Zonisamide (Zonegran) is an epilepsy drug similar to topiramate in its mechanism of action. Unfortunately, it shares its side effects as well. These include fatigue, difficulty with concentration and memory, nausea, and other. However, because they are not identical drugs, some patients tolerate zonisamide better than topiramate.

One study showed that 44% of 172 patients who did not respond to topiramate did respond to zonisamide with 13% having an excellent response. A similar study in 63 patients who did not respond to topiramate also showed benefit from zonisamide as did 34 patients in another study. Zonisamide also helped 8 out of 12 children who did not respond to other medications.

The dose of zonisamide ranges from 50 to 400 mg a day, but most patients need 100-200 mg.

Zolmitriptan (Zomig, Zomig ZMT, Zomig NS) is one of seven triptans sold in the US. It is available in tablets, orally disintegrating tablets, and nasal spray. The nasal spray is approved for children 12 and older. Both tablets and the spray are available in 2.5 mg and 5 mg strength. The maximum daily dose is 10 mg.

However, it is washed out of the body within a few hours. This means that taking three 5 mg tablets spread out over 24 hours poses no danger. Three doses a day is the approved limit for rizatriptan (Maxalt). There is no reason why this should not apply to zolmitriptan and other triptans except for the long-lasting frovatriptan. Fortunately, it is uncommon that a patient requires three doses in one day. And if a patient does need to take a triptan more than twice a day, we usually try a different drug that may work with a single dose.

One advantage of the nasal spray is that it tends to have a faster onset of action. Another advantage is that can be taken when severe nausea or vomiting precludes the use of oral medications. My impression is that zolmitriptan spray is more effective than the original sumatriptan spray. The amount of fluid in a single dose of Zomig is less than that in sumatriptan and the spray droplets are of smaller size. This leads to better retention of fluid in the nasal passages and better absorption.

The new version of sumatriptan spray, Tosymra contains 10 mg of sumatriptan while the original spray contains 20 mg. However, it comes out in smaller droplets and contains an ingredient that allows for better absorption. This formulation of sumatriptan spray appears to be as effective as Zomig NS.

Zolmitriptan nasal spray is expensive (as is Tosymra) because it is available only as a branded product. It will lose its patent protection in 2021.

Verapamil (Calan, Isoptin) is an effective drug for the prevention of cluster headaches. It is sometimes used for migraines as well. However, the evidence for its efficacy is weak. A double-blind crossover trial by Dr. Glen Solomon and his colleagues in Ohio examined the effect of 320 mg of verapamil on 12 migraine patients. The drug was more effective than the placebo. Other small studies also suggested that it might help some patients.

Verapamil has a reputation among headache specialists as being effective for the prevention of frequent migraine auras and other neurological symptoms that occur with migraines. Unfortunately, there are no controlled trials to support this impression.

The starting dose of verapamil is 120 mg a day with a possible escalation up to 480 mg. For cluster headaches, the starting dose is 240 mg and the maximum dose is as high as 960 mg. Verapamil can cause arrhythmia (irregular heartbeat), especially at higher doses. I recommend an electrocardiogram before every increase of the dose above 240 mg.

The two most common side effects of verapamil are constipation and swelling of the feet. In some of my patients, constipation was severe and resistant to treatment. They had to stop taking the drug.

Venlafaxine (Effexor) is the first drug in the serotonin-norepinephrine reuptake inhibitors (SNRI) class. It was approved by the FDA for the treatment of depression in 1993.

At low doses, venlafaxine works as a selective serotonin reuptake inhibitor (SSRI) such as fluoxetine (Prozac). SNRIs are considered to be effective for the treatment of pain and migraine headaches. SSRIs are not. A review of studies that involved a total of 418 patients showed that SNRIs are effective for the prevention of migraines. The class of SNRIs includes duloxetine (Cymbalta), desvenlafaxine (Pristiq), milnacipran (Savella), and levomilnacipran (Fetzima). Milnacipran is the only SNRI that is approved by the FDA for the treatment of fibromyalgia rather than depression.

In treating migraines, a 60-patient trial showed that the 150 mg dose is more effective than 75 mg.

Another double-blind crossover study comparing venlafaxine with amitriptyline showed them to be equally effective. Venlafaxine had fewer side effects than amitriptyline.

Venlafaxine is started at 37.5 or 75 mg dose. After a week or two, the dose is increased to 150 mg. The maximum daily dose of venlafaxine is 450 mg.

Potential side effects include insomnia, drowsiness, fatigue, nausea, dizziness, suicidal thoughts in depressed children and young adults, and others.

Just like with other SNRIs, sudden discontinuation of venlafaxine can cause withdrawal symptoms. These may include one or more of the following: dizziness, headache, nausea, diarrhea, paresthesia (pins-and-needles), irritability, vomiting, insomnia, anxiety, sweating, and fatigue. SNRIs are stopped after a slow and gradual reduction of the dose.

Timolol (Blocadren), is the second of the two beta-blockers approved by the FDA for both hypertension and the prevention of migraines. Among the dozen or so beta-blockers, it is not very popular for either hypertension or migraine. An ophthalmic solution of timolol is often used for glaucoma.

A study of 107 migraine patients compared prophylactic treatment with timolol, 20 to 30 mg per day with matching placebo. The study was a double-blind crossover study that lasted 20 weeks. Timolol was significantly better than the placebo in decreasing the frequency of headaches, numbers of patients who had a 50% reduction in headache frequency, global response, and patient preference. The overall response was 65% with timolol compared with 40% with placebo. The severity and duration of headaches that occurred were unchanged. Few side effects were reported with either timolol or placebo.

Another study compared timolol, 10 mg twice a day with propranolol, 80 mg twice a day, and with placebo in 83 migraine patients. Timolol and propranolol were equally effective and had a similar rate of side effects.

The side effects of timolol are typical of all beta-blockers – chest discomfort, tiredness, lightheadedness, dizziness, fainting, shortness of breath, slow or irregular heartbeat.

The usual dose of timolol is 10 mg twice a day.

You can read about the use of timolol eye drops to treat acute migraines in a previous post.

Lisinopril (Prinivil, Zestril) is a blood pressure medicine in the family of angiotensin-converting enzyme inhibitors (ACEI). At 20 mg a day it was effective in the prevention of migraine headaches, according to a double-blind cross-over study of 60 patients. Three patients stopped the drug due to cough.

An open-label study of 5 mg of lisinopril in 21 patients was also positive but 3 patients stopped it because of cough. ACEIs but not angiotensin receptor blockers (ARBs) which are similar to ACEIs can cause cough. The occurrence of cough is not dose-dependent.

A review of a large database of prescriptions showed that patients taking ACEIs or ARBs were getting 50% fewer prescriptions for abortive migraine drugs compared to those taking a diuretic, which is another type of drug to treat hypertension.

The advantage of ACE inhibitors and ARBs over beta-blockers such as propranolol is that they do not lower the heart rate, which can make exercise difficult. Both can cause fatigue and dizziness due to the lowering of blood pressure, but the weight gain and depression, occasionally seen with propranolol does not happen with ACEIs and ARBs. On the other hand, beta-blockers can sometimes help reduce anxiety and palpitations.