Nortriptyline (Pamelor) is a tricyclic antidepressant approved by the FDA only for the treatment of depression. However, with the introduction of SSRI family of antidepressants such as fluoxetine (Prozac) which have fewer side effects, the use of tricyclic antidepressants for depression has declined.

Tricyclic antidepressants are still in wide use, but mostly for the treatment of headaches and pain. Nortriptyline is very similar to amitriptyline (Elavil) and is thought to cause fewer and milder side effects, although this has not been proven. This could be due to the fact that amitriptyline is broken down into nortriptyline, which is the active metabolite. Amitriptyline tends to be more sedating, which can be useful in patients with insomnia.

There are no good blinded studies of nortriptyline for the prevention of migraines and they are not likely to be done. We assume it is as good as amitriptyline, although studies of amitriptyline also lack in size and scientific rigor.

There are many trials of amitriptyline and nortriptyline for various pain conditions, but they are also not up to our modern standards. Amitriptyline was approved in the US in 1961.

Besides sedation, nortriptyline can cause dry mouth, constipation, urinary retention in older patients, and other side effects. The dose to treat migraines and pain is usually lower than the dose used to treat depression. Pain and headaches sometimes respond to as little as 10 or 25 mg while for depression, the dose goes up to 100 mg and higher.

In short-term studies of major depression, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults. This is less likely to occur when treating pain, but many pain patients also experience depression.

Eptienzumab (Vyepti) was just approved by the FDA for the preventive treatment of migraine headaches. Eptinezumab is another monoclonal antibody that blocks the effect of CGRP, a chemical released during a migraine attack. It joins erenumab (Aimovig), fremanezumab (Ajovy), and galcanezumab (Emgality), three other monoclonal antibodies approved for the preventive treatment of migraine headaches.

Eptinezumab is different from the other three drugs in that it is administered intravenously. It is given every three months by an infusion over 30 minutes. The other three drugs are self-administered subcutaneously every month, although fremaezumab can be also given every 3 months.

Eptinezumab may also have a faster onset of action because it is administered intravenously and quickly reaches its peak concentration in the blood. The other three drugs take up to a week to reach their maximum concentration. The reason for such a long delay (most drugs injected subcutaneously take less than an hour to peak) is that the monoclonal antibodies are large molecules and are distributed not by blood vessels, but the slow-moving lymphatic system. On the other hand, these are preventive therapies, so the speed of onset is less critical than for abortive drugs, such as NSAIDs, triptans, and gepants (ubrogepant, rimegepant).

Theoretically, it is possible that eptinezumab could work for patients who do not respond to the other three drugs because of a better distribution of the drug and because these drugs are not identical. About 10% of my patients report significantly better response when switched from erenumab, which was first to be approved, to either fremanezumab or galcanezumab.

We don’t know yet what the drug will cost and how well the insurance companies will pay for it. All three subcutaneous drugs cost about $650 a shot and all three manufacturers offer a one-year free trial if the insurance refuses to pay. This does not apply to patients who have Medicare or Medicaid, which do not allow free trials or discount coupons. Fortunately, more and more insurers, including the government plans, are covering these drugs, albeit with some paperwork that needs to be completed by the doctor. The cost of eptinezumab will consist of two parts – the cost of the drug and the cost of the infusion.

Milnacipran (Savella) is a drug that is approved by the FDA for the treatment of fibromyalgia. Fibromyalgia is a chronic disorder characterized by widespread musculoskeletal pain, fatigue, and tenderness in localized areas.

Milnacipran belongs to the category of selective serotonin and norepinephrine reuptake inhibitors (SNRIs), which are used to treat anxiety, depression, and pain. There are four other SNRIs that are approved for the treatment of anxiety and depression, and in case of duloxetine (Cymbalta) also for fibromyalgia, peripheral nerve damage due to diabetes and musculoskeletal pain.

The manufacturer of milnacipran decided not to seek approval for the treatment of depression to avoid the stigma of being an antidepressant drug. Many patients feel that if they are prescribed an antidepressant, their pain is not perceived as real physical pain, but rather purely psychological.

Milnacipran was tested for the preventive treatment of migraines only in one unblinded observational study. Not surprisingly, it was effective. We often use duloxetine and venlafaxine (Effexor) for the treatment of migraines. Fibromyalgia, back pain, and other pains are comorbid with migraines, meaning that if you have one condition, you are more likely to have the other as well. Such patients are ideal candidates for SNRIs, although tricyclic antidepressants such as amitriptyline also work well for any pain and migraines.

Just like with other SNRIs, the most common side effects include nausea, headache, constipation, dizziness, insomnia, hot flushes, hyperhidrosis (excessive sweating), vomiting, palpitations, increased heart rate, dry mouth, and hypertension. Another common problem with these drugs is that many patients develop very unpleasant withdrawal symptoms if the drug is stopped abruptly.

Theoretically, antidepressants when used with triptans, such as sumatriptan can cause serotonin syndrome, but it is extremely rare and millions of people take both without any problems.

When sumatriptan (Imitrex) was introduced in 1992 it was truly a breakthrough drug – the first drug specifically developed for the acute treatment of migraines. Sumatriptan and six other triptans have alleviated suffering of millions of people. Sumatriptan is considered to be the gold standard therapy for an acute migraine. Unfortunately, 27 years later many millions of migraine sufferers have not had a chance to try these drugs.

A study by R. Lipton and his colleagues presented earlier this year surveyed 15,133 migraine sufferers. Only 37% had ever used a triptan and only 16% were using them at the time of the survey. Most patients used tablets, but 11% also tried either a nasal spray or an injection. Lack of efficacy (in 38%) and side effects (in 22%) were the most common reason for stopping the drug and the most common side effects were dizziness, nausea, and fatigue.

My guess is that lack of efficacy is often due to the suboptimal dose of a triptan that is often prescribed. I see many patients who tell me that they’ve tried sumatriptan and it did not work, but many of them took 25 or 50 mg, while an effective dose for most patients is 100 mg. Most other triptans are also available in two different strengths and the lower, less effective dose is often prescribed.

Another common problem is that patients who fail one triptan due to side effects or lack of efficacy are not prescribed a different triptan. Many of my patients find that one triptan is more effective than another or if one triptan causes side effects, a different one may not. Also, if a tablet does not work, an injection or a nasal spray might, especially in patients with a quick buildup of pain or when nausea is present.

A big reason for the underutilization of triptans is misdiagnosis of headaches. Almost half of migraine sufferers are told that they have sinus or tension headaches, which means they are missing out on receiving effective treatment.

Safety of triptans is a concern of many physicians and patients. The package insert warns about strokes and heart attacks and it is true that if you have untreated hypertension, coronary artery disease or many risk factors for coronary artery disease it is better to avoid triptans. However, triptans have been available without a prescription for over 10 years in most European countries.

A panel of leading headache specialists published a “Consensus Statement: Cardiovascular Safety Profile of Triptans in the Acute Treatment of Migraine” that states “The incidence of serious cardiovascular events with triptans in both clinical trials and clinical practice appears to be extremely low “.

Another unfounded concern of many physicians is that frequent use of triptans will make migraines more frequent and severe. There is no good scientific evidence for this concern. You can read my two previous blog posts on this topic here and here. The first of these two posts is by far the most popular on this site with over 300 comments. Many patients report how relieved they are to hear that they are not risking their lives by taking triptans often or even daily and also how frustrated they are not being able to find a doctor who would prescribe a sufficient amount of this medicine.

Sumatriptan was first released in a pack of 9 tablets, but not because it was dangerous to take more, but mostly because this was the average number of tablets people used in one month in clinical trials. Cost used to be another limiting factor and some insurers still limit triptans to 6 or 9 tablets a month. However, generic sumatriptan now can be found for as little as $12-20, so patients can bypass their insurance and buy as many additional tablets as they might need.

Memantine (Namenda) is an Alzheimer’s drug that has been used for the treatment of pain and migraine headaches. This drug blocks the NMDA receptor in the brain, which is involved in the processing of pain messages and in other neurological conditions such as epilepsy, stroke and traumatic brain injuries.

NMDA receptor antagonist dizocilpine, or MK801 was a drug with a potential to treat all these conditions, but unfortunately it had serious side effects and after spending hundreds of millions of dollars, Merck stopped its development. It is possible that strong inhibition of the NMDA receptor will always lead to serious side effects. We do have several other milder NMDA inhibitors, besides memantine – dextromethorphan, which is used as a cough suppressant and ketamine.

Memantine, 10 to 20 mg a day was studied in 28 patients with migraines that were not responding to at least two standard medications and was found to be effective. A double-blind, placebo-controlled trial of 10 mg of memantine in 52 patients was also positive. Another double-blind placebo-controlled trial of 60 patients also showed some benefit. A review of case reports and two controlled studies concluded that memantine, 10 to 20 mg a day may be an effective treatment for the prevention of migraines. A study of 40 mg of memantine for chronic tension-type headaches did not show any efficacy, although women seemed to benefit more than men. The only side effects of this relatively high dose (the Alzheimer’s dose is 20 mg) were nausea and dizziness. Overall, memantine tends to be well tolerated, even in the elderly with Alzheimer’s.

I do occasionally prescribe memantine and tend to increase the dose to 20 mg twice a day. I have only a few patients who obtained very good relief and remain on the drug. It is certainly not the first, second, or third drug I prescribe, but when many other drugs fail, it is worth a try since potential side effects are relatively mild.