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9 Articles in Volume 14, Issue #8
New Perspectives on Neurogenic Thoracic Outlet Syndrome
Dialysis, Opioids, and Pain Management: Where’s the Evidence?
Difficult to Treat Chronic Migraine: Outpatient Medication Approaches
Difficult to Treat Chronic Migraine: The Bipolar Spectrum and Personality Disorders
Arachnoiditis Part 2—Case Reports
Editor's Memo: The Conundrum of Epidural Corticosteroid Injections
Ask the Expert: Central Sensitization
Ask the Expert: NSAIDs After Bariatric Surgery
Letters To the Editor: September 2014

Difficult to Treat Chronic Migraine: Outpatient Medication Approaches

Refractory chronic migraine often is a disabling, debilitating, and challenging illness. Patients who have medication overuse headache or psychological comorbidities require a combination of therapeutic approaches.

Patients with refractory chronic migraine (RCM) experience a great deal of disability and loss of their quality of life. Chronic migraine occurs in approximately 2% of the population, but we do not know the epidemiology or rate of occurrence of RCM.

To provide a framework for other physicians and health care providers, the Refractory Headache Special Interest Section of the American Headache Society was formed in 2001. This committee of headache specialists seeks to define a standard of diagnosis for health practitioners and raise awareness of improved treatments for headache.

The definition of chronic migraine (CM) is outlined in Table 1, and the current proposed criteria for the definition of RCM is a work in progress and is summarized in Table 2.1,2 The committee may want to add modifiers related to the degree of refractoriness (mild, moderate, or severe). In some patients, RCM improves or resolves over time, whereas in others it worsens. These differences need to be addressed in the definition.3

Challenges of Refractory Migraine

RCM presents a number of major challenges, with each challenge necessitating a change in approach.3 These challenges include:

  • What role does disability play, and should disability help to define RCM?
  • What constitutes resistance to treatment(s)?
  • There are no accepted, identifiable biological marker(s) for RCM. Therefore, how does one diagnose RCM?
  • The degree of disease can change over time, improving or worsening. What role does the varying severity play?
  • There are various subsets of RCM—post-traumatic headache, RCM with or without medication overuse headache (MOH), RCM with or without major psychiatric comorbidities, etc. How is the diagnosis and treatment affected by these subsets?
  • How does the treatment differ for various ages: adolescent vs. young adult vs. middle age vs. older ages?


We are just beginning to look beneath the surface of what causes RCM.4 Some of the issues include:

  • What is the role of genetics in drug resistance and inheritance of chronic headaches?
  • What structural changes (in white matter or iron deposition) play a role?
  • What role does central sensitization and neuroplasticity play?
  • How much involvement is peripheral vs. central nervous system?
  • How does MOH affect the structure and function of the nervous system?
  • What is the physiologic impact of psychiatric comorbidities? Do depression and/or anxiety fuel the headaches?

Continuing research is critical to answer these questions.

Several risk factors are posited to drive the development of RCM. These include lifestyle issues such as medication overuse, sleep habits, caffeine overuse, and obesity.5 While pharmacotherapy may be the cornerstone of treatment, other modalities are no less important. The patient must manage his or her triggers with regards to sleep, food, and caffeine intake. Exercise and weight reduction are encouraged. Stress, another major trigger, may be relieved by practicing biofeedback and/or yoga. Depending on the origin of the pain, physical therapy and massage may help. Problems with the teeth, jaw, eyes, and neck should be addressed.

Medication Overuse Headache

Medication overuse headache is a critical issue that must be addressed early in the treatment of any form of headache.6 The overuse of abortive migraine medication, used at the onset of a headache, is a major risk factor for the progression of migraine into RCM. Some patients have medication overuse without an increase in headache. In others, overuse of abortive medications is the principal cause of the headaches.

The criteria for diagnosing MOH are listed in Table 3. Note that the headache progresses, instead of subsides, over time, and the calls for prescription refills will become more frequent with the progression. When treating patients with MOH, the offending drugs will need to be withdrawn or limited. While we do not know with any certainty the percentage of RCM patients in whom MOH is a major contributor, we know that MOH should be one of the first considerations when a patient presents with worsening headaches.

While medication overuse is common, not all overusers suffer from increased headaches as a result of the abortive medications. The current definition of MOH conflates medication overuse with MOH, and, as a result, many patients are incorrectly labeled as having MOH.

Treatments for RCM

There is no algorithm for migraine treatment. The choices of medication will vary for each patient, depending on headache severity and comorbidities. For a RCM patient, the choice of therapy depends on a number of variables, including age, psychiatric comorbidities (For more on psychiatric comorbities, click here), tendency towards addiction, sleep, medical conditions, etc. Comorbidities often steer where we go with medications: conditions such as irritable bowel syndrome (IBS), fatigue, and psychiatric conditions have to be considered. Of course, the familiarity and confidence with a particular therapy on the part of the treating physician plays a major role in selection. It also is crucial to resolve medication overuse, and eliminate rebound in all RCM patients. For the remainder of this article, the author has highlighted a number of possible approaches (opioids, onobotulinum toxin, daily or frequent triptans, stimulants, monamine oxidase inhibitors, injections, and miscellaneous), some of which may be combined.


In my practice, long-acting opioids are the most commonly used approach for RCM. The best candidate for long-acting opioids is the person who has done well on short-acting opioids and who does not have characteristics of a personality disorder (PD).

Phases in Opioid Use

There are 3 distinct phases in the use of opioids. The first phase is the initiation of treatment. This includes the initial screening and risk assessment, the doctor’s decision as to which opioid to use, and the doctor-patient discussion and signing of an opioid agreement. Prior to initiation of long-acting opioids, an assessment of the following should be done: pain level, moods, social and family functioning, work status, physical functioning, and activities of daily living.7

The intermediate phase is comprised of the diligent monitoring of the patient while he/she is on the opioid. This must include ongoing assessment of the patient’s pain level and overall functioning, with a watchful eye for signs of abuse. On return visits, the physical exam needs to assess for slurring of words, abnormal gait, and pupillary abnormalities. Do not assume that low-risk patients will never abuse the opioids. During the maintenance phase of opioid prescribing, it is remarkable how many seemingly low-risk patients misuse the drugs.

Patients usually respond fairly quickly to an opioid; if they have not responded by 2 to 4 weeks on a low dose, there usually will not be an adequate response.8 If patients do not report an improvement in functioning, or if functioning declines, consideration should be given to withdrawal the opioid. Some patients have an improvement in pain but a decline in physical activity, possibly due to sedation or other opioid-related side effects.

The third phase is switching or withdrawing the opioids when abuse has occurred or there is lack of efficacy. Withdrawing or switching an opioid may be exceedingly difficult in some patients. Each of these phases involves a learning curve on the part of the practitioner and proper documentation by staff members.

In my experience, using higher doses of the opioid rarely works out in the long term. Higher doses place the patient at increased risk for addiction and abuse as well as complications from withdrawal. It may be thought that, given the great variation in individual responses, the opioid should be increased or “pushed” to whatever level is beneficial. However, medical and regulatory considerations should be limiting factors in keeping the opioid dose at a low level.

The choice of opioid may be key; some have been shown to have less abuse potential. The once- or twice- daily, long-acting morphine preparations have not been subjected to widespread abuse. Methadone may be more effective than some of the other medications, but has a litany of problems associated with it. Besides the social stigma, high protein binding is a risk, which may lead to irregular drug levels, difficulty with withdrawal, and an increased risk for sudden death.9 If methadone is used, it should be started at a very low dose of no more than 5 to 10 mg a day, and titrated slowly. Patients placed on methadone require close monitoring, and other sedatives must be reduced or discontinued. The usual dosing range in my practice is:

  • methadone, 5 to 40 mg per day
  • morphine, 20 to 90 mg per day
  • oxycodone, 20 to 60 mg per day
  • hydrocodone, 15 to 40 mg per day

Some type of written opioid agreement should be part of the doctor-patient alliance, although there is a lack of evidence that these agreements do much good for the majority of the patients. There is no standard opioid contract; practices should adapt one for their own purposes. There are several resources on opioid agreements (www.painmed.org; www.ampainsoc.org; www.fsmb.org; www.usdoj.gov/dea). In addition there is an excellent article on agreement contracts by Fishman.10

The treatment of breakthrough pain is controversial. Most of the breakthrough studies have been concerned with cancer pain, where the average number of breakthroughs is 4 per 24 hours.11 For patients with non-cancer breakthrough pain, such as chronic daily headache, I tend to minimize the total opioid and avoid layering pain medicines on top of each other. Prescribing short-acting medications for chronic headaches greatly increases the abuse rate. The occasional patient can remain on a low dose of the long-acting opioid, with 1 or 2 short-acting opioids per day, but, in general, clinicians should try to avoid short-acting opioids.

Long-acting Opioids

The following summarizes certain long-acting opioid studies and describes guidelines for using long-acting opioids in chronic migraineurs.

In 1997, Saper and associates assessed refractory chronic daily headache with scheduled long-acting opioids, particularly methadone.12 There was a small subset of patients who did well. Subsequently, Saper and his associates soured on the use of the opioids.

Similar results were obtained from Rothrock.13 An unpublished study from Rothrock indicated that of the chronic migraine patients who were responsive at 2 months to methadone treatment, over 70% continued to maintain a response at 1 year.8 Rothrock found that patients tend to either respond to relatively low doses, or not at all. His studies also indicated that virtually all of the positive responders, when tapered off of the methadone, relapsed into their frequent headache patterns.8

In 2007, our group evaluated 115 patients with RCM who were treated with long-acting opioids during a 6-year period. This was a select group of patients who previously had all done well on short-acting opioids. Avoidance of opioid-induced hyperalgesia is important in patients taking opioids long term; however, all of the patients in this study already had been on short-acting opioids for at least 1 year.14

Sixty-five percent of the patients did well for at least 9 months on the opioid. This was a significantly higher rate of success than that found in a previous study (13%) that used a different standard of success.15 The average duration of use of the opioid was 4.5 years. Forty-four percent of the patients reported adverse events. Patients with an increased chance of success included younger patients, patients with high coping skills, and those without a history of opioid abuse. Predictors of failure were comorbid PDs, older age, and, in particular, previous abuse of the short-acting opioids. In this study, anxiety, depression, bipolar depression, attention deficit disorder, exercise, work status, disability, fatigue, and cigarette smoking did not significantly change the long-term outcome.

Short-acting vs Long-acting Opioids

The term short-acting opioid generally refers not only to how long a drug carries the desired effect but also the speed of onset of the drug and how fast it drops off toward the end of the dose. Quick onsets and fast dropoffs are major determinants for abuse.16 Short-acting opioids are not necessarily quick-onset medications. Most oral short-acting opioid tablets are slow to take effect. A short duration of action then leads to frequent administration by the patient, and overuse may occur. However, it has not been proven conclusively that short-acting opioids lead to more abuse than long-acting opioids. Although certain long-acting drugs have been easily abused, such as oxycodone CR, it is the person, not the drug, who governs abuse. While some abusers have only 1 drug of choice, many will tend to abuse a succession of drugs.

Several previous studies have evaluated daily opioids for severe chronic daily headache.12,13,17 While success rates have been relatively low, they represent patients who have failed the usual ministrations, and who have few options available. Table 4 outlines the advantages and disadvantages of long-acting opioids.

Opioid Abuse

Opioid abuse is much more common than true addiction. In general, using opioids for therapeutic reasons other than pain constitutes abuse. In a headache practice, the most common reasons for abuse are using the opioids to alleviate moods, anxiety, or depression.

Patients in our previous study were assessed for behaviors typical of opioid abuse or overuse. The criteria that we used included: early refill requests, dose escalations, insistence on increasing doses, abusive treatment of the staff regarding refills, false reports of stolen or lost medications, using the opioid for depression or anxiety, using the opioid for other pains not discussed with the physician, receiving similar medication from other physicians, unexpected or abnormal urine screening test results, using illicit drugs or alcohol, missing, canceling, or refusing appointments, selling the drugs, obtaining opioids from non-medical arenas, frequent ER visits for opioids, hoarding, forging or altering scripts, borrowing or stealing similar medications from family and friends, physical signs of overuse or addiction, and calls to the physician from family members with concerns about patient overuse.18,19

There is a range of abuse, from the person who samples his spouse’s codeine prescription once in a while to the addict who obtains hundreds of opioid tablets from the Internet. We cannot paint all abusers with one broad brush. Some situations need watching, such as the patient who took her mom’s pills because she had excess pain; this behavior is a red flag and the patient may be an abuser. For a different patient, one who already has been prescribed low-dose, long-acting morphine, the discovery of undisclosed opioid prescriptions from other sources must be regarded as severe abuse. In this situation, discontinuation of the opioids is necessary.

It is not always clear how serious the abuse is. Minor aberrant behaviors often are overlooked. It is not as if any one aberrant behavior warrants immediate discontinuation of an opioid, but most of the serious overuse situations follow a number of previous minor abuse occurrences. Physicians must pay attention to red flags, particularly those that arise early in the relationship with the patient. In my experience, pain patients who raise objections to urine tests usually have a drug problem. Specimen collections should be random and not scheduled. Urine testing serves 2 purposes: to identify other substances that are present but should not be; and to measure the levels of the prescribed substance for compliance. When there is no opioid present, there sometimes is laboratory error or test insensitivity, but it may be that the patient has been binging early on and has run out of drugs before the visit.20 Another possibility is that the patient is selling the drugs.

In those who self-medicate, a drug is used for a purpose other than the intended one, such as using an opioid as a mood stabilizer or enhancer. Opioids can be both calming and stimulating, often giving a brief burst of energy followed by a tranquil period. Chemical coping is all too common but is poorly understood and under-researched.21 All addicts are chemical copers to some degree, but not all people who cope chemically are addicts. The person who uses 1 or 2 pills of hydrocodone a day for stress and anxiety is not an addict by definition but is certainly using chemicals to cope. The severe patients basically live for the drug; their lives are controlled by its procurement, and they have few coping skills outside of using the drug.22 They will self-escalate their drug use, particularly during periods of high stress.

As much as 35% of patients with chronic pain may fall under the definition of chemical copers.23 There are gender differences, with women using the substances primarily for anxiety, stress, and depression. Women are at somewhat of an increased risk for chemically coping than are men.22 Men may use the drugs for anxiety and depression, but they also use them out of boredom, particularly when they are disabled by their pain. For some men, there is a strong relationship between substance abuse and sensation seeking.22

While physical dependence and tolerance are to be expected with long-term opioid use, addiction is not. Addiction constitutes a biologic and behavioral disease. Most abusers can stop using the drug when harm occurs, but an addict cannot. Whether a patient with previous addictions should be treated with long-acting opioids is a complicated issue. It should be approached on a case-by-case basis and depends on a number of factors. Among the considerations:

  • What substances were abused?
  • How many years has the patient been clean?
  • Has the patient successfully completed treatment for addiction?
  • What is the quality of the patient’s support system?
  • Does the patient have any comorbid psychiatric conditions?24
  • What are the patient’s risk factors?

Previous studies have indicated that risk factors for opioid abuse include cigarette smoking, previous drug abuse, a strong family history of drug abuse, stress, young age, early sexual abuse, poor support, low level of functioning due to headache or other pain, pain embellishment, and certain psychiatric conditions.25-27

A National Institute of Mental Health analysis identified certain problems that carried an increased risk for substance abuse.28 Of patients with anxiety, 25% had a substance use problem, as did 33% of those with obsessive compulsive disorder, and 61% in the Bipolar I category. Unipolar depression also carried a higher risk, but not as much as bipolar disorder. Among PD patients, Webster found that 84% of those with antisocial PDs were substance abusers.29 Also, patients with somatization are probably at a higher risk. In a study by Biederman et al, untreated attention deficit hyperactivity disorder (ADHD) in older adolescent boys carried a 75% risk for substance abuse, whereas those with treated ADHD in this age group had a 25% risk. The boys without ADHD had an 18% overall abuse rate.30

As noted, our study indicated that those with PDs were at increased risk for abuse but that other psychiatric conditions did not lead to more abuse.14

Successful Management
Of Long-acting Opioids

The physician must have knowledge and experience in the use of these drugs. The patient has to be reliable and well known to the practitioner. Many of the problems occur with new patients; it is prudent to wait several visits before prescribing long-acting opioids—after the physician can establish that there has been little or no previous abuse.

In our practice, patients must have demonstrated an adequate response to short-acting opioids. To avoid opioid-induced hyperalgesia, we restrict use to patients who have received short-acting opioids for 1 year or more. The patient must truly be refractory to the typical ministrations, with multiple adequate trials of the usual preventive medications. Previous abuse of opioids should exclude patients from this treatment approach. In this author’s view, previous abuse of short-acting opioids almost always leads to abuse of the long-acting opioids. Pseudoaddiction certainly is encountered, but it seems to be rare in headache patients. Be wary of the patient who claims he or she can tolerate almost no medications except for opioids.

In older patients, particularly those over age 65, the brain has lost the ability to do the “neuronal gymnastics” necessary for the development of tolerance to the analgesic effect. Therefore, older patients may remain on the same low dose for a number of years. In contrast, the use of opioids in patients under thirty years of age should be restricted because younger patients are more likely to develop tolerance to the analgesic effects. If a younger patient fulfills all the requirements, such as truly being refractory, is normal psychologically, and is at low risk for addiction, he or she may be the exception to the age rule.

Management of those with chronic migraine involves a biopsychosocial approach. Patients must not rely on the drug to function. While medications may be a mainstay of therapy, other interventions must be employed. Active coping should be strongly encouraged with each visit, and may involve a variety of approaches, including seeing a psychotherapist, physical therapist, or other practitioner, or using self-help approaches such as exercise or biofeedback. Passive coping is a major predictor of disability in chronic pain patients. Patients who rely only on opioids have less of a chance of sustaining long-term relief. Even though pharmacotherapy is the cornerstone of treatment, it is only part of a more comprehensive plan.

Botulinum Toxin Injections

Onabotulinum toxin Type A (Botox, Xeomin, and Dysport) has been used as a migraine and chronic daily headache preventive since the 1990s.31 Botox is the only brand that is FDA indicated for chronic migraine.

The results of studies have varied widely. Two Phase III studies (PREEMPT 1 and 2) with 1,384 chronic migraine patients, found onabotulinum toxin useful for improving functioning and reducing disablility. One of the studies was very positive in reducing headache days.32 The preponderance of evidence points to onabotulinum toxin as being safe and efficacious, and this author concurs.

There are a number of possible explanations as to why onabotulinum toxin may alleviate pain. One of its mechanisms of action is that it is anti-inflammatory at the neuronal level. Onabotulinum toxin may block the release of substance P. More importantly, it may also inhibit the level of secretion of calcitonin gene-related peptide (CGRP).31 CGRP has been recognized as a key inflammatory mediator, a vital cog in the cascade leading to headache. Efforts are underway to develop drugs that are CGRP antagonists. Onabotulinum toxin also may block the release of certain other neuropeptides that contribute to the “inflammatory soup.” This neuropeptide blockage and onabotulinum toxin’s inhibitory effects on the excitatory neurotransmitter glutamate result in a lessening of peripheral sensitization.

With the use of onabotulinum toxin, there is also a decrease in central sensitization.33 Relatively few other compounds have an effect on central sensitization, which is so vital to the pathophysiology of chronic migraine.

As with a number of migraine treatments, the results of onabotulinum toxin studies vary. A number of variables may explain some of the differences, including:31

  • Headache severity, chronicity and degree of refractoriness
  • Medication overuse
  • Different types of pain (“imploding” vs. “exploding”)
  • Different methods of assessing outcomes
  • Different numbers of units of onabotulinum toxin used and different locations of injections.

In a number of onabotulinum toxin studies, the high placebo response rate has been difficult to overcome in proving efficacy. The optimal mechanics of onabotulinum toxin administration are still a work in progress.34,35 The FDA’s indicated dose for Botox is 155 units, administered in 31 injections about the head. Some patients do well with much less, which is off-label.

For some patients, we “chase the pain” and administer additional injections around the area of pain, which is also off-label. For those with occipital pain, posterior injections may be very helpful. If patients do not respond to the first treatment, it is worthwhile to repeat onabotulinum toxin at least once more. Onabotulinum toxin is expensive but relatively safe. It may be combined with various medication approaches.

Side effects to onabotulinum toxin tend to be minimal; occasionally patients experience a mild droop of one eye. Some have reported numbness or other sensations around the areas of injection. Generalized weakness should not occur with the low doses that are used. On occasion, patients experience an increase in headaches for a short time.

Daily or Frequent Triptans

It has been over 20 years since triptans were first introduced, and they appear to be much safer than was originally thought. Very few serious adverse events have been reported, considering that over 100 million patients have taken triptans. Several studies have described the use of daily triptans for the preventive treatment of chronic daily headache.36,37 Some patients respond only to triptan medications—sumatriptan (Imitrex, Alsuma, others), naratriptan (Amerge, others), rizatriptan (Maxalt, others), almotriptan (Axert), zolmitriptan (Zomig, others), frovatriptan (Frova), eletriptan (Relpax).

Short-lasting adverse events are often encountered with triptan use. These include paresthesias, fatigue, chest heaviness, and jaw or neck discomfort.38 Chest symptoms are, with rare exceptions, not of cardiovascular origin. Echocardiography and electrocardiography generally have been normal after triptan use, even in the presence of chest symptoms.

The primary issue with frequent triptan use, assuming rebound headache is not present, is long-term adverse events. Chronic ischemic changes, valvular abnormalities, and fibrosis are theoretical considerations. Cardiac ischemia due to triptan use is rare,38 and, despite widespread triptan use, the number of adverse cardiac events has been limited. These risks have not been systematically studied, however. The number of patients throughout the world who have used triptans on a near-daily basis is unknown. Until these patients have been studied, it is reasonable and prudent to do cardiac monitoring, as well as hematologic tests.

To study the cardiac safety of frequent triptan use, we studied patient who “on their own” had discovered that daily use of a triptan would alleviate headaches for most or all of the day.36 Most patients in the study had a long history of headaches that were refractory to usual medications. Most of the patients had been using frequent triptans, prescribed by their primary care physician. A minority of our patients had increased the amount of triptans they used on their own.

Patients were withdrawn from triptans to determine if rebound headache was present. The only patients who continued on triptans were those who had been determined truly to be refractory to other approaches, experienced no or minimal side effects, had rebound headaches excluded, and signed a “Frequent Triptan Informed Consent” form. A summary of patient dose and usage can be found in Table 5.

Routine laboratory (hematologic) tests, including complete blood counts and chemistries, were done, and no abnormalities were felt to be due to triptans. Electrocardiograms were performed on all of the 118 patients, and 8 patients (7%) had abnormal findings that were determined not to be from the triptan. Echocardiograms (with Doppler) were done on 57 of the 118 patients (48%), and 10 of those patients (17%) had abnormal findings. The attending cardiologist did not feel that any of these abnormalities were due to triptan use. Twenty patients underwent stress tests, and all were normal.36

Of the 118 patients, 9 felt that the triptans contributed to fatigue; 5 had mild chest tightness at times that was possibly due to the triptans, but cardiac disease was ruled out; and 3 felt that the triptans contributed to nausea.36

Because the patients in the study decided to use triptans on a daily basis on their own, adverse events would be expected to be low. If patients were not tolerating the medication well or were having significant adverse effects, they would not choose to continue the triptan on a frequent basis. There were no adverse consequences from frequent triptan use over a prolonged period. So, frequent triptan use is not ideal, but may actually be safer than some other approaches.


When prescribed for headache patients, stimulants may be beneficial for various comorbidities, such as ADHD, depression, and fatigue. In addition, stimulants do not cause the weight gain that is seen with a number of other headache preventive medications. Amphetamines have been shown to possess intrinsic analgesic properties, primarily through brain catecholamine activity. They also intensify the analgesic effects of certain opioids.39 Stimulants have been used to counteract the sedation encountered by opioids. An excellent review article on stimulants as adjuncts for opioids concluded that “evidence suggests that amphetamine drugs may enhance the effect of opioids and, at the same time, decrease somnolence and increase cognitive performance.”40

As a group, central nervous system (CNS) stimulants cause excitement and euphoria, decrease feelings of fatigue, and increase motor activity.41 Caffeine, the most widely consumed stimulant in the world, is believed to have several mechanisms of action in the pre-frontal cortex and other areas of the brain. These include translocation of extracellular calcium, inhibition of phosphodiesterase, and adenosine receptor antagonism, resulting in decreased fatigue and increased mental alertness.41

Nicotine, the active ingredient in tobacco, specifically stimulates nicotinic receptors in the autonomic ganglia, resulting in euphoria, arousal, relaxation, and improved attention, learning, problem solving, and reaction time.41 However, in very high doses, nicotine causes blockade of autonomic ganglia, resulting in respiratory depression and severe hypotension.

Amphetamine and its derivatives, such as methylphenidate, demonstrate indirect CNS and peripheral nervous system (PNS) effects similar to cocaine. Like cocaine, they initially increase levels of catecholamines. However, amphetamines do this by a different mechanism of action. They accomplish this effect by causing the release of intracellular stores of catecholamines and inhibiting monamine oxidase.41 The major cause of the behavioral effects of amphetamines is thought to be due more to release of dopamine than norepinephrine.41 This, ultimately, results in increased alertness, decreased fatigue, decreased appetite, and insomnia, as well as the usual “fight or flight” response that is characteristic of adrenergic stimulation in the PNS.

Amphetamines have been known to possess independent analgesic activity, possibly due to release of norepinephrine. The effect was felt to be about the same as that of ibuprofen. As noted, stimulants may potentiate the analgesic actions of opioids.40 The most commonly studied combination has been dextroamphetamine and morphine. Methylphenidate also has been studied as an opioid adjunctive medication. In one small study, the use of dextroamphetamine for patients with tension and migraine headache was assessed. It concluded that dextroamphetamine was viable as a preventive medication for chronic tension and migraine headaches in some subjects.42 In another case report, a man was successfully treated with methylphenidate for his refractory episodic cluster headaches.43

One of our previous studies assessed 73 chronic migraineurs who had been prescribed stimulants in addition to their other medications. While the stimulants were primarily prescribed for certain comorbidities, their effect on headaches was also assessed. Seventy-five percent of the patients who were placed on the stimulants remained on them for at least 9 months; 34% of the patients both remained on the stimulants and reported positive efficacy with regard to headache; 41% of the patients suffered at least 1 adverse event, wherease only 2 patients abused the stimulant.44

Advantages of stimulants include enhanced cognition and alertness, with no weight gain. Disadvantages primarily revolve around the side effects, such as anxiety or insomnia. Abuse certainly may occur, but it is uncommon in adults. Stimulants should be considered in patients with certain comorbidities. The few studies conducted to date have indicated a positive role for stimulants, but further studies on stimulants for headache would help to clarify that role.

Monoamine Oxidase Inhibitors

For those with RCM and unipolar depression, monamine oxidase inhibitors (MAOIs) may be of help. MAOIs sometimes are effective for treatment-resistant depression.45 They are also effective for alleviating anxiety. MAOIs were commonly prescribed in the 1980s, but with the advent of selective serotonin reuptake inhibitors (SSRIs) and triptans, they fell out of favor. The available literature on MAOIs for headache treatment dates to the 1970s and 1980s. For a select group of RCM patients, the MAOIs greatly enhance quality of life. At this point, I believe that MAOIs are underused.

The traditional, classical MAOIs form an irreversible complex with the enzyme monamine oxidase. Monamine oxidase is located in a number of tissues, including the brain. The mechanism of action is most likely receptor-mediated pre- and post-synaptic events, not simply an increase in serotonin.45 The traditional MAOI phenelzine has been the one most commonly used for headache.

The transdermal selegiline patch is a selective MAO-B inhibitor that does not require patients to eat a tyramine-restricted diet. Another non-traditional reversible MAOI is moclobemide, which is not available in the US. Moclobemide has fewer dietary and medication restrictions than the classic MAOIs. The efficacy of these non-traditional MAOIs is not as clearly established as the more traditional MAOIs (phenelzine).46

Careful patient selection is crucial when using the MAOIs. Patients need to carefully observe the restrictions on diet and medications. I usually prescribe low doses of phenelzine and start patients with 15 mg at night, increasing after 1 week to 30 mg at night. If no response is noted after 3 to 4 weeks, I usually increase the dose to 45 mg at night; 75 mg is the usual maximum dose. By always taking the MAOI at night, the patient is less likely to encounter a food interaction. Side effects include insomnia, weight gain, sedation, and orthostatic hypotension. The MAOIs have a reputation as being somewhat dangerous and difficult to use, but they usually are well-tolerated.

The previous MAOI diets were overly restrictive. The risk of most foods was based on anecdotal cases. Newer evidence-based diets are easier to follow (Table 6). 47 The hypertensive crisis that may occur with a food interaction is due to a number of factors, primarily the amount of tyramine absorbed into the bloodstream. The tyramine content of food has been difficult to accurately establish. When patients consume phenelzine at night in low doses and avoid the major tyramine-rich foods, interactions are less likely.

Serotonin syndrome may occur due to the administration of serotonergic drugs (ie, SSRIs) and MAOIs. Other drugs that should be avoided include amphetamines, sympathomimetics, pseudoephedrine, certain opioids (meperidine), dextromethorphan, and others. Most triptans are not combined with MAOIs, but low doses of triptans (frovatriptan and several others) may be used with caution.

For patients suffering from both refractory chronic headache and treatment-resistant depression, MAOIs may offer some measure of hope and are not as dangerous as their reputation might imply.

Injections and Nerve Blocks

Various injections and blocks are used for refractory headache. For frontal headaches, sphenopalatine ganglion (SPG) blocks may be useful. Posteriorly, occipital injections are used. For cervical and occipital pain, various cervical blocks or injections may be helpful.

SPG Blocks

For frontal headache, blocking the SPG can be helpful. This has been done for 100 years, but 2 newer devices make it easy to do. These are the SphenoCath and the Tx360. Both are well designed, shrinking the time required from
1 hour to a few minutes. SPG blocks, usually performed with bupivacaine, are safe, with few reported adverse events. For (frontal) chronic migraines, the blocks are helpful if done 2 (or 3) days per week for several weeks.

Cervical Blocks/Injections

Various cervical procedures may be helpful, particularly if cervicogenic headache is present. When the pain is primarily in the posterior occipital area, and/or the neck, these procedures may be beneficial. Cervical epidurals may provide temporary relief. Facet injections often are useful as well. If the temporary blocks help, then procedures that are longer lasting might be more beneficial.

Occipital Nerve Blocks

For posterior head pain, blocking one or both occipital nerves may help, at least for a period of time. Occipital blocks are the treatment of choice when occipital neuralgia is present. If the pain is anterior and posterior, combining SPG and occipital blocks may provide relief.


Rational polypharmacy is commonly used for RCM. Comorbidities influence medications selection. Two (or more) preventives may be more effective than one. However, we also strive to minimize the number of medications used. If a patient is hypertensive and depressed, an angiotensin-receptor blocker plus an antidepressant might lessen the headache. Weight gain often is a concern, and with these patients, we avoid certain medications (valproate, amitriptyline, propranolol, etc.). Many RCM patients complain of being chronically tired. A number of headache medications may exacerbate fatigue. For patients with IBS, we would attempt to choose medications that may help treat the IBS and the headache. Some medications may help the diarrhea of IBS, but constipation tends to be a difficult problem in patients with IBS and headache because a number of headache drugs exacerbate constipation. Unfortunately there are no algorithms that apply to complicated RCM patients. Each patient, with their comorbidities, is unique.


Methylergonovine (Methergine) is a smooth muscle constrictor that primarily is used to stop bleeding after childbirth. Methylergonovine is useful for a small number of RCM patients. The usual dose is 1 tablet 3 times daily. Triptans usually are not used concurrently. Availability has been a problem.

Muscle relaxants occasionally help those with RCM. We usually stick with non-addicting muscle relaxants, such as baclofen (Lioresal) or cyclobenzaprine (Flexiril, Amrix). Fatigue is a common side effect. Another muscle relaxant, metaxolone (Skelaxin), minimizes fatigue. These agents may be beneficial for treating insomnia as well.

Memantine (Namenda) is a drug used for the treatment of Alzheimer’s disease and dementia. Memantine is a N-methyl-D-aspartate receptor antagonist that may be helpful for pain management. Memantine is a safe, well-tolerated drug. The usual dose of memantine is 14 to 21 mg a day.

New Developments

New approaches, such as transcranial magnetic stimulation (TMS), are becoming available. In December 2013, the US Food and Drug Administration approved the first TMS device specifically for the management of migraine (Cerena TMS). According to the FDA, nearly 38% of subjects who used the Cerena TMS when they had migraine pain were pain-free 2 hours after using the device compared to about 17% of patients in the control group. After 24 hours, nearly 34% of the Cerena TMS users were pain-free compared to 10% in the control group.48 TMS has few side effects and has been in testing for 10 years. Patients can have a unit at home that delivers several quick, magnetic pulses to the occipital cortex in the brain. Over time we will see how effective TMS is for severe headaches.

Occipital nerve stimulation has been beneficial for a small number of RCM patients. Techniques of implantation have improved, but the technical challenges need to be overcome. The leads tend to migrate away from the occipital nerve, for example. While it is invasive and is associated with serious side effects, nerve stimulation is viable for a small number of patients.

In pharmacotherapy, there are a number of emerging compounds that may eventually come to market. These include newer preventive techniques, such as an injection of a CGRP antibody.


Refractory chronic migraine often is a disabling and debilitating illness. We face major challenges in attempting to define RCM. The definition must allow for severity of illness; also, degrees of refractoriness may change over time.

Other major areas of study within RCM include pathophysiologic mechanisms, the role of medication overuse, a search for biomarkers, psychological comorbidities, non-medication approaches, and pharmacotherapy.

Patients with RCM who have MOH or psychological comorbidities require a combination of approaches. It “takes a village” to help those with severe, refractory headaches, and we need to guide the patient into comprehensive treatments. There are a number of viable therapeutic approaches, a number of approaches are presented in this article. However, we desperately need breakthrough medications and technologies that can prevent headache pain. 



Last updated on: May 18, 2015
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