Treatment-resistant Migraines (ημικρανίες)


Triptans have been available since 1992 and are now generally accepted to be the most predictable of treatments for migraines. However, triptans do not work for everyone. The fast acting oral triptan preparations (Imitrex, Maxalt, Zomig, Axert, Relpax) all work in approximately the same percentage of patients varying from 60 to 70% in different studies. The 30 or 40 % of patients that do not respond to one triptan may well respond to one of the other triptans.1 Eletriptan has been found in one study to be effective in patients who found oral sumatriptan to be poorly effective or to cause side effects.1 In another study, the 30% of the participants who failed with oral sumatriptan for migraine treatment responded to Zomig 71% of the time and to Maxalt 81% of the time.2 Use of other formulations, such as Imitrex or Zomig nasal spray or the Imitrex injection, also increases the percentage of patients that may respond.

There is still a percentage of migraine patients that are triptan non-responsive. This article will deal with possible reasons for treatment-resistant migraines. (See table 1.)

Transformed Migraine

Transformed migraine initially has a typical migraine presentation. The migraines have an obvious start and finish with discrete headache-free periods between attacks. Gradually the headaches increase in duration with fewer and fewer pain-free days. The use of analgesics may increase over time with less and less response. The etiology of transformation may be time, under-treatment, or a comorbid condition. Transformed migraine can be sub-classified as pseudo-transformed, rebound, or psychological and are discussed in the following sections.

Pseudo-transformed Migraine

The evolution of migraines into treatment resistance can be caused by incomplete treatment with triptans themselves. While triptans are the best treatment for migraines, they are sometimes not used in the correct fashion. For instance, frequently a patient single doses triptans and does not know that he or she can take a second dose in the same day. The patient may be so happy that the migraine was partially relieved by the first triptan that a second dose is not taken because (1) the patient does not know he or she can, (2) cost issues, (3) side effect issues, or (4) he or she is simply happy with a 50-75% improvement in the pain. However, 87% of patients desire to be pain-free.3

Incomplete treatment of headaches can lead to transformed migraines by a kindling effect.4 It is important that triptans, when utilized, be used properly and the patient is always encouraged to completely relieve the headache. Patients using an oral triptan should be encouraged to dose as soon as possible at headache onset, then use a second dose within an hour or two to attempt to resolve the headache completely. Early treatment significantly improves the likelihood of aborting headaches.4

It may be advantageous to advance to the nasal spray form when an oral triptan is not 100% effective. The nasal spray works more rapidly — in a larger percentage of cases — to completely relieve the headache. Also available is the subcutaneous injectable formulation. The injection has been used quite successfully as rescue for tablet and nasal spray users.5 Many patients experience different levels of severity in migraines. These patients have what can be called oral headaches and subcutaneous headaches. This means a patient may have migraines that come on slowly, are mild and respond to oral triptans. At other times he or she may have headaches that come on rapidly, are more severe or simply do not respond to the oral medication and require the subcutaneous injection. Therefore, sending the patient home with sumatriptan oral, nasal spray and injectable for the various types of headaches may be an advantage in completely relieving the headaches as soon as possible in order to prevent transformed migraines. If only one oral triptan is used then, at best only 60-70% of migraines will be resolved. The remaining 30-40% will then be labeled “triptan unresponsive,” when in fact, the migraine responds to a different triptan or to the nasal spray or injection form.

Rebound Migraine

A common etiology of transformed migraine is rebound. Rebound is caused by use of short-acting analgesics. It can occur with any type of analgesic and can even occur with triptans. Rebound is actually a form of withdrawal syndrome characterized by excess or uncontrolled central nerve transmission.6 A common example is butalbital.It may only lessen the pain without treating the underlying condition of 5HT binding site activation. Initially butalbital may be required several times per month progressing to several times per week, then to daily use and quickly progressing to multiple doses per day. Use can escalate to as much as six, eight or even twenty doses per day. The concern is heightened considering that 4gm of acetominophen a day can be a hepatotoxic dose. As infrequently as 2-3 doses per week can cause rebound in a susceptible individual.

The evolution of migraines into treatment resistance can be caused by incomplete treatment with triptans themselves. While triptans are the best treatment for migraines, they are sometimes not used in the correct fashion.

Presentation is usually an individual with a history of headaches that have worsened and increased in frequency. Often the patient is worsening the headaches by the overuse of short-acting analgesics that incompletely treat the headaches. In the prescriptive medication case, it is the treating physician that is inadvertently worsening the rebound migraine by continuing to prescribe the offending medication.

In a physician survey of rebound-causing medicines, butalbital combinations are one of the greatest offenders in this area, with 24% of physicians reporting routine overuse by patients.6Although, even mild analgesics such as APAP and ASA were also reported as overused.6 Use of as little as two to three times per week of an analgesic such as ASA or APAP on a regular basis may lead to rebound. Medications obtained over the counter may not even be reported by the patient, making the diagnosis difficult.

Once rebound occurs it may be necessary to temporarily stop all medication to halt the rebound phenomenon.6,7,8 This problem may be extremely difficult to treat because the patient is extremely reluctant to stop the offending analgesic. He or she is convinced that the analgesic is the only thing that makes life bearable. Certainly, stopping the analgesic may improve the overall situation but the patient may “get worse before getting better.” Patients may be resistant to this treatment phase and the physician must be prepared to carry the patient through this difficult period — even with emergency medication measures.

The potential for rebound is a reason to generally avoid butalbital-containing combinations. When butalbital products are used the physician should closely monitor the patient.

When the uncontrolled migraine patient—having a history of butalbital combination in multiple doses per day—sees a migraine specialist, the problem may be obvious. The migraine specialist then has the task of stopping the patient’s daily overuse of analgesic. It may be helpful to explain to the patient that this is a medication that is useful for occasional headache, but once the headache progresses into a long-term situation the medication’s utility diminishes. It is not necessarily wrong for the initial treating physician to prescribe it. It is simply necessary to change the program when the situation goes from acute to chronic. Even at that point many patients may resist change.

Since the offending agent may be causing the patient’s headache pattern to worsen, it may not be advisable to continue to prescribe such a medication since it may be causing more harm than good.

A common physician complaint is not knowing “how to get the patient off the drug.” While the process itself may be complicated, it starts by simply telling the patient that this pattern is harmful and should no longer continue. Then inform him or her that the analgesic will no longer continue to be prescribed. The patient’s only choice will then be to either follow the weaning protocol or obtain a new physician. Allowing the patient to leave the practice and obtain a new physician is much preferable to allowing the patient to continue using a medication that is known to make the problem worse.

Transformed with Psychological Overlay

Migraines can become transformed and difficult to treat if a person has a history of treatment-responsive migraines but then experiences a psychological problem. The transformer, for example, could be a divorce, death of a loved one or anxiety. See the next category for further discussion of treatment-resistant psychological migraines.

Psychological Overlay

The difference between a transformed psychological migraine and a migraine caused by psychological issues is the timing of the migraines and the psychological issue. In transformed migraines, treatment-responsive migraines were present prior to a new psychological issue. The migraine then becomes transformed and no longer responds to a previously successful migraine treatment. However, many times the psychological problem is the trigger to migraines that previously did not occur. When the psychological problems are present and left untreated migraines develop. Certainly if the patient has a psychological problem contributing to his or her headache, the triptans will be less responsive as the baseline problem is not being addressed. Bipolar is a very common problem in migraines with some studies suggesting that as many as 10% of all migraineurs have a bipolar tendency. Depression and insomnia also co-exist with many migraines. It is important that when a physician treats someone with migraines that he or she also checks for concomitant depression, anxiety and insomnia.Certainly if the patient has concomitant unaddressed depression, any treatment of the migraine will not be complete. Lack of restful sleep is a common migraine trigger. Not addressing the patient’s insomnia will cause the migraines to be less responsive to treatment. If the patient has an ongoing stressful situation such as a divorce or work situation, the triptans or other treatment of migraines will be less effective.

Three-fourths of migraineurs are female, and this is most likely due to estrogen and other hormonal manifestations.9,10 Changes in hormonal levels are known to precipitate migraines

Hormonal Imbalances

Three-fourths of migraineurs are female, and this is most likely due to estrogen and other hormonal manifestations.9,10 Changes in hormonal levels are known to precipitate migraines. The usual times for hormonal changes are puberty, childbirth, menses and menopause. For example, many women start with migraines at puberty.

Women who experience migraines may have an increased sensitivity to changes in hormone levels. There is no difference in menstrual cycles in women who do experience migraines from those who do not.11 Approximately half of all female migraineurs relate that migraines occur around the menstrual cycle. The exact time around the cycle varies from woman to woman. It may be before, during or after menses. This is usually related to each particular woman’s hormonal trigger (e.g. either estrogen level rising or dropping). Menstrual migraines are commonly thought to be less responsive to treatment, however two-thirds to three-fourths of menstrual migraines treated with a triptan report relief. Treatment can be both preventative and abortive. To prevent transformed migraine, it is important to treat early when the pain is mild.11 Triptans, with different formulations, can be used for both. Triptans should be used for abortive therapy, but if the woman experiences more than three migraines per month, prevention needs to be considered.12 Prevention is not recommended for less frequent migraines due to prolonged dosing and complex regimens compared to acute therapy. Prevention is also not recommended in unpredictable menses.11

Migraines are also very common during pregnancy. Women may relate that their migraines appeared with the first child, disappeared with the second and reappeared with the third child. The hormone changes in pregnancy may make the migraines disappear or they may make them worse and less responsive to treatment. Again, hormone changes affect migraines but the effect may be unpredictable in each individual.

Menopausal migraines are an interesting phenomenon. While it is known that many females with migraines will cease having migraines after menopause, many also experience worsening of migraines during the menopausal time itself. This is almost certainly due to the spiking of estrogen, the same effect that causes the hot flashes women encounter during menopause.13Migraine prevalence decreases with age and is believed to be caused from the decrease in estrogen after menopause.13 It may be an assurance to the woman that while her migraines may worsen during menopause, migraines will generally improve after menopause. It is also important to administer a stable hormone level when using hormone replacement therapy after menopause for women with migraine tendencies. Treatment should incorporate a steady dose of hormones on a daily basis during the month. Cycling hormones, such as using an estrogen product for 25 days and cycling off for five, will simply lead to migraines during the five days that the patient is without the estrogen.

Table 1. Patient Characteristics Prior to Prolotherapy
Type Cause Potential Strategy
Transformed Migraines:



Transformed with Psychological Overlay
Incomplete treatment with triptans

Overuse of short-acting analgesics

Psychological problem transforms previously responsive migraines
Early and complete treatment with stratified triptan options

Stop or switch to long-acting medication

Treat the psychological problem
Psychological Overlay Underlying psychological disorder causes migraines Treat the psychological problem
Homone Imbalances Changes in estrogen levels during menses, puberty, pregnancy, and menopause Abortive: short-acting triptans.

Preventative: estrogen therapy or long-acting triptans.
Post-Traumatic Migraines Head injury of concussion May require non-triptan medication
Chronic Central Sensitization Increased and prolonged exposure to pain May require non-triptan medication
Misdiagnosed Migraine Close resemblance to resistant migraines Consider: temporal arteritis, muscle-tension, complicating factors, or brain disorder

Post-traumatic Migraines

Head injuries or post-concussion migraine headaches commonly do not respond as readily to triptans nor other treatments. A patient may have migraines that are transformed by the injury process or they may have had latent migraines that were triggered by the head injury process itself.14 In patients who have experienced a mild head injury, 30-50% experience post-traumatic headaches.14 These migraines typically do not respond as readily to triptan therapy or to preventative therapy. They may require an unusual, non-standard, or innovative approach to achieve even a modicum of control.

Chronic Migraines

Central sensitization is a chronic condition of increased awareness and sensitization to pain that occurs with increased and prolonged exposure to pain. The patient becomes more sensitive to all pain, not just the original pain. Due to repeated exposure to pain, the brain learns to read pain signals more acutely and becomes unable to modulate, or turn off, the pain signal. Increased frequency of headaches increases the likelihood of future headache episodes being more easily triggered and more severe.15 There is no therapy available once sensitization has occurred. Prevention is imperative. Treat headaches early and use preventative measures to limit the exposure to repeated pain episodes.15

Misdiagnosed Migraines

If treatment with a triptan is not successful, it is important to rethink your migraine diagnosis. Conversely, treatment and resolution of pain with a triptan does not necessarily rule out a separate medical condition. Not all treatment-responsive migraines are benign. Other conditions to consider are temporal arteritis, muscle-tension headache, other complicating factors, or even a brain disorder.

Temporal arteritis is easily mistaken for migraines. Diagnosis is made with biopsy and a sedimentation rate. Treatment is with steroids, not triptans.

Muscle-tension headaches (MTHA) can also be easily confused with migraine. Intra-cranial issues such as depression or anxiety or extra-cranial issues of the neck can cause pure muscle tension pain. One model presents headache pain as being on a continuous spectrum from migraine to muscle-tension headache.16

Other complicating factors to headache disorders need to be considered during diagnosis. One common one is insomnia (either primary or secondary, such as sleep apnea). Benign or malignant brain disorders such as a subdural hematoma, aneurysm or tumor can be migraine triggers and the headache may respond initially to triptans. Yet the initial headache response to a triptan does not guarantee a benign headache process.


When treating migraine patients it is important to remember that triptans are usually the best and most predictable for migraines in regard to (1) stopping the headache as soon as possible, (2) treating the associated symptoms of nausea, vomiting, photophobia, phonophobia and cognitive dysfunction, and (3) stopping the transformation process. The triptan initially selected should be tailored to the individual patient. For instance, the subcutaneous product has the widest utility because it will generally work the fastest and most completely. It also has the widest range of usage, such as in the patient with nausea and vomiting. Patients generally prefer oral preparations.3 If one oral preparation fails, remember that other oral preparations may still have utility.16 Failure of one triptan does not mean failure of all oral triptans. When trying one triptan or another it is important to give each triptan a sufficient trial of a minimum of three different migraine events before determining that it is a failure. Even injectable triptan can have a first, second or even third-pass failure before it becomes effective. Stratified care will result in the greatest number of migraines resolved. Classification as triptan resistance may be premature if only one or two triptans have been tried when maybe the person will find relief with a different oral triptan, nasal spray or injection formulation.

When triptans, including the injectable version, are found ineffective, one should first look to the reasons why. First, one should reconsider the diagnosis. If it is confident, one should consider transformed migraine, such as rebound or incomplete migraine treatments, or co-morbid conditions such as a psychological problem, hormonal problems or head injury.

When dealing with headaches, whether triptan-responsive or not, it is always appropriate to investigate and modify any medication that appears to possibly worsen headaches.Even nonprescriptive over-the-counter medications may be an offending agent.

Πηγή: practical pain management