“The Medication Maze”

Norton Headache and Concussion CenterHeadache School

April 2013

Disclaimer

This talk is not inclusive of all medications used to treat migraine; this is a simplified discussion

of the common medications used in treating migraine. There is likely going to be a

medication you are on or have been treated with not discussed in this lecture, that does not

mean it is not effective or not used in the treatment of migraine.

Treating migraine• One of the biggest factors that we stress in the treatment of

migraine is thorough evaluation of triggers and lifestyle modifications– Diet– Sleep– Exercise– Hydration– Stress management

• These are all topics that at various times are discussed in other headache school sessions

• This is a talk about medications, assuming that we are already looking into and discussing other lifestyle modifications

Strategies for treating migraine

• Treating the headache attacks– Rescue medications / abortive therapy

• Preventing headache– Prophylactic / preventative therapy– Goal of preventative therapy is reducing the frequency,

severity, and duration of attacks– Success is defined as a 50% reduction– Important to remember that it is management, not a “cure”

Rationale for treating migraine

• When to choose a preventative therapy?– There is no set in stone guideline– Individualized

• Is the patient willing to take a daily medication knowing that there is a potential for side effects?

• Is the patient failing rescue medications?• Is the patient experiencing disability (missed work,

school, or family functions)?

Rescue Medications

• Primary goal is to achieve relief of pain, associated symptoms, and disability within 2 hours of use

• Goal is to use rescue medications 2 or fewer times per week to prevent developing medication overuse headache

Rescue Medications

• It is important to treat the headache as soon as possible, as time goes on the medications become less effective

• Allodynia is defined as pain resulting from stimulation that would not normally be perceived as noxious (ie. light touch of the skin)– To the patient this is perceived as scalp tingling or pain

when lightly touched during a migraine– To physicians this means that the deep parts of the brain

have been stimulated by the migraine attack and it is often times more difficult to treat

Allodynia

• Once the deeper parts of the brain are activated the migraine attack becomes much more difficult to treat– A study using injectable sumatriptan (to be discussed later)

found that in patients without allodynia 93% were free of pain at 2 hours, but only 15% of patients with allodynia were pain-free at 2 hours

• The take home message is to treat aggressively and treat early to improve chances of becoming pain-free with minimal medication use

Rescue Medications

Rescue Medications

• In treating migraine unlike treating other conditions (ie. high blood pressure) we often times suggest using higher dose medications initially and backing down the dose if side effects are experiences, rather than over time escalating doses– So it is important to understand what potential side effects

can occur with medications and understand that the goal is being pain-free with TOLERABLE side effects rather than being with pain and no side effects

Rescue Medications

• Need to use caution to avoid medication overuse headache by using rescue medications frequently

Medication Overuse Headache

• Headache present on ≥15 days/month• Regular overuse for ≥3 months of one or

more drugs that can be taken for acute and/or symptomatic treatment of headache

• Headache has developed or markedly worsened during medication overuse

• Headache resolves or reverts to its previous pattern within 2 months after discontinuation of overused medication

Medication Overuse Headache

The Cleveland Clinic Manual of Headache Therapy p. 156

Bigal ME, et al. Headache. 2008;48:1157-1168.

Bigal ME, et al. Pain. 2009;142:179-182.

Nonspecific Migraine Medications• Nonsteroidal Anti-inflammatory Drugs (NSAIDs)• Over 20 forms of NSAIDs available in the US, many

available over-the-counter• Have anti-inflammatory effects as well as analgesic

(pain relief) effects• Not processed through the liver• Kidney metabolism

– Very important for patients with kidney disease, on other medications that have effects on the kidneys, and in patients with extreme vomiting (dehydration can lead to kidney problems)

• Can lead to stomach bleeding with frequent use

NSAIDs

• Can be used alone or in combination with other medications (ie. triptans)

• Are non-sedating• Have been shown to be effective in treatment

of patients with allodynia• Because of the availability there is significant

problems with overuse, particularly leading to medication overuse headache

NSAIDs

• Ibuprofen (Advil, Motrin) 400-800mg• Naproxen (Aleve) 500-550mg

– Available combined with sumatriptan (Treximet)

• Diclofenac (Cambia, Cataflam, Voltaren) 50mg– Orally disintegrated packets (Cambia) have very rapid

onset of action

• Ketorolac (Toradol)– Oral form not frequently used– IV or IM form can be used for prolonged migraine

Acetaminophen

• Acetaminophen (Tylenol)• Most people do not find useful for severe migraine• Can be used for mild headache• Typical dose is 1000mg at onset of headache• Often times used in combination products (ie.

Fioricet, Midrin, etc)• Can lead to medication overuse headache• With heavy usage can lead to liver toxicity,

otherwise no significant side effects

Isometheptene

• Midrin– Contains isometheptene, acetaminophen, and

dichloralphenzone– Two capsules at onset, followed by one capsule

every hour until relief is achieved (max of 5 per 12 hours)

– Side effects similar to components, dizziness is common

– Modest effects– Sparsely available

Butalbital• Combination product• Butalbital / acetaminophen / caffeine

– Esgic, Fioricet• Butalbital / aspirin / caffeine

– Fiorinal• Side effects include incoordination, disinhibition, memory

problems, drowsiness• If used for extended periods of time and then discontinued

can cause withdrawal seizures• Significant risk of medication overuse headache

– Studies show when used as few as 5 times per month can lead to MOH

Excedrin

• Combination of aspirin, acetaminophen, and caffeine• Can be used for mild to moderate migraine• Due to the multiple products combined there is

significant risk of medication overuse headache• Available OTC (unregulated by treating physicians

patients can take unlimited amounts)• In specialty headache clinics this is probably the

most frequently overused medication and causes more frequent headache

Anti-nausea medications

• Can often times alone or in combination be effective in treating migraine– Metoclopramide (Reglan)– Prochlorperazine (Compazine)– Promethazine (Phenergan) to a lesser extent

• Most common side effects are drowsiness and dizziness

• More significant side effects include dystonia (sustained muscle contraction) and akathisia (sense of restlessness) which can be treated with Benadryl

Opiates

• Worth mentioning, but in the hands of headache specialists are not frequently used

• In migraine, opiates are not well absorbed, they are associated with increased nausea, and sedation

• Very quickly can lead to physical dependence and are quite notorious for causing medication overuse headache

Why opiates are bad

Migraine specific medications

Triptans

• Introduced in the 1990s• Often times considered the drug of choice in

treating migraine• Selective agonists (activators) of serotonin

blocking the release of other inflammatory chemicals during a migraine attack

Triptans

• Available in many different brand names with varying time of onset and duration of action

• Available in a variety of delivery methods– Oral tablet– Oral disintegrating– Nasal– Injection– Patch (in development)

Triptans

• Side effects– Narrow coronary blood vessels by 10-20% (avoid use in

individuals with a history of coronary or cerebro-vascular disease or uncontrolled risk factors)

– Tighten of the throat, chest, jaw, neck, and limbs– Numbness of the limbs and around the mouth– Hot and cold sensations

• Through to be due to esophageal (not heart) related spasm and muscle contractions

• If warned in advance, most patients can tolerate side effects with the benefit that they give

Triptans

• “Patients vary more than triptans”• Meaning, just because one did not help or caused

side effects does not mean that another will do the same– I give the example of Coke and Pepsi – it’s basically the

same stuff but some people like one and some people like another, and you won’t know until you’ve tried them

• Or that different routes of administration won’t have a different effect

Triptans

Sumatriptan• Imitrex, Statdose, Sumavel, Alsuma• First triptan brought to market (1991)• Available oral, nasal, and subcutaneous injection• Available as a generic• Oral dose is 25, 50, 100mg – maximum per 24 hours is 200mg

– Available in combination with naproxen as Treximet• Subcutaneous (SC) forms (Statdose, Sumavel, Alsuma) are

6mg (max 12mg / 24 hours)– Have much quicker onset of action (10 minutes) and are great for

patients with significant nausea and vomiting– Statdose and Alsuma use a needle, Sumavel is needle-less

• Nasal spray is not used all that frequently

Quick acting triptans• Almotriptan (Axert)

– 6.25mg / 12.5mg; max per day is 25mg• Rizatriptan (Maxalt)

– 5mg / 10mg / 10mg MLT (dissolvable tablet); max per day is 30mg

• If using propranolol need to use 5mg dose

• Eletriptan (Relpax)– 20mg / 40mg; max is 80mg per day

• Zolmitriptan (Zomig)– 2.5 / 5mg; available as nasal spray (5mg); max is 10mg per

day

Slow acting triptans

• Naratriptan (Amerge)– 1, 2.5mg; max is 5mg per day– Available as generic

• Frovatriptan (Frova)– 2.5mg; max is 7.5mg per day

• These are useful for menstrual migraine (as a week-long preventative)

• Also used in combination with another drug (ie. naproxen or Cambia)

Ergots

• Ergotamine tartrate available since 1925• Dihydroergotamine (DHE) more refined

version available since 1945– These were the only available migraine specific

medications until triptans introduced in 1990s• Effect many chemicals in the nervous system

which explains why they are so effective, but also explains the side effects

Ergots / DHE• Nausea is the major side effect

– May actually increase nausea of migraine rather than improve it• Again contraindicated in patients with vascular disease,

coronary artery disease, etc.• Available IV (hospital use)• Intramuscular – can be administer at home• Intranasal (Migranal) – very easy to use at home

– Inhaled in each nostril and then repeated in 15 minutes– Much less effective than IV / IM

• Orally inhaled DHE (Levadex) coming to market soon– Inhaled orally at home with blood levels as high as IV, but with less

nausea• Should be a great drug when commercially available (maybe later this

year)

Preventative Medications

Preventative Medications

• There are no “migraine specific” medications used in the prevention of migraine

• Use medications from other classes– Blood pressure medications– Antiseizure medications– Antidepressants– Serotonin antagonists– Vitamin supplements– Botox

Preventative Medications

• Important to identify patients that are using frequent rescue medications and may be on the way to developing medication overuse headache

• Patients who have disabling headache that is not easily treated with rescue medications

• Ideally treat multiple conditions with a single medicatio– ie. high blood pressure and migraine

Antidepressants• Tricyclic antidepressants

– Amitriptyline (Elavil)– Nortriptyline (Pamelor)– Protriptyline (Vivactil)

• Side effects– Elavil and Pamelor are sedating and taken at night (useful

for patients with sleep trouble)– Vivactil is stimulating, but needs to be taken 3x per day– Cause dry mouth, constipation, weight gain– At high doses can cause heart related issues that may

require an EKG to be checked

SSRI / SNRI• SSRI

– Fluoxetine (Prozac)– Paroxetine (Paxil)– Fluvoxamine (Luvox)

• SNRI– Venlafaxine (Effexor)– Duloxetine (Cymbalta)– Desvenlafaxine (Pristiq)

• SNRIs tend to be more effective for migraine than SSRIs– Venlafaxine (Effexor) has the best evidence for use in

prevention of migraine

SSRI / SNRI

• Side effects– Weight gain– Sexual dysfunction– Sedation– Nervousness

Antiseizure Medications

• Recently have become most frequently used medications for prevention of migraine– Topiramate (Topamax)– Valproate (Depakote)– Gabapentin (Neurontin)– Zonisamide (Zonegran)

Topiramate (Topamax)

• One of the most frequently used medications in the prevention of migraine

• Has several advantages, but also does have some side effects to be aware of

• Effective in nearly 50% of patients that use it• Rather than weight gain, often times causes weight

loss• Optimal dose is 50mg twice per day

– If side effects occur, sometimes may use nighttime only dosing

Topiramate (Topamax)• Side effects

– Up to 13% of patients experience cognitive dysfunction of trouble with processing information and trouble finding words

– Numbness / tingling of fingers, toes, face• Actually a predictor of which patients will benefit from topiramate use• Potassium supplementation can help

– Risk of kidney stones– Glaucoma– Reduced sweating (important in athletes / overheating)

• Recently identified birth defects– Oral cleft (palate, lip) 11 times higher than general population– Rated as Category D for pregnancy

• Reduced oral contraceptive effectiveness– At doses greater than 200mg / day

Valproate (Depakote)• Quite effective, but less commonly used due to side

effect potential• Optimal dose is 500 – 1,500mg per day• Side effects

– Weight gain– Hair loss– Pancreatitis– Liver problems

• Significant effects with women of child-bearing potential– Neural tube defects (ie. spina bifida)

Gabapentin (Neurontin)• Less commonly used• Optimal dosing is 900 – 2,400mg

– Needs to be dosed 3x per day• Side effects

– Drowsiness– Dizziness

• No drug interactions, no effect on kidneys or liver

• Sometimes used as a rescue medication

Zonisamide (Zonegran)

• Similar to topiramate• Sometimes effective in patients that respond

to topiramate but experience side effects• Side effect profile similar• Optimal dosing not exactly known, but most

suggest around 200mg at night

Blood Pressure Medications

• Beta blockers• Calcium channel blockers• Other blood pressure medications

– Not frequently used• Useful in patients with co-existent high blood

pressure

Beta Blockers• Propranolol• Timolol• Atenolol• Metoprolol• Nadolol

– Lower blood pressure and heart rate• Can lead to light-headedness

– Can reduce aerobic capacity– Worsen asthma– Avoid in diabetics– Can worsen depression

Calcium Channel Blockers

• Verapamil• Diltiazem

– Generally well tolerated– Often times more useful in patients with migraine

with aura– Side effects include light-headedness,

constipation, and swelling of legs

Serotonin antagonists

• Rarely used outside of headache specialty clinics

• Methylergonovine (Methergine)– Similar to methysergide (Sansert) which is no

longer readily available– Usually used 3-4x per day– Triptans should not be given concominantly

Vitamin Supplements• Not as well studied as prescription medications (product of

financing of studies)• Magnesium

– 400+mg / day– Diarrhea can occur

• Riboflavin (B2)– 25 – 400mg / day– Will discolor urine

• Coenzyme Q10– 100mg 3x / day– Costly (sometimes)

• Butterbur and Feverfew also felt to be effective

Botox

• OnabotulinumtoxinA• Famous for being used for “wrinkles”• Found to be effective in patients with chronic

migraine– Greater than 15 days of headache per month for

greater than 3 months• In clinical trials patients using opiates and

butalbital were excluded as they tend to do worse

Botox

• 155 units injected into 31 sites given every 3 months

• Minimal side effects– Injection site pain is largest

• Up to 9 days less per month of headache• FDA approved

PREEMPT Protocol Fixed-dose, Fixed Injection Sites; one size fits all

Blumenfeld A et al. Headache 2010;50:1406-1418 .

• In the US, Botox is available in 2 vial strengths with 100 or 200 Units

• Normal Saline is the diluent

• For the 100 unit vial, 2 cc Normal Saline; For the 200 unit vial, 4 cc NS

• This comes out to 4 (1 ml) syringes, all 30 gauge ½ inch needles

• Each injection is 0.1 cc

• There are 5 units onabot/0.1 ml

PREEMPT pooled analysis: mean change from baseline in frequency of headache days (primary)

Dodick DW et al. Headache 2010;50:921–936.

Headache days at baseline: 19.9 onabot vs 19.8 placebo, p=0.498.

• Patients treated with onabot averaged of 8.2 fewer HA days/month at Wk 24 vs placebo, 6.2 HA d/mo; p<0.001)

• Patients receiving placebo first, that is 3 cycles, never catch up to those who received 5 cycles, suggesting cumulative benefit

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Double-blind phase: patients on onabot or pbo

Open-label phase: all patients on onabot

• Onabot (n=688)

• Pbo (n=696)

• Onabot (n=688)

• Pbo (n=696)

Conclusions

• Rescue medications– Use migraine specific medications as much as

possible– Treat as early as possible in the attack– Add NSAIDs to triptans if necessary– Avoid opiates and butalbital as much as possible– Limit rescue medications to 10x per month if

possible

Conclusions

• Preventative treatment– When migraine is frequent or disabling

pharmacologic prevention should be used to avoid medication overuse

– Individualize treatment with other medical conditions

– Give medications 2-3 months to see if they are effective

– Set realistic expectations (not a cure)

Questions?Discussion

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Norton Headache and Concussion CenterHeadache School

• How Diet Affects Headaches

May 16 • 6 to 7:30 p.m. • Women and Headaches

June 13 • 6 to 7:30 p.m. • Biofeedback and stress

managementJuly 11 • 6 to 7:30 p.m.

• Headache related to injuryAugust 8 • 6 to 7:30 p.m.

• What is a migraine aura? September 12 • 6 to 7:30

p.m.

• Alternative headache treatments

October 17 • 6 to 7:30 p.m.