The Upsides and Downfalls of Topiramate

Twelve years ago, the American Headache Society (AHS) and the American Academy of Neurology (AAN) released a set of guidelines to rank the effectiveness of various medications for prevention of episodic migraine. Drugs such as amitriptyline, divalproex, propranolol and timolol made the top tier (see "2012 Migraine Prevention Guidelines" below).

Topiramate, a common migraine preventive drug, had not yet been approved by the U.S. Food & Drug Administration (FDA) for prevention of episodic migraine. The medication was placed in the third tier in the 2000 AHS/AAN guidelines, as a drug that “may” be considered for migraine prevention.¹

In the 2012 update to the AAN/AHS guidelines, topiramate graduated to the top tier of migraine preventive meds. According to a summary of the guidelines, clinical trials in the past 12 years have established the drug as effective for prevention of episodic migraine (i.e., migraines that occur six to 14 times per month).² One could conclude that the FDA’s approval of topiramate for episodic migraine in 2004³ as the reason for the upgrade, but this is not the case: “Assignment of drugs to levels was based solely on grading by quality and the strength of clinical trial evidence,” says Elizabeth Loder, MD, MPH, lead author of the guidelines summary.

Topiramate’s recent advancement in the guidelines could lead more headache specialists to prescribe the medication. But before beginning any kind of treatment plan, migraineurs and headache specialists should weigh the drug’s benefits and risks.

The Upsides

Topiramate was introduced to the United States in 1996 as an anti-seizure medication (also known as an anti-convulsant or anti-epileptic).⁴ Similarities between epilepsy and migraine suggested the drug could work for headache. For instance, both migraine and epilepsy affect how neurons fire and both are associated with hyperexcitability in neurons.⁵

In cortical spreading depression, which may be related to migraine pain, neurons in the brain’s outer layer (the cortex) become hyperexcited. The hyperexcitability then moves in a wave across the brain. People who have migraine with visual aura can actually see this effect, as blinking lights or geometric patterns move through their field of vision with the same timing as the cortical waves, about two to five millimeters per minute.⁶

A study published this year in the journal Cephalalgia examined topiramate’s effect on cortical waves. Researchers induced cortical spreading depression in groups of anesthetized rats (some had been treated with topiramate daily for six weeks, while others had never received the drug). Among the untreated rats, waves of hyperexcitability traveled across their brains unimpeded. But in rats treated with topiramate, cortical spreading depression faded significantly and the time between wave episodes increased.⁷

Headache specialists recommend a certain dosage and regimen to receive the full benefit of the drug.

“When topiramate is selected, the average dose for the average person looking to prevent their headaches is 100 mg, divided into two doses daily,” says Mark W. Green, MD, FAAP, director of Headache and Pain Medicine at the Mount Sinai School of Medicine in New York City. “It is best to start with 15 or 25 mg and increase that dose weekly over four to six weeks, to 90 to 100 mg.”

But the regimen generally doesn’t end at six weeks.

“The longer we keep you on it, the higher the chances are that you’ll do well without it,” Dr. Green says. “We don’t assume that we are going to treat you forever. I might treat someone for a year and slowly reduce the drug and see if they still need it, and often, they do fine.”

In a 2006 study of 970 migraineurs, patients who received topiramate (regardless of dose) during a clinical trial saw their migraines decrease from three to 12 attacks per month, to an average of 3.4 attacks per month after the first six months of treatment. After eight months, patients saw their migraines decrease to an average of 2.2 attacks per month.⁸ It is not known how long this trajectory continues, but it seems to be maintained even after the drug is discontinued.¹

Patti Havens, 52, is among those who saw the benefit increase over time.

“[At first] I was like, ‘Oh my gosh, that stuff is brutal! I don’t want to take it!’” says Havens, who lives in Claremont, Calif. and works in her husband’s law office.

But Havens says she was missing out on life and needed to manage her migraines. Shortly after she started taking Topamax® (topiramate), the number of migraines decreased from 12 to 15 a month to just three migraines during her first 18 months on the drug. Then suddenly, her migraines disappeared altogether.

Slimming Effect

In addition to curbing migraines, some migraineurs have also noticed that topiramate triggers weight loss. In a 2012 study, which compared topiramate to the antidepressant medication amitriptyline, patients treated with topiramate lost an average of five pounds during the 26-week trial, while patients treated with amitriptyline gained about five pounds.⁹

“It’s one of the few migraine drugs that can cause weight loss and doesn’t cause weight gain,” Dr. Green says. “Obesity is a risk factor for the progression of headaches, so if you can help reduce weight, this can have a therapeutic effect on migraine.”

Still, while the drug may commonly cause weight loss, it is not approved by the FDA for that effect. Therefore, though migraineurs may find themselves losing weight on the drug, headache specialists prescribe it for migraine prevention alone—not for the promotion of weight loss. (On a separate note, the drug Qsymia^TM, which combines topiramate and phentermine, was approved by the FDA for weight loss in July 2012.¹⁰

The Downsides

Though weight loss may be a welcome side effect for some, other side effects of topiramate are more concerning. Topiramate is linked to a long list of potentially negative side effects, from fatigue and anxiety to kidney stones and word-retrieval problems.¹¹

“I jokingly call it Dopamax,” Havens says. “I was foggy for months when I started using it.”

While on the drug, Havens says she will occasionally have trouble thinking of the right words to say, but the effect has largely faded over time. Word retrieval is a particularly frightening cognitive side effect of the drug, Dr. Green says.

“It makes you a little loopy—I don’t think I’m as sharp a thinker when I take it,” says Anne Brinkley, a retired North Carolina high school chemistry teacher who had to retire early due to incapacitating migraines. “It’s a tradeoff. I’d rather not think as well than have more migraines.”

The drug’s most worrying side effect is the slight but serious risk for glaucoma, Dr. Green says, as topiramate has been associated with increased pressure inside the eye, which can lead to blindness if left untreated.

But overall, the most common side effects are less alarming. About one-third of patients in one trial complained of paresthesia, the most common side effect, which involves a pins-and-needles feeling in the hands and feet.⁸ The tingling does not damage nerves and resolves in most patients, Dr. Green says. In that same trial, some 17 percent of patients complained of fatigue, 11 percent said their sense of touch was blunted and about 10 percent experienced nausea. Perhaps most frustrating, many of these side effects appear before the drug’s benefits start, Dr. Green says.

These side effects make it even more important for physicians to use a “start low/go slow” approach to treatment, easing patients up to their effective dose, Dr. Green says, adding that most side effects disappear over time.

Birth Defect Dilema

Topiramate could also have worrying side effects for the unborn. In May 2011, the FDA announced an association between topiramate exposure during pregnancy and increases in certain types of birth defects. The agency found that women taking topiramate during the first trimester were more likely to give birth to infants with oral clefts. Specifically, the prevalence of oral clefts was 1.4 percent in topiramate-exposed patients, compared to 0.38-0.55 percent in infants exposed to other anti-epileptic drugs and 0.07 percent in infants who weren’t exposed to any anti-epileptic drug.¹²

Due to these findings, the FDA recommends pregnant women not be prescribed the drug, except under dire circumstances. The FDA has also dropped the drug’s pregnancy category rating from Category C (which means the risk of the drug to a baby is unknown) to Category D (which means there is evidence of fetal risk).¹³

Other studies do not support the FDA’s conclusion. For example, a 2012 study, which was published in the journal Headache (Mark W. Green, MD, FAAP, was the lead author), found littleor no increase in risk from topiramate compared to other anti-epileptic drugs. The study followed insurance claims related to 4,485 infants born from mothers exposed to topiramate (870 infants) and other anti-epileptic drugs (3,615 infants) during the first trimester of pregnancy. The study found little or no increase in risk from topiramate compared to other anti-epileptic drugs. Comparatively, in the topiramate group, oral clefts occurred in 0.23 percent of births. Among those exposed to other anti-seizure medications, the birth defect occurred in 0.17 percent of births.¹⁴

“Ultimately physicians need to weigh the risks and benefits accurately in cases in which migraine control is necessary,” Dr. Green says.

Case by Case

While no drug is a cure-all and no one medication will work for every migraineur, a better understanding of the benefits and risks of preventive medications could help headache specialists and migraineurs to determine the best possible treatment plan.

“The 2012 prevention guidelines are an important starting point to understand the need and scope of migraine therapies for prevention,” Dr. Cady says. “Beyond this starting point is the need for clinicians and patients to form an ongoing collaborative partnership that is outcome-based and directed to the individual needs of the patient.”

This partnership, coupled with research into a drug’s efficacy and a review of the patient’s medical history, is a necessary step in understanding and treating migraine and other headache conditions. If you are searching for a headache specialist, visit the National Headache Foundation’s website at www.headaches.org or call 888-NHF-5552 for help.

 

2012 Migraine Prevention Guidelines

In the 2012 “Guidelines for Prevention of Episodic Migraine,” preventive medications were organized into five categories:

• Level A drugs have been established as effective for the treatment of episodic migraine, based on clinical trials.
• Level B drugs are labeled “probably effective” and should be considered for migraine prophylaxis.
• Level C drugs “may” be considered for preventive treatment.
• Level U includes drugs that have insufficient data.
• A separate category was created for drugs considered ineffective.

In the updated guidelines, Level A drugs now include three beta-blockers (metoprolol, propranolol and timolol), anti-epileptic drugs (e.g., topimarate and sodium valproate) and the herbal treatment butterbur. Amitriptyline, which was in Level A in 2000, has been downgraded to Level B. It is accompanied by the herbal treatment feverfew, vitamin B2, venlafaxine (an antidepressant), and several NSAIDs (e.g., ibuprofen). Level C drugs included coenzyme Q10 (coQ10) and several NSAIDs as well (e.g., flurbiprofen). Among the drugs considered ineffective for migraine prevention were the anti-epileptic drug lamotrigine as well as oxcarbazepine and telmisartan.

Other guidelines—such as those for chronic migraine, pregnant women or pediatric migraineurs—were outside the scope of the study. Researchers working on the updated guidelines also excluded onabotulinumtoxin A (Botox®) because the AAN has previously identified it as ineffective for treatment of episodic migraine.¹

Despite researchers’ conclusions about the efficacy of various preventive medications, the authors of the updated prevention guidelines have noted, “A majority of migraine sufferers who would benefit from prevention therapies do not receive them.” According to one study sponsored by the National Headache Foundation in 2005, some 43 percent of migraineurs have never used preventive therapies, despite having migraine frequencies that would benefit from treatment.¹⁵ A lack of physician awareness and confidence in the quality of medication guidelines could be to blame, the guideline authors suggest.

Topiramate for Chronic Migraine Too?

Although the FDA approval and prevention guidelines only cover episodic migraine, some studies suggest topiramate could also work in chronic migraine (or migraine that occurs 15 or more times per month).

Currently, onabotulinumtoxin A (Botox®) is the only FDA-approved treatment for chronic migraine (although it is considered ineffective in the prevention of episodic migraine).¹⁶ In one 2011 study, 59 chronic migraineurs were divided into two groups: one that received topiramate and one that received onabotulinumtoxin A. After four weeks of treatment, both groups took a Physician Global Assessment that measured improvement in chronic migraine. Of the topiramate group, 74 percent had improved; of the onabotulinumtoxin A group, 60.7 percent had improved. By week 12, 70.8 percent of the topiramate group had improved and 79.2 percent of the onabotulinumtoxin A group had improved. Ultimately, the treatments showed near-equal efficacy.¹⁷

 

References:

1. Silberstein. “Practice Parameter: Evidence-based Guidelines for Migraine Headache (an Evidence-based Review).” AAN report for the Quality Substands Subcommittee of the American Academy of Neurology. 2000.
2. Loder et al. “The 2012 AHS/AAN Guidelines for Prevention of Episodic Migraine: A Summary and Comparison with Other Recent Clinical Practice Guidelines.” Headache. 2012;52:930-945.
3. Warner. “FDA Approves Topamax for Preventing Migraines.” WebMD. Aug. 12, 2004.
4. National Institutes of Health. “Topamax.” Dailymed.nlm.nih.gov. January 2012.
5. Haut et al. “Chronic Disorders with Episodic Manifestations: Focus on Epilepsy and Migraine.” Lancet Neurology. 2006;5(2):148-157.
6. Mulleners et al. “Visual Cortex Excitability in Migraine with and Without Aura.” Headache. 2001;41(6):565-572.
7. Unekawa et al. “Suppressive Effect of Chronic Peroral Topiramate on Potassium-induced Cortical Spreading Depression in Rats.” Cephalalgia. 2012;32(7):518-527.
8. Rapoport et al. “Long-term Migraine Prevention with Topiramate: Open-label Extension of Pivotal Trials.” Headache. 2006;46(7):1151-1060.
9. Dodick et al. “Topiramate Versus Amitriptyline in Migraine Prevention: A 26-week Multicenter, Randomized, Double-blind, Double- dummy, Parallel-group Noninferiority Trial in Adult Migraineurs.” Clinical Therapeutics. 2009;31:542-559.
10. FDA. “FDA Approves Weight-Management Drug Qsymia.” Press release. July 17, 2012.
11. Drugs.com. “Topiramate Side Effects.” 2012.
12. FDA. “Topamax (topiramate): Label Change – Risk for Development of Cleft Lip and/or Clef Palate in Newborns.” www.fda.gov/ Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm245777.htm
13. FDA. “FDA Drug Safety Communication: Risk of Oral Clefts in Children Born to Mothers Taking Topamax (topiramate).” www.fda. gov/Drugs/DrugSafety/ucm245085.htm
14. Green et al. “Utilization of Topiramate During Pregnancy and Risk of Birth Defects.” Headache. 2012;52(7):1070-1084.
15. National Headache Foundation. “Largest Study of Migraine Sufferers Reveals Preventive Therapies Are Underused.” Head Lines. Sept./Oct. 2005.
16. Mathew et al. “A Double-blind Comparison of Onabotulinumtoxina (BOTOX) and Topiramate (TOPAMAX) for the Prophylactic Treatment of Chronic Migraine: A Pilot Study.” Headache. 2009;49(10):1466-1478.
17. Cady et al. “A Multi-center Double-blind Pilot Comparison of Onabotulinumtoxin A and Topiramate for the Prophylactic Treatment of Chronic Migraine.” Headache. 2011;51(1):21-32.