Rimegepant (Nurtec ODT) was just approved by the European Medicines Agency for marketing in 27 EU countries as well as Iceland, Liechtenstein, and Norway. It was approved for both the acute treatment of migraine with or without aura, and prophylaxis (prevention) of episodic migraine in adults who have at least four migraine attacks per month. The drug will be sold under the name VYDURA.
Read MoreHeadache medications
If you are “overusing” acute migraine medications, preventive migraine treatments still work very well. This was the conclusion of a study that was just published in the journal of the American Academy of Neurology, Neurology.
The concept of medication overuse headache (MOH) has remained controversial. The majority of headache specialists believe in its existence. And that is what it is, a belief. There are correlational studies showing that those who take acute migraine drugs tend to have them more often as time goes on. This obviously does not mean that the drug is responsible for the increase in frequency. It is more likely that people take drugs more often because their headaches have gotten worse. There is proof for the existence of MOH only for two drugs – caffeine and opioid (narcotic) pain drugs. Triptans and NSAIDs have no such proof and in my 30 years of experience, they rarely cause MOH.
The daily use of triptans is the topic of my most popular post in the 15 years of writing this blog. It received about 400 comments. Many people commented how relieved they are that taking triptans daily can be safe and effective. They often lament that they can’t get their doctors to prescribe a sufficient quantity of pills.
I am not suggesting that taking triptans daily is the first or second option. It is always better to try Botox and non-drug approaches. Taking a triptan daily, however, is probably safer than taking FRA-approved epilepsy drugs such as topiramate (Topamax) or divalproex (Depakote), or even an antidepressant.
The article in Neurology describes a large study with over 700 participants who were “overusing” acute migraine medications. Half of them were taken off these drugs and started on preventive therapies and the other half were given preventive therapies without stopping acute drugs. Both groups did equally well. This goes against the old dogma that preventive therapies will be ineffective if the daily abortive drugs are not stopped first. The most common preventive treatments in this study were topiramate, Botox, and amitriptyline (Elavil).
Read MoreCluster headaches are considered to cause the worst pain imaginable. We have a variety of medications – both acute and preventive – that help relieve the pain of cluster headaches. For some, none of these treatments work and we do need additional medications. Ketamine could be one such drug.
Ketamine has been in use for over 50 years. Its main indication is intravenous anesthesia. Recently, the FDA approved ketamine nasal spray for depression. It is also being widely used intravenously and by mouth for depression, chronic pain, and migraine headaches. A group of researchers at the Danish Headache Center in Glostrup, Denmark tested the efficacy of ketamine nasal spray for the acute treatment of cluster headaches.
Anja Petersen and her colleagues selected 20 cluster patients whose attacks did not respond sufficiently well to sumatriptan or oxygen – the two most effective acute therapies for cluster headaches. Patients treated a single cluster attack with 15 mg of intranasal ketamine. They could repeat this dose every 6 minutes, for up to 5 times. Four patients took another medication after 15 minutes. Of the 16 remaining ones, 11 had a drop in pain severity by an average of four points, to four or lower on a one to 10 scale. Half of the patients preferred ketamine to oxygen and/or sumatriptan injection. No patient had any serious side effects from ketamine during the trial.
Ketamine nasal spray that is approved for depression is a more potent version of ketamine called esketamine (Spravato). It is a patented and branded product and it is very expensive. Ketamine itself, however, is a cheap drug. A compounding pharmacy can prepare a nasal spray for as little as $60 for a month supply. Most insurers do not cover compounded drugs, so you’d have to pay for it.
Read MoreKetamine was approved by the FDA in 1970 and was originally used for the induction of anesthesia. It has been shown to relieve depression and is also widely used to treat pain. For depression, it is approved by the FDA in a nasal spray form. For severe pain, it is often given intravenously. Oral ketamine is probably the least effective.
In a recent study, Australian researchers compared the pain-relieving effect of oral and sublingual ketamine in 16 patients. The study was double-blind. Sublingual administration of ketamine resulted in a faster onset of pain relief – 7 minutes with sublingual and 13 with oral. Side effects were also more common with the sublingual route. In all other measures, sublingual and oral administration produced similar pain-relieving effects.
Oral and sublingual ketamine are not available at regular pharmacies. It is, however, easily made up by compounding pharmacies. The sublingual ketamine is available as a lozenge which is also called troche. I usually prescribe ketamine infusions or troches only after a wide variety of other treatments do not provide relief.
Ketamine is a controlled drug with a potential for misuse. It can also cause psychiatric side effects such as hallucinations, disinhibition, delusional thinking, and depression.
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With Swiss colleagues Drs. Caterina Podella, Livia Granata, and Reto Agosti at the headache conference held on November 4, 2021, in Zürich.
Dr. Podella presented a very comprehensive approach to the treatment of migraine headaches. Dr. Granata expertly covered the topic of cluster headaches. I spoke about the challenges of treating refractory migraine headaches and Dr. Agosti provided a lively and insightful discussion of all these topics.
The placebo effect is a bane of clinical trials. It is, however, a great tool in clinical practice. It is unethical to prescribe an actual placebo but there is no reason not to try to enhance the placebo effect when prescribing any treatment, pharmacological or non-drug.
German researchers decided to study what is called social observational learning (SoL). This was a double-blinded randomized controlled clinical trial in 44 patients with chronic low-back pain (CLBP). They compared the effects of observing positive treatment outcomes in a sham or pretend patient versus hearing the same sham patient report neutral effects. In the SoL group, the sham patient told study patients about his improved pain due to amitriptyline and he also demonstrated his improved mobility by bending forwards and sideways. The same sham patient told the control group only that he was taking amitriptyline. The researchers collected data before and after the intervention and two weeks later. After the intervention, pain decreased in both groups with no difference between groups. The SoL group, however, showed a significantly larger decrease in perceived disability.
The authors concluded that “The CLBP patients’ direct observation of positive treatment outcomes in the sham patient appears to have enhanced the treatment effects, while indirect verbal reports of reduced pain did not.”
These findings are not surprising. I often have patients ask for a particular treatment because their friend or relative had a very good response to it. If it is a reasonable treatment for a particular patient, I usually oblige, hoping for an enhanced placebo effect.
Read MoreTo gain FDA approval a drug has to be shown to be better than a placebo. The placebo effect is a well-established psychological contributor to the efficacy of most treatments.
They evaluated chronic migraine patients who were treated with erenumab (Aimovig). Erenumab is a monoclonal antibody that targets CGRP, a neurotransmitter involved in the development of migraine attacks.
Monthly erenumab injections were given for one year to 75 patients with chronic migraine who had already failed at least three other oral preventive drugs. A full psychological evaluation assessed personality disturbances, mood and anxiety disorders, as well as childhood traumas, and ongoing stressors.
After 12 months of treatment, 53 patients had at least a 50% drop in the number of headache days per month. The other 22 did not. When compared to responders, non-responders were more likely to have personality disorders with anxious-fearful, avoidant, dependent, and obsessive-compulsive features. Non-responders were also more likely to suffer anxiety disorders and had a higher number of current major stressors.
A very practical application of these findings is that doctors need to address anxiety when treating migraine and chronic pain patients. I’ve seen a number of patients whose migraines improved with an SSRI antidepressant such as fluoxetine (Prozac) or escitalopram (Lexapro). SSRIs do not possess pain-reliving properties. However, they are good at relieving anxiety and so can indirectly improve migraines. Most of the time, I prescribe SNRIs such as duloxetine (Cymbalta) or a tricyclic antidepressant such as nortriptyline (Pamelor) because they relieve anxiety and can have a direct pain-relieving effect.
The old dogma in psychology was that you cannot change your personality. We now know that such change is possible. Different types of cognitive-behavioral therapy (CBT) can be very helpful. Swedish researchers showed that even a brief internet-based CBT can produce long-term changes in personality traits.
Read MoreAtogepant (Qulipta) is a new migraine drug that was just approved by the FDA for the preventive treatment of migraines. It is the third drug in the family of gepants. Gepants block the CGRP receptor. CGRP is a chemical released during a migraine attack. In the past three years, the FDA approved four injectable preventive migraine drugs that also block CGRP. Gepants are taken by mouth.
The dose of atogepant is 10 mg, 30 mg or 60 mg taken daily, once a day. The primary efficacy endpoint in clinical trials was the change from baseline in mean monthly migraine days over the 12-week treatment period. There was a drop of 3.7, 3.9, and 4.2 in the number of mean monthly migraine days in the 10 mg, 30 mg, and 60 mg doses, respectively.
Side effects – assessed in almost 2,000 patients – were infrequent and mild. Nausea occurred in 5%, 6%, and 9% on 10 mg, 30 mg, and 60 mg respectively, constipation in 6% on all three doses, and fatigue or somnolence in 4%, 4%, and 6%.
Ubrogepant and rimegepant, two other gepants, were first approved to be taken as needed, whenever a migraine strikes. Rimegepant recently was also approved for the prevention of migraines. Even though gepants are very similar they often differ in how they work in an individual patient. Some of my patients find that ubrogepant works much better than rimegepant while for others the opposite is true. I am certain that some patients will find a big difference in the way rimegepant and atogepant work for them. This is why it is useful to have a few drugs in every therapeutic category.
Read MoreTrudhesa is a new formulation of dihydroergotamine (DHE) nasal spray just approved by the FDA. It appears to be more effective than the original DHE nasal spray (Migranal) that was introduced in 1997.
Ergotamine, the first migraine-specific drug was developed in 1926. It is still available in tablet form but is not widely used because it causes nausea, constriction of blood vessels, and other side effects. DHE, approved in 1946, was the first synthetic migraine drug. It was derived from ergotamine in an attempt to reduce side effects. DHE is not effective when taken by mouth and was originally approved for intravenous use. It is still being used now – 75 years later – intravenously, intramuscularly, and subcutaneously. DHE injection is a very effective medicine, often used when no other migraine drug provides relief. It does cause nausea and vomiting in a significant number of patients. This is why it is often given along with an anti-nausea drug such as ondansetron (Zofran), prochlorperazine (Compazine), or metoclopramide (Reglan).
The original DHE nasal spray has been a relative disappointment. It is not very effective, although there are some patients for whom it works well. Despite being on the market for over 20 years, it is still very expensive – $100 a dose. The manufacturer of Trudhesa, which is a better product than Migranal, is promising to make their product more affordable. Nasal delivery of DHE causes less nausea than an injection.
Trudhesa is more effective despite delivering a smaller dose of DHE than Migranal. This is because Trudhesa is delivered as a fine mist into the upper reaches of the nasal cavity. It will become available in about two months. I will prescribe it to patients for whom oral medications are ineffective.
Read MoreThe placebo effect is a bane of clinical trials. A drug is considered ineffective if it is only as good as a placebo. And placebo can be quite good. Intriguingly, the placebo effect in clinical trials has been getting stronger over the past few decades. Lately, placebo has been receiving a lot of attention from researchers.
A rigorous study just published in the journal Pain looked at the effect of a placebo when patients were clearly told that they are taking a placebo. These patients were compared to those who were given a placebo in a double-blind study of peppermint oil capsules for irritable bowel syndrome (IBS). These two different types of placebo were compared to a control group of patients who were not given any pills.
Participants treated with an open-label placebo and a double-blind placebo reported similar and clinically meaningful improvements in IBS symptoms. These improvements were significantly greater than in those who were not given any pills. The results were statistically significant for the primary outcome measure (IBS Symptom Severity Scale) as well as for mean global improvement scores.
Twice as many patients in the double-blind placebo group had side effects (mostly gastrointestinal, such as heartburn) than those in the open-label placebo. It is probably because the first group was told about the possible side effects of peppermint oil.
The authors concluded that an open-label placebo “could play a role in the management of patients with refractory IBS”.
Just like migraines, IBS involves central sensitization and hypersensitivity of the nervous system. And just like with migraines, placebo response in clinical trials of IBS tend to be high. This is not to suggest that these conditions are psychological. Especially with migraines, the biological basis is well documented. Psychological factors, however, cannot be ignored. About 40% of patients with chronic pain, including migraines, have a history of emotional, physical, or sexual abuse. Post-traumatic stress disorder of other types also causes hypersensitivity of the central nervous system. Psychological factors can even be the cause of such potentially deadly conditions as broken heart syndrome (Takotsubo cardiomyopathy). It is likely that the placebo effect is stronger in conditions where psychological factors are more pronounced.
It is considered unethical to prescribe a placebo to patients without telling them that they are getting a placebo. This latest study suggests that some patients may improve even if they know that they are taking a placebo.
I do prescribe herbal supplements such as feverfew and boswellia and on a rare occasion, a homeopathic remedy, all of which lack rigorous proof of their efficacy. For that matter, many drugs we prescribe for migraines lack such definitive proof. I would suggest that we should first prescribe less harmful unproven remedies rather than unproven prescription drugs.
Read MoreIn the US, we are lucky to have seven different triptans available in the pharmacies. Five of them – sumatriptan, rizatriptan, zolmitriptan, eletriptan, and almotriptan are considered to be more effective than the other two – naratriptan and frovatriptan. Frovatriptan has the longest duration of effect because its half-life is 26 hours. Its initial efficacy, however, is not as good as that of other triptans. Naratriptan has a half-life of 6 hours, while the leading five triptans, only 2-4 hours. Naratriptan is also considered to be less effective but it could be because the marketed dose is too low.
In an article in the latest issue of Cephalalgia Peer Tfelt-Hansen argues that naratriptan is as effective as sumatriptan. In fact, if you inject an adequate dose of naratriptan it works better than an injection of sumatriptan. Naratriptan, however, is not available as an injection, only sumatriptan is.
Naratriptan (Amerge) was introduced by the same company that made sumatriptan (Imitrex), the very first triptan. They decided to market it as a “gentle” triptan and selected a relatively low dose of 2.5 mg that had as few side effects as the placebo.
In clinical trials, 2.5 mg of oral naratriptan is less effective than 100 mg of oral sumatriptan. However, clinical trials have shown that 10 mg of naratriptan has similar efficacy to 100 mg of sumatriptan. Naratriptan, 10 mg had slightly fewer side effects than sumatriptan, 100 mg.
The author also mentions the conclusion of the 2004 review by the American Triptan Cardiovascular Safety Expert Panel: “Incidence of triptan-associated serious cardiovascular adverse events in both clinical trials and clinical practice appears to be extremely low”. For more than a decade now, all European countries have at least one of the triptans available without a prescription.
The practical implication of this information is that it is safe to exceed the FDA-approved dose of naratriptan. If taking one 2.5 mg tablet provides some relief, taking two or three at once will not result in dangerous side effects. I’ve also had patients tell me that they need to take a double dose of sumatriptan – 200 mg instead of 100 or 20 mg of rizatriptan instead of the maximum recommended single dose of 10 mg. In the US, eletriptan is available only in 20 and 40 mg strength. Some European countries have 80 mg tablets as well.
Since all triptans are now available in a generic form, three of them are very inexpensive and patients can bypass the insurance limits and pay out-of-pocket for additional tablets. That is if your doctor is willing to prescribe a larger number of tablets – many erroneously believe that triptans are a common cause of medication overuse, or rebound headaches. You can find naratriptan, rizatriptan, and sumatriptan in some pharmacies for less than $2 a pill.
Read MoreTrigeminal neuralgia (TN) is an extremely painful and often debilitating condition. Many people respond to the standard therapy with epilepsy drugs such as carbamazepine (Tegretol) or oxcarbazepine (Trileptal). Botox injections can be helpful as well. A significant minority of patients, however, do not respond to these treatments and sometimes require brain surgery.
Fortunately, we have a new class of drugs that has allowed some of my patients to avoid having an operation. These drugs are CGRP monoclonal antibodies (mAbs). They have been approved by the FDA only for the prevention of migraine headaches, so their use for TN is considered to be “off-label”.
Erenumab was the first CGRP mAb. It was approved in May of 2018. Another two, galcanezumab (Emgality) and fremanezumab (Ajovy) were approved about six months later. These are given by a monthly subcutaneous injection. About a year ago, an intravenous CGRP mAb, eptinezumab (Vyepti) was also approved. These four drugs are very similar. However, some patients find one to be more effective than others. I’ve found this to be true not only in migraine patients but also in those with TN. Erenumab is slightly different in its mechanism of action and it is the only one that has a warning about the potential for causing severe constipation and increased blood pressure. Since TN patients tend to be older and more prone to these side effects, I prefer galcanezumab or fremanezumab. Unlike eptinezumab, they can be self-administered.
Off-label use is totally legitimate. However, insurance companies are not likely to pay for an expensive drug that is not explicitly approved by the FDA for a specific indication. And these drugs are not cheap – about $600 to $700 for each monthly shot. Because of the competition among pharmaceutical companies, they provide us with plenty of free samples (except for eptinezumab). TN is a relatively rare disorder so we can provide free samples to all of our TN patients who respond to these drugs. This is true for most neurologists’ private offices. This may not be true in big hospitals where sampling is not allowed.
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