Headache Drugs

Question 1

What are the proposed pathophysiology for migraines?

Answer 1

Vascular Hypothesis: vasoconstriction in cerebrum results in aura due to changes in blood flow…then vasodilation in extracranial/intracranial vessels leading to pain (serotonin-mediated?)

Neuronal Dysfunction: trigeminovascular system initiates and promotes tissue inflammation when activated, resulting in neuropeptide release that causes vasodilation and inflammation = pain

Question 2

What medications may trigger migraines?

Answer 2

Cocaine, nicotine, nitroglycerin, hormones, Indomethacin, Cimetidine, Nifedipine, Fluoxetine

Question 3

What is the difference between a common migraine versus a classic migraine?

Answer 3

Majority of migraines are “common” (without aura) and must fit 2/4 criteria (worse with physical activity, pulsating, unilateral, moderate/severe pain)…and 1/2 (N/V or photophobia/phonophobia)

“Classic” migraine has aura with 2/3 criteria (homonymous visual symptoms/unilateral sensory symptoms), 1+ aura symptom over 5+ minutes or aura symptoms in succession over 5+ minutes, each symptom lasting 5-60min)… and aura needs to have at least 1 of the following (fully reversible visual symptoms or dysphasic speech or sensory symptoms)

Question 4

What is the difference between the two guidelines for migraine therapy 1st line? (ACP-ASIM vs. USHC)

Answer 4

ACP-ASIM (step therapy): Use NSAIDs or Combo, then migraine specific agents if it does not work

USHC (stratified therapy): use migraine specific agents in severe migraine

Question 5

List the types of non-specific and migraine-specific drug categories used to manage migraines

Answer 5

Non-specific: NSAIDs (inhibits prostaglandin synthesis), Analgesics (for pain), Antiemetics (for vomiting), Corticosteroids (for inflammation)

Migraine-Specific: Ergot derivatives, 5-HT1B/1D agonists

Question 6

What non-specific meds are used as first-line treatment for migraines?

Answer 6

NSAIDs

Meant to be 1st line for mild to moderate migraines (inhibits prostaglandin synthesis to inhibit inflammation in trigeminovascular system)

i.e. Aspirin, Naproxen, Ibuprofen, APAP (acetominophen) + ASA + Caffeine (Excedrin Migraine)

Question 7

What is the exception for using opioids for migraine?

Answer 7

Reserved ONLY for severe migraine headache that is unresponsive to other treatments

Little data to support use for migraine

Question 8

What class of migraine drugs does Butorphanol (Stadol nasal spray) belong to?

Answer 8

Opioid and has abuse potential

It is a synthetic narcotic antagonist-agonist

Question 9

Barbituate Combinations (hypnotics) for non-specific migraine therapy

Answer 9

Combined with analgesics or codeine

Potential for overuse for moderate-severe migraine

i.e. Fiorinal (Butalbital, aspirin, caffeine)…
Fioricet (which is the same formula but replacing aspirin with acetaminophen) is no longer on market because of liver toxicity

Butalbital is a CNS depressant

Drug interactions: Butalbital is affected by barbiturates (either increased or decreased effects)

• Increased by Phenothiazine, Quinidine, Cyclosporine, Theophilline, and beta blockers
• Decreased by Chloramphenicol, Benzodiazepines, CNS depressents

Question 10

Ergot Alkaloids (migraine-specific)
i.e. Ergotamine tartrate and dihydroergotamine

Answer 10

5-HT1 (serotonin receptor) agonist…also activity of alpha, beta-adrenergic receptors and DA receptors (meaning is not very specific to serotonin)

Constricts intracranial vessels and inhibits development of neurogenic inflammation in the trigeminovascular system

Question 11

Ergotamine Tartrate ACUTE side effects

Answer 11

Due to the fact it is not very specific

N/V (pre-treat with antiemetic), diarrhea, weakness, tremor, dizziness, syncope, etc.

It is good at constricting vessels so also chest pain, intermittent claudication, and syndrome of ergotism (peripheral ischemia, cold, numb extremities, diminished peripheral pulses)

Question 12

Ergotamine Tartrate CHRONIC side effects

Answer 12

Cerebral/peripheral ischemic disorders, hypertension, tachy/bradycardia, medication overuse headache, renal issues, withdrawal signs (severe HA, N/V, malaise)

Question 13

Ergotamine contraindications

Answer 13

Sepsis, renal/hepatic failure, pregnancy/lactation, glaucoma, peptic ulcer disease
Uncontrolled HTN, CHD/stroke/PVD
Potential interactions with protease inhibitors

Do not use if have used a triptan within the same 24 hours
(Triptan contraindications are also similar)

Question 14

Ergotamine drug interactions, what liver enzyme is it a substrate for?

Answer 14

Ergotamine is a CYP3A4 substrate so it interacts strongly with 3A4 inhibitors (i.e. Azole Antifungals, Macrolides, Protease inhibitors)

Has an additive vasoconstrictive effect if combined with Triptans (which has a similar MOA)

And since it competes for 3A4 metabolism, it has an interaction with Fluoxetine and Fluvoxamine

Question 15

How are Triptans different from Ergotamines for treating migraines?

Answer 15

Triptans are SELECTIVE 5-Ht1B/1D agonists and they are 1st line for moderate-severe migraine

Results in intracranial vasoconstriction, inhibition of neuropeptide release from trigeminovascular nerves, and interrupts pain signal within brain stem trigeminal nuclei

Question 16

Name 3 Triptans

Answer 16

Sumatriptan (Imitrex)
Rizatriptan (Maxalt)
Zolmitriptan (Zomig) - substrate for CYP1A2

Sumatriptan and Zolmitriptan are also available as nasal sprays, Sumatriptan is also available as an SQ injection

Question 17

Triptan side effects

Answer 17

Dizziness, fatigue, nausea
Chest tightness, pressure, heaviness, pain
Injection reaction
Taste perversion from the nasal sprays

Question 18

Triptan contraindications

Answer 18

Do not take if took an ergot alkaloid in last 24 hours or MAOI in the last 2 weeks

Since is a vasoconstrictor…
Do not take if have ischemic heart disease, cerebrovascular disease, uncontrolled HTN, hemiplegic and basilar migraine

Question 19

Triptan drug interactions

Answer 19

MAOI inhibits clearance of Triptans, which causes a risk of serotonin syndrome

SSRIs (selective serotonin reuptake inhibitors) increase risk of serotonin syndrome

Ergotamine containing products can add onto the vasoconstrictive effects of Triptans

Question 20

What is Serotonin Syndrome?

Answer 20

Predictable consequence of excess serotonin on CNS or PNS

Hyperthermia, muscle rigidity, rapid change in mental status and vitals

Question 21

What is considered prophylactic (preventative) drug therapy for migraines?

Answer 21

Migraines occurring 2-3 times monthly are in a predictable pattern, but may want to prevent in patients unable to take or are refractory to abortive therapy OR if migraines are long lasting/severely impairing (3+ days disabled monthly)

Medications selected based on side effects and patient comorbid conditions (therapy consists of trial period, continuation until decreased recurrence/severity, then taper off)

*unable to take abortive therapy i.e. patients with ischemic disorders or severe HTN

Question 22

What is 1st line treatment for prophylactic migraine therapy?

Answer 22

Beta-blockers and also Tricyclic Antidepressants (TCA)

Question 23

Beta-blocker examples and how do they work against migraines?

Answer 23

Beta-blockers i.e. propranalol, metoprolol, atenolol and nadolol

Mechanism unknown, possible that regulates serotonin transmission in cortical pathways

Contraindicated in patients with peripheral vascular disease, depression, and asthma

ADR: fatigue, vivid dreams, depression, bradycardia, and hypotension

Question 24

Tricyclic Antidepressants (TCA) examples and how do they work against migraines?

Answer 24

TCA i.e. imipramine, nortriptyline, and amitriptyline

Mechanism through antagonism of 5-HT2 (reuptake) receptors resulting in inhibited reuptake of serotonin

Contraindicated for glaucoma or pregnancy

ADR: sedation, constipation, blurred vision, hypotension

Drug interaction with MAOI

Question 25

Anticonvulsant examples and how they might work against migraines (prophylaxis)

Answer 25

Valproic Acid and Divalproex Sodium
(also carbamazepine, topiramate, and gabapentin but these haven’t been as studied):

Mechanism is through increased availability of GABA-inhibitory transmitter

Contraindicated for liver disease

ADR: tremor, weight gain, nausea, hair loss

Drug interactions with other anticonvulsants, CNS depressants, absence seizure in combo with clonazepam

Question 26

Examples of calcium channel blockers that may be prophylactic against migraines?

Answer 26

Verapamil, Nimodipine, and Diltiazem

These cause vasodilation that decrease muscle tone and vascular resistance (on the premise that the start of migraines are due to initial vasoconstriction)

Question 27

Why is Methysergide (Sansert) not 1st line for migraines?

Answer 27

It is a peripheral 5-HT inhibitor but central 5-HT agonist

Effective but has serious side effects i.e. fatal pulmonary fibrosis

Must only use for 6 months followed by 3-4 week drug free period

Question 28

Although it is not FDA approved, how might Botulinum Toxin Type A (Botox) help treat migraines?

Answer 28

Inhibits Ach release which should inhibit overactive peripheral neurons. It may also modulate substance P. It does not cross the BBB.

Question 29

What are some natural products for migraine treatment?

Answer 29

Effective for acute therapy: caffeine with APAP and ASA (since acute, means is not an effective prophylactic long-term option)

Possibly effective or prevention: Butterbur, Coenzyme Q-10, Feverfew, magnesium (especially at high dose in patients with low magnesium levels), riboflavin

Ineffective or not enough evidence = fish oil, capsaicin intranasally, ginger, L-arginine, melatonin, olive oil

Question 30

What drugs should be tried for intractable migraines?

Answer 30

DHE (a type of ergotamine) SQ, IV, or IM
Sumatriptan injectable (try this first before ergotamine)
Prochlorperazine or chlorpromazine for antimigraine and antiemetic properties
Narcotics
Corticosteroids to suppress perivascular inflammation or resistant headache

Question 31

What is the most common primary headache and how is it classified?

Answer 31

Tension-type headache

Pathophysiology unknown but thought to be similar to migraine

Headache must last 30min-7 days and have 2/4 criteria (bilateral, pressure/tightening non-pulsating quality, mild or moderate intensity, not worse with routine physical activity)..no N/V

Precipitants include anxiety, depression, situational stress

Question 32

What are some drug therapies for tension-type headaches?

Answer 32

Analgesics (possibly with caffeine) for mild-moderate i.e. APAP, ASA, Ibuprofen, Naproxen
Sedatives: Butalbital i.e. Fiorinal
Prophylactic: TCAs, muscle relaxants even though there is no data to support it (i.e. methocarbamol/Robaxin, orphenadrine/Norflex, cyclobenzaprine/Flexeril)
Botulinum toxin

Question 33

What is a cluster headache?

Answer 33

Unknown pathophysiology, thought to have extracerebral vasodilation component

Intense, stabbing, unilateral behind the eye, ipsilateral tearing and nasal stuffiness with possible ptosis and miosis
Usually at night for 30-90 minutes and in clusters for a while…then gone and then returns months or years later

Question 34

What are possible acute treatments and prophylaxis for cluster headache?

Answer 34

Acute treatment: Imitrex SQ (since nasal is less effective, oxygen 100%, ergotamine, DHE-45, Lidocaine nasal spray

Prophylaxis: Verapamil, Prednisone, Ergotamine, Methysergide, Lithium