶
Healthy individuals experiencing difficulty swallowing can benefit from strategies such as adjustments in posture, teaching of swallowing techniques, modification of pills (cutting/crushing when safe), and mixing medications with food or drink when safe. Psychological factors such as fear of swallowing can also impact pill-swallowing capabilities. In these cases, patients may benefit most from psychological interventions and would not be appropriate candidates for pill-swallowing strategies.⁷
The aging process can lead to impaired swallowing ability and conditions such as dysphagia, or difficulty swallowing due to physiological factors. Dysphagia may occur from disease states including Parkinson’s disease, head and neck cancer, gastroesophageal reflux disease, and stroke. Common symptoms include choking, coughing, or a lump-in-the-throat feeling.⁷ Since other pill-swallowing strategies are not always appropriate, these patients may benefit from an alternative dosage form.⁸
Alternative dosage forms exist for some migraine prevention therapies. Topiramate and divalproex sprinkle capsules have been manufactured to modify swallowing a tablet or capsule whole by sprinkling the contents of the capsule onto soft food. The use of oral solutions can also allow easier swallowability for patients. With FDA approval of a topiramate oral solution in November 2021, there are now three treatment options with oral solutions on the market (see Table II).
|Drug||Oral Dosage Form||Available Strength(s)|
|topiramate⁵||Tablet||Topamax/Generic: 25 mg, 50 mg, 100 mg, 200 mg|
|Capsule ER 24 Hour||Trokendi XR: 25 mg, 50 mg, 100 mg, 200 mg|
|Sprinkle Capsule||Topamax Sprinkle/Generic: 15 mg, 25 mg|
|Sprinkle Capsule ER 24 Hour||Qudexy XR/Generic: 25 mg, 50 mg, 100 mg, 150 mg, 200 mg|
|Oral Solution||Eprontia: 25 mg/mL|
|valproate⁵||Capsule, valproic acid||Depakene/Generic: 250 mg|
|Capsule DR Sprinkle: divalproex sodium||Depakote Sprinkles/Generic: 125 mg|
|Oral Solution, valproate sodium||Depakene/Generic: 250 mg/5 mL|
|Tablet DR: divalproex sodium||Depakote/Generic: 125 mg, 250 mg, 500 mg|
|Tablet ER 24 HR: Divalproex Sodium||Depakote ER/Generic: 250 mg, 500 mg|
|propranolol⁵||Tablet||Generic: 10 mg, 20 mg, 40 mg, 60 mg, 80 mg|
|Capsule ER 24 Hour||Inderal LA and Generic: 60 mg, 80 mg, 120 mg, 160 mg|
|Inderal XL: 80 mg, 120 mg|
|InnoPran XL: 80 mg, 120 mg|
|Oral Solution||Hemangeol: 4.28 mg/mL|
|Generic: 20 mg/5 mL, 40 mg/ 5 mL|
Topiramate 25 mg/mL oral solution (Eprontia) was approved for three indications:
- prevention of migraine in patients 12 years and older
- monotherapy for partial-onset or primary generalized tonic-clonic seizures in patients 2 years and older
- adjunctive therapy for partial-onset seizures, primary generalized tonic-clonic seizures, and Lennox-Gastaut associated seizures in patients 2 years and older⁹
This new dosage form was FDA approved via the 505 (b)(2) pathway, which is similar to an abbreviated new drug application but applies to drugs in a different dosage form than the reference product.¹⁰ As a part of the approval process, a bioavailability study comparing topiramate 25 mg/mL to sprinkle capsule topiramate 25 mg (Topamax) was conducted. Findings showed bioavailability within the FDA-approved range of 80% to 125% under fasting and fed conditions, showing that topiramate oral solution can be administered without regard to food.
Prior to the FDA approval of topiramate oral solution, a compound could be prepared if a patient’s needs could not be met with available products. There are important similarities and differences between the ready-to-use topiramate oral solution and compounded products.¹² Newly approved drugs may be expensive, but the pure ingredient cost to compound an equivalent amount of topiramate oral solution is comparable to the average wholesale price of topiramate oral solution.
The beyond-use date is 60 days for topiramate oral solution once opened and 90 days for the compounded solution.Ready-to-use solutions may reduce the risk of compounding errors and allow for consistent potency throughout the solution.¹⁵ These considerations lead to the question of what additional benefits are provided by this newly available formulation.
Oral solutions allow for customized dosing, which may be important for children 6 to 11 years due to a weight-based target dose. Tablets in 25 mg, 50 mg, 100 mg, and 200 mg strengths and sprinkle capsules in 15 mg and 25 mg strengths are currently available, which may make a patient-specific dose difficult to achieve (see Table III).
|Children (6 to 11 years)²˒¹⁶||Adolescents (12+ years)²˒³||Adults (18+ years)³|
|Initial: 15 mg once daily for 1 week||Initial: 25 mg once daily for 1 week||Initial: 25 mg once daily for 1 week|
|Titration: Increase to 15 mg twice daily for 1 week, increase to 25 mg twice daily for 1 week, titrate up to target dose||Titration: Increase by 25 mg weekly as tolerated||Titration: Increase by 25 to 50 mg weekly as tolerated|
|Target Dose: 2 to 3 mg/kg/day over 2 divided doses||Target Dose: 100 mg/day over 1-2 divided doses||Target Dose: 100 mg/day over 1-2 divided doses|
|Maximum Dose: 200 mg/day||Maximum Dose: 200 mg/day||Maximum Dose: 200 mg/day|
Medication Adherence and Administration Strategies in Children
Strategies to improve medication adherence among children are improving taste and using nonsolid oral dosage forms. Specifically, solutions and suspensions are preferred in children due to ease of swallowing and are the most used dosage form for pediatric patients. Topiramate tablets are listed on the Institute for Safe Medication Practices (ISMP) Do Not Crush list due to a bitter taste when crushed. The newly approved oral solution has a mixed berry flavor to combat the issue of bitter taste seen with topiramate tablets.
Due to the variability in pediatric patients, different barriers to adherence exist between age groups. Strategies that may improve adherence in adolescents include motivational therapy, incorporating their medications into a routine, scheduling refills and appointments at the same time, and patient counseling.
Liquid formulations may provide challenges regarding administration. Measurability of liquids can be difficult due to changes in dose, inability to use a calibrated device, and small volume. Proper counseling and instructions regarding dose titration and oral syringe use should be provided to patients to mitigate the potential for these errors.
As more options become available for people with specific needs to treat their migraine, different factors should direct selection of therapy. There are no first-line treatments noted for pediatric patients, but in the comparison of evidence, amitriptyline plus CBT has more favorable outcomes than topiramate. In adults, there are several first-line treatment options for migraine prophylaxis, however, only topiramate, valproate, and propranolol have oral solutions available. Due to limited data supporting the use of topiramate, available therapeutic alternatives should be considered when appropriate.
Individuals who experience efficacy with topiramate for migraine prophylaxis and express the need for an alternative dosage form may benefit from the use of topiramate oral solution. Factors to consider when recommending the use of an oral solution include affordability, administration ability, the need for dosing customizability, and the potential impact on adherence. When determining the best treatment option for patients experiencing migraine, efficacy, safety, and patient-specific factors should be taken into consideration.
- Migraine prophylaxis treatment recommendations differ between pediatric and adult patients
- Topiramate, valproate, and propranolol have oral solutions available on the market
- Sprinkle capsules may also play a role in combatting pill-swallowing issues
- Affordability, beyond-use-dating, and liquid measurement capability should be considered when recommending an oral solution
- Oral solutions provide benefits including dosing customizability, a decrease in compounding-related errors, and potential for increased medication adherence
- Pediatric and geriatric patients may see the most benefit from an oral solution
- Topiramate oral solution does not currently have FDA approval for migraine prophylaxis in patients ages 6 to 11, which may limit its place in therapy