Review of Position Statement on Integrating New Migraine Treatments into Clinical Practice
Francine Kim, PharmD Candidate 2020, Kayla Ryan, PharmD, University of Virginia Health
Background
Migraine is a chronic or episodic headache disorder associated with intense pain that is often unilateral in nature, accompanied by symptoms such as nausea and vomiting, photosensitivity, and phonosensitivity.1 About one-third of individuals experience an aura prior to an attack, which can be characterized by seeing flashing lights, experiencing numbness or tingling in the face or extremities, or increased sensitivity to odors.1 Around 1 out of every 7 Americans is affected by migraines annually, with an increased prevalence in women especially during their reproductive years.2 Symptoms of migraine cause an average of 50% loss in productivity leading to a substantial economic burden. 2 Treatment options for migraine aim to abort a current migraine, prevent future migraines, or both.3 Severity and frequency of migraine vary both between patients and over time for individual patients. Thus, treatments must be individualized and modified to optimize efficacy. Current migraine treatment options include acetaminophen, NSAIDs, triptans (sumatriptan, frovatriptan, zolmitriptan, etc), ergot derivatives, select beta blockers (propranolol, metoprolol), and select anticonvulsants (topiramate, divalproex). Recent advent of novel medications, device technologies, new formulations of established drug therapies, and biologics have added new treatment options. To address the integration of these novel treatments with current clinical practice, the American Headache Society released a position statement updating guidance on preventive and acute treatment of migraine. This article will address indications for acute and preventive treatments, guideline-based recommendations for the use of novel agents, and data supporting use of new agents.
Preventive Treatment
The indications for preventive treatment remain unchanged from previous guidelines. Preventive treatment should be considered for patients in whom attacks significantly interfere with their daily lives, experience frequent attacks, experience adverse effects with acute treatments, possess contraindication to, failure of, or overuse with acute treatments, or have migraine of uncommon subtypes (hemiplegic migraine, migraine with brainstem aura, migraine with prolonged aura, and those who have previously experienced a migrainous infraction).4 Prior to starting preventive therapy, ensure that acute treatments have been optimized by finding the most appropriate drug type, route and timing of administration, and frequency of use. Additionally, acute treatments should be accompanied by education and lifestyle modifications (e.g. massage therapy, limiting dietary triggers, aromatherapy).4 Agents chosen for preventive treatments should have established evidence supporting their use.4 The guidelines classify preventive agents as those that have established efficacy, are probably effective, and are possibly effective. Oral agents with established efficacy include antiepileptic drugs (divalproex, valproate, topiramate) and beta-blockers (metoprolol, propranolol, timolol).4 In the setting of short-term preventive use for menstrual migraine, frovatriptan has established efficacy. For short-term prophylaxis frovatriptan dosing is 2.5 mg twice daily starting two days prior to menstrual onset and continued for a total of six days, which is different from acute treatment dosing.5 Treatment options that are probably effective and should be considered for migraine prevention are: antidepressants (amitriptyline, venlafaxine), beta-blockers (atenolol, nadolol), and angiotensin receptor blockers (candesartan).4
The principles guiding use of preventive migraine agents are consistent with previous recommendations. Oral treatments should be initiated at low doses and titrated slowly. Dose titration should continue until one of the following occurs: desired response is achieved, maximum or target dose is reached, or once a patient is unable to tolerate adverse effects (AEs). Combination drug therapy may be beneficial when a partial response is achieved or AEs are dose-limiting.4 Prior to changing therapy, ensure patients are given an adequate trial of oral therapy. Adherence to preventive therapy may be difficult to achieve due to results that do not meet patients' expectations and AEs, thus patient education and shared decision making are crucial in improving adherence. Given the dynamic nature of the quality and frequency of migraine, it is important to reevaluate therapeutic response every six to eight weeks.
Since publication of previous migraine guidelines, four injectable preventive therapies have been FDA approved for migraine prophylaxis. The injectable therapy options include: onabotulinumtoxinA and three calcitonin gene-related peptide (CGRP) antagonist monoclonal antibodies (mAbs). OnabotulinumtoxinA is approved for chronic migraine, while the mAbs are approved for episodic and chronic migraine. There are several differences with injectable treatment compared to oral: dose titration is not required, therapeutic benefits are observed early, and agents are generally well tolerated. Similar to oral agents, patient centered and validated outcome measures should be used to guide clinical decision making in regard to efficacy and decisions to escalate dose or switch treatment agents.4
OnabotulinumtoxinA is the only botulinum toxin on the market that is approved for chronic migraine prophylaxis. The agent is delivered as 155 units divided between 31 sites across 7 specific head and neck muscle areas, and is administered every 12 weeks.5 OnabotulinumtoxinA inhibits the release of acetylcholine at the neuromuscular junction thereby inhibiting striated muscle contraction and peripheral sensitization.6 Adverse reactions associated with onabotulinumtoxinA include musculoskeletal/connective disorders, headache, and eyelid ptosis. Additionally, a boxed warning for distant spread of toxin effect is included in the labeling. Support for the efficacy of onabotulinumtoxinA as prophylactic treatment for chronic migraine comes from the results of the PREEMPT study. The PREEMPT study investigated onabotulinumtoxinA's effect on mean change from baseline in frequency of headache days at 24 weeks compared to placebo. Pooled analyses revealed a statistically significant greater decrease in number of headache days in patients treated with onabotulinumtoxinA compared to placebo (-8.4 vs -6.6; p < 0.01). 7 Most study participants reported mild to moderate adverse events, with more patients in the onabotulinumtoxinA treatment arm discontinuing therapy compared to placebo (3.8% vs 1.2%).7
If patients are unable to tolerate oral agents or onabotulinumtoxinA therapy, calcitonin-gene related peptide (CGRP) antagonists may be indicated.4 CGRP is a neuropeptide released from activated trigeminal sensory nerves and leads to intracranial and extracranial vessel dilation. CGRP also centrally modulates vascular nociception.16 Thus, CGRP plays an important role in the pathophysiology of migraine. Currently, erenumab, fremanezumab, and galcanezumab are the three CGRP antagonists that are FDA approved for prophylaxis. These monoclonal antibodies are the first drugs specifically created to prevent migraine and have fewer adverse drug reactions than previous medications used (i.e. beta-blockers, antiepileptics, and antidepressants). Erenumab is a CGRP receptor blocker, while fremanezumab and galcanezumab target the CGRP ligand. CGRP antagonists avoid hepatic metabolism and renal clearance, thus do not require dose adjustments and avoid possible drug interactions, making them ideal candidates for combination therapy with oral agents. 4 Given the very low/nonexistent risk of drug-mAb interactions, it is reasonable to add a mAb to an existing regimen without other therapeutic changes until effectiveness of the mAb is determined. 5 Principles guiding evaluation of outcomes of treatment are consistent with those mentioned previously; however, evaluation of efficacy of mAb treatment requires 3 or 6 months of outcome data in patients receiving monthly or quarterly injections respectively. 4 Information regarding the dosing, criteria for use, and efficacy data for the CGRP antagonists are summarized in tables 1-4.
Table 1. Monoclonal Antibody Summary8-12
|
Monoclonal Antibody
|
Route
|
Dose
|
Frequency
|
Mechanism of Action
|
|
Erenumab
|
SQ
|
70 mg or 140 mg
|
monthly
|
IgG2 CGRP receptor blocker
|
|
Fremanezumab
|
SQ
|
225 mg or 675 mg*
|
monthly or every 3 months*
|
IgG2 CGRP ligand antagonist
|
|
Galcanezumab
|
SQ
|
240 mg LD then 120 mg MD
|
monthly
|
IgG4 CGRP ligand antagonist
|
Table 2. Indications for Monoclonal Antibody Prophylaxis4
| A. Age ≥ 18 years B. ICDH-3 diagnosis of migraine with or without aura (4-7 monthly headache days), plus:
- MIDAS score > 11 or HIT-6 score >50
- Unable to tolerate or inadequate response to at least 2 other oral prophylactic regimens with a 6-week trial
|
| C. Migraine with or without aura (8-14 monthly headache days), plus:
Unable to tolerate or inadequate response to at least 2 other oral prophylactic regimens with a 6-week trial
|
| D. Chronic migraine diagnosis, plus one of the following:
- Unable to tolerate or inadequate response to at least 2 other oral prophylactic regimens with a 6-week trial
- Unable to tolerate or inadequate response to 2 quarterly injections of onabotulinomtoxinA
|
Table 3. Criteria for Continuing Biologic Therapy4
| A. Reduction in average headache days by ≥ 50% from pretreatment baseline
B. Clinically meaningful improvement in one of the following measures |
- MIDAS: reduction of ≥ 5 with baseline score 11-20 or 30% reduction with baseline score >20
- MPFID: reduction ≥ 5 points
- HIT-6: reduction ≥ 5 points
|
Table 4. Summary of Clinical Trials Supporting Efficacy of Monoclonal Antibodies8-12
|
Monoclonal Antibody
|
Trial (Year)
|
Outcome Measured
|
Efficacy
|
|
Erenumab
|
ARISE (2018)
|
Change in MMD* from baseline during 3rd month of therapy
|
Reduction in MMD* by 2.9 days in episodic migraine vs 1.8 in placebo
|
|
Erenumab
|
STRIVE (2017)
|
Change in MIDAS score from baseline
|
Dose dependent MIDAS score improvement
|
|
Fremanezumab
|
Dodick et al. (2018)
|
Change in mean MMD* at 12 weeks after first dose
|
1.3 to 1.5-day reduction in mean MMD over 12-week period
|
|
Galcanezumab
|
REGAIN (2018)
|
Change in MMD* from baseline over 3 months in chronic migraine
|
120 mg and 240 mg monthly resulted in ≥ 50% decrease in MMD
|
|
Galcanezumab
|
EVOLVE-2 (2018)
|
Change in mean MMD* from baseline in episodic migraine
|
MMD* reduction:
120 mg: 4.3 days
240 mg: 4.2 days
Placebo: 2.3 days
|
Monthly migraine days*
Migraine Disability Assessment (MIDAS) score: a questionnaire used to measure impact of headaches on daily life
Headache Impact Test (HIT-6): measures adverse impact of headache on social functioning, role functioning, vitality, cognitive functioning and psychological stress
Migraine Physical Function Impact Diary (MPFID): capture experiences on days with migraine as well as the days in-between migraines
Acute Treatment
The guidelines state that all patients with migraine should be offered a trial of acute treatment. For mild-to-moderate attacks, treatment options include NSAIDs, acetaminophen, and combination analgesic + caffeine.4 Moderate or severe attacks or mild-to-moderate attacks with suboptimal response to nonopioid analgesics or caffeinated combos should be treated with triptans or a dihydroergotamine.4 Choosing the appropriate route of administration given symptoms of migraine are also emphasized i.e. sublingual, subcutaneous, and intramuscular administration of abortive therapy in the setting of nausea and vomiting.4 Consideration of side effects and safety issues remains important to ensure treatment use. A key point in acute treatment is to avoid medication overuse as it may lead to medication overuse headache. It is suggested that patients overusing abortive therapy in the setting of preventive treatment may need dose escalation, modification of preventive therapy, or addition of another preventive agent.4
Novel acute migraine treatment options have also recently emerged. When acute treatment with triptan fails, defined as trial of at least two triptans, clinicians may consider ubrogepant, rimegpant, lasmiditan, or a neuromodulation device.4 Patients should try novel agents for at least two attacks in order to evaluate efficacy and tolerability.4 Guidelines suggest that patients who prefer non pharmacologic options may try neuromodulation therapy. Additionally, evidence supporting biobehavioral therapies is growing. Studies have shown improved patient response to pharmacologic therapy when combined with biobehavioral therapy.4
Table 5. Monoclonal Antibodies for Acute Treatment13-15
|
Novel Agent
|
Drug Class
|
Trial (Year)
|
Outcome Measured
|
Efficacy
|
Common Side Effects
|
|
Ubrogepant+
|
CGRP receptor antagonist
|
ACHIEVE II (2019)
|
Headache pain freedom and absence of MBS* 2 hours after initial dose
|
Significantly greater proportion of patients achieved 2-hour pain freedom and 2-hour absence of MBS*
|
Nausea, somnolence, dry mouth
|
|
Rimegpant+
|
CGRP receptor antagonist
|
Croop et al. (2019)
|
Headache pain freedom and absence of MBS* 2 hours after initial dose
|
Significantly greater proportion of patients achieved 2-hour pain freedom and 2-hour absence of MBS*
|
Nausea and urinary tract infection
|
|
Lasmiditan++
|
Serotonin 5-HT1F receptor agonist
|
Goadsby et al. (2019)
|
Headache pain freedom and absence of MBS* 2 hours after initial dose
|
Significantly greater proportion of patients achieved 2-hour pain freedom and 2-hour absence of MBS*
|
Dizziness, somnolence, paresthesia
|
+Currently in pipeline for treatment of acute migraine, not FDA approved
*Most bothersome migraine-associated symptom
++FDA approved for acute migraine treatment
Conclusion
The American Headache Society's Position Statement provides guidance for clinicians on integrating new treatment options in their approach to migraine therapy. OnabotulinumtoxinA is a second line agent for prophylaxis in those that qualify for prophylactic treatment. The mAbs (erunumab, fremanezumab, and galcanezumab) are well-tolerated prophylactic treatment options for those meeting criteria previously mentioned. Notable advantages of injectable therapies are quick onset and the lack of dose titration. Lasmiditan became the first FDA approved mAb within this past year. The updated position statement does not go into detail about these treatment options; however, they are options for individuals who have failed therapy with two different triptans.
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