What a Long, Strange Triptan It’s Been

Headaches for the RITE

Worst headache of life, artist’s depiction

Ryan Jacobson

This Lecture: Why & What• Identified as an area of deficiency in many years• Many questions pertain to headache pathophysiology and management

each year• Case-based scenarios and review based on data from the last 4ish years

Case 1

• A 29-year-old baker has been busy tasting pies. Eventually he develops symptoms of flushing, palpitations, tingling in his extremities, and a severe headache. He is hallucinating. He does not have a history of migraine. Which ingredient has he over-indulged in?

Case 1

• Nutmeg. • Mediated by a chemical in nutmeg myristicin,

which acts as a hallucinogen• Symptoms improve over several hours.

Benzodiazepines can be used for agitation• Tested multiple times

Case 2• A 29-year-old woman with no previous history

presents with a left-sided headache. Photophobia and vomiting are present. She endorses seeing flashing lights in her vision, a symptom that began just before the headache. She notes poor sleep over the previous 3 days. Family history notable for sister with migraine.

• Exam: afebrile. no papilledema. No nuchal rigidity.

• What is your next step?– Lumbar puncture– PET scan– IV phenytoin load– Triptan

Case 2• Migraine

• Can treat for migraine with triptan. Triptans work at 5HT1 receptors, 1b 1d subtypes.

• Remember triptans are contraindicated with known CAD

• Note: if they give you a scenario where a woman is being abused and has migraines, address the abuse first. Tested 2013.

• “This patient's symptoms are most compatible with migraine. There are no features of her history or examination to suggest a more serious underlying disorder such as meningitis, subarachnoid hemorrhage, or a space occupying lesion. Parenteral symptomatic therapy is warranted of which sumatriptan would likely be most effective.”

Case 3

• A 43 year old man presents with head pain that wakes him up in the early morning hours. He describes pain behind his right eye that occurs in severe attacks. He has noticed tears coming out of the right eye during the attacks.

• He cannot provoke episodes by touching the right side of his face. He denies trauma.

Case 3

• Cluster Headache• There is an association with smoking.• Oxygen should abort headache. DHE less

effective. Prednisone can potentially prevent recurrence of headache.

• “What can prevent the next headache?”

• We will re-visit some details of cluster headache in a few slides

Case 4

• A 33-year-old woman presents for evaluation of episodes of head pain. She has not seen a doctor for these, because the attacks of pain only last about 5-8 minutes. The pain is located over her left eye and temple. During the attacks, she has noticed some discharge from her left eye and nose on some occasions. Which treatment should be offered?

Case 4

• The diagnosis is paroxysmal hemicrania. • Some autonomic features.• The headaches are Indomethacin responsive.• “Side-locked”• Minutes long, several times a day.• More common in women. • Tested multiple times, essentially every year

Contrast with Hemicrania Continua

• Constant unilateral headache, temporal or periorbital

• Also more common in women • Can have exacerbations that sound

migrainous or cluster-like • Child with hemicrania continua was on

2011 exam. Adult in 2012. Child in 2015 (why?!)

• Also indomethacin responsive (by definition)

• “A continuous, unilateral headache is most likely hemicrania continua, one of the trigeminal cephalgias. It is very responsive to indomethacin, and this can be used as both a treatment and diagnostic trial.”

Contrast with Cluster Headache

• More common in men• Associated with smoking (appears to

have been tested in 2012) • Remember, oxygen is useful. This

was tested in 2012 and 2013. • Time duration between that of

paroxysmal hemicrania and hemicrania continua

Case 4-A

• A 33-year-old man presents with unusual head pains. He says that he gets sudden bouts of brief of right eye and temple pain. They are so short, that they last for one commercial on TV.

Nothing provokes them. His wife notes that he has no pain tolerance, since tears are always coming out of his right eye during the episodes of pain. What is the best diagnosis, and what are the next steps?

Case 4A

• SUNCT – short-lasting unilateral neuralgiform headache with conjunctival injection and hearing

• Think BUNCT - these are the briefest of the TACs - 5-240 seconds

• Conjunctival injection and tearing prominent in story

• SUNCT (5-240 seconds) < Paroxysmal Hemicrania (women!) < Cluster < Hemicrania Continua

Case 4A, continued

• In SUNCT, consider imaging to rule out skull base lesion.

• Some role for IV Lidocaine

Does patient have HA?

Just a Headache? Not Just a Headache?

MELAS INFECTION CADASIL SAH

MIGRAINOUS POSITIONAL/MENINGEAL ENHANCEMENT PAPILLEDEMA/OBESE AUTONOMIC/TAC

CSF HYPOTENSION. RECOMMEND

BLOOD PATCH. PSEUDOTUMOR. Consider if on Vitamin

A derivatives.

PROPHYLACTIC NEEDED? ABORTIVE NEEDED? MEDICATION OVERUSE?

-CONSIDER TOPIRAMATE. -TRIPTAN IF NO C/I -DISCONTINUE OFFENDING AGENT

-NO VPA IF WOMAN.

-AVOID BB IN ASTHMA

MAN/MANY MINUTES MAN/FEW SECONDS WOMAN/SECONDS-MINUTES WOMAN/CONTINUOUS

CLUSTER SUNCT PAROXYSMAL HEMICRANIA HEMICRANIA CONTINUA

OXYGEN INDOMETHACIN

DID I MISS SOMETHING… IS IT A TAC?

NO YES

Consider lidocaine

Case 5

• A 76-year-old retired horticulturist presents for evaluation of headaches. She is distraught, as she has never had headaches before. She has pain over the right temple. The pain has been worsening over time. She has lost weight in the past 10 days, because her jaw and tongue hurt with chewing.

• Review of Systems notable for fatigue and shoulder aches

• What are your next steps, and in which order?

Case 5

• The diagnosis is temporal arteritis.• Next steps:

– Check ESR– Give steroids urgently– Temporal artery biopsy to follow as soon as

possible2014: steroids before biopsy may result in scar tissue

rather than inflammation in biopsy specimen

Case 6• A 38-year-old migraineur has been relatively headache free for the last 6 months.

She slips on an icy sidewalk, striking her neck. She now has a new type of headache, described as severe, diffuse head pain. Associated features include nausea and tinnitus. She notes that the pain is 10/10 when upright, and 1/10 when supine. Her MRI is shown.

Case 6

• Answer: intracranial hypotension. • They have given a traumatic precipitant. • Imaging shows diffuse dural enhancement.

(HOPEFULLY they give you an image with smooth, diffuse enhancement to steer you away from cancer)

• If no image is given, they want you to identify it with MR imaging or CT myelogram. Do not go for LP or cytology.

Case 6 continued

• The patient wishes for a medication that will be safe with breast feeding. Which of the following is the safest option?

• 1. Aspirin• 2. Heavy duty barbituates• 3. Sumatriptan• 4. Amitriptyline • 5. Hydrocodone-Acetaminophen

Case 6 continued

• They want you to say that narcotics are safest.

• While the amount of most drugs excreted in breast milk is 1% to 2% of the maternal dose, there is some variability depending on both the drug's characteristics and breast milk's characteristics. Barbiturates may cause sedation; aspirin is considered less safe than acetaminophen; triptans and tricyclic antidepressants are of unknown risk to the infant; while narcotics are safe.

Case 7 • In peds clinic you see 2 patients -

• Patient 1 Savannah is a 9 year old girl with frequent headaches for the past 2 months. They are located over the temple, and occasional cause vomiting. They are getting no better. Exam is normal.

• Patient 2 Dylan is a 10 year old boy with headaches for the past 2 months. They are gradually worsening. When the headache is most severe, he loses vision. Examination is notable for right hemibody ataxia.

• Which one needs imaging?

Case 7

• The second patient (obviously)

• “The majority of children with recurrent headaches, with complete clearing between episodes, do not need neuroimaging. The following would mandate neuroimaging in a child presenting with headaches: auras lasting more than an hour, persistent neurologic findings, abnormal neurologic exam between headaches, predominantly occipital headaches, loss of vision at headache peak, or recent significant change in headache pattern.”

Case 7 continued

• Which treatment is best for Patient 1?

• Dietary Modification? Sumatriptan? Valproate? Stress Management? Topiramate?

Case 7 continued

• Which treatment is best for Patient 1?• Dietary Modification? Sumatriptan?

Valproate? Stress Management? Topiramate?

• Prescribe topiramate instead of valproate in a young woman for a prophylactic medication. Choose a medication over a behavioral modification.

Case 7 continued

• Savannah comes back 6 months later. She notes episodic flank pain and hematuria. Which of the following is most likely responsible?

• -struvite stones• -calcium phosphate stones• -calcium oxalate stones• -stress reaction

Case 7 continued

• Calcium oxalate stones.

• Remember - “topamaxalate”

• Tested multiple times

Other Topiramate side effects?Paresthesias, Cognitive Symptoms, Fatigue,

Insomnia, Loss of appetite, anxiety, dizziness

• Savannah’s mom also requests a triptan in addition to the topiramate. Which one has the longest half life?

Case 7 Continued

• Savannah’s mom also requests a triptan in addition to the topiramate. Which one has the longest half life?

-Frovatriptan has the longest half life “Frova” - 26 hours

Was on the test twice in 2015. Why, I don’t know. I’m just giving the lecture.

Triptans

• Fast Onset, High Efficacy at 2 hours– Sumatriptan, zolmitriptan, rizatriptan,

almotriptan, eletriptan

• Slow onset, lower response rate at 2 hours – Naratriptan (Amerge), frovatriptan

Case 7, continued.

• Savannah the migraineur’s history is most likely to include the following?

• -Episodes of extremities turning red • -Episodes of dizziness/vertigo• -Episodes of teeth itching• -Gravel in the stool • -Transient Monocular Vision loss• -Giraffe bite between ages of 18

months and 3 years

Case 7, continued.

• -Episodes of Dizziness/Vertigo

• “benign paroxysmal vertigo, a syndrome that occurs in children in the first 5 years of life and is a frequent precursor of migraine. Investigations (MRI, EEG) are normal. The episodes usually resolve by the end of the first decade.”

Case 8

• A 34-year-old woman has never had headaches before. Over the past 3 months, she has had a constant headache located over both temples, 6/10 in severity. There is no photophobia or nausea. Of note, she had a febrile illness with lymphadenopathy in the two weeks before this illness started.

• What is the best diagnosis?

Case 8

• New daily persistent headache.

• Do not have a history of headaches and gradual worsening

• May be related to viral infection around the time of headache onset.

Case 9 • A 43-year-old man presents with

headaches and abnormal brain MRI. He has headaches 3 times per week, unilateral, throbbing, and associated with photophobia and phonophobia. His MRI is shown.

Case 9

• What should you advise?• 1. Admit now, consult neurosurgery• 2. Refer to neurosurgery as an

outpatient.• 3. Reassure.

Case 9 • Reassure. It’s a Developmental Venous Anomaly. It is incidental.

• A developmental venous anomaly (DVA) or venous angioma is occasionally identified in the work-up of patients with neurological symptoms. Headache is the most common symptom. Seizures are also commonly associated. There is no real evidence, however, that either headaches or seizures are caused by the DVA, and in most instances the DVA is incidental. It is very important to understand that the DVA represents the venous drainage of the brain tissue in which it is situated. Removal of the DVA may cause a venous infarction.

• Radiographically these can have a “caput medusae” type appearance, are common around the periventricular white matter, and will be more obvious on post-contrast images.

Case 10

• A migraine patient comes to clinic. His medication list includes:

• -Sumatriptan• -Fentanyl Patch• -Butalbital• -Lisinopril• -Lamotrigine• He complains of increased sweating. Also

he has rebound headaches. Which medications are most likely responsible?

Case 10, continued.

• Fentanyl and opioid agonists can be associated with hyperhidrosis

• Lamotrigine, lisinopril, triptan “should not cause rebound headache”

• Medication overuse headache tested in 2011/2012 - “often responds to withdrawal of minor analgesics, with or without the addition of prophylactic medication.”

Case 11

• A 23-year-old woman presents to clinic and has been getting 4 headaches per week. PMHx is notable for asthma and Raynaud’s phenomenon. Which medication is best?

• Propranolol• Verapamil• Depakote• Prednisone• Homeopathic Remedies

Case 11

• Choose Verapamil - remember that beta blockers are contraindicated in asthma, and not ideal in Raynaud’s.

• Read the question to see if they want you to choose a prophylactic or abortive

• Do not choose VPA in a woman of child bearing age

Case 12 • A 7-year-old girl presents with headaches and

double vision. She gets headaches twice weekly. They last for 2 hours. They are located over the right side of the head, and can be accompanied by nausea and phonophobia. She has a headache now. Exam is notable for aniscoria with right pupil being larger, and slightly limited adduction supraduction and infraduction of the right eye. What is the best Diagosis?

• Aneurysm• Complicated Migraine• Myasthenia Gravis• Miller-Fisher Syndrome • Likely history of giraffe bite between 18 months

and 3 years

Case 12

• Complicated Migraine

• “A partial third nerve palsy associated with headache in young children is most commonly due to ophthalmoplegic migraine. Cerebral aneurysms presenting as a partial third nerve palsy would be extremely unusual in young children. Myasthenia gravis does not present with pain, and pupillary involvement would be unusual. Cerebral aneurysm, Miller-Fisher syndrome, and a brainstem tumor would have other findings on careful neurologic examination.”

Case 13

A 23-year-old obese woman presents with headaches and vision loss. Her fundoscopic image is shown. Which medication does she most likely take?

-Isotretinoin-Amlodipine-St. Johns Wort-Ceftriaxone

Case 13

• Isotretinoin. Pseudotumor cerebri can be associated with derivatives of Vitamin A.

• Tested 2012, 2013

Case 14• A 33 year old woman presents with worst

headache of her life. She has a history of severe migraines, but the headaches in the last week have been worse. She has had at least 5 headaches in the past week, all of which began like a sudden thunderclap. She had left hand numbness which resolved, and her husband noticed a right face droop which resolved. She recently started a new medication.

• LP and CT head are normal. What is the most likely diagnosis?

Case 14• Diffuse Cerebral Vasoconstriction

Syndrome• (AKA RCVS, AKA Call Fleming). The RITE

appears to call it Diffuse Cerebral Vasoconstriction Syndrome.

• Can result in SAH • Story will sound like SAH - they want to

know if you’ll chase it or think of the diagnosis

• Angiogram will show segmental arterial narrowing which improves over time.

• Tested 2X in 2014 and in 2015. • Which medications are most commonly

responsible for attacks?

Case 14, continued

• SSRIs

• Any vasoactive medication can provoke worsening symptoms

Case 15

• A 33-year-old migraine patient calls at 5:05 pm for a refill of her Tramadol. What is the mechanism of this drug?

1. Works peripherally to decrease epinephrine release

2. Works centrally at mu opioid receptors, inhibits norepinephrine and serotonin reuptake.

3. Works centrally at delta and kappa opioid receptors, inhibits norephinephrine and serotonin reuptake.

4. Decreases production of bad humors, particularly black

bile

Case 15

• The correct answer is B• Tested in 2014• Tramadol, a centrally acting analgesic structurally

related to codeine and morphine, consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+)-Tramadol and the metabolite (+)-O-desmethyl-tramadol (M1) are agonists of the mu opioid receptor. (+)-Tramadol inhibits serotonin reuptake and (-)-tramadol inhibits norepinephrine reuptake, enhancing inhibitory effects on pain transmission in the spinal cord. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate.

Headache Greatest Hits• Cluster Headache - Give ‘em oxygen. Men.• SUNCT – The S is for Short. Men. Rule out skull base lesion.• Paroxysmal Hemicrania - women. Minutes long. Look for it. • Hemicrania Continua - continuous. Women. Indomethacin. MOST

TACs on exam MOST YEARS.• Pseudotumor - Vitamin A derivatives. May show fundoscopic

picture.• Low Pressure headache - after an LP or fall. Diffuse dural

enhancement. Don’t say meningitis. • Medication Overuse headache - acetaminophen, caffeine,

barbituates. Solution, don’t use those things.• CADASIL - yes, migraine, but also focal symptoms, very abnormal

imaging. NOTCH3 mutation on chr.19.

Does patient have HA?

Just a Headache? Not Just a Headache?

MELAS INFECTION CADASIL SAH

MIGRAINOUS POSITIONAL/MENINGEAL ENHANCEMENT PAPILLEDEMA/OBESE AUTONOMIC/TAC

CSF HYPOTENSION. RECOMMEND

BLOOD PATCH. PSEUDOTUMOR. Consider if on Vitamin

A derivatives.

PROPHYLACTIC NEEDED? ABORTIVE NEEDED? MEDICATION OVERUSE?

-CONSIDER TOPIRAMATE. -TRIPTAN IF NO C/I -DISCONTINUE OFFENDING AGENT

-NO VPA IF WOMAN.

-AVOID BB IN ASTHMA

MAN/MANY MINUTES MAN/FEW SECONDS WOMAN/SECONDS-MINUTES WOMAN/CONTINUOUS

CLUSTER SUNCT PAROXYSMAL HEMICRANIA HEMICRANIA CONTINUA

OXYGEN INDOMETHACIN

DID I MISS SOMETHING… IS IT A TAC?

NO YES

Consider lidocaine

Medication Overuse Headache

According to the International Classification of Headache Disorders, 2nd edition, the definition of medication overuse headache (MOH) continues to evolve over time. The recently published new appendix criteria for a broader concept of chronic migraine of the International Headache Society define MOH as 1) headache present > 15 days/month; 2) regular overuse for 3 months of one or more acute/symptomatic treatment drugs, defined as: ergotamine, triptans, opioids, or combination analgesic medication on 10 days /month on a regular basis for >3 months; or simple analgesics or any combination of ergotamine, triptans, analgesics, opioids on 15 days/month on a regular basis for >3 months without overuse of any single class alone.

-May use phenobarbital to help wean off barbituates.

CGRP

• Calcitonin gene-related peptide (CGRP) is derived, with calcitonin, from the CT/CGRP gene located on chromosome 11. It is primarily produced in nervous tissue; however, its receptors are expressed throughout the body. It is found in every location described in migraine genesis and processing, including meninges, trigeminal ganglion, trigeminocervical complex, brainstem nuclei, and cortex. It is released in animal models following stimulation of the CNS similar to that seen in migraine, and triptans inhibit this release. Injection of CGRP into migraineurs results in delayed headache similar to migraine. Elevation of CGRP occurs during migraine, resolving following migraine- specific treatment. Finally, and most importantly, CGRP receptor antagonists terminate migraine with efficacy similar to triptans.

Migraine Pathophysiology

• Unclear what they were asking about here. Buzzwords: trigeminovascular reflex, peripheral sensitization

• The pathophysiology of migraine is complex. The first phase of a migraine

attack involves activation of the trigeminovascular reflex, resulting in release of vasoactive peptides (calcitonin gene-related peptide, neurokinin A, substance P) from trigeminal afferents supplying dural blood vessels. This produces vasodilation and sterile inflammation in dural vessels, leading to activation of first-order trigeminal afferents (peripheral sensitization) and manifested clinically by throbbing head (and neck) pain. As the attack progresses, second- and third-order trigeminothalamic and thalamocortical neurons become activated, mediated primarily by nitric oxide and glutamate transmission, resulting in central sensitization. This is clinically reflected by cutaneous allodynia.