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11 Articles in Volume 6, Issue #7
An Overview of Sleep Medications
Editor's Memo
Ernest Syndrome and Insertion of the SML at the Mandible
Low Level Laser Therapy – A Clinician’s View
Microcurrent Electrical Therapy (MET): A Tutorial
Observational Study of Dural Punctures
Pain as Disease and Illness: Part Two
Practice Patterns of Clinicians Treating Vulvar Pain
Share the Risk Model
Treating Sports-related Injury and Pain with Light Therapy
Using Topiramate in the Treatment of Migraine

Using Topiramate in the Treatment of Migraine

The number one drug used by neurologists for migraine and daily headache, topirimate, is still reluctantly used by primary care physicians. This article is an attempt to demystify a very effective medication in the physician's migraine armentarium.

In the past decade, advances in the headache diagnosis and treatment have revolutionized the field of headache medicine. The American Migraine Study of 19991 demonstrated the astounding number of migraine patients in this country (on the order of thirty million) and also the embarrassing 50% diagnosis rate. Continuing research has elucidated the pathophysiology of migraine2 and, more recently, the concept of central sensitization,3 the process by which migraine may evolve into a continuous process or chronic migraine. The importance of early intervention4 or early treatment of migraine has been demonstrated in studies using numerous triptans by a variety of pharmaceutical companies. The use of triptans, first introduced as imitrex injections in Europe (1989), has significantly improved the immediate treatment of the disorder as can be attested by the great majority of migraineurs who have discovered this therapy.5

The frequent migraine sufferer, however, still may require the use of prophylaxis or preventer-type medications to further improve ‘headache numbers’ and to avoid potential analgesic rebound. The first medications showing significant benefit in migraine prophylaxis appeared in the seventies and included the tricyclic antidepressants and beta-blockers,6 used either together or separately. A long list of prophylaxis medications in various classes have been used since then including the whole gamut of tricyclic antidepressant beyond amitriptyline, a collection of beta blockers beyond propranolol, ARB’s, calcium channel blockers, SSRI’s and SNRI’s, and anticonvulsants. The rest of the list might include a longer list of medications with limited exposure in the literature having claims of headache benefit — such as levetiracetam and Trileptal.7,8

In recent years, topiramate (Topamax®) has assumed the number one position in medications prescribed by neurologists for the treatment of frequent migraine. Primary care has held back and continues to use beta-blockers as their primary first choice.9 As a headache specialist, it has always been the author’s opinion that primary care physicians have tended toward the older traditional choices of treatment, ones which have less issues and complexity. In other words: treatment options that fit better in the context of a busy primary care practice.

The choice of topiramate in the neurological community has been an evolution, particularly derived from all the previous negative experiences with other prophylaxis medications and their major adverse event profiles. It has basically been an escape from mediocrity.10

Which patients should be considered for migraine prophylaxis therapy? Basically, migraine prophylaxis should be considered when all the self-help treatments and abortive therapy have failed to offer sufficient benefit. There is no simple formula for this decision since it depends on multiple factors: number of headaches, severity of headache, and associated symptoms (such as hemiplegia).11,12 The general consensus among neurologists and headache specialists has been that ‘four or five difficult to control headaches a month’ might be sufficient justification to prescribe a daily prophylaxis medication. If these migraines were easily managed with a single Imitrex or Relpax tablet, however, the decision might be to hold off on the prevention treatment. On the other hand, five severe headaches a month—poorly managed with analgesics or triptans—and lasting a day or more apiece would be another matter and completely justify the use of prophylaxis medication. Another indication for migraine prophylaxis would be the association with neurological features such as aphasia or hemiplegia. One episode of this type of phenomenon might justify prophylaxis therapy.

In our clinic, chronic daily headache is also added to the reasons for prophylaxis therapy and includes ‘patient preference’ in the decision making process. One might add one last complexity to this formula, that being the nature of the patient and the doctor. In spite of all the author’s best efforts, there is a small percentage of patients with their own ideas of appropriate therapy. They may refuse any particular form of treatment based on misconceptions or the experience of a distant relative. On the doctor’s side, there may be basic conservatism that resists any complex or new treatment and, at the other extreme, there are some physicians—described by some as overly aggressive—ready to try any new ideas before they’re studied in any way.

It is important to emphasize that adding a prophylaxis medication does not mean withholding required abortive therapy. The patient on topirimate may also be carrying a triptan and promethazine in her blouse pocket, just to be on the safe side.

Which Prophylaxis Medication In Which Patient?

Medications are chosen for prophylaxis in any particular case based on their ‘adverse event profile,’ meaning that their potential side effects make the decision. Efficacy of these medications is less significant as a criterion since the principal choices all have similar documented efficacy (an average of 50% reduction in migraine days). Considering these ‘usual choices’ of preventer medications, there are considerable issues to ponder. First and foremost, the typical patient will be a younger woman, somewhere between 20 and 50. These patients often have low blood pressure, concerns about body weight, desire to exercise, potential for pregnancy, and a disinclination toward sedating or depressing medications.

Whenever possible, it would be reasonable to select a migraine prophylaxis medication that would not interfere with these concerns. It would also be reasonable, whenever possible, to find a treatment that meets other needs such as hypertension or neuropathy. Basically meaning ‘getting two-for-one.’

Evaluating our traditional medication choices, it is immediately apparent why the evolution has been toward topiramate in the neurological community.

Consideration of Topiramate for the Migraine Patient

The recent popularity of Topiramate arose out of the inadequacy of many of our previous choices. The efficacy concerns with the older medications were overshadowed by the adverse event profiles of the drugs. Young to mid-life women—the primary patient population in the headache world—protested about the risk of birth defects, fatigue, exercise intolerance, weight gain, and many other issues. Topiramate appeared to answer many of these concerns, even though it produced its own unique set of side effects. Most of the side effects could be tolerated and were often transient. Topiramate adverse events included parasthesias, memory loss, GI distress, kidney stones, and many other less common issues. A drop-out rate of 10-25% was in line with most of the other preventer drugs used in headache.13

Because topiramate is a ‘seizure medication,’ something neurologists use on a daily basis in their practices, it was quickly embraced by neurologists for the treatment of migraine. It was, however, only reluctantly accepted by primary care physicians. Whether it was perceived as the ‘best new answer’ or not, it was foreign territory to most primary care physicians. Beyond being a seizure drug, it was the next generation of anticonvulsants, significantly more difficult to use than the old Dilantin and Phenobarbital, and associated with a list of novel adverse events. It seemed to be ‘beyond the scope of primary at first glance’ and not worth the time and trouble. Patients needing topiramate would be sent to a neurologist or headache specialist. These latter comments are based on conversations with hundreds of local primary care doctors in meetings and office luncheons.

Considering the position of the primary care doctor in the community and recent changes in the practice of medicine, their attitude can be readily understood. There are always advances and new therapy considerations for hundreds of disease states, any of which might be residing in the reception area waiting to be seen. The doctor has to make a choice how far she or he will take every ‘difficult or special case’ and which new therapy might be considered. Further, time and complexity is of primary concern in primary care, where the average office visit is seven to ten minutes.

Most primary care doctors will add something new to their armamentarium periodically after they are satisfied of efficacy and safety of the newer choices. This can be a particular problem with headache management since so much of that business is ‘off label’ or waiting for studies. Elizabeth Loder, MD from Harvard has reported 48% of the medications used in her practice were off-label in a study last year.14 We would certainly agree with that number in our clinic.

Efficacy of Topiramate

There have been numerous studies demonstrating efficacy of topiramate in the management of migraine. The largest study, reported in JAMA by Brandes et al, showed a 50% reduction in migraine days on a dose of 50mg BID. A dose of 100mg BID afforded an average of 60% reduction in migraine days. There was a 20% drop out rate related to adverse events in their study. Most of us in the headache business have seen this and other studies as our introduction to the use of the medication rather than the last word.13

We have had more favorable results with topiramate in our experience with five hundred patients. With considerable effort, we have closer to a 10% dropout rate in our clinic and efficacy closer to 80%, meaning that patients are reporting a significant benefit. That is accomplished with individualizing therapy in terms of dosing. A year ago, our final dose was usually 100mg a day but this year it is closer to 200mg. We now feel that we were significantly under-dosing our patients a year ago.

Suggested primary care guidelines for the use of topiramate for migraine headache patients.
Topiramate Guidelines
  1. Establish the need for prophylaxis therapy, specifically for the use of topiramate.
  2. Give the patient information about the special features of topiramate, specifically the adverse events possible. Preferably the patient should be given a simple handout.
  3. Begin treatment with 25mg HS and increase the dose no faster than 25mg per week. We prefer going up 25mg every two weeks.
  4. Our first dose goal is 100mg a day. It is our practice to switch to 50mg BID at that time. BID dosing can be started from the beginning also. All dosing at HS is usually equally effective.
  5. Patients should be seen regularly, every 4 to 8 weeks, as treatment is started.
  6. The dose can be adjusted on revisit, depending on efficacy and adverse events.
  7. The duration of treatment would also be determined by the response to treatment. It will often be a year or more.

Adverse Events with Topiramate

There are a number of adverse events associated with topiramate use. The majority of these are transient when they occur and not sufficient to require discontinuation of the drug.15

Parasthesias or tingling can occur in 60% or more of cases. In our practice, virtually every patient on topiramate reports this side effect if asked. It is often described as transient and involving the limbs or face. It may be the sensation of a frozen limb coming back to life. Sometimes it can be so severe that patients describe it as ‘numbness.’ There has been a single brief report in Headache recommending adding potassium in these patients to relieve the parasthesias—either in the form of foods or supplements. We’ve had some success with this approach in our clinic.

Diarrhea can be an issue and require treatment. We’d had several patients who had to stop the medication because of this side effect. We have used diarrhea medications such as loperimide and other bowel calming drugs in these patients in an attempt to pass through this adverse event.

Abnormality in taste is common, particularly with ‘carbonated beverages.’ A few of the 500 patients on the drug have had more significant issues with this. One of our frequent migraine people, who was also a chef, discontinued the drug because she complained of being unable to taste her own culinary creations.

Forgetfulness or ‘problems with word finding’ are common, particularly at higher doses. Occasionally, patients will complain bitterly about this at the lowest dose (25mg). There is a small percentage of patients in whom this can be very notable. Confusion is a word they might use. In one of these patients, coming in for a visit, we noted a significant hesitancy in speech and word retrieval, to the point of an expressive aphasia. This was completely reversed by lowering the dose of the medication.16

At times, patients have collected a variety of medication (particularly our bipolar patients) on top of which they take the topirimate. In these patients, it would be unreasonable to blame topiramate as the sole reason for memory impairment and one may want to recommend patience since this type of complaint may resolve with more time on the drug. In other cases, it may be required to lower the dose or reduce the dose of an associated medication being used (such as amitryptiline). In cases where we were anxious to continue topiramate and were encountering significant memory issues, we’ve had some success using modifinil (Provigil®) along with topiramate as an effective treatment. We’ve had no drug interaction or complication with that trial (although decidedly off-label).

Glaucoma is a rare adverse event associated with the use of topiramate. The incidence is about one in 50,000 patients and would require immediate cessation of the drug. The condition results from narrow angle closure and often occurs in the first few weeks of therapy. This adverse event is more likely to occur in far-sighted individuals. Treatment is generally conservative requiring only discontinuation of the medication.17

Other visual aberrations can occur with topiramate. The most peculiar of these is palinopsia, or visual after-images. We originally wrote up nine patients, then noted the same complaint with many other patients who were ‘asked’ about it. Nearly every case described the adverse event as being like ‘tracers’, or a line following any bright light source in the dark. Several other drugs can cause this side affect (including LSD). None of them appear to have much in common with topiramate. None of our patients with this adverse events had any complications except one patient who described her night driving as hazardous.18

Psychiatric side effects can occur with any medication effecting the central nervous system. In the case of topiramate, depression, anxiety, and mood disorders have been observed but were generally transient. Psychotic reactions have been described and would require immediate cessation of the drug.19

Nephrolithiasis or kidney stones may occur in 1.3% of patients on topiramate. It appears to be more likely if there is a prior history of kidney stones. The stones result from the renal tubular acidosis produced by topiramate. The stones are of the calcium phosphate variety. Drinking extra fluid daily may help to prevent them. We have read opinions that kidney stones can be prevented by adding citric acid to diet (lemonade or lemon juice) or alkalinization of the urine, but the only official recommendation in the headache literature is to drink extra fluids. Many patients elect to continue the topiramate even after having had a kidney stone; other patients will go off the medication. If our patients with a kidney stone elect to stay on it, we will have them see a urologist, drink extra fluids, add citric acid to their diet, and have an abdominal plate of the abdomen twice a year to see if there is apparent calcium deposition in the kidneys (CT scanning of the kidneys is always suggested by our radiologists whenever we order the PLAIN abdominal film.) One of our recent patients developed a large kidney stone only in the context of a severe viral syndrome associated with days of vomiting and dehydration.20

Significant drug interactions with topiramate are infrequent. When other anticonvulsants are used, such as phenobarbital and phenytoin that are enzyme inducers, the blood level of topiramate is reduced. When topiramate is used along with birth control pills (ethinyl estradiol) there can be a reduction in the blood level of the ethinyl estradiol. At a dose of 200mg of topiramate, this can be about 13%. An even greater reduction occurs with higher doses of topiramate. This should be considered by patients in order to avoid an undesired pregnancy.21

Weight loss is a well recognized side effect of topiramate, often one welcomed by the patient. This side effect results from appetite suppression. Generally, the effect is most notable in obese individuals over the first six months of use. It is more likely to occur at higher doses. In unfortunate patients, the weight loss can be a problem and produce a state of anorexia.22

Many other adverse events may occur and would have to be evaluated. Other literature, in particular, has demonstrated hypohidrosis and metabolic acidosis as significant issues in very rare cases. The adverse events discussed above have been the ones most commonly described as an issue in the headache literature.

Office Use of Topiramate

The two most important rules in the use of topiramate are to exercise patience and discuss side effects in advance.

We begin the use of topiramate by confirming the necessity to use it in the first place. In general, at least four or five days a month of difficult to control headaches would be the usual indication. More severe headaches or headaches with complications would also encourage use of the medication.

Dosing of topiramate should begin low, no more than 25mg at night, but some physicians use even less. The label recommends increasing by 25mg a week but we feel that it is preferable to only increase 25mg every two weeks. If side effects intervene, it may be necessary to slow down the titration process or drop the dose back. Except in the case of the worst adverse events, such as an allergic reaction, we encourage our patients to continue the medication even if mild side effects are encountered.

Patients may improve during the first month of treatment and continue to improve on the same dose for months. There is no recommended final dose with migraineurs, but it is very clear that 100mg a day is not the top dose even though that is the most common dose in the headache community. Patients may improve from topiramate in a number of ways. First, the worst headaches are often improved. I’ve had numerous patients tell me that they ‘never had to go to the ER’ after they started topiramate. Second, there is a reduction in the number of migraine days per month. Third, there may be a reduction in the level of chronic daily headache. Fourth, the patients report that their headache drugs work better when they are on topiramate. Several beneficial side effects may also be reported including improvement of mood disorders (bipolar disease) and weight loss.

Once A Day vs BID Dosing

Physicians often have their patients use topiramate once a day at night because the drug has a seventeen to twenty one hour half life. That method of treatment is often effective even when much higher doses are used. The problem, however, is that HS dosing results in a significant variation in the blood level throughout the day (up to a 40% variation). With BID dosing, however, the blood level remains within a twenty percent range throughout the day. We have observed that our patients nearly always tolerate BID dosing and often do better in terms of their headache conditions.23

Topiramate Blood Levels

We have found topiramate blood levels a valuable addition to the treatment program. The usual range of levels is as follows: the level is about 3ng/ml at 50mg BID; the level is about 6ng/ml at 100mg BID; the level is about 12ng/ml at 200mg BID.

Topiramate levels are not particularly useful with single dosing per day because of the great variation in blood levels throughout the day. We only do blood levels with BID dosing so that the level has some meaning and reflects a fairly consistent level throughout the day.

One very good reason to do blood levels is to identify ‘outliers,’ or patients with very low or very high levels. We have often noted patients with much lower levels than would be expected.

How Long Should a Patient Take Topirimate?

There should be no pre-established time for topiramate therapy any more than there is for any other migraine prophylaxis medication. Patients have to be individualized in this area as well. A women with a ten year history of frequent severe and disabling migraine is unlikely to be ‘cured’ by a few months of topiramate. We tell our patients they are likely to be on topiramate for years before we attempt to taper off.

The whole idea of prophylaxis therapy for migraine begins with the concepts of improving quality of life and reducing disability. And since a migraine condition is often progressive, prophylaxis therapy serves to stop that progression. In the headache specialty, we’ve all seen that on a regular basis. Patients arrive having increasing headaches and, with preventer therapy, begin to have a declining number of disabling headache. Does kindling take place with migraine? Do headaches beget headaches just as has been said for many decades in epilepsy? Are chronic severe headache a form of learned behavior and worsen by the process of pathway formation?

We would say yes from the observations at our clinic with our 75,000 headache patients. Looking at the process this way, the prophylaxis therapy may be curative in certain patients.

We have found that many of our worst patients are never able to discontinue prophylaxis therapy for migraine. Given their memories of pain and their nocturnal trips to the ER over the years, many of them have no desire to taper these preventer meds at all. One of the fortunate features of topiramate is that, as an anticonvulsant, it is intended for long term or permanent use.

The patients who are able to discontinue their prophylaxis therapy have often had subsequent headaches for a shorter period of time. It is also helpful in this process if the patients have been changing as many other ‘headache-promoting behaviors’ as possible, such as stress management, dietary change, or reduction in other triggers (such as birth control pills).

What Should Be Done If Topiramate Fails?

When a headache patient begins to have more headaches, the first thing to do is go back and take more history. What else has changed with this patient? Perhaps the problem isn’t the topiramate at all but one of the other myriad factors that can influence headache. Analgesic rebound is always our first concern. When the patient calls and informs the office person they’ve had ‘23 days of headache straight’ and the ‘topiramate isn’t working any more,’ the first question should be related to which other medications they might be taking for that extended headache.

If topirimate doesn’t work right from the beginning or presents too many adverse events, then other prophylaxis medications should be considered. There is a very long list of these available, beginning with beta blockers and tricyclic antidepressants. Lately, we’ve had some success with zonisamide in patients who’ve failed on topirimate. This medication has the advantage of a very long half life, three times that of topiramate. It is our impression that it has less problems with encephalopathy. It is, however, a sulfa drug and that presents the remote possibility of a serious rash.

Summary

Topiramate is an effective prophylaxis medication available for the management of migraine and chronic daily headache. It’s adverse event profile is complex, however, and does create special issues that must be considered in the treatment process. Because of these complexities and issues, those utilizing topirimate for migraine headaches are mostly limited to neurologists and headache specialists. It is our impression that primary care physicians would be more likely to use the medication if they were more familiar with the medication—particularly the adverse event profile.

Last updated on: January 5, 2012
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