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Home , Prevention of migraines

MEDICAL TREATMENT OF HEAD PAIN

MIGRAINE PAIN

JASSIN M. JOURIA, MD Dr. Jassin M. Jouria is a practicing Emergency Medicine physician, professor of academic medicine, and medical author. He graduated from Ross University School of Medicine and has completed his clinical clerkship training in various teaching hospitals throughout New York, including King’s County Hospital Center and Brookdale Medical Center, among others. Dr. Jouria has passed all USMLE medical board exams, and has served as a test prep tutor and instructor for Kaplan. He has developed several medical courses and curricula for a variety of educational institutions. Dr. Jouria has also served on multiple levels in the academic field including faculty member and Department Chair. Dr. Jouria continues to serve as a Subject Matter Expert for several continuing education organizations covering multiple basic medical sciences. He has also developed several continuing medical education courses covering various topics in clinical medicine. Recently, Dr. Jouria has been contracted by the University of Miami/Jackson Memorial Hospital’s Department of Surgery to develop an e- module training series for trauma patient management. Dr. Jouria is currently authoring an academic textbook on Human Anatomy & Physiology.

ABSTRACT

While the common headache does not usually drive a patient to seek medical attention, migraine headaches often do. More than just a severe headache, a migraine headache is typically accompanied by intense pain and a sensitivity to light and sound that often results in nausea and vomiting. Providing relief from these headaches — through medication, lifestyle changes, or alternative therapies — is more than just a medical treatment; it frequently allows the patient a quality of life that would not exist without the treatment.

1 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Policy Statement

This activity has been planned and implemented in accordance with the policies of NurseCe4Less.com and the continuing nursing education requirements of the American Nurses Credentialing Center's Commission on Accreditation for registered nurses. It is the policy of NurseCe4Less.com to ensure objectivity, transparency, and best practice in clinical education for all continuing nursing education (CNE) activities.

Continuing Education Credit Designation

This educational activity is credited for 3 hours. Nurses may only claim credit commensurate with the credit awarded for completion of this course activity. Pharmacy content is 1 hour.

Statement of Learning Need

Health clinicians need to understand the various types of , as well as the recommended testing for accurate diagnosis and treatment of all age groups. Knowing the difference between types of headaches is not always straightforward, and migraine auras may develop or may not. In certain types of migraines, the pain may occur in a body area other than the head or prodromal signs may involve an odd smell or sensation. Clinical competency to accurately diagnose different types of migraine is multifactorial, such as specific training to understand genetic and other risk factors, migraine pain, and the ability to recognize clinical features that require a patient undergo neuroimaging and investigation of a condition other than migraine.

2 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Course Purpose

To provide health clinicians with knowledge of the types of migraine pain and treatment, including differential diagnosis, testing, medication, lifestyle and alternative therapies.

Target Audience

Advanced Practice Registered Nurses and Registered Nurses (Interdisciplinary Health Team Members, including Vocational Nurses and Medical Assistants may obtain a Certificate of Completion)

Course Author & Planning Team Conflict of Interest Disclosures

Jassin M. Jouria, MD, William S. Cook, PhD, Douglas Lawrence, MA Susan DePasquale, MSN, FPMHNP-BC – all have no disclosures

Acknowledgement of Commercial Support

There is no commercial support for this course.

Please take time to complete a self-assessment of knowledge, on page 4, sample questions before reading the article. Opportunity to complete a self-assessment of knowledge learned will be provided at the end of the course.

3 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. When a patient uses medication to control the pain associated with a migraine headache, the medication

a. has equal effectiveness no matter when it is taken during the migraine episode. b. provides the best results if it is taken when the headache is most intense. c. is only effective if it is taken before the headache starts. d. is more effective if it is taken at the first sign of migraine pain.

2. is a pain reliever that has anti-inflammatory and anti- platelet properties and that may successfully manage

a. mild migraine pain if it is taken early on. b. severe migraine pain taken at any time during the episode. c. severe migraine pain by increasing production of prostaglandins. d. mild migraine pain but only if given with metoclopramide.

3. ______given in conjunction with aspirin, may help control nausea and vomiting among migraine patients with these symptoms.

a. NSAIDs b. Metoclopramide c. Prostaglandins d.

4. Children with migraine headaches should not be given compounds containing ______for pain because it increases the risk of Reye’s Syndrome.

a. acetylsalicylic acid b. acetaminophen c. a d. an analgesic

5. Ibuprofen administered to treat migraine headache pain should be taken

a. without food for maximum effectiveness. b. first thing in the morning. c. with food to minimize gastrointestinal irritation. d. regularly even if there is no sign of a headache.

4 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Introduction

Researchers do not fully understand why some people experience migraines and others do not. The various causative mechanisms associated with migraines make coming up with an effective treatment strategy difficult to apply generally to people who suffer from this type of pain. The treatment specifically for migraine headaches fall within two approaches: preventative medications that are used to reduce the risk of a migraine headache from occurring; and, abortive treatment, which attempts to stop the migraine pain after it has started. Under either approach, there is not one universal drug that is given for all patient situations. Both approaches may be used together to address a patient’s individual condition. Consideration must be given to a patient’s response to the treatment plan and the potential side effects that may arise.

Selection of Migraine Pain Treatment

The type of treatment prescribed for migraine pain depends on a migraineur’s (person who experiences migraine pain) unique condition, the frequency of migraine symptoms and how debilitating the migraine pain is when it occurs. If a person suffers from severe and intense headache pain on a frequent basis, most likely some form of abortive treatment is needed to decrease the pain when it occurs to allow the person to function at a normal level.5 In other cases, such as with menstrual migraines, analgesics may be effective in women who experience headaches with the condition but estrogen supplementation may be necessary to resolve the symptoms.70 Choosing the appropriate depends on the patient’s symptoms and condition.

Any medications prescribed for the treatment of migraines must be considered in terms of overall efficacy, potential side effects, and possible

5 nursece4less.com nursece4less.com nursece4less.com nursece4less.com interactions with other drugs or therapies before being prescribed for specific patients. Abortive and preventative measures may be prescribed simultaneously to not only decrease the frequency of migraines but to also control the pain when migraines occur.

Abortive Treatment

Abortive treatment describes those strategies that focus on stopping the migraine pain once it has started. Abortive strategies differ from preventive strategies in that they are more likely to be employed when an individual is already suffering from a migraine attack, instead of preventing the migraine from developing at all. Patients who use these types of medications tend to have more success with controlling migraine pain when they take the drugs early on when the pain is still developing, rather than waiting until it is intense. People often wait until the pain of the migraine has already started to take pain medicine, but this is typically less effective. Patients should be counseled to take pain medication at the first sign of a headache for maximum effectiveness.

Analgesics

Analgesics make up a significant number of medications used as abortive treatment for migraine pain control. For example, abdominal migraines are often treated with abortive treatment. Patients may take analgesics such as triptans or a non-steroidal anti-inflammatory drug (NSAID) as preventative measures to reduce the frequency of attacks.71

Aspirin

Aspirin (acetylsalicylic acid) is a salicylate and all-purpose pain reliever that has anti-inflammatory and anti-platelet properties and that may successfully

6 nursece4less.com nursece4less.com nursece4less.com nursece4less.com manage mild migraine pain if it is taken early on. Aspirin is also classified as an antipyretic drug that controls fever. It has been used for decades, and became available as a prescription pain medication in 1899. During the middle of the 20th century, aspirin was one of the most commonly used medications for pain and fever control.45 Aspirin acts as a cyclooxygenase inhibitor (COX-1 and COX-2) to decrease production of prostaglandins that can cause pain and inflammation.

Because it is also an antiplatelet drug, aspirin is often prescribed for adults with heart disease as a preventive measure against heart attack. Its anti- inflammatory properties make it useful for reducing inflammation associated with arthritis or muscle aches. It is sometimes viewed as being a weaker medication when compared to some other analgesics that may be available, however, many people have found success with using aspirin for treatment of migraine pain. When taken during the prodrome phase, aspirin can prevent serious pain from occurring during the actual migraine attack.

A meta-analysis published in the Journal of Family Practice reviewed evidence regarding the effectiveness of aspirin for treatment of migraine headache in different research studies. Despite many patients desiring prescription drugs or “stronger” medication to treat their migraines, non- prescription aspirin has been shown to be a valid form of treatment. The analysis showed that 900 to 1000 mg of aspirin was superior to placebo in treating migraine headaches and that treatment with aspirin was equivalent to treatment with 50 mg .43 Because aspirin can cause gastrointestinal (GI) irritation, there were some studies reviewed that also included metoclopramide given in conjunction with aspirin. Metoclopramide provided better control of nausea and vomiting among patients who suffered

7 nursece4less.com nursece4less.com nursece4less.com nursece4less.com from migraines without reducing the efficacy of aspirin co-administered to treat the headache.

Aspirin is typically administered as an oral preparation. In a standard, non- prescription form, oral aspirin is usually available in 325 mg tablets. The drug may also be administered as a chewable tablet, liquid preparation, or rectal suppository, the latter of which could be beneficial for some patients who otherwise cannot swallow tablets because of nausea associated with migraine. Aspirin is also available as a prescription-strength preparation, which typically consists of a larger dose than is available over the counter. A routine dose of aspirin administered for migraine is approximately 900 to 1000 mg.7,43 This dose has been shown to be effective in controlling headache pain within two hours of taking the drug. The dose can be repeated after four hours, if needed.

Children with migraine headaches should not be given aspirin for pain. While over-the-counter analgesics have been shown to be effective in treating migraines among children and adolescents, aspirin and other salicylate compounds should not be given to children under 19 years. The use of aspirin in children and teens increases the risk of Reye’s Syndrome, a metabolic condition that causes encephalopathy and swelling in the liver, causing seizures, confusion, irritability, and loss of consciousness. This applies to other pain medications that may also contain salicylates, including Anacin®, Excedrin®, Ecotrin®, Bayer® Aspirin, or magnesium salicylate (Doans®), among others.44

Patients who have bleeding disorders in addition to migraines should not take aspirin for pain because it can lead to hemorrhage. This includes conditions such as hemophilia or a history of GI bleeding. Aspirin can be

8 nursece4less.com nursece4less.com nursece4less.com nursece4less.com irritating to the stomach and many people avoid using it over a long period of time, instead taking it occasionally on an as-needed basis. While aspirin may be effectively combined with some medications as an adjunct treatment for pain control, some drugs administered for treatment of migraines should not be combined with aspirin, including beta blockers.45 Other drugs that are also anti-inflammatories should not be administered along with aspirin.

While there are various analgesics available that may be used for migraine pain, plain aspirin is often all that is needed for some people to control their symptoms. For many migraine sufferers, starting with aspirin or using aspirin as an adjunct treatment can be very successful in controlling their pain.

Ibuprofen

Ibuprofen is an NSAID that is beneficial for treatment of mild-to-moderate pain, including pain of headaches. It has a mechanism of action that is similar to aspirin in that it acts as a COX inhibitor to control release of prostaglandins that can cause pain. Ibuprofen has been established through the American Headache Society guidelines as being an effective form of treatment for migraines.65

A review by Marmura, et al., and published in the journal Headache discussed the evidence regarding treatment options for acute migraines according to the standards set forth by the American Headache Society. One of the studies outlined in the review compared the use of 200 mg or 400 mg of ibuprofen in the treatment of migraines against placebo. The study found that subjects who took ibuprofen as treatment had greater pain relief at two hours (42% of those following ibuprofen 200 mg and 41% of those following ibuprofen 400 mg) when compared to placebo. Further, the subjects in the

9 nursece4less.com nursece4less.com nursece4less.com nursece4less.com study who were given ibuprofen 400 mg had greater relief of severe migraine symptoms (37%) when compared to those who were given placebo (22%).65

Ibuprofen is available as an over-the-counter preparation, but larger doses can be made available by prescription. Oral preparations of ibuprofen, administered for its analgesic effects can be given at doses of 200 mg to 400 mg, given every 4 to 6 hours, without giving more than 1200 mg each day. Ibuprofen lysine (NeoProfen®) is an injectable form of the drug that is administered intravenously. While most commonly given to infants as treatment for closure of patent ductus arteriosus, NeoProfen could also be administered for severe pain in adults. Intravenous doses of ibuprofen for pain relief are given at 400 mg to 800 mg every 6 hours, without giving more than 3200 mg per 24 hours.66

Because certain NSAIDs such as ibuprofen may irritate the lining of the GI tract, the patient should avoid taking too much ibuprofen at one time. The drug should be taken with food, which may be difficult for some people with migraines who also suffer from nausea. If possible, the person should try to take the ibuprofen with a little bit of food at the first sign of a headache before the onset of nausea. Alternatively, use of anti-nausea medications administered through injection or transdermal preparations, may curb nausea for long enough that the person can take analgesics such as ibuprofen with some food.

As with other abortive medications, taking ibuprofen at the beginning of the migraine attack is often more successful at controlling pain than by waiting until the headache pain is worse. The patient should take the maximum allowable dose of ibuprofen at the beginning instead of taking smaller doses

10 nursece4less.com nursece4less.com nursece4less.com nursece4less.com and increasing as the pain worsens.7 Patients with migraines who take ibuprofen should consider the potential for allergic reactions to this drug if they are already allergic to similar drugs or NSAIDs, including aspirin. Although some people who suffer from very severe pain from migraines may need to take medications that are specifically designed to treat headache pain, ibuprofen can be a very successful alternative for pain relief, especially when the migraine is mild or moderate in severity.

Acetaminophen

Another type of analgesic that controls mild-to-moderate pain is acetaminophen, which is available as an over-the-counter preparation or by prescription. Acetaminophen (Tylenol®) has been used since the middle of the 20th century. It has long been considered to be similar to aspirin because of its mild analgesic and anti-pyretic properties, but the two drugs are chemically and structurally different. Acetaminophen, when given at the first signs of migraine pain, can be successful in controlling many migraine symptoms.

A study by Goldstein, et al., published in Cephalalgia compared the effects of several types of drugs on controlling migraine pain. The study evaluated a combination of acetaminophen, acetylsalicylic acid, and caffeine against ibuprofen or placebo among subjects who suffered from migraines. The goal of the study was to determine drug effectiveness and time of onset for treatment of acute pain of migraine. Among the subjects with migraines, ibuprofen and the acetaminophen combination of drugs both significantly relieved the pain and disabling effects of migraines, but the acetaminophen combination produced its effects of pain relief at a faster rate when compared to ibuprofen (16 minutes faster). The effects of the acetaminophen, acetylsalicylic acid, and caffeine were more successful at

11 nursece4less.com nursece4less.com nursece4less.com nursece4less.com controlling migraine pain after 45 minutes to 4 hours after dosing. Patients also reported a greater difference in pain intensity and freedom from photophobia, among other elements after using the acetaminophen drug combination.64

Acetaminophen is most commonly administered as an oral preparation, but as with other analgesics, this route may not be preferable for migraine sufferers who also have nausea. In addition to tablets, gelcaps, or caplets, acetaminophen is produced as concentrated drops (usually used among children), liquid suspension, rapidly dissolving tablets, rectal suppositories, and intravenous preparations. Excedrin® Migraine is composed of a combination of acetaminophen, aspirin, and caffeine. It is recommended by neurologists as the analgesic of first choice for migraine relief (among over- the-counter analgesics that are specifically formulated for migraines). Although outcomes can vary depending on the severity of the headache pain, many people who take Excedrin Migraine are able to control their headache pain after one dose of the drug.112

The amount of acetaminophen taken for a migraine attack is larger than a standard amount in an over-the-counter preparation. People who have migraines may take 1000 mg of acetaminophen at the earliest onset of migraine pain; repeat doses may be needed but the patient should not take more than 4000 mg per day.113 Acetaminophen is metabolized in the liver, so any patient who suffers from migraines and who also has liver disease should not take acetaminophen. Even without concomitant liver disease, large doses of acetaminophen, taken over time, can cause liver damage. Although acetaminophen has been designed to control pain because of various conditions and is not considered to be a migraine specific analgesic,

12 nursece4less.com nursece4less.com nursece4less.com nursece4less.com it is still an effective form of pain control when pain from migraine is mild or moderate.

Triptans

Triptans are prescription medications that have been shown to treat migraine pain effectively for some people, along with delivering relief of nausea. They are considered the gold standard of medications used for migraine treatment and there are many different formulations that have been developed.10 Up to 60 percent of people who take medications experience relief of migraine pain, typically within 2 hours after taking the drugs.8 Triptans act as selective serotonin agonists to stimulate production of serotonin.

As discussed, there are several different types of serotonin receptors within the body, also known as 5-hydroxytriptamine (5-HT) receptors. Triptans act as agonists for the 5-HT1 receptors, which are actually further classified as 5-HT1B, 5-HT1D, and 5-HT1F receptors.10 Many of these receptors are found in the blood vessels of the brain as well as within nerve endings. When the triptan drugs activate these receptors, they produce effects similar to serotonin.

When triptan drugs stimulate these specific receptors, they can cause vasoconstriction within parts of the brain, thus reducing some of the pain of migraines. Stimulation of the 5-HT1B receptors found in the brain causes constriction of several arteries, including the middle meningeal artery, the extra- and intracerebral arteries, and the dural arteries. The constriction of these arteries through the use of triptan medications is what results in the relief of migraine pain.10 Triptans have been shown to specifically target these receptors to impact blood flow in the brain and central nervous

13 nursece4less.com nursece4less.com nursece4less.com nursece4less.com system, in comparison to significantly affecting blood vessels in the peripheral nervous system.

Triptans can also impact 5-HT1D receptors that are found on trigeminal nerve fibers. When triptans inhibit these fibers, they impede the release of calcitonin-gene-related peptide (CGRP), a type of neurotransmitter, from the trigeminal nerve. Because it is released from the nerves, CGRP has an impact on nociception; however, CGRP also acts as a vasodilator and plays a protective role against cardiovascular disease. Increased levels of CGRP are often found among people who suffer from migraines.85 Inhibition of CGRP levels could be associated with greater pain control, and triptan medications also seem to provide better pain control because of their effects on CGRP.

Unlike some other types of analgesics that effectively treat pain encountered with a headache, drugs such as triptans are migraine specific. This means that they have been developed to control or limit some of the physiological causes that are particular to migraines, rather than treating pain in general.10 Sumatriptan was the original triptan medication that was developed for migraine treatment. Following the success that occurred after its release, various other second-generation triptans were also developed and released on the market, which are now available in various formulations.

Some of the more commonly prescribed types of triptans include sumatriptan (Imitrex®), (Zomig®) oral tablet or nasal spray, and (Amerge®).8 Treximet® is a combination of sumatriptan and sodium, which is an NSAID. These two drugs work together to provide more complete relief of migraine pain in some patients. Treximet works by controlling the pain of a migraine through various mechanisms between its drug combination. The sumatriptan causes vasoconstriction and

14 nursece4less.com nursece4less.com nursece4less.com nursece4less.com blocks pain messages in the nervous system, while the naproxen portion controls inflammation and reduces production of prostaglandins that can contribute to pain. Treximet is thought to work faster than other conventional oral medications because it is designed to break down faster once it reaches the stomach. The tablet has been created with a specific type of technology that is alleged to dissolve 3.5 times faster than other types of oral triptan tablets, which can provide quicker relief of migraine pain.9

Some people with migraines suffer from the additional symptom of allodynia, which is the experience of feeling pain during otherwise normal situations of touch. In other words, a person with allodynia may feel pain from any type of touch to the skin, even in situations that are not normally painful, such as the feel of the wind, or the touch of clothing against the skin. Allodynia may be more likely to be associated with migraines if the headache has developed as a result of inflammation of the nerves and overstimulation of the central nervous system. It is also more commonly associated with some other chronic pain syndromes, including fibromyalgia and irritable bowel syndrome.79 The presence of allodynia along with a migraine headache can be exceedingly painful and disabling for the affected patient. The use of triptans can be somewhat successful among patients who suffer from allodynia in association with migraines. Use of triptans as part of treatment seems to be more successful when the drugs are taken as early as possible to offset some of the pain.77

Concomitant administration of an anti-inflammatory drug may increase the effectiveness of triptan drugs in controlling migraine headache pain.7 Alternatively, triptan medications should not be administered with some other types of drugs used to treat migraines, including ergots.

15 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Because triptans cause vasoconstriction, some people have experienced side effects of chest pain and high blood pressure. Some patients have described a feeling of flushing in the face and neck, as well as dizziness, drowsiness, dry mouth; and numbness, tingling, and heaviness in the arms and legs when using triptans. Triptans have also been associated with serotonin syndrome because their effects on the serotonin receptors prevent the inhibition of serotonin. These drugs should not be used by patients with heart disease, as the vasoconstriction can significantly affect circulation and could cause high blood pressure. When used among people who smoke, triptans also cause hypertension and should be avoided in these cases. Coronary arteries also contain 5-HT1 receptors that can be stimulated by triptans to cause circulatory changes and can negatively affect the heart.

Although there are a number of medications classified as triptans, not all of these drugs work in the same way for migraineurs. Some patients find that they do not respond to taking one kind of drug but they may achieve headache relief with another, even when both drugs are considered triptan medications. This means that some people may need a period of trial and error to find the triptan medication that is most effective in relieving their migraine pain. The health clinician prescribing medication will begin with a specific drug and dosage. After observing the efficacy of the prescription, the clinician may need to adjust the dosage, or change the type of drug. This is done based on the patient’s response to the drug and dosage.

The same principle applies to potential side effects of triptans. Some people experience intense side effects, such as tingling, weakness, nausea, or drowsiness while taking one type of triptan. The health clinician will adjust the dose or prescribe a different drug until the side effects have resolved.

16 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Triptans, like other abortive medications for migraines, should be taken when the pain from the migraine attack is first developing. Although they are not classified as analgesics, the effects of triptans can be enough on their own if they are taken at the first sign of a headache. People who take medication for pain during an , even when pain is not present, are not necessarily more successful in treating their pain by pre-eminently taking the drugs. There is some evidence that taking pain medication too early, such as during an aura, is less effective than waiting until the pain starts.7 In the case of triptans, as with analgesics for headache pain, taking the drugs at the beginning of the actual attack when the pain begins is most effective.

Triptans and Serotonin Syndrome

The combination of triptans and ergots can result in severe vasoconstriction and possibly serotonin syndrome. Serotonin syndrome is thought to be a risk associated with use of some medications, including selective serotonin reuptake inhibitors (SSRIs) or serotonin norepinephrine reuptake inhibitors (SNRIs). Serotonin syndrome occurs when serotonin levels rise to dangerously high levels, causing symptoms of tachycardia, flushing, headache, increased blood pressure and confusion. Patients with concomitant depression who take antidepressant medications as well as drugs to combat migraine pain are at higher risk because of the combination of the drugs’ effects on serotonin levels.

Serotonin plays many roles in the body and is an essential neurotransmitter. However, the modification of its levels within the body can lead to various effects, including migraines or serotonin syndrome. By understanding the impact that serotonin levels have on migraine development, clinicians have been able to find more success in migraine prophylaxis and treatment.

17 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Triptans and Medication Overuse Headache

A condition called medication overuse headache may develop with the repeated use of triptan medications for migraine. These rebound headaches occur when a person repeatedly takes triptans or other acute medications. The condition is sometimes called analgesic rebound headache.77 The body has adjusted to the medication and a headache can form as a type of withdrawal. This results in a constant, daily headache that may be accompanied with other symptoms such as nausea, difficulty concentrating, anxiety, or irritability. The affected person may experience relief from the headache by taking an analgesic but the headache returns as soon as the medicine wears off.7,16 Other symptoms that may be associated with this type of headache include depression, anxiety, irritability, memory problems, restlessness, and difficulty concentrating. Unfortunately, this type of headache is self-perpetuating, as an affected person may have head pain from withdrawal of the original medication and may take another dose of analgesic to combat the headache, leading to a vicious cycle.

A patient who uses triptan medications more than three times per week is at risk of medication overuse headaches, which may be difficult to differentiate between migraines. The main method of controlling medication overuse headache is to limit the prescription of triptans, and to focus on migraine prophylaxis. Often, when medications are the cause of overuse headaches, it is essential to discontinue their use as a first step in treatment.

Ergotamine

Ergotamine (an ergot alkaloid) is a vasoconstricting medication that can be used for the treatment of migraine headaches by impacting vessel diameter among the blood vessels in the brain. The drug is thought to affect central blood vessels in the brain to decrease blood flow without impacting cerebral

18 nursece4less.com nursece4less.com nursece4less.com nursece4less.com hemispheric blood flow. Ergotamine also has an affinity for certain neurotransmitter receptors, acting as an agonist to influence their actions.

Ergotamine and Cafergot

Ergotamine is often used in combination with caffeine (Cafergot®), as caffeine has also been known to affect the circulatory system. The combination of these drugs can significantly impact circulation to control blood flow.

Cafergot can be administered in different formulations, depending on patient tolerance. It is available as an oral tablet, but also as a rectal suppository for some patients who have such intense nausea associated with migraine that they are unable to keep any food down. Ergotamine with caffeine is typically prescribed at a dose of 1 mg ergotamine/100 mg caffeine per tablet. As with many other types of drugs taken for headache pain, the patient should take ergotamine at the first sign of migraine pain, rather than waiting until the pain is intense. The affected individual can take 2 Cafergot tablets at the beginning of the migraine and may increase the dose by 1 tablet every 30 minutes. The person should not take more than 6 tablets during one migraine attack and no more than 10 tablets per week.73

Some studies have shown that ergotamine alone, when taken as a rectal suppository or as an oral preparation, is less effective in treating migraine pain.77 However, the combination of ergotamine with caffeine may be more likely to be effective. Overall, ergots are not as effective in treating migraine headache pain when compared to triptans. They are most successful in cases where patients have been suffering from migraine pain for over 48 hours and continue to take the drugs.

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Dihydroergotamine (DHE) is a type of ergot alkaloid that also may be used in the treatment of migraines. DHE works by binding to certain serotonin receptors, as well as noradrenaline receptors and dopamine receptors. When it binds to serotonin receptors in the brain, it can cause vasoconstriction of the intracranial vessels. Additionally, its agonist effects on these receptors can affect certain nerve endings, particularly trigeminal nerves in the face and head, thereby decreasing their inflammatory responses.67

Analysis of DHE was part of a review in the journal Headache, which found several studies that showed the efficacy of DHE in controlling headache pain compared to placebo. In one study, subjects were given either 0.5 mg or 1.0 mg of DHE or placebo, and the study found that those who received 0.5 mg had more significant headache relief when compared to the second dose of DHE or placebo. A second study reviewed in the journal showed that when subjects were given DHE 1.0 mg inhaled or placebo, those who had received the DHE had greater headache relief at 2 hours after dosing as well as freedom from light and noise sensitivities, and from nausea and vomiting, and for sustained headache relief (up to 24 hours, post dose).65

When given intravenously, DHE may increase the risk of nausea and subsequent vomiting for the migraine patient. Consequently, it is typically administered with an anti-emetic drug such as metoclopramide to reduce the risk of this side effect. Studies have shown that the combination of DHE with an anti-emetic such as metoclopramide is just as much or more effective than administration of certain abortive migraine medications on their own, including ketorolac and meperidine.77 DHE can be given at a dose of 1 mg/1 mL, either intravenously (IV) or as an intramuscular (IM) or subcutaneous (SQ) injection. The DHE dose can be repeated by 1 mg after an hour, and

20 nursece4less.com nursece4less.com nursece4less.com nursece4less.com then repeated an hour later, for a maximum dose of 3 mg when given IV or 2 mg when given as injection within 24 hours. Further, the total dose of DHE should not exceed 6 mg within one week and it cannot be given as a daily preparation.67

Dihydroergotamine can be administered at home by the patient or caregiver if they have been taught the proper methods of IM or SQ injections. Patients should be educated on the factors of use with DHE and about common side effects to report. Nasal DHE is also available and typically administered at a dose of 1 to 2 mg through a prefilled dosing syringe. An inhaled form of DHE known as MAP0004 has been developed that shows promise of similar efficacy to DHE injection but without some of the stronger side effects, such as nausea and vomiting. Aerosol DHE binds to the receptors to control migraine pain, but it does not bind to dopaminergic and adrenergic receptors, so there are fewer side effects.6

Ergot medications such as DHE have been shown to exhibit more side effects when compared to some other drugs for migraine control. Because of the effects on the cardiovascular system, ergots should not be used among some patients with migraines who have co-existing heart or blood vessel conditions, such as high blood pressure, peripheral artery disease, or ischemic heart disease.65 Further, certain types of migraines, such as hemiplegic migraines that cause symptoms similar to a stroke, should not be treated with ergots because of the effects on the circulatory system. Some patients have also experienced a worsening of symptoms of nausea and vomiting after taking ergotamine.

Ergot medications should also not be used with macrolide antibiotics such as erythromycin, as their combined use can cause severe vasospasm that could

21 nursece4less.com nursece4less.com nursece4less.com nursece4less.com lead to tissue ischemia. The combination of these drugs with ergot medications has been known to lead to ergotism in some cases. Ergotism occurs when an individual experiences a form of poisoning that causes nausea and vomiting, as well as vasospasm and severe tissue ischemia. Despite the potential drawbacks to ergot medications, they have been successful in the treatment of migraine pain for many people. Patients may need to try different preparations and classes of drugs to learn what is best for them to control migraine symptoms.

Opioids

Opioid medications are potent drugs that are available by prescription from a health clinician. Opioids are typically prescribed for the treatment of moderate-to-severe pain when other analgesics have not been effective. They may be used in combination with non-opioid analgesics to better control the pain and disability of migraine headaches. Although they can be very effective in treating migraine pain, they should not be considered for long-term use.65

Opioids are compounds similar to naturally-occurring opiates, which derive from the opium poppy plant. Use of opium dates back thousands of years, as its analgesic properties were identified early on and it was used among various cultures as a sedative or for persons undergoing primitive medical procedures. Laudanum was one of the earliest creations given to patients by early physicians for pain relief; later, morphine was developed in the early 1800s and became the gold standard of analgesics for decades as treatment of a variety of painful conditions. Morphine remains a powerful opioid analgesic that is still used frequently in various clinical settings today, but over time, research has come up with other powerful analgesics that may be used as well, including oxycodone, hydromorphone, and fentanyl.11

22 nursece4less.com nursece4less.com nursece4less.com nursece4less.com After administration, an opioid medication is absorbed into the bloodstream, where its components attach to one of several different kinds of receptors in the brain and spinal cord. The main opioid receptors are the delta, kappa, and mu receptors. Opioids act as receptor agonists in that they stimulate these specific receptors to activate them. Once opioids bind to these certain receptors, they can decrease pain signals between the brain and the spinal cord so that an affected person feels less pain. The main receptor that opioids bind to are the mu receptors. Some opioids bind more effectively to mu receptors; their strength and level of effectiveness is contingent on how successful they are able to bind.12 Opioids that are considered to be strong or more powerful drugs bind more sufficiently to mu receptors when compared to weaker opioids.

There are various drugs that are considered to be opioids; among these, some are further classified as strong opioids, while others are weak opioids. Examples of strong opioids include oxymorphone, hydromorphone, morphine, and fentanyl. Some other “weaker” opioids include codeine or tramadol. Although these drugs are sometimes called “weak” opioids, they can still be very effective in controlling the pain of migraine headaches.

Opioids may also be classified according to the length of time that they exert their effects. Some opioid drugs are long-acting in that they exert their effects over longer periods of time, which can be beneficial for controlling ongoing pain of a headache. Fentanyl is a long-acting opioid when it is administered as a transdermal patch that delivers the medication slowly through the skin. Alternatively, morphine, when administered in certain forms such as an oral tablet, is considered a short-acting drug.15 Its effects may curb some of the pain of a migraine but they may not last very long. In general, the length of time it takes for an opioid to take effect against a

23 nursece4less.com nursece4less.com nursece4less.com nursece4less.com migraine varies with the route of administration. The IV route is the most rapid acting because the drug is administered directly into circulation. The analgesic effects peak at about 10 minutes when a drug is given IV. It takes longer for intramuscular and oral preparations to exert the same effects, leading to peak effects at 45 minutes and 90 minutes, respectively.15

In the previously cited study published in Cureus, the authors were seeking to find an alternative medication that could be used for migraine treatment in place of opioids to try to reduce some of the impact of opioid use and addiction among patients suffering from chronic pain. The study suggested the use of metoclopramide in place of opioids, and that metoclopramide should be a first choice of treatment when a patient presents with a migraine headache, rather than administering opioid medications right away.78 Additionally, there is some evidence that consistent use of opioids may increase a patient’s levels of sensitivity to other medications. Consequently, if patients are given another drug later for a migraine that is a non-opioid analgesic, they may not experience adequate pain relief because they have learned to tolerate the level of pain control provided by the opioids instead.78

Opioids, while being very successful at treating the pain of headaches as well as multiple other painful conditions, have some drawbacks. There have been times when opioids are over prescribed and are given to patients in situations where they may not be warranted or where other treatment measures have not been previously attempted. There has been a significant rise in the numbers of people who struggle with substance use disorders. Opioids can be so powerful that prescribing clinicians must implement safety measures to ensure that they are reducing the risks of a substance use disorder associated with opioids. Patients treated with opioids as a first choice in the acute care setting for management of migraines are more likely

24 nursece4less.com nursece4less.com nursece4less.com nursece4less.com to return to the same setting within a week of the first visit, and those treated with opioids for migraines are more likely to have repeatedly visited the same emergency department where they receive these medications within the previous 12 months.14,77

Opioids have obvious side effects, including nausea and vomiting, which occur in up to 30 percent of patients who use these drugs.12 Nausea is thought to occur more commonly as a side effect because opioid receptors are near to chemoreceptor trigger zones in the brain that can stimulate vomiting. The side effects of nausea and vomiting with opioid use make them less than ideal for migraine sufferers, since these same effects are similarly encountered with migraines.

One study by Friedman, et al., published in Cephalalgia evaluated the use of opioids administered to patients who presented to emergency departments for the treatment of migraine headaches and compared the results with previous data to determine if trends of opioid administration were changing over time. The study analyzed the National Hospital Ambulatory Medical Care Survey data (information collected by the Centers for Disease Control and Prevention (CDC)) and found that in 2010, there were 1.2 million migraine-related visits to emergency departments. Of these, opioid medications were administered as treatment in 59 percent, most commonly hydromorphone. This level is up significantly over data from 1998, in which less than 1 percent of patients with migraines received hydromorphone in the acute care setting.14 This suggests that even though non-opioid methods of treatment are available and have been shown to be effective, opioid medications are still being largely used in a number of acute cases of migraines. Some medications are used less often (meperidine) for migraine

25 nursece4less.com nursece4less.com nursece4less.com nursece4less.com pain, but other types of opioids have been prescribed more often to take their place.

Prescribing opioids for treatment of migraines should be done very carefully, to avoid combining the drugs with other preparations that can increase the risk of complications and side effects. Some drugs are long-acting preparations that are designed to control pain for longer periods; however, when these are combined with other drugs that can depress the respiratory drive or cause drowsiness, the long-acting effects of the opioids may not have worn off before the side effects set in.

Opioids and Medication Overuse Headaches

Use of opioids for the treatment of migraines may also lead to a further complication of medication overuse headache. As with triptans, a patient who uses opioids more than three times per week is at risk of medication overuse headaches, which may be difficult to differentiate between migraines.

Some researchers disagree with the consistent use of opioids for treatment of migraines, stating that these types of drugs are not appropriate for this type of chronic pain. In other words, while opioids can manage acute pain of a procedure that is meant to resolve within a relatively short time, the use of opioids for migraines is more controversial because of overuse headaches. Long-term use of opioids by migraine sufferers can lead to potential substance use disorder. In order to achieve the same amount of relief, the patient may feel the need to take more opioids with the next headache. An opioid medication may relieve a migraine headache but if a person continues to suffer from repeated migraines – sometimes over the course of years – the ongoing use of opioids is not the best option.13

26 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Glucocorticoids

Glucocorticoids are types of corticosteroid drugs that have anti-inflammatory properties. Glucocorticoids work by decreasing some of the activity of leukocytes in response to infection or inflammation; they also increase capillary permeability and can impact the metabolic and immune systems’ functioning. In many cases, they are administered to control inflammation, but they may also be given for pain control, such as that associated with migraine headaches.

Examples of glucocorticoids used in clinical practice include betamethasone, hydrocortisone, prednisone, prednisolone, and dexamethasone.74 Glucocorticoids work by binding to receptors found throughout the body. Glucocorticoid receptors are found in almost all types of cells, and the body actually produces a certain amount of natural glucocorticoids through the adrenal gland. Drugs that are classified as glucocorticoids are synthetic versions of the naturally-occurring substances. Glucocorticoids cross cell membranes and bind to glucocorticoid receptors within the cell to form complexes that enter the nucleus of the cell to change the production of certain cell proteins. They can inhibit production of proteins that cause inflammation as well as activate lipocortins, which are enzymes that decrease the release of arachidonic acid from cell membranes, which also impacts inflammation.90 Glucocorticoids have also been shown to inhibit COX-2 and inflammatory prostaglandins, thereby reducing pain and inflammation, in a manner somewhat similar to the action of NSAIDs.

Glucocorticoids such as dexamethasone (Decadron®) can be given as adjunct therapy along with other analgesics to control headache pain. Several studies have also shown glucocorticoid administration is associated with a decreased rate of recurrence of migraines, although dexamethasone

27 nursece4less.com nursece4less.com nursece4less.com nursece4less.com is the drug most commonly used.77 Often, glucocorticoids may be considered when a patient has suffered from repeat migraines that are not totally resolved with other abortive treatments. The combination of an analgesic with a glucocorticoid may not only help to better control a patient’s pain from the headache, but it may then reduce the risk of migraine recurrence.

Studies have been done on some different types of glucocorticoids to assess efficacy in controlling migraine pain. A study published in the American Journal of Clinical Medicine Research investigated the use of prednisolone for the treatment of migraine headaches, based on the effects of migraines on the metabolic and nervous systems and possible steroid deficiency in the body related to excess stress. The study evaluated over 1000 patients with migraines and administered prednisolone as treatment of pain and other associated effects. Patients in the study responded to the prednisolone with either reduction or complete resolution of migraine symptoms with the treatment. The authors recommended a dose protocol of 0.5 mg/kg/day for 7 days for migraine pain, followed by tapering by 5 mg every 7 days.75 Of note, while the results of this study were positive and showed the benefits of steroid use for migraine headache resolution, prompting the authors to make recommendations for migraine protocol using prednisolone, there was no discussion that debated the disadvantages of ongoing steroid use for migraines. Although the short-term results can be beneficial, many people also experience significant side effects when they use steroids on a long- term basis.

Dexamethasone, used for management of inflammation and a naturally- occurring hormone produced by the adrenal glands, may be one of the more frequently used types of glucocorticoids for migraine attacks. Although the drug can cause side effects of increased hair growth, acne, and GI distress,

28 nursece4less.com nursece4less.com nursece4less.com nursece4less.com it is still implemented in many cases of migraine because it can potentially relieve inflammation that causes the migraine, as well as decrease the overall recurrence rate of migraines. A study by Mazaheri, et al., in the journal PLOS One compared the efficacy of sodium with dexamethasone in treatment of acute migraines. Sodium valproate is an typically used for the treatment of seizures associated with epilepsy. It may have been prescribed for treatment of migraine in this study because of the effects of the drug on nerve endings that could subdue pain levels in the head and neck. The subjects in the study received either sodium valproate or dexamethasone and the severity of their headaches was analyzed at 30 minutes and 2 hours post-dosing. The study noted that patients with aura responded better to sodium valproate than to dexamethasone, but patients in the study without aura responded well to both valproate and to dexamethasone. Overall, the study was designed to compare the efficacy of the two drugs against each other, and found no significant differences. It also restated that dexamethasone, when given at the appropriate dose (in this study, 16 mg IV) can effectively control headache pain and associated symptoms of migraines.76

Dexamethasone is approved by the U.S., Food and Drug Administration (FDA) for a variety of health conditions, including 1) skin disorders such as pemphigus and psoriasis, 2) blood and GI disorders such as thrombocytopenic purpura, red cell aplasia, ulcerative colitis, or regional enteritis, 3) conditions affecting the joints, including rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, and lupus, and 4) many other dermatological, renal, and endocrine disorders.89 When used for migraines, dexamethasone is prescribed as off-label. Its effects on nerve swelling when it is used following neurosurgery may make it beneficial in the treatment of migraines if the trigeminal nerve is inflamed, causing headache pain.

29 nursece4less.com nursece4less.com nursece4less.com nursece4less.com People with migraines who take glucocorticoids as part of treatment should be monitored closely for side effects of the drugs. Migraines that are associated with some type of infection should not be treated with glucocorticoids, as the drugs can affect the immune system. They also can affect blood glucose levels, so patients with diabetes should be given the drugs with caution. Other side effects associated with glucocorticoid use include gastrointestinal irritability, insomnia, and metabolic changes, including hypokalemia and fluid retention.74 Patients given the drug should be weighed frequently and should have routine laboratory testing during drug administration to ensure that electrolytes and leukocyte levels remain within normal limits. Overall, long-term administration of glucocorticoids is not typically recommended, as the drugs can impact the patient’s metabolic system over time and can cause physical changes such as swelling and skin changes, as well as increased risks of diabetes and osteoporosis.

For treatment of migraine headaches, dexamethasone may be administered IV at a dose of 10 mg to 25 mg. The drug could also be given IM if IV access is not immediately available.77 Other forms of administration include oral tablets or elixirs, which should be given with food, if possible, since the drug can cause GI upset. Glucocorticoid administration for the treatment of migraine has various side effects and long-term use is not always the best option. Alternatively, in crisis situations, particularly when migraine pain is severe, glucocorticoids can be beneficial in controlling pain in the acute care setting.

Migraine Attacks and Nausea

Nausea is frequently associated with migraine attacks; consequently, anti- nausea medications are sometimes prescribed. Taken when a person starts having symptoms of nausea, these drugs do not necessarily control the pain

30 nursece4less.com nursece4less.com nursece4less.com nursece4less.com of migraines but they can prevent other negative symptoms such as vomiting. When nausea is under control, the affected patient may be able to function more throughout the migraine attack.

Some evidence has shown that gastric stasis may partly cause some of the nausea that often occurs during migraine attacks. Patients who have been given anti-emetic drugs with mechanisms of action that treat gastric stasis, such as metoclopramide, have shown some relief of nausea when these drugs are administered during migraines. Most likely, gastric stasis is related to nausea and migraines, rather than the actual cause of all nausea that occurs with migraines. As mentioned, gastric stasis refers to delayed gastric emptying, so that the rate of absorption is slowed and the affected person may feel full or even bloated after eating. This can contribute to nausea overall, but there have been many cases of patients who have had nausea associated with migraines but the nausea remains until the actual pain is treated, not the gastric stasis.6 It is better to treat both pain and nausea during a migraine instead of trying to control gastric stasis to stop the nausea and vomiting.

Nausea and associated vomiting are thought to affect up to 60 percent of patients who suffer from migraines.6 People who experience nausea related to migraine headaches typically have lower quality of life because of its effects. In addition to the pain of the headache, nausea may lead to inactivity, as the affected person spends more time lying down. Weight loss may also happen over time due to decreased food intake. For many, the thought of vomiting after eating because of nausea is enough to restrict food intake. Complications of dehydration and malnutrition are not uncommon when food and fluid intake is significantly restricted during migraine attacks.

31 nursece4less.com nursece4less.com nursece4less.com nursece4less.com It is thought that increased nausea preceding or during the time of the migraine attack may worsen the pain of the headache.6 For some people, the nausea that accompanies the migraine makes the pain of the headache even worse and more difficult to handle because symptoms are so severe. Nausea that occurs as part of a migraine can make treating the actual migraine attack difficult. The vomiting that often accompanies nausea prevents retention of oral medications long enough to be absorbed into circulation. As a result, many anti-nausea medications are administered in other routes beyond oral drugs so that their absorption and distribution will remain unaffected if the individual vomits because of nausea. Many anti- nausea medications are administered as IM injection, sublingually, or through transdermal patch. In severe cases, anti-emetic drugs can be administered intravenously.

Anti-emetic Medication

Medications including metoclopramide or prochlorperazine can be particularly beneficial in providing relief of nausea connected to migraines. These drugs act as dopamine receptor antagonists in the central nervous system to prevent onset of nausea when triggered by outside stimuli. A review published in Cureus evaluated the use of metoclopramide for treatment of acute migraines because of its effects on the central nervous system (CNS), but also for its impact on the GI system in relieving gastric stasis. The review cited several studies that supported the evidence that metoclopramide is effective in treating acute migraine, although it can have some negative side effects, including tardive dyskinesia, with long-term use.78

With short-term, acute use for migraines, metoclopramide (brand name Reglan) is effective with few side effects. The drug can be administered as

32 nursece4less.com nursece4less.com nursece4less.com nursece4less.com an orally-disintegrating tablet, which dissolves quickly in case severe nausea is present. When given IV in the acute care setting, a recommended dose of 10 mg is typically sufficient to control nausea.77 Metoclopramide is also frequently administered in combination with the ergot medication DHE to control both pain and nausea due to migraines.

Prochlorperazine (brand name Compazine) is an antipsychotic medication that is normally used for the treatment of schizophrenia. However, it has also been shown to improve symptoms of nausea and vomiting in various situations, including among patients suffering from migraine headaches. As such, its use is considered to be off label. It may be administered as an oral tablet, but when nausea is severe, administration via injection through intramuscular or IV dose is often more tolerable. A dose of 10 mg prochlorperazine may be administered IV or IM in the acute care setting to control nausea and vomiting if a patient presents with a migraine.77 Although it has been developed specifically for the treatment of psychosis, patients have been using prochlorperazine for a number of different kinds of health issues. In addition to its use for nausea and vomiting, it may also be prescribed for management of anxiety and psychosis. It is frequently administered following surgery when patients are more likely to develop severe nausea related to anesthesia medications.

It should be noted that some medications taken to control nausea, such as prochlorperazine, have been associated with cardiac changes seen in some patients that could lead to life-threatening arrhythmias. The drugs can cause prolongation of the QT interval, leading to torsades de pointes, a type of ventricular tachycardia.77 A patient who presents for care of migraine headaches combined with severe nausea and who also has a history of cardiac arrhythmias or electrolyte abnormalities that could affect the heart

33 nursece4less.com nursece4less.com nursece4less.com nursece4less.com rhythm should be considered at higher risk for complications when considering certain anti-emetic drugs for treatment.

Status Migrainosus and Intravenous Medication

Status migrainosus is often treated with intravenous pain medications and anti-emetic drugs, as many people also have intense nausea. Other treatments for status migrainosus may include IV steroids, magnesium sulfate, lidocaine, or valproic acid.72 Many of these treatments are administered in the emergency department setting, as the onset of such a debilitating headache often prompts the patient to seek urgent care.

Migraine Headache and Preventative Treatment

Preventative measures have also been shown to have other benefits in addition to migraine prophylaxis. Taking preventative measures may improve the patient’s response to abortive treatment methods for migraines, supporting prescription medications and possibly improving their effectiveness. Patients who utilize preventative measures also generally report a higher quality of life and reduced overall disability due to migraine symptoms.95

Preventative medications are taken regularly to reduce the risk of a migraine attack. Preventative medications are typically employed before a person suffers from headache pain, with the idea of averting the situation before it even starts. This is in contrast to abortive medications, which are designed to treat headache pain after it has already developed. Many preventative medications are prescribed to be taken on a daily basis, whether headache triggers are present or not. Preventative medications may not completely preclude all migraines, but they can significantly reduce the frequency with which some individuals develop these headaches.

34 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Some people who regularly take preventative medications may still develop migraines. When this happens, they can take an abortive medication in addition to their preventative drug to try to control the pain. Preventative medications should be considered when a person suffers from migraine attacks on a regular basis to the point that the pain significantly disrupts his quality of life. Some people find that they need to use larger or more frequent doses of abortive medications to manage the pain of frequent migraines. These situations might also better respond to use of preventative medication to avoid the need for frequent analgesic use.

Preventative medications, when prescribed and then taken on a daily basis, may still take several weeks to reach their full potential effects. People who have been prescribed preventative drugs may start to take these medications on a daily basis but may not see a change in the frequency of migraines for several months. Even with daily medication usage, many preventative drugs do not eliminate migraines. However, many have been shown to be successful enough that the number of migraines that occur, as well as their intensity, is significantly reduced, and patients who continue to take the drugs daily find that these outcomes are worth it. A preventative drug is considered to be successful in migraine prophylaxis if it reduces the frequency of attacks or the frequency of days of migraines by at least 50 percent over a period of three months.95

Cardiovascular Medication

There are various types of cardiovascular medications, typically taken for heart disease, that also may prevent onset of migraines when used on a regular basis. Their effects on the circulatory system can also impact blood flow to the head, which could prevent pain from occurring.

35 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Cardiovascular medications such as beta blockers are one type of drug prescribed for the prevention of migraines. Beta blockers are normally used as treatment for hypertension or angina. The exact mechanism of how beta blockers can prevent migraine headaches is not entirely clear. Typically, patients must take beta blockers on a daily basis for a period of several weeks before they start to notice an effect on the frequency of their migraines. Among the possible beta blockers available for prescription, the most frequently prescribed and successful medications are , (Lopressor®), and . Other drugs, including (Tenormin®) and (Corgard®) may also be effective.95 Of note, not all beta blockers have been used successfully to prevent migraines.

Propranolol (Inderal®) is a frequently-prescribed that works by increasing vasodilation to improve blood flow, as well as by slowing the heart rate to decrease extra stress on the heart and to improve circulation. Unlike some other types of cardiovascular medications, propranolol has been approved by the FDA for the prevention of migraines. A study by Stovner, et al., in Cephalalgia compared the use of candesartan and propranolol for migraine prophylaxis. Candesartan is used for treatment of hypertension. Subjects in the study were given either 16 mg candesartan oral, 160 mg slow-release propranolol, or placebo. Both candesartan and propranolol were successful in reducing the number of migraine days per month when compared to placebo.92 Candesartan (Atacand®) may be successful in preventing migraines because its mechanism of action results in blood vessel dilation, similar to the effects of some other cardiovascular drugs.

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) have been shown in some situations to be effective in preventing migraines by reducing overall number of days of migraines per

36 nursece4less.com nursece4less.com nursece4less.com nursece4less.com month.95 Candesartan is an ARB that is typically used for the treatment of hypertension or heart failure. It produces vasodilatory effects, which is why it may be beneficial for the treatment of migraine. Candesartan may be administered at doses ranging from 16 to 32 mg orally each day to prevent migraine attacks or reduce their frequency. Of note, many cardiovascular medications such as propranolol and candesartan have the effects of vasodilation, which is why they may improve cerebral blood flow and reduce the frequency of migraine attacks. However, not all cardiovascular medications with vasodilatory effects have been shown to prevent migraines. Only those that have been evaluated through research studies and/or have FDA approval should be considered for migraine prophylaxis.

Calcium channel blockers have also been shown to have some effectiveness in the prevention of migraines. is a (CCB) that may be more effective for patients who experience migraines with aura. , is a calcium channel blocker that is often prescribed in the United Kingdom and Canada for the prevention of migraines but it is not available in the United States.

Verapamil is prescribed for patients with angina or certain cardiac arrhythmias. It is not approved by the FDA for migraine prophylaxis, but it may be prescribed as treatment in an off-label manner. As a calcium channel blocker, verapamil prevents the influx of calcium across the cell membranes. It decreases systemic vascular resistance and is therefore able to control blood pressure among some people who take the drug for hypertension. The effects on the blood vessels may improve blood flow enough in the head, neck, and face to prevent migraine development. Verapamil is typically prescribed at doses between 40 mg and 360 mg daily for cardiovascular conditions, however the exact dose prescribed for migraine prophylaxis may

37 nursece4less.com nursece4less.com nursece4less.com nursece4less.com vary.94 In general, the prescribing clinician should start at a lower dose of the drug and then increase the dose as needed for control of pain and other symptoms.

As with other types of prescription drugs, cardiovascular medications may cause some side effects and should be considered carefully for treatment. Beta blockers can cause some side effects of drowsiness, fatigue, lethargy, sleep disorders, and memory problems. Some people report more frequent GI distress while taking beta blocker medications. Additionally, the drugs are contraindicated among patients who have migraines but who also suffer from some circulatory conditions such as Raynaud’s phenomenon, as well as some respiratory illnesses, including asthma and chronic obstructive pulmonary disease.95

Medications that are normally prescribed for treatment of cardiovascular disease can usually be safely administered for prevention of migraines, however, they should be used with caution in some patients. The side effects associated with many cardiovascular medications are often related to increases in circulation. For instance, some of these drugs are meant to lower blood pressure in patients with hypertension, however, if an individual does not normally have high blood pressure but takes the medication for migraines, it may cause hypotension along with other related symptoms of dizziness, lightheadedness, or syncope.

People with migraines who already have existing heart disease should not be prescribed cardiovascular medications for migraine prevention, as the effects of the drugs could cause further heart disturbances, such as cardiac arrhythmias. For example, a side effect of verapamil includes atrioventricular (AV) block, a heart arrhythmia in which the heart beats very slowly.93 A

38 nursece4less.com nursece4less.com nursece4less.com nursece4less.com person with heart disease who takes this drug and then develops AV block could develop a life-threatening arrhythmia related to severe bradycardia because of side effects.

People who take cardiovascular medication for migraine prevention should only take one type of cardiovascular drug. They should not combine them. For instance, a person who takes a calcium channel blocker should not try to combine the drug with a beta blocker for further effects. The impact of the two types of drugs together could affect the patient’s cardiovascular system, including causing changes in heart rate and rhythm and cardiac contractility.94 Cardiovascular medications, although proven to prevent migraines in some cases and approved by the FDA, need to also be monitored closely with use. Patients who have co-existing heart disease may need to consider another type of drug for migraine prophylaxis to protect their wellbeing.

Antidepressant Medication

Although depression is commonly seen among patients with migraines, may also be prescribed when migraine sufferers have not been diagnosed with clinical depression. The antidepressants have effects on neurotransmitter levels that not only treat depression but that also can prevent migraine pain.

Antidepressants may prevent migraine development by impacting serotonin levels in the brain. Tricyclic antidepressants are the class most commonly prescribed for prevention of migraines. is a (TCA) that may be used in an off-label manner. Amitriptyline affects serotonin levels by suppressing the reuptake of serotonin and norepinephrine, thereby making these two neurotransmitters available for

39 nursece4less.com nursece4less.com nursece4less.com nursece4less.com regulating various activities, including mood regulation. Amitriptyline is also frequently used to control pain, particularly nerve-related pain, which could then also control migraine attacks if the cause is related to the trigeminal nerve. There have also been various studies that showed amitriptyline is effective in reducing the frequency of migraine headaches as well as reducing the number of days of migraines per month among affected patients.95 In general, TCAs are more effective than serotonin reuptake inhibitors, even though SSRIs are more commonly prescribed for depression.

Tricyclic antidepressants are associated with certain side effects; in particular, weight gain is a frequent side effect seen among many patients who take these drugs. Other side effects that may be seen with amitriptyline use include dry mouth, fatigue, sedation, and dizziness.95 The dose of amitriptyline for migraine prophylaxis varies depending on the patient’s condition, but can range from 10 to 200 mg daily.95 Because it can cause drowsiness, the patient should be counseled to take amitriptyline at bedtime, which may also improve sleep in cases where the migraine sufferer also has concomitant insomnia. A patient who already has depression may need a different dosage for treatment of the depression and there are potential risks of over-treatment of the depressed state, leading to mania or delirium.

Antidepressants classified as SSRIs are not necessarily more effective in controlling migraine attacks. A review by Banzi, et al., in Cochrane evaluated the effects of SSRIs in migraine prevention through recent studies in comparison to placebo. Overall, the review showed that SSRIs were more tolerable than TCAs but did not show greater efficacy in preventing migraines when compared to placebo.96 SSRIs such as escitalopram may be administered for the management of comorbid depression with migraine, but

40 nursece4less.com nursece4less.com nursece4less.com nursece4less.com generally require further adjunctive treatment, such as with triptans, for greater control of migraine attacks.

Alternatively, some SNRI medications may be more effective at preventing migraine attacks. As with TCA medications, SNRIs may also be prescribed for pain control, particularly nerve-related pain. These drugs are able to impact levels of both serotonin and norepinephrine, which helps them to not only regulate mood and reduce depression, but also to control some pain. There is some evidence that SNRIs can control inflammation as well by correcting the dysregulation of cytokine and immune system responses.97 They have also been used successfully for the treatment of common comorbid disorders seen with migraines, including fibromyalgia. Venlafaxine (Effexor®) is one example of an SNRI that has been shown to reduce the risk of migraines.80 Duloxetine (Cymbalta®) is also an SNRI that may be prescribed in some cases.

The SNRI medications are not without side effects and should be carefully considered for migraine prevention, with or without concomitant depression. Common side effects can be managed relatively easily and often include dry mouth, fatigue, and constipation. Some people have reported some more serious side effects with SNRI medications, including dizziness, insomnia, and sexual dysfunction. Discontinuation of these drugs may also be difficult for some people, as withdrawal symptoms are common.

A person who does not have clinical depression but who still suffers from migraines can benefit from antidepressant medications as preventative therapy for migraine pain. Alternatively, some antidepressants are not considered to be effective in preventing migraines because they only treat the depression in the migraine sufferer. Typically, the dosage levels of

41 nursece4less.com nursece4less.com nursece4less.com nursece4less.com antidepressants, when used as migraine prophylaxis, are usually lower than when the drugs are prescribed for depression.

Anti-Seizure Medication

Anti-seizure medications, also known as , are commonly prescribed for the management of seizure disorders such as epilepsy. These drugs are also prescribed for some patients who suffer from bipolar disorder. They are successful because they reduce excessive electrical activity in the brain. In cases of seizures or mania associated with bipolar disorder, the activity of anticonvulsant medications is beneficial in controlling symptoms.

Anticonvulsant medications have also been successfully used in the prevention of migraines among some people. While there are some patients who have concomitant epilepsy and migraine headaches, those who have been prescribed anti-seizure medications who do not have seizure disorders can still benefit from use of these drugs for migraine treatment. While several anticonvulsant medications could be effective for migraine treatment or may be used in an off-label manner, there are only two types that have been approved in the U.S. specifically for the treatment of migraines; these include divalproex (Depakote®) and (Topamax®).

Divalproex sodium is most commonly used for the treatment of mania associated with bipolar disorder as well as for prevention of seizures associated with epilepsy. Divalproex extended-release tablets have also been approved for the prevention of migraines but they have not been shown to be effective in controlling pain of migraines after the attack has started. The drug was originally approved by the FDA for the treatment of migraines in 1996.109 It works by increasing levels of the GABA neurotransmitter, which has a calming effect in the central nervous system. GABA is an inhibitory

42 nursece4less.com nursece4less.com nursece4less.com nursece4less.com neurotransmitter that keeps neurons from becoming overly excited, such as with what occurs during seizures. People with migraines may also experience overstimulation of neurons, which is why GABA works in these situations, as well.

A typical dose of valproate (divalproex) for migraine prevention is approximately 500 to 2000 mg daily, taken as an oral preparation. The patient should not be prescribed more than 60 mg/kg/day.95 In addition to tablet formulations, the drug can also be administered as an oral syrup. Divalproex administered IV is known as Depacon® and may also be given for migraine prevention, particularly in cases where other drugs have not been successful.

Another anti-seizure drug that has been approved for migraine prevention is topiramate, which is also commonly prescribed for the management of tonic- clonic seizures associated with epilepsy. Topiramate works by not only impacting GABA levels in the brain, but it also inhibits some of the excitatory neurotransmitters and acts as a carbonic anhydrase inhibitor to increase carbon dioxide levels and affect blood flow to the brain.108

A study by Choudhary, et al., in the Pakistan Journal of Medical Sciences compared the effectiveness of valproate sodium with topiramate among patients with migraine headaches. The subjects in the study were randomized to receive one of the two drugs; each subject was given either 1000 mg valproate or 100 mg topiramate to take twice a day for six weeks. At the end of the time-period of administration, the study found that over 64 percent of subjects who were given valproate experienced a reduction in frequency of migraines, while 35 percent of subjects given topiramate experienced a reduction in migraine frequency.108 Other studies have shown

43 nursece4less.com nursece4less.com nursece4less.com nursece4less.com similar results, however both drugs are able to be used successfully and are frequently prescribed.

Some studies have shown that topiramate is as effective as some other types of prescription medications, such as amitriptyline, in preventing migraines and reducing overall frequency of migraine days per month. Dosage amounts for topiramate range between 50 and 200 mg orally each day.95 It is better to start at a lower dose of topiramate to assess effectiveness and then increase the dose if needed.

When compared to valproate and topiramate, may be less effective in preventing migraines and is not prescribed as regularly. However, it may be beneficial for some patients in cases where other treatment types have not been successful. A total dose of carbamazepine is between 600 and 1200 mg daily.95 Additional anti-seizure drugs may also be considered, depending on patient circumstances, however it is important to consider the outcomes of clinical research in assessing their efficacy when prescribing.

Anti-seizure medications are associated with some more common side effects of dizziness, drowsiness and nausea. Some people experience mild swelling in the hands and feet as well. More serious side effects have included memory problems, difficulty concentrating, and blurred vision. Divalproex should not be administered to women with migraines who are pregnant, as administration of the drug has been associated with fetal anomalies. Despite these side effects, anti-seizure medications can be a valid option for preventative migraine treatment. Patients with migraines do not need to be diagnosed with seizures or a mental illness such as bipolar disorder to benefit from certain anti-seizure drugs.

44 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Onabotulinumtoxin A (Botox)

Onabotulinumtoxin A, also known as Botox, is a type of treatment developed from the bacterium Clostridium botulinum. It is primarily known for its use in cosmetic procedures to reduce the size of skin wrinkles. Onabotulinum has been found to have a variety of other uses as treatment for many conditions, including migraine headaches. The primary effects of Botox are the temporary paralysis of nerves that affect muscle activity. Botox is a neurotoxin, and it is able to alter some of the effects of the nervous system through neuromuscular blocking activity. For this reason, people who have comorbid neuromuscular conditions should only use onabotulinumtoxin with caution. Botox is prepared as an injection that is reconstituted before administration. It is given by a health clinician, administered as an intramuscular injection into the muscles near to the affected areas. In the case of migraine treatment, Botox is injected into several areas around the face and neck.36

Onabotulinumtoxin A has been shown to be very effective in the treatment of a number of health conditions, improving symptoms and enhancing quality of life for people who struggle with certain chronic diseases. Botox is approved and indicated for the treatment of bladder dysfunction, including overactive bladder and overactive detrusor muscle activity, upper and lower limb spasticity, cervical dystonia, also referred to as spasmodic torticollis, axillary hyperhidrosis (excessive sweating from the underarms), blepharospasm, strabismus, and migraine headaches.37

The U.S., FDA approved Botox for the treatment of migraine headaches in 2010. It is successful because after injection, the drug blocks the activation of pain networks in the brain.38 When given for treatment of migraines, Botox is diluted and administered at the recommended dose of 155 units,

45 nursece4less.com nursece4less.com nursece4less.com nursece4less.com which are distributed in small amounts at various sites in the head and neck. The clinician uses a small, 30-gauge needle no longer than ½ inch in length, except for in cases where there are larger muscles in the neck. There are seven different areas of muscle groups through which the injections may be divided, including 1) the frontalis, on the forehead, 2) the corrugator, found near each of the eyes, 3) the procerus, which extends from the middle of the nose into the forehead, 4) temporalis, located on either side of the head above the ears, 5) occipitalis, found at the base of the head near the neck, 6) the trapezius in the lower neck and upper shoulders, and 7) the cervical paraspinal muscle group, in the upper neck at the back of the head, on either side of the spinal vertebrae.37 Because the needle gauge is small, most people do not experience considerable pain with the injections.

A study by Lipton, et al., in Cephalalgia assessed the quality of life of patients who were given onabotulinumtoxin A in comparison with placebo for the management of migraine headaches. Overall, the study process was in two parts, with some subjects receiving onabotulinumtoxin A during both parts, and some subjects initially receiving placebo in the first stage and then receiving onabotulinumtoxin A in the second stage. The study used different tools that acted as surveys for participants to assess quality of life at various time points during the process. The 6-item Headache Impact Test (HIT-6) assesses the effects of a headache on different areas, including pain, social or role limitations, cognitive functioning, vitality, and psychological distress. The Migraine Specific Quality of Life Questionnaire (MSQ) assesses the effect of migraine on daily functioning in social or work-related habits and performance of activities associated with these items, as well as the emotional response to the migraine. During the time that subjects received placebo or onabotulinumtoxin A, there were significantly larger improvements in HIT-6 scores among subjects who were given the drug

46 nursece4less.com nursece4less.com nursece4less.com nursece4less.com versus those who received placebo. Subjects who received onabotulinumtoxin A during the first stage of the study showed greater quality of life, as evidenced by improved scores on the HIT-6 and the MSQ questionnaires. Additionally, during the second stage of the study when all participants were given onabotulinumtoxin A, those who had initially received placebo showed significant improvements in quality of life as evidenced by improved questionnaire scores, in a manner similar to those who had received the drug from the beginning.39 Overall, the study showed that treatment with onabotulinumtoxin A significantly reduced some of the negative impacts of migraine headaches.

Botox works as a preventive measure to preclude migraines in people who suffer from chronic migraine headaches.37 Chronic migraines differ from episodic migraines, based on the number of times they occur each month. People who suffer from chronic migraines have more than 15 headache days per month; alternatively, those with episodic migraines have 14 or fewer headache days per month. Those who have very frequent migraines seem to respond to Botox even better than those who might suffer from these headaches less often.38 Each treatment is designed to provide coverage against headache pain that lasts up to three months.

Overall, people who receive onabotulinumtoxin A for the prevention of migraines experience a reduction in the number of days that they have headaches. Botox may be used in combination with other types of treatments, such as pain medication or alternative therapies, to further control headache pain from migraines. Because it is a neurotoxin that is injected into the muscles, there is a chance that some of the medication may spread beyond the boundaries of its intended treatment area. This can lead to unintentional weakness or paralysis of muscle groups. The Botox

47 nursece4less.com nursece4less.com nursece4less.com nursece4less.com prescribing information states that people who have had this response following injection have developed issues such as difficulties with walking, urinary incontinence, drooping of the upper eyelids, difficulty speaking, and even problems swallowing or breathing, which could be life-threatening.37

Summary

Headaches are one of the more commonly experienced disorders, with causes of different types of headaches varying from stress and tension to chronic illness. Alternatively, migraine headaches are related to a disorder that can affect the neurosensory and circulatory systems and that can cause severe pain and disability. The treatment plans for migraine headaches fall within two approaches. These are preventative medications that are used to reduce the risk of a migraine headache occurring, and abortive treatment, which attempts to stop the migraine pain after it has started. Under either approach, there is not one universal drug that is given for all patient situations. Both approaches may be used together to address a patient’s individual condition. Consideration must be given to a patient’s response to the treatment plan and the potential side effects that may arise. Choosing the appropriate treatment depends on the patient’s symptoms and condition. These treatments may be combined with lifestyle modifications or alternative therapies to improve patient outcomes and quality of life.

Please take time to help NurseCe4Less.com course planners evaluate the nursing knowledge needs met by completing the self-assessment of Knowledge Questions after reading the article, and providing feedback in the online course evaluation.

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48 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 1. When a patient uses medication to control the pain associated with a migraine headache, the medication

a. has equal effectiveness no matter when it is taken during the migraine episode. b. provides the best results if it is taken when the headache is most intense. c. is only effective if it is taken before the headache starts. d. is more effective if it is taken at the first sign of migraine pain.

2. Aspirin is a pain reliever that has anti-inflammatory and anti- platelet properties and that may successfully manage

a. mild migraine pain if it is taken early on. b. severe migraine pain taken at any time during the episode. c. severe migraine pain by increasing production of prostaglandins. d. mild migraine pain but only if given with metoclopramide.

3. ______given in conjunction with aspirin, may help control nausea and vomiting among migraine patients with these symptoms.

a. NSAIDs b. Metoclopramide c. Prostaglandins d. Triptans

4. Children with migraine headaches should not be given compounds containing ______for pain because it increases the risk of Reye’s Syndrome.

a. acetylsalicylic acid b. acetaminophen c. a placebo d. an analgesic

5. Ibuprofen administered to treat migraine headache pain should be taken

a. without food for maximum effectiveness. b. first thing in the morning. c. with food to minimize gastrointestinal irritation. d. regularly even if there is no sign of a headache.

49 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 6. True or False: Patients who have bleeding disorders in addition to migraines should not take aspirin for pain because it can lead to hemorrhage.

a. True b. False

7. As with other abortive medications, ibuprofen should be taken

a. in regular intervals, even if there is no sign of a headache. b. only first thing in the morning. c. in maximum allowable doses, at the earliest sign of a headache. d. in smaller doses that increase only if the pain worsens.

8. Acetaminophen is similar to aspirin because

a. the two drugs are chemically the same. b. the two drugs are structurally the same. c. neither should be combined with other drugs. d. of its mild analgesic and anti-pyretic properties.

9. The amount of acetaminophen taken for a migraine attack is

a. larger than the over-the-counter preparation. b. the same as a standard, over-the-counter preparation. c. is 4000-4500 mg per day. d. lower than the over-the-counter preparation.

10. ______are considered the gold standard of medications used for migraine treatment.

a. NSAIDs b. Anti-inflammatory drugs c. Triptans d. Analgesics

11. True or False: Acetaminophen given in large doses over long periods of time can cause liver damage even in patients without concomitant liver disease.

a. True b. False

50 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 12. Triptans act as selective serotonin agonists to stimulate production of serotonin, which causes ______within parts of the brain, thus reducing some of the pain of migraines.

a. overstimulation b. vasoconstriction c. enervation d. vasodilation

13. When triptans inhibit ______nerve fibers, they impede the release of calcitonin-gene-related peptide (CGRP).

a. vestibular b. cochlear c. vagus d. trigeminal

14. Some people with migraines suffer from ______, which is the experience of feeling pain during otherwise normal situations of touch.

a. allodynia b. dyskinesia c. hyperacusis d. dysautonomia

15. ______have been associated with serotonin syndrome because their effects on the serotonin receptors prevent the inhibition of serotonin.

a. Anti-emetics b. Antagonists c. Triptans d. Antihistamines

16. Dihydroergotamine (DHE) is a type of ______that also may be used in the treatment of migraines.

a. NSAID b. triptan c. ergot alkaloid d. anti-emetic

51 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 17. The vomiting that often accompanies nausea prevents retention of oral medications, in which case anti-nausea medications may be administered

a. as an intramuscular injection. b. sublingually. c. through a transdermal patch. d. All of the above

18. Many preventative medications for migraine headaches are prescribed to be taken

a. only if headache triggers are present. b. daily, whether headache triggers are present or not. c. only if the patient has a comorbid condition. d. during the aura phase of the migraine headache.

19. Calcium channel blockers such as ______may be more effective in treating migraines with aura.

a. propranolol b. nadolol c. verapamil d. candesartan

20. True or False: People who take a cardiovascular medication for migraine prevention should only take one type of cardiovascular medication- they should not combine different cardiovascular medication types.

a. True b. False

21. A person who does not have clinical depression but suffers from migraines

a. should not take antidepressants to treat the migraines. b. must use higher doses of antidepressants for them to be effective. c. can benefit from any antidepressant as preventative therapy. d. may use certain antidepressants that are effective but usually at lower doses.

52 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22. Anticonvulsant medications have been successfully used among patients with migraines

a. who have concomitant epilepsy only. b. who have reduced electrical activity in the brain. c. as an abortive treatment for migraine pain. d. as a preventative treatment.

23. Topiramate is an anti-seizure drug that has been approved for migraine prevention that works by

a. impacting GABA levels in the brain. b. stimulating some of the excitatory neurotransmitters. c. stimulating carbonic anhydrase to decrease carbon dioxide levels. d. All of the above

24. When compared to valproate and topiramate, carbamazepine

a. is the preferred anticonvulsant for treating migraine pain. b. provides a better result once the migraine headache has started. c. is preferred because it does not have the common side effects associated with anticonvulsants. d. may be less effective in preventing migraines.

25. Onabotulinumtoxin A, also known as Botox, has been

a. unsuccessful as a treatment for migraines because it may only be administered by injection. b. promotes the release of calcitonin-gene-related peptide (CGRP). c. FDA approved for the treatment of migraine headaches. d. effective as an anti-emetic for nausea associated with migraines.

53 nursece4less.com nursece4less.com nursece4less.com nursece4less.com CORRECT ANSWERS:

1. When a patient uses medication to control the pain associated with a migraine headache, the medication

d. is more effective if it is taken at the first sign of migraine pain.

“Abortive strategies differ from preventive strategies in that they are more likely to be employed when an individual is already suffering from a migraine attack, instead of preventing the migraine from developing at all. Patients who use these types of medications tend to have more success with controlling migraine pain when they take the drugs early on when the pain is still developing, rather than waiting until it is intense. Often, people will wait until the pain of the migraine has already started to take pain medicine, but this is typically less effective. Patients should be counseled to take pain medication at the first sign of a headache for maximum effectiveness.”

2. Aspirin is a pain reliever that has anti-inflammatory and anti- platelet properties and that may successfully manage

a. mild migraine pain if it is taken early on.

“Aspirin is a salicylate and all-purpose pain reliever that has anti- inflammatory and anti-platelet properties and that may successfully manage mild migraine pain if it is taken early on. Aspirin acts as a cyclooxygenase inhibitor (COX-1 and COX-2) to decrease production of prostaglandins that can cause pain and inflammation.”

3. ______given in conjunction with aspirin, may help control nausea and vomiting among migraine patients with these symptoms.

b. Metoclopramide

“Because aspirin can cause gastrointestinal irritation, there were some studies reviewed that also included metoclopramide given in conjunction with aspirin. Metoclopramide provided better control of nausea and vomiting among patients who suffered from migraines without reducing the efficacy of aspirin co-administered to treat the headache.”

54 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 4. Children with migraine headaches should not be given compounds containing ______for pain because it increases the risk of Reye’s Syndrome.

a. acetylsalicylic acid

“... aspirin (acetylsalicylic acid) and other salicylate compounds should not be given to kids under age 19 years. The use of aspirin in children and teens increases the risk of Reye’s Syndrome, a metabolic condition that causes encephalopathy and swelling in the liver, causing seizures, confusion, irritability, and loss of consciousness. This applies to other pain medications that may also contain salicylates, including Anacin®, Excedrin®, Ecotrin®, Bayer® Aspirin, or magnesium salicylate (Doans®), among others.”

5. Ibuprofen administered to treat migraine headache pain should be taken

c. with food to minimize gastrointestinal irritation.

“Because certain NSAIDs such as ibuprofen may irritate the lining of the gastrointestinal tract; the patient should avoid taking too much ibuprofen at one time. The drug should be taken with food, which may be difficult for some people with migraines who also suffer from nausea. If possible, the person should try to take the ibuprofen with a little bit of food at the first sign of a headache before the onset of nausea. Alternatively, use of anti-nausea medications administered through injection or transdermal preparations, may curb nausea for long enough that the person can take analgesics such as ibuprofen with some food.”

6. True or False: Patients who have bleeding disorders in addition to migraines should not take aspirin for pain because it can lead to hemorrhage.

a. True

“Patients who have bleeding disorders in addition to migraines should not take aspirin for pain because it can lead to hemorrhage.”

55 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 7. As with other abortive medications, ibuprofen should be taken

c. in maximum allowable doses, at the earliest sign of a headache.

“As with other abortive medications, taking ibuprofen at the beginning of the migraine attack is often more successful at controlling pain than by waiting until the headache pain is worse. The patient should take the maximum allowable dose of ibuprofen at the beginning instead of taking smaller doses and increasing as the pain worsens.”

8. Acetaminophen is similar to aspirin because

d. of its mild analgesic and anti-pyretic properties.

“Acetaminophen (Tylenol®) has been used since the middle of the 20th century. It has long been considered to be similar to aspirin because of its mild analgesic and anti-pyretic properties, but the two drugs are chemically and structurally different.”

9. The amount of acetaminophen taken for a migraine attack is

a. larger than the over-the-counter preparation.

“The amount of acetaminophen taken for a migraine attack is larger than a standard amount in an over-the-counter preparation. People who have migraines may take 1000 mg of acetaminophen at the earliest onset of migraine pain. Repeat doses may be needed but the patient should not take more than 4000 mg per day.”

10. ______are considered the gold standard of medications used for migraine treatment.

c. Triptans

“Triptans are prescription medications that have been shown to effectively treat migraine pain for some people, along with delivering relief of nausea. They are considered the gold standard of medications used for migraine treatment and there are many different formulations that have been developed.”

56 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11. True or False: Acetaminophen given in large doses over long periods of time can cause liver damage even in patients without concomitant liver disease.

a. True

“Even without concomitant liver disease, large doses of acetaminophen, taken over time, can cause liver damage.”

12. Triptans act as selective serotonin agonists to stimulate production of serotonin, which causes ______within parts of the brain, thus reducing some of the pain of migraines.

b. vasoconstriction

“Triptans act as selective serotonin agonists to stimulate production of serotonin.... When triptan drugs stimulate these specific receptors, they can cause vasoconstriction within parts of the brain, thus reducing some of the pain of migraines.”

13. When triptans inhibit ______nerve fibers, they impede the release of calcitonin-gene-related peptide (CGRP).

d. trigeminal

“Triptans can also impact 5-HT1D receptors that are found on trigeminal nerve fibers. When triptans inhibit these fibers, they impede the release of calcitonin-gene-related peptide (CGRP), a type of neurotransmitter, from the trigeminal nerve.”

14. Some people with migraines suffer from ______, which is the experience of feeling pain during otherwise normal situations of touch.

a. allodynia

“Some people with migraines suffer from the additional symptom of allodynia, which is the experience of feeling pain during otherwise normal situations of touch.”

57 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 15. ______have been associated with serotonin syndrome because their effects on the serotonin receptors prevent the inhibition of serotonin.

c. Triptans

“Triptans have also been associated with serotonin syndrome because their effects on the serotonin receptors prevent the inhibition of serotonin.”

16. Dihydroergotamine (DHE) is a type of ______that also may be used in the treatment of migraines.

c. ergot alkaloid

“Dihydroergotamine (DHE) is a type of ergot alkaloid that also may be used in the treatment of migraines.”

17. The vomiting that often accompanies nausea prevents retention of oral medications, in which case anti-nausea medications may be administered

a. as an intramuscular injection. b. sublingually. c. through a transdermal patch. d. All of the above [correct answer]

“The vomiting that often accompanies nausea prevents retention of oral medications long enough to be absorbed into circulation. As a result, many anti-nausea medications are administered in other routes beyond oral drugs so that their absorption and distribution will remain unaffected if the individual vomits because of nausea. Many anti-nausea medications are administered as intramuscular injection, sublingually, or through transdermal patch.”

18. Many preventative medications for migraine headaches are prescribed to be taken

b. daily, whether headache triggers are present or not.

“Many preventative medications are prescribed to be taken on a daily basis, whether headache triggers are present or not.”

58 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 19. Calcium channel blockers such as ______may be more effective in treating migraines with aura.

c. verapamil

“Calcium channel blockers have also been shown to have some effectiveness in the prevention of migraines. Verapamil is a calcium channel blocker that may be more effective for patients who experience migraines with aura.”

20. True or False: People who take a cardiovascular medication for migraine prevention should only take one type of cardiovascular medication- they should not combine different cardiovascular medication types.

a. True

“People who take cardiovascular medication for migraine prevention should only take one type of cardiovascular drug. They should not combine them. For instance, a person who takes a calcium channel blocker should not try to combine the drug with a beta blocker for further effects.”

21. A person who does not have clinical depression but suffers from migraines

d. may use certain antidepressants that are effective but usually at lower doses.

“A person who does not have clinical depression but who still suffers from migraines can benefit from antidepressant medications as preventative therapy for migraine pain. Alternatively, some antidepressants are not considered to be effective in preventing migraines because they only treat the depression in the migraine sufferer. Typically, the dosage levels of antidepressants, when used as migraine prophylaxis, are usually lower than when the drugs are prescribed for depression.”

59 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 22. Anticonvulsant medications have been successfully used among patients with migraines

d. as a preventative treatment.

“Anti-seizure medications, also known as anticonvulsants, ... are successful because they reduce excessive electrical activity in the brain.... those who have been prescribed anti-seizure medications who do not have seizure disorders can still benefit from use of these drugs for migraine treatment.... Divalproex extended-release tablets have also been approved for the prevention of migraines but they have not been shown to be effective in controlling pain of migraines after the attack has started.”

23. Topiramate is an anti-seizure drug that has been approved for migraine prevention that works by

a. impacting GABA levels in the brain.

“Another anti-seizure drug that has been approved for migraine prevention is topiramate,.... Topiramate works by not only impacting GABA levels in the brain, but it also inhibits some of the excitatory neurotransmitters and acts as a carbonic anhydrase inhibitor to increase carbon dioxide levels and affect blood flow to the brain.”

24. When compared to valproate and topiramate, carbamazepine

d. may be less effective in preventing migraines.

“When compared to valproate and topiramate, carbamazepine may be less effective in preventing migraines and is not prescribed as regularly.”

25. Onabotulinumtoxin A, also known as Botox, has been

c. FDA approved for the treatment of migraine headaches.

“Onabotulinumtoxin A, also known as Botox, has been found to have a variety of other uses as treatment for many conditions, including migraine headaches.... The U.S., FDA approved Botox for the treatment of migraine headaches in 2010. It is successful because after injection, the drug blocks the activation of pain networks in the brain.”

60 nursece4less.com nursece4less.com nursece4less.com nursece4less.com Reference Section

The References below include published works and in-text citations of published works that are intended as helpful material for your further reading. [References are for a multi-part series on MIGRAINE PAIN].

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61 nursece4less.com nursece4less.com nursece4less.com nursece4less.com 11. The Atlantic (2015). A brief history of opioids. Retrieved from http://www.theatlantic.com/sponsored/purdue-health/a-brief-history- of-opioids/184/ 12. Chan, Y., Ng, K. and Sum, D. [Eds.]. (2015). Pharmacological basis of acute care. Switzerland: Springer International Publishing 13. American Migraine Foundation. (2015). Opioid narcotics and headache. Retrieved from https://americanmigrainefoundation.org/understanding- migraine/opioid-narcotics-and-headache/ 14. Friedman, B., et al. (2014). Current management of migraine in US emergency departments: an analysis of the National Hospital Ambulatory Medical Care Survey. Cephalalgia 35: 301-309 15. National Safety Council (2014). Opioid painkillers: how they work and why they can be risky. Retrieved from http://www.nsc.org/RxDrugOverdoseDocuments/opioid-painkillers- how-they-work-and-why-they-are-risky.pdf 16. American Migraine Foundation (2016). Medication overuse headache. Retrieved from https://americanmigrainefoundation.org/understanding- migraine/medication-overuse-headache-2/ 17. Noseda, R., et al. (2017). Neural mechanism for hypothalamic- mediated autonomic responses to light during migraine. Proc Natl Acad Sci U S A.; 11;114(28):E5683-E5692. 18. Noseda, R., et al. (2016). Migraine photophobia originating in cone- driven retinal pathways. Brain: A Journal of 139(1): 1971- 1986 19. Malone, C., Bhowmick, A., Wachholtz, A. (2015). Migraine: treatments, comorbidities, and quality of life, in the USA. J Pain Res. 8; 537-547 20. University of Maryland Medical Center (2015). Vitamin B2 (Riboflavin). Retrieved from http://www.r2ms.net/health/medical/altmed/supplement/vitamin-b2- riboflavin 21. National Institutes of Health Office of Dietary Supplements (2018). Riboflavin. Retrieved from https://ods.od.nih.gov/factsheets/Riboflavin-HealthProfessional/ 22. United Mitochondrial Disease Foundation (2017). What is mitochondrial disease? Retrieved from https://www.umdf.org/what-is-mitochondrial- disease/ 23. Mito Action. (n.d.). Headache. Retrieved from http://www.mitoaction.org/guide/headache 24. Marashly, E. and Bohlega, S. (2017). Riboflavin has neuroprotective potential: focus on Parkinson’s disease and migraine. Frontiers in

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