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Headache medications

Nausea is a very common symptom that accompanies migraine attacks. Effective treatment of migraine with a drug like sumatriptan often stops the headache, nausea, and other associated symptoms. However, sometimes pain subsides, while nausea does not, or nausea is much more bothersome than the headache. Nausea can also be a side effect of the most effective injectable migraine drug, dihydroergotamine (DHE-45). We often administer this drug in our office after other injectable drugs (magnesium, sumatriptan, ketorolac, dexamethasone, etc) fail. If nausea is already present, we will always give an intravenous injection of a nausea drug such as ondansetron (Zofran) or metoclopramide (Reglan) before giving DHE. Sometimes these drugs are ineffective in preventing nausea and vomiting induced by DHE and we have to look for other options.

Phenothiazine family of drugs, including prochlorperazine (Compazine), chlorpromazine (Thorazine), and promethazine (Phenergan) are very old and effective anti-nausea drugs. However, they have a potential for a rare but devastating side effect, which consists of persistent involuntary movements of the face (grimacing and lip smacking) and body. The onset of this side effect can be delayed, which is why it is called tardive dyskinesia. It is not unusual for these drugs to cause an immediate severe and very unpleasant restlessness (akathisia), which patients sometimes describe as wanting to crawl out of one’s skin. Metoclopramide (Reglan) can also cause these side effects, but less often.

Ondansetron (Zofran) does not cause any such side effects and should be the preferred drug for nausea of migraine, although it is only approved for nausea caused by chemotherapy or radiation and for post-surgical nausea. Since it has become generic and inexpensive, it can be used for other causes of nausea, including migraines. It is available as an injection or as a tablet.

Aprepitant (Emend) is an anti-nausea drug that has a totally different mechanism of action than the medications described above, so it is possible that it can help when other drugs do not or when other drugs cause side effects.

A study just published in Neurology by Dr. Denise Chou and her colleagues describes the use of oral aprepitant in the treatment of DHE-induced nausea in hospitalized patients.

The authors reviewed hourly diary data and clinical notes of patients admitted to the hospital for the treatment of refractory migraine headaches (status migrainosus) with DHE infusions between 2011 and 2015.

They identified 74 such patients, of whom 24 had daily diaries. In 36 of 57 cases in which aprepitant was given, there was a 50% reduction in the number of other anti-nausea medications given to patients. Of 57 patients, 52 reported that the addition of aprepitant improved nausea. Among 21 of 24 patients with hourly diary data, nausea scores were reduced. In all 12 patients with vomiting aprepitant stopped it. Aprepitant was well tolerated and caused no side effects.

The authors concluded that aprepitant can be effective in the treatment of refractory DHE-induced nausea and vomiting. They also suggested that perhaps this drug could be used for nausea of migraine even when DHE is not given. The only problem, and it is a very big problem, is the cost. This drug is not going to be available in a generic form until 2018. A single capsule of Emend costs $105 with a coupon you can get on GoodRx.com. Without a coupon, it is $145. A single vial for injection costs $345, so we are not going to use this drug for nausea due to migraine or DHE for at least two years, when cheaper generic copies become available.

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Medication overuse headache (MOH), which is sometimes called rebound headache, is included in the International Classification of Headache Disorders. However, this is one of several headache types whose existence is still debated. After years of indocrination, most neurologists and headache specialists strongly believe that every drug taken for acute treatment of headaches can cause MOH. However, we have good evidence only for caffeine and for opioid (narcotic) pain medications. It is far from proven in case of triptans (sumatriptan or Imitrex, and other) or NSAIDs (ibuprofen or Advil, naproxen or Aleve, and other).

Last week, I attended the annual scientific meeting of the American Headache Society (AHS) and was happy to see that despite an almost universal acceptance of the diagnosis of MOH, the organizers set up a debate on the existence of MOH. The debaters included two top experts in the field, Drs. Richard Lipton of Montefiore Headache Clinic in the Bronx and Ann Scher of the Uniformed Services University in Bethesda. Dr. Lipton and Scher have collaborated on many research projects and have published many important articles on headaches together, so the debate was friendly and based on facts.

Dr. Scher quoted the American Council on Headache Education, an affiliate of the AHS:

“It is important to know that intake of medications for acute treatment should be limited to less than twice a week. Some methods which can prevent the onset of medication overuse headache include following instructions on how to take medications, avoid use of opioid medications and butalbital combination medications and limit use of simple analgesics to less than 15 days a month and triptans less than 10 days a month”.

And then she posed a question: How many are being harmed vs helped by this advice?

While Dr. Lipton quoted scientific articles supporting the existence of MOH, Dr. Scher’s conclusions reflected my clinical experience that MOH is not a proven entity as it relates to triptans and NSAIDs. I see it only in those who overuse caffeine or caffeine-containing drugs (Excedrin, Fioricet, etc) or narcotic pain killers (Percocet or oxycodone, Vicodin or hydrocodone, and other).

Dr. Scher concluded that, “Since the existence of MOH has not been proven (and may be non-provable for practical purposes), one is obligated to remain agnostic about this entity. And the corollary is that there is no evidence that undertreating will prevent headache frequency progression and may harm more people than help”.

In fact, the same headache experts who limit abortive therapies to twice a week, recommend aggressive abortive therapy for migraines because undertreatment of episodic migraine can lead to its transformation into chronic migraine.

She also indicated that “Quality of evidence for medication withdrawal alone as treatment for MOH is poor” and “Medication withdrawal alone is not clearly better than doing nothing and may be worse”. Meaning that in addition to withdrawal of the acute medication, patients should be given prophylactic treatment.

Studies indicate that after one year, 60% and after two years, 70% of those with chronic migraines (15 or more headache days in a month) revert to episodic ones (less than 15 headache days a month) regardless of treatment. In 15% headaches decrease to less than one a week. This is because fortunately, migraines often improve with time on their own.

We have evidence that Botox injections and some preventive medications can make discontinuation of acute medications easier. We always try to stop Fioricet (butalbital, acetaminophen, and caffeine), Fiorinal (butalbital, aspirin, and caffeine), Excedrin (caffeine, acetaminophen, aspirin) with the help of regular aerobic exercise, biofeedback or meditation, magnesium and other supplements, Botox injections, and sometimes preventive medications.

However, we do have several dozen patients whose headaches are controlled by the daily intake of triptans. These patients have tried given prophylactic medications, Botox injections and other treatments, but find that only triptans provide good relief and eliminate migraine-related disability. The most commented on post on this blog (with 175 comments to date) is one on the daily use of triptans.

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My most commented on blog post (over 150 comments) is on the daily use of triptans. A new report confirms the safety of long-term daily use of sumatriptan injections in cluster patients. Cluster headaches are arguably the most severe type of headaches and the name comes from the fact that they tend to occur in clusters lasting several weeks to several months. However, in some patients headaches become persistent without any remissions and then they are called chronic cluster headaches. The only FDA approved treatment for cluster headaches is injectable sumatriptan (Imitrex). Most patients have one cluster attack in 24 hours, but some have many. A report mentioned in one of my other previous blogs describes a woman (although men are more commonly affected by cluster headaches) who has been injecting sumatriptan daily on average 20 times a day for 15 years.

A recent report by Massimo Leone and Alberto Cecchini is entitled, Long-term use of daily sumatriptan injections in severe drug-resistant chronic cluster headache.

The authors investigated occurrence of serious side effects in patients with chronic cluster headaches who were using sumatriptan injections continuously at least twice daily (the official limit) for at least 2 years. They found fifty three such patients with chronic cluster headaches seen in their clinic between 2003 and 2014. During the 2-year period, all patients were carefully followed with regular visits at their center. Headaches and sumatriptan consumption were recorded in headache diaries. Patients were questioned at each visit about serious side effects and had at least two electrocardiograms. Brain MRI was normal in all patients. None of the patients had a history of stroke, TIA, ischemic heart disease, myocardial infarction, or arrhythmia, or diseases affecting systemic vessels.

In the 2-year study period, no serious side effects were observed and no patients needed to discontinue sumatriptan use. No electrocardiogram abnormalities were found. All patients needed a full dose (6 mg) of sumatriptan injection (prefilled syringes with 4 and 6 mg available). At the end of the study period, 42% noticed some reduction in the efficacy of sumatriptan injections both in terms of time of onset of effect and on pain intensity, but still considered the drug their first choice to treat the attacks.

In the study period, 36 of the 52 patients (69%) used more than 12 mg of sumatriptan in 24 hours (maximum 36 mg in 24 hours) but no increase in number or severity of side effects was observed during the course of the study. Complete loss of efficacy was not reported by any of the patients.

The authors mention that since the launch of sumatriptan injections in 1992 and until 1998, approximately 451 serious cardiac side effects have been reported to occur within 24 hours after administration of sumatriptan injections, tablets or nasal spray, but this is out of more than 236 million migraine attacks and more than 9 million patient exposures between 1992 and 1998. The majority of patients who developed serious cardiac events within 1 to 3 hours of sumatriptan administration had risk factors for coronary artery disease.

The authors concluded that their results showed that long-term daily sumatriptan use in patients free of heart disease did not cause serious side effects and this is in line with observations from previous studies.

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Magnesium deficiency is a regular topic on this blog. Up to half of migraine sufferers are deficient in magnesium, but magnesium levels are rarely checked by doctors. Even when magnesium level is checked, it is usually the serum level, which is totally unreliable. The more accurate test is RBC magnesium or red blood cell magnesium because 98% of body’s magnesium resides inside cells or in bones. At the New York Headache Center we often don’t bother checking even the RBC magnesium level, especially if other signs of magnesium deficiency besides migraines are present. These include coldness of hands and feet or just always feeling cold, leg muscle cramps, palpitations, anxiety, brain fog, and in women, premenstrual syndrome or PMS (bloating, breast tenderness, irritability). For these patients we recommend daily magnesium supplementation and sometimes monthly magnesium infusions.

About 20 to 30 million women suffer from moderate or severe PMS, and a recent study published in the American Journal of Epidemiology indicates that having PMS increases the risk for hypertension (high blood pressure) later in life.

This study was done at the University of Massachusetts, Amherst and it involved 1,260 women who suffered from moderate or severe PMS as well as more than 2,400 women with mild or no PMS. Women with moderate or severe PMS were 40 percent more likely to develop high blood pressure than those with mild or no PMS symptoms. The researchers adjusted the risk for other risk for hypertension, such as being overweight, smoking, drinking, inactivity, use of birth control pills, postmenopausal hormone use, and family history of high blood pressure.

The association between moderate or severe PMS and high blood pressure was most pronounced among women younger than 40, who were three times more likely to develop hypertension.

Interestingly, the risk of high blood pressure was not increased in women with moderate or severe PMS who were taking thiamine (vitamin B1) and riboflavin (vitamin B2). Other researchers found that women who consumed high levels of those vitamins were 25 to 35 percent less likely to develop PMS.

Unfortunately, the researchers did not look at magnesium levels or magnesium consumption in these women. A strong association exists between magnesium deficiency and high blood pressure. There is also an association between an increased magnesium (and potassium) intake and reduced risk of strokes. Supplementation with magnesium during pregnancy decreases the risk of hypertension during pregnancy. There is also a strong association between magnesium and depression.

There are literally hundreds of scientific articles on beneficial effects of magnesium, but unfortunately magnesium remains ignored by mainstream physicians. However, consumers are ahead of most doctors and many do take magnesium supplements. This is helped by many print and online articles and many books. Some of these books include Magnificent Magnesium, Magnesium Miracle, Magnesium – The Miraculous Mineral of Calm, and my two books – The Headache Alternative: A Neurologist’s Guide to Drug-Free Relief and What Your Doctor May Not Tell You About Migraines.

Migralex is a product I patented and developed for the treatment of headaches. It contains an extra-strength dose of aspirin and magnesium. Magnesium in Migralex acts as a buffering agent and reduces the risk of stomach irritation by aspirin. Migralex is available at CVS stores, Amazon.com, and Migralex.com.

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Zecuity, a skin patch containing a migraine drug sumatriptan was approved by the FDA almost two years ago, but it became available (by prescription) only last month (see my previous post about Zecuity). The product is not available in retail pharmacies, only from a specialty pharmacy. The doctor who prescribes the patch will usually provide information on where to get it. Otherwise, go to zecuity.com, where you can find a section entitled Migraine Support Solutions. At this site you can verify that your insurance covers this product, get it shipped to you, and then get information on how to apply the patch. A discount coupon is also available on the site and it promises that the copay will be as low as $15. That is a good thing, because it looks like (on GoodRx.com) each patch costs $300. Yes, not $30, but $300 a piece, or $1,200 for a box of 4. I don’t think too many people will be buying this patch if their insurance does not cover it.

So, who is the best candidate for Zecuity? Half of migraine sufferers experience nausea and/or vomiting with their attacks. This makes the absorption of oral drugs, such as triptans (Imitrex, Maxalt, Zomig, etc) so slow as to make them ineffective. In such patients we try to bypass the stomach, which until now was possible to do with a nasal spray, suppository, or an injection. Sumatriptan (Imitrex) is available in the US in tablets, nasal spray and self-administered injections. Nasal spray of sumatriptan is not very effective, but injections work better than tablets. Relief from an injection can occur in as quickly as 10 minutes, but injections can cause more side effects, which are mostly unpleasant rather than dangerous. Obviously, most people would rather not get a shot. One form of injectable sumatriptan delivers the medicine through the skin without a needle (Sumavel), but not without pain see this post.

One other triptan, zolmitriptan (Zomig) is available in a nasal spray and it is more effective than sumatriptan nasal spray, but it is not available in a generic form, making it less accessible because of the high cost and restricted insurance coverage.

The perfect patient for Zecuity is someone who experiences nausea and/or vomiting with their migraine attacks and who does not respond to tablets and has side effects from or aversion to injections. Zecuity provides good relief for such patients with the main side effect being skin irritation from the patch. The patch is fairly large, the size of a palm. It uses a miniature battery to generate an electric current, which helps drive the medicine through the skin. Iontopheresis is the name of this process. Iontopheresis has been known for decades, but Zecuity is the first product approved by the FDA to utilize this technology.

Disclosure – Teva Pharmaceuticals, manufacturer of Zecuity pays me to give lectures about Zecuity to doctors.

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Propranolol was first introduced as a blood pressure drug 50 years ago and about 40 years ago it was discovered to be effective for the prevention of migraines. This is quite a remarkable drug because it is also used for rapid heart beat, heart attacks, tremor, and performance anxiety. Public speakers, musicians, and others take a small dose before performances and the drug reduces the physical stress responses such as sweating, tremulousness, weakness, and other. Blinded studies showed that musicians perform better when given a beta blocker compared to musicians who are given a placebo pill.

Since the introduction of propranolol, another two dozen beta blockers have been developed. The newer, so called selective beta blockers (they attach to only one type of stress receptor) tend to have fewer side effects than propranolol and other non-selective beta blockers. Selective beta blockers can be given to patients with well-controlled asthma, while non-selective ones can cause an asthma attack.

Recent studies have shown that chronic stress promotes the growth and spread of cancers. Researchers at MD Anderson Cancer Center decided to review the records of 1,425 patients who were treated for ovarian cancer at four hospitals between 2000 and 2010. Of these, 268 had been treated with a beta blocker while receiving chemotherapy for their ovarian cancer. The average survival of those who were on a beta blocker was 48 months compared to 42 months for those who were not. A more dramatic difference was found between those who were taking a non-selective beta blocker (propranolol in almost all cases): they lived 95 months – twice as long as women not on a beta blocker.

Considering these findings, if I decide to prescribe a beta blocker, I may start prescribing propranolol as the first-line drug for the prevention of migraines. And only if the patient has side effects, will I switch them to a selective beta blocker, such as atenolol or nebivolol (Bystolic). Common side effects of beta blockers are fatigue and dizziness from a drop in blood pressure and difficulty exercising because the heart rate cannot increase high enough to provide for the increase in demand for oxygen. Because regular aerobic exercise is my first recommendation for the prevention of migraines, I tend to reserve beta blockers for patients whose blood pressure is high or at the high end of normal range, whose pulse is fast, and for those who fail other preventive drugs and Botox (however, most insurers approve Botox for chronic migraines only if the patient fails 2 or 3 preventive drugs, including a beta blocker).

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Ayurvedic medicine has many healthy aspects. However, a recent story on NPR described the risks involved with the traditional Ayurvedic medicines from India. A very high percentage of Ayurvedic supplements in the category called bhasmas sold in the US contains large amounts of lead and other toxic elements. There is a lot more to Ayurvedic medicine than these supplements, so it is important to separate dangerous parts from things like healthy diet, yoga, and other.

Unfortunately, the US government does not regulate supplements, so there is always a question of safety of these products, especially those made outside the US. The one exception is products made in Germany, where supplements are as strictly regulated as drugs (please note that Petadolex, a butterbur product is made in Germany, but is not allowed for sale there). Many patients ask me about not only Indian but also Chinese herbal medicines, which are often combined with acupuncture and other treatment methods. As a rule, I recommend avoiding products made in China or India, where quality controls are very poor. Instead, you should buy products made by major US manufacturers, although they do not make many traditional Chinese and Indian products. However, you cannot always count on products sold in major US store chains either – recently, herbal products sold at Walgreens, WalMart, Target and GNC were found to have no active ingredients. Thankfully, there were no toxic ingredients in those products.

The largest mass poisoning with a Chinese herbal dietary weight loss product occurred in Europe where 18 patients developed kidney failure and urinary cancer.

In summary, no matter how promising a Chinese or an Indian herbal product may sound, it is not worth the risk.

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Hopefully, your doctor has given you many treatment options, so that you can manage even the most severe attacks at home (including Compazine or Phenergan anti-nausea suppositories for when you are very nauseated or vomit and Imitrex or sumatriptan injection pen for severe pain). However, many people end up in an ER, where they are usually given an injection or intravenous medications. Unfortunately, there is no standard protocol for the best way to treat an acute migraine that does not respond to oral medications. Ideally, the first step should be an infusion of magnesium, which can provide fast relief for up to 50% of patients. Some ER doctors give an injection of sumatriptan or a non-narcotic pain killer ketorolac (Toradol). Others will give a nausea drug which can also help pain such as metoclopramide (Reglan) or prochlorperazine (Compazine). An allergy medicine, diphenhydramine (Benadryl) is also a popular choice.

A study by Dr. Benjamin Friedman and his colleagues at the Albert Einstein COllege of Medicine in the Bronx compared the efficacy of intravenous Reglan combined with Benadryl and Reglan without Benadryl. This was a double-blind study, meaning that neither the doctor giving the medicine nor the patient knew what was being given. They recruited 208 patients, which is a high enough number to produce reliable results. And the results showed that Reglan without Benadryl provided as much relief as with Benadryl.

Benadryl is not a dangerous drug, but can make you drowsy, so if you can, ask the doctor not to give it to you. It is not easy to tell a doctor what to do, especially during a severe migraine attack. But if doctor is agreeable, ask for intravenous magnesium followed by either sumatriptan or ketorolac injection as well as metoclopramide for nausea.

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Topiramate (Topamax) is a drug used for the prevention of migraine headaches (and epilepsy) in adults and last year it was also approved for adolescent migraine sufferers. This drug is notorious for causing cognitive side effects, kidney stones,osteoporosis, overheating, and many other side effects. It is contraindicated (just like another migraine drug, Depakote) in pregnancy because of the risk of birth defects.

A new report published in the journal Pediatrics documents an increased risk of eating disorders in adolescents who take Topamax. This report describes 7 female teenagers who developed an eating disorder or whose eating disorder got worse on topiramate.

Considering that we have many other effective preventive drugs for migraine headaches, topiramate should be used only when several other treatments fail.

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Several million Americans suffer from chronic migraines, headaches that occur on at least half of the days and often daily.

A new study suggests one of the way to prevent this disabling disease. In the American Migraine Prevalence and Prevention Study, people with episodic migraines (those occurring on less than half of the day each month) completed the Migraine Treatment Optimization Questionnaire and provided outcome data in 2006 and in 2007. They were asked four questions about the efficacy of their acute migraine therapies and the responses were divided into: very poor, poor, moderate, and maximum treatment efficacy.

Among 5,681 study participants with episodic migraine in 2006, 3.1% progressed to chronic migraine in 2007. Only 1.9% of the group with maximum treatment efficacy developed chronic migraine. Rates of new-onset chronic migraine increased in the moderate treatment efficacy (2.7%), poor treatment efficacy (4.4%), and very poor treatment efficacy (6.8%) groups. The very poor treatment efficacy group had a more than 2-fold increased risk of new-onset chronic migraine compared to the maximum treatment efficacy group.

The authors concluded that inadequate acute treatment efficacy was associated with an increased risk of new-onset chronic migraine over the course of 1 year. They speculated that improving acute treatment outcomes might prevent chronic migraine. However, they also said that reverse causality cannot be excluded, meaning that it is possible that those who would go on to develop chronic migraine had poor response to acute treatment because their headaches were worse and that they would develop chronic migraine regardless of how well their acute treatment worked. However, it makes a lot of sense to assume that effective treatment of individual attacks may prevent headaches from becoming chronic, especially because we know that each migraine attack leaves the brain more excitable for weeks and this makes the next attack more likely.

Effective treatment of acute attacks usually involves the use of triptans, (drugs like sumatriptan, or Imitrex, eletriptan, or Relpax, rizatriptan or Maxalt, and other), although NSAIDs, such as aspirin, iboprofen and other can also help, both alone or in a combination with a triptan. Medications that should not be used are drugs such as Fioricet or Fiorinal (butalbital, caffeine, and acetaminophen / aspirin), codeine, Percocet (oxycodone / acetaminophen), Vicodin (hydrocodone / acetaminophen). These drugs are not only ineffective, but can make it more likely that episodic migraines will turn into chronic. This also applies to other caffeine-containing drugs (Excedrin and other) and even dietary caffeine.

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Epilepsy drugs Depakote and Topamax are two of only four drugs approved by the FDA for the prevention of episodic migraines (the other two are blood pressure medications in the beta blocker family, propranolol and timolol, while Botox is the only drug approved for the preventive treatment of chronic migraines). However, these two drugs are contraindicated in pregnancy. Considering that the majority of migraine sufferers are young women, this is a topic that needs to be revisited regularly, especially when additional data appears.

A new study just published in the journal Neurology followed children in the British National Health Service whose mothers suffered from epilepsy and who were taking Depakote (valproate) or Tegretol (Carbamazepine) or Lamictal (lamotrigine). Only Depakote caused a significant drop in IQ in children whose mother was taking more than 800 mg of Depakote a day. Children whose mother took less than 800 mg (the usual dose for migraines is 500 mg, but sometimes 1,000 mg is needed) did not have a lower IQ, but had impaired verbal abilities and a 6-fold increase in needing educational intervention.

Unfortunately, Tegretol and Lamictal are not effective for the prevention of migraine headaches, while Topamax which is effective, can cause birth defects. Neurontin (gabapentin) is a relatively benign medication, which is safe in pregnancy and it is somewhat effective in the prevention of migraines, including chronic migraines.

Ideally, all drugs should be avoided in pregnancy. We usually advise non-drug approaches, including regular sleep, healthy diet, exercise, biofeedback or meditation, and magnesium supplementation. If this is insufficient, we usually recommend Botox if migraines remain frequent (they often improve in pregnancy). Botox is not approved for use in pregnant women, but considering that it acts locally on nerve endings with very little of it getting into the blood stream, it is most likely safer than any drug that is ingested.

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Cyclic vomiting syndrome (CVS) is usually seen in children. The attacks of vomiting often stop as the child gets older, but then they usually go on to develop migraine headaches. A recent report in Headache describes three adults with CVS. The article also mentions a previous report which described another 17 adults with this syndrome.

CVS typically consists of recurrent stereotypical attacks of incapacitating nausea and vomiting, separated by symptom-free periods. Supporting evidence that helps diagnose this condition include personal or family history of migraine and other symptoms, such as headaches, motion sickness, and sensitivity to light.

Just like in children, CVS in adults is a diagnosis of exclusion, meaning that other causes of vomiting must be considered and ruled out. I mentioned in a previous post that one out of three children with CVS turned out to have another medical problem rather than migraine.

CVS in adults seems to respond well to an injection of sumatriptan (Imitrex). This allows for a quick relief of symptoms and makes this debilitating condition very manageable. Besides Imitrex injections, Zomig (zolmitriptan) nasal spray can sometimes be effective as well.

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