Access to the PPM Journal and newsletters is FREE for clinicians.
11 Articles in Volume 15, Issue #2
Chronic Headache Management: Outpatient Strategies
Magnesium Sulfate Helpful in Treatment of Acute Migraines
New Guide to Migraine Rx Garners Mixed Reviews
Pain Education Across VA Clinics
12 Classes Offered at VA Pain School
Practical Guide to the Safe Use of Methadone
Chronic Pain Patients Who Fail Standard Treatment
Balancing State Opioid Policies With Need for Access to Pain Therapies
New Mexico’s Approach to Improving Pain and Addiction Management
Editor's Memo: Prescription Opioid Abuse is Declining
Ask the Expert: Lupus and Suicidal Ideation

Chronic Headache Management: Outpatient Strategies

Up to 4% of adults suffer from chronic headaches, mostly migraines. This article reviews what we know about migraine types, comorbidities, as well as migraine triggers, and treatments.

When we assess patients who seek medical treatment for headache pain, they usually suffer from migraine, tension, or chronic migraine. Only about 5% of patients fall outside of that realm. Chronic daily headache, the majority of which are chronic migraine, occurs in 3% to 4% of adults in the United States,1 and often results in a markedly decreased quality of life.2 There are numerous medications for episodic migraine but fewer options that are effective for chronic migraine. The following discussion reviews what we know about migraine types, comorbidities that commonly occur in patients with migraines, as well as migraine triggers, and treatments.


It is estimated that between 25 to 28 million people in the United States suffer from migraines, making it one of the most common illnesses—this includes a prevalence of 18% among women and 6% among men.3 Many migraine patients successfully alleviate their headaches with over-the-counter (OTC) medications, but most are disabled to some degree during their migraines.

Migraine is an inherited, chronic illness characterized by moderate to severe pain that often is unilateral but can be bilateral. Migraine usually is accompanied by features such as nausea, dizziness, photophobia, sonophobia, or osmophobia. Exacerbation of the headache from bending or other movement is common, as is neck pain. Aura is fairly common; up to 25% of migraineurs experience an aura but not with every headache. Prodromal and/or postdromal fatigue and mood changes are common.

Migraine may begin at any age, and it is surprisingly common in children and adolescents. At least 1% of 6-year-olds and 4% of 10-year-olds suffer from episodic migraine. Until age 12, boys and girls suffer from migraine in equal numbers. During puberty, the familiar female-to-male ratio of 3:1 is reached, and that ratio is maintained throughout the rest of life.4

When diagnosing migraine, it helps to look at consistent triggers, such as menses, weather, and insufficient sleep. If weather changes bring on migraine, it can be confusing because the migraineur often is told (and feels) that they have a sinus headache. To further confuse the picture, OTC sinus medications often help all types of headache. However, several large studies have indicated that 95% of people presenting with chronic sinus headaches actually have migraines, so one must think “migraine first” when patients present with pain in the sinus area.5


With a new-onset headache—especially in a patient in middle or later life—more extensive work-up is needed. This also is true for new neurological symptoms such as numbness, a change in mental status, or visual problems. The patient with chronic daily headaches warrants an MRI more often than the patient with sporadic migraines. Children with migraine may not need an MRI. If a 12-year old presents with a history of 2 migraines per month since age 6, an MRI is not absolutely necessary. However, if patients continue to have migraines and are followed until college age, they are likely to have a headache that warrants MRI scanning at some point.

Most headache patients should undergo routine hematologic exams, primarily to assess liver and kidney function. Patients often take OTC medicines that they don’t tell their physicians about. Either they don’t remember or don’t have a sense of how many OTCs they take for pain relief. It is not unusual for headache sufferers to consume 8 to 10 or acetaminophen-caffeine (Excedrin, others) or ibuprofen (Advil, Motrin, others) a daily basis, putting their liver or kidneys at risk.


One of the primary things pain practitioners can do for their patients with headache is educate them about triggers. Certain triggers cannot be controlled, but when a patient has a headache every time the weather changes, or the first day of every menstrual period, clinicians can prescribe medication to be taken the day or night before as a preventive.

The top triggers tend to be stress (daily hassles), menses, and weather. When they occur simultaneously, patients get the worst, most prolonged migraines. Of course, missing meals, under- or over-sleeping, bright lights, and certain foods also contribute, but the role of foods tends to be overemphasized.

Many books concentrate on diet and foods, but these are low on the list of important triggers. Caffeine, however, is a major trigger. We need to limit the patient’s intake, although the limit varies from person to person. Some people can consume 800 mg of caffeine a day and not have rebound headaches or withdrawal. Other people get headaches from a small amount of caffeine in their diet.

Caffeine is an adjunct for pain relief because in small amounts it helps enhance the effect of analgesics. But, patients should be advised to watch out for the specialty coffeehouse effect. For example, Starbucks coffee has approximately 23 mg of caffeine per ounce. In an oversized cup of Starbucks, a patient can ingest 400 mg of caffeine (twice the daily maximum recommended), or more. Most home-brewed coffees have manageable doses. For example, Folgers or Hills Brothers brewed coffees have about 150 mg per cup, whereas instant coffee has half that amount. Tea, if it has caffeine, will generally have 30 to 60 mg per cup. Cola drinks have 40 to 60 mg and Mountain Dew has a little more. The new energy drinks may have 200 mg in 12 ounces. Patients should be advised to watch for accumulated caffeine from these sources and OTC medications. Each tablet of the acetaminophen-caffeine combination analgesic has 65 mg of caffeine, whereas the aspirin-caffeine combination product has 33 mg. I attempt to limit a patient’s daily caffeine intake to 150 mg, with 200 mg as the maximum.6


A word on disability. One might think that pain level is the major predictor of disability. It has been shown, in well-done studies, that other factors probably are more important. Catastrophizing, such as thinking one’s headache is always a 14 on a scale of 1 to 10, is one of these factors. Part of the pain practitioner’s job is to turn down the volume and limit the drama. We can talk to people about catastrophizing and try to reduce the fear that underlies it.

Catastrophizing by proxy also happens, such as when a parent thinks his child has the worst headaches on the planet. Fear of pain also plays a role in disability. Some people have more fear and anticipation of pain than others and, as with catastrophizing, fear of pain may be lessened through psychotherapy.

Psychological Comorbidities

When a patient comes into the pain practitioner’s office, we are not looking at a just a headache, we are assessing the whole person. By concurrently managing the patient’s comorbidities, we can help them achieve a better quality of life.

Comorbidities guide what we suggest as treatment for headache patients. Psychiatric comorbidities are relatively common in headache patients, primarily due to shared genetic susceptibilities. I tell patients that migraine is an inherited medical problem just like having asthma or diabetes. Clinicians should refrain from telling patients that it’s all in their heads. If we “medicalize” these ailments and remove some of the stigma, patients will allow us to explore more of their psychological conditions, which often drive where we go with treatment.

Attention Deficit Disorder

Attention deficit disorder (ADD) is another important comorbidity. Although ADD is common in adults, with studies showing that about 4.7% of adults have ADD, it often goes unrecognized and untreated. It is critical to treat ADD in adults because the stakes increase with age for untreated ADD. At age 6, kids may not be doing well in school, but by age 26, they are losing their families and their jobs, and are at a much higher risk for addiction. The risk of addiction for older (8-20 year olds) adolescent boys with untreated ADD is almost 75%; this usually manifests as an alcohol problem. If the ADD is treated, the risk of addiction decreases to 20% to 25%.7 The stimulants prescribed for ADD often help the headaches as well. Addictions are a comorbidity that complicates the treatment of a refractory patient. Treating pain patients in the face of addiction is complex, often requiring a combined psychiatric and medical approach.


When the comorbidity is anxiety, it usually is generalized anxiety disorder. Obsessive compulsive disorder also is common, and panic attacks are actually 10 times more common in migraine patients than in the general population. Separation anxiety tends to begin early in childhood. High school kids who are homebound, or miss days and even months of school, often experience social anxiety. Simply prescribing medications for these children is not enough; they need to see psychotherapists to address the comorbid anxiety, depression, etc.

Whether any adolescent should be homebound because of headaches is controversial. We usually take a nuanced approach to adolescents with severe headaches who miss school. Some do better with online schooling, homebound, or a combination. Certain adolescents require more of a “tough love” approach. If an adolescent has been homebound, it helps to ease them back into school, possibly with a lighter schedule for some period.

Depression and Bipolar Spectrum

When the comorbidity is depression, it is usually major depression or dysthymia. Of course, many adults with depression actually are bipolar, or fit into the mild bipolar spectrum. Depression often is comorbid in headache patients, most likely due to shared inherited and environmental factors. It is vital to treat both pain and depression because they fuel one another. Patients say, “Of course I am depressed. Wouldn’t anyone be with severe headaches?” My answer is, “Headaches do make the depression worse, but many people [60%] with chronic pain are not depressed. Depression is a separate, biological problem.”

The relationship between bipolar illness and migraine has not been as well studied as depression and migraine. However, in several studies, the bipolar spectrum has been found at an increased rate in migraineurs. Approximately 4.5% of the general population fits into the bipolar spectrum.8 Studies of people with bipolar found that approximately 40% of bipolar patients also have migraines.

It is the milder end of the bipolar spectrum that tends to be missed. Look for patients with persistently agitated, angry personalities, with frequent depressions and/or, “too much energy,” and having a strong bipolar or depressive family history. Family history also may include substance abuse. Patients may not necessarily have had a clear hypomanic or manic episode. Soft bipolar signs include: early depression (beginning as teens), severe depression, quick onset depression, bipolar reaction to certain meds (up all night, thoughts racing, etc.), agitated and angry depression, very high anxiety and mood swings, poor response to medication, and moody personality. Sleep disorders are commonly seen. Cyclical depression, “for no reason,” along with high anxiety is common for bipolar depression.

The therapeutic implications for recognizing bipolarity are enormous. These patients tend to bounce from antidepressant to antidepressant with predictably poor results. Mood stabilizers—lithium, lamotrigine, and atypicals such as quetiapine and aripiprazole—are much more effective.

Personality Disorders

It is crucial to recognize personality disorders within your practice. Approximately 10% of people have strong features of a personality disorder. Approximately 5% of migraineurs have one of the more severe personality disorders: borderline, narcissistic, antisocial, paranoid. In general, characteristics of personality disorders include: lack of insight, poor response to psychotherapy or other therapeutic interventions, difficulty with attachments and trust, a sense of entitlement, the creation of a great deal of chaos and distress in family, friends and co-workers, etc. The small percentage of patients with moderate-to-severe personality disorders in a typical pain practice are the ones who create the majority of the drama, as well as legal and regulatory problems for the treating physicians.9

Personality disorders have a wide range of severity, from mild to very severe. These individuals often flip between victim, rescuer, and persecutor. When they turn persecutor, they can be dangerous to the person they have their sights set on. Personality disorder patients often create chaos and drama, and comorbid substance abuse is common. They also bring chaos and drama to the medical clinic. The more difficult personality disorders include paranoid, antisocial, borderline, and narcissistic behaviors. In general, therapy helps people with personality disorders only over long periods of time. Dialectical therapy is usually preferred for those with a PD. Seeing a therapist for 5-7 years may help to some degree. However, our goals and expectations are limited. The concept of plasticity of the brain is very important, as some people do improve naturally over time. One study of borderline personality disorder in adolescents indicated that, by age 30, one third of the subjects no longer had borderline personality disorder. Many people do not fit neatly into any of these categories, but have features of two or three personality disorder types. Failure to identify those with personality disorders leads to increased risk for the provider and the patient. The small percentage of patients with moderate-to-severe personality disorders in a typical practice are the ones who create the majority of the drama, as well as legal and regulatory problems for the treating physicians.9

Medical Comorbidities

Central sensitization syndromes, including chronic migraine, irritable bowel syndrome (IBS), fibromyalgia, and chronic pelvic pain, can occur together with migraine, which complicates treatment.

A common site for medical comorbidities in headache patients is the gastrointestinal (GI) tract, with IBS being the most common comorbid GI disorder. IBS frequently is encountered in migraine patients, and very often practitioners try to use medications that help the GI symptoms as well as the headache. Most of one’s serotonin is in the gut, and certain medicines that help IBS increase or decrease serotonin. It is much easier to help patients who primarily have diarrhea because some of our medicines, such as the older tricyclic antidepressants (tricyclics), slow the gut transit time. Constipation, on the other hand, is tougher to ameliorate.

Many people with fibromyalgia also have chronic daily headaches and insomnia. These groups overlap, not only with pain but with psychological comorbidities as well. Fibromyalgia patients share the allodynia commonly felt by headache patients. A number of medicines are used for both headache and fibromyalgia, such as tricyclics and muscle relaxants.

Some other common medical comorbidities are hypertension, insomnia, and fatigue. If you ask large groups of headache or migraine patients what their biggest problem is other than headache pain, it tends to be excessive daytime sleepiness. Fatigue is such a prevalent problem that clinicians need to make sure they don’t add medications that make patients more fatigued. It is challenging because there are no algorithms for headache patients since everyone is different. For example, suppose a 45-year-old woman who is 25 pounds overweight presents with chronic headache and complaints of excessive fatigue. Amitriptyline or valproate would make her more tired and lead to weight gain. Some medications, such as protriptyline (Vivactil, others) and ARBs do not exacerbate fatigue, and, occasionally, small doses of stimulants can be effective. Modafinil (Provigil, others) or armodafanil (Nuvigil) may offset the fatigue but do not help headaches. These are expensive medications, but they can improve quality of life for many headache patients.

The fatigue that headache patients frequently encounter is, in part, related to the insomnia they experience. Clinicians should encourage patients to follow sleep rules and should prescribe behavioral treatments. Sedating tricyclic antidepressants and certain muscle relaxants, such as tizanidine (Zanaflex, others) or cyclobenzaprine (Amrix, others), may help both conditions. More effective insomnia medications are needed.

In patients with hypertension, treatment with many of the antihypertensives can reduce migraine pain in addition to lowering blood pressure. Most beta-blockers will help, as will the calcium channel blockers. More recently, the angiotensin II receptor blockers (ARBs) have been used with success.


Nonpharmaceutical Approaches

It does take a village to treat a severe pain patient. Pharmacotherapy may be important, but we want to try everything else, whether it’s physical therapy, yoga, biofeedback, active coping, etc. Psychotherapy often is important and I strongly recommend it as part of treatment. However, whether it is because of money or time, most people will not see a therapist. Cognitive-behavioral therapy is the usual approach, but with personality disorders one must take more of a dialectical tack. It is important to identify the best therapists in your area because the skill levels of psychotherapists vary widely (Table 1).10


Pharmacologic Approaches

Most people with migraines do not need preventive medicines, particularly when they don’t have comorbidities or infrequent headaches. However, there is no good algorithm that applies to headache treatment to determine how many headaches a month are too many. We might use preventive medicine in a patient with as few as 2 headaches a month if they are severe and prolonged and are not relieved by drugs. In contrast, we may choose not to use preventive medicine for another patient who has 5 headaches a month but can take an acetaminophen-caffeine or a triptan and obtain relief, because all medications have possible side effects.

Abortive Therapy

For abortive therapy, there are many choices among the triptans. All of the triptans are effective, but they each have different clinical characteristics. The generic tablets include sumatriptan (Imitrex, others), rizatriptan (Maxalt, others), naratriptan (Amerge, others), and zolmitriptan (Zomig, others). Sumatriptan, rizatriptan, zolmitriptan, and eletriptan (Relpax) have slightly better efficacy than naratriptan and frovatriptan (Frova). Naratriptan and frovatriptan have a slower onset and are longer acting than the other triptans. The triptan nasal sprays, particularly zolmitriptan, are fast acting. If one triptan is ineffective, I usually will try 1 or 2 other triptans before giving up on the class. Since 1992, more than 180 million people have been treated with the triptans, and their safety has been well established. Side effects of tingling and pressure can occur initially with these agents.

We have become more comfortable using triptans in higher risk populations. During pregnancy, particularly after the first trimester, triptans may be safer than many of the other migraine medications.11 The 16-year sumatriptan/naratriptan pregnancy registry demonstrated the relative safety during pregnancy.

Other than the triptans, OTC products, such as ibuprofen, naproxen (Naprosyn, Aleve, others), aspirin and caffeine combinations, can be effective, as can aspirin combined with metoclopramide (Reglan, others). Prodrin, a combination of a small amount (20 mg) of caffeine, acetaminophen, and a mild vasoconstrictor isometheptene mucate can be a nonaddicting option for intermediate headaches. This agent is similar to Midrin, but it contains caffeine and does not contain the sedative in Midrin, dichloralphenazone.

Dihydroergotamine (DHE) probably is underused. The nasal spray (Migranal, others) often leads to severe nasal congestion and the injections (D.H.E. 45, others) are much more effective, but they are expensive and often are not available. Since 1945, when DHE was introduced, there have been relatively few severe side effects reported. An inhaled version of DHE is expected be available soon. DHE is primarily a venoconstrictor, so it actually safer than other ergotamines, which are arterial constrictors.12

Butalbital and opioids, including butorphanol nasal spray, or various forms of fentanyl oral preparations, can be used as a last resort in some patients, with some caveats. Butalbital compounds are controversial and are not used in Europe. Butalbital results in rebound headaches more than do simple analgesics. Additionally, use of butalbital and opioids in headache patients has been found to increase the risk of transformation from episodic headache into daily headache. Butorphanol and fentanyl are highly addicting and frequently cause side effects. The opioids with quicker onset tend to be overused and have more withdrawal symptoms. These parenteral opioids should be used very sparingly in carefully selected patients.

When sedation is needed, we will occasionally use medications such as quetiapine (Seroquel, others) or benzodiazepines off label. When nothing works for refractory headaches, particularly for prolonged menstrual migraines, corticosteroids can be used in limited amounts. It is important to minimize the cortisone dose. We use 2 to 4 mg of dexamethesone or 10 to 20 mg of prednisone every 12 hours as needed. The dose packs deliver a higher dose than usually is necessary. I would usually limit these to three or four tablets a month.

Abortives and Rebound Headache

Triptans should not be used on a daily basis, except in unusual circumstances. Rebound headache always is a consideration and is a remarkably complex subject. The term medication overuse headache has been overused. Many patients are labeled as having medication overuse headache, when in fact they simply have frequent migraines. The major question with rebound headache is which drugs, and how much of these drugs, will trigger rebound. It appears that the butalbital and opioid medications, and the high caffeine drugs—such as the acetaminophen-caffeine combination product—may be more likely to cause rebound. It appears that in some patients NSAIDs may contribute to rebound, but in general they do not.

Other Therapy

Transcranial magnetic stimulation (TMS) is a safe, non-invasive, nondrug abortive treatment. Patients may use the stimulator at home. Over the next few years, I predict that TMS will achieve a larger role as an abortive.

Antiemetics are important adjuncts for those with nausea. Ondansentron (Zofran, others) lets people get on with their day without sedation. We also use other antiemetics, such as metoclopramide or prochlorperazine (Compazine, others), which are somewhat sedating. The goal is to keep people out of the ER, and antiemetics help in this regard.

Preventive Therapies

Chronic migraine, defined as headaches occurring at least 15 days per month, of which at least 8 fulfill the criteria for probable migraine, greatly decreases one’s quality of life. It is a major problem, is difficult to treat, and contributes to analgesic overuse. Preventive therapy is used more often in patients with chronic daily headache than in those whose migraines occur a few times a month.

When it comes to preventives, each person is unique. Although comorbidities guide how we proceed, patient preferences also are important. Patients have to be willing to put up with possible side effects. The severity of the chronic headache is important. Some people will say, “My daily headaches don’t bother me, they’re mild; it’s the severe migraines that are important.” Other people say, “It’s these daily headaches that are the problem, the moderate or severe migraines are easily taken care of.”

We aim our preventive medications at the predominant, more bothersome type of headache and strive to limit the drugs prescribed as abortives. If patients are taking OTC medications and need to take more than 2 a day, we must consider daily preventive medicine. We might consider NSAIDs or Prodrin, neither of which is addicting. Triptans may be used, but overuse may lead to rebound. Tramadol (Ultram, others) is a mild opioid that may be useful if patients can limit use to 200 mg or less per day. Any medication used abortively for chronic daily headache should be strictly limited to 2 doses.

The goal with preventives is to help reduce the headache by 25% to 75%. If patients believe that their headaches are going to be completely cured, they may return and state, “The medicines are not working because I still have some migraines.” A 50% improvement often is the best that can be achieved. Headache diaries (or apps, such as ChronicPainTracker) may help, but we also need to convey realistic goals to the patient. In my experience, only 50% of people do well for the long-term on preventives. I’ve done 2 studies looking at usage over a year’s time, with a total of nearly 800 patients on preventives.13 Only 46% of patients found any preventive that they could tolerate and that remained effective for at least 9 months. The rest of the patients discontinued preventives for various reasons. We desperately need more effective preventives with fewer side effects.


Tricyclics remain a mainstay of headache treatment. Amitriptyline and nortriptyline can cause weight gain, dry mouth, and constipation, but we use small to medium doses for most patients. For example, I will start a patient on 5 mg of amitriptyline. Some people remain on 10 or 20 mg of amitriptyline per day for years and do very well. Amitriptyline is metabolized into nortriptyline, which has fewer side effects. Protriptyline is one of the only tricyclics that does not cause weight gain, but it may cause anticholinergic side effects. With protriptyline, patients experience dry mouth and constipation, but there is minimal sedation and no weight gain. One benefit is that the generic tricyclics are very inexpensive.


Topiramate (Topamax, topiramate ER, others) and sodium valproate (Depakote, others) are the anticonvulsants primarily used for headache prevention. These are indicated for migraine. Headache patients often discontinue these agents due to annoying side effects, so it is crucial to keep the dosage to a minimum, starting with a low dose and tapering upward.

With topiramate, memory difficulties and mental fog are common. Depression or anxiety may occur as well. As the dose is increased, tingling of the extremities can occur due to carbonic anhydrase effects. Topiramate can enhance weight loss, but these anorexic effects wane over a number of months. With topiramate, many patients do well on 25 or 50 mg, so I will slowly increase to 50 mg and then, if needed, to 100 mg. Topiramate ER is longer-acting. In 2011, the FDA warned that topiramate increased the risk of cleft lip and cleft palate birth defects, and should not be used by women who are our could become pregnant.11

With sodium valproate, the average dose of 500 mg to 1,000 mg often leads to weight gain, which can result in discontinuation. I will start with 250 mg of sodium valproate and move up very slowly. Patients should be strongly advised not to become pregnant while on sodium valproate.

Many other anticonvulsants have been used for headache, without solid studies to back up use. Oxcarbazepine (Trileptal, others) has failed in several headache studies, though it probably is an effective mood stabilizer for some patients. Zonisamide (Zonegran, otheres) also has been used. This once-a-day, longer-acting anticonvulsant is relatively safe and well tolerated, with fatigue as its primary side effect. It has not been associated with weight gain. Zonisamide usually is started at a dosage of 25 mg per day taken at night, and slowly titrated up to 100 mg per day. Gabapentin (Neurontin, others) has been widely used, as has pregabalin (Lyrica), but evidence is lacking for positive efficacy.

Antihypertensives and Muscle Relaxants

Antihypertensive medications are useful as preventives agents. Beta blockers and calcium channel blockers are the ones most commonly prescribed, but there also have been studies on the ARBs, which have fewer side effects. Tiredness and weight gain are major problems in migraineurs, and beta blockers exacerbate fatigue and weight gain, so I often use one of the ARBs. Candesartan (Atacand, others) is the primary ARB that has been studied, but others have been used.

Muscle relaxants may help the associated neck pain and may aid sleeping, but the other side of the coin is that they may cause unwanted sedation. Tizanidine is non-addicting and is fairly safe, but we use it mostly at night due its sedative effects. Cyclobenzaprine is inexpensive, and the tablets can be cut in half.

Natural Remedies

Natural remedies may help, without the common side effects seen with our usual preventives. Petadolex is an improved form of the herb butterbur that limits the amount of the molecule that we worry about in butterbur. Petadolex is effective, and held up well in randomized controlled trials. It is popular in a number of countries—for instance, in Germany where Petadolex is the number one preventive. I find it is more effective than feverfew, etc. In my years of experience with Petadolex, my patients have reported very few side effects. Occasionally, there is an upset stomach or a bad taste in the mouth. There still is a concern with carcinogenic properties, particularly with the parent compound butterbur. For this reason, we stop the Petadolex periodically for 1 to 2 months. In the United States patients can order Petadolex directly from the company (1-888-301-1084, Petadolex.com), or from Amazon.

We also use magnesium oxide or magnesium citrate, 400 to 600 mg daily. I believe that the Petadolex and magnesium are the most consistently helpful of the natural supplements. Feverfew lags behind as far as efficacy, but it is fairly safe. I have not found vitamin B2 to be very helpful in the long-term, but occasionally it has been effective.

Refractory Headache

Botulinum Toxin Type A

Onabotulinumtoxin A (Botox) is the only FDA-indicated preventive for chronic migraine. It has been daunting to prove that it works better than placebo because the placebo response has been high in several of the onabotulinumtoxin A studies. In one major study, the placebo response was only about 21%, but in others, it has been higher. Placebo response in migraine preventive studies, across all trials, averages about 20%-23%. For unknown reasons, the placebo response is about 5% lower in North America than in Europe.14 The placebo response also differs among countries in Europe. In a number of onabotulinumtoxin A studies, the placebo response led to failure in achieving the primary end point, but the Premium Botox study in North America was positive.15

Over the years (since 1996), one could make a strong case that onabotulinumtoxin A use for migraine is probably safer than most of the other drugs that we use, with fewer side effects. The mechanism for why it works could be due to calcitonin-gene related peptide (CGRP) antagonism, or a similar anti-inflammatory effect.

The FDA indicated dose is 155 units, distributed about the head in 31 injections. Onabotulinumtoxin A usually takes 5 days to 2 weeks to become effective, and there is evidence that it becomes more effective over time. Many patients find that it works well for 10 to 14 weeks. They use considerably less medicine in the 2 to 3 months after onabotulinumtoxin A, and then they say they can feel the effects wearing off at 2.5 to 3.5 months.

Money is the primary barrier to the use of onabotulinumtoxin A, but many insurance companies and Medicare provide some coverage.

Long-acting Opioids

When nothing else works, long-acting opioids are a possibility for refractory patients. Over a period of 6 years, I assessed patients who used long-acting opioids, looking at comorbidities and predictors of overuse.16 The people who tend to overuse long-acting opioids are those who previously overused short-acting opioids. If they abused hydrocodone, they tended to overuse the long-acting Morphine ER (Kadian, others), oxycodone ER (Oxycontin, others), or methadone (Dolophine, others). I have not encountered many cases of pseudoaddiction. As a result, I am reluctant to prescribe the long-acting opioids to patients who previously overused short-acting opioids.

We also assessed the effects of ADD, depression and anxiety, and bipolar and personality disorders and found that the other predictor for overuse of opioids is the presence of a personality disorder. If people have more than a mild personality disorder, opioids are not a good choice.

However, for the right person for whom nothing else works, long-acting morphine, buprenorphine, oxycodone, methadone, or hydrocodone in low doses can improve quality of life and functioning. Careful patient selection and good psychiatric screening are crucial, as are solid documentation at each visit. The ideal candidate for long-acting opioids is one who did well on short-acting opioids (without overuse), has no personality disorder, is older than 30 years of age, and does not develop tolerance to the analgesic effects. Older patients, whose brains cannot do the “neuronal gymnastics” that results in tolerance, may do well on the same low dose for many years.

Frequent Triptans

There are chronic migraine sufferers who do well only with the triptans and many patients take daily, or near-daily, triptans. Some of these patients experiencing rebound headaches from the triptans, but they say, “If I don’t take my triptan, I have a severe headache and need to take 6 to 10 Excedrin!” This patient population needs to be studied to determine whether such chronic use of triptans is associated with adverse events.

I published a study of 100 patients who averaged near-daily triptans for almost 4 years and found no long-term adverse effects using cardiac echocardiograms and ECGs.17 I don’t encourage frequent use, but many people do lapse into it. I recommend that physicians attempt to withdraw their patients from frequent triptans for a period of time, assessing for medication overuse headache.


A case can be made for using stimulants in selected patients with refractory headache, and I believe that these agents are underused in this setting. There have been several stimulant studies in daily headache patients. These agents can help lessen fatigue and improve concentration and mood. In the right person, low doses of stimulants are remarkably useful. For some people, stimulants not only improve the quality of life, they also help alleviate the headache pain.

MAO Inhibitors

Although drug interactions and dietary restrictions limit the use of monoamine oxidase inhibitors (MAOIs), occasionally they provide excellent relief for selected patients. Phenelzine (Nardil, others) is the usual MAOI for headache patients. Low doses (15-45 mg/d) are used; if they are used all at night, food interactions are minimized. MAOIs should be considered for patients with refractory headache and comorbid unipolar depression.

Occipital, Transcranial, and Vagal Nerve Stimulation

Implantation of an occipital stimulator is a controversial technique used in refractory patients. The stimulator can help for a time, but it is difficult to anchor the leads, and migration away from the occipital nerve often occurs. Many patients require another surgery for a variety of reasons. Long-term efficacy and safety is questionable.

In contrast, TMS, which was mentioned in the abortive therapy section, is a non-invasive approach that patients can do at home. I predict this technique also will play a larger role in preventive therapy the next several years.

Vagal nerve stimulation (VNS) is also a non-invasive therapy, stimulating the vagus nerve with a hand-held stimulator. Designed by the Electrocore company, VNS could be helpful for a certain percentage of migraineurs. It is placed on the neck twice daily for a short period of time. Side effects have been very minimal.

Patent Foramen Ovale And Migraines

The jury is still out on the relationship between patent foramen ovale (PFO), the hole in the heart, and headache. One recent trial did not reach its primary end point, but the end point chosen was a very difficult one.18 Several trials assessing whether closure of a PFO will decrease migraines are in progress. It is likely that, in a select group of migraineurs with a sizable PFO, closure will significantly decrease the headache frequency.


Comorbidities often drive how we approach therapy for headache patients. It “takes a village” to help a severe headache patient. We consider involving psychotherapists and physical therapists, among others. We want to achieve a balance between headaches and medication, and try to minimize drug usage. Most patients do well with the usual ministrations, but for the refractory patient we need to consider other approaches. When used appropriately, some of these “out of the box” therapies are the key to restoring a patient’s quality of life.

Last updated on: April 14, 2015
close X