Oral Migraine Preventatives

Preventing a Migraine Headache (Oral Generic Preventative Medications)

Are you trying to chose an oral agent to prevent your migraines. Fortunately there are many choices and they are all inexpensive. In general, the selections process initially begins with one of the highly effective migraine preventatives and then moves to less proven or less robust agents when the better agents are either not successful, not tolerated, or have side effects that makes patients want to avoid them completely. Dr. Loftus calls this method “intelligent trial and error.” Dr. Loftus considers 8 agents potential oral agents for first line therapy for frequent migraine prevention and chronic migraine prevention. They are amitriptylene, duloxetine, propranolol, candesartan, topiramate, zonisamide, valproic acid and memantine.  Verapamil gets an honorable mention as the 9th oral agent but is less effective for migraine prevention than the initial 8.

Elavil® (amitriptylene)

The primary advantage of Amitriptylene is that it is one of the cheapest preventative available. The monthly cost can literally be $3 per month. Unfortunately, the medication has a high percentage of side effects. Dry mouth, sedation, constipation, and weight gain are typically limiting side effects. Given the low cost of medications that have fewer side effects, Dr. Loftus rarely uses this medication.  Still a good choice for the underweight and young patient that tends to be less susceptible to the side effects.

Inderal® (propranolol or propranolol ER)

The next oldest, well established preventative is propranolol. This medication can worsen asthma or depression, makes patients fatigue, and limit aerobic exercise but in general is fairly well tolerated. Pricing is about $10 per month or less. It is generally thought of as a weight neutral medication but all patients should be monitored for weight. It is one of the most common medications used for women who need prevention and need oral prevention at time of conception. If continued into the 2nd trimester and beyond, it can be associated with lower birth weight babies.

Atacand® (candesartan)

Candesartan has been demonstrated to prevent migraines in multiple placebo controlled trials.  It seems to have less side effects than propranolol.  It belongs to a group of medications known as ACE Receptor Blockers or ARBs.  It is more expensive than other generic ARBs on the market but it is the only one well proven for migraine prevention.  Therefore, this is Dr. Loftus’ choice if he goes to an ARB.  It is definitely unsafe in the 2nd and 3rd trimester of pregnancy. There is some data (from diabetic hypertension and renal protection trials) that is can be used and stopped in the first trimester safely.

Topamax® (topiramate) and Zonegran® (zonisamide)

A third preventative is topiramate or Topamax®. This medication, first licensed as an antiepileptic medication, is the most popular medication currently prescribed by neurologists for headache prevention. While not more effective than the other first line agents, it is the only FDA approved migraine preventative that is clearly associated with weight loss. The average obese patient can expect to lose about 5-10% of their body weight over one year. Since obesity is a risk factor for frequent migraines over time, a large number of migraine patients who need preventatives are medically overweight or obese. Unfortunately topiramate does have a lot of side effects. Some side effects are more of a nuisance. Carbonated drinks taste badly while taking this drug and some patients experience tingling around the mouth, finger, or toes. Renal or kidney stones occur about 1-2% of the time and is the only side effect which does not go away when topiramate is discontinued without additional therapy. A small percentage of patients have an altered ability to think on the medication that commonly expressed as a word finding problem. This returns to normal with reduction or discontinuation of the medication. Finally there is a very rare condition of acute narrow angle glaucoma that is very painful but again resolves with discontinuation of the medication and specific medical therapy. The cost of generic topiramate is as low as $10 per month. Generic, only daily forms of topiramate are significantly more expensive.  Generic Qudexy® ($300-700 per month with higher doses being cheaper) and Trokendi® ($700-1200 per month). These medications have different methods to slow absoprion. Slower absorpion allows for lower peak doses of topiramate and higher trough doses. These medications therefore imply better migraine control with fewer side effects. They have very similar pharmacokinetics (the highs and lows) but the generic Qudexy has a few advantages over the generic Trokendi. Qudexy is cheaper at all of the commonly used doses and is much cheaper at 150 mg per day dose where Qudexy has a tablet of this size and Trokendi does not. Qudexy absorption is not changed by alcohol but Trokendi is affected by alcohol intake.  Qudexy is not affected Dr. Loftus will switch patient from generic to these more expensive trade name medications if a patient gets a side effect to generic topiramate but finds the medication useful.

Zonegran® or zonisamide is another antiepileptic medication with weight loss similar to topiramate. It has fewer mental side effects. In the only head to head study done between the two, they were equally effective for migraine prevention. Zonegran or zonisamide is generally avoided in sulfa allergic patients and tends to have a higher incidence of nausea than topiramate. The cost is typically $20-$40 per month. The half life of zonisamide is much longer than topiramate (63 hours vs 21 hours) and therefore it can be used once per day. According to the North American Epilepsy Registry (last accessed in 2023), it is also safe for pregnancy. Since zonisamide can be tolerated at a higher equivalent dose compared to topiramate so in practice it works better with more weight loss than topiramate.

Depakote ER®(divalproex ER)

The last of the big four preventatives (amitriptyline, topiramate, propranolol) is divalproex and is typically $10-20 per month. The most convenient form for patients is divalproex ER which is a once daily migraine prevention agent. Divalproex can cause birth defects and therefore, Dr. Loftus generally will not prescribe it to women who could become pregnant. In addition, divalproex can cause weight gain, liver issues, and pancreatitis. Despite these warnings, the medication is generally well tolerated and can be used quite safely. However, given the issue with birth defects it is most commonly prescribed to males with migraines who are not overweight.

Cymbalta® (duloxetine) or Effexor XR® (venlafaxine ER)

Venlafaxine ER and Duloxetine are both SNRIs. These are medications that raise levels of serotonin (5HT) and norepinephrine (NE) in some synapses in the brain. Venlafaxine has been demonstrated in two double blind placebo controlled studies to help prevent migraines at doses of 150 mg per day and above. Duloxetine is more balanced than velafaxine and in animal models of pain, the balance is important in pain relief. Therefore, Dr. Loftus favors duloxetine. They cause equal amounts of nausea but duloxetine appears to be associated with less sexual dysfunction. Duloxetine is FDA approved in depression, anxiety, fibromyalgia, pain from osteoarthritis, and diabetic neuropathic pain. Since 33% to 66% of patients with chronic migraine also have depression, the use of Duloxetine as a first line agent makes sense for those patients with depression. The cost of duloxetine and venlafaxine ER is in the $5-10 per month range.

Namenda® (memantine ).

Memantine is a medication developed for Alzheimer’s that is surprising useful for migraine prevention.  In placebo controlled studies, it seems to work as well as our more typical oral choices.  It is not generally recognized as an oral preventative by insurance companies.  To get newer, more expensive medications covered for migraine prevention, you typically have to fail a couple of oral migraine preventatives.  Therefore, sticking with the earlier agents will count but using memantine will not.  The drug is felt to be generally safe for pregnancy but given its positioning as an Alzheimer’s agent, this is based on animal data.

Verapamil

There are studies demonstrating verapamil to be a good anti-migraine agent although not as robust as the medications previously mentioned. It is relatively side effect free so it does have some uses.

The most important thing to remember is that there are numerous agents that one can try for migraine prevention. It is most likely that at least one of them will work well for you. Unfortunately prevention therapies are under utilized, resulting in excessive disability for migraine patients. If you are having frequent headaches, please see your neurologist and ask to be placed on prevention. If you have frequent headaches and are not being offered prevention, then you really need to change physicians.