CLINICAL RATIONALE

Migraine and Cluster Headache Management

Migraine is a common disabling primary headache disorder with high prevalence, ranking second globally in terms of years lost to disability.(5) Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and association with nausea and/or photophobia and phonophobia. Migraines can present with or without aura, unilateral fully reversible visual, sensory, or other central nervous system symptoms that usually develop gradually and are most-often followed by headache and associated migraine symptoms.(3)

The International Classification of Headache Disorders 3rd Edition (ICHD-3) Diagnostic Criteria:(3)

The IHS notes that cluster periods usually last between 2 weeks and 3 months.(3)

The 2024 American Headache Society (AHS) position statement update states that for those with episodic migraine (4-14 monthly migraine days) based on ICHD-3 with at least moderate disability (Migraine Disability Assessment [MIDAS] score greater than or equal to 11 or Headache Impact Test [HIT-6] score greater than 50), and those with chronic migraine (greater than or equal to 15 headache days/month) based on ICDH-3, CGRP-targeting agents are a first line migraine prevention treatment options and initiation of CGRP-targeting agents should not require the trial and failure of other migraine preventative medications.(2)

The 2021 American Headache Society Consensus Statement recommends the following indications for initiating treatment acute treatment with gepants and ditans agents:(11)

• Prescribed by a licensed clinician
• Patient is at least 18 years of age
• Diagnosis of ICHD-3 migraine with aura, migraine without aura, or chronic migraine
• Either of the following: 
  • Contraindication to or inability to tolerate triptans
  • Inadequate response to two or more oral triptans, as determined by either of the following: 
    • Validated acute treatment patient-reported outcoming questionnaire (mTOQ, Migraine-ACT, PPMQ-R, FIS, PGIC)
    • Clinician attestation

Lasmiditan is a selective serotonin 5HT-1F receptor agonist that lacks vasoconstrictor activity. Lasmiditan is structurally different than triptans and therefore constitutes a new class of drugs called “ditans”.(11) Ditans are selective for the 5HT-1F receptor and its mechanism of action is neuronal without evidence of vasoactive effects.(15) Triptans non-specifically bind to the 5HT-1B and 5HT-1D receptors and with varying affinity bind the 5HT-1F receptors, causing direct vascular vasoconstriction. The safety, tolerability, and efficacy of co-administering lasmiditan with a triptan or a gepant has not been assessed.(11) Patients who do not respond to initial therapy with a triptan, may benefit from a second triptan or different therapy such as use of a gepant (ubrogepant or rimegepant) or a ditan (lasmiditan).(5)

The Medical Letter Treatment Guidelines (2023) and Institute for Clinical Systems Improvement Guideline Diagnosis and Treatment of Migraine Headache - Drugs for Migraine states that a triptan is the drug of choice for moderate to severe migraine. The short-acting oral serotonin (5-HT1B/1D) receptor agonists (triptans) sumatriptan (IMITREX, and others), almotriptan (Axert, and generics), eletriptan (RELPAX), rizatriptan (Maxalt, and generics), and zolmitriptan (Zomig, and generics) are similar in efficacy.(12,13) Onset of pain relief generally occurs 30-60 minutes after administration. The longer-acting oral triptans naratriptan (Amerge, and generics) and frovatriptan (Frova, and generics) have a slower onset of action and lower initial response rate than other triptans, but they are better tolerated. Patients with migraine who have nausea or vomiting may not be able to take an oral triptan. Intranasal triptan formulations have a more rapid onset of action than oral tablets, but their efficacy is partially dependent on GI absorption of the portion of the dose that is swallowed. Use of sumatriptan nasal powder (ONZETRA Xsail) results in a faster rise in sumatriptan plasma concentrations and higher peak concentrations than use of a similar dose of sumatriptan nasal spray, suggesting that a larger portion of the dose is absorbed intranasally with the powder. Subcutaneously administered sumatriptan relieves pain faster (in about 10 minutes) and more effectively than other triptan formulations, but it causes more adverse effects.(13)

American Headache Society (AHS) (2015): Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan [oral, nasal spray, injectable, transcutaneous patch], zolmitriptan [oral and nasal spray]) are effective (Level A) and considered by AHS guidelines (2015) to be the gold standard for acute treatment of moderate to severe migraine headaches.(6) Dihydroergotamine is recommended for use as a second- or third-line therapy for select patients or for those with refractory migraine. Intranasal dihydroergotamine has strong evidence of effectiveness but more adverse effects than triptans because of its decreased receptor specificity.(4) An assessment of new migraine treatments by the AHS (2018; updated 2021) reaffirms previous migraine guidelines. The update lists triptans, dihydroergotamine, the oral gepants (Nurtec ODT [rimegepant] and UBRELVY [ubrogepant]), and REYVOW (lasmiditan) as effective treatment of moderate or severe acute attacks and mild to moderate attacks that respond poorly to non-specific nonsteroidal anti-inflammatory drugs (NSAIDs), non-opioid analgesics, acetaminophen, or caffeinated combinations (e.g., aspirin/acetaminophen/caffeine). The recommendation remains that prescribers must consider medication efficacy and potential medication-related adverse effects, potential adverse events, patient-specific contraindications to use with a particular medication, and drug-drug interactions when prescribing acute medications for migraine.(5,6,11)

The American Academy of Neurology (AAN) 2010 Guideline: Acute and preventive pharmacologic treatment of Cluster Headache (CH) state that sumatriptan subcutaneous injection and zolmitriptan nasal spray are first-line options for acute treatment of CH.(10,12) Since the publication of the 2010 AAN review, and re-reviewed in 2016, there is no new data from randomized, double-blind, controlled trials that contribute to determining the efficacy or safety for a number of acute treatments, including specifically sumatriptan and zolmitriptan. For acute treatment, sumatriptan subcutaneous, zolmitriptan nasal spray, and high flow oxygen remain the treatments with a Level A recommendation.(14) Guidelines suggest that prophylactic therapy should be started and continued for the duration of the CH period. Prophylactic pharmacological therapy includes verapamil, corticosteroids, lithium, topiramate, melatonin, gabapentin, valproic acid, ergotamine, and capsaicin. Verapamil is commonly considered the first option for prophylactic therapy in practice.(10,19,20) Corticosteroids can be used as transitional or bridging therapy until another prophylaxis agent is established.(19) Corticosteroids may be used by some practitioners for short periods of CH.(10,20) The American Academy Neurology lists the following agents as option that maybe considered or should be advised as preventative treatments:

• Civamide
• Suboccipital steroid injection
• Melatonin
• Verapamil
• Lithium

The European Headache Federation and WHO consensus article (2019) states the following:(7)

• Individuals with migraine headaches should always be managed in primary care with the exception being chronic migraine, which likely requires specialist management
• Any headache not responding satisfactorily in primary care or chronic migraine, should be referred to a specialist
• In adults and children, regular high frequency use (greater than 2 day/week) of acute medication risks the development of MOH
• Treatment of episodic acute migraine headaches should be approached in a step wise manner and should treat three attacks at each step before moving to the next step if needed:
  • Step 1:
    • Use non-opioid analgesics, plus an antiemetic when needed
  • Step 2 for adults:
    • Use triptan products
    • Triptans should not be used regularly for 10 or more days per month to avoid the risk of MOH
    • Triptan efficacy is highly variable between individuals, so patients should try different triptans and formulations. Sumatriptan subcutaneous injection should be considered when all other triptans are ineffective.
    • When vomiting is present, zolmitriptan nasal spray or sumatriptan subcutaneous injection may be preferred
  • Step 2 for children and adolescents:
    • Failure of Step 1 in children should lead to specialist referral. No specific anti-migraine drugs have shown efficacy in children under 12 years of age.
    • Failure of Step 2 in adolescents (12-17 years of age), the following have shown efficacy and are approved:
      • Sumatriptan nasal spray
      • Zolmitriptan nasal spray
• Episodic migraine prophylaxis:
  • Indication for migraine prophylaxis include:
    • Attacks cause disability on two or more days per month, and
    • Acute therapy has been optimized but does not prevent this, or is poorly tolerated, or there is a risk of over-frequent use of acute therapy, even when it is effective, and
    • Patient is willing to take daily medication
    • Failure of acute therapy is an indication for migraine prophylaxis
    • For children, frequent absence from school is an additional indication for prophylaxis
  • Migraine prophylaxis agents may take 2-3 months to show efficacy
  • Children requiring prophylactic medication should be referred to a specialist
  • Medications which are effective in adult prophylaxis of episodic migraine include:
    • Beta blockers:
      • Atenolol, bisoprolol, metoprolol, propranolol
    • Amitriptyline
    • Topiramate
    • Candesartan
    • Sodium valproate
    • Flunarizine
    • CGRP
  • Onabotulinum toxin A is not effective in episodic migraine and not recommended
  • When prophylaxis therapy fails:
    • May be due to subtherapeutic dosage or duration of therapy
    • Failure of one therapy does not predict the failure of another therapy in a different class
    • Review of the following are recommended:
      • Diagnosis
      • Adherence
      • Other medications, especially for MOH causes
    • The prophylaxis therapy should be discontinued if it fails to show clear benefit
    • If all prophylaxis therapies fail, a specialist should be referred
• Chronic migraine management:
  • Chronic migraine patients should be referred to a specialist
  • Medications with efficacy in chronic migraine include:
    • Topiramate
    • Onabotulinum A
    • CGRP
• Cluster Headache management: 
  • Patients should be referred to a specialist
  • Acute therapies include: 
    • Triptans: 
      • Sumatriptan subcutaneous injection
      • Sumatriptan nasal spray
      • Zolmitriptan nasal spray
    • Oxygen
  • Transition and maintenance therapies include: 
    • Prednisone
    • Greater occipital nerve blockade
    • Verapamil
    • Lithium carbonate
    • Topiramate 
  • Neuromodulation is another treatment option
  • Failure of one prophylactic therapy does not predict the failure of other therapies
  • Combination prophylaxis therapy can be considered though the potential for toxicity is high
  • Long-term prophylaxis therapy may need to be continued

The European Headache Federation guideline states the following on combining migraine prophylaxis therapy:(8)

• In episodic migraine, guidelines suggest to stop oral prophylaxis migraine agents before starting CGRPs, unless the patient previously had chronic migraine prior to prophylaxis. In such patients, the suggestion is to add CGRP to the ongoing oral prophylaxis therapy
• In chronic migraine, guidelines suggest to add CGRP to ongoing oral prophylaxis therapy
• In chronic migraine patients on onabotulinum A therapy and are receiving inadequate treatment response, guidelines suggest to stop onabotulinum A therapy before starting CGRPs
• In patients with chronic migraine who are on treatment with CGRP and may benefit from additional prevention, guidelines suggest to add on oral preventative agents
• In patients with medication overuse, guidelines suggest to use CGRPs before or after withdrawal of acute medications

The clinical trials referenced in FDA labeled package inserts for the preventative CGRP agents excluded patients that had received botulinum toxin within 4 months prior to receiving the CGRP agent.(9,16,17,18) However the 2021 American Headache Society consensus statement states that CGRP monoclonal antibody treatment (e.g., eptinezumab-jjmr, erenumab, fremanezumab, galcanezumab) may be added to greater than or equal to one established preventative treatment, based on clinical judgement, in adults who meet the ICHD-3 migraines.(3,11)

Medication overuse headache (MOH)

The European Headache Federation and WHO consensus article (2019) states the following:(7)

·          

o    Prevention is preferred

o    The four objectives of management are:

§  Stop the overused medication

§  Recovery from MOH

§  Review and reassess the underlying headache disorder

§  Prevent relapse while allowing acceptable use of medications

o    Comorbidities may require management

Safety

Vyepti is contraindicated in patients with serious hypersensitivity to eptinezumab-jjmr or to any of the excipients.(1)