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Headache medications

It is not surprising that when a doctor is tired or hurried he or she is more likely to make a mistake. A new study published in JAMA Network Open provides some hard data on doctor performance as it relates to the prescribing of opioid (narcotic) analgesics. Opioids are still overprescribed, especially for migraine headache patients.

The researchers at the University of Minnesota discovered that doctors were 33% more likely to prescribe an opioid pain medicine at the end of the workday than in the beginning. If the doctor was running an hour or more behind schedule her or she was 17% more likely to prescribe an opioid. Prescribing of nonsteroidal anti-inflammatory drugs and referral to physical therapy did not display similar patterns. This was a very large study which means that the results are likely to be reliable. The study looked at 5,603 primary care practitioners who were involved in 678,319 primary care encounters for a painful condition.

Prescribing an opioid seems like a quick fix for a problem that saves doctors time, but usually is not be the best treatment for the patient.

Nobel Prize winner Daniel Kahneman in his book, Thinking Fast and Slow suggests that there are additional and easily correctable factors that may be contributing to poor decision making. Here are some quotes from the book.

“The most surprising discovery made by Baumeister’s group shows, as he puts it, that the idea of mental energy is more than a mere metaphor. The nervous system consumes more glucose than most other parts of the body, and effortful mental activity appears to be especially expensive in the currency of glucose. When you are actively involved in difficult cognitive reasoning or engaged in a task that requires self-control, your blood glucose level drops.

The bold implication of this idea is that the effects of ego depletion could be undone by ingesting glucose, and Baumeister and his colleagues have confirmed this hypothesis in several experiments… Restoring the level of available sugar in the brain had prevented the deterioration of performance.

A disturbing demonstration of depletion effects in judgment was recently reported in the Proceedings of the National Academy of Sciences. The unwitting participants in the study were eight parole judges in Israel. They spend entire days reviewing applications for parole. The cases are presented in random order, and the judges spend little time on each one, an average of 6 minutes. (The default decision is denial of parole; only 35% of requests are approved. The exact time of each decision is recorded, and the times of the judges’ three food breaks—morning break, lunch, and afternoon break—during the day are recorded as well.) The authors of the study plotted the proportion of approved requests against the time since the last food break. The proportion spikes after each meal, when about 65% of requests are granted. During the two hours or so until the judges’ next feeding, the approval rate drops steadily, to about zero just before the meal. As you might expect, this is an unwelcome result and the authors carefully checked many alternative explanations. The best possible account of the data provides bad news: tired and hungry judges tend to fall back on the easier default position of denying requests for parole. Both fatigue and hunger probably play a role.”

So for best results you may want to try to see your doctor right after lunch and hope that he or she had time to eat lunch.

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Mefenamic acid (Ponstel) is one the nonsteroidal antiinflammatory drugs (NSAIDs) and like all other NSAIDs it is being used for the treatment of acute migraine attacks.

Mefenamic acid is popular for the treatment of menstrual migraines, which probably stems from the fact that in addition to the treatment of mild or moderate pain, it is also approved for the treatment of dysmenorrhea, or pain of menstruation. In a small study mefenamic acid was found to be specifically effective for the treatment of menstrual migraines, which can be more severe and more difficult to treat than non-menstrual attacks.

Mefenamic acid was found to be superior to acetaminophen (called paracetamol in Europe), which is no surprise since acetaminophen has little antiinflammatory action and therefore does not reduce inflammation that occurs during a migraine attack.

Ergotamine was the mainstay of migraine treatment before the introduction of triptans in 1992. A study comparing ergotamine with mefenamic acid was found them to be equally effective, but ergotamine caused more side effects, especially nausea, which is a common side effect of ergot derivatives.

A small trial suggests that it can be also used for the prevention of migraines and it is as effective as propranolol.

For the treatment of pain and primary dysmenorrhea, the initial dose is 500 mg, followed by 250 mg every 6 hours, as needed. Just like other NSAIDs, it can cause heartburn, stomach upset, bleeding ulcers, and other side effects.

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Lidocaine (Xylocaine) is an old local anesthetic used by surgeons, dentists, and other doctors to numb parts of the body. Lidocaine drops given into the nostrils were compared to saline drops for the acute treatment of migraine attacks in a double-blind placebo-controlled 113-patient trial by Dr. Morris Meizels and his colleagues. This study showed that lidocaine nose drops were much more effective than saline drops, but relieved migraines in only about one third of patients. Another, but smaller (49 patients) study did not find a difference between lidocaine and saline.

I’ve had a handful of patients with difficult to control migraines respond to an intravenous infusion of lidocaine and one of these patients continues to do well with a monthly infusion of lidocaine. There have been no double-blind studies of intravenous lidocaine for migraines, but an observational study of 68 hospitalized patients who failed to respond to other treatments, suggests that this treatment can be effective for some patients.

Intravenous administration of lidocaine is usually done in a hospital or an outpatient facility that has cardiac monitoring because lidocaine can cause arrhythmias (irregular heart beat). Otherwise, lidocaine is safe and well tolerated.

The widest use of lidocaine in migraine is for nerve blocks. An occipital nerve block has been scientifically proven to relieve an acute migraine attack. Combining blocks of occipital nerves (in the back of the head) with a block of supraorbital nerves (in the forehead) has been also shown to be more effective than injections of saline. We often add blocks of the temporal branches of the trigeminal nerve (in the temples) when a patient has pain in those areas.

Nerve blocks sometimes help stop a persistent migraine when other treatments fail. It is also a very good option for pregnant women who cannot or would rather not take any medicine by mouth.

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Levetiracetam (Keppra) is an epilepsy drug that has been reported to help some patients with migraines. However, unlike divalproex sodium (Depakote) and topiramate (Topamax, Trokendi, Qudexy), the evidence for its efficacy in migraines is weak.

This evidence consists mostly of uncontrolled observational studies without a comparison to placebo. One small double-blind placebo-controlled study compared 500 mg of levetiracetam (27 patients) to 500 mg of divalproex sodium (32 patients) and to placebo (26 patients). Both epilepsy drugs were superior to placebo.

In one of the reports the mean dose of levetiracetam was 1,125 (and up to 2,000), while the maximum dose for epilepsy is 3,000). It is possible that the drug may work better at a higher dose. However, with an increase in the dose there is an increase in side effects. These include weakness, drowsiness, dizziness, anxiety, depression, irritability and aggressive behavior, and other.

Since this drug is not proven to be effective and can have serious side effects, I never prescribe this drug.

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Ketorolac (Toradol) is one of many nonsteroidal anti-inflammatory (NSAID) pain medications used to treat migraine headaches. In a tablet form it is no more effective than ibuprofen, naproxen or any other NSAID, but has more side effects and its use is limited to 5 days. On the other hand, ketorolac in an injection is a unique and very useful drug. It provides pain relief comparable to that of opioid (narcotic) drugs without the side effects or addiction potential of those drugs.

Intravenous ketorolac has been proven to be an effective drug for the treatment of severe migraine attacks. A study done by Dr. B. Friedman and his colleagues at the emergency department of the Montefiore Medical Center in the Bronx compared intravenous infusion of 30 mg of ketorolac with an infusion of 10 mg of metoclopramide (Reglan) and 1,000 mg of valproate (Depacon). There were over 100 patients in each group, making this a highly reliable study. Ketorolac and metoclopramide were more effective than valproate, but metoclopramide caused severe restlessness in 6 (6%) of patients. This is a well known side effect of metoclopramide and a similar drug, prochlorperazine (Compazine). This side effect is extremely unpleasant, but can be relieved by diphenhydramine (Benadryl).

Intramuscular injection of 60 mg of ketorolac was compared to intravenous infusion of 25 mg of chlorpromazine (Thorazine) and they were found to be equally effective. Just like prochlorperazine, chlorpromazine carries a risk of restlessness, as well as involuntary movements and sedation. These two drugs belong to the phenothiazine family of drugs, which are also used for severe nausea and vomiting, and psychiatric disorders.

A review of eight published trials of ketorolac found it to be more effective than meperidine (Demerol) and sumatriptan and a little less effective than metoclopramide, chlorpromazine and prochlorperazine. However, ketorolac lacks the addiction potential and the risk of severe restlessness, sedation, and involuntary movements.

We given intravenous ketorolac to our patients whose migraine has not responded to an injection of sumatriptan or oral triptans, although we almost always give an infusion of magnesium before or along with ketorolac.

Here is a blog post with my advice on what to ask for if your migraine lands you in an emergency room.

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Ketoprofen (Orudis, the branded version, is no longer available) is a prescription nonsteroidal antiinflammatory drug (NSAID) without any outstanding features. Just like all other NSAIDs, it is effective for the acute treatment of migraine headaches.

A double-blind placebo-controlled randomized trial compared ketoprofen, 75 mg, 150 mg and 2.5 mg of zolmitriptan (Zomig). All three active therapies were equally effective in relieving migraines and were much more effective than placebo. This does not mean that ketoprofen and zolmitriptan are equally effective in any particular migraine sufferer because some people will respond better to an NSAID and other to a triptan. Also, the usual dose of zolmitriptan is 5 mg, so it is possible that even on average, a 5 mg dose might be superior to ketoprofen. We often combine a triptan with an NSAID such as ibuprofen (Advil) or naproxen (Aleve, Naprosyn) and ketoprofen can also be combined with a triptan.

Another double-blind study compared 100 mg ketoprofen suppository (a compounding pharmacy can prepare such a suppository) with 2 mg ergotamine suppository and ketoprofen was found to be superior to ergotamine. Since the introduction of triptans ergotamine has not been widely used because it causes more side effects, particularly nausea.

Just like with other NSAIDs, the most common side effects are gastrointestinal – heartburn, stomach pain, bleeding ulcers, etc. NSAIDs can also cause tinnitus (ringing in the ears), rashes, and with long-term use, kidney and heart problems.

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Dihydroergotamine (DHE-45) is a very old migraine drug in the family of ergot alkaloids. It is one of the most effective migraine drugs when it is given intravenously and it is often used when patients are admitted to the hospital for migraines that do not respond to other therapies.

Dihydroergotamine (DHE) is also available as a nasal spray (Migranal), but it works well only in a limited number of patients and is very expensive. This poor consistency of effect is partly due to the amount of liquid that needs to be sprayed for one dose, most of which is either swallowed or leaks out. A form of DHE to be inhaled into the lungs had been in development for many years, but is not likely to become available due to manufacturing difficulties.

A promising new way to deliver DHE as a nasal powder is being developed by Satsuma Pharmaceuticals. The company presented their preliminary data at the recently concluded scientific meeting of the American Headache Society in Philadelphia. Their study showed that powdered form of DHE delivered into the nose gets into the blood faster and better than the existing nasal liquid form, although not as well as when it is given as an intramuscular injection. The device to administer DHE is small and easy to use, unlike another device that is also being developed for intranasal delivery of DHE powder. The company is initiating a large clinical trial, which will hopefully lead to the approval of their product.

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Ketamine (Ketalar) was officially approved for human use by Food and Drug Administration (FDA) in 1970 and, because of its wide margin of safety, was even administered as a field anaesthetic to soldiers during the Vietnam war. Concerns over the psychedelic effects of ketamine and the arrival of new intravenous hypnotics such as propofol led to a marked decrease in the use of ketamine for anesthesia, but in the recent years its use has been increasing. Its unique properties have led many researchers to do clinical trials for the treatment of pain and depression. Intranasal ketamine was just approved by the FDA for treatment-resistant depression.

True efficacy of ketamine for the treatment of pain and migraine headaches is less clear. There have been no double-blind studies of ketamine for the treatment of migraine headaches. A major obstacle to doing such studies is that it is very difficult to blind patients to the effect of ketamine. We do have anecdotal evidence, that is a description of series of patients who were given intravenous ketamine. A report entitled, Ketamine Infusions for Treatment Refractory Headache describes 77 chronic migraine patients who “failed aggressive outpatient and inpatient treatments”. These patients were hospitalized and were receiving ketamine infusions for an average of 5 days. Over 70% of these patients improved, although only 27% had sustained improvement.

In a report published in The Journal of Headache and Pain authors describe 6 patients admitted to the hospital whose refractory migraines improved with intravenous ketamine, albeit the improvement was only short-term. One patient reported a transient out-of-body hallucination, which resolved after decreasing the rate of infusion.

Intranasal ketamine was shown to relieve severe migraine aura in 5 of 11 patients with familial hemiplegic migraine. In some patients, the aura can be more debilitating than the headache or other symptoms of migraine and we have no effective treatment to stop the aura once it stops.

A Randomized Controlled Trial of Intranasal Ketamine in Migraine With Prolonged Aura, was a study of 18 patients published in Neurology. It showed that intranasal ketamine reduces the severity but not the duration of migraine aura.

I have referred a small number of patients whose migraines fail to respond to a wide variety of treatments for outpatient intravenous ketamine infusions. A few of these patients found ketamine to be very helpful. This is not a fair test of the drug’s efficacy because those who failed to respond to 20 different treatments are not likely to respond to the 21st one. Considering that ketamine is fairly safe (the dose given is much smaller than the dose used for anesthesia), it would be useful to have a controlled randomized trial in less refractory patients.

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Indomethacin (Indocin) is one of the strongest non-steroidal anti-inflammatory drugs (NSAIDs), but unfortunately it is rarely used for the treatment of migraines. It has a higher chance of causing gastro-intestinal (GI) side effects than other NSAIDs, but some patients tolerate it very well, especially if it is used sporadically. The drug can be compounded into a rectal suppository, which reduces (but does not eliminate) GI side effects and provides faster onset of effect than an oral capsule. Even if nausea is not obviously present, migraine is often accompanied by gastric stasis, which means that absorption of oral drugs is slowed down. This is why pharmaceutical companies often try to formulate migraine drugs into nasal sprays, injections, patches and inhalers. Rectal route also bypasses the stomach, but suppositories are less popular in the US than they are in Europe. The dose of oral indomethacin is 25, 50 or 75 mg taken up to three times a day, while suppositories usually contain 50 mg.

Indomethacin has some unique properties that differentiate it from other NSAIDs and it is often the only NSAID that is highly effective for episodic and chronic paroxysmal hemicrania and hemicrania continua, rare conditions that are often mistaken for migraines. They are even described as indomethacin-sensitive headaches because no other drug provides such dramatic relief. Paroxysmal hemicrania also resembles cluster headache in that it is always one-sided and is often accompanied by nasal congestion and tearing on the side of the headache. Unlike cluster headaches, which last 30 minutes to 3 hours and occur once or a few times a day, the attacks of hemicrania last a few minutes but occur many times throughout the day. Hemicrania continua is also always one-sided and the pain is continuous without any pain-free periods. If indomethacin causes GI side effects, in some patients an anti-inflammatory herbal supplement, Boswellia can be as effective but without causing any side effects. Botox injections is another treatment that can provide relief of indomethacin-sensitive headaches.

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Ibuprofen (Advil, Motrin, Nuprin, Nurofen, etc) is a very effective migraine drug. Of course, patients with severe migraines tell me that for them taking ibuprofen is like eating candy, but even those patients can get better relief if they add ibuprofen (or naproxen) to a triptan such as sumatriptan (Imitrex).

Over-the-counter ibuprofen (Advil Migraine, Motrin Migraine) is officially approved by the FDA for the treatment of migraines, which means that it has been studied in large placebo-controlled trials to prove that it is safe and effective. Ibuprofen was shown to be more effective than acetaminophen in children. The adult dose is 400 mg, while in children it is 10 mg per kilogram of weight.

Liquified form of ibuprofen (Advil Liquigels, Advil Migraine)) and liquid ibuprofen for children tend to work faster than a solid tablet.

Frequent intake of ibuprofen (and other NSAIDs and triptans) is thought to lead to medication overuse headache (MOH), but if this does occur, it is rare and the entire concept of MOH remains controversial. Only caffeine and opioid (narcotic) pain killers have been proven to worsen headaches if taken often. It is not to say that frequent or daily intake of ibuprofen is the best way to manage frequent migraines. Many preventive therapies such as Botox, magnesium, propranolol, and other may be more effective and safer. Frequent use of ibuprofen can cause kidney problems and stomach ulcers, which can bleed and even be fatal.

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Galcanezumab (Emgality) was just approved by the FDA for the prevention of episodic cluster headaches. Galcanezumab is one of the three new drugs recently approved for the prevention of migraines (the other two are erenumab, or Aimovig and fremanezumab, or Ajovy). These are monoclonal antibodies (mAbs) that block CGRP, a chemical released during attacks of migraine and cluster headaches.

The manufacturer of fremanezumab also conducted trials for the prevention of cluster headaches, but could not prove that the drug was more effective than placebo. Galcanezumab was also tested for chronic cluster headaches and it did not seem to help. Only 10-15% of cluster headache sufferers have the chronic form. About 250,000 Americans suffer from cluster headaches. Compared to migraines, which affect over 35 million Americans, this is a rare disease. This makes it difficult to conduct clinical trials of new treatments. The only abortive drug approved for the treatment of an acute cluster attack is sumatriptan (Imitrex) injection.

The dose of galcanezumab for the prevention of migraines is 240 mg injection at the start and then, 120 mg every month. The dose for cluster headaches is 300 mg. Of the 106 patients in the cluster headache study only 2 stopped the drug because of side effects. Just like in migraine trials, which involved thousand of patients, the only side effect which occur in more than 2% of patients was injection site reactions, but serious allergic reaction can also occur.

Since erenumab was approved for migraines before the other two mAbs and because preliminary evidence suggested that these drugs may work for cluster headaches, we’ve tried erenumab and then, fremanezumab in our cluster patients who did not respond to usual therapy. Although our numbers are too small to make any sweeping conclusions, it appears that just like with migraines, two out of three patients obtain some benefit. Now that galcanezumab is officially approved, we will be using it for all of our cluster headache patients since insurance companies will have to pay for it. Based on our experience with these drugs in migraines, it is likely that the insurers will require that patients first try and fail some of the other preventive therapies, even if none of those have been approved by the FDA. The most commonly used drug for the prevention of cluster headaches is a blood pressure medicine in the calcium blocker family, verapamil. We also try to abort the entire cluster with an occipital nerve block or a course of prednisone, a steroid medication. Epilepsy drugs such as topiramate (Topamax) and a psychiatric drug, lithium can also help.

Cluster headaches affect more men than women and cause more severe pain than migraines, leading some to call them suicide headaches. Women do suffer from cluster headaches as well and they are more often misdiagnosed. Unfortunately men don’t fare well either – 46% of men are misdiagnosed, compared with 61% of women. It takes 5-6 years before the correct diagnosis is made. Cluster headaches are often mistaken for migraines because pain is on one side of the head and for sinus headaches because cluster headaches are usually accompanied by a runny nose.

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Hydroxyzine (Vistaril) is an underutilized old anti-histamine drug with some unique properties. Just like diphenhydramine (Benadryl) and other older anti-histamine drugs, hydroxyzine causes some sedation. However, it is the only anti-histamine that is officially approved for “anxiety and tension”. It is also approved for itching due to allergic conditions. Off-label (i.e. without FDA-approval) it is used to treat motion sickness, nausea, vomiting, and dizziness.

Hydroxyzine is often used as and adjuvant analgesic, that is as an add-on drug that makes pain medications work better.

A study comparing injections of hydroxyzine, 50 mg with a pain medication nalbuphine 10 mg, with a combination of hydroxyzine and nalbuphine, and with placebo found no benefit from adding hydroxyzine when treating migraines.

A study comparing an injection of hydroxyzine 50 mg plus meperidine (Demerol, a narcotic pain killer), 100 mg was similar to an injection of ketorolac (Toradol) 60 mg in its relief of an acute migraine. Nausea and drowsiness were similar in two groups.

Another study compared hydroxyzine 75 mg intravenously plus meperidine 75 mg intramuscularly to DHE 1 mg IV plus metoclopramide (Reglan) 10 mg IV. Pain reduction was greater with DHE/metoclopramide.

There have been no studies examining the efficacy of hydroxyzine alone, whether as an intravenous or intramuscular injection or as a tablet. It is likely that it will remain an adjuvant or add-on medication for the treatment of migraine headaches.

I sometimes prescribe it to be taken daily to patients whose allergies worsen their migraine headaches or even when there is only a suspicion of an allergic component. It is also useful when anxiety is a contributing factor, which is not unusual since those suffering from migraines are 2-3 times more likely to also have anxiety. For many patients it is too sedating to be taken during the day, unless they are treating an acute attack. Most people take 25 or 50 mg nightly, although some tolerate and benefit from 25 mg taken three times a day.

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