Pharmacotherapy: Prophylactic

Prophylaxis of Tension-Type Headache

• Overview of tension-type headaches (TTH), the most common primary headache disorder.
• Explanation of the need for prophylactic treatment in frequent and chronic TTH.

Prophylactic Treatment Strategies

First-line Agents for TTH Prophylaxis:

• Amitriptyline (Tricyclic Antidepressant)
  • Dosing: Start with a low dose (e.g., 10-25 mg PO at night) and titrate slowly to minimize side effects. The effective dose typically ranges between 25-75 mg per day.
  • Adverse Effects: Drowsiness, dry mouth, constipation, weight gain, and potential cardiac effects in high doses or in patients with pre-existing heart conditions.

• Venlafaxine (Serotonin-Norepinephrine Reuptake Inhibitor)
  • Dosing: Begin with a low dose (e.g., 37.5 mg PO daily) and gradually increase based on response and tolerance. Usual therapeutic doses range from 75-150 mg per day.
  • Adverse Effects: Nausea, dry mouth, dizziness, insomnia, and increased blood pressure at higher doses.

Second-line Agents for TTH Prophylaxis:

• Mirtazapine (Atypical Antidepressant)
  • Dosing: Initial dose is often 15 mg at bedtime, with possible increases to 30 mg if tolerated and needed.
  • Adverse Effects: Sedation, increased appetite, weight gain, and dry mouth.

• Tizanidine (Muscle Relaxant)
  • Dosing: Start with 2 mg at bedtime, with gradual increases to 4-6 mg as needed. The maximum dose is generally 12-24 mg per day, divided into three or four doses.
  • Adverse Effects: Drowsiness, dry mouth, weakness, and hypotension.

General Considerations:

• Titration: Slow titration is important to minimize side effects and improve patient adherence.
• Monitoring: Regular follow-up is needed to assess efficacy, side effects, and the need for dosage adjustment.
• Treatment Duration: Prophylactic treatment is typically continued for at least 6 months. If effective, it may be continued for longer periods based on individual patient needs.

• Muscle Relaxants: Tizanidine or baclofen may be considered in some cases.
• NSAIDs: Long-term use is generally not recommended due to potential side effects but may be considered for episodic use.

Choosing the Right Medication

• Individualization based on patient’s medical history, comorbid conditions, and medication side effects.
• Consider lower starting doses, particularly with TCAs, to minimize side effects.

Duration of Prophylactic Therapy

• Typically, a trial period of 6-12 months is recommended.
• Gradual tapering and discontinuation if headache frequency significantly decreases.

Non-Pharmacological Approaches

• Physical Therapy
  • Neck exercises, posture training, and relaxation techniques.
  • Biofeedback and cognitive-behavioral therapy (CBT) to manage stress and muscle tension.

• Lifestyle Modifications
  • Regular exercise, adequate hydration, balanced diet, and proper sleep hygiene.
  • Avoidance of known headache triggers.

Monitoring and Follow-Up

• Regular follow-up appointments to monitor treatment efficacy and side effects.
• Adjustments to treatment plan based on patient response and preferences.

Patient Education

• Importance of medication adherence and potential side effects.
• Encouragement of self-management strategies, including stress reduction and lifestyle modifications.

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Management of Cluster Headaches

• Overview of cluster headaches, characterized by severe, unilateral pain typically around the eye or temple.
• Description of the episodic and chronic forms of cluster headache.

Acute Treatment of Cluster Headache Attacks

• Oxygen Therapy
  • High-flow oxygen (100% at 7-15 L/min) for 15-20 minutes.
  • Effective for rapidly aborting attacks in up to 70% of patients.

• Triptans
  • Sumatriptan: Subcutaneous injection (6 mg) or intranasal spray (20 mg).
  • Zolmitriptan: Intranasal spray (5-10 mg).
  • Rapid onset, but limitations include frequency of attacks and potential cardiovascular side effects.

Prophylactic Treatment

• Verapamil
  • First-line prophylactic agent.
  • Initial dose: 240 mg/day in divided doses, titrated upwards as needed and tolerated.
  • Effective dose range: 240-960 mg/day.
  • Monitor for cardiac side effects; ECG recommended before and during treatment.

• Lithium Carbonate
  • Used particularly in chronic cluster headache.
  • Dosing: 300-900 mg/day, aiming for serum levels of 0.6-1.2 mEq/L.
  • Requires monitoring for lithium levels, renal function, and thyroid function.

• Corticosteroids
  • Prednisone or prednisolone: Used for short-term prophylaxis.
  • Typical starting dose: 60 mg/day, tapered over 2-3 weeks.
  • Effective for rapid relief but not suitable for long-term use due to side effects.

• Other Agents
  • Topiramate, melatonin, and greater occipital nerve injections may be considered based on individual response and tolerability.

Transition Treatments

• Used to bridge the gap between initiation of prophylactic therapy and its onset of action.
• Short course of corticosteroids often used for this purpose.

Surgical and Neuromodulation Therapies

• Reserved for patients with refractory chronic cluster headaches.
• Options include deep brain stimulation, occipital nerve stimulation, and sphenopalatine ganglion stimulation.

Patient Education and Lifestyle Considerations

• Importance of avoiding triggers (e.g., alcohol, certain foods).
• Regular sleep patterns and stress management.

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CGRP Antagonists in Headache Management

• Overview of the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology and the development of CGRP antagonists as a novel therapeutic approach.

CGRP Antagonists for Abortive Treatment of Migraines

1. Ubrogepant

• Oral CGRP receptor antagonist for acute treatment of migraine with or without aura.
• Dosing: 50-100 mg as needed, up to a maximum of 200 mg per day.
• Effective in reducing pain and migraine-associated symptoms.

1. Rimegepant

• Oral CGRP receptor antagonist for acute migraine treatment.
• Dosing: 75 mg as needed, not to exceed one dose in 24 hours.
• Demonstrates efficacy in pain relief and symptom reduction.

CGRP Antagonists for Migraine Prophylaxis

1. Erenumab

• Human monoclonal antibody targeting the CGRP receptor.
• Dosing: 70-140 mg subcutaneously once monthly.
• Shown to reduce monthly migraine days and acute medication use.

1. Fremanezumab

• Humanized monoclonal antibody targeting CGRP.
• Dosing: 225 mg monthly or 675 mg every three months.
• Effective in reducing the frequency of migraine headaches.

1. Galcanezumab

• Humanized monoclonal antibody that binds to and inhibits CGRP.
• Dosing: 120 mg subcutaneously monthly, with a 240 mg loading dose.
• Reduces the number of migraine days and acute medication use.

Mechanism of Action

• CGRP antagonists inhibit the action of CGRP, a neuropeptide involved in migraine pathogenesis, thereby reducing neurogenic inflammation and vasodilation.

Adverse Effects

• Generally well-tolerated with a favorable safety profile.
• Common side effects include injection site reactions, constipation, and nasopharyngitis.

Clinical Trials

1. STRIVE Trial: Erenumab for Episodic Migraine Prophylaxis

Study Title: “Efficacy and Safety of Erenumab in Preventing Migraines”

Publication: New England Journal of Medicine, 2017.

Study Design:

• Phase 3 randomized, double-blind, placebo-controlled trial.
• Participants: Patients with episodic migraine.

Methods:

• Participants were randomized to receive either placebo, 70 mg erenumab, or 140 mg erenumab subcutaneously once per month for six months.
• Primary endpoints were the change in mean monthly migraine days and safety/tolerability.

Results:

• Both doses of erenumab significantly reduced the mean number of migraine days per month compared to placebo.
• Erenumab also reduced the use of acute migraine-specific medication.
• Well-tolerated with a safety profile similar to placebo.

Conclusion:

• Erenumab is effective in reducing migraine frequency in patients with episodic migraine and has a favorable safety profile.

2. ACHIEVE II Trial: Ubrogepant for Acute Migraine Treatment

Study Title: “Ubrogepant for the Treatment of Migraine”

Publication: The Lancet, 2019.

Study Design:

• Phase 3 randomized, double-blind, placebo-controlled trial.
• Participants: Adults with a history of migraine with or without aura.

Methods:

• Participants were randomized to receive placebo, 25 mg ubrogepant, or 50 mg ubrogepant to treat a single migraine attack of moderate-to-severe intensity.
• The primary endpoints were pain freedom and freedom from the most bothersome symptom (MBS) two hours after treatment.

Results:

• A significantly greater percentage of patients achieved pain freedom at two hours with both doses of ubrogepant compared to placebo.
• Both doses also demonstrated higher rates of freedom from the MBS at two hours.
• Ubrogepant was well-tolerated, with adverse event rates similar to placebo.

Conclusion:

• Ubrogepant is an effective and well-tolerated treatment for acute migraine attacks, offering a new option for patients seeking non-triptan-based therapies.

These trials are significant as they demonstrate the efficacy and safety of CGRP antagonists, representing a new era in migraine treatment for both prophylaxis and acute management.