January 2006 Meeting
TOPIC: “THE GOOD, THE BAD AND THE UGLY: RX
TREATMENT FOR MIGRAINE”
The East Bay Headache Support Group celebrated ten years of educating and
supporting headache sufferers with an exciting meeting on January 10, 2006,
which included refreshments and a raffle, and 8 volunteers were awarded
Certificates of Appreciation. Mostly because an article appeared in the Contra
Costa Times featuring the group’s co-founders Dr. Michael Stein and his patient
Leslie Davis, 109 persons attended the meeting (the most since our first meeting
in 1996 when we had 120). We were originally scheduled to use the much smaller
Sequoia/Sterns Conference Room at John Muir Medical Center, but found it
necessary to take over the Ball Auditorium for the meeting.
Our guest speaker was Dr. Lori Reisner, PharmD, Associate Clinical Professor of Pharmacy at the University of California, San Francisco, School of Pharmacy, and Associate Director of Drug Policy at the UCSF Medical Center. She also serves as a consultant to the National Pain Education Council. Using a 59-slide PowerPoint presentation, Dr. Reisner talked about medicines for migraine and other chronic types of headaches, and particularly emphasized the risk of rebound headache from medications.
Most of information from her slides is included in the meeting notes that follow, along with additional comments made by Dr. Reisner during her presentation. Be aware the notes were taken by a lay person and may not include all of the material presented by Dr. Reisner.
To begin, Dr. Reisner made the statement, “Research is a ways off from marketable products,” meaning that it takes many years for a pharmaceutical company to develop a new headache medication, get approval by the FDA, and finally sell it to the public.
She said a phenomenon about migraines is that they usually peak in one’s 20s and 30s and then get better as we age.
Slide 1: Headache Prevalence
According to surveys of people in the U.S., 90%
say they’ve experienced a headache, 75% say they have episodic headaches, and
25% have severe headaches. And about one-half of these have been diagnosed with
migraine based on the International Headache Society (IHS) criteria.
Slide 2: Prevalence of Migraine – Age and Sex
 | Peak prevalence at age 40 years |
| Greatest impact on ages 25 to 55 years |
| 56% increase in migraine incidence |
Of 28 million migraineurs:
| 13 million discussed headaches with a doctor |
| Only 3.5 million were diagnosed as having migraine |
| Migraine with prodrome |
| Migraine without prodrome |
| Migraine with aura |
| Migraine without aura |
| Migrainous (IHS 1.7) |
| Early-morning migraine |
| Menstrual migraine |
| Slow-to-differentiate migraine |
| Tension-type headache |
| Migraine with aura or without aura |
| Migrainous headache |
| Tension-type headache |
Dr. Reisner talked about the trigeminal nerve, a
major nerve in the head. She explained that trigeminal neuralgia is when one of
the three branches of nerve is constricted. The constricted nerve talks to the
other nerves at an intersection.
She said that migraine isn’t always just experienced as pain in the head. There
is also a condition called abdominal migraine.
Slide 7: Clinical Spectrum
| Neurological |
| Gastrointestinal |
| Autonomic |
| Musculoskeletal |
| Mood |
| Pain |
Pre-headache: premonitory/prodrome and aura
Headache: headache
Post-headache: postdrome
Dr. Reisner said it is very important that you treat your migraine before it gets to the extreme stage.
Slide 9: Phase I – Prodrome
Common Symptoms:
| Fatigue |
| Mood change |
| Cognitive change |
| Food craving |
| Muscle ache |
| Yawning |
| Reversible focal neurologic disruptions |
| Electrical vs vascular |
| Visual, somatosensory |
| Occur in only 15% of attacks |
Common Features:
| 4 to 72 hours duration |
| Unilateral – 60% |
| Throbbing – 60% |
| Aggravated by activity |
| Moderate-to-severe pain |
Common Symptoms:
| Nausea +/- vomiting |
| Sensory disruption |
| Cognitive slowing |
| Musculoskeletal pain |
| Hibernation (avoidance of stimulation) |
Slide 12: Neuroinflammatory and Pain Phase
This was a drawing of the basic mechanisms in vascular headache.
Slide 13: Phase IV – Resolution
| Restoration of homeostatic balance
| ||||
| Sleep or rest | ||||
| Sudden resolution
|
| Period of continued agitation following resolution of pain | ||||||||
| Clinical symptoms
|
| Hormones |
| Chronobiologic changes |
| Vasodilators |
| Diet |
| Drugs |
| Sensory input |
| Stress |
| Trauma |
| Regular sleep |
| Regular meals |
| Regular exercise |
| Biofeedback |
| Healthy lifestyle |
Slide 17: Common Drug-induced Headaches
| Serotonin-selective reuptake inhibitors |
| Antimicrobials |
| Oral contraceptives |
| Hormone replacement therapy |
| ANALGESICS – rebound or paradoxical |
| NSAIDs, APAP, opioids, ergots, “triptans” |
She said that antimicrobials are antibiotics. Germs are mutating and our existing antibiotics don’t work so well on them. And it’s scary because there are no new antibiotics coming down the pipeline. Dr. Reisner stressed that we should never take an antibiotic if we have a virus, as they don’t work on viruses. It is important not to overuse antibiotics.
If you’re taking opiates (such as Vicodin or
Tylenol 3 w/ codeine) for your headaches, be aware that it only takes 4 days to
a week of the drug to cause rebound headaches. The triptans can also trigger
rebound headaches, though each one has a different time course.
Slide 18: Headache History (I)
How many major headache types?
| Age at onset |
| Frequency |
| Location |
| Time from onset to peak intensity |
| Associated symptoms |
| Duration |
| Aggravating and relieving factors |
| Triggers |
| Previous medications (dose, schedule, efficacy) |
| Do your headaches interfere with activities?
| ||||||
| How frequently do headaches occur? | ||||||
| Is the headache pattern stable? | ||||||
| How effective are your current treatment attempts? | ||||||
| Comfort signs |
Slide 20: Headache Treatment Diary
| Calendar of all headache days |
| Record all treatment |
| Record all responses to treatment |
| Adjust treatment needs based on diary |
Slide 21: Migraine Transformation or Evolution
| Episodic Migraine |
| Tension-Type Migraine |
| Mixed Headache |
| Chronic Daily Headache |
Jigsaw puzzle with 4 pieces:
| Rx treatment strategies |
| Patient education |
| Non-pharmacologic strategies |
| Preventative medication |
Slide 23: Acute Treatment: Goals
| Rapidly relieve attack | ||
| Consistently relieve attack | ||
| No recurrence | ||
| Restore ability to function | ||
| Minimize need for backup medications | ||
| Optimize self-care
| ||
| Cost-effective | ||
| Minimize or avoid adverse events |
Optimization of self-care is most important,
stated Dr. Reisner.
Slide 24: Principles of Acute Treatment
| Treat early in the attack |
| Use an appropriate drug, dose, and formulation |
| Use migraine-specific agents in patients |
| With (temporarily) disabling headaches |
| Who respond poorly to nonspecific agents (stratified care) |
| Use nonoral therapy for patients with prominent nausea or vomiting |
| Offer rescue medication |
| Guard against medication overuse |
Treating early in the attack is most important. Dr. Reisner said that surgery patients are told to say when their pain is a 4 out of 10 so they can be treated earlier rather than later. This way the drugs work better and less is required.
She also said that we must guard against
medication overuse.
Slide 25: Early Treatment
“…neurons respond to the pain of a migraine in stages, and if the pain can be stopped early, the cascade of pain responses can be controlled.”
“The time is very, very important. In order to treat with the most effect, we have to catch it while is in the first-order neurons. That means giving drugs, usually in a class called triptans, within 20 minutes of the first twinge of pain.”
Dr. Reisner said that Excedrin is now specifically marketed for treatment of migraine. But you need to be aware that Excedrin is one of the worst offenders for rebound (drug-induced) headache.
Editor’s Note: Dr. Stein, medical advisor for the East Bay Headache Support Group, has stated the following in the past: Did you know the only difference between Extra-Strength Excedrin and Migraine Excedrin is the label? The ingredients are the same.
Slide 26: Benefits of Early Treatment
| Early pain-free response |
| Less recurrence |
| Prevents progression of the attack |
| Less disability |
| Less need for multiple doses and rescue medication |
| Effective early treatment from early age may prevent transformed (chronic) migraine (type of chronic daily headache) |
Specific
| Triptans |
| Ergotamine/DHE |
Nonspecific
(simple and combination analgesics)
| Acetaminophen-Aspirin-Caffeine |
| Aspirin |
| Ibuprofen |
| Naproxen |
Rescue Medications
Dr. Reisner said that ergots and DHE were popular
for migraine treatment 20 years ago—that was all we had. She said they are
effective, but do cause significant vasoconstriction which is bad for people
with blood supply problems. Dr. Reisner knew of one woman who almost lost her
toes due to using too much ergot, but added that some still use ergot sparingly.
Slide 28: Therapeutic Phases of Migraine
| Pre-Headache Prodrome |
| Aura |
| Headache |
| Post-Headache Postdrome |
Dr. Reisner stated that triptans work best early on, but you can still get some benefits at the peak of the migraine. She sometimes has patients put on DHE to withdraw them from other drugs that are causing rebound headaches. It has been noted that if a triptan is used for many years, it tends not to work as well.
Some people can rid themselves of a headache, like Dr. Reisner, by just taking an Advil or other over-the-counter NSAID. She admits she’s lucky, though, and knows that’s not the case for most people with migraine.
Slide 29: Common Triptan Side Effects
| Tingling |
| Warmth |
| Flushing |
| Chest discomfort |
| Dizziness, somnolence |
Slide 30: Triptans: Contraindications (I)
| Ischemic heart disease
| ||||||
| Coronary vasospasm (including Prinzmetal’s angina) | ||||||
| Multiple risk factors for coronary artery disease, unless workup is fully negative |
Slide 31: Triptans: Contraindications (II)
| Hemiplegic or basilar migraine |
| Uncontrolled hypertension |
| Concomitant use of MAO inhibitors (or use within 2 weeks), except naratriptan |
| Use within 24 hours of an ergot |
| Pregnancy category C |
Slide 32: Triptans: Practical Clinical Issues
Recurrence
| Second dose |
| Use a triptan with low recurrence |
| Early treatment |
| Combination with NSAIDs |
| Second dose |
| Double dose (next attack) |
No Response
| After at least 3 trials, try another triptan earlier on |
Multiple Recurrences (rebound)
| Switch to longer-acting triptan with low recurrence |
| Add prophylaxis |
Dr. Reisner stated you should try a triptan at
least 2 or 3 times before giving up on it.
Slide 33: Nonpharmacologic Strategies
Supported by Class A evidence
| Relaxation training and/or thermal biofeedback |
| EMG biofeedback |
| Cognitive behavioral therapy |
Slide 34: Stepped Care vs Stratified Care
Stepped care across attacks
Stepped care within attacks
Stratified care
Dr. Reisner said that typically in medicine, the plan of attack is to try the mild medication first, and then get stronger. But for treating migraine, it is different: treat your migraines aggressively up front. She said the stratified approach (not stepped care) is better for migraineurs.
Slide 35: Pitfalls of Stepped Care Across Attacks
| The average patient with migraine fails at 4.6 medications before finding success | ||||
| Patients who find effective therapy may suffer for months or years | ||||
| Failed therapy is costly | ||||
| Patients drop out of care thinking that:
|
Slide 36: Pitfalls of Stepped Care Within Attacks
| Patients suffer needlessly if first-line therapy is ineffective |
Slide 37: Stratified Care
Description:
| Patients with high disability scores are initiated on high-end therapy |
| Patients with less disability begin on low-end therapy and escalate as needed |
Rationale:
| Headache-disabled patients have greater treatment needs |
| Headache-disabled patients are much less likely to consistently respond to low-end therapy |
| Stratified care produces better outcomes in a cost-effective manner |
Slide 38: Basis of Stratification
Severity
| Mild |
| Moderate |
| Severe |
Time to Peak
| “Crash migraine” |
| Intermediate |
| Slow onset |
Associated Symptoms
| Early onset |
Disability
| Mild |
| Moderate |
| Severe |
Frequency
| For prophylaxis |
| Migraine significantly interferes with daily routine despite acute treatment |
| Frequent headaches (more than 2 per week) |
| Acute treatments fail, are contraindicated, or produce side effects |
| Patient preferences |
| Hemiplegic or basilar migraine, migraine with prolonged aura |
Slide 40: Migraine Medications
| Acute: Analgesics – NSAIDs, opioids, ergots, isometheptene, “triptans,” OTC products |
| Preventive: Beta-blockers, anticonvulsants, methysergide, antidepressants, calcium-channel antagonists |
| Others: Riboflavin, magnesium, herbals |
Slide 41: Medications for Acute Headache (I)
| Isometheptene/dichloralphenazon |
| NSAIDs ─ multiple analgesic mechanisms: anti-inflammatory, central analgesic properties |
| Opioids ─ CNS depression, antagonism of excitatory neurotransmitters (e.g., neurokinins) and modulation of Na/K/Ca channels |
| Bultalbital/caffeine ─ sympathomimetic/sedative |
| Dopamine antagonists ─ metoclopramide, chlorpromazine, droperidol |
Slide 42: Medications for Acute Headache (II)
| Serotonin type 1 receptor agonists
|
Slide 43: Medications for Acute Headache (III)
| “Triptans” ─ serotonin (5-HT) 1B and 1D agonists |
| 5-HT 1B: zolmitriptan >> 5-HT 1D (also 1A and 1F) |
| 5-HT 1B/5-HT 1D: frovatriptan, naratriptan, rizatriptan, almotriptan (also 5-HT 1F receptors; weak affinity for 5-HT 1A and 5-HT 7) |
| 5-HT 1D: sumatriptan |
| RESULT: decrease pro-inflammatory neuropeptides, including substance P, Calcitonin Gene-related peptide (CGRP), vasoactive intestinal peptide (VIP) |
Slide 44: Serotonin Type 1 Receptor Agonists (I)
Drug Dose Tmax (hr) F PrBind T-1/2 (hrs)
Almotriptan (Axert) 12.5 mg -2 -70% -35% 3-4
Frovatriptan (Frova) 2.5 mg 2-4 -30% -15% 26
Naratriptan (Amerge) 2.5 mg 2-3 70% -30% 6
Rizatriptan (Maxalt) 10 mg 1-1.5 -45% -15% 2-3
Sumatriptan (Imitrex) 100 mg -2 15% 15-20% 2.5
Zolmitriptan (Zomig) 10 mg 2-3.5 -50%
25% -3 (1.5-3.7)
Slide 45: Serotonin Type 1 Receptor
Agonists (II)
| Onset: about the same for all |
| Duration (rebound): fewer with almotriptan, more with sumatriptan |
| Long-acting: Frovatriptan |
| Alternate routes: sumatriptan, rizatriptan |
| ADRs: sumatriptan more chest tightness |
From Slide 44 above, we see that Frovatriptan (Frova) has a half-life of 26 hours, which means it can be used as a preventive.
Slide 46: Migraine
| Preventative medicines | ||||
| Recurrent, disabling migraine | ||||
| Frequent episodes (more than 2 per week) that increase risk of acute medication overuse | ||||
| Uncommon migraine conditions:
|
Slide 47: Transformed, CDH, “Rebound”
| Can occur with any underlying headache pathogenesis |
| Increasing use of acute medications leads to a state of increased headache frequency requiring multiple daily doses of medicines |
| Manifestation of a rebound state, related to the analgesic(s) taken |
| Occurs with nearly all acute therapies |
| Difficult to treat once established; best to prevent |
Dr. Reisner said that virtually any medication can cause transformed, CDH (chronic daily headache), or rebound headaches. She added that the shotgun drugs tend to be the worst offenders. The only drug that does not cause rebound headache is Midrin®. She also stated that Vicodin is still the #1 prescribed medication in the U.S. Be aware that Vicodin causes liver disease and usually a liver transplant is required as a result of using lots of Vicodin.
Slide 48: Drug Overuse and Rebound Headache
Silberstein SD, Liu D. Curr Pain Headache Rep 2002;6(3):240-7
Jefferson Headache Center, Philadelphia, PA 19107, USA
The overuse of acute medications in patients who are headache-prone poses a great challenge to headache management. Medication overuse-induced headache represents one of the most common iatrogenic disorders. It is the reason that most patients visit headache subspecialty clinics worldwide and often is the cause of an intractable or worsening headache in primary headache sufferers. The recent development of acute headache medications, especially the triptans, has provided increased migraine relief; however, the incidence of triptan-overuse headache has also increased. Awareness of medication overuse-induced headache and familiarity with the diagnosis and the treatment of this disorder are important to physicians who treat patients with headache.
Slide 49: Analgesic Rebound Headache
Strategies:
| Gradual tapering of offending agent(s) |
| Opioid conversion and tapering |
| Barbiturate reduction |
| Utilization of buprenorphine |
| Institute preventive therapies |
Slide 50: Recommended Agents for Migraine Prophylaxis
Class Group 1 (mg per day) Group (mg per day)
Beta blockers Propranolol 20-160 mg Atenolol 25-100 mg
Nadolol 20-120 mg Metropolol 50-100 mg
Tricyclic antidepressants Amitriptyline 10-100 mg Protriptyline 5-30 mg
Nortriptyline 10-150 mg
Anticonvulsants Divalproex sodium 125-1000 mg Topiramate 25-200 mg
Calcium channel blockers Verapamil 120-320 mg
Dr. Reisner said that she prefers Propranolol and also Amitriptyline (which restores sleep pattern). There are problems with tricyclics—one is weight gain. She advised not to take Topamax if you have glaucoma. Topamax also can cause kidney stones, and it causes cognitive dysfunction, which unfortunately doesn’t go away with time.
Slide 51: Herbal Medications Used for Pain (I)
| Volatile Oils, flavinoids and/or alkaloids: |
| Feverfew (headache) |
| Marigold (inflammation, toothache) |
| Roman chamomile (headache, toothache) |
| Catnip (migraine) |
| Valerian (stress, headache, neuralgia) |
| Purine alkaloids (caffeine, methylxanthines) – Cola |
| Indole alkaloids (strychnine) – Nux vomica |
| Drug Interactions:
| ||||||||
| Problem: little data, few controlled studies | ||||||||
| Patients may not report herbal use |
Dr. Reisner said that taking feverfew is the equivalent of taking a low dose of Advil. She also mentioned the 4 Gs: ginger, garlic, ginkgo and ginseng.
Slide 53: Alternative Medications Used for Pain
Side Effects:
| GI: Primrose (O.D.), Valerian |
| Sensitization: Marigold, Roman chamomile, Feverfew, Valerian |
| Hyperexcitability, restlessness: Cola, Nux vomica (strychnine), Valerian |
|
